CHAPTER 102: HIV/AIDS AND THE CARDIOVASCULAR SYSTEM

The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has become an important clinical entity in cardiovascular medicine. As a result of behavioral changes and improved therapy, HIV/AIDS patients are surviving longer and the prevalence of cardiovascular diseases in this population now more closely mirrors that of the non-HIV/AIDS population. Key factors in the development of cardiovascular disease in HIV/AIDS are the cardiovascular effects of HIV/AIDS and side effects of therapy, such as highly active antiretroviral therapy (HAART), and it is important to be aware of them.

AIDS was first recognized in 1981 and is caused by the human immunodeficiency virus HIV-1.¹ HIV-2 causes a similar illness to HIV-1, but is less aggressive and has so far been observed mostly in western Africa. HIV-1 is acquired through exposure to infected body fluids, particularly blood and semen. The commonest modes of spread are sexual (heterosexual or men who have sex with men [MSM]), parenteral (blood or blood product recipients, injection drug users, and occupational exposure to contaminated products), and vertical transmission (mother to fetus).

HIV/AIDS is now the second leading cause of death in the world, with a continuing global prevalence of 0.8%.² According to the World Health Organization, 35 million people are living with HIV/AIDS, with 2 million new infections and 1.2 million AIDS-related deaths reported in 2014.² The vast majority of deaths have occurred in sub-Saharan Africa, where over 13 million children have been orphaned and approximately two-thirds of the global HIV/AIDS burden exists.³ More than 2.4 million people have been infected by HIV in North America and Europe, although many are still unaware of their infectious status.⁴ Prevention strategies may have helped reduce HIV prevalence rates in some countries where HIV infection may be on the decline,⁵ and it is estimated that up to 15 million people worldwide are now accessing antiretroviral therapy.^2,5

Many cultural and social factors impact demographic patterns of HIV/AIDS.^6,7 In the United States and northern Europe, HIV had predominantly involved MSM, although heterosexual transmission now is the dominant route of infection.^8,9,10,11,12 In Southern and Eastern Europe, Vietnam, Malaysia, Northeast India, and China the incidence has been greatest in injection drug users. However, in Africa, the Caribbean, and much of Southeast Asia, the dominant route of transmission has been heterosexual or vertical from mother to child, reflecting the high global proportion of relatively young women with HIV.¹³

HIV-1 is a single-stranded RNA retrovirus from the Lentivirus family that invades cells containing specific membrane receptors and incorporates a DNA copy of itself into the host’s genome. Immune deficiency is the result of viral and immune-mediated destruction of CD4⁺ lymphocytes caused by continuous high-level HIV-1 replication. The reduction in the number of CD4⁺ cells circulating in peripheral blood is tightly correlated with the plasma viral load. Both viral load and CD4⁺ count can be monitored from peripheral blood samples and are used as measures of disease progression and therapeutic efficacy. Virus-specific CD8 cytotoxic T-cell lymphocytes develop rapidly after infection and can lyse infected CD4⁺ cells. They play a crucial role in controlling HIV-1 replication after infection and may therefore determine the rate of disease progression.

Any depletion in CD4⁺ cells renders the body susceptible to opportunistic infections and oncogenic virus-related tumors. The predominant opportunistic infections seen in HIV-1 disease are caused by intracellular parasites (eg, Mycobacterium tuberculosis) or pathogens that are more susceptible to cell-mediated, rather than antibody-mediated, immune responses. After the initial infection there is a dormant period before symptoms and disease supervenes (Fig. 102–1). In the absence of antiretroviral therapy (HAART), the average length of life after infection is approximately 10 years.¹⁴ By contrast, HAART can essentially eliminate detectable HIV-1 viremia and transform the patients' prognosis to one of a chronic disease with associated organ-specific illnesses that require specialized treatment.

Primary infection is usually established 2 to 6 weeks after exposure.¹⁵ Most (70% to 80%) patients experience a self-limiting illness, similar to infectious mononucleosis, characterized by fever, fatigue, pharyngitis, lymphadenopathy, and maculopapular rash. In many patients the illness is mild and only identified by retrospective enquiry at later presentation. Over 95% of patients seroconvert (ie, become serologically positive for HIV-1 infection) within 6 months. This usually coincides with a surge in plasma HIV-1 RNA levels to > 1 million copies/mL (peak between 4 and 8 weeks following exposure), and a fall in the CD4⁺ count to 300–400 cells/mm³. Symptomatic recovery is accompanied by a rise in the CD4⁺ count and a fall in viral load. Nevertheless, the CD4⁺ count rarely recovers to its original value (see Fig. 102–1).

Classification of HIV/AIDS

A simple Centers for Disease Control and Prevention (CDC) classification has been used to describe the phases of disease (Table 102–1). With regard to cardiovascular diseases in HIV/AIDS, premature coronary artery disease (CAD), infective endocarditis (IE), and problems associated with intravenous drug abuse may supervene at any time. Pericardial effusion and cardiomyopathy (CM) are more frequently described in late-stage (CDC Category C) disease, and may have been more prevalent before HAART. The classification is noted on the CDC website and updated occasionally in Morbidity and Mortality Weekly Report (MMWR).

Asymptomatic Infection (CDC Category A Disease)

Viral replication takes place in the lymphoid tissue throughout this stage; there is sustained viremia and the CD4⁺ count falls steadily (typically by between 50 and 150 cells/year). Although there may be persistent generalized lymphadenopathy, the patient remains well.

Mild Symptomatic Disease (CDC Category B Disease)

The median interval from infection to the development of symptoms is around 7 to 10 years. A variety of diseases known as AIDS-related complex conditions (eg, oral hairy leukoplakia, weight loss, night sweats, and chronic diarrhea) may supervene, but are not AIDS-defining.

Acquired Immunodeficiency Syndrome (CDC Category C Disease)

HIV/AIDS is defined by the development of one or more specific opportunistic infections, tumors, and other conditions. These include esophageal candidiasis, cytomegalovirus (CMV) retinitis, pulmonary or extra-pulmonary tuberculosis, Kaposi sarcoma (KS), and HIV-1 associated dementia. Most forms of HIV/AIDS CM and pericardial effusion occur at this stage.

Early in the HIV/AIDS Epidemic: The Era Before HAART

Early in the epidemic, and before the significant clinical advances from HAART, it was suggested that more than 6% of HIV/AIDS patients had cardiovascular diseases with the heart as the principal target.¹⁶ Pathological studies revealed nonbacterial thrombotic endocarditis (NBTE), CM and myocarditis, pericarditis and pericardial effusions, and metastatic neoplasms (predominantly KS and lymphoma).^{16,17,18,19,20} Many of these pathological lesions were mild and HIV/AIDS heart disease probably caused symptoms in fewer than 10% and death in fewer than 2% of all patients with HIV/AIDS. Cardiovascular mortality and morbidity was primarily caused by the overwhelming problems of immune dysfunction and opportunistic infection that were so prevalent in the pre-HAART era. The common cardiovascular manifestations of HIV-1 infection are listed in Table 102–2. The interaction between environmental stresses, therapeutic toxicities, and the increased longevity afforded by the efficacy of HAART have together changed the spectrum of cardiovascular disease in HIV/AIDS (Fig. 102–2).

Contemporary Cardiovascular Disease in HIV/AIDS

Some of the cardiovascular illnesses seen early in the epidemic persist in contemporary patient cohorts, but some are more prominent in resource-limited settings. A recent meta-analysis of patients treated with HAART demonstrated left ventricular (LV) systolic dysfunction in 8.3% and diastolic dysfunction in 11% in minimally symptomatic patients, and the risk of heart failure appears doubled for HIV patients compared to risk factor controls without infection.^21,22,23 Ischemic CM may be increasing in HIV/AIDS, as suggested by higher rates of CAD hospitalizations in patients with HIV/AIDS compared to those without HIV/AIDS.^24,25,26

Tuberculous pericarditis remains an important cardiac manifestation of the disease, particularly in Africa.^23,27,28,29 In the developed world with improved access to HAART, cardiovascular, pulmonary, and renal diseases predominate, bolstered by increased survival from HIV/AIDS and opportunistic infections. Atherosclerotic disease, which was rarely noted in the early days of the epidemic, is now more common and clinically relevant in the care of HIV/AIDS patients.^24,30

It should be recognized clearly that survival with HIV/AIDS improved because of HAART combinations that frequently utilize two nucleoside reverse transcriptase inhibitors (NRTIs) and one or two protease inhibitors (PIs). Newer HAART preparations additionally utilize an integrase inhibitor and a CYP3A inhibitor in place of a PI in a single tablet. Other regimes may include non-nucleoside reverse transcriptase inhibitors (NNRTIs).³¹ Such combinations prevent or attenuate HIV-1 replication through a “multiple hit” approach to infection analogous to anti-tuberculous therapy and to some antineoplastic therapies. The success of HAART has resulted in a concomitant increase in the roles of age-related illnesses in patients with HIV/AIDS that have no direct connection to the retroviral infection. This subset of chronic diseases, like cardiovascular diseases, with prevalent comorbidities, is termed HANA (HIV-associated non-AIDS illnesses).^32,33,34

Some HANA conditions may be due (in part) to HAART-induced metabolic problems (particularly insulin resistance and hyperlipidemia), independent cardiovascular risk factors (like smoking and preexisting lipid abnormalities in HIV/AIDS), or side effects from HIV/AIDS therapeutics (see below).³⁵ HAART has, therefore, changed the pattern of disease in developed countries where premature CAD, metabolic syndrome, and other manifestations of atherosclerosis are emerging as key cardiovascular disorders in the HIV/AIDS patient.

It seems likely that as survival increases with improved therapy, more HIV/AIDS patients will be seen by cardiologists, and indeed the number of reports of cardiovascular problems in HIV/AIDS will grow.^27,36,37,38 Screening for cardiovascular disease in HIV/AIDS patients combines established principles with an evolving understanding of HIV/AIDS-specific pathophysiology and pharmacology. Known risk factors still contribute to cardiovascular disease in HIV/AIDS, and as such all HIV/AIDS patients should be subjected to cardiovascular risk stratification and periodic monitoring.³⁹

Although it may have been possible to overlook the importance of blood pressure control and lipid management in this population,⁴⁰ traditional cardiovascular risk factors (dyslipidemia, insulin resistance, hypertension, smoking, sedentary lifestyle, weight, and family history) should routinely be assessed as part of the general care of HIV/AIDS patients. A fasting lipid panel is recommended when enrolling in HIV/AIDS care and 1 to 3 months after HAART initiation,^41,42,43 and hemoglobin A1_c is a useful marker of metabolic derangement after starting HAART.⁴³

Heart disease may be overlooked in HIV/AIDS patients because symptoms of breathlessness, fatigue, and poor exercise tolerance are frequently ascribed to other conditions associated with HIV infection.³⁶ As such, electrocardiography should be performed routinely to confirm sinus rhythm and allow assessment of the QT interval. The electrocardiogram (ECG) may also alert the cardiologist to the possibility of CAD (Q-waves and ST/T-wave changes) or LV hypertrophy. Echocardiographic assessment of HIV/AIDS patients is extremely useful and can be used easily to identify those cardiac conditions common in HIV/AIDS patients that may be associated with a poor outcome, including pericardial effusion,^23,29 LV systolic dysfunction, heart muscle disease (cardiomyopathy), and intracardiac masses.^36,44 Echocardiography may also provide useful information on the appearance of the right ventricle, provide an indirect assessment of pulmonary pressures, and reveal regional wall-motion abnormalities potentially suggestive of CAD.

A history of palpitation or near syncope may indicate the need for ambulatory ECG monitoring, as with Holter monitoring.⁴⁵ Functional stress testing may be useful for the investigation of anginal chest pain, while computed tomography (CT) coronary angiography or cardiac magnetic resonance (CMR) may be used in specific clinical circumstances.⁴⁶

It has been suggested that any HIV/AIDS patient with traditional risk factors for the development of, or who demonstrates any potential clinical manifestation of, cardiovascular disease should have a baseline echocardiogram performed and, thereafter, serial echocardiography performed every 1 to 2 years (Table 102–3);⁴⁷ unfortunately, logistical limitations make it unlikely that these goals can be achieved in the developing world. Similarly, it may be justifiable to perform a baseline echocardiographic study at the time of diagnosis of HIV/AIDS with annual to biannual examination of select asymptomatic patients (see Table 102–3).⁴⁸ Clearly, more aggressive monitoring may be guided by the cardiologist on discovery of abnormalities or in those patients with significant, potentially cardiotropic viral infections or unexplained pulmonary symptoms.

Pericardial effusion and pericarditis were the commonest cardiac abnormalities found in early HIV/AIDS autopsy studies and remain a significant problem in Africa, where the largest number of HIV/AIDS patients are found.^{27, 29} Pericardial effusion is still found in up to 40% of patients, particularly in association with generalized fluid retention and advanced disease, and pulmonary hypertension.¹⁹ Small effusions are common in patients with heart failure or malignant infiltration, but cardiac tamponade is rare. The finding of new cardiomegaly on chest radiography should prompt early echocardiographic assessment to evaluate for pericardial effusion.⁴⁹

Clinically significant pericardial effusions are usually caused by viral or bacterial infection or malignant infiltration, particularly with KS or non-Hodgkin lymphoma. In Africa, pericardial effusion itself is suggestive of HIV-1 infection, and up to 72% of African patients with serosanguinous effusions have been found to be infected with HIV-1.^27,28,29 Pericarditis caused by M. tuberculosis or M. avium-intracellulare infection remains a pressing problem in Africa. Other unusual pathogens, including Nocardia asteroides, herpes simplex virus, and CMV, should be considered and appropriate antituberculous or antiviral therapies may be helpful. Culture of pericardial biopsy or fluid from symptomatic effusions may also be also useful in identifying treatable opportunistic infections or malignancy.

Surgical intervention is not always beneficial in AIDS patients with large pericardial effusions, and there are no data are available on the long-term outcome of such measures. Pericardiocentesis and pericardiectomy was used to treat a Staphylococcus aureus pericardial tamponade in an HIV/AIDS drug user, who remained well for more than 5 years.^50,51

Myocarditis

Numerous pathological studies confirmed the presence of varying histological patterns of lymphocytic myocarditis in HIV/AIDS patients, although many do not fulfill the Dallas criteria formulated to secure the histopathological diagnosis.^19,52 Clinical correlation with myocarditis has been described in HIV/AIDS studies, and opportunistic infections were prominent comorbid conditions.⁵³ Interstitial mononuclear infiltrates have also been reported in other forms of CM (and non-CM), which further confounds diagnosis of authentic myocarditis.⁵⁴ The apparent difference in the prevalence of myocarditis in different studies may relate to clinical factors, sampling errors, and HAART. As such, estimates of the prevalence of myocarditis in HIV/AIDS varies from 53% in the pre-HAART era to much lower levels today in the developed world, with the conditions remaining prevalent and problematic in the developing world.^27,55 Of note, it is relatively uncommon for HIV/AIDS patients in the developed world to present initially with cardiac manifestations of HIV/AIDS, but it can be seen and merits consideration (Fig. 102–3).

Myocarditis may be precipitated by a variety of viral infections, and the inflammatory reaction can progress after the viral infection has apparently resolved. An immune reaction, either to viral antigen or to altered myocardial protein, may precipitate myocardial necrosis and inflammatory cell infiltration.⁵⁶ However, simple histopathological methods alone may be insufficient to exclude the diagnosis of myocarditis in HIV/AIDS patients. Infiltrating CD8 and CD45 lymphocytes have been found in association with increased major histocompatibility complex (MHC) class I antigen expression in histologically normal endomyocardial biopsies from HIV/AIDS with cardiac failure.⁵⁷

It remains possible that a subgroup of HIV/AIDS patients may have immune-mediated heart disease despite pathologically nondiagnostic biopsies. An inflammatory process remains the likeliest substrate for the development of cardiac dysfunction, but this is not proven. There are several hypotheses regarding the etiology of myocarditis in HIV/AIDS including:

1. Primary HIV-1 myocarditis

2. Secondary HIV-1 myocarditis

3. Opportunistic infection

Primary HIV-1 Infection of the Myocardium

Despite histopathological evidence supporting a myocardial inflammatory component in HIV/AIDS, HIV-1 has neither been universally accepted nor unambiguously proven as a causative agent of myocarditis. HIV-1 gains entry into cells through binding between its envelope glycoprotein group 120 and CD4⁺ receptors, which are found on T4 (helper) lymphocytes and some other cell types. Although HIV-1 can infect monocytes/macrophages and myocardial interstitial cells, evidence proving that HIV-1 can infect human cardiac myocytes is less clear.

Some reports of cardiac infection by HIV-1 utilized in situ hybridization (ISH), which did not require extraction of target sequences, and thus preserved the histological architecture.⁵⁸ However, ISH is limited in defining the responsible cell that undergoes hybridization with HIV-1 probes. That signal could be masked by the dense silver reaction that occurs as part of that technique. Accordingly, precise localization and definite assignment of the hybridization signal to the cardiac myocyte was not possible. Cell culture and polymerase chain reaction (PCR) were equally limited, as such samples could easily be contaminated by the patient’s own infected blood cells where a single virion contaminant (eg, from an infected interstitial cell) could be a contaminant and confuse interpretation. Similarly, examination of hearts from nonhuman primates (macaques) infected with simian immunodeficiency virus (SIV) has been accomplished using such methods. Those studies confirmed that SIV infected the cardiac monocytes rather than actual myocytes.⁵⁹

HIV-1 gene sequences were detected by PCR in microdissected endomyocardial biopsies from HIV-1 positive patients, some of whom had cardiac symptoms.⁶⁰ HIV-1 has also been shown to gain entry into the human fetal cardiac myocyte by ingestion through a specific Fc receptor, and it remains possible that this or other unidentified mechanisms may promote HIV-1 entry into the myocyte and facilitates a primary HIV-1 myocarditis.⁶¹ It should be noted that such cardiomyocyte infection was only described before extensive use of HAART.

Secondary Myocarditis in HIV/AIDS

With respect to the pathogenesis of myocarditis, analogies may be made between HIV/AIDS immune responses and those responses that cause inflammatory damage in other infections. For example, in Chagas CM, uninfected cardiac myocytes are damaged by the host response to Trypanosoma cruzi. Interstitial lymphocytes and macrophages may form contact with myocytes, causing a focal loss of basement membrane through a local reaction. Proteolytic enzymes released through HIV-1 replication in the interstitium could also damage myocytes. Such “innocent bystander destruction” may be particularly relevant to diseases of the myocardium here.⁶²

The HIV-1 envelope glycoprotein group 120 can induce tumor necrosis factor (TNF)-α expression from macrophages and has been shown to enhance interleukin (IL)-1β induced nitric oxide production in neonatal rat cardiac myocytes.⁶³ Cytokine IL-6, which has some effect on immune response and viral replication in murine myocarditis models, has been found in excess in a small number of HIV/AIDS patients with biopsy-proven myocarditis.⁶⁴ Therefore, just as cytokines may have a role in the development of congestive heart failure in absence of HIV/AIDS, they also may be important in HIV/AIDS myocarditis and cardiomyopathy.

Myocardial Opportunistic Infections in HIV/AIDS

Autopsy has confirmed a variety of opportunistic infections of the myocardium in patients with AIDS. Infectious agents included Toxoplasma gondii in the hearts of adults and children, Cryptococcus species, CMV, Candida species, Pneumocystis carinii, Microsporidium species, Histoplasma capsulatum, atypical mycobacteria, and Aspergillus species involving the myocardium. Most of these have been part of a disseminated infection and are infrequently associated with localized myocarditis.¹⁷ Acute Chagas myocarditis in HIV/AIDS also has been reported and may be associated with a more frequent rate of myocarditis in up to 30% of cases in HIV/AIDS patients.⁶⁵

Clinical Features of Myocarditis in HIV/AIDS

Myocarditis can be diagnosed clinically based on symptoms and physical findings, although this is often difficult in the HIV/AIDS patient. The symptoms are protean and include fatigue, dyspnea, and pleuritic chest pain, which may wrongly be ascribed to other conditions. The finding of an unexplained tachycardia, third heart sound, or a friction rub should alert the physician to the possibility of the myocarditis and guide investigation accordingly.

The ECG may be helpful, possibly demonstrating nonspecific conduction defects, repolarization abnormalities and ST–T wave changes. The chest x-ray may be normal or suggest cardiac enlargement with pulmonary congestion. Echocardiography is usually nondiagnostic, but can show hyperdynamic LV function in HIV-1 positive children with myocarditis or occasionally LV dyskinesia in adult patients.⁶⁶ The utility of a myocardial biopsy remains unclear, but it may be helpful in some cases to try to fully establish a diagnosis of CM or myocarditis. However, sampling errors may reduce the diagnostic yield from this invasive procedure and finding a treatable cause of biopsy-proven myocarditis is rare.

Treatment of Myocarditis in HIV/AIDS

Immunomodulatory therapy for HIV-1 patients remains largely unproven. Etanercept, a TNFα antagonist, and pentoxifylline, a TNFα inhibitor, have been used in non-HIV/AIDS patients with some success.^67,68 Intravenous immunoglobulin therapy has been used successfully in children with symptomatic HIV/AIDS CM and may be protective against the development of LV dysfunction.⁴⁸ The mode of action is not clear, but the treatment could be considered in pediatric patients with deteriorating cardiac function.

CM and LV Dysfunction in HIV/AIDS

CM as a complication of HIV/AIDS was first described in 1986 and was identified frequently thereafter in the pre-HAART era.¹⁸ The pathogenesis remains obscure, but there is overlap in clinical and pathological features of CM in HIV/AIDS and other forms of CM in uninfected individuals. An association between cardiac dysfunction and the lymphocytic myocarditis that was reported in HIV/AIDS postmortem series seems plausible, particularly in the pre-HAART era. Isolated LV dysfunction in HIV/AIDS patients may resolve spontaneously and may suggest self-limiting myocarditis.

In studies performed early in the epidemic, a cohort of 136 HIV/AIDS patients exhibited an incidence of systolic dysfunction of approximately 2% every 3 months.⁶⁹ Another showed 69 HIV/AIDS patients with an annual incidence of LV dysfunction of 18%.⁶⁴ CM in adults with HIV/AIDS was primarily seen in patients with low CD4⁺ counts.

Diastolic dysfunction in asymptomatic HIV/AIDS patients was felt to be a marker of heart disease later in life.⁷⁰ In a small cohort of well-controlled HIV-1-infected patients with a low burden of cardiovascular risk factors, the estimated incidence was 8.2/100 person-years.⁷¹

It is not unreasonable to assess the impact of and role of any comorbid conditions or risk behavior before associating HIV/AIDS as the solitary etiological factor for CM in HIV/AIDS. The differential diagnosis, as for non-HIV/AIDS patients (see Chap. 70), includes LV dysfunction secondary to ischemic heart disease, diabetes or hypertension, reactions to or side effects of therapeutic drugs, toxins, or foreign injected material, and coronary spasm secondary to toxins.⁷²

HIV/AIDS patients with evidence of LV systolic dysfunction should be assessed for micronutrient deficiency. Abnormally low levels of selenium and antioxidant vitamins in particular have been demonstrated and “oxidative stress” may be an important mechanism for cellular damage in HIV/AIDS.⁷³ Selenium deficiency is implicated in the pathogenesis of Keshan disease, a specific form of CM in China that may respond to dietary supplementation. In the same way decreased selenium content has been demonstrated in HIV/AIDS hearts and selenium replacement was associated with an improvement in LV dysfunction in a small group of HIV/AIDS patients.⁷⁴ L-Carnitine deficiency has also been described in HIV-1 patients possibly in association with cardiac symptoms, and supplementation may be advantageous.⁷⁵

Overall, the prevalence of CM in HIV/AIDS appears to be around 4.4% for CM and 6.4% for isolated LV dysfunction, and these conditions may cause symptoms in up to 5.5% of HIV/AIDS patients.⁷⁶ CM is an ominous harbinger that is associated with poor survival in HIV/AIDS compared to similar HIV/AIDS patients with structurally normal hearts. This poor outlook remains after correcting for CD4⁺ counts. A 1-year consecutive enrollment study of patients admitted to the intensive care unit in an urban center revealed 6% of admissions with HIV/AIDS had echocardiographically documented CM with a short-term mortality of 25%.⁷⁷ The pathological features of CM in untreated HIV/AIDS are less commonly seen in the developed world presently (see Fig. 102–3).

In the HAART era, a cohort of 105 well-controlled HIV/AIDS patients (median CD4⁺ count 350 cells/mm³, 78% with HIV-1 RNA levels < 500 copies/mL) reported a prevalence of CM of 2.9%.^{69,78,79,80,81} However, 1042 HIV/AIDS patients reported less cardiac involvement in HAART-treated compared to NRTI-only treated patients (1.8 vs 8.1%, P< 0.001), suggesting that toxicity from NRTIs may be a consideration.⁸² Others reported mild systolic dysfunction, but there is growing recognition of abnormalities of diastolic function.^83,84,85,86 Multiple studies demonstrated that HIV/AIDS patients with good virologic control exhibited abnormalities of diastolic function in 26% to 64% of cases.^{71,83,85,86,87} Through meta-analysis of 11 studies in the HAART era, 2242 well-controlled, asymptomatic HIV/AIDS patients were studied. A prevalence of systolic dysfunction of 8.3% and diastolic dysfunction of 43.4% was found.²¹ Risk factors for systolic dysfunction included high sensitivity C-reactive protein > 5 mg/L, tobacco use, and past myocardial infarction (MI); whereas for diastolic dysfunction, risk factors were hypertension and older age.

The growing burden of coronary artery atherosclerosis in HIV/AIDS individuals may also significantly modify the risk for an ischemic CM in HIV/AIDS. It is well known that coronary disease can predispose patients to the development of CM and the mechanisms responsible for such diseases in this population are complex, though similar in many respects to those in non-HIV/AIDS patients.⁸⁸

Mechanisms of CM in HIV/AIDS

The pathogenesis of CM in HIV/AIDS is likely multifactorial. The proposed causes include direct infection of the myocardium by the HIV-1 virus with or without histopathologically documented inflammatory myocarditis, toxicity from the medications used to treat HIV-1 infection, opportunistic infections, as well as nutritional disorders, toxins, drugs of abuse, and other factors.^{89, 90}

Autoimmunity and CM in HIV/AIDS

Autoimmune processes have been described in association with HIV/AIDS.⁹¹ The significance of some autoantibodies such as antineutrophil cytoplasmic autoantibody or antiphospholipid antibodies in HIV/AIDS remains unclear. However, the presence of such antibodies with hypergammaglobulinemia, and elevated circulating immune complexes suggests an as yet undefined autoimmune process may occur in HIV/AIDS patients.⁹²

Autoantibodies against α-myosin have been identified in HIV/AIDS patients both with CM and histologically proven active myocarditis. Antibodies to α-myosin, which are more highly cardiac specific, have also been found more frequently and in higher levels in HIV/AIDS patients with CM than in those with normal hearts.⁹³

These findings support a possible autoimmune process in the pathogenesis of HIV/AIDS CM. In experimental models, susceptible mice developed CM with anti-myosin antibodies after exposure to Coxsackie B3 infection or immunization with α-myosin. Common cardiotropic viruses could facilitate development of cardiac autoimmunity in HIV/AIDS patients by modifying myocyte surface antigens. CMV infection is a common opportunistic infection in HIV/AIDS patients, but has been described only infrequently as a cause of myocarditis.¹⁹ Although this might suggest that CMV is not strongly implicated, in situ hybridization studies have identified transcripts of CMV-specific DNA within the myocytes of HIV/AIDS patients with myocarditis and CM in the absence of typical histological features such as inclusion bodies.⁵⁷

Both HIV-1 infection per se and HAART, particularly where NRTIs are included, may have a negative impact on myocardial function.^94,95 NRTIs are key elements of HAART, and zidovudine has been implicated in the development of some cases of HIV/AIDS CM. In addition to inhibiting HIV-1 reverse transcriptase, the drug causes a dose-dependent reversible skeletal muscle myopathy by altering mitochondrial DNA replication.⁹⁶ Changes have been identified in the myocardium of rodents fed zidovudine, but have been rarely seen in patients for many reasons.⁹⁷ Recent reports suggest that mitochondrial toxicity can also be caused by nucleoside analog therapy for hepatitis B, a common coinfection in patients with HIV-1, and makes treatment of both infections potentially more complex.^{98, 99} The subcellular mechanism responsible for zidovudine CM in human HIV/AIDS remains unclear. Anecdotally, small numbers of HIV/AIDS patients developed LV dysfunction while taking the drug, which improved with its discontinuation.⁸¹ Other evidence exists. Related antiviral thymidine analogs have exhibited profound toxicity to heart and liver. This was evident in a clinical trial with fialuridine (FIAU; (1-[2-deoxy-2-fluoro-β-D-arabinofuranosyl]-5-iodouracil) where FIAU treatment caused mitochondrial pol γ inhibition, mtDNA depletion in organs, and significant morbidity and mortality.¹⁰⁰ It established the antiviral class of drugs that includes NRTIs as group with bona fide mitochondrial toxicity. Moreover, NRTI-induced mtDNA depletion was amplified by a specific pol γ mutation that occurred with patients treated with antiretrovirals for hepatitis B virus infection.^101,102 Severe toxic mitochondrial skeletal myopathy resulted from treatment with NRTI clevudine (L-FMAU; (1-[2-fluoro-5-methyl-beta, L-arabinofuranosyl] uracil)), a congener of FIAU.^98,99 Lodenosine, a purine NRTI (2′-fluoro-2′,3′-dideoxyadenosine) also caused severe mitochondrial toxicity.^103,104 The US Food and Drug Administration (FDA) warned manufacturers of nucleotide analogs for treatment of hepatitis C because of cardiac toxicity events and death that appear to be mitochondrially driven, but some investigators suggested that the toxic target may be the mitochondrial RNA polymerase.¹⁰⁵

Diagnostic Features of CM in HIV/AIDS: Echocardiographic Features

It has been suggested that any HIV-1 positive patient who is at high risk of developing, or who demonstrates any potential clinical manifestation of, cardiovascular disease should have a baseline echocardiogram performed (see Table 102–3). Thereafter, serial echocardiography should be performed every 1 to 2 years.⁴⁷ Unfortunately, logistical limitations make it unlikely that these goals can be achieved in the developing world. Similarly, it may be justifiable to perform a baseline echocardiographic study at the time of diagnosis of HIV/AIDS, with annual to biannual examination of select asymptomatic patients.⁴⁸ Clearly, more aggressive monitoring may be guided by the cardiologist on discovery of abnormalities or in those patients with significant, potentially cardiotropic viral infections or unexplained pulmonary symptoms.

Characteristic echocardiographic features of CM that occur in absence of HIV/AIDS are detailed elsewhere and (see Chapters 15 and 70) remain relevant to HIV/AIDS. The hallmark in CM associated with HIV/AIDS is global LV systolic dysfunction. Abnormalities of mitral inflow, specifically reduced early mitral peak velocity (E) and other indices of diastolic dysfunction have been noted early in the course of HIV/AIDS in patients with both reduced and preserved ejection fraction.⁷⁰ The importance of these Doppler findings requires further investigation. However, the utility of echocardiography should not be underestimated, particularly as ECG and chest x-ray may be unrewarding in these patients.

CMR imaging may also be useful in patients with reduced ejection fraction by echocardiography. The test may help exclude an ischemic etiology, but may also reveal evidence of myocardial fibrosis and increased myocardial lipid levels in asymptomatic HIV patients on HAART.⁴⁶ Prospective CMR study may further help our understanding of cardiac disease in HIV/AIDS.

Treatment of LV Dysfunction in HIV/AIDS

To date, randomized trials have not been reported to specifically examine effectiveness of current heart failure therapies in patients with HIV/AIDS. However, the prognostic significance of LV dysfunction, either in isolation or as part of a cardiomyopathic process, cannot be overlooked (Figs. 102–3 and 102–4).⁷⁶ Evidence-based treatment may prove applicable to HIV/AIDS patients to improve morbidity and mortality. Therefore, even in the presence of a seemingly poor prognosis, HIV/AIDS patients with LV dysfunction should be offered appropriate treatment.

Essentially the same armamentarium of heart failure drugs is available for use in HIV/AIDS patients with LV dysfunction as is for the non-HIV/AIDS population (see Chap. 70). Common agents such as diuretics, aldosterone antagonists, and digoxin may bring about symptomatic improvement. Angiotensin-converting enzyme inhibitors may be poorly tolerated in patients who may already have a low systemic vascular resistance.⁷⁶ The use of cardiac resynchronization has not been described in the HIV/AIDS population. Case reports document successful use of LV assist devices and orthotopic heart transplant exist, although these remain uncommon treatments in the HIV/AIDS population.^106,107,108

Right Ventricular Dysfunction and Pulmonary Hypertension in HIV/AIDS

Isolated pulmonary hypertension is a rare and serious complication in HIV/AIDS. It occurs much more frequently than primary pulmonary hypertension in the non-HIV/AIDS population, with an incidence of 0.5%, which has remained static despite advances in treatment^109,110 and still has a grave prognosis with a survival rate of 50% at 1 year.

The association between pulmonary hypertension and HIV/AIDS is unclear, but appears unrelated to CD4⁺ count or history of pulmonary infections.¹¹¹ No detectable HIV-1 DNA, RNA, or p24 antigens have been found in the lung parenchyma or vasculature of HIV/AIDS patients with pulmonary hypertension, which indirectly supports the concept of inflammation-mediated damage to the pulmonary vasculature. The condition has been linked to HIV-1 gp120-induction of inflammatory cytokines (IL-1, IL-6, endothelin-1, and platelet-derived growth factor) and alpha-1-adrenoceptor activation^111,112; and in vitro data suggest that both PIs and HIV gene products may be implicated in the development of pulmonary hypertension through downregulation of endothelial nitric oxide synthase and pulmonary vasomotor dysfunction.¹¹³

Although the mechanisms underlying pulmonary hypertension in HIV/AIDS may be different from those of primary pulmonary hypertension found in non–HIV-infected individuals, it is characterized by similar pathological lesions, including intimal fibrosis, remodeling, and plexiform lesions, and thus similar therapies may be useful.^110,114,115 Right heart catheterization may be worthwhile to determine whether patients demonstrate vasoreactivity with challenge with such agents as nitric oxide.¹¹⁶ Continuous or intermittently delivered home oxygen therapy, calcium channel antagonists, and nitric oxide therapy may be as useful for the HIV/AIDS patient as for primary pulmonary hypertension patients (see Chap. 74).

The utilization of anticoagulation may be limited by thrombocytopenia in HIV/AIDS and heightened bleeding risk. Curiously, despite concerns about possible effects on pulmonary endothelial function, HAART itself may be beneficial in affecting outcomes from pulmonary hypertension.⁵⁵ Agents such as oral bosentan, intravenous epoprostenol, subcutaneous treprostinil, or sildenafil could improve feeling of well-being without necessarily altering prognosis.^116,117 However, sildenafil and bosentan should be used with care in HIV/AIDS patients who receive heart HAART because of potential drug interactions.

HIV/AIDS can also lead to pulmonary hypertension through other pathways including congestion from LV dysfunction (WHO Class II) or through a predisposition to chronic thromboembolic disease of the pulmonary arteries (WHO Class IV).^112,118,119 Irrespective of mechanism, treatment is similar to that applied to non-HIV/AIDS patients (see Chap. 74).

Right ventricular (RV) dysfunction may occur as part of HIV/AIDS pulmonary disease and should be treated accordingly. Isolated RV dysfunction without pulmonary hypertension is of unknown significance.⁷⁶ Therefore, bronchopulmonary infections should be treated aggressively and intravenous drug use, which may result in microvascular pulmonary emboli, should be discouraged.

Endocarditis is the principal cardiac endocardial lesion identified pathologically in HIV/AIDS, and both infectious and noninfectious forms have been described.¹⁷ At present, the prevalence of noninfectious endocarditis is lower than originally reported, and HIV-1 itself has not emerged as a significant risk factor for IE. Nonetheless, these conditions remain a potential cause of significant morbidity.

Nonbacterial Thrombotic Endocarditis in HIV/AIDS

NBTE (marantic endocarditis) is a condition in which friable clumps of platelets and red blood cells adhere to the cardiac valves. Unlike bacterial endocarditis, these lesions are not infective and show no evidence of an inflammatory reaction. The pathogenesis of NBTE is not fully understood, but hypercoagulability, immune complex deposition, or specific vitamin deficiency may be important in conjunction with endothelial damage from intracardiac catheters or injected particulate matter.

Any heart valve may be affected, and multiple lesions are frequently found on different valves.¹⁷ Systemic thromboembolism is a common sequela and contributes to the morbidity and mortality associated with the condition.^120,121 NBTE was common in early postmortem series in HIV/AIDS, but is now rarely reported. The reasons for this decline are not clear, but are likely related to improvements in nutrition and HIV/AIDS therapy, including HAART.

Infective Endocarditis

The immunological abnormalities associated with HIV/AIDS render patients susceptible to bacterial infections, but despite this, there are few reports of IE in HIV/AIDS. Injection drug use, rather than HIV-1 infection, appears to be the major risk factor for IE in the HIV/AIDS population.¹²² IE has a similar presentation to non-HIV-1 patients, but runs a more fulminant course in the late stages of HIV/AIDS.¹²³ However, asymptomatic HIV-1 infection appears to have little effect on the susceptibility to, or the mortality from, IE.

As with IE in patients without HIV/AIDS but who are intravenous drug users, the most common valve involved is the tricuspid valve, although left-sided involvement is possible.¹²³ The most frequently isolated organisms are S. aureus and Streptococcus viridans, but A. fumigatus, Pseudallescheria boydii, and other forms of fungal endocarditis can occur.

Clearly there is a need for adequate bacteriological investigations in cases of suspected IE in HIV/AIDS, just as it would be for the non-HIV/AIDS population. However, an initial choice of antimicrobial treatment may have to be adjusted, particularly if fungal endocarditis is suspected. Valvular heart surgery has been performed in cases of IE in HIV/AIDS patients who are intravenous drug users, In these cases, lymphopenia that is associated with cardiopulmonary bypass was not associated with HIV/AIDS progression, although prognosis was related to other factors such as continued drug use.^124,125 Given this, the indications for surgery for IE in HIV/AIDS patients remain the same as for the non-HIV/AIDS population (see Chap. 67).

Other Valvular Heart Diseases in HIV/AIDS

It appears now that diseases of cardiac valves, like mitral stenosis and aortic stenosis, are seen more frequently than seen previously in the HIV/AIDS population. This demographic change again is possibly related to the improved survival from HAART, and the valve lesions are pathologically indistinguishable from those of non- HIV/AIDS patients (Fig. 102–5). Valvular regurgitation can complicate CM through LV dilation and mitral annular distortion, and mitral regurgitation has also been described in HIV/AIDS patients with IE.¹²⁶ This may contribute to secondary pulmonary hypertension and RV dilatation, although this more frequently occurs as part of CM, in isolation or in association with pulmonary hypertension.⁷⁶

Kaposi Sarcoma and the Heart in AIDS

KS may remain the commonest HIV/AIDS-related neoplasm that affects the heart. In contrast to the classical dermatological disease, there is often widespread and potentially fatal visceral KS involvement in HIV/AIDS. Therefore, although KS involving the heart is rare in the absence of HIV/AIDS, it is well recognized in HIV/AIDS patients. However, the prevalence of cardiac KS in HIV/AIDS appears to have decreased significantly since early reports, and appears to relate to effective HIV-1 suppression with HAART.

KS is an endothelial cell neoplasm and may infiltrate the sub-pericardial fat around coronary arteries in HIV/AIDS. The parietal pericardium or myocardium may also be involved.¹⁷ Although fatal tamponade and heart failure associated with extensive KS have been reported, cardiac KS is not usually associated with symptoms.

KS may be treated with anthracyclines, although care is required as these drugs may themselves be cardiotoxic. Liposomal-encapsulated daunorubicin has an improved pharmacokinetic profile and may therefore be preferred in HIV/AIDS patients with KS, although there are few reports of these treatments being used specifically for cardiac involvement.¹²⁷ (See Chap. 101.)

Cardiac Lymphoma in HIV/AIDS

Primary cardiac lymphoma is rare in HIV-1-negative individuals, accounting for less than 10% of all primary malignant cardiac tumors. Disseminated lymphoma may involve the myocardium more frequently, but usually only as part of widespread tumor involvement. However, both patterns of malignant cardiac involvement occur more commonly in HIV/AIDS, and although primary lymphoma involving the heart alone is uncommon in HIV/AIDS, surgical resection of a right atrial lymphoma was reported in an HIV-1-positive patient with limited short-term success.¹²⁸

Non-Hodgkin lymphoma can similarly involve the pericardium or myocardium in HIV/AIDS. Echocardiography is useful to detect any related intracavity masses or concomitant pericardial effusions. Radionuclide and magnetic resonance imaging (MRI) scans may be required to detect more diffuse cardiac involvement. In contrast to KS, lymphoma may more commonly lead to tamponade and heart failure, and conduction abnormalities, and should be considered in HIV/AIDS patients whose cardiovascular symptoms progress rapidly.

Overview

Vascular diseases, primarily arterial, have been described in HIV/AIDS, but today an emphasis on atherosclerotic disease is worthwhile. A number of clinical studies have documented an increased risk of adverse cardiovascular events in patients with HIV/AIDS who receive HAART. Although there is some variation among these different studies, the consensus is that HIV/AIDS patients have higher risk for atherosclerotic cardiovascular disease and MI than uninfected controls.^{30,129,130,131,132,133,134,135}

The Data Collection on Adverse Events of Anti-HIV-1 Drugs (D:A:D) study generated a risk equation for cardiovascular disease in HIV/AIDS while incorporating traditional risk factors (age, sex, family history of atherosclerotic disease, systolic blood pressure, smoking status, total cholesterol:high-density lipoprotein [HDL] ratio) with duration of PI therapy, given their association with atherosclerotic cardiovascular disease.^129,130 The D:A:D study offered improved estimates for the risk of developing cardiovascular disease compared to the Framingham risk score, and identified duration of HAART as a positive association factor.^129,130,136

Lipodystrophy and the Metabolic Syndrome in HIV/AIDS

Lipodystrophy is an ill-defined syndrome comprising central fat accumulation and peripheral lipoatrophy in association with dyslipidemia and insulin resistance. A variety of antiretroviral agents may be implicated in the development of this syndrome in HIV/AIDS.⁴² Patients with HIV/AIDS lipodystrophy exhibit both the metabolic and anthroprometric abnormalities that are associated with increased risk of cardiovascular diseases, and lipodystrophy in HIV/AIDS patients closely resembles that of their non-HIV/AIDS counterparts.¹³⁷ It includes hypertriglyceridemia, hypercholesterolemia (particularly raised total and low-density lipoprotein [LDL] cholesterol), insulin resistance, type II diabetes mellitus, lactic academia, and hepatic dysfunction.^{137, 138}

The prevalence of these abnormalities may be dependent on the type and duration of HAART, but lipodystrophy can be seen in up to 35% of HIV/AIDS patients after 12 months of PI or NRTI therapies, particularly with older drugs.¹³⁹ Use of less lipotoxic HAART regimens and earlier initiation of therapy may be beneficial in reducing the risk of metabolic syndrome and cardiovascular disease in HIV/AIDS patients.

Fat wasting, as a characteristic side effect in early-generation PI-related lipodystrophy, extends from the face, buttocks, and extremities. It coexists with abnormal fat accumulation in the torso and neck.^{41,111,140,141,142,143} These characteristic and disabling phenotypic changes lead to plasma lipid derangements with increased triglycerides, total cholesterol, and LDL-cholesterol and decreased HDL-cholesterol levels.

The pathogenesis of HIV/AIDS lipodystrophy is not known, but may include lipid and adipocyte regulatory protein dysfunction through PI binding or NRTI-induced mitochondrial toxicity.^137,138,144 The syndrome does not appear to be a direct effect of HIV/AIDS itself, as lipodystrophy appears to occur exclusively in patients receiving antiretroviral therapy.¹⁴⁵ Similarly, although the dyslipidemia noted in these patients may merely be a consequence of insulin resistance and lipodystrophy, PI therapy in non-HIV/AIDS patients results in abnormal cholesterol, triglyceride, apolipoprotein B, and lipoprotein levels and rapidly induces insulin resistance.¹⁴⁶ Some PIs (ritonavir, indinavir, and amprenavir) can also lead secondarily to an upregulation of CD-36-dependent cholesteryl ester within vascular macrophages that promote atherosclerotic plaque formation.^111,142,147

It should be noted that data suggest NRTI therapy also contributes to increased cardiovascular risk.^{111,142,148,149,150} The HIV/AIDS Outpatient Study (HOPS) cohort helped define how HIV-specific factors contribute to the risk of atherosclerosis. Their investigation yielded the “attributable risk” for different factors on overall risk. A CD4⁺ count of < 500 cells/mm³ had an attributable risk of 25.6% that was comparable to tobacco use (26.7%) and less than the attributable risks of age (49.2%) and hypertension (34.4%). The attributable risk of a CD4⁺ count of < 500 cells/mm³ was higher than the attributable risk associated with an elevated LDL (21.5%), low HDL (21.5%), male gender (20.9%), and diabetes (2.4%).¹⁵¹

As mentioned previously, HIV/AIDS patients should be assessed for traditional risk factors for premature cardiovascular disease that are prevalent in HIV/AIDS patients irrespective of therapy. Thus, family history and sedentary lifestyle that could be associated with the development of the metabolic syndrome in HIV/AIDS should be noted. Hypertension, diabetes, and tobacco use are more common in HIV/AIDS patients in comparison to non-HIV/AIDS patients, and because HIV-1 infection often leads to early decreases in HDL-cholesterol and elevations in triglycerides,^{111,142,152,153,154,155} preexisting lipid abnormalities will be an additional risk for cardiovascular disease.

Therapy for Lipodystrophy and Related Conditions in HIV/AIDS

Dietary therapy for dyslipidemia in HIV/AIDS remains contentious and has not been fully evaluated, although healthy diets rich in fruit, vegetables, and fish oils (possibly through supplementation) are encouraged. Drug therapy may also be necessary, particularly if antiretroviral treatment cannot be changed or interrupted. Bile acid sequestrants, although attractive from the point of view of drug interactions, may have adverse effects on serum triglyceride levels or impair absorption of antiretrovirals.

Most HMG-CoA reductase inhibitors (statins) are metabolized in the liver through the cytochrome P450 system. Simvastatin, lovastatin, and atorvastatin use the CYP 3A4 enzyme, and fluvastatin’s metabolism is through the CYP 2C9 enzyme. Pravastatin is unique in that its breakdown takes place in absence of this enzyme system. Given that PI and NNRTI metabolism is also CYP 3A4 dependent, co-prescription of some statins may be associated with increased risk of myopathy and rhabdomyolysis through competitive inhibition and significantly increased plasma statin levels.

For this reason, pravastatin and fluvastatin are attractive as agents of choice in patients receiving HAART. However, these statins are relatively weak and may not achieve target cholesterol levels. At present, it is recommended that hypercholesterolemia in HIV/AIDS patients treated with PIs is initially treated with pravastatin 20 mg/d with careful monitoring of virologic parameters and serum creatine kinase levels. Low-dose atorvastatin (10 mg/d) may be used with care and is generally well tolerated, but simvastatin and lovastatin are not recommended. Rosuvastatin is highly effective and is metabolized through the CYP 2C19 system. As such, it may be attractive for patients who do not respond to other statins (Table 102–4).¹⁵⁶

HIV/AIDS patients may develop severe hypertriglyceridemia, and traditional secondary causes such as high alcohol consumption, hypothyroidism, renal disease, and diabetes mellitus should be excluded. A low-fat diet together with reductions in alcohol and refined carbohydrate intake should be advised. When this nondrug therapy fails to correct hypertriglyceridemia, gemfibrozil (600 mg twice daily) or fenofibrate (200 mg once daily) may be used in isolation, although combination of fibrates, gemfibrozil in particular, and statins are not recommended.⁴² Other potential major cardiovascular drug interactions with specific HIV/AIDS therapies are noted in Table 102–5.

The treatment of glucose intolerance and diabetes also requires care, but if healthy diet and exercise are insufficient, drug treatment may again be necessary. Metformin reduces visceral adiposity and insulin resistance and remains the drug of choice in overweight individuals, but may infrequently cause lactic acidosis, particularly in the setting of renal dysfunction. Short-acting sulfonylureas may also be used in patients with normal renal function. Thiazolidinediones should be avoided in patients with liver disease, and although rosiglitazone, which is not metabolized through the P450 system, has been studied in HIV/AIDS patients, bringing about improvements in insulin sensitivity, at present it remains unlicensed for HIV/AIDS patients. In some cases insulin may be the safest drug therapy available.^41,157

Tesamorelin is a growth–hormone-releasing agent that is associated with a 15% to 18% reduction in visceral fat in HIV/AIDS lipodystrophy, which may be useful for some patients.^158,159,160 Alternatives to HAART compound medication may also be helpful in the management of some aspects of lipodystrophy, but should be carried out only after careful assessment of the potential risk to the patient’s long-term management.

Clinical Evidence for Atherosclerotic Disease in HIV/AIDS

Overall, controversy persists regarding the effect of HIV/AIDS on the development of atherosclerotic diseases. The D:A:D study of 23,437 patients demonstrated a risk of MI that was related to the duration of HAART treatment. This finding was refined to focus on PI therapy and the absence of such risk in patients treated with combinations that contained non-nucleosides (NNRTI).^130,133,161 HIV/AIDS disease markers such as CD4⁺ count and viral load were not predictive of cardiovascular risk compared to correlates with traditional risk factors (age, gender, diabetes mellitus, smoking, hypertension, dyslipidemia).^130,155 However, it must be noted that the D:A:D study period examined the effects of the therapy that was available at the time, some of which was more toxic than current HAART.

The SMART study evaluated cut-offs for HAART termination and initiation as they reflected on HIV/AIDS-related deaths and cardiovascular diseases.¹⁶² Participants received either continuous HAART or intermittent HAART treatment based on regularly assessed CD4⁺ counts (initiation: CD4⁺ < 250 cells/mm³; discontinuation CD4⁺ > 350 cells/mm³). Interim analysis led to premature study termination because of a clear increase in adverse outcomes, including cardiovascular diseases in the intermittent treatment HAART cohort.¹⁶³

A contemporary meta-analysis¹⁶⁴ points to an overall increased risk of 2.68 for acute MI in patients exposed to PI treatment. The reported incidence of acute MI was 9.42% with an in-hospital death rate of 8% attributable to both cardiovascular events and cardiogenic shock. CAD, however, was relatively infrequent (3%) in a large observational survey of South African HIV/AIDS patients, more than half of whom were taking HAART.²⁹ This indirectly contradicts previous evidence and is in keeping with an earlier meta-analysis that suggested that HIV-1 infection and PI exposure are not strong independent risk factors for subclinical atherosclerosis.¹⁶⁵

Although controversy persists, it should be remembered that the benefits of consistent, early HAART are “highly favorable” over risks of HAART-associated cardiovascular complications.^131,142 A Veterans Affairs system study demonstrated that the overall death rate among HIV/AIDS patients dropped significantly after HAART initiation, most likely through reduction in viral loads and improvement in CD4⁺ counts.^131,166,167

Coronary Artery Disease and Myocardial Ischemia in HIV/AIDS

It remains likely that some HIV/AIDS patients are at risk of acute MI and coronary heart disease (CHD). Compared with national registries of non-HIV/AIDS patients, CHD in HIV/AIDS patients occurs mostly in men and at a younger age, suggesting that the age-adjusted incidence may be significantly higher.^164,168,169 The incidence of CHD appears to be up to three times that of a general male population and results in up to 40% higher rates of acute MI, hospitalization, and in-hospital deaths for acute coronary syndromes (ACS) compared with non-HIV/AIDS patients.^{134,170,171,172,173} With the improvement in survival with HIV/AIDS, the therapy for cardiovascular diseases should be similar to that in the non-HIV/AIDS population.

The full mechanism underlying ACS in HIV patients remains unclear. Acute MI appears to be a common presentation of CHD, and a high ratio of acute MI to stable angina exists in HIV/AIDS populations.¹⁶⁸ Because these ACS may involve low-volume, lipid-rich plaques, the metabolic syndrome of HIV/AIDS lipodystrophy may promote development of vulnerable lesions or influence acute plaque rupture. However, in a study of South African HIV/AIDS patients presenting with acute MI, coronary intravascular ultrasound typically revealed fresh thrombus in the absence of underlying atherosclerotic disease and HAART did not appear to be a specific risk factor.²⁹ It remains difficult, therefore, to establish an absolute link between PI exposure and CHD, and further long-term studies are required.¹⁶⁴

HIV-1 infection itself and HAART may contribute to a pro-thrombotic state, which increases proportionally with viral load and reduced CD4⁺ count, or be further implicated in the atherosclerotic process through direct effects on cholesterol processing and intimal monocyte activation. ACS are, however, not clearly related to HIV replication because HIV RNA may be undetectable in up to one-third of patients at the time of presentation.¹⁶⁸ Rapid changes in the immune state (immune reconstitution inflammatory syndrome [IRIS]) may emerge as a factor in future studies, but therapeutic improvements in immunological, metabolic, and cardiovascular risk profiles through time may counterbalance these factors and paradoxically result in an overall reduced cardiovascular risk.^174,175

As a definitive diagnostic test, coronary angiography can be carried out safely in HIV/AIDS patients and frequently reveals patterns of coronary disease similar to that in young non-HIV/AIDS patients, including proximal vessel involvement and single artery disease.¹⁶⁸ Treatment with percutaneous coronary intervention, fibrinolysis, and coronary artery bypass are all described with reasonable survival rates, although nonfatal reinfarction and restenosis after percutaneous coronary intervention is unexpectedly high.¹⁷⁶ Care is required over choice of antiplatelet agents for use in ACS to avoid potential interactions with HAART.¹⁷⁷ However, it seems reasonable that the clinical situation should determine the use of invasive and noninvasive coronary investigations and treatments, rather than the HIV status of patients.¹⁷⁸

Myocardial Infarction (MI) and a Side Effect of Therapy in HIV/AIDS

Abacavir ((1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate; ABC) is associated with MI in HIV/AIDS.^179,180,181 The relationship was emphasized in a World Health Organization report on adverse drug events that was published in 2005.¹⁸² Clinical side effects of ABC include hypersensitivity in 5% to 8% of patients that is associated with HLA-B*5701, and suggests genetic screening to prevent the reaction in susceptible patients.^{183,184,185,186,187} Other reports showed ABC was associated with increased risk of MI in HIV/AIDS.¹⁸⁸

Sudden cardiac death (SCD) is common in HIV infection and accounts for up to 80% of cardiac-related deaths in this group. SCD occurs much more commonly than expected in the general population with similar risk factors.¹⁸⁹ As would be expected, SCD may be secondary to other cardiac pathology, including CM and pulmonary hypertension, while CHD, previous arrhythmia, hypertension, and hyperlipidemia are all prevalent comorbidities in patients with SCD.¹⁸⁹

HIV/AIDS patients may be predisposed to QT prolongation, possibly as a consequence of some forms of treatment⁴⁴; for example, pentamidine, which was used previously in the treatment and prophylaxis of P. carinii infection in select patients, is structurally similar to procainamide and may cause torsades de pointes when used intravenously or intramuscularly. Ganciclovir, an acyclic nucleoside used in the treatment of severe CMV infection, may also be arrhythmogenic.

Concomitant electrolyte disturbance may be important in the development of cardiac arrhythmia, and careful evaluation of the QT interval and magnesium concentration should be used to minimize cardiac toxicity. ECG abnormalities and rhythm disturbances are common findings in HIV/AIDS patients with myocarditis or heart muscle disease, and ectopy and ventricular tachycardia have all been reported.

With increased life expectancy in HIV/AIDS, atrial fibrillation is emerging as a significant health problem. The dysrhythmia may be found in 2.6% of HIV patients and is associated with markers of HIV disease severity, namely CD4⁺ cell count and high viral load,¹⁹⁰ as well as traditional risk factors. It has yet to be established if oral anticoagulation improves outcomes in this population, but anticoagulation should be considered as for the non-HIV/AIDS population. However, caution is required as there are potential important interactions between oral anticoagulants, particularly some novel oral anticoagulants and HAART drugs.¹⁷⁷ Careful monitoring is mandatory if warfarin is used. Caution is also required for the use of amiodarone and digoxin for rhythm or rate control in such circumstances, because further potential drug interactions exist.^191,192

Autonomic dysfunction is common in patients with HIV infection, and this may predispose to syncopal events and dysrhythmias because of excessive sympathetic tone.¹⁹³ Conduction abnormalities and arrhythmias have been demonstrated in HIV/AIDS children with ECG abnormalities, possibly related to small vessel vasculitis, neural tissue fibrosis, or myocarditis.¹⁹³ At the other extreme, as the age of HIV-infected people treated with HAART increases, coincidental cardiac rhythm disturbances will become more common. Sick sinus syndrome with symptomatic bradycardia requiring permanent pacing has been described in HIV/AIDS patients.¹⁹⁴

Vascular changes, particularly vasculitis and endothelial cell structural changes, have been documented in HIV/AIDS. Examination of aortic endothelial cells from HIV-infected patients showed a disturbed intima, increased leukocyte adherence, and upregulation of vascular cell adhesion molecules.¹⁹⁵ This indicated profound and repeated activation of aortic endothelial cells in HIV/AIDS. It is possible that some HIV-1 structural proteins may play an integral role in the process.

The clinical importance of such findings is not clear and lesions affecting small- and medium-sized arteries are usually only evident by microscopy. However, fusiform aneurysms of the right coronary artery were found in a child who died suddenly.¹⁹⁶ These lesions were histologically distinct from other arteriopathies, but other vascular abnormalities in children have been reported in the brain, thymus, spleen, and lymph nodes. Kawasaki disease, which may have a similar presentation, should be considered as a differential diagnosis that is excluded pathologically.

HIV/AIDS survival has improved. Consideration of cardiac surgery for treatment of cardiovascular diseases unrelated directly to HIV/AIDS, HANA, is now becoming increasingly common. Although studies are limited, excellent clinical outcomes are reported with 25 patients with HIV/AIDS with an in-hospital mortality of 4%.^197,198 There is neither increased perioperative risk from HIV/AIDS infection alone nor does surgery negatively impact the clinical course of HIV/AIDS or its therapy. Lesions seen in the hearts of patients with HIV/AIDS and HANA heart diseases, like aortic stenosis, are similar pathologically to those of patients without HIV/AIDS (see Fig. 102–5).¹⁹⁹ Some advocate consideration of HIV/AIDS patients as candidates for cardiac transplantation for appropriate cardiovascular indications and in the absence of detractors, although fears remain that immunosuppressant therapies in that scenario (peri- and post-transplant) may impact viral replication and interact with HAART agents.²⁰⁰

In the era of universal precautions and rapid treatment of accidental infection in the workplace, the burden of HIV/AIDS is becoming more a routine event. Fear of becoming infected with HIV-1 is understandable, but universal precautions should limit potential risk to healthcare workers and as such should not preclude the HIV/AIDS patient from possible therapies should they be felt appropriate.

As alluded to throughout the chapter, over 30 million individuals worldwide carry a diagnosis of HIV/AIDS and more may be unaware of their infection.² HAART prevents or attenuates HIV-1 replication and improves survival, making HIV/AIDS a chronic illness, and with this, cardiovascular diseases are becoming increasingly prominent in this patient group.²⁰¹ Of note, long-term side effects from antiretroviral agents remain poorly understood and may be incompletely recognized despite the growing number of patients who have received decade-long HAART therapy.

The population with HIV/AIDS that is surviving into “senior citizenship” is growing because of those same therapeutic advances. This argues for the increased prevalence and recognition of important side effects. Both HIV/AIDS per se and its therapy contribute to the phenotype of immune senescence, including cardiovascular diseases, which are prevalent in aging in absence of HIV/AIDS.^{202,203,204,205,206,207,208,209,210,211} The interplay between HIV/AIDS and HAART is complex, but many features are shared between aging, cardiovascular diseases, and HAART toxicity in HIV/AIDS. As clinical studies unfold more information about this growing aspect of the population, therapy can be tailored to specific needs of HIV/AIDS patients with cardiovascular diseases.²¹²