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type I&#44; caused by anthracyclines&#44; which induce irreversible dose-dependent cardiac injury&#59; and type II&#44; caused by trastuzumab&#44; which is not related to the cumulative dose and is often reversible after treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The second type will not be discussed in this review article&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this review the authors discuss strategies in patients being treated with anthracyclines in order to prevent or mitigate their main adverse effects on the heart&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Initial assessment</span><p id="par0025" class="elsevierStylePara elsevierViewall">In view of the cardiotoxicity of anthracyclines&#44; all patients referred for chemotherapy should undergo a cardiac assessment to establish their baseline cardiovascular characteristics&#44; which can then be used during the treatment regimen for purposes of comparison&#46; This assessment should include clinical history and physical examination&#44; electrocardiography to determine cardiac rhythm and detect signs of ischemia&#44; and cardiac imaging&#44; usually transthoracic echocardiography with complete Doppler study &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>&#41;&#46; When the echocardiogram is provides insufficient information&#44; cardiac magnetic resonance imaging &#40;CMRI&#41; is recommended&#46; Baseline troponin levels should also be measured for future comparisons&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Monitoring during therapy</span><p id="par0030" class="elsevierStylePara elsevierViewall">It is important to monitor for signs and symptoms of cardiotoxicity during chemotherapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#41;&#46; The 12-lead electrocardiogram can be used routinely to screen for arrhythmias due to anthracycline-related cardiotoxicity&#44; while 24-hour Holter monitoring or an event recorder can be useful to investigate the etiology of syncope presumed to result from arrhythmia or advanced atrioventricular block&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Cardiac function should be monitored by echocardiography in patients under anthracycline therapy&#46; Global longitudinal strain &#40;GLS&#41; as assessed by two-dimensional speckle tracking is a more sensitive predictor of HF than left ventricular ejection fraction &#40;LVEF&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> since during anthracycline therapy changes in GLS precede reduction in LVEF&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; in clinical practice&#44; fractional shortening and LVEF have been the most widely used parameters&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> although fractional shortening is proving to be less reliable in this context&#46; These parameters&#44; being dependent on pre- and afterload&#44; are less sensitive for early detection of preclinical cardiac disease&#46; Various studies have suggested that assessment of diastolic function by Doppler echocardiography may enable early detection of anthracycline-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> If LVEF is &#60;53&#37;&#44; GLS below the limit of normal &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 6</a>&#41;&#44; and&#47;or troponins are elevated&#44; a cardiology consultation should be considered&#44; with discussion between the cardiologist and oncologist of the risk&#47;benefit ratio of chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A fall in LVEF during anthracycline therapy is associated with increased risk for cardiac events&#44; and although a reduction in GLS of &#60;8&#37; compared to baseline appears not to be significant&#44; a reduction of &#62;15&#37; is likely to indicate cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The study should be repeated two to three weeks after the baseline study to confirm the diagnosis&#46; CMRI can detect subtle changes in the myocardium and increases in extracellular volume&#44; which suggest edema or diffuse fibrosis&#46; Although it is highly sensitive and reproducible for assessment of cardiac function and characterization of myocardial tissue&#44; CMRI has the disadvantages of limited availability and high cost&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Radionuclide angiography is reproducible and more easily available&#44; but exposes patients to ionizing radiation&#44; increasing their cumulative dose&#44; especially when serial studies are required&#44; and provides only limited information on diastolic function and valve morphology&#44; and so should not be the method of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Endomyocardial biopsy has greater sensitivity and specificity for detection and monitoring of the adverse effects of anthracyclines&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> enabling visualization of loss of myofibrils&#44; vacuolization of cytoplasm&#44; dilatation of the sarcoplasmic reticulum&#44; increased numbers of lysosomes and mitochondrial swelling&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; the invasive nature of the procedure limits its use in clinical practice&#46; Biomarkers have been validated in various studies&#59; they are specific not only in detecting cardiovascular injury but also in determining its extent and reversibility&#46; While troponin T and I are indicators of cardiomyocyte damage&#44; BNP and the N-terminal portion of pro-BNP &#40;NT-proBNP&#41; reflect increased myocardial stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> According to the literature&#44; elevation of troponins is an early indicator of cardiotoxicity&#44; while BNP is less consistent&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">If the dose of anthracyclines exceeds 240 mg&#47;m<span class="elsevierStyleSup">2</span>&#44; cardiac assessment should be repeated before administering further cycles &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prevention of cardiotoxicity</span><p id="par0040" class="elsevierStylePara elsevierViewall">Prevention of anthracycline-induced cardiotoxicity&#44; while maintaining the drugs&#8217; therapeutic effectiveness&#44; can be achieved by pharmacological and non-pharmacological means&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Non-pharmacological prevention</span><p id="par0045" class="elsevierStylePara elsevierViewall">Cardiovascular risk factors should be identified and treated appropriately as soon as cancer is diagnosed&#46; Patients should be encouraged to adopt a healthy lifestyle&#44; including a diet low in saturated fat and a maximum of 2&#46;5 g of sodium per day&#44; avoid toxic substances such as alcohol and tobacco&#44; and maintain their body mass index close to 25 kg&#47;m<span class="elsevierStyleSup">2</span>&#46; Exercise&#44; whether of low or high intensity&#44; during anthracycline therapy increases cardiovascular reserve<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and studies in animal models have indicated that it may reduce the cardiotoxic effects of these agents&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Although exercise has shown promise in improving cardiopulmonary function in breast cancer survivors&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> there have been no clinical trials in humans that confirm their cardioprotective role&#46; Another measure is to reduce or avoid the use of drugs that prolong QT interval&#44; particularly 5-hydroxytryptamine 3 antagonists &#40;frequently used to prevent adverse effects of chemotherapy including nausea and vomiting&#41; and antihistamines&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> It is also important to minimize radiation exposure&#44; to correct electrolyte disturbances and to treat comorbidities &#40;<a class="elsevierStyleCrossRef" href="#tbl0040">Table 7</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Decreasing the dose of anthracyclines is another way to reduce the incidence of left ventricular systolic dysfunction &#40;LVSD&#41;&#44; as shown by a study of patients taking 400&#44; 500 or 550 mg&#47;m<span class="elsevierStyleSup">2</span> of doxorubicin&#44; in which the incidence of congestive HF was 5&#37;&#44; 16&#37; and 26&#37; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although anthracyclines appear to be cardiotoxic independently of the dose administered&#44; several studies have shown that continuous infusion of lower doses for between 24 and 92 hours<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> can reduce the severity of cardiac injury&#44; and has been described as an effective way of doing so&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Prolonging infusion time reduces cardiotoxicity without compromising the effectiveness of chemotherapy&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> but infusion lasting longer than 96 hours is associated with a high incidence of stomatitis&#46; The only case in which continuous infusion of doxorubicin appears to have no cardioprotective effect compared to rapid infusion is in children with acute lymphoblastic leukemia &#40;ALL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Other clinical trials using endomyocardial biopsy to assess anthracycline-induced cardiac injury in different drug regimens concluded that continuous perfusion leads to far less significant damage than rapid intravenous administration&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> These trials also showed that patients receiving continuous infusion had greater tolerance for higher cumulative doses of doxorubicin&#46; Although animal studies demonstrated that anthracycline levels in tumor tissue were the same however the drugs were administered &#40;continuous or rapid infusion&#41;&#44; this was not true of cardiac tissue&#44; in which rapid infusion led to higher concentrations and thus greater toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pharmacological prevention</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Antioxidants</span><p id="par0055" class="elsevierStylePara elsevierViewall">Although antioxidants neutralize free radicals formed by anthracycline therapy and thus theoretically reduce or prevent cardiotoxicity&#44; clinical trials of N-acetylcysteine&#44; coenzyme Q&#44; L-carnitine&#44; phenethylamines&#44; amifostine and a combination of vitamins E and C and N-acetylcysteine did not show a cardioprotective effect&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Erythropoietin and iloprost<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> have been shown to protect against the cardiotoxic effects of doxorubicin in vitro&#44; without affecting its anticancer effectiveness&#44; but their cardioprotective ability will have to be demonstrated in vivo&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Liposomal formulations</span><p id="par0060" class="elsevierStylePara elsevierViewall">One way to combat the adverse cardiac effects of anthracyclines is to change the formulation of the drugs such as encapsulating them in liposomes&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Studies comparing unencapsulated and liposome-encapsulated doxorubicin found no difference in anti-tumor response rate&#44; overall survival or progression-free survival&#44; but the incidence of HF and LVSD was lower in patients treated with the liposomal formulation&#44; and this group also had a lower incidence of other adverse effects including neutropenia&#44; nausea&#44; vomiting and diarrhea&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Due to their high cost&#44; these formulations are not widely used and the US Food and Drug Administration &#40;FDA&#41; has approved their use only for ovarian cancer&#44; AIDS-related Kaposi&#39;s sarcoma&#44; and patients with multiple myeloma who have not responded to a year of treatment with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Dexrazoxane</span><p id="par0065" class="elsevierStylePara elsevierViewall">Administration of dexrazoxane concomitantly with anticancer regimens can have a cardioprotective effect&#44; preventing elevation of troponins and reducing the incidence of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Some authors attribute the cardioprotective effect of this iron chelator to its reduction of the quantity of intracellular iron&#44; which may decrease doxorubicin-induced free radical generation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> However&#44; studies on other iron chelators have not demonstrated cardioprotection&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> It has also been suggested that dexrazoxane&#39;s cardioprotective effect is due not only to its antagonizing topoisomerase II cleavage complex formation&#44; but also to its induction of rapid degradation of topoisomerase II beta&#44; which suggests that this enzyme is involved in anthracycline-induced cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> A study of dexrazoxane in over 200 children with ALL showed that it reduced troponin T elevation in both sexes&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and limited reduction of fractional shortening and maintained left ventricular thickness-to-dimension ratio at five years&#44; but only in girls&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Recently three cases have been reported of adults undergoing chemotherapy combined with dexrazoxane for breast cancer who developed acute myeloid leukemia&#46; However&#44; two studies comparing dexrazoxane with placebo in children with ALL followed for five and 10 years showed no difference in the incidence of secondary malignancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Nevertheless&#44; in view of its known adverse effects&#44; the FDA and the European Medicines Agency have restricted the use of dexrazoxane to adult patients with advanced or metastatic breast cancer who have already received a cumulative dose of doxorubicin of more than 300 mg&#47;m<span class="elsevierStyleSup">2</span> and who will benefit from additional anthracycline therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Beta-blockers</span><p id="par0070" class="elsevierStylePara elsevierViewall">The cardioprotection afforded by beta-blockers &#40;BBs&#41; appears to derive from their antioxidant and anti-apoptotic properties&#46; One BB&#44; carvedilol&#44; has shown particular promise in reducing the incidence of anthracycline-induced cardiomyopathy and preserving systolic and diastolic function&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In children&#44; carvedilol limited troponin I elevation and improved both fractional shortening and peak global systolic strain&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> According to some studies&#44; BBs and angiotensin-converting enzyme &#40;ACE&#41; inhibitors &#40;see below&#41; can prevent the remodeling associated with HF by reducing adrenergic response&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> However&#44; no cardioprotective effects have been seen with either metoprolol or enalapril&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers</span><p id="par0075" class="elsevierStylePara elsevierViewall">ACE inhibitors and angiotensin receptor blockers &#40;ARBs&#41; show cardioprotective properties&#44; possibly by reducing oxidative stress&#44; left ventricular remodeling&#44; and apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> When administered for at least two years after discontinuation of chemotherapy in children with anthracycline-induced LVSD&#44; enalapril showed no benefit in terms of reducing left ventricular end-systolic wall stress or preserving fractional shortening&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> By contrast&#44; in adults treated with high-dose anthracyclines&#44; enalapril prevented HF and worsening of parameters of cardiac function such as LVEF&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Studies in angiotensin II type I receptor knockout mice showed that doxorubicin did not have a cardiotoxic effect in these animals and that the administration of ARBs can prevent daunorobucin-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Although to our knowledge there have been only two randomized trials on ARBs in chemotherapy patients&#44; valsartan was shown to prevent acute prolongation of corrected QT&#44; left ventricular diastolic dilatation and elevation of BNP during one week of chemotherapy&#44; although with no effect on LVEF&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> and telmisartan prevented reduction in peak strain rate during high-dose anthracycline therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Further studies are required with longer follow-up to confirm these effects&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statins</span><p id="par0080" class="elsevierStylePara elsevierViewall">Statins have antioxidant and anti-inflammatory properties&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Studies in animal models demonstrate that fluvastatin mitigates anthracycline-induced cardiotoxicity&#44; reducing oxidative stress and enhancing the expression of the antioxidant enzyme mitochondrial superoxide dismutase 2&#44; resulting in reduced cardiac inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> In one clinical trial assessing the effect of continuous statin treatment in patients with breast cancer receiving anthracycline-based chemotherapy&#44; patients receiving statins had a lower incidence of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In another study in patients with previously normal LVEF undergoing anthracycline chemotherapy&#44; LVEF was unchanged at six months in those treated with atorvastatin&#44; compared to a fall of 8&#37; in the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Finally&#44; it should be emphasized that there is as yet no solid evidence for the effectiveness of pharmacological prevention of anthracycline-induced cardiomyopathy&#44; and so the main preventive strategy remains thorough prior cardiovascular assessment of patients and appropriate monitoring&#44; selection and adjustment of chemotherapy dosages&#46;</p></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of heart failure</span><p id="par0090" class="elsevierStylePara elsevierViewall">After the development of signs or symptoms of HF or a reduction in LVEF due to chemotherapy-related cardiotoxicity&#44; treatment should be based on the current guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Although selection of the best therapy is obviously important&#44; one study has shown that the main factor determining successful treatment is the time between the end of chemotherapy and the start of HF therapy&#44; since if this is longer than six months&#44; LVEF is unlikely to recover completely&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Prospects for the future</span><p id="par0095" class="elsevierStylePara elsevierViewall">Several clinical trials are currently under way aiming to assess various therapeutic strategies&#44; pharmacological and non-pharmacological&#44; for the prevention of anthracycline-induced cardiomyopathy &#40;<a class="elsevierStyleCrossRef" href="#tbl0045">Table 8</a>&#41;&#46; It will be some years before the results are known&#44; and there is still a pressing need for evidence-based guidelines for the assessment and clinical monitoring of these patients&#46;</p><elsevierMultimedia ident="tbl0045"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusion</span><p id="par0100" class="elsevierStylePara elsevierViewall">The longer survival of patients undergoing anticancer therapy and the consequent increase in the incidence of anthracycline-induced cardiomyopathy mean that it is necessary to investigate and determine the precise mechanisms leading to adverse cardiac effects&#44; in order to prevent them&#46; Further research will enable specific and validated prevention plans to be established&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Initial assessment"
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          "titulo" => "Prevention of cardiotoxicity"
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                  "titulo" => "Liposomal formulations"
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                  "titulo" => "Dexrazoxane"
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                3 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Beta-blockers"
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                4 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers"
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                  "titulo" => "Statins"
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          "titulo" => "Treatment of heart failure"
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          "titulo" => "Conclusion"
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          "titulo" => "Conflicts of interest"
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    "fechaRecibido" => "2015-07-27"
    "fechaAceptado" => "2015-12-20"
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            0 => "Anthracyclines"
            1 => "Cardiotoxicity"
            2 => "Prevention"
            3 => "Chemotherapy"
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            0 => "Antraciclinas"
            1 => "Cardiotoxicidade"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The increasing use of anthracyclines&#44; together with the longer survival of cancer patients&#44; means the toxic effects of these drugs need to be monitored&#46; In order to detect&#44; prevent or mitigate anthracycline-induced cardiomyopathy&#44; it is essential that all patients undergo a rigorous initial cardiovascular assessment&#44; followed by close monitoring&#46; Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise&#44; healthy lifestyles&#44; control of risk factors and treatment of comorbidities&#59; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers&#44; angiotensin-converting enzyme inhibitors&#44; angiotensin receptor antagonists&#44; statins&#44; dexrazoxane and liposomal formulations&#46; However&#44; there are currently no guidelines for managing prevention in these patients&#46; In this review the authors discuss the state of the art of the assessment&#44; monitoring&#44; and&#44; above all&#44; the prevention of anthracycline-induced cardiotoxicity&#46;</p></span>"
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      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">O crescente uso de antraciclinas&#44; aliado ao aumento da sobrevida dos doentes oncol&#243;gicos&#44; motiva a necessidade de monitorizar os efeitos t&#243;xicos destes f&#225;rmacos&#46; Para que a sua cardiotoxicidade possa ser detetada&#44; prevenida ou atenuada&#44; torna-se essencial que todos os doentes sejam&#44; do ponto de vista cardiovascular&#44; submetidos a uma rigorosa avalia&#231;&#227;o inicial e a um estreito acompanhamento&#46; Diversos ensaios cl&#237;nicos comprovaram o efeito cardioprotetor produzido por medidas n&#227;o farmacol&#243;gicas como o exerc&#237;cio f&#237;sico&#44; a ado&#231;&#227;o de um estilo de vida saud&#225;vel&#44; o controlo de fatores de risco e o tratamento de comorbilidades&#59; foi tamb&#233;m verificado um efeito cardioprotetor com estrat&#233;gias farmacol&#243;gicas como o uso de bloqueadores-beta&#44; inibidores da enzima de convers&#227;o da angiotensina&#44; antagonistas do recetor da angiotensina&#44; estatinas&#44; dexrazoxane ou derivados lisossomais&#46; No entanto&#44; atualmente n&#227;o existe qualquer diretriz cient&#237;fica que oriente as estrat&#233;gias de preven&#231;&#227;o nestes doentes&#46; Com esta revis&#227;o propomo-nos abordar o estado da arte relativo &#224; avalia&#231;&#227;o&#44; monitoriza&#231;&#227;o e&#44; principalmente&#44; &#224; preven&#231;&#227;o da cardiotoxicidade provocada pelas antraciclinas&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Cruz M&#44; Duarte-Rodrigues J&#44; Campelo M&#46; Cardiotoxicidade na terap&#234;utica com antraciclinas&#58; estrat&#233;gias de preven&#231;&#227;o&#46; Rev Port Cardiol&#46; 2016&#59;35&#58;359&#8211;371&#46;</p>"
      ]
    ]
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      0 => array:7 [
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        "etiqueta" => "Figure 1"
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        "figura" => array:1 [
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Initiation of a regimen potentially associated with anthracycline-induced cardiotoxicity&#46; 2DE&#58; two-dimensional echocardiography&#59; 3DE&#58; three-dimensional echocardiography&#59; GLS&#58; global longitudinal strain&#59; LLN&#58; lower limit of normal&#59; LVEF&#58; left ventricular ejection fraction&#46;</p>"
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      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AV&#58; atrioventricular&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;58&#44;59</span></a>&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanisms of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanisms of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anthracycline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">The formation of a DNA complex by conjugation of flat rings with nucleotides inhibits DNA and RNA and protein synthesis&#46; This triggers DNA cleavage by topoisomerase II&#44; resulting in cytotoxicity&#46;<br><br>Anthracyclines inhibit helicase&#44; preventing enzymatic cleavage of the DNA double strand and thus interfering with replication and transcription&#46;<br><br><br>They cause redox reactions through formation of cytotoxic free radicals&#46;</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">Main mechanisms&#58;<br>- topoisomerase II beta-mediated DNA damage<br>- lipid peroxidation<br>- oxidative stress<br>- apoptosis and necrosis of cardiac cells<br><br>Impaired synthesis of DNA&#44; RNA and proteins and of transcription factors involved in regulation of genes specific to the heart&#46;<br><br>Negative balance of sarcomeric proteins in cardiac cells caused by reduced protein expression and increased myofilament degradation&#46; Combination therapy exacerbates myofilament loss&#46;<br>Mitochondrial DNA damage and changes in mitochondrial bioenergetics&#46;<br><br>Disruption of the dynamic regulation of cardiac function&#44; altering adrenergic and adenylyl cyclase activity and calcium homeostasis&#46;</td><td class="td" title="table-entry  " align="left" valign="middle">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced stomach cancer<br>Bladder cancer<br>Breast cancer<br>Ovarian cancer<br>Small cell lung cancer<br>Thyroid cancer<br>Hodgkin disease<br>Acute leukemia<br>Non-Hodgkin lymphoma<br>Neuroblastoma<br>Sarcoma<br>Wilms tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Hypotension<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Tachycardia<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Subacute&#58;<br><span class="elsevierStyleHsp" style=""></span>Pericarditis<br><span class="elsevierStyleHsp" style=""></span>Myocarditis<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Daunorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Acute lymphoblastic leukemia<br>Acute myeloid leukemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Sinus tachycardia<br><span class="elsevierStyleHsp" style=""></span>Tachyarrhythmias<br><span class="elsevierStyleHsp" style=""></span>Ventricular extrasystoles<br><span class="elsevierStyleHsp" style=""></span>AV block<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Epirubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced ovarian cancer<br>Stomach cancer<br>Breast cancer<br>Lung cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Ventricular tachycardia<br><span class="elsevierStyleHsp" style=""></span>AV block<br><span class="elsevierStyleHsp" style=""></span>Bundle branch block<br><span class="elsevierStyleHsp" style=""></span>Bradycardia<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Idarubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Acute lymphocytic leukemia<br>Acute myeloid leukemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Atrial fibrillation<br><span class="elsevierStyleHsp" style=""></span>Myocardial infarction<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Mitoxantrone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced breast cancer<br>Acute myeloid leukemia in adults<br>Non-Hodgkin lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Myocarditis<br><span class="elsevierStyleHsp" style=""></span>Hypertension<br><span class="elsevierStyleHsp" style=""></span>Myocardial ischemia<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cardiotoxicity&#44; pharmacokinetics and therapeutic use of anthracyclines&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CHF&#58; congestive heart failure&#59; LVEF&#58; left ventricular ejection fraction&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;60</span></a>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Any one of the criteria is sufficient to confirm a diagnosis of cardiac dysfunction&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiomyopathy characterized by a decrease in cardiac LVEF that is either global or more severe in the septum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Symptoms of CHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Detection of S3 gallop&#44; tachycardia&#44; or both&#59;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decline in LVEF of at least 5&#37; to less than 55&#37; with accompanying signs or symptoms of CHF&#44; or a decline in LVEF of at least 10&#37; to below 55&#37; without accompanying signs or symptoms&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Criteria to confirm or revise a preliminary diagnosis of chemotherapy-induced cardiac dysfunction&#44; according to the Cardiac Review and Evaluation Committee&#46;</p>"
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">2D&#58; two-dimensional&#59; 3D&#58; three-dimensional&#59; ASE&#47;EAE&#58; American Society of Echocardiography&#47;European Association of Echocardiography&#59; BP&#58; blood pressure&#59; GLS&#58; global longitudinal strain&#59; HR&#58; heart rate&#59; IAC-Echo&#58; Intersocietal Accreditation Commission Echocardiography&#59; IV&#58; intravenous&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; MAPSE&#58; mitral annular plane systolic excursion&#59; RV&#58; right ventricle&#59; TAPSE&#58; tricuspid annular plane systolic excursion&#59; VTI&#58; velocity-time integral&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Standard transthoracic echocardiography</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In accordance with ASE&#47;EAE guidelines and IAC-Echo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging acquisition</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Apical 3-&#44; 4-&#44; and 2-chamber views&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Acquire &#8805;3 cardiac cycles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Images obtained simultaneously maintaining the same 2D frame rate and imaging depth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Frame rate between 40 and 90 frames&#47;s or &#8805;40&#37; of HR</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Aortic VTI &#40;aortic ejection time&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging analysis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Quantify segmental and global longitudinal strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Display the segmental strain curves from apical views in a quad format&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Display the global strain in a bull&#39;s-eye plot&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging pitfalls</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Ectopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Breathing translation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">3D imaging acquisition</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Apical 4-chamber full volume to assess LV volumes and to calculate LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Single and multiple beats optimizing spatial and temporal resolution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Reporting</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Timing of echocardiography with respect to the IV infusion &#40;number of days before or after&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Vital signs &#40;BP&#44; HR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; 3D LVEF&#47;2D biplane Simpson method&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; GLS &#40;echocardiography machine&#44; software&#44; and version used&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In the absence of GLS&#44; measurement of medial and lateral s&#8242; and MAPSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; RV&#58; TAPSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1386612.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Recommended cardio-oncology echocardiogram protocol&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">2DE&#58; two-dimensional echocardiography&#59; 3DE&#58; three-dimensional echocardiography&#59; ASE&#47;EAE&#58; American Society of Echocardiography&#47;European Association of Echocardiography&#59; GLS&#58; global longitudinal strain&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; STE&#58; speckle-tracking echocardiography&#59; TDI&#58; tissue Doppler imaging&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LV systolic function</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Echocardiography is the method of choice for the assessment of patients before&#44; during and after cancer therapy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Accurate calculation of LVEF should be done with the best method available in the echocardiography laboratory &#40;ideally 3DE&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; When using 2DE&#44; the modified biplane Simpson technique is the method of choice&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; LVEF should be combined with the calculation of wall motion score index&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In the absence of GLS by STE&#44; quantification of LV longitudinal function using MAPSE and&#47;or peak systolic velocity &#40;s&#8242;&#41; of the mitral annulus by pulsed-wave TDI is recommended&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; LVEF assessed by 2DE often fails to detect small changes in LV contractility&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Diastolic function</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Although diastolic parameters have not been found to be prognostic of anthracycline-induced cardiomyopathy&#44; a conventional assessment of LV diastolic function&#44; including grading of diastolic function and non-invasive estimation of LV filling pressures&#44; should be added to the assessment of LV systolic function&#44; according to ASE&#47;EAE recommendations for the evaluation of LV diastolic function with echocardiography&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Echocardiographical assessment of systolic and diastolic function in the cancer patient&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;12&#44;61</span></a>&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">2D&#58; two-dimensional&#59; CAD&#58; coronary artery disease&#59; CV&#58; cardiovascular&#59; ECG&#58; electrocardiography&#59; GFR&#58; glomerular filtration rate&#59; GLS&#58; global longitudinal strain&#59; HF&#58; heart failure&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic exam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Advantages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disadvantages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Electrocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low cost<br>Measures QT interval&#44; prolongation of which is a known marker of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Does not measure LVEF<br>Intra- and inter-observer variability in measurement of QT interval&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Doppler echocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low cost<br>Assessment of functional and morphological diastolic &#40;pulmonary venous flow&#44; E&#47;A ratio&#44; isovolumic relaxation time&#41; and systolic &#40;wall thickening during systole&#44; LVEF&#44; fractional shortening&#41; parameters&#44; valve structure and pericardium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intra- and inter-observer variability<br>Measurement of LVEF subject to variability and dependent on image quality<br>Doubtful predictive value for early detection of subclinical lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tissue Doppler imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Excellent temporal resolution<br>Early detection of subclinical lesions &#40;in combination with markers of inflammation and oxidative stress&#41;<br>Functional assessment of filling pressures &#40;E&#47;e&#8242; ratio&#41;&#44; velocities&#44; strain and strain rate of ventricular walls in systole and diastole<br>Detection of isolated diastolic dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">More time-consuming analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2D strain&#47;speckle tracking and GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Superior to LVEF for predicting cardiovascular mortality in the general population<br>Better risk stratification in HF patients<br>Able to recognize early LV dysfunction in patients undergoing cardiotoxic therapy<br>Reproducible when performed by an experienced operator&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heavily dependent on image quality of 2D echocardiography<br>Lack of long-term clinical trials assessing the ability of GLS to predict persistent falls in LVEF or symptomatic HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stress echocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Assessment of myocardial contractile reserve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Semi-invasive<br>Controversial and limited data on early detection of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radionuclide angiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High reproducibility<br>Low intra- and inter-observer variability<br>Validated for measurement of LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Low spatial and temporal resolution<br>Underestimates ventricular volumes<br>Underestimates LVEF in small ventricles &#40;women and children&#41;<br>Does not assess valve function<br>Little information on diastolic function<br>Limited predictive value for early detection of subclinical lesions and changes in LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Magnetic resonance imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reproducible<br>No ionizing radiation<br>Assessment of myocardial perfusion and function and pericardium&#44; and detection of myocardial masses<br>Useful in patients with poor echocardiographic image quality<br>Gold standard for calculation of LV volumes and of LVEF<br>T2 sequences&#58; detects segmental or global changes in myocardial water content resulting from inflammation or microvascular or myocyte damage<br>T1 sequences&#58; provides information on myocardial lesions and fibrosis&#59; with gadolinium contrast&#44; detects histopathological alterations including intracellular vacuolization&#44; enabling prediction of subsequent decrease in LVEF<br>Late enhancement&#58; detection of myocardial fibrosis associated with poor prognosis in patients with CAD&#44; hypertrophic cardiomyopathy and infiltrative disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High cost<br>Limited availability<br>Contraindicated in patients with devices incompatible with magnetic resonance &#40;pacemakers&#44; cardiac resynchronization devices and implantable cardioverter-defibrillators&#41;<br>Risk of contrast nephrotoxicity in patients with renal failure &#40;GFR &#60;30 ml&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Computed tomography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High-resolution image<br>Identifies pericardial calcification or thickening in patients undergoing radiotherapy or surgery<br>Visualizes and assesses calcification of the coronary arteries&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Documented coronary calcification prior to anticancer therapy is not predictive of CV risk in patients undergoing anthracycline chemotherapy<br>Little used for detection and monitoring of subclinical changes in cardiac function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Scintigraphy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Functional and structural assessment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Limited availability<br>Low temporal resolution<br>Limited data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Biomarkers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low inter-observer variability<br>Assessment of CV function and potential signs of cardiac damage<br>Promising for early detection of myocardial injury&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Endomyocardial biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Detects histological evidence of cardiac damage&#44; including loss of myofibrils&#44; vacuolization of cytoplasm&#44; dilatation of the sarcoplasmic reticulum&#44; increased numbers of lysosomes and mitochondrial swelling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Invasive<br>Histological interpretation requires specialist knowledge<br>No functional information<br>Results limited by quantity and quality of biopsy sample&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Assessment of endothelial damage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alternate parameters of cardiotoxicity such as cytokines&#44; adhesion molecules and carotid artery intima-media thickness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetic analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Minimally invasive<br>Assesses individual susceptibility to cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Advantages and disadvantages of diagnostic exams in the assessment of anthracycline-induced cardiotoxicity&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">V1&#58; Vivid 7 or Vivid E9 &#40;GE Healthcare&#41;&#59; V2&#58; iE33 &#40;Philips Medical Systems&#41;&#59; V3&#58; Artida or Apilo &#40;Toshiba Medical Systems&#41;&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="7" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">0-19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">20-29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">30-39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">40-49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50-59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8805;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V1</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;1&#177;2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;2&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;1&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;4&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;0&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;3&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0218&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;7&#177;3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;6&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;0&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;7&#177;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1982&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;4&#177;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;3&#177;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;8&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;6&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-23&#46;3&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0348&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4292&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0029&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1381&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V2</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;9&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;0&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;5&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;2&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;6&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;7&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;4&#177;2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;8&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;1&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;9&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;9&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-15&#46;8&#177;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;5&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;6&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;3&#177;0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;3&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1349&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0248&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1083&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0294&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0928&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V3</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;4&#177;1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;4&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;5&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;8&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;6&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;8&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;7&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;3&#177;3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;2&#177;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;7&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;3&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;6&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0141&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6076&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9787&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9201&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7374&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0668&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cumulative doses exceeding&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Recommended maximum &#40;mg&#47;m<span class="elsevierStyleSup">2</span>&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#58;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">400-550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daunorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">550-800&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Epirubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">900-1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idarubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">150-225&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mitoxantrone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100-140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pre-existing CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Diabetes</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Coronary artery disease</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Peripheral vascular disease</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Hypertension</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Genetic predisposition&#58; female gender&#44; black race</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Previous or concomitant mediastinal radiation</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Intravenous bolus administration</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Combination with other agents including cyclophosphamide&#44; trastuzumab or paclitaxel</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Length of time since end of chemotherapy</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Electrolyte disturbances&#58; hypocalcemia&#44; hypomagnesemia</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Hemochromatosis &#40;C282Y mutation&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Hyperthermia</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Liver disease</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Patients aged over 65 and children may develop cardiotoxicity with lower cumulative doses&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;24</span></a>&#46;</p>"
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          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Risk factors for anthracycline-induced cardiotoxicity&#46;</p>"
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          "leyenda" => "<p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">CT&#58; computed tomography&#59; GLS&#58; global longitudinal strain&#59; LVDF&#58; left ventricular diastolic function&#59; LVEF&#58; left ventricular ejection fraction&#59; LVSD&#58; left ventricular systolic dysfunction&#59; MRI&#58; magnetic resonance imaging&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lead author and ClinicalTrials&#46;gov no&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Condition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chemotherapy agent&#40;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary outcome measure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Planned trial conclusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mavrudis D<br><span class="elsevierStyleInterRef" id="intr0005" href="ctgov:NCT01120171">NCT01120171</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cyclophosphamide vs&#46; liposome-encapsulated doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overall response rate by CT or MRI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Campbell K<br><span class="elsevierStyleInterRef" id="intr0010" href="ctgov:NCT02006979">NCT02006979</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single blind&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">An acute bout of exercise performed 24 hours prior to every anthracycline infusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">December 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cipolla C<br><span class="elsevierStyleInterRef" id="intr0015" href="ctgov:NCT01968200">NCT01968200</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enalapril after appearance of cardiac injury vs&#46; enalapril concomitantly to chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Up to one year after completion of chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cardiac troponin levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">July 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Virani S<br><span class="elsevierStyleInterRef" id="intr0020" href="ctgov:NCT01708798">NCT01708798</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&#44; phase 2&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eplerenone vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Change in LVDF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bocchi E<br><span class="elsevierStyleInterRef" id="intr0025" href="ctgov:NCT01724450">NCT01724450</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Carvedilol vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LVSD &#40;10&#37; reduction in LVEF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">October 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Livi L<br><span class="elsevierStyleInterRef" id="intr0030" href="ctgov:NCT02236806">NCT02236806</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single blind&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines and trastuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bisoprolol vs&#46; ramipril&#44; bisoprolol vs&#46; placebo&#44; ramipril vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">480&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">November 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smith K<br><span class="elsevierStyleInterRef" id="intr0035" href="ctgov:NCT02096588">NCT02096588</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simvastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">April 2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                      "titulo" => "AHA&#47;ACCF&#47;HRS recommendations for the standardization and interpretation of the electrocardiogram&#58; Part IV&#58; The ST segment&#44; T and U waves&#44; and the QT interval&#58; a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee&#44; Council on Clinical Cardiology&#59; the American College of Cardiology Foundation&#59; and the Heart Rhythm Society&#46; Endorsed by the International Society for Computerized Electrocardiology"
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Review article
Cardiotoxicity in anthracycline therapy: Prevention strategies
Cardiotoxicidade na terapêutica com antraciclinas: estratégias de prevenção
Margarida Cruza, Joana Duarte-Rodriguesb, Manuel Campeloa,b,
Corresponding author
mcampelo@hotmail.com

Corresponding author.
a Faculdade de Medicina, Universidade do Porto, Porto, Portugal
b Serviço de Cardiologia, Hospital de S. João, Porto, Portugal
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daunorubicin&#44; epirubicin&#44; mitoxantrone and idarubicin are the most commonly used chemotherapy drugs in cancer&#46; They are a known cause of cardiotoxicity &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; with acute or&#47;and subacute effects that can manifest as electrocardiographic changes&#44; ventricular and supraventricular arrhythmias&#44; cardiac conduction disturbances &#40;atrioventricular or branch block&#41;&#44; ventricular dysfunction&#44; rises in brain-type natriuretic peptide &#40;BNP&#44; a marker of increased preload and heart failure &#91;HF&#93;&#41;&#44; myocarditis and pericarditis&#44; and that may occur at any time between beginning of treatment and two weeks after the end of treatment&#46; These effects are relatively uncommon and most revert a week after treatment cessation&#46; Chronic cardiomyopathy is defined as early if it begins within a year of ending chemotherapy and late after that period&#46; In either case&#44; systolic or diastolic dysfunction are observed &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; that can progress to severe cardiomyopathy and may even lead to death&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Although some studies have suggested that the risk of developing ventricular dysfunction and its severity can be predicted on the basis of acute myocardial injury&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> the relationship between acute and chronic toxicity is not fully understood&#46; Diagnosis of cardiac dysfunction induced by cancer therapy has been the subject of various studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5</span></a> one of which<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> is considered the reference publication on the subject&#44; and is based on HF symptoms&#44; physical examination and parameters of left ventricular function&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">One proposed classification divides chemotherapy-induced cardiomyopathy into two types&#58; type I&#44; caused by anthracyclines&#44; which induce irreversible dose-dependent cardiac injury&#59; and type II&#44; caused by trastuzumab&#44; which is not related to the cumulative dose and is often reversible after treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The second type will not be discussed in this review article&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this review the authors discuss strategies in patients being treated with anthracyclines in order to prevent or mitigate their main adverse effects on the heart&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Initial assessment</span><p id="par0025" class="elsevierStylePara elsevierViewall">In view of the cardiotoxicity of anthracyclines&#44; all patients referred for chemotherapy should undergo a cardiac assessment to establish their baseline cardiovascular characteristics&#44; which can then be used during the treatment regimen for purposes of comparison&#46; This assessment should include clinical history and physical examination&#44; electrocardiography to determine cardiac rhythm and detect signs of ischemia&#44; and cardiac imaging&#44; usually transthoracic echocardiography with complete Doppler study &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>&#41;&#46; When the echocardiogram is provides insufficient information&#44; cardiac magnetic resonance imaging &#40;CMRI&#41; is recommended&#46; Baseline troponin levels should also be measured for future comparisons&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Monitoring during therapy</span><p id="par0030" class="elsevierStylePara elsevierViewall">It is important to monitor for signs and symptoms of cardiotoxicity during chemotherapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 5</a>&#41;&#46; The 12-lead electrocardiogram can be used routinely to screen for arrhythmias due to anthracycline-related cardiotoxicity&#44; while 24-hour Holter monitoring or an event recorder can be useful to investigate the etiology of syncope presumed to result from arrhythmia or advanced atrioventricular block&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Cardiac function should be monitored by echocardiography in patients under anthracycline therapy&#46; Global longitudinal strain &#40;GLS&#41; as assessed by two-dimensional speckle tracking is a more sensitive predictor of HF than left ventricular ejection fraction &#40;LVEF&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> since during anthracycline therapy changes in GLS precede reduction in LVEF&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; in clinical practice&#44; fractional shortening and LVEF have been the most widely used parameters&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> although fractional shortening is proving to be less reliable in this context&#46; These parameters&#44; being dependent on pre- and afterload&#44; are less sensitive for early detection of preclinical cardiac disease&#46; Various studies have suggested that assessment of diastolic function by Doppler echocardiography may enable early detection of anthracycline-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> If LVEF is &#60;53&#37;&#44; GLS below the limit of normal &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 6</a>&#41;&#44; and&#47;or troponins are elevated&#44; a cardiology consultation should be considered&#44; with discussion between the cardiologist and oncologist of the risk&#47;benefit ratio of chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A fall in LVEF during anthracycline therapy is associated with increased risk for cardiac events&#44; and although a reduction in GLS of &#60;8&#37; compared to baseline appears not to be significant&#44; a reduction of &#62;15&#37; is likely to indicate cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The study should be repeated two to three weeks after the baseline study to confirm the diagnosis&#46; CMRI can detect subtle changes in the myocardium and increases in extracellular volume&#44; which suggest edema or diffuse fibrosis&#46; Although it is highly sensitive and reproducible for assessment of cardiac function and characterization of myocardial tissue&#44; CMRI has the disadvantages of limited availability and high cost&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Radionuclide angiography is reproducible and more easily available&#44; but exposes patients to ionizing radiation&#44; increasing their cumulative dose&#44; especially when serial studies are required&#44; and provides only limited information on diastolic function and valve morphology&#44; and so should not be the method of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Endomyocardial biopsy has greater sensitivity and specificity for detection and monitoring of the adverse effects of anthracyclines&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> enabling visualization of loss of myofibrils&#44; vacuolization of cytoplasm&#44; dilatation of the sarcoplasmic reticulum&#44; increased numbers of lysosomes and mitochondrial swelling&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; the invasive nature of the procedure limits its use in clinical practice&#46; Biomarkers have been validated in various studies&#59; they are specific not only in detecting cardiovascular injury but also in determining its extent and reversibility&#46; While troponin T and I are indicators of cardiomyocyte damage&#44; BNP and the N-terminal portion of pro-BNP &#40;NT-proBNP&#41; reflect increased myocardial stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> According to the literature&#44; elevation of troponins is an early indicator of cardiotoxicity&#44; while BNP is less consistent&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">If the dose of anthracyclines exceeds 240 mg&#47;m<span class="elsevierStyleSup">2</span>&#44; cardiac assessment should be repeated before administering further cycles &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prevention of cardiotoxicity</span><p id="par0040" class="elsevierStylePara elsevierViewall">Prevention of anthracycline-induced cardiotoxicity&#44; while maintaining the drugs&#8217; therapeutic effectiveness&#44; can be achieved by pharmacological and non-pharmacological means&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Non-pharmacological prevention</span><p id="par0045" class="elsevierStylePara elsevierViewall">Cardiovascular risk factors should be identified and treated appropriately as soon as cancer is diagnosed&#46; Patients should be encouraged to adopt a healthy lifestyle&#44; including a diet low in saturated fat and a maximum of 2&#46;5 g of sodium per day&#44; avoid toxic substances such as alcohol and tobacco&#44; and maintain their body mass index close to 25 kg&#47;m<span class="elsevierStyleSup">2</span>&#46; Exercise&#44; whether of low or high intensity&#44; during anthracycline therapy increases cardiovascular reserve<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and studies in animal models have indicated that it may reduce the cardiotoxic effects of these agents&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Although exercise has shown promise in improving cardiopulmonary function in breast cancer survivors&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> there have been no clinical trials in humans that confirm their cardioprotective role&#46; Another measure is to reduce or avoid the use of drugs that prolong QT interval&#44; particularly 5-hydroxytryptamine 3 antagonists &#40;frequently used to prevent adverse effects of chemotherapy including nausea and vomiting&#41; and antihistamines&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> It is also important to minimize radiation exposure&#44; to correct electrolyte disturbances and to treat comorbidities &#40;<a class="elsevierStyleCrossRef" href="#tbl0040">Table 7</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Decreasing the dose of anthracyclines is another way to reduce the incidence of left ventricular systolic dysfunction &#40;LVSD&#41;&#44; as shown by a study of patients taking 400&#44; 500 or 550 mg&#47;m<span class="elsevierStyleSup">2</span> of doxorubicin&#44; in which the incidence of congestive HF was 5&#37;&#44; 16&#37; and 26&#37; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Although anthracyclines appear to be cardiotoxic independently of the dose administered&#44; several studies have shown that continuous infusion of lower doses for between 24 and 92 hours<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> can reduce the severity of cardiac injury&#44; and has been described as an effective way of doing so&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Prolonging infusion time reduces cardiotoxicity without compromising the effectiveness of chemotherapy&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> but infusion lasting longer than 96 hours is associated with a high incidence of stomatitis&#46; The only case in which continuous infusion of doxorubicin appears to have no cardioprotective effect compared to rapid infusion is in children with acute lymphoblastic leukemia &#40;ALL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Other clinical trials using endomyocardial biopsy to assess anthracycline-induced cardiac injury in different drug regimens concluded that continuous perfusion leads to far less significant damage than rapid intravenous administration&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> These trials also showed that patients receiving continuous infusion had greater tolerance for higher cumulative doses of doxorubicin&#46; Although animal studies demonstrated that anthracycline levels in tumor tissue were the same however the drugs were administered &#40;continuous or rapid infusion&#41;&#44; this was not true of cardiac tissue&#44; in which rapid infusion led to higher concentrations and thus greater toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pharmacological prevention</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Antioxidants</span><p id="par0055" class="elsevierStylePara elsevierViewall">Although antioxidants neutralize free radicals formed by anthracycline therapy and thus theoretically reduce or prevent cardiotoxicity&#44; clinical trials of N-acetylcysteine&#44; coenzyme Q&#44; L-carnitine&#44; phenethylamines&#44; amifostine and a combination of vitamins E and C and N-acetylcysteine did not show a cardioprotective effect&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Erythropoietin and iloprost<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> have been shown to protect against the cardiotoxic effects of doxorubicin in vitro&#44; without affecting its anticancer effectiveness&#44; but their cardioprotective ability will have to be demonstrated in vivo&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Liposomal formulations</span><p id="par0060" class="elsevierStylePara elsevierViewall">One way to combat the adverse cardiac effects of anthracyclines is to change the formulation of the drugs such as encapsulating them in liposomes&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Studies comparing unencapsulated and liposome-encapsulated doxorubicin found no difference in anti-tumor response rate&#44; overall survival or progression-free survival&#44; but the incidence of HF and LVSD was lower in patients treated with the liposomal formulation&#44; and this group also had a lower incidence of other adverse effects including neutropenia&#44; nausea&#44; vomiting and diarrhea&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Due to their high cost&#44; these formulations are not widely used and the US Food and Drug Administration &#40;FDA&#41; has approved their use only for ovarian cancer&#44; AIDS-related Kaposi&#39;s sarcoma&#44; and patients with multiple myeloma who have not responded to a year of treatment with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Dexrazoxane</span><p id="par0065" class="elsevierStylePara elsevierViewall">Administration of dexrazoxane concomitantly with anticancer regimens can have a cardioprotective effect&#44; preventing elevation of troponins and reducing the incidence of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Some authors attribute the cardioprotective effect of this iron chelator to its reduction of the quantity of intracellular iron&#44; which may decrease doxorubicin-induced free radical generation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> However&#44; studies on other iron chelators have not demonstrated cardioprotection&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> It has also been suggested that dexrazoxane&#39;s cardioprotective effect is due not only to its antagonizing topoisomerase II cleavage complex formation&#44; but also to its induction of rapid degradation of topoisomerase II beta&#44; which suggests that this enzyme is involved in anthracycline-induced cardiotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> A study of dexrazoxane in over 200 children with ALL showed that it reduced troponin T elevation in both sexes&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and limited reduction of fractional shortening and maintained left ventricular thickness-to-dimension ratio at five years&#44; but only in girls&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Recently three cases have been reported of adults undergoing chemotherapy combined with dexrazoxane for breast cancer who developed acute myeloid leukemia&#46; However&#44; two studies comparing dexrazoxane with placebo in children with ALL followed for five and 10 years showed no difference in the incidence of secondary malignancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Nevertheless&#44; in view of its known adverse effects&#44; the FDA and the European Medicines Agency have restricted the use of dexrazoxane to adult patients with advanced or metastatic breast cancer who have already received a cumulative dose of doxorubicin of more than 300 mg&#47;m<span class="elsevierStyleSup">2</span> and who will benefit from additional anthracycline therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Beta-blockers</span><p id="par0070" class="elsevierStylePara elsevierViewall">The cardioprotection afforded by beta-blockers &#40;BBs&#41; appears to derive from their antioxidant and anti-apoptotic properties&#46; One BB&#44; carvedilol&#44; has shown particular promise in reducing the incidence of anthracycline-induced cardiomyopathy and preserving systolic and diastolic function&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In children&#44; carvedilol limited troponin I elevation and improved both fractional shortening and peak global systolic strain&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> According to some studies&#44; BBs and angiotensin-converting enzyme &#40;ACE&#41; inhibitors &#40;see below&#41; can prevent the remodeling associated with HF by reducing adrenergic response&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> However&#44; no cardioprotective effects have been seen with either metoprolol or enalapril&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers</span><p id="par0075" class="elsevierStylePara elsevierViewall">ACE inhibitors and angiotensin receptor blockers &#40;ARBs&#41; show cardioprotective properties&#44; possibly by reducing oxidative stress&#44; left ventricular remodeling&#44; and apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> When administered for at least two years after discontinuation of chemotherapy in children with anthracycline-induced LVSD&#44; enalapril showed no benefit in terms of reducing left ventricular end-systolic wall stress or preserving fractional shortening&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> By contrast&#44; in adults treated with high-dose anthracyclines&#44; enalapril prevented HF and worsening of parameters of cardiac function such as LVEF&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Studies in angiotensin II type I receptor knockout mice showed that doxorubicin did not have a cardiotoxic effect in these animals and that the administration of ARBs can prevent daunorobucin-induced cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Although to our knowledge there have been only two randomized trials on ARBs in chemotherapy patients&#44; valsartan was shown to prevent acute prolongation of corrected QT&#44; left ventricular diastolic dilatation and elevation of BNP during one week of chemotherapy&#44; although with no effect on LVEF&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> and telmisartan prevented reduction in peak strain rate during high-dose anthracycline therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Further studies are required with longer follow-up to confirm these effects&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statins</span><p id="par0080" class="elsevierStylePara elsevierViewall">Statins have antioxidant and anti-inflammatory properties&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Studies in animal models demonstrate that fluvastatin mitigates anthracycline-induced cardiotoxicity&#44; reducing oxidative stress and enhancing the expression of the antioxidant enzyme mitochondrial superoxide dismutase 2&#44; resulting in reduced cardiac inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> In one clinical trial assessing the effect of continuous statin treatment in patients with breast cancer receiving anthracycline-based chemotherapy&#44; patients receiving statins had a lower incidence of HF&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In another study in patients with previously normal LVEF undergoing anthracycline chemotherapy&#44; LVEF was unchanged at six months in those treated with atorvastatin&#44; compared to a fall of 8&#37; in the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Finally&#44; it should be emphasized that there is as yet no solid evidence for the effectiveness of pharmacological prevention of anthracycline-induced cardiomyopathy&#44; and so the main preventive strategy remains thorough prior cardiovascular assessment of patients and appropriate monitoring&#44; selection and adjustment of chemotherapy dosages&#46;</p></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment of heart failure</span><p id="par0090" class="elsevierStylePara elsevierViewall">After the development of signs or symptoms of HF or a reduction in LVEF due to chemotherapy-related cardiotoxicity&#44; treatment should be based on the current guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Although selection of the best therapy is obviously important&#44; one study has shown that the main factor determining successful treatment is the time between the end of chemotherapy and the start of HF therapy&#44; since if this is longer than six months&#44; LVEF is unlikely to recover completely&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Prospects for the future</span><p id="par0095" class="elsevierStylePara elsevierViewall">Several clinical trials are currently under way aiming to assess various therapeutic strategies&#44; pharmacological and non-pharmacological&#44; for the prevention of anthracycline-induced cardiomyopathy &#40;<a class="elsevierStyleCrossRef" href="#tbl0045">Table 8</a>&#41;&#46; It will be some years before the results are known&#44; and there is still a pressing need for evidence-based guidelines for the assessment and clinical monitoring of these patients&#46;</p><elsevierMultimedia ident="tbl0045"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusion</span><p id="par0100" class="elsevierStylePara elsevierViewall">The longer survival of patients undergoing anticancer therapy and the consequent increase in the incidence of anthracycline-induced cardiomyopathy mean that it is necessary to investigate and determine the precise mechanisms leading to adverse cardiac effects&#44; in order to prevent them&#46; Further research will enable specific and validated prevention plans to be established&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Initial assessment"
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              "titulo" => "Monitoring during therapy"
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          "titulo" => "Prevention of cardiotoxicity"
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              "titulo" => "Non-pharmacological prevention"
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              "titulo" => "Pharmacological prevention"
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                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Antioxidants"
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                1 => array:2 [
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                  "titulo" => "Liposomal formulations"
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                  "identificador" => "sec0045"
                  "titulo" => "Dexrazoxane"
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                3 => array:2 [
                  "identificador" => "sec0050"
                  "titulo" => "Beta-blockers"
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                4 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers"
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                  "titulo" => "Statins"
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          "titulo" => "Treatment of heart failure"
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          "titulo" => "Prospects for the future"
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          "titulo" => "Conclusion"
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          "titulo" => "Conflicts of interest"
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    "fechaRecibido" => "2015-07-27"
    "fechaAceptado" => "2015-12-20"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Anthracyclines"
            1 => "Cardiotoxicity"
            2 => "Prevention"
            3 => "Chemotherapy"
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      ]
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          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec821214"
          "palabras" => array:4 [
            0 => "Antraciclinas"
            1 => "Cardiotoxicidade"
            2 => "Preven&#231;&#227;o"
            3 => "Quimioterapia"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The increasing use of anthracyclines&#44; together with the longer survival of cancer patients&#44; means the toxic effects of these drugs need to be monitored&#46; In order to detect&#44; prevent or mitigate anthracycline-induced cardiomyopathy&#44; it is essential that all patients undergo a rigorous initial cardiovascular assessment&#44; followed by close monitoring&#46; Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise&#44; healthy lifestyles&#44; control of risk factors and treatment of comorbidities&#59; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers&#44; angiotensin-converting enzyme inhibitors&#44; angiotensin receptor antagonists&#44; statins&#44; dexrazoxane and liposomal formulations&#46; However&#44; there are currently no guidelines for managing prevention in these patients&#46; In this review the authors discuss the state of the art of the assessment&#44; monitoring&#44; and&#44; above all&#44; the prevention of anthracycline-induced cardiotoxicity&#46;</p></span>"
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      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">O crescente uso de antraciclinas&#44; aliado ao aumento da sobrevida dos doentes oncol&#243;gicos&#44; motiva a necessidade de monitorizar os efeitos t&#243;xicos destes f&#225;rmacos&#46; Para que a sua cardiotoxicidade possa ser detetada&#44; prevenida ou atenuada&#44; torna-se essencial que todos os doentes sejam&#44; do ponto de vista cardiovascular&#44; submetidos a uma rigorosa avalia&#231;&#227;o inicial e a um estreito acompanhamento&#46; Diversos ensaios cl&#237;nicos comprovaram o efeito cardioprotetor produzido por medidas n&#227;o farmacol&#243;gicas como o exerc&#237;cio f&#237;sico&#44; a ado&#231;&#227;o de um estilo de vida saud&#225;vel&#44; o controlo de fatores de risco e o tratamento de comorbilidades&#59; foi tamb&#233;m verificado um efeito cardioprotetor com estrat&#233;gias farmacol&#243;gicas como o uso de bloqueadores-beta&#44; inibidores da enzima de convers&#227;o da angiotensina&#44; antagonistas do recetor da angiotensina&#44; estatinas&#44; dexrazoxane ou derivados lisossomais&#46; No entanto&#44; atualmente n&#227;o existe qualquer diretriz cient&#237;fica que oriente as estrat&#233;gias de preven&#231;&#227;o nestes doentes&#46; Com esta revis&#227;o propomo-nos abordar o estado da arte relativo &#224; avalia&#231;&#227;o&#44; monitoriza&#231;&#227;o e&#44; principalmente&#44; &#224; preven&#231;&#227;o da cardiotoxicidade provocada pelas antraciclinas&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Cruz M&#44; Duarte-Rodrigues J&#44; Campelo M&#46; Cardiotoxicidade na terap&#234;utica com antraciclinas&#58; estrat&#233;gias de preven&#231;&#227;o&#46; Rev Port Cardiol&#46; 2016&#59;35&#58;359&#8211;371&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Initiation of a regimen potentially associated with anthracycline-induced cardiotoxicity&#46; 2DE&#58; two-dimensional echocardiography&#59; 3DE&#58; three-dimensional echocardiography&#59; GLS&#58; global longitudinal strain&#59; LLN&#58; lower limit of normal&#59; LVEF&#58; left ventricular ejection fraction&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AV&#58; atrioventricular&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;58&#44;59</span></a>&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanisms of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanisms of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anthracycline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">The formation of a DNA complex by conjugation of flat rings with nucleotides inhibits DNA and RNA and protein synthesis&#46; This triggers DNA cleavage by topoisomerase II&#44; resulting in cytotoxicity&#46;<br><br>Anthracyclines inhibit helicase&#44; preventing enzymatic cleavage of the DNA double strand and thus interfering with replication and transcription&#46;<br><br><br>They cause redox reactions through formation of cytotoxic free radicals&#46;</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">Main mechanisms&#58;<br>- topoisomerase II beta-mediated DNA damage<br>- lipid peroxidation<br>- oxidative stress<br>- apoptosis and necrosis of cardiac cells<br><br>Impaired synthesis of DNA&#44; RNA and proteins and of transcription factors involved in regulation of genes specific to the heart&#46;<br><br>Negative balance of sarcomeric proteins in cardiac cells caused by reduced protein expression and increased myofilament degradation&#46; Combination therapy exacerbates myofilament loss&#46;<br>Mitochondrial DNA damage and changes in mitochondrial bioenergetics&#46;<br><br>Disruption of the dynamic regulation of cardiac function&#44; altering adrenergic and adenylyl cyclase activity and calcium homeostasis&#46;</td><td class="td" title="table-entry  " align="left" valign="middle">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced stomach cancer<br>Bladder cancer<br>Breast cancer<br>Ovarian cancer<br>Small cell lung cancer<br>Thyroid cancer<br>Hodgkin disease<br>Acute leukemia<br>Non-Hodgkin lymphoma<br>Neuroblastoma<br>Sarcoma<br>Wilms tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Hypotension<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Tachycardia<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Subacute&#58;<br><span class="elsevierStyleHsp" style=""></span>Pericarditis<br><span class="elsevierStyleHsp" style=""></span>Myocarditis<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Daunorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Acute lymphoblastic leukemia<br>Acute myeloid leukemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Sinus tachycardia<br><span class="elsevierStyleHsp" style=""></span>Tachyarrhythmias<br><span class="elsevierStyleHsp" style=""></span>Ventricular extrasystoles<br><span class="elsevierStyleHsp" style=""></span>AV block<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Epirubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced ovarian cancer<br>Stomach cancer<br>Breast cancer<br>Lung cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Ventricular tachycardia<br><span class="elsevierStyleHsp" style=""></span>AV block<br><span class="elsevierStyleHsp" style=""></span>Bundle branch block<br><span class="elsevierStyleHsp" style=""></span>Bradycardia<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Idarubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Acute lymphocytic leukemia<br>Acute myeloid leukemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Atrial fibrillation<br><span class="elsevierStyleHsp" style=""></span>Myocardial infarction<br><span class="elsevierStyleHsp" style=""></span>Thromboembolism<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="middle">Mitoxantrone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="middle">Advanced breast cancer<br>Acute myeloid leukemia in adults<br>Non-Hodgkin lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute&#58;<br><span class="elsevierStyleHsp" style=""></span>Arrhythmias<br><span class="elsevierStyleHsp" style=""></span>Myocarditis<br><span class="elsevierStyleHsp" style=""></span>Hypertension<br><span class="elsevierStyleHsp" style=""></span>Myocardial ischemia<br>Chronic&#58;<br><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy<br><span class="elsevierStyleHsp" style=""></span>Contractile dysfunction<br><span class="elsevierStyleHsp" style=""></span>Congestive heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cardiotoxicity&#44; pharmacokinetics and therapeutic use of anthracyclines&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CHF&#58; congestive heart failure&#59; LVEF&#58; left ventricular ejection fraction&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;60</span></a>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Any one of the criteria is sufficient to confirm a diagnosis of cardiac dysfunction&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiomyopathy characterized by a decrease in cardiac LVEF that is either global or more severe in the septum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Symptoms of CHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Detection of S3 gallop&#44; tachycardia&#44; or both&#59;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decline in LVEF of at least 5&#37; to less than 55&#37; with accompanying signs or symptoms of CHF&#44; or a decline in LVEF of at least 10&#37; to below 55&#37; without accompanying signs or symptoms&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Criteria to confirm or revise a preliminary diagnosis of chemotherapy-induced cardiac dysfunction&#44; according to the Cardiac Review and Evaluation Committee&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">2D&#58; two-dimensional&#59; 3D&#58; three-dimensional&#59; ASE&#47;EAE&#58; American Society of Echocardiography&#47;European Association of Echocardiography&#59; BP&#58; blood pressure&#59; GLS&#58; global longitudinal strain&#59; HR&#58; heart rate&#59; IAC-Echo&#58; Intersocietal Accreditation Commission Echocardiography&#59; IV&#58; intravenous&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; MAPSE&#58; mitral annular plane systolic excursion&#59; RV&#58; right ventricle&#59; TAPSE&#58; tricuspid annular plane systolic excursion&#59; VTI&#58; velocity-time integral&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Standard transthoracic echocardiography</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In accordance with ASE&#47;EAE guidelines and IAC-Echo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging acquisition</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Apical 3-&#44; 4-&#44; and 2-chamber views&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Acquire &#8805;3 cardiac cycles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Images obtained simultaneously maintaining the same 2D frame rate and imaging depth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Frame rate between 40 and 90 frames&#47;s or &#8805;40&#37; of HR</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Aortic VTI &#40;aortic ejection time&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging analysis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Quantify segmental and global longitudinal strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Display the segmental strain curves from apical views in a quad format&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Display the global strain in a bull&#39;s-eye plot&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">2D strain imaging pitfalls</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Ectopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Breathing translation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">3D imaging acquisition</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Apical 4-chamber full volume to assess LV volumes and to calculate LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Single and multiple beats optimizing spatial and temporal resolution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Reporting</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Timing of echocardiography with respect to the IV infusion &#40;number of days before or after&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Vital signs &#40;BP&#44; HR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; 3D LVEF&#47;2D biplane Simpson method&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; GLS &#40;echocardiography machine&#44; software&#44; and version used&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In the absence of GLS&#44; measurement of medial and lateral s&#8242; and MAPSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; RV&#58; TAPSE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Recommended cardio-oncology echocardiogram protocol&#46;</p>"
        ]
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      4 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at4"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">2DE&#58; two-dimensional echocardiography&#59; 3DE&#58; three-dimensional echocardiography&#59; ASE&#47;EAE&#58; American Society of Echocardiography&#47;European Association of Echocardiography&#59; GLS&#58; global longitudinal strain&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#59; STE&#58; speckle-tracking echocardiography&#59; TDI&#58; tissue Doppler imaging&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LV systolic function</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Echocardiography is the method of choice for the assessment of patients before&#44; during and after cancer therapy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Accurate calculation of LVEF should be done with the best method available in the echocardiography laboratory &#40;ideally 3DE&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; When using 2DE&#44; the modified biplane Simpson technique is the method of choice&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; LVEF should be combined with the calculation of wall motion score index&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; In the absence of GLS by STE&#44; quantification of LV longitudinal function using MAPSE and&#47;or peak systolic velocity &#40;s&#8242;&#41; of the mitral annulus by pulsed-wave TDI is recommended&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; LVEF assessed by 2DE often fails to detect small changes in LV contractility&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Diastolic function</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8226; Although diastolic parameters have not been found to be prognostic of anthracycline-induced cardiomyopathy&#44; a conventional assessment of LV diastolic function&#44; including grading of diastolic function and non-invasive estimation of LV filling pressures&#44; should be added to the assessment of LV systolic function&#44; according to ASE&#47;EAE recommendations for the evaluation of LV diastolic function with echocardiography&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Echocardiographical assessment of systolic and diastolic function in the cancer patient&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;12&#44;61</span></a>&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">2D&#58; two-dimensional&#59; CAD&#58; coronary artery disease&#59; CV&#58; cardiovascular&#59; ECG&#58; electrocardiography&#59; GFR&#58; glomerular filtration rate&#59; GLS&#58; global longitudinal strain&#59; HF&#58; heart failure&#59; LV&#58; left ventricular&#59; LVEF&#58; left ventricular ejection fraction&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnostic exam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Advantages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disadvantages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Electrocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low cost<br>Measures QT interval&#44; prolongation of which is a known marker of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Does not measure LVEF<br>Intra- and inter-observer variability in measurement of QT interval&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Doppler echocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low cost<br>Assessment of functional and morphological diastolic &#40;pulmonary venous flow&#44; E&#47;A ratio&#44; isovolumic relaxation time&#41; and systolic &#40;wall thickening during systole&#44; LVEF&#44; fractional shortening&#41; parameters&#44; valve structure and pericardium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intra- and inter-observer variability<br>Measurement of LVEF subject to variability and dependent on image quality<br>Doubtful predictive value for early detection of subclinical lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tissue Doppler imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Excellent temporal resolution<br>Early detection of subclinical lesions &#40;in combination with markers of inflammation and oxidative stress&#41;<br>Functional assessment of filling pressures &#40;E&#47;e&#8242; ratio&#41;&#44; velocities&#44; strain and strain rate of ventricular walls in systole and diastole<br>Detection of isolated diastolic dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">More time-consuming analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2D strain&#47;speckle tracking and GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Superior to LVEF for predicting cardiovascular mortality in the general population<br>Better risk stratification in HF patients<br>Able to recognize early LV dysfunction in patients undergoing cardiotoxic therapy<br>Reproducible when performed by an experienced operator&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heavily dependent on image quality of 2D echocardiography<br>Lack of long-term clinical trials assessing the ability of GLS to predict persistent falls in LVEF or symptomatic HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stress echocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Assessment of myocardial contractile reserve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Semi-invasive<br>Controversial and limited data on early detection of cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radionuclide angiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High reproducibility<br>Low intra- and inter-observer variability<br>Validated for measurement of LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Low spatial and temporal resolution<br>Underestimates ventricular volumes<br>Underestimates LVEF in small ventricles &#40;women and children&#41;<br>Does not assess valve function<br>Little information on diastolic function<br>Limited predictive value for early detection of subclinical lesions and changes in LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Magnetic resonance imaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reproducible<br>No ionizing radiation<br>Assessment of myocardial perfusion and function and pericardium&#44; and detection of myocardial masses<br>Useful in patients with poor echocardiographic image quality<br>Gold standard for calculation of LV volumes and of LVEF<br>T2 sequences&#58; detects segmental or global changes in myocardial water content resulting from inflammation or microvascular or myocyte damage<br>T1 sequences&#58; provides information on myocardial lesions and fibrosis&#59; with gadolinium contrast&#44; detects histopathological alterations including intracellular vacuolization&#44; enabling prediction of subsequent decrease in LVEF<br>Late enhancement&#58; detection of myocardial fibrosis associated with poor prognosis in patients with CAD&#44; hypertrophic cardiomyopathy and infiltrative disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High cost<br>Limited availability<br>Contraindicated in patients with devices incompatible with magnetic resonance &#40;pacemakers&#44; cardiac resynchronization devices and implantable cardioverter-defibrillators&#41;<br>Risk of contrast nephrotoxicity in patients with renal failure &#40;GFR &#60;30 ml&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Computed tomography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">High-resolution image<br>Identifies pericardial calcification or thickening in patients undergoing radiotherapy or surgery<br>Visualizes and assesses calcification of the coronary arteries&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Documented coronary calcification prior to anticancer therapy is not predictive of CV risk in patients undergoing anthracycline chemotherapy<br>Little used for detection and monitoring of subclinical changes in cardiac function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Scintigraphy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Functional and structural assessment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ionizing radiation<br>Limited availability<br>Low temporal resolution<br>Limited data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Biomarkers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-invasive<br>Low inter-observer variability<br>Assessment of CV function and potential signs of cardiac damage<br>Promising for early detection of myocardial injury&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Endomyocardial biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Detects histological evidence of cardiac damage&#44; including loss of myofibrils&#44; vacuolization of cytoplasm&#44; dilatation of the sarcoplasmic reticulum&#44; increased numbers of lysosomes and mitochondrial swelling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Invasive<br>Histological interpretation requires specialist knowledge<br>No functional information<br>Results limited by quantity and quality of biopsy sample&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Assessment of endothelial damage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alternate parameters of cardiotoxicity such as cytokines&#44; adhesion molecules and carotid artery intima-media thickness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetic analysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Minimally invasive<br>Assesses individual susceptibility to cardiotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Undetermined predictive value&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Advantages and disadvantages of diagnostic exams in the assessment of anthracycline-induced cardiotoxicity&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at6"
            "detalle" => "Table "
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          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">V1&#58; Vivid 7 or Vivid E9 &#40;GE Healthcare&#41;&#59; V2&#58; iE33 &#40;Philips Medical Systems&#41;&#59; V3&#58; Artida or Apilo &#40;Toshiba Medical Systems&#41;&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Adapted from <a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="7" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">0-19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">20-29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">30-39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">40-49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50-59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8805;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V1</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;1&#177;2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;2&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;1&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;4&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;0&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;3&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0218&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;7&#177;3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;6&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;0&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;7&#177;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1982&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;4&#177;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;3&#177;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;8&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-22&#46;6&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-23&#46;3&#177;1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;9&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0348&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4292&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0029&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1381&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V2</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;9&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;0&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;5&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;2&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;6&#177;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;7&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;4&#177;2&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;8&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;1&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;9&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;9&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-15&#46;8&#177;1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;5&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;6&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;3&#177;0&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;3&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1349&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0248&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1083&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;4316&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0294&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0928&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="8" align="left" valign="top"><span class="elsevierStyleItalic">V3</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;4&#177;1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;4&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;5&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-17&#46;8&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;6&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-19&#46;8&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;7&#177;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-16&#46;3&#177;3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-21&#46;2&#177;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;2&#177;2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-20&#46;4&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;7&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;3&#177;2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-18&#46;6&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0141&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>p &#40;male vs&#46; female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6076&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9787&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9201&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;7374&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0668&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cumulative doses exceeding&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Recommended maximum &#40;mg&#47;m<span class="elsevierStyleSup">2</span>&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#58;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">400-550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daunorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">550-800&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Epirubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">900-1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idarubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">150-225&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mitoxantrone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100-140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pre-existing CV disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Diabetes</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Coronary artery disease</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Peripheral vascular disease</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Hypertension</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Genetic predisposition&#58; female gender&#44; black race</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Previous or concomitant mediastinal radiation</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Intravenous bolus administration</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Combination with other agents including cyclophosphamide&#44; trastuzumab or paclitaxel</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Length of time since end of chemotherapy</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Electrolyte disturbances&#58; hypocalcemia&#44; hypomagnesemia</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Hemochromatosis &#40;C282Y mutation&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Hyperthermia</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Liver disease</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Patients aged over 65 and children may develop cardiotoxicity with lower cumulative doses&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Adapted from <a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;24</span></a>&#46;</p>"
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          "leyenda" => "<p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">CT&#58; computed tomography&#59; GLS&#58; global longitudinal strain&#59; LVDF&#58; left ventricular diastolic function&#59; LVEF&#58; left ventricular ejection fraction&#59; LVSD&#58; left ventricular systolic dysfunction&#59; MRI&#58; magnetic resonance imaging&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Lead author and ClinicalTrials&#46;gov no&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of trial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary outcome measure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Planned trial conclusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mavrudis D<br><span class="elsevierStyleInterRef" id="intr0005" href="ctgov:NCT01120171">NCT01120171</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cyclophosphamide vs&#46; liposome-encapsulated doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overall response rate by CT or MRI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Campbell K<br><span class="elsevierStyleInterRef" id="intr0010" href="ctgov:NCT02006979">NCT02006979</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single blind&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">An acute bout of exercise performed 24 hours prior to every anthracycline infusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">December 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cipolla C<br><span class="elsevierStyleInterRef" id="intr0015" href="ctgov:NCT01968200">NCT01968200</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Enalapril after appearance of cardiac injury vs&#46; enalapril concomitantly to chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Up to one year after completion of chemotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cardiac troponin levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">July 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Virani S<br><span class="elsevierStyleInterRef" id="intr0020" href="ctgov:NCT01708798">NCT01708798</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&#44; phase 2&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eplerenone vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Change in LVDF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">May 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bocchi E<br><span class="elsevierStyleInterRef" id="intr0025" href="ctgov:NCT01724450">NCT01724450</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Carvedilol vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LVSD &#40;10&#37; reduction in LVEF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">October 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Livi L<br><span class="elsevierStyleInterRef" id="intr0030" href="ctgov:NCT02236806">NCT02236806</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single blind&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines and trastuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bisoprolol vs&#46; ramipril&#44; bisoprolol vs&#46; placebo&#44; ramipril vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">480&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">November 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smith K<br><span class="elsevierStyleInterRef" id="intr0035" href="ctgov:NCT02096588">NCT02096588</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Breast cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Simvastatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GLS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">April 2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">Clinical trials on prevention of anthracycline-induced cardiomyopathy&#46;</p>"
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