Outline
What Is Human Immunodeficiency Virus-Associated Heart Failure?, 395
Historical Perspective, 395
Contemporary Shifts in Epidemiology, 396
Pathophysiology of Heart Failure in Human Immunodeficiency Virus, 396
Poor Human Immunodeficiency Viral Control, Opportunistic Infections, and Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Cardiomyopathy, 396
The Role of Atherosclerosis, Thrombosis, and Myocardial Infarction, 397
Inflammation, Immune Dysfunction, and Diastolic Dysfunction in Human Immunodeficiency Virus, 397
Pulmonary Arterial Hypertension, 398
Cardiac Effects of Antiretroviral Therapy, 398
Nucleoside Reverse Transcriptase Inhibitors, 398
Protease Inhibitors, 398
Cardiac Effects of Antiretroviral Therapy in Children, 398
Comorbidities and Behavioral Factors, 398
Manifestations of Heart Failure, 400
Low Left Ventricular Ejection Fraction, 400
Myocardial Strain and Fibrosis, 400
Poor Inotropic Contractile Reserve, 401
Diastolic Dysfunction, 401
Clinical Management of Patients with Human Immunodeficiency Virus and Heart Failure, 401
Human Immunodeficiency Virus-Specific Management, 401
Coronary Artery Bypass Surgery, 401
Devices and Advanced Heart Failure Therapies, 401
Summary and Future Directions, 402
What Is Human Immunodeficiency Virus-Associated Heart Failure?
As antiretroviral therapy (ART) has become widely adopted, acquired immune deficiency syndrome (AIDS)–defining infections and malignancies have become less common, and the burden of chronic noncommunicable diseases has increased. Parallel to this transition, human immunodeficiency virus (HIV)–associated heart failure (HF) has evolved from an end-stage AIDS-related complication to a more heterogeneous disease state representing diverse HIV-related pathophysiologies. HF is more common among people living with HIV (PLWH) than in the HIV-uninfected, even after adjustment for demographic and relevant clinical factors. Worse immune function and more HIV viral replication exacerbate HIV-associated HF risk. Traditional cardiovascular risk factors for HF, ranging from hypertension to smoking, are also more common in PLWH, underscoring the role of both traditional and HIV-specific factors in HF pathogenesis. While there is no uniform definition for HIV-associated HF, most society guidelines and recommendations acknowledge that HIV infection carries with it a risk for a unique HF syndrome differentiated from others by the role of HIV infection, immune dysfunction, or ART on the development of HF.
Historical Perspective
Since the first reports of HF due to AIDS-related cardiomyopathy in the mid-1980s, HF has been a known complication of HIV. The initial case reports of cardiac involvement in HIV were notable in that these cases occurred in the absence of Kaposi sarcoma, in which cardiac involvement was common. Throughout the 1980s and 1990s, the presence of HF in PLWH was mainly in the context of myocarditis, opportunistic infections, nutritional deficiencies and/or severe immunosuppression. Most patients had concomitant opportunistic infections. Numerous terms were introduced to describe this syndrome, including AIDS cardiomyopathy, HIV-associated cardiomyopathy, HIV-associated dilated cardiomyopathy, HIV-associated HF, and HIV-associated left ventricular (LV) dysfunction.
In the pre-ART era, HIV-associated HF was classically defined by progressive HIV/AIDS and associated global LV systolic dysfunction. In an observational study of 136 Italian PLWH followed with serial echocardiography from 1988 through 1992, seven (5.1%) developed symptomatic global LV dysfunction over a mean follow-up of 415 days. All patients with incident HF had AIDS, and myocarditis was a prominent feature. In the pre-ART era, very low CD4 count (<100 cells/mm 3 ) was a common factor associated with LV dysfunction and HF. Overall, the prevalence of HIV-associated cardiomyopathy was 30% to 40% based on clinical-pathological studies in the pre-ART era with an annual incidence of 15.9 per 1000 patients.
Prognostically, the syndrome was initially characterized by severe symptoms and high mortality. Median survival was 101 days for patients with dilated cardiomyopathy, compared to 472 days for patients with normal findings on echocardiogram at a similar level of immunosuppression. Gross autopsy findings demonstrated striking four-chamber dilatation, myofibrillar loss, and focal myocarditis. In the wake of this ostensibly new syndrome, researchers at the time foreshadowed, “Cardiac disease secondary to multiple causes can be expected to complicate the clinical course of these patients.”
Although the relative contribution of AIDS cardiomyopathy to HIV-associated HF has declined with wide ART adoption, ART access and adherence are not ubiquitous. Therefore, AIDS cardiomyopathy remains a relevant disease state, particularly in settings with low ART uptake. Sub-Saharan Africa (SSA), for example, accounts for 12% of the global population but is disproportionately affected by HIV with 69% of all adults and 90% of all children living with HIV residing in the region ( see also Chapter 29 ).
Contemporary Shifts in Epidemiology
Access to effective ART has significantly altered the epidemiology of HF in HIV ( Table 30.1 ). The syndrome has shifted from a severe, dilated cardiomyopathy to one that is often minimally symptomatic and accompanied by mildly decreased LV systolic function. While the prevalence of severe systolic dysfunction has definitely diminished, data from the US Veterans Aging Cohort Study (VACS) show that PLWH on ART remain at higher risk of developing HF compared to the uninfected for HF with preserved, reduced, or borderline ejection fraction (EF). HF risk was greater among PLWH despite having a lower burden of traditional risk factors, including hypertension, diabetes, high low-density lipoprotein (LDL) cholesterol, and obesity. In subgroup analyses adjusted for numerous clinical variables, the most common HF phenotype for white, black, and young (<40 years of age) veterans was HF with reduced EF (HFrEF). PLWH with consistently low CD4+ T-cell counts had significantly elevated risk for HFrEF (hazard ratio [HR] 1.87; 95% confidence interval [CI] 1.36–2.57) and HF with preserved EF (HFpEF) (HR 1.87; 95% CI 1.28–2.73) in comparison to PLWH with higher CD4+ T-cell counts; however, compared with uninfected patients, HF risk among PLWH with CD4+ T-cell count greater than 500 cells/mm 3 remained elevated (HR 1.25; 95% CI 1.08–1.43). Consistently detectable viremia was associated with increased risk for HFrEF (HR 1.63; 95% CI 1.28–2.08). In sensitivity analyses, the risk of HF attributed to HIV persisted after restricting the dataset to those without hypertension, alcohol or cocaine abuse, and never smokers, and adjusted for incident myocardial infarction (MI).
| Characteristics | Pre-ART | With access to ART a |
|---|---|---|
| Causes | Myocarditis, viral and nonviral opportunistic infections, tuberculous myopericarditis, micronutrient deficiency | Cardiac autoimmunity, chronic inflammation, ART toxicity |
| Presentation | Predominantly severe systolic dysfunction and advanced heart failure | Mild systolic dysfunction, diastolic dysfunction |
| Clinical | Symptomatic | Symptomatic or asymptomatic |
| Echocardiographic Features | Dilated cardiomyopathy, Reduced ejection fraction | Reduced, borderline or preserved ejection fraction, abnormal myocardial strain |
| Mortality | Median survival ∼100 days after diagnosis | Unknown |
a Features can mimic those in pre-ART era in patients who are not taking ART and with ischemic etiologies that progress to severe systolic dysfunction.
Recent analyses suggest that HFpEF is becoming an increasingly common manifestation of HIV-associated HF. In contrast to the global LV dysfunction-predominant manifestation of HF in the pre-ART era, investigators found that HFrEF comprised only 37.1% of incident HF among HIV-infected veterans. Another US Department of Veterans Affairs (VA) study suggests that the HIV-associated risk of HF may be even higher among women (incidence rate ratio 2.5; 95% CI 1.5-4.5, HIV vs. control). Similarly, higher risks were seen for women in an analysis of a large nationally representative electronic health records database ( Fig. 30.1 ).
A substantial portion of PLWH have abnormal diastolic parameters, with or without symptoms. Investigations into asymptomatic cardiac dysfunction among PLWH show a higher prevalence of diastolic dysfunction and higher LV mass index compared with controls. These differences are not solely explained by differences in traditional risk factors and are independently associated with HIV infection.
Pathophysiology of Heart Failure in Human Immunodeficiency Virus
HF reflects a final common pathway of various cardiovascular and systemic disorders. These diverse pathophysiologies are particularly apparent when examining HIV-associated HF. Here, we outline several mechanisms that appear to contribute to HIV-associated HF.
Poor Human Immunodeficiency Viral Control, Opportunistic Infections, and Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Cardiomyopathy
Progressive infection and resulting low CD4+ T-cell counts, often less than 100 cells/mm, make PLWH particularly vulnerable to opportunistic infection, which may in turn contribute to infectious myocarditis. In a study from the pre-ART era, which included necropsy results from five HIV-infected persons who died from acute systolic HF, three of the patients were found to have acute lymphocytic myocarditis and one was found to have cryptococcal myocarditis. The role of myocarditis in AIDS cardiomyopathy was further reinforced by an autopsy study of 60 Scandinavian patients with AIDS and no known heart disease, which found myocarditis in 25 patients (42%) and diffuse myocardial fibrosis in 40 patients (67%).
Myocardial dysfunction in advanced HIV/AIDS may also relate to nutritional deficiencies common in this condition. AIDS-related deficiencies in micronutrients including L-carnitine and selenium have been proposed as contributors to cardiomyopathy among AIDS patients. There is no clear consensus on whether HIV itself directly infects the myocardium or whether advanced HIV/AIDs merely predisposes to infectious, immune dysregulatory, and inflammatory conditions that lead to myocardial damage.
The Role of Atherosclerosis, Thrombosis, and Myocardial Infarction
Persistent inflammation, immune activation, endothelial dysfunction, and dyslipidemia occur commonly in chronic HIV infection, even when well controlled. Most studies evaluating associations of HIV-related inflammation and immune dysfunction with cardiovascular events have focused primarily on atherosclerotic and thrombotic endpoints (which may lead to myocardial dysfunction) rather than HF itself. Dyslipidemia is common among persons with treated HIV, particularly those taking protease inhibitors (PIs), and is associated with atherosclerosis in HIV. Chronic inflammation and immune activation are hallmarks of chronic HIV infection and persist even with effective ART. A seminal analysis of the Strategies for Management of Anti-Retroviral Therapy (SMART) study of PLWH and the multi-ethnic study of atherosclerosis (MESA) of uninfected persons demonstrated that high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and D-dimer were significantly elevated among PLWH and remained persistently elevated even after effective HIV viral suppression on ART. Elevated levels of inflammatory and coagulation markers have, in turn, been associated with higher risks of MI and overall mortality among PLWH. Perhaps not surprisingly, several large cohort studies have found elevated rates of MI among PLWH that persist after accounting for demographics and traditional cardiovascular risk factors. Low CD4+ T-cell count, in particular, has been associated with greater rates of MI. Although data regarding ischemic etiologies of HF in HIV are sparse, it is reasonable to infer that these elevated rates of HIV-associated MI may contribute to elevated rates of HF in HIV, as has been described. The contribution of ischemic heart disease to HF in HIV may be particularly important given the potential role of T regulatory cells in myocardial wound healing, and the findings that PLWH may have larger scars following MI than uninfected persons.
Inflammation, Immune Dysfunction, and Diastolic Dysfunction in Human Immunodeficiency Virus
In addition to contributing to atherosclerosis and MI, chronic HIV-related inflammation may contribute directly to myocardial dysfunction. In a cross-sectional study of 196 HIV-infected adults and 52 uninfected controls without known cardiovascular disease, HIV-infected adults had 2.4-fold greater odds of diastolic dysfunction after adjustment for age and traditional cardiovascular risk factors, as well as significantly higher LV mass index. Persons with a history of advanced HIV-associated immune suppression have a higher risk of left ventricular hypertrophy and diastolic dysfunction compared with those with preserved immune function. Another potential contributor to impaired or restrictive patterns of myocardial relaxation in HIV is subepicardial/pericardial fat, which has been associated with inflammation and atherosclerosis among PLWH. Extensive fibrosis has been demonstrated in persons with well-controlled HIV as well, and may contribute to myocardial dysfunction in HIV. A cross-sectional study evaluating cardiac magnetic resonance imaging (MRI) for 90 PLWH and 39 age-matched controls, all of whom had no known cardiovascular disease, found that myocardial fibrosis was present in 76% of PLWH versus 13% uninfected persons; PLWH also had higher intramyocardial lipid levels. In a separate study of PLWH without known cardiovascular disease, markers of cardiac stress and fibrosis (soluble ST2 and growth differentiation factor 15) were independently associated with diastolic dysfunction and mortality. In light of these findings, it is not surprising that a large study of HIV-infected and uninfected veterans in the United States demonstrated a significantly elevated risk of HFpEF among PLWH. Low CD4+ T-cell count was associated with greater risk for HFpEF and HFrEF among PLWH, further underscoring the potential contribution of immunosuppression to HF in HIV.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension is significantly more common among PLWH than uninfected persons. Pulmonary arterial hypertension, a recognized complication of HIV in the pre-ART era, has persisted in the modern ART era. Several factors appear to contribute to pulmonary arterial hypertension in HIV, including polymorphisms in the HIV-Nef protein, chronic immune activation, endothelial dysfunction, and coinfection with other viruses. Few large studies have evaluated the contribution of pulmonary arterial hypertension to right ventricular dysfunction and failure in HIV. Nevertheless, one may infer that the outsize contribution of pulmonary arterial hypertension in HIV also leads to elevated risks for right ventricular dysfunction and failure.
Cardiac Effects of Antiretroviral Therapy
Few interventions in the history of medicine have so dramatically changed the course of human disease as the discovery of effective combination ART for HIV/AIDS. Since the first ART “cocktails” were introduced in the mid-1990s, data from the Centers for Disease Control indicate mortality due to HIV has plummeted from an annual age-adjusted death rate of ∼17 per 100,000 in 1995 to ∼2 per 100,000 in 2014 ( https://www.cdc.gov/hiv/statistics/index.html ). The first generations of these drugs were associated with significant metabolic toxicities, including cardiotoxicity; however, more metabolically friendly regimens composed of new drug classes, such as integrase inhibitors, have since been developed ( Table 30.2 ).
| Class and Name of ART | Known Effects on Myocardial Dysfunction | Other Cardiovascular Side Effects |
|---|---|---|
| Nucleoside reverse transcriptase inhibitors (NRTIs) | ||
| Abacavir (ABC) | No | ± Myocardial infarction, dyslipidemia, inflammation |
| Didanosine (ddI) | Yes | Myocardial infarction |
| Emtricitabine (FTC) | No | |
| Lamivudine (3TC) | No | |
| Stavudine (d4T) | Yes | Dyslipidemia |
| Tenofovir (TDF) | ± | |
| Zalcitabine (ddC) | Yes | |
| Zidovudine (AZT) | Yes | Dyslipidemia |
| Protease inhibitors (PIs) | ||
| Atazanavir (ATV) | No | PR prolongation when given with RTV |
| Darunavir (DRV) | No | ± cardiovascular events |
| Fosamprenavir (FPV) | No | ± cardiovascular events |
| Indinavir (IDV) | No | Myocardial infarction |
| Lopinavir/ritonavir (LPV/r) | No | Myocardial infarction, PR and QT prolongation |
| Nelfinavir | No | ± Dyslipidemia |
| Ritonavir (RTV) | No | All RTV “boosted” PIs carry risk of dyslipidemia |
| Saquinavir (SQV) | No | ± Dyslipidemia, PR prolongation when given with RTV, QT prolongation |
| Tipranavir | No | |
| Non-nucleoside reverse transcriptase inhibitors (NNRTIs) | ||
| Efavirenz (EFV) | No | Dyslipidemia, QT prolongation |
| Nevirapine | No | Dyslipidemia |
| Rilpivirine (RPV) | No | QT prolongation |
Randomized trials such as SMART (continuous vs. intermittent ART) and START (Strategic Timing of AntiRetroviral Treatment) (early vs. delayed initiation of ART), have consistently pointed to improved outcomes with ART. The benefit appears to extend to cardiovascular disease specific outcomes, although HF is a rare outcome in these trials of younger patients. Thus, despite some toxicity, dramatic declines in clinical cardiomyopathy cases since the pre-ART era would suggest that on balance ART reduces the risk of HF. Here, we review the toxicities and potential benefits of specific ART drugs and drug-classes.
Nucleoside Reverse Transcriptase Inhibitors
The cardiotoxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is thought to be primarily due to the effect on mitochondrial function. The heart is highly dependent on mitochondria to efficiently generate adenosine triphosphate and to perform other metabolic functions, and is thus highly sensitive to mitochondrial toxic drugs. Commercially licensed NRTIs are associated with varying degrees of mitochondrial dysfunction in the following order of toxicity: zalcitabine (ddC) > didanosine (ddI) > stavudine (d4T) > zidovudine (AZT). Other NRTIs, such as tenofovir, abacavir, lamivudine, and emtricitabine, are associated with little to no mitochondrial toxicity. Accordingly, the mitochondrial toxic NRTIs have been associated with clinically significant myopathy, cardiomyopathy, lipodystrophy, and other complications in animal models and humans. More specifically, AZT and ddC cause mitochondrial enlargement, disruption of crystal architecture, and decreased mitochondrial DNA in cardiomyocytes leading to cardiomyopathy. Currently, the clinical use of these drugs is extremely limited. They may be encountered among patients with highly resistant virus, or among patients who are resistant to changing an ART regimen that has been working for many years.
Other mechanisms besides mitochondrial toxicity are relevant to HF risk profile of certain NRTIs, and this is particularly relevant for two of the most widely prescribed NRTIs: abacavir and tenofovir. Recent use of abacavir and didanosine have been associated with MI risk in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with relative rates of MI of 1.90 (95% CI 1.47–2.45) and 1.49 (95% CI 1.14–1.95), respectively, compared to those without recent use of those drugs. Subsequent observational analyses from this cohort and others appear to confirm the association with abacavir, but a meta-analysis of randomized trial evidence showed no effect of abacavir on MI. Although there is some debate, most experts advise avoidance of abacavir among those with high cardiovascular risk. On the other hand, cumulative tenofovir disoproxil fumarate (TDF) use was recently associated with a 21% lower risk of HF per year of use among US veterans. The finding was consistent across a number of different statistical models, patient subgroups, and sensitivity analyses, and merits future investigation into the mechanism. It is unknown whether the benefit will be seen among users of the newer generation tenofovir alafenamide, which has been associated with lower rates of nephrotoxicity compared to TDF.
Protease Inhibitors
PIs are now widely known for their adverse metabolic effects and drug interactions with commonly prescribed cardiovascular disease therapies such as statins. Older PIs have been associated with risk of MI, but this may not be true for atazanavir, a newer generation PI. PIs may also contribute to HF risk through alterations in glucose metabolism in the heart; although few studies have been powered to test the effect of ART drugs and drug classes on HF outcomes in HIV. There are no long-term data available on the risk of HF due to therapies such as integrase inhibitors.
Cardiac Effects of Antiretroviral Therapy in Children
Cardiac toxicity of ART remains an important consideration for children who are at potentially greater risk of toxicity due to a lifetime of exposure. Fetuses exposed to ART in utero tend have greater chamber and wall size, and more pericardial effusions compared with fetuses not exposed to ART. In addition, there is in utero evidence of worse systolic (by mitral systolic annular peak velocity) and diastolic (by isovolumic relaxation time) function. In one study, zidovudine use was the only factor significantly associated with these structural cardiac changes. Furthermore, many children—especially in high-prevalence regions of SSA—are exposed to ART in utero, even if they are not ultimately infected with HIV (i.e., HIV-exposed uninfected). HIV-exposed uninfected children appear to have subtly reduced LV mass and mildly reduced diastolic function but no significant differences in systolic function. For children who are infected with HIV, treatment with modern combination ART is associated with better LV structure and function by echo over time compared to single-drug regimens or no ART.
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