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Cardiac dysfunction prevalent in patients with HIV. - Editorial - Myocardial Dysfunction With Contemporary Management of HIV Prevalence, Pathophysiology, and Opportunities for Prevention - Belly Fat-Lipodystrophy Connection
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Download the PDF here
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• Patients with HIV were more likely to have cardiac dysfunction, according to a systematic review and meta-analysis published in JACC: Heart Failure.
https://www.healio.com/cardiology/hf-transplantation/news/online/{4430ddfd-80a2-4993-8d28-e0efe63bdea2}/cardiac-dysfunction-prevalent-in-patients-with-hiv
"Together, these data suggest that early detection of cardiac dysfunction in [people living with HIV] could provide a window of opportunity in which it may be possible to institute intervention to reverse the course, as has been proposed for individuals in the general population with asymptomatic cardiac dysfunction," Sebhat Erqou, MD, PhD, assistant professor of medicine at Brown University Alpert Medical School in Providence, Rhode Island, and staff cardiologist at VA Providence Medical Center and Lifespan Cardiovascular Institute in Providence, and colleagues wrote.
"In Massachusetts, 59% of PLHIV are now 50 years of age or older.....Cardiac dysfunction is frequent in people living with HIV. Additional prospective studies are needed to better understand the burden and risk of various forms of cardiac dysfunction related to HIV and the associated mechanisms. (Cardiac dysfunction in people living with HIV-a systematic review and meta-analysis......Mortality is still higher in PLHIV than in the general population, and excess mortality in PLHIV occurs now in large part due to noninfectious illnesses with major adverse cardiovascular events (MACE), including related myocardial infarction, and rates of stroke and death are estimated to be 2-fold higher in HIV patients than in those without HIV .....aging population of PLHIV, for whom symptomatic HF will become increasingly common. development of prevention strategies for HF is an imperative for those infected with HIV to continue to enjoy hard-won victories to improve duration and quality of life.....Other mechanisms may uniquely contribute to HFpEF in PLHIV. Recently the MESA (Multi-Ethnic Study of Atherosclerosis) trial identified a strong association between the extent of pro-inflammatory visceral adipose tissue (VAT) and incident HFpEF (4). This finding may be particularly germane to PLHIV, who frequently have fat redistribution with loss of subcutaneous fat (SAT) and/or VAT accumulation. The present authors have shown that increased VAT in PLHIV is associated with not only generalized inflammation markers such as high-sensitivity C-reactive protein but also with progressive myocardial injury, as measured using hs-cTnT.....early detection of cardiac dysfunction in PLHIV could provide a window of opportunity in which it may be possible to institute intervention to reverse the course, as has been proposed for individuals in the general population with asymptomatic cardiac dysfunction....There is a significant paucity of data detailing the natural course of cardiac dysfunction identified in PLHIV. There is also a need to further characterize and understand the pathogenesis of HIV cardiac dysfunction to foster the development of evidence-based and effective preventive interventions. In the past, smaller scale studies using cardiac magnetic resonance imaging have demonstrated a higher prevalence of cardiac steatosis, edema, and fibrosis in PLHIV, which may underlie the mechanism of cardiac dysfunction (34-36). Finally, this review, by pooling data from available studies on the subject, provides more precise estimates of the various HIV-associated cardiac dysfunction outcomes than was possible before. These data highlight the urgency for finding strategies to reduce the potential HIV-related burden of HF and associated cardiac disorders....
Perspectives
COMPETENCY IN MEDICAL KNOWLEDGE: In meta-analysis of available observational studies in PLHIV, we found that the incidence of cardiac dysfunction was substantial. These findings should help raise awareness of clinicians taking care of PLHIV to consider early investigation and referral of those with cardiac dysfunction and allow institution of guideline-based treatment, while ongoing research seek to identify further preventive and therapeutic strategies.
TRANSLATIONAL OUTLOOK: There is a need for prospective epidemiological studies to better understand the burden and progression of cardiovascular complications in PLHIV, including a comprehensive evaluation of left and right ventricles that views them as a continuum rather than separate entities, and leveraging new imaging modalities such as cardiac magnetic resonance imaging to increase precision of diagnoses. Extensive phenotyping of patients with HIV-associated cardiac dysfunction, including genetic, proteomic, and metabolic studies, can form the basis for translational research."
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Editorial - Myocardial Dysfunction With Contemporary Management of HIV Prevalence, Pathophysiology, and Opportunities for Prevention
JACC Heart Failure - Feb 2019 Christopher R. deFilippi and Steven K. Grinspoon
With the success of antiretroviral therapy (ART), long-term survival of patients living with HIV (PLHIV) worldwide has improved dramatically, and the population of PLHIV is aging. It was estimated in 2015 that a patient living with HIV survived to a median of 50 years of age (Online Ref. 1). In Massachusetts, 59% of PLHIV are now 50 years of age or older (Online Ref. 2). With patients' advancing age has come the recognition of HIV as a chronic disease with factors that promote remaining inflammation, including HIV-mediated immune activation, co-infection with other pathogens, and HIV-mediated breakdown of the intestinal mucosa with microbial translocation (Online Ref. 3). Mortality is still higher in PLHIV than in the general population, and excess mortality in PLHIV occurs now in large part due to noninfectious illnesses with major adverse cardiovascular events (MACE), including related myocardial infarction, and rates of stroke and death are estimated to be 2-fold higher in HIV patients than in those without HIV (Online Ref. 4). Coronary arterial disease is recognized as an inflammatory disorder, a finding directly applicable to PLHIV (Online Refs. 5,6). Conventional MACE risk algorithms used in the general population have not been found to accurately estimate cardiovascular risk in PLHIV (Online Ref. 7). To address this issue, the U.S. National Institutes of Health funded the 7,500-person REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV [NCT02344290]) study to compare the efficacy of a statin strategy with that of placebo for primary prevention in PLHIV determined to be at low to moderate 10-year risk for MACE. A secondary endpoint will be incident heart failure hospitalization.
It has long been recognized that HIV infection, particularly in the presence of AIDS, is associated with a high incidence of cardiomyopathy. Multiple causes have been proposed, including direct infection of the myocardium by the HIV virus, opportunistic infections, an autoimmune response, nutritional deficiencies, and specific ART that includes an early generation therapy using zidovudine (Online Refs. 8,9). In the current era of ART, the prevalence of left ventricular (LV) systolic dysfunction has declined (Online Refs. 8,9), and there is a greater recognition of the presence of diastolic dysfunction (Online Ref. 10). A recent, large U.S. Veterans Affairs study identified a higher incidence of both heart failure with reduced ejection fraction (HFrEF) and HF with preserved EF (HFpEF) in HIV-infected veterans than in veterans not infected with HIV after adjustment for multiple characteristics including conventional risk factors, findings that were still present, particularly for HFrEF, when evaluating just those patients with viral suppression or normalized CD4 counts (Online Ref. 11). When considering HF prevention strategies in PLHIV, assessment of different mechanisms of cardiac dysfunction needs to be considered, given the multiple unique factors in PLHIV, including regional differences in nutritional status or co-infections, availability and type of ART, degree of immune dysfunction, and aging of the HIV population, as reflected in more recent studies comparing older study populations.
To this end, the meta-analysis by Erquo et al. (1) addresses the challenging task of providing well-characterized prevalence rates that account for the many variables that may have opposing directionality with respect to cardiac dysfunction (i.e., aging of PLHIV and greater use of ART). Interesting findings from their meta-analysis includes the prevalence of asymptomatic LV systolic dysfunction in those studies of ART use >80% that is similar in prevalence to that estimated in general population cohorts (4.86; 95% confidence intervals [CIs]: 1.88 to 7.84 vs. 4.69; 95% CI: 2.29 to 7.09, respectively) (1,2). However, it is notable that PLHIV in these studies of high ART adherence were typically 2 to 3 decades younger than those included in the general population cohorts (2), suggesting biological differences despite similarities in overall rates of systolic dysfunction. Moreover, greater differences were found between rates of diastolic dysfunction with an increased relative risk of 3.0 for any grade of diastolic dysfunction in PLHIV compared to those in healthy controls. Notably, the analysis by Erquo et al. (1) demonstrates a prevalence rate of diastolic dysfunction that is higher than rates found in recent publications within the past several years, reinforcing the observation that more availability of ART and other management strategies directed at PLHIV may not be sufficient to ensure normal cardiac function, compared to those used in comparable, aged controls.
What mechanisms then may explain this high prevalence of systolic and diastolic dysfunction in contemporary cohorts of PLHIV being treated with ART? The first mechanism may be the common pathophysiology shared with accelerated atherosclerotic cardiovascular disease in the form of ongoing vascular inflammation. Using positron emission tomography imaging, aortic vascular inflammation remains unchanged despite initiation of successful ART and, thus, may contribute to vascular stiffening and diastolic dysfunction (3, Online Ref. 12). However, the impact of HIV-related vascular inflammation on vascular stiffness is controversial (Online Ref. 13). Second, cardiac magnetic resonance studies using late gadolinium enhancement have shown evidence of focal fibrosis and increased myocardial lipid content in PLHIV in the presence of a normal LVEF and adequate ART, compared to matched noninfected controls (Online Refs. 14,15). The present authors have shown that the soluble biomarker of subtle myocardial injury, high-sensitivity cardiac troponin T (hs-cTnT), was higher in PLHIV than in controls but was not associated with the presence of coronary plaque, suggesting myocardial injury is not the result of ischemic injury from epicardial plaque rupture (Online Ref. 16).
Other mechanisms may uniquely contribute to HFpEF in PLHIV. Recently the MESA (Multi-Ethnic Study of Atherosclerosis) trial identified a strong association between the extent of pro-inflammatory visceral adipose tissue (VAT) and incident HFpEF (4). This finding may be particularly germane to PLHIV, who frequently have fat redistribution with loss of subcutaneous fat (SAT) and/or VAT accumulation. The present authors have shown that increased VAT in PLHIV is associated with not only generalized inflammation markers such as high-sensitivity C-reactive protein but also with progressive myocardial injury, as measured using hs-cTnT (5). The present authors also previously showed in the MESA trial that higher hs-cTnT levels are associated with a higher prevalence of cardiac fibrosis, as measured by using cardiac magnetic resonance, in patterns not consistent with ischemic injury and with subsequent incident HF (Online Ref. 17). The mechanisms of the way in which increased VAT in PLHIV could result in progression to symptomatic HF are complex. The present authors showed that angiotensin II and aldosterone concentrations during a low-sodium diet are higher in PLHIV than in HIV-negative controls under similar conditions of sodium intake and are highly related to VAT in PLHIV but not in controls (Online Ref. 18). Furthermore, B-type natriuretic peptide levels remain suppressed in PLHIV compared to those in HIV-negative controls under conditions that stimulate renin-angiotensin-aldosterone system (RAAS) activation (Online Ref. 19). In a small pilot study comparing eplerenone with placebo in PLHIV, 6 months of eplerenone therapy resulted in a decrease in intramyocellular lipids and monocyte chemoattractant protein-1 with trends toward reduction in the generalized inflammatory biomarkers including C-reactive protein and interleukin-6 (Online Ref. 20). With the high prevalence of diastolic dysfunction in contemporary cohorts of PLHIV, the greater abundance of VAT, relative to that of SAT, and VAT's association with RAAS activation and cardiac injury make suppression or blockade of RAAS activity and augmentation of B-type natriuretic peptide a potentially attractive target for preventing progression to incident HF in PLHIV. In summary, the meta-analysis by Erquo et al. (1) is an important step in defining the prevalence of pre-HF phenotypes in the contemporary management of an aging population of PLHIV, for whom symptomatic HF will become increasingly common. Similar to the prevention of atherosclerotic disease in PLHIV, development of prevention strategies for HF is an imperative for those infected with HIV to continue to enjoy hard-won victories to improve duration and quality of life.
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Cardiac Dysfunction Among People Living With HIV
A Systematic Review and Meta-Analysis
Sebhat Erqou, Bereket Tessema Lodebo, Ahmad Masri, Ahmed M. Altibi, Justin B. Echouffo-Tcheugui, Anastase Dzudie, Feven Ataklte, Gaurav Choudhary, Gerald S. Bloomfield, Wen-Chih Wu and Andre Pascal Kengne
Abstract
Objective To synthesize existing epidemiological data on cardiac dysfunction in HIV.
Background Data on the burden and risk of human immunodeficiency virus (HIV) infection-associated cardiac dysfunction have not been adequately synthesized. We performed meta-analyses of extant literature on the frequency of several subtypes of cardiac dysfunction among people living with HIV.
Methods We searched electronic databases and reference lists of review articles and combined the study-specific estimates using random-effects model meta-analyses. Heterogeneity was explored using subgroup analyses and meta-regressions.
Results We included 63 reports from 54 studies comprising up to 125,382 adults with HIV infection and 12,655 cases of various cardiac dysfunctions. The pooled prevalence (95% confidence interval) was 12.3% (6.4% to 19.7%; 26 studies) for left ventricular systolic dysfunction (LVSD); 12.0% (7.6% to 17.2%; 17 studies) for dilated cardiomyopathy; 29.3% (22.6% to 36.5%; 20 studies) for grades I to III diastolic dysfunction; and 11.7% (8.5% to 15.3%; 11 studies) for grades II to III diastolic dysfunction. The pooled incidence and prevalence of clinical heart failure were 0.9 per 100 person-years (0.4 to 2.1 per 100 person-years; 4 studies) and 6.5% (4.4% to 9.6%; 8 studies), respectively. The combined prevalence of pulmonary hypertension and right ventricular dysfunction were 11.5% (5.5% to 19.2%; 14 studies) and 8.0% (5.2% to 11.2%; 10 studies), respectively. Significant heterogeneity was observed across studies for all the outcomes analyzed (I2 > 70%, p < 0.01), only partly explained by available study level characteristics. There was a trend for lower prevalence of LVSD in studies reporting higher antiretroviral therapy use or lower proportion of acquired immune deficiency syndrome. The prevalence of LVSD was higher in the African region. After taking into account the effect of regional variation, there was evidence of lower prevalence of LVSD in studies published more recently.
Conclusions Cardiac dysfunction is frequent in people living with HIV. Additional prospective studies are needed to better understand the burden and risk of various forms of cardiac dysfunction related to HIV and the associated mechanisms. (Cardiac dysfunction in people living with HIV-a systematic review and meta-analysis; CRD42018095374)
About 36.7 million people are infected with human immunodeficiency virus (HIV) globally. In the United States, it was estimated that 1.1 million people were living with HIV in 2016 (1). The advent of highly active antiretroviral treatment (HAART) signified a defining moment for people living with HIV (PLHIV), with patients achieving longer life expectancy (2). This shift to longer-term survival has led to increased prevalence of chronic diseases in PLHIV, including cardiovascular disease (CVD) (3-5). A significant proportion of the CVD morbidity and mortality in PLHIV is due to HIV-associated cardiac dysfunction (3,5). Although the frequency of HIV-associated cardiomyopathy is thought to have decreased in the past decade, HIV patients still have a nearly 1.5- to 2-fold higher risk of clinical cardiac dysfunction (5-7). The proposed mechanisms include chronic inflammation, toxicity from certain HAART regimens, opportunistic infections, direct viral infection of the myocardium, nutritional disorders, and cardiac autoimmunity, among others (6,8).
Accruing epidemiological studies have reported on the frequency of cardiac dysfunction among PLHIV and the risk of cardiac dysfunction in relation to HIV infection; however, in these studies, the extent of cardiac dysfunction burden or risk is highly variable. In addition, differences in burden or risk by type of ventricular dysfunction (i.e., left ventricular systolic dysfunction [LVSD], left ventricular diastolic dysfunction [DD], right ventricular dysfunction [RVSD]) have not been well established. There is a need for a quantitative synthesis of the evidence to allow easier interpretation and application of the extant data.
We sought to perform a systematic review and meta-analysis of published literature on the frequency and relative risk of clinical heart failure (HF), LVSD, dilated cardiomyopathy (DCM), DD, pulmonary hypertension (PH), or RVSD among PLHIV.
Discussion
Summary of findings
In this meta-analysis comprising 125,382 PLHIV and 12,665 cases of cardiac dysfunction, we found a significant burden cardiovascular dysfunction among PLHIV across the spectrum of immune dysfunction, HIV disease, or treatment. The pooled prevalence estimates for LVSD, DCM, grades I to III DD, grades II to III DD, PH, and RVSD were 12.3%, 12.0%, 29.3%, 11.7%, 11.5%, and 8.0%, respectively. The pooled incidence and prevalence estimates of clinical HF were 0.9 per 100-person years and 6.5%, respectively. The pooled relative risk of HF and DD across a few studies comparing PLHIV with non-HIV-infected control patients was 1.7 and 3.0, respectively. We found that studies with a higher proportion of participants with AIDS or a lower proportion using ART reported a higher prevalence of LVSD. Studies from the African region reported a higher prevalence of DCM.
Comparison with previous studies and explanation of results
The present meta-analysis provides a comprehensive quantitative synthesis of available data on the epidemiology of cardiac dysfunction in the context of HIV. Compared with previous reviews (2,6,10-14), our study included a larger number of participants, and provided significant complementary information through the comprehensive inclusion of several outcomes including both left- and right-sided cardiac dysfunction (LVSD, DCM, DD, and RVSD), and PH. We also investigated the potential effects of several characteristics, including ART, immunodeficiency (as assessed by CD4 count, or symptomatic HIV infection or AIDS), and age, by performing meta-regression and subgroup analyses. Previously, Cerrato et al. (11) performed quantitative meta-analyses of studies reporting the prevalence of HIV-associated systolic and diastolic dysfunction with focus on pauci symptomatic HIV patients in the HAART era (11). The review included 11 studies published after the year 2000, with >75% of participants known to be on HAART, yielding pooled analyses in up to 2,242 patients with HIV.
The frequency of cardiomyopathy in PLHIV reported in this review is materially higher than that reported by studies of general populations, which is in the range of 4% to 6% (22,23). Similarly, the prevalence of DD is 1.5- to 2-fold higher when compared with those reported for individuals in general populations (23,24). Such differences are likely to be underestimates because the participants represented in the general populations were significantly older than the studies on PLHIV included in this meta-analysis. PLHIV have also been shown to have materially higher risk of ischemic heart disease compared with non-HIV-infected patients (3), which taken together with nonischemic heart disease represents a substantial burden of CVD in this population.
The higher frequency of cardiac dysfunction related to the proportion of participants with AIDS might reflect the role that immunodeficiency, and opportunistic infections, play in the pathogenesis of cardiac dysfunction (6,7). Given the proposed role of immunodeficiency and opportunistic infections (among other factors) in pathogenesis of HIV-associated cardiac dysfunction, we anticipated that studies published in the pre-ART era and those from regions with lower coverage of ART would report higher prevalence. We did find that studies from the African region reported higher prevalence of DCM. Similarly, although we did not find significant difference in subgroup analyses of LVSD between studies published pre- and post-ART era, we found lower prevalence of LVSD in more recently published studies after taking into account the effect of regional variation. These findings suggest that regional variations in ART uptake may influence the previously reported decline in LVSD in post-HAART era.
Studies published in more recent years and those with higher average CD4 count reported a significantly lower prevalence of DD. The finding of reduced prevalence of DD in more recent studies is likely a reflection of the change in the standardized echocardiographic diagnostic criteria over the years (25-27). On the other hand, the finding of inverse association between average study CD4 T-cell count and prevalence of advanced DD is consistent with the report by Hsue et al. (28) that showed LV mass in PLHIV is inversely proportional to CD4 T-cell count nadir. It is important to take caution in interpreting these findings because these are study-level associations and may not hold true for individuals because of ecological fallacy.
Implications of our findings
Our findings are important in several ways. First, the substantial risk of various types of cardiac dysfunction in PLHIV helps create awareness within the medical community caring for these patients to watch for complications and implement early intervention when indicated (6). In addition to subclinical cardiac dysfunction identified using imaging modalities, PLHIV have materially increased risk of clinical HF, indicating that asymptomatic cardiac dysfunction identified on imaging can be progressive in a subset of participants. Epidemiological studies indicate that HIV-associated ventricular dysfunction and PH are associated with increased risk of mortality (2). Together, these data suggest that early detection of cardiac dysfunction in PLHIV could provide a window of opportunity in which it may be possible to institute intervention to reverse the course, as has been proposed for individuals in the general population with asymptomatic cardiac dysfunction (22,29). Our study specifically highlights the clinical importance of RVSD and PH in HIV infection because these conditions are associated with worse survival, especially in the context of HF with preserved ejection fraction (30,31), keeping in mind that the echocardiogram is not sensitive for PH diagnosis (32) or RV dysfunction (33). Second, our review highlights the need to understand the course of asymptomatic cardiac dysfunction in PLHIV through imaging and longitudinal follow-up, as has been done for general populations (22). There is a significant paucity of data detailing the natural course of cardiac dysfunction identified in PLHIV. There is also a need to further characterize and understand the pathogenesis of HIV cardiac dysfunction to foster the development of evidence-based and effective preventive interventions. In the past, smaller scale studies using cardiac magnetic resonance imaging have demonstrated a higher prevalence of cardiac steatosis, edema, and fibrosis in PLHIV, which may underlie the mechanism of cardiac dysfunction (34-36). Finally, this review, by pooling data from available studies on the subject, provides more precise estimates of the various HIV-associated cardiac dysfunction outcomes than was possible before. These data highlight the urgency for finding strategies to reduce the potential HIV-related burden of HF and associated cardiac disorders.
Study limitations
First, the study is based on generally small-scale, medium quality, cross-sectional and retrospective studies that somewhat limited the quality of the data used to calculate the pooled estimates. Some of these studies are older and the definition of DD has changed across the years. Indeed, former DD grading systems not using tissue Doppler imaging, strain, and strain rates could lead to significant misclassifications; however, we found similar estimates between smaller and larger studies and between studies published at different times, suggesting that the effect of such bias is likely limited. Second, there was significant heterogeneity across the studies for all outcomes evaluated that was only partially explained by available study level characteristics, which limits the generalizability of the findings. We used random-effects model meta-analysis to mitigate the effect of heterogeneity, which assumes that the underlying population parameter is different across studies and attempts to determine the mean of those parameters. Another consequence of heterogeneity is that the meta-analysis yielded wider confidence intervals than would be expected for the size of the data. Third, there was evidence of significant publication bias for DCM, PH, and RVSD outcomes, which indicate that the smaller studies were more likely to be published if they reported more extreme estimates compared with the larger studies. Comparison of pooled estimates between the smaller and larger studies, or meta-regression of the estimates by the study size (i.e., number of participants or number of cases), however, yielded similar results between larger and smaller studies, indicating that the magnitude of any such bias is likely to be small.
Perspectives
COMPETENCY IN MEDICAL KNOWLEDGE: In meta-analysis of available observational studies in PLHIV, we found that the incidence of cardiac dysfunction was substantial. These findings should help raise awareness of clinicians taking care of PLHIV to consider early investigation and referral of those with cardiac dysfunction and allow institution of guideline-based treatment, while ongoing research seek to identify further preventive and therapeutic strategies.
TRANSLATIONAL OUTLOOK: There is a need for prospective epidemiological studies to better understand the burden and progression of cardiovascular complications in PLHIV, including a comprehensive evaluation of left and right ventricles that views them as a continuum rather than separate entities, and leveraging new imaging modalities such as cardiac magnetic resonance imaging to increase precision of diagnoses. Extensive phenotyping of patients with HIV-associated cardiac dysfunction, including genetic, proteomic, and metabolic studies, can form the basis for translational research.
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