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Abstract

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

The relationship between human immunodeficiency virus (HIV) infection and cardiovascular disease is still under debate, but it appears that the risk of myocardial infarction in those with HIV infection who are receiving highly active antiretroviral therapy (HAART) is increased. There has been less focus, however, on the effect of HIV and HAART on left ventricular function. Evidence from the past 20 years in both Westernized and developing countries has indicated that subclinical left ventricular dysfunction in HIV-infected individuals with and without well-controlled HIV infection is prevalent and may represent emerging cardiac disease. The specific roles of HIV infection and HAART are unclear, but they may exert independent direct and indirect effects on the myocardium. These effects may include chronic inflammation, metabolic complications (ie, insulin resistance, lipotoxicity, dyslipidemia), and mitochondrial toxicity. The objective of this article is to review the evidence for HIV- and HAART-related left ventricular dysfunction in persons infected with HIV.

The relationship between human immunodeficiency virus (HIV) infection and cardiovascular disease (CVD), specifically the increased risk of myocardial infarction in those with HIV infection who are receiving highly active antiretroviral therapy (HAART), has recently received international attention.1 There has been less focus on the effect of HIV infection and HAART on left ventricular (LV) function, however. Evidence from the past 20 years in both Westernized2 and developing countries3 indicates that along with dilated cardiomyopathy associated with late-stage HIV disease, subclinical LV dysfunction (LVD) in HIV-infected individuals with and without well-controlled HIV infection2 is prevalent and may represent emerging cardiac disease. The specific roles of HIV infection and HAART are unclear, but they may exert independent effects on the myocardium. The objective of this article is to review the evidence for HIV- and HAART-related LVD in persons infected with HIV.

Evidence of LVD in HIV Infection

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

Early manifestations of HIV-related LVD were associated with late-stage HIV disease, or AIDS. Myocarditis in individuals with AIDS was common, with a prevalence as high as 80%.4,5 HIV-related myocarditis has been closely linked with AIDS-defining opportunistic infections (OIs), such as Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans.4 AIDS-related dilated cardiomyopathy, another frequent early finding, was associated with viral infections of the myocardium such as cytomegalovirus, Coxsackie virus, and Epstein-Barr virus,6 as well as HIV.7 Prior to the advent of HAART in the mid 1990s, approximately one-third of cohorts studied were found to have cardiomyopathy,4,8 and it was associated with a poor prognosis when compared with patients with AIDS who did not have cardiomyopathy.9 With the recent advances in HAART and subsequent improvements in morbidity and mortality, AIDS-related cardiomyopathy is less frequently found in Westernized countries.10

In contrast with the effects of advanced HIV disease on the myocardium, in the post-HAART era, LVD appears to manifest subclinically, primarily as diastolic dysfunction. Impaired early to late diastolic filling rate (E/A ratio) measured by Doppler echocardiography is the most frequently reported lesion.2,11–14 Other reported diastolic abnormalities in HIV include increased isovolumic relaxation time2,14,15 and increased LV diastolic diameter.15

Subclinical systolic function abnormalities have also been reported, although less frequently. Ejection fraction was preserved in several studies; however, in 3 separate studies it was reported to be depressed in HIV-positive individuals12,15 when compared with HIV-seronegative controls. Depressed ejection fraction was related to the later stages of HIV infection rather than to HAART or intravenous drug use.15 Another parameter of systolic function that has been more often reported as abnormal in HIV is LV fractional shortening. LV fractional shortening has been reported to be lower in HIV-infected children16–18 and adults,15 and it appears to worsen over time.18 Systolic wall motion abnormalities of the myocardium have also been reported.2

HIV Infection as a Mechanism for LVD

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

Very early in the HIV/AIDS epidemic, the presence of HIV infection in the myocardium was noted, and this suggested a link between the virus and LVD.7,19,20 Shortly after AIDS emerged in the United States in the early 1980s, Calabrese and colleagues19 isolated HIV from hearts obtained at autopsy from 2 infants with AIDS-related cardiomyopathy. Subsequently, other investigators detected HIV viral nucleic acid sequences in hearts obtained at autopsy from a 13-month-old vertically infected child20 and 23 children and adults ranging in age from 6 to 72 years7 with AIDS (incidence ≈27%).7 It is unclear how HIV infects the cardiac myocyte, a cell that lacks CD4 receptors. Infiltrating infected macrophages and other inflammatory dendritic cells have been hypothesized as mechanisms of HIV entry.7 OIs such as Pneumocystis carinii, cytomegalovirus, and Kaposi's sarcoma have also been associated with LVD, specifically AIDS-related cardiomyopathy.15,21 Other evidence suggests that immune function is more predictive of LVD than are OIs, which demonstrates that diastolic dysfunction, specifically isovolumic relaxation time, was shortened in HIV-positive persons with depressed immune function and was associated with lower CD4 cell count.22 A finding of subclinical diastolic dysfunction may be important because diastolic dysfunction with preserved systolic function is considered an early clinical indicator of other cardiovascular conditions such as coronary artery disease, hypertension, and hypertrophic cardiomyopathy.23

Additional evidence for the role of HIV infection in LVD comes from vertically infected children. LV fractional shortening was lower and resting heart rate and LV mass was higher in HIV-positive vertically infected infants than in non-HIV-infected controls.16–18 In this study, lower LV fractional shortening and greater LV mass predicted increased mortality.17 A 5-year followup of this cohort revealed persistent LVD and increased LV mass; ≈12% of the children progressed to heart failure.24 It is unclear whether these abnormalities in cardiac function are a result of direct HIV infection of the infant myocardium (only ≈30% of HIV-positive mothers took antiretroviral therapy during pregnancy) or by an abnormal intrauterine environment caused by HIV-related inflammation, poor nutrition, smoking, or alcohol consumption.25

Last, evidence of the role of HIV infection in LVD has been reported in animal models of HIV infection. Overexpression of HIV viral proteins in the rodent myocardium resulted in CVD26 and LVD27,28 that were hypothesized to be related to mitochondrial structural damage.27 The HIV-mediated mitochondrial damage hypothesis is supported by other studies in which skeletal muscle biopsies from HIV-positive individuals contained abnormal mitochondrial shape and size and cristae disruption.29 Because the heart relies primarily on oxidative metabolism to meet its energy needs, disruption of the mitochondria could hypothetically alter cardiac energetics30 and contribute to LVD. The role of mitochondrial toxicity in LVD will be discussed further in the following section. These findings appear to provide further evidence that HIV contributes to LVD in persons infected with HIV.

HAART as a Mechanism for LVD

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

The independent effects of HAART on LVD are difficult to ascertain because of the simultaneous presence of HIV infection, the use of multiple anti-HIV drug classes, different medications in each class, and the heterogeneous HAART histories of each HIV-infected person. Early animal studies using the first US Food and Drug Administration-approved antiretroviral medication, zidovudine, a nucleoside analog reverse transcriptase inhibitor (NRTI) commonly prescribed in HAART regimens, reported cardiomyopathic effects when administered in high doses.31 Subsequent animal studies reported that NRTI exposure was associated with myocardial mitochondrial damage, specifically ultrastructural abnormalities32 and mtDNA depletion and mutations33 through the inhibition of DNA polymerase gamma (mtDNA replication enzyme).34 Although there was no direct correlation, functional effects of NRTI-mediated mtDNA abnormalities may include impaired myocardial oxidative metabolism35 and disrupted cardiac energetics. Recent evidence from studies in animals36 and obese humans37 suggests a strong link between impaired aerobic (oxidative) capacity and an increased risk of CVD and mortality. Clinical manifestations of impaired oxidative function may include lactic acidosis38 and reduced LV fractional shortening.39

Another frequently prescribed class of HAART, protease inhibitors (PIs), has been associated with vascular dysfunction40 and an increased risk of CVD.1 The PI ritonavir reduced endothelium-dependent vasorelaxation, increased oxidative stress in cultured porcine carotid arteries,41 and was cytotoxic (led to mtDNA damage) in human endothelial cells,42 suggesting a direct effect of this PI on endothelial function. In addition, a deleterious effect of PIs on potassium channels in cardiac myocytes, potentially leading to repolarization abnormalities, was also demonstrated.43

In HIV-infected patients, one report has suggested that PI use is associated with diastolic dysfunction, specifically lower E/A ratio in a group of HIV-infected drug users.11 Another study reported findings of electrical conduction abnormalities: QT prolongation or torsades de pointes in 24 HIV-positive patients taking a PI.43 Although unproven in HIV infection, select PIs may also induce myocardial insulin resistance, as they have been associated with peripheral insulin resistance.44 In HIV-seronegative persons with diabetes, myocardial insulin resistance was associated with impaired cardiac energetics and cardiomyopathy.45 These potential interrelationships need to be studied in HIV-infected patients. Other components of HAART, such as non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, and chemokine receptor 5 antagonists, do not appear to have direct effects on the myocardium/myocytes; however, these drugs need to be studied further for their effects on myocardial metabolism and function.

Indirect Metabolic Effects of HIV and HAART on LVD

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

Approximately 50% of individuals infected with HIV who are taking HAART develop a cluster of metabolic complications that may include insulin resistance, dyslipidemia (hypertriglyceridemia, decreased high-density lipoprotein cholesterol level, elevated serum free fatty acid level), and fat redistribution (central adiposity, peripheral lipoatrophy), frequently called HIV-related lipodystrophy syndrome.44 There has been much debate over the mechanisms for HIV-related lipodystrophy syndrome. It appears to be a multifactorial problem with contributions from HIV infection, HAART (specifically PI and NRTI therapy), advancing age, genetic predisposition, and lifestyle/behavioral factors (poor nutrition, physical inactivity/poor fitness, and substance abuse).44 The effects of these metabolic complications (ie, insulin resistance, dyslipidemia) on LVD have not been investigated in the HIV-infected population. In the general population, this clustering of metabolic complications (the metabolic syndrome) is known to increase the risk of cardiovascular events (including coronary artery disease and congestive heart failure) and is associated with increased morbidity and mortality.46 Recent evidence has also linked the metabolic syndrome to diastolic dysfunction (impaired global myocardial relaxation in diastole as measured by tissue Doppler imaging) in non-HIV-infected individuals.47 Because the HIV-related and non-HIV-related metabolic syndromes share some common characteristics, it is reasonable to hypothesize that HIV/metabolic complications may increase the risk of diastolic dysfunction in those infected with HIV. Further, with the advances in echocardiographic imaging (ie, tissue Doppler imaging), subclinical diastolic dysfunction may be better and more frequently detected in HIV-infected persons.

Treatment of LVD in HIV

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

There are few safe and effective treatments for diastolic dysfunction with preserved systolic function in the general population, and none have been tested in HIV-related diastolic dysfunction. For diastolic dysfunction in the general population, small studies have indicated that calcium channel blockers and angiotensin receptor blockers may be safe and effective.48 Other small studies have examined β-blockers, angiotensin-converting enzyme inhibitors, and digoxin; however, the results have been unclear and the effects of these drugs on diastolic function need further investigation in both HIV- and non-HIV-infected populations.48

Another potential treatment for HIV-related LVD is aerobic exercise training. Exercise intolerance from significantly decreased aerobic capacity is well known in HIV-infected individuals49 and is a strong risk factor for increased cardiovascular mortality in the general population.37 Exercise training in non-HIV-infected individuals appears to improve LV diastolic function, potentially via improvements in glucose metabolism.50 Exercise training in HIV-positive patients is well tolerated, does not harm immune/virologic status, improves exercise tolerance, decreases CVD risk factors, and improves quality of life.49 Therefore, increased physical activity along with traditional lifestyle/behavior modifications (eg, tobacco cessation, nutrition counseling, and weight and stress management) appear to be logical and appropriate initial strategies for HIV-positive persons with subclinical diastolic dysfunction. The presence of hypertension, a common finding in HIV infection51 and a known risk factor for diastolic dysfunction,47 should also be evaluated and treated in HIV infection. Switching HAART medications to less metabolically toxic drugs is another strategy for improving CVD risk profiles that has been somewhat successful.52 Other potential interventions might include glucose- and lipid-lowering medications that might also lower CVD risk in HIV infection.44 Clearly, there is a lack of evidence in this area and further work is needed.

Conclusions

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References

LVD in HIV-infected individuals is established through manifestations of AIDS-related cardiomyopathy and subclinical systolic and diastolic abnormalities. The former is less frequently seen in Westernized countries with availability of HAART, control of viral replication, and restoration of immune function. Subclinical LVD, particularly diastolic abnormalities, appears to be prevalent and frequently undetected. Possible mechanisms for HIV-related diastolic dysfunction include myocardial viral infection; direct myocardial mitochondrial toxicity by NRTI therapy; indirect HAART-mediated myocardial metabolic abnormalities; chronic hypertension; nutritional deficiencies; tobacco, alcohol, and illegal substance abuse; and physical inactivity/poor fitness (Figure). A traditional CVD assessment is recommended for HIV-infected patients. Screening for subclinical LVD and evaluating exercise capacity may provide useful information for outlining a treatment plan. Further research into the prevalence, pathogenesis, and treatments for LVD in HIV infection are warranted.

image

Figure Figure. Potential mechanisms for left ventricular dysfunction in human immunodeficiency virus (HIV)-positive persons. HAART indicates highly active antiretroviral therapy; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; IR, insulin resistance; HTN, hypertension; LVH, left ventricular hypertrophy.

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References

  1. Top of page
  2. Abstract
  3. Evidence of LVD in HIV Infection
  4. HIV Infection as a Mechanism for LVD
  5. HAART as a Mechanism for LVD
  6. Indirect Metabolic Effects of HIV and HAART on LVD
  7. Treatment of LVD in HIV
  8. Conclusions
  9. Disclosure:
  10. References
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