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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Early in the epidemic of human immunodeficiency virus &#40;HIV&#41;&#44; opportunistic infections related to acquired immune deficiency syndrome &#40;AIDS&#41; inevitably led to death and palliative care was the rule&#46; Fortunately&#44; effective therapy emerged during the so-called highly active antiretroviral era&#44; leading to improved survival&#46; Nowadays&#44; the long-term care of people living with HIV&#47;AIDS &#40;PLWHA&#41; has led to increased focus on the chronic management of comorbidities&#44; particularly those related to the aging of the HIV-infected population and to cardiovascular disease &#40;CVD&#41;&#46; While acute life-threatening cardiac manifestations &#40;especially infective endocarditis&#44; myocarditis and pericarditis&#41; dominated the clinical picture in the early HIV epidemic&#44; premature atherosclerosis and its consequences are currently the leading cardiovascular presentation of PLWHA&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although the survival of well-managed PLWHA on antiretroviral therapy is now comparable to that of healthy controls&#44; deaths due to CVD have been proportionately increasing in the former&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Several mechanisms may be responsible&#44; including a higher prevalence of traditional cardiovascular risk factors in HIV-infected patients than in age- and gender-matched controls&#44; a chronic inflammatory state and low-grade systemic inflammation even in patients with apparently controlled HIV infection&#44; atherothrombotic risk factors&#44; and adverse events related to combined antiretroviral therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> These may account for the pervasiveness of coronary artery disease &#40;CAD&#41;&#44; microvascular disease&#44; heart failure &#40;HF&#41; and atrial fibrillation&#44; among others&#44; in PLWHA&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Surprisingly&#44; a large study by Tseng et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> enrolling 2860 consecutive PLWHA showed that&#44; over a median 3&#46;7 years of follow-up&#44; non-AIDS mortality was mostly due to sudden cardiac death &#40;SCD&#41;&#44; which accounted for 86&#37; of all cardiac deaths&#46; These patients had a higher prevalence of prior myocardial infarction compared to those who had a non-SCD &#40;17&#37; vs&#46; 1&#37;&#44; p&#60;0&#46;0005&#41;&#46; The mean SCD rate reported was 2&#46;6 per 1000 person-years over a 10-year period&#46; Moreover&#44; Mongardon et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> retrospectively assessed 99 PLWHA successfully resuscitated after cardiac arrest&#44; and demonstrated that a third of these were due to a cardiac cause&#44; roughly half of which were clearly unrelated to myocardial infarction&#46; In addition&#44; these authors suggested that outcomes were not associated with HIV status &#40;i&#46;e&#46;&#44; CD4 and viral counts&#41;&#44; as per propensity-score matching to a control cohort with a similar presentation&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Altogether&#44; the available evidence supports the idea that SCD occurs at a higher rate than expected in PLWHA&#46; This may be due to various factors that are yet to be elucidated&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> which may include the following&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Host-related factors&#58; increased atherogenic burden and SCD as a manifestation of CAD and HF&#46; However&#44; it has been suggested that SCD has a higher incidence than would be expected solely as a direct consequence of the aforementioned clinical scenarios&#59; additionally&#44; substance abuse &#40;particularly amphetamines and alcohol&#41; may also play a role&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">HIV-related factors&#58; mechanisms may include systemic inflammation leading to rapidly progressive CAD&#44; featuring vulnerable plaques known to be associated with a higher risk of atherothrombotic events and arrhythmogenic manifestations&#59; in addition&#44; HIV-related rhythm disturbances that may be the result of electrical cardiac remodeling and prolonged QTc due to autonomic dysfunction&#44; may also facilitate SCD&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment-related factors&#58; several drugs used in PLWHA &#40;such as lopinavir-ritonavir&#44; trimethoprim-sulfamethoxazole and methadone&#41; are associated with both metabolic derangements and acquired prolonged QTc interval &#40;hence torsades de pointes&#41;&#59; furthermore&#44; hypokalemia&#44; hypomagnesemia and hypocalcemia are frequently found in HIV-infected patients&#44; often as a consequence of drug-related diarrhea&#44; gastrointestinal opportunistic infections and&#47;or HIV enteropathy&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">It is indisputable that SCD is worrisome in PLWHA and may account for many &#40;if not most&#41; premature and late deaths&#46; As of now&#44; we lack tools that can predict SCD risk in PLWHA and that may guide effective prevention&#46; Other than systematically measuring QTc interval&#44; particularly when introducing QTc-prolonging drugs&#44; and selecting patients who may benefit from an implantable cardioverter-defibrillator &#40;ICD&#41;&#44; no other interventions are known to prevent arrhythmic SCD in HIV-infected patients&#46; Moreover&#44; identification of PLWHA with HF who may benefit from an ICD as primary prevention is done by extrapolating data from HF trials that have not properly addressed HIV-related cardiomyopathy&#46; There are too many unknowns&#44; and there is a need for urgent action in a matter of utmost importance&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The current issue of the <span class="elsevierStyleItalic">Journal</span> sees the publication of a single-center prospective case-control study of 89 PLWHA &#40;antiretroviral therapy in 74&#37; and controlled viral counts in 53&#37;&#41; and 62 age and gender-matched healthy controls&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Cetina et al&#46; found that PLWHA had significantly increased Tp-e &#40;measured from the peak to the end of the T wave&#41; and corrected Tp-e &#40;Tp-ec&#41; intervals&#44; as well as a higher Tp-e&#47;QT ratio&#44; in comparison to controls&#46; Furthermore&#44; these variables had a moderate but significant inverse correlation with CD4 T-cell counts&#46; These findings add to the known increased risk of SCD in HIV-infected patients&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> but also extend it to those with apparently controlled infection &#40;as per CD4 T-cell counts and viral loads&#41;&#46; Moreover&#44; they unveil a potential role in PLWHA for easily measured electrocardiographic markers known to be linked to arrhythmogenic burden and SCD&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Tp-e interval&#44; Tp-ec interval and Tp-e&#47;QT ratio&#44; indices of repolarization heterogeneity&#44; have been shown to be increased in several clinical scenarios in comparison to healthy controls&#44; such as in pediatric patients with dilated cardiomyopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> acute myocarditis<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a> and sleep apnea&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> to name a few&#44; and it has been suggested that they may indicate increased SCD risk&#46; Future investigations should focus on large studies with long-term follow-up to elucidate whether these markers may aid in arrhythmogenic stratification of PLWHA and&#44; ultimately&#44; facilitate interventions to further improve management in a population already at higher risk of both atherogenic and SCD events&#46; In addition&#44; the question whether QTc prolongation due to HIV treatment and known pathophysiological mechanisms shared with premature CAD play a major role in SCD is worth investigating further&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In conclusion&#44; the shift of HIV from a life-threatening acute condition to a chronic manageable disease&#44; in parallel with the aging of PLWHA&#44; has led to a new paradigm of increased need to focus on treating related comorbidities and to draw on a wide range of medical specialties&#44; especially cardiology&#44; oncology&#44; and geriatric medicine&#46; Finally&#44; the role of the cardiologist caring for PLWHA not only includes prevention of cardiovascular risk factors to mitigate atherogenic burden but may also extend&#44; in the future&#44; to SCD prevention once suitable tools are available to enable appropriate risk stratification to be integrated into clinical practice&#46; The present study<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> adds a small but important piece to the puzzle of SCD in PLWHA&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Commentary
Challenges in patients living with HIV: The sudden cardiac death conundrum
Desafios em doentes com HIV: o problema da morte súbita cardíaca
Bruno Rocha, Carlos Aguiar
Autor para correspondência
ctaguiar@gmail.com

Corresponding author.
Cardiology Department, Hospital de Santa Cruz, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Early in the epidemic of human immunodeficiency virus &#40;HIV&#41;&#44; opportunistic infections related to acquired immune deficiency syndrome &#40;AIDS&#41; inevitably led to death and palliative care was the rule&#46; Fortunately&#44; effective therapy emerged during the so-called highly active antiretroviral era&#44; leading to improved survival&#46; Nowadays&#44; the long-term care of people living with HIV&#47;AIDS &#40;PLWHA&#41; has led to increased focus on the chronic management of comorbidities&#44; particularly those related to the aging of the HIV-infected population and to cardiovascular disease &#40;CVD&#41;&#46; While acute life-threatening cardiac manifestations &#40;especially infective endocarditis&#44; myocarditis and pericarditis&#41; dominated the clinical picture in the early HIV epidemic&#44; premature atherosclerosis and its consequences are currently the leading cardiovascular presentation of PLWHA&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although the survival of well-managed PLWHA on antiretroviral therapy is now comparable to that of healthy controls&#44; deaths due to CVD have been proportionately increasing in the former&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">4</span></a> Several mechanisms may be responsible&#44; including a higher prevalence of traditional cardiovascular risk factors in HIV-infected patients than in age- and gender-matched controls&#44; a chronic inflammatory state and low-grade systemic inflammation even in patients with apparently controlled HIV infection&#44; atherothrombotic risk factors&#44; and adverse events related to combined antiretroviral therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">1</span></a> These may account for the pervasiveness of coronary artery disease &#40;CAD&#41;&#44; microvascular disease&#44; heart failure &#40;HF&#41; and atrial fibrillation&#44; among others&#44; in PLWHA&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Surprisingly&#44; a large study by Tseng et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> enrolling 2860 consecutive PLWHA showed that&#44; over a median 3&#46;7 years of follow-up&#44; non-AIDS mortality was mostly due to sudden cardiac death &#40;SCD&#41;&#44; which accounted for 86&#37; of all cardiac deaths&#46; These patients had a higher prevalence of prior myocardial infarction compared to those who had a non-SCD &#40;17&#37; vs&#46; 1&#37;&#44; p&#60;0&#46;0005&#41;&#46; The mean SCD rate reported was 2&#46;6 per 1000 person-years over a 10-year period&#46; Moreover&#44; Mongardon et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">6</span></a> retrospectively assessed 99 PLWHA successfully resuscitated after cardiac arrest&#44; and demonstrated that a third of these were due to a cardiac cause&#44; roughly half of which were clearly unrelated to myocardial infarction&#46; In addition&#44; these authors suggested that outcomes were not associated with HIV status &#40;i&#46;e&#46;&#44; CD4 and viral counts&#41;&#44; as per propensity-score matching to a control cohort with a similar presentation&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Altogether&#44; the available evidence supports the idea that SCD occurs at a higher rate than expected in PLWHA&#46; This may be due to various factors that are yet to be elucidated&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">7</span></a> which may include the following&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Host-related factors&#58; increased atherogenic burden and SCD as a manifestation of CAD and HF&#46; However&#44; it has been suggested that SCD has a higher incidence than would be expected solely as a direct consequence of the aforementioned clinical scenarios&#59; additionally&#44; substance abuse &#40;particularly amphetamines and alcohol&#41; may also play a role&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">HIV-related factors&#58; mechanisms may include systemic inflammation leading to rapidly progressive CAD&#44; featuring vulnerable plaques known to be associated with a higher risk of atherothrombotic events and arrhythmogenic manifestations&#59; in addition&#44; HIV-related rhythm disturbances that may be the result of electrical cardiac remodeling and prolonged QTc due to autonomic dysfunction&#44; may also facilitate SCD&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment-related factors&#58; several drugs used in PLWHA &#40;such as lopinavir-ritonavir&#44; trimethoprim-sulfamethoxazole and methadone&#41; are associated with both metabolic derangements and acquired prolonged QTc interval &#40;hence torsades de pointes&#41;&#59; furthermore&#44; hypokalemia&#44; hypomagnesemia and hypocalcemia are frequently found in HIV-infected patients&#44; often as a consequence of drug-related diarrhea&#44; gastrointestinal opportunistic infections and&#47;or HIV enteropathy&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">It is indisputable that SCD is worrisome in PLWHA and may account for many &#40;if not most&#41; premature and late deaths&#46; As of now&#44; we lack tools that can predict SCD risk in PLWHA and that may guide effective prevention&#46; Other than systematically measuring QTc interval&#44; particularly when introducing QTc-prolonging drugs&#44; and selecting patients who may benefit from an implantable cardioverter-defibrillator &#40;ICD&#41;&#44; no other interventions are known to prevent arrhythmic SCD in HIV-infected patients&#46; Moreover&#44; identification of PLWHA with HF who may benefit from an ICD as primary prevention is done by extrapolating data from HF trials that have not properly addressed HIV-related cardiomyopathy&#46; There are too many unknowns&#44; and there is a need for urgent action in a matter of utmost importance&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The current issue of the <span class="elsevierStyleItalic">Journal</span> sees the publication of a single-center prospective case-control study of 89 PLWHA &#40;antiretroviral therapy in 74&#37; and controlled viral counts in 53&#37;&#41; and 62 age and gender-matched healthy controls&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> Cetina et al&#46; found that PLWHA had significantly increased Tp-e &#40;measured from the peak to the end of the T wave&#41; and corrected Tp-e &#40;Tp-ec&#41; intervals&#44; as well as a higher Tp-e&#47;QT ratio&#44; in comparison to controls&#46; Furthermore&#44; these variables had a moderate but significant inverse correlation with CD4 T-cell counts&#46; These findings add to the known increased risk of SCD in HIV-infected patients&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">5</span></a> but also extend it to those with apparently controlled infection &#40;as per CD4 T-cell counts and viral loads&#41;&#46; Moreover&#44; they unveil a potential role in PLWHA for easily measured electrocardiographic markers known to be linked to arrhythmogenic burden and SCD&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Tp-e interval&#44; Tp-ec interval and Tp-e&#47;QT ratio&#44; indices of repolarization heterogeneity&#44; have been shown to be increased in several clinical scenarios in comparison to healthy controls&#44; such as in pediatric patients with dilated cardiomyopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">9</span></a> acute myocarditis<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">10</span></a> and sleep apnea&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">11</span></a> to name a few&#44; and it has been suggested that they may indicate increased SCD risk&#46; Future investigations should focus on large studies with long-term follow-up to elucidate whether these markers may aid in arrhythmogenic stratification of PLWHA and&#44; ultimately&#44; facilitate interventions to further improve management in a population already at higher risk of both atherogenic and SCD events&#46; In addition&#44; the question whether QTc prolongation due to HIV treatment and known pathophysiological mechanisms shared with premature CAD play a major role in SCD is worth investigating further&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In conclusion&#44; the shift of HIV from a life-threatening acute condition to a chronic manageable disease&#44; in parallel with the aging of PLWHA&#44; has led to a new paradigm of increased need to focus on treating related comorbidities and to draw on a wide range of medical specialties&#44; especially cardiology&#44; oncology&#44; and geriatric medicine&#46; Finally&#44; the role of the cardiologist caring for PLWHA not only includes prevention of cardiovascular risk factors to mitigate atherogenic burden but may also extend&#44; in the future&#44; to SCD prevention once suitable tools are available to enable appropriate risk stratification to be integrated into clinical practice&#46; The present study<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">8</span></a> adds a small but important piece to the puzzle of SCD in PLWHA&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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