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Heart Failure among People with HIV: Evolving Risks,
Mechanisms, and Preventive Considerations
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People with HIV (PHIV) with access to modern antiretroviral therapy (ART) face a two-fold increased risk of heart failure as compared with non-HIV-infected individuals. The purpose of this review is to consider evolving risks, mechanisms, and preventive considerations pertaining to heart failure among PHIV.
October 2019 - Current HIV/AIDS Reports - Mabel Toribio1 & Tomas G. Neilan2 & Markella V. Zanni1 - Metabolism Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, 5 LON 207, Boston, MA 02114, USA
Cardiac MR PET CT Program, Division of Cardiology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Today, PHIV with access to modern ART continue to face significant health threats from heart failure. Heart failure is a disease of aging, whereby the general-population prevalence increases steadily across successive age deciles [5]. Adjusting for age, PHIV with access to ART confront an approximately two-fold increased risk of heart failure [6, 7•, 8, 9•, 10•]. Thus, as the global population of PHIV ages [11, 12, 13], heart failure prevalence in this group of 37 million individuals may be anticipated to spike. Of further concern, heart failure outcomes in the general population are poor [14] and worse still among PHIV: indeed, the 5-year mortality rate among PHIV diagnosed with heart failure approaches 50% [15].
Erqou et al. selected 54 studies conducted in diverse regions (Africa, Asia, Europe, and North America) and published anywhere between 1988 and 2017 [16••]. Analyzing data from 125,382 PHIV (82% men), Erqou et al. determined a pooled heart failure prevalence of 6.5% (4.4%, 9.6%). This observed heart failure prevalence among PHIV was surprisingly high, given the relatively low average age of the cohort (47 years). Of note, among those PHIV studied, only 77% were on ART and a significant proportion had untreated, uncontrolled HIV/AIDS [16••]. Importantly, key North American studies analyzing incident heart failure by HIV status in contemporary cohorts consistently suggest an increased relative risk of heart failure among PHIV with access to ART [6, 7•, 8, 9•]. Butt et al. examined data from an all-male cohort of US Veterans without prior cardiovascular disease (CVD), including 2391 PHIV and 6095 controls followed from 2000 through 2007 [6]. Median age in both groups was 48 years. Age- and race-adjusted heart failure incidence per 1000 person-years (based on diagnosis codes) was 7.21 among PHIV (95% confidence interval, CI, 6.90-7.34) and 4.82 (95% CI 4.72-4.91) among controls. Overall, the hazard ratio for heart failure among individuals with vs. without HIV was 1.81 (95% CI 1.39-2.36), after adjustment for traditional heart failure risk factors [6]. Of note, this hazard ratio was not adjusted for history of depression, renal dysfunction, or liver dysfunction-all parameters subsequently associated with incident heart failure in this cohort [17, 18, 19]. Feinstein et al. explored data from a predominantly male US cohort including 4640 PHIV (83% men) and 4250 matched control subjects (80% men)-all without prior heart failure-followed from 2000 to 2016 [7•]. In this study, the hazard ratio for incident physician-adjudicated heart failure among PHIV vs. controls was 2.10 (95% CI 1.38-3.21) after adjustment for traditional heart failure risk factors. Compared with the VA Cohort, this cohort was slightly younger (average age 40-41 years) [7•]. Notably, in both cohorts, only approximately half of PHIV evidenced viral loads < 500 copies/ml [6, 7•]. In the study by Butt et al., the increased risk of heart failure among PHIV was only significant among those with uncontrolled viremia. By contrast, in the study by Feinstein et al., higher viral load (and lower CD4+ T cell count) tracked with heart failure risk among PHIV, but even those PHIV with suppressed viremia saw increased heart failure risk as compared with controls [6, 7•]. Finally, the US Partners Healthcare Database heart failure study-focused on 1388 women with HIV (WHIV) and 13,781 matched control subjects without prior heart failure-demonstrated a nearly four-fold increased incidence of physician-adjudicated heart failure among WHIV [9•]. In this study, led by Janjua et al., the average age of both cohorts was 59 years. Among the WHIV, 92% were on ART, though again, only approximately 50% had achieved viral suppression [9•].
Medicare Claims Comorbidities Study: http://www.natap.org/2019/HIV/090419_06.htm
Abstract
Purpose
People with HIV (PHIV) with access to modern antiretroviral therapy (ART) face a two-fold increased risk of heart failure as compared with non-HIV-infected individuals. The purpose of this review is to consider evolving risks, mechanisms, and preventive considerations pertaining to heart failure among PHIV.
Recent Findings
While unchecked HIV/AIDS has been documented to precipitate heart failure characterized by overtly reduced cardiac contractile function, ART-treated HIV may be associated with either heart failure with reduced ejection fraction (HFrEF) or with heart failure with preserved ejection fraction (HFpEF). In HFpEF, a "stiff" left ventricle cannot adequately relax in diastole-a condition known as diastolic dysfunction. Diastolic dysfunction, in turn, may result from processes including myocardial fibrosis (triggered by hypertension and/or immune activation/inflammation) and/or myocardial steatosis (triggered by metabolic dysregulation). Notably, hypertension, systemic immune activation, and metabolic dysregulation are all common conditions among even those PHIV who are well-treated with ART. Of clinical consequence, HFpEF is uniquely intransigent to conventional medical therapies and portends high morbidity and mortality. However, diastolic dysfunction is reversible-as are contributing processes of myocardial fibrosis and myocardial steatosis.
Summary
Our challenges in preserving myocardial health among PHIV are two-fold. First, we must continue working to realize UNAIDS 90-90-90 goals. This achievement will reduce AIDS-related mortality, including cardiovascular deaths from AIDS-associated heart failure. Second, we must work to elucidate the detailed mechanisms continuing to predispose ART-treated PHIV to heart failure and particularly HFpEF. Such efforts will enable the development and implementation of targeted preventive strategies.
Preventive Considerations-Including Knowledge Gaps and Future Directions
The first strategy to consider is immediate ART. Ample evidence supports the notion that unchecked HIV/AIDS and associated conditions adversely affect the heart muscle [1]. Further, the START study confirmed that immediate ART upon HIV diagnosis reduces all-cause mortality [86]. Thus, immediate ART, as recommended by the WHO, may help protect myocardial health among PHIV. However, we must augment our understanding as to which antiretroviral therapeutic regimens exert fewest cardiotoxic effects and work to expand access to these. The first strategy to consider is immediate ART. Ample evidence supports the notion that unchecked HIV/AIDS and associated conditions adversely affect the heart muscle [1]. Further, the START study confirmed that immediate ART upon HIV diagnosis reduces all-cause mortality [86]. Thus, immediate ART, as recommended by the WHO, may help protect myocardial health among PHIV. However, we must augment our understanding as to which antiretroviral therapeutic regimens exert fewest cardiotoxic effects and work to expand access to these. Second, we must identify and target region-specific risk factors for myocardial damage. Such risk factors may include co-infections (e.g., tuberculosis), nutritional deficiencies, and/or toxic exposures [87, 88, 89, 90]. Third, we must target behavioral and traditional metabolic risk factors for myocardial disease including sedentary lifestyle, cigarette smoking, excess alcohol use, cocaine use, obesity, hypertension, dyslipidemia, and dysglycemia. Behavioral and traditional metabolic risk factors feed into several general myocardial injury mechanisms which are not specific to PHIV (ischemic heart disease, coronary microvascular disease, myocardial toxicity, valvular disease, and arrhythmia) [91] but which may be synergistically activated by HIV-specific mechanisms. Fourth, we must determine the specific mechanisms by which systemic immune activation and metabolic dysregulation predispose to myocardial fibrosis and steatosis among PHIV and identify safe, targeted strategies to forestall these processes. Future research in the field will need to be attentive to the influence of underlying genetics, as well as sex, gender identity, race/ethnicity, and region-specific risk factors. Finally, educational outreach emphasizing heart failure risks among ART-treated PHIV will facilitate early detection of pre-heart failure phenotypes (e.g., exercise-induced dyspnea) and obviate diagnostic overshadowing (i.e., false attribution of heart-failure suggestive symptomatology to HIV itself or secondary infection). Though heart failure portends a poor prognosis, particularly among PHIV, general-population studies highlight the promise of efforts geared toward heart failure prevention [92].
Taken together, studies from North America and Asia reveal an approximately 2-fold increased risk of heart failure among contemporary cohorts of PHIV with access to ART. Within these cohorts, even when ART has been prescribed, suboptimal viral control is common and appears to be associated with augmented risk...... low-level viral replication, viral co-infection, and enhanced microbial translocation may be culprits: Among ART-treated PHIV, systemic immune activation may drive myocardial fibrosis while ongoing metabolic dysregulation may predispose to myocardial steatosis. Systemic immune activation persists even among those individuals with HIV whose virus is completely suppressed by combined antiretroviral therapy [53, 54, 55]. ART, even when administered early in the course of the disease, dampens select indices of systemic immune activation, but many indices of systemic immune activation remain elevated [56].......While select early ART regimens tended to evoke overt lipodystrophy (peripheral lipoatrophy with or without central lipohypertrophy) [60], many modern regimens are better-tolerated. Nevertheless, ART initiation continues to be associated with weight gain [61], accumulation of excess adiposity [62], and ectopic fat deposition [63, 64]-all processes associated with development of traditional cardiometabolic risk factors......Of interest, theoretically, systemic immune activation may predispose to myocardial fibrosis either by prompting inflammation in the myocardial structural space (inflammatory mechanism) or by contributing to arterial inflammation [65, 66] and downstream coronary microvascular dysfunction [67] (inflammatory-ischemic mechanism)........
Building on these findings, two North American studies elucidated important functional consequences of myocardial steatosis among PHIV.: While PHIV exhibited increased rates of smoking, diabetes, and lipid-lowering medication use, Framingham risk scores (FRS) were comparable between groups. Among PHIV, myocardial steatosis was noted (MRS: intramyocardial triglyceride content 1.14 vs. 0.58%, P = 0.04), as was an increased burden of diffuse myocardial fibrosis (MRI: extracellular volume).. In multivariable modeling, women's sex and visceral adiposity independently predicted steatosis among PHIV while women's sex, hypertension, and HIV status predicted fibrosis among the whole group.
Two European studies employing cardiac MRI/MRS to study a predominantly male cohort revealed PHIV (vs. controls) have an increased prevalence of patchy focal fibrosis, suggestive of prior myocarditis, as well as diffuse fibrosis and steatosis [80•, 81, 82]. Further, these studies showed evidence of diastolic dysfunction among PHIV [80•, 81, 82]: PHIV evidenced signs of diastolic function (MRI: circumferential diastolic strain rate) as well as subtle systolic dysfunction (MRI: circumferential systolic strain rate). In multivariable modeling, HIV status remained an independent predictor of myocardial steatosis as well as both diastolic dysfunction and subtle systolic dysfunction [80•].
Heart failure is subclassified based on left ventricular ejection fraction (EF), which is the percentage of blood leaving the left ventricle each time it contracts [27]. Patients with clinical heart failure may thus have heart failure with reduced ejection fraction (HFrEF; EF < 40%), heart failure with preserved ejection fraction (HFpEF; EF ≥ 50%), or heart failure with borderline ejection fraction (EF 40-49%). Several experts believe HFrEF and HFpEF constitute distinct disease processes, whereby HFpEF may not represent a stage en route to HFrEF [27]. Indeed, differences abound in HFrEF vs. HFpEF etiology, triggering risk factors, and ensuing pathophysiology.....parameters predisposing to HFrEF include traditional metabolic risk factors (hypertension, dyslipidemia, dysglycemia, cigarette smoking) as well as infectious risk factors and toxic exposures.....HFpEF, by contrast, is typically caused by processes which incite the myocardium to stiffen, resulting in inadequate relaxation during diastole (or "diastolic dysfunction") [30]. Examples include diffuse myocardial fibrosis and myocardial steatosis. Risk factors for HFpEF include select traditional metabolic risk factors such as hypertension and dysglycemia, as well as female sex and advanced chronological age.....By inference, it appears that among PHIV, ART access, chronologic age, and women's sex may represent risk factors for HFpEF. Thus, as ART access expands and the global population of PHIV ages, we may expect to see a surge in HFpEF cases-particularly in Sub-Saharan Africa. ......Among PHIV, while the prevalence of overt systolic dysfunction appears to be declining over time, rates of diastolic dysfunction-a pre-clinical phenotype, which progresses at a rate of 2%/year to symptomatic heart failure......Myocardial fibrosis and myocardial steatosis are two pathologic processes which may be expected to contribute to diastolic dysfunction among contemporary cohorts of ART-treated PHIV......Focal myocardial fibrosis, by contrast, is most frequently caused by acute myocardial infarction [42]. Myocardial steatosis is a pathologic process characterized by increased deposition of lipids (predominantly triglycerides) within cardiomyocytes-increased intramyocardial triglyceride content.
Soberingly, multiple studies across regions suggest heart failure outcomes are worse among PHIV vs. non-HIV-infected individuals. In the general population, a diagnosis of heart failure is associated with recurrent hospitalization, decreased quality of life, and high rates of mortality within 5 years.
Analysis of data from the predominantly male US Veterans Cohort suggests that among PHIV with heart failure, 5-year mortality rates approached 50% [15]. Analogously, Janjua et al. showed through the US Partners Healthcare Database heart failure study that among women with heart failure, HIV positivity conferred an increased risk of all-cause mortality, cardiovascular mortality, and heart failure hospitalization [9•]. Indeed, the hazard ratio for recurrent heart failure hospitalization among WHIV vs. non-HIV-infected women was 2.58 (95% CI 1.55-4.29) after adjustment for traditional heart failure risk factors [9•]
A recent mixed-sex study of heart failure outcomes among US PHIV vs. controls suggested worse outcomes only among those PHIV with unchecked viremia [22]. In this study, Alvi et al. studied all individuals admitted with heart failure to an urban academic medical center (Montefiore) in 2011 and followed for 2 years.
Of potential clinical relevance, additional analyses performed within the cohort of PHIV showed that use of ritonavir-boosted protease inhibitors (PIs) was associated with a 2-fold increased risk of cardiovascular mortality and 30-day heart failure readmission [23]. This finding ran in contrast to early work implicating older NRTIs in mitochondrial injury and attendant cardiotoxicity [24, 25, 26].
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