Anu Elizabeth Abraham, MD and Sheilah Bernard, MD

1. How have the cardiac manifestations of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) changed over the years?

    Cardiac manifestations of AIDS up until the early 1990s would not infrequently include pericardial disease, myocarditis, dilated and infiltrative cardiomyopathy, pulmonary disease with pulmonary hypertension, arrhythmias, and marantic or infectious endocarditis. Because patients tended to be younger, very little coronary atherosclerosis was noted. As highly active antiretroviral therapy (HAART) has emerged as an effective treatment for HIV, HIV has transformed from a fatal infection to a chronically managed disease.

    Cardiovascular disease is now the second most common cause of death in antiretroviral therapy (ART)-treated patients worldwide. HIV patients have a higher incidence of traditional cardiovascular risk factors, such as male gender, smoking, advanced age, glucose intolerance, insulin resistance, and dyslipidemia. They also have a higher incidence of nontraditional cardiac risk factors, including polysubstance abuse, lifestyle choices, immune dysregulation, and effects of ART.

    Over the next decades, children born with vertically transmitted HIV will survive to adulthood, with attendant cardiac complications from chronic inflammation, drug therapy, and immunosuppression.

2. What are HIV-related cardiac complications?

    Since the advent of ART in the 1990s, the incidence of HIV-related complications has significantly decreased, but cardiac complications include:

3. How common is pericardial effusion?

    Pericardial effusion is an incidental finding in about 11% of HIV-infected patients and up to 30% of AIDS patients with CD4+ T cell counts (CD4 counts) less than 400 cells/μL who have cardiac echocardiograms. The effusions are typically small and patients are usually asymptomatic. The presence of an effusion is an independent predictor of mortality in these patients. It only rarely progresses to tamponade, which is more common in end-stage, cachectic patients who develop elevated intrapericardial pressures caused by low right-sided filling pressures (low-pressure tamponade). The effusion is mostly transudative. Mycobacterium tuberculosis and M. avium are the principal causes of infectious pericarditis. Rarely, Kaposi sarcoma can bleed into the pericardium, causing tamponade physiology.

4. Is HIV myocarditis or cardiomyopathy common?

    In different series, one-third to one-half of patients in the pre-HAART era (or where HAART therapy was not available) dying of AIDS had lymphocytic infiltration at autopsy. Of these patients, 80% had no other pathogens identified. Additionally, up to 10% of endomyocardial specimens in HIV patients have evidence of other infections (e.g., Coxsackie B, Epstein-Barr virus, adenovirus, and cytomegalovirus).

    The initiation of HAART therapy has significantly reduced the incidence of cardiomyopathy, likely due to both reduction in HIV itself and reduction in the presence of opportunistic infections.

    HIV is thought to cause myocarditis from direct action of HIV on myocytes or indirectly through toxins. Patients with HIV and cardiomyopathy have a worse prognosis than those with cardiomyopathy due to other causes of cardiomyopathy (Fig. 46-1). Heart failure caused by HIV-associated left ventricular dysfunction is most commonly found in patients with the lowest CD4 counts and is a marker of poor prognosis. Despite the association of HIV and myocarditis and cardiomyopathy, in patients with HIV and with cardiomyopathy, other possible causes of heart failure (e.g., ischemic, valvular, and toxin-related heart failure) should be excluded.

5. How is HIV cardiomyopathy treated?

    A standard heart failure regimen should be used as tolerated, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta-adrenergic blocking agents (β-blockers), aldosterone antagonists, diuretics for volume overload, and digoxin for advanced disease. Additionally, nutritional and electrolyte deficiencies should be replenished.

6. Why is infective valvular endocarditis a rarity in AIDS?

    Valvular devastation usually seen with bacterial infections does not occur in HIV patients because of impairment of autoimmune response. Patients who have hemodynamically significant valvular disease warrant valve replacement if their HIV is well controlled. Fulminant infective endocarditis can occur in late AIDS with high mortality. Patients with AIDS rarely will develop marantic (noninfectious) endocarditis, with large, friable, sterile thrombotic vegetations. These can be associated with disseminated intravascular coagulation (DIC) and systemic embolization.

7. What malignancies can affect the heart in AIDS/HIV?

    Kaposi sarcoma is associated with herpesvirus 8 in homosexual AIDS patients. This tumor is often found in the subepicardial fat around surface coronary arteries. About 25% of AIDS patients with systemic Kaposi sarcoma had incidental cardiac involvement, with death as a result of underlying opportunistic infections. Non-Hodgkin lymphoma is more common in HIV-positive patients, with a poor prognosis. Leiomyosarcoma is rarely associated with Epstein-Barr virus in AIDS patients.

8. Can nutritional deficiencies be responsible for HIV myopathy?

    HIV infection leads to immune impairment and malnutrition, which can contribute to rapid progression to AIDS. Malnutrition can be linked to poor appetite (perhaps due to inability to eat foods due to infections such as oral thrush or esophagitis) and poor absorption in the gastrointestinal (GI) tract. Nutritional deficiencies are seen in late-stage, untreated AIDS. This may ultimately lead to electrolyte losses. Selenium deficiency increases the virulence of Coxsackie virus to cardiac tissue and is reversed by replenishing selenium. Low levels of B₁₂, carnitine, growth hormone, and thyroxine (T₄) can cause a reversible myopathy.

9. How common is HIV-associated pulmonary arterial hypertension (PAH)?

    The prevalence of PAH was estimated to be 0.5% of HIV-infected patients in 1997, before the advent of ART. Since that time, despite the increase of ART, the prevalence of PAH remains stable, based on more recent studies. PAH can be diagnosed in any stage and is not thought to be related to CD4 count. A recent case study showed median survival of 3.6 years and 84% of patients survived to 1 year. On histology, HIV-infected PAH patients do not differ from uninfected patients and exhibit concentric laminar fibrosis, medial hypertrophy, and plexiform lesions. It is not known whether HIV infects the pulmonary vascular system, but HIV proteins can lead to abnormal endothelial function. Therapy includes those used for primary pulmonary hypertension, including intravenous epoprostenol and endothelin antagonists. The benefit of ART on the progression of PAH is still controversial.

10. How should HIV patients be screened for coronary artery disease?

    The Framingham Risk Score (age, gender, blood pressure, total cholesterol, high-density lipoprotein [HDL], diabetes, and smoking) has been applied to HIV patients on therapy and reasonably predicts coronary artery disease (CAD) events. It has been shown to underestimate the risk of cardiovascular disease (CVD) in HIV patients who are also smokers. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) group has tried to incorporate HIV-specific risks (such as exposure to protease inhibitors or PIs) in addition to traditional risk factors, but these risk models are not yet validated. The Infectious Disease Society of America (IDSA) recommends fasting lipid panels and fasting glucose levels before and 4 to 6 weeks after initiation of HAART. Use of diagnostic stress testing is performed in these patients according to the current guidelines for the general population. Carotid intimal medial thickening, coronary artery calcium scores, highly sensitive C-reactive protein (CRP), adiponectin and other markers of CVD are also being investigated in the HIV patient population to predict early disease.

11. What is the pathology of accelerated atherosclerosis in HIV patients?

    Histopathologically, atherosclerosis in HIV patients is distinct from that in noninfected patients. Based on autopsy studies, these lesions have features of both atherosclerosis and transplant vasculopathy. These lesions reveal diffuse circumferential involvement with smooth muscle cell proliferation and elastic fibers, leading to endoluminal projections.

12. What is the pathophysiology of accelerated atherosclerosis in HIV patients?

    The relative risk of myocardial infarction (MI) in HIV patients compared to non-HIV patients is increased by 1.7- to 1.8-fold, and may increase further with increasing age. There is a complex relationship between HIV-related side effects, ART-related side effects, and traditional risk factors that result in a higher prevalence of atherosclerotic disease in HIV patients. ART is associated with increased visceral adiposity, insulin resistance, and abnormal glucose tolerance, therefore increasing the risk of CVD. Traditional risk factors such as hypertension (which may be associated with ART use) and tobacco use are highly prevalent in this population. HIV infection is known to lead to a state of increased inflammation, which has been identified as a factor for early atherosclerosis. HIV infection directly leads to endothelial dysfunction and HIV envelope proteins have been linked to higher levels of endothelin-1 concentrations. In fact, the level of viremia and CD4 counts are predictive of cardiovascular disease.

13. What dyslipidemias occur with HIV disease?

    Before therapy, in early HIV infection, triglycerides increase and HDL and low-density lipoprotein (LDL) levels decline. After ART is initiated, LDL and total cholesterol levels appear to increase. This may be due to general improvement in health or due to medication effects. The prevalence of hyperlipidemia in HIV patients is between 28% and 80% in various studies.

14. What are the effects of ART on cardiovascular risk?

    Many ARTs have been associated with dyslipidemia (Table 46-1). Protease inhibitors (PIs) are associated with a small to moderate increase in total cholesterol and LDL and a significant rise in triglyceride levels. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with dyslipidemia, but less so than are PIs. They typically result in a small increase in total cholesterol, LDL, as well as HDL (which is potentially beneficial). In general, the nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with insulin resistance and the lipid profile changes are less severe than with PIs and NNRTIs. While PIs and NNRTIs have well-established effects on lipid profiles, the new agents such as fusion inhibitors, chemokine inhibitors, or integrase inhibitors have not shown these changes.

15. What is acquired lipodystrophy?

    This is a disorder characterized by selective loss of adipose tissue from subcutaneous areas of the face, arms, and legs, with redistribution to the posterior neck (buffalo hump) and visceral abdomen. Visceral adiposity is associated with increased inflammatory markers. Lipodystrophy is also associated with attendant development of diabetes mellitus (DM), dyslipidemia, hepatic steatosis, hypertension, and acanthosis nigricans. It can occur in 20% to 40% of HIV patients taking PIs for more than 1 to 2 years. Exercise, with or without treatment with metformin, has been reported to improve body composition in patients with lipodystrophy.

16. How are these dyslipidemias treated?

    In an effort to improve cardiovascular risk profiles, treatment of dyslipidemia should also include attempts to improve diet, increase exercise, lose weight, promote smoking cessation, and manage hypertension and diabetes. Physicians can consider transitioning to a different class of antiretroviral drugs, such as replacing PIs with NNRTIs and/or NRTIs if the new regimen has the same ability to suppress viral replication. Several statins are degraded by cytochrome P-450 isoform 3A4 (CYP3A4), which is inhibited by PIs. Therefore, simvastatin is contraindicated with PI use, but others, such as atorvastatin and rosuvastatin, are less affected and still used to treat HIV-associated dyslipidemia. Pravastatin and ezetimibe, which are not metabolized by the cytochrome P-450 pathway, are also safe to use in this setting. Niacin has been shown to reduce triglyceride levels, but also increases insulin resistance. As a result, its benefit is unclear. Fish oil (omega-3 fatty acids) is well tolerated and has been shown to decrease triglyceride levels. Unfortunately, some studies have also noted an increase in LDL, so its overall clinical benefit is unclear.

17. Can cardiothoracic surgery be performed safely in HIV patients?

    HIV patients can undergo cardiothoracic surgery (e.g., valve replacement, coronary artery bypass grafting [CABG]) with similar mortality to non-HIV patients, but with slightly higher morbidity (as a result of sepsis, sternal infection, bleeding, prolonged intubation, and readmission). There have not been large surgical series, but smaller studies have shown 81% event-free survival at 3 years for HIV patients undergoing CABG. CD4 counts do not drop postoperatively. Needlestick injuries of care givers remain a health care issue with all HIV patients.

18. What oral hypoglycemics are recommended?

    Metformin is an attractive agent to use for glucose control because it reduces appetite, induces weight loss, and treats steatosis. The nucleoside analog abacavir and metformin can both cause lactic acidosis, so this combination of agents should be used cautiously. Insulin is used for more difficult diabetes management.

19. What other drugs used in AIDS/HIV treatment can have cardiac complications?

    The nucleoside analogue abacavir can cause hypotension and lactic acidosis, and zidovudine can cause skeletal myopathy. The antiparasitic pentamidine, antiviral ganciclovir, and antibiotic erythromycin have been associated with acquired QT prolongation and torsades de pointes (polymorphic ventricular tachycardia). Chemotherapeutic agents, such as vincristine, interferon, interleukin, and doxorubicin, can lead to cardiomyopathy.

20. What is the risk of mother-to-child transmission (MTCT) of HIV?

    Worldwide, approximately 3 million infants are born to mothers infected with HIV per year, but only 530,000 infants develop HIV per year. Of these new pediatric infections, 95% occur in sub-Saharan Africa or in South- and Southeast Asia. MTCT can occur during gestation, intrapartum (during delivery), or postpartum via breast feeding. Maternal HIV load is a strong predictor of MTCT. In 1994, a randomized controlled trial showed reduction in MTCT rates from 25.5% to 8.3% with zidovudine therapy of mothers during pregnancy and during delivery. Therapy was also provided to infants within 24 to 48 hours of delivery. With ART therapy and avoidance of breast feeding, overall MTCT rates in developed countries have decreased to 2%.

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