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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Continuous improvements in pharmacologic and nonpharmacologic therapies have markedly improved the prognosis of chronic heart failure &#40;HF&#41;&#46; Even so&#44; up to 10&#37; of patients progress to an advanced stage of the disease&#44; defined by severe symptoms&#44; low cardiac output &#40;CO&#41;&#44; persistent congestion and end-organ damage&#46; At this point patients experience very low quality of life &#40;QoL&#41;&#44; frequent hospitalizations and high mortality&#46; Conventional treatments are no longer sufficient to control symptoms and improve prognosis&#44; and these patients require advanced therapeutic strategies&#44; including heart transplantation and durable mechanical circulatory support&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> For those deemed candidates&#44; maintaining end-organ function is critical for ultimate success&#46; In this context&#44; periodic infusion of inotropes can be helpful as a bridge therapy to transplantation&#44; left ventricular assist device &#40;LVAD&#41;&#44; or even palliative therapy&#44; in the event of the first two solutions being unfeasible due to patient&#39;s characteristics&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Inotropes aim at increasing CO by enhancing cardiac contractility&#46; They are the drugs of choice in patients with acute HF with hypoperfusion&#44; but the history of their use in chronic HF is filled with disappointment&#46; Despite hemodynamic and symptomatic improvement&#44; there is no compelling evidence of a survival benefit&#46; In fact&#44; some inotropes can increase short- and long-term mortality&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> a negative outcome attributed to a series of detrimental effects&#44; including increased myocardial oxygen consumption&#44; hypotension&#44; tachycardia&#44; and arrhythmogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> However&#44; most of the studies that reported detrimental outcomes predated the use of modern HF medications&#44; implantable electronic devices &#40;implantable cardioverter-defibrillators and cardiac resynchronization therapy devices&#41;&#44; and even beta-blockers&#46; More recent evidence has shown that treatment with intermittent low-dose inotrope infusions&#44; in an outpatient clinic or at home&#44; improves QoL without impairing survival&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Levosimendan has some theoretical advantages in the setting of advanced HF due to its prolonged-action active metabolites&#44; which have long-lasting effects &#40;up to 14 days&#41;&#46; Unlike other inotropes&#44; levosimendan does not increase intracellular calcium or myocardial oxygen consumption&#44; and thus enhances cardiac contractility with a lower risk of the ventricular arrhythmias that plague older inotropes&#46; Levosimendan also has anti-inflammatory and antiapoptotic properties that may benefit patients with advanced HF&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In advanced HF&#44; levosimendan has been studied in the setting of intermittent outpatient administration&#46; In the LevoRep trial&#44; four six-hour cycles &#40;0&#46;2 &#956;g&#47;kg&#47;min&#41; were administered at two-week intervals&#46; There was no improvement in functional capacity or quality of life compared with placebo after 24 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> However&#44; the authors found a non-statistically significant 50&#37; reduction in the composite outcome of risk of death&#44; heart transplant&#44; or acute HF&#46; In the more recent LION-HEART trial&#44; levosimendan significantly reduced N-terminal pro-B-type natriuretic peptide &#40;NT-proBNP&#41; levels&#46; This translated into clinical improvement&#44; with reductions in composite endpoints&#44; including hospitalization &#40;all-cause&#44; cardiovascular or HF&#41; and terminal events with similar safety and tolerability to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> These results suggest that cyclic administration of levosimendan in an outpatient setting is a safe treatment with clinically beneficial effects&#46; The ongoing LeoDOR trial tests the hypothesis that repetitive levosimendan infusions improve outcomes when applied during the vulnerable post-discharge period&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A special population within advanced HF patients consists of those awaiting heart transplantation&#46; Irreversible pulmonary hypertension puts potential heart transplant candidates at high risk of post-transplant right ventricular &#40;RV&#41; failure&#46; Appropriate and frequent pre-transplant assessment of cardiopulmonary hemodynamics is therefore crucial to risk stratification in patients with increased pulmonary vascular resistance&#46; This may be improved by using vasodilators or inotropes to provide a dynamic assessment of pulmonary circulation&#46; Recent evidence from our center suggests that when used for vasodilatory challenge&#44; levosimendan had a more significant impact on cardiac index&#44; and increased both left and right ventricular stroke work&#44; compared to nitric oxide and iloprost&#46; Levosimendan was the only drug that reduced filling pressures&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> With its favorable effects on end-organ function&#44; particularly in the kidney&#44; levosimendan could serve as the ideal bridge for patients awaiting heart transplantation&#46; Recently&#44; Ponz de Antonio and colleagues have shown that in a population of 11 patients waiting for heart transplantation&#44; a fixed-time scheduled infusion of levosimendan reduced the rehospitalization rate and the need for urgent transplantation compared to historical data&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The beneficial hemodynamic and non-hemodynamic effects of levosimendan have similar importance for patients awaiting LVAD implantation&#46; As pulmonary hypertension and RV failure are also significant hazards post-implantation&#44; levosimendan can play a unique beneficial role&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Small case series also suggest that the adjunctive use of levosimendan in patients with severe mitral regurgitation and left ventricular &#40;LV&#41; dysfunction undergoing edge-to-edge mitral repair may increase technical success&#44; by reducing LV volumes and mitral valve annular dimensions&#44; and be associated with a lower risk of hemodynamic deterioration&#46; Although these results are promising&#44; they derive from small&#44; uncontrolled local experiences&#44; and their external validity and applicability must be viewed with caution&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Reis et al&#46; present the first Portuguese experience of intermittent levosimendan administration in outpatient advanced HF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> They deserve to be congratulated for their excellent work&#46; Despite the limitations of a pragmatic design&#44; they performed clinical&#44; biochemical&#44; and&#44; most importantly&#44; advanced echocardiographic and functional assessments using cardiopulmonary exercise testing &#40;CPET&#41;&#46; The population was highly symptomatic&#44; with more than 50&#37; of patients in New York Heart Association &#40;NYHA&#41; functional class IV referred as a bridge to heart transplantation or LVAD&#46; The care of these patients is highly challenging and&#44; we dare to state&#44; is among the most specialized and high-value forms of healthcare a cardiology department can offer&#44; even in the era of devices and complex structural interventions&#46; The excellent results achieved&#44; including five patients eventually receiving a heart transplant&#44; cannot be attributed solely to levosimendan or any current or future drug&#46; Such success is only possible by including these patients in a structured multidisciplinary program led by specialist heart failure professionals&#44; in which levosimendan administration&#44; coupled with a multitude of other interventions&#44; ultimately leads to better outcomes&#46; Significant reductions in NYHA class&#44; hospitalizations and NT-proBNP were observed&#44; without any significant adverse effects&#46; The authors also performed advanced echocardiographic assessments&#44; reporting significant improvements in LV systolic function&#44; as measured by LV ejection fraction and global longitudinal strain&#46; One of this work&#39;s most innovative aspects is its use of CPET to measure functional capacity&#46; The improvements in both peak oxygen uptake &#40;&#43;2&#46;5 ml&#47;kg&#47;min&#41; and ventilatory efficiency &#40;&#8722;3&#46;1 in VE&#47;VCO<span class="elsevierStyleInf">2</span> slope&#41; could have both symptomatic and prognostic significance&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Although evidence in its favor is mounting&#44; the story of intermittent inotrope infusions in advanced HF has only just begun&#44; and many questions are still unanswered&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">What is the optimal dose and duration of treatment for outpatient advanced HF&#63;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Is the effect maintained over time&#44; or does tachyphylaxis develop&#63;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Can patients with HF with preserved ejection fraction derive similar benefits&#63;</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">Those of us who care for these patients are eager for answers&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Editorial comment
Redefining the role of inotropes in advanced heart failure
Redefinindo o papel dos inotrópicos na insuficiência cardíaca avançada
Roberto Pintoa,b,
Autor para correspondência
robrpinto@gmail.com

Corresponding author.
, Marta Tavares-Silvaa,c
a Serviço de Cardiologia, Centro Hospitalar e Universitário de São João, Porto, Portugal
b Departamento de Biomedicina, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
c UnIC@RISE, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Continuous improvements in pharmacologic and nonpharmacologic therapies have markedly improved the prognosis of chronic heart failure &#40;HF&#41;&#46; Even so&#44; up to 10&#37; of patients progress to an advanced stage of the disease&#44; defined by severe symptoms&#44; low cardiac output &#40;CO&#41;&#44; persistent congestion and end-organ damage&#46; At this point patients experience very low quality of life &#40;QoL&#41;&#44; frequent hospitalizations and high mortality&#46; Conventional treatments are no longer sufficient to control symptoms and improve prognosis&#44; and these patients require advanced therapeutic strategies&#44; including heart transplantation and durable mechanical circulatory support&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> For those deemed candidates&#44; maintaining end-organ function is critical for ultimate success&#46; In this context&#44; periodic infusion of inotropes can be helpful as a bridge therapy to transplantation&#44; left ventricular assist device &#40;LVAD&#41;&#44; or even palliative therapy&#44; in the event of the first two solutions being unfeasible due to patient&#39;s characteristics&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Inotropes aim at increasing CO by enhancing cardiac contractility&#46; They are the drugs of choice in patients with acute HF with hypoperfusion&#44; but the history of their use in chronic HF is filled with disappointment&#46; Despite hemodynamic and symptomatic improvement&#44; there is no compelling evidence of a survival benefit&#46; In fact&#44; some inotropes can increase short- and long-term mortality&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> a negative outcome attributed to a series of detrimental effects&#44; including increased myocardial oxygen consumption&#44; hypotension&#44; tachycardia&#44; and arrhythmogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> However&#44; most of the studies that reported detrimental outcomes predated the use of modern HF medications&#44; implantable electronic devices &#40;implantable cardioverter-defibrillators and cardiac resynchronization therapy devices&#41;&#44; and even beta-blockers&#46; More recent evidence has shown that treatment with intermittent low-dose inotrope infusions&#44; in an outpatient clinic or at home&#44; improves QoL without impairing survival&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Levosimendan has some theoretical advantages in the setting of advanced HF due to its prolonged-action active metabolites&#44; which have long-lasting effects &#40;up to 14 days&#41;&#46; Unlike other inotropes&#44; levosimendan does not increase intracellular calcium or myocardial oxygen consumption&#44; and thus enhances cardiac contractility with a lower risk of the ventricular arrhythmias that plague older inotropes&#46; Levosimendan also has anti-inflammatory and antiapoptotic properties that may benefit patients with advanced HF&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In advanced HF&#44; levosimendan has been studied in the setting of intermittent outpatient administration&#46; In the LevoRep trial&#44; four six-hour cycles &#40;0&#46;2 &#956;g&#47;kg&#47;min&#41; were administered at two-week intervals&#46; There was no improvement in functional capacity or quality of life compared with placebo after 24 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> However&#44; the authors found a non-statistically significant 50&#37; reduction in the composite outcome of risk of death&#44; heart transplant&#44; or acute HF&#46; In the more recent LION-HEART trial&#44; levosimendan significantly reduced N-terminal pro-B-type natriuretic peptide &#40;NT-proBNP&#41; levels&#46; This translated into clinical improvement&#44; with reductions in composite endpoints&#44; including hospitalization &#40;all-cause&#44; cardiovascular or HF&#41; and terminal events with similar safety and tolerability to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> These results suggest that cyclic administration of levosimendan in an outpatient setting is a safe treatment with clinically beneficial effects&#46; The ongoing LeoDOR trial tests the hypothesis that repetitive levosimendan infusions improve outcomes when applied during the vulnerable post-discharge period&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A special population within advanced HF patients consists of those awaiting heart transplantation&#46; Irreversible pulmonary hypertension puts potential heart transplant candidates at high risk of post-transplant right ventricular &#40;RV&#41; failure&#46; Appropriate and frequent pre-transplant assessment of cardiopulmonary hemodynamics is therefore crucial to risk stratification in patients with increased pulmonary vascular resistance&#46; This may be improved by using vasodilators or inotropes to provide a dynamic assessment of pulmonary circulation&#46; Recent evidence from our center suggests that when used for vasodilatory challenge&#44; levosimendan had a more significant impact on cardiac index&#44; and increased both left and right ventricular stroke work&#44; compared to nitric oxide and iloprost&#46; Levosimendan was the only drug that reduced filling pressures&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> With its favorable effects on end-organ function&#44; particularly in the kidney&#44; levosimendan could serve as the ideal bridge for patients awaiting heart transplantation&#46; Recently&#44; Ponz de Antonio and colleagues have shown that in a population of 11 patients waiting for heart transplantation&#44; a fixed-time scheduled infusion of levosimendan reduced the rehospitalization rate and the need for urgent transplantation compared to historical data&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The beneficial hemodynamic and non-hemodynamic effects of levosimendan have similar importance for patients awaiting LVAD implantation&#46; As pulmonary hypertension and RV failure are also significant hazards post-implantation&#44; levosimendan can play a unique beneficial role&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Small case series also suggest that the adjunctive use of levosimendan in patients with severe mitral regurgitation and left ventricular &#40;LV&#41; dysfunction undergoing edge-to-edge mitral repair may increase technical success&#44; by reducing LV volumes and mitral valve annular dimensions&#44; and be associated with a lower risk of hemodynamic deterioration&#46; Although these results are promising&#44; they derive from small&#44; uncontrolled local experiences&#44; and their external validity and applicability must be viewed with caution&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Reis et al&#46; present the first Portuguese experience of intermittent levosimendan administration in outpatient advanced HF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> They deserve to be congratulated for their excellent work&#46; Despite the limitations of a pragmatic design&#44; they performed clinical&#44; biochemical&#44; and&#44; most importantly&#44; advanced echocardiographic and functional assessments using cardiopulmonary exercise testing &#40;CPET&#41;&#46; The population was highly symptomatic&#44; with more than 50&#37; of patients in New York Heart Association &#40;NYHA&#41; functional class IV referred as a bridge to heart transplantation or LVAD&#46; The care of these patients is highly challenging and&#44; we dare to state&#44; is among the most specialized and high-value forms of healthcare a cardiology department can offer&#44; even in the era of devices and complex structural interventions&#46; The excellent results achieved&#44; including five patients eventually receiving a heart transplant&#44; cannot be attributed solely to levosimendan or any current or future drug&#46; Such success is only possible by including these patients in a structured multidisciplinary program led by specialist heart failure professionals&#44; in which levosimendan administration&#44; coupled with a multitude of other interventions&#44; ultimately leads to better outcomes&#46; Significant reductions in NYHA class&#44; hospitalizations and NT-proBNP were observed&#44; without any significant adverse effects&#46; The authors also performed advanced echocardiographic assessments&#44; reporting significant improvements in LV systolic function&#44; as measured by LV ejection fraction and global longitudinal strain&#46; One of this work&#39;s most innovative aspects is its use of CPET to measure functional capacity&#46; The improvements in both peak oxygen uptake &#40;&#43;2&#46;5 ml&#47;kg&#47;min&#41; and ventilatory efficiency &#40;&#8722;3&#46;1 in VE&#47;VCO<span class="elsevierStyleInf">2</span> slope&#41; could have both symptomatic and prognostic significance&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Although evidence in its favor is mounting&#44; the story of intermittent inotrope infusions in advanced HF has only just begun&#44; and many questions are still unanswered&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">What is the optimal dose and duration of treatment for outpatient advanced HF&#63;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Is the effect maintained over time&#44; or does tachyphylaxis develop&#63;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Can patients with HF with preserved ejection fraction derive similar benefits&#63;</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">Those of us who care for these patients are eager for answers&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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