Reversible right ventricular dysfunction in patients with HIV infection.

Abstract: Human immunodeficiency virus-related cardiomyopathy is characterized by global left ventricular (LV) dysfunction commonly associated with biventricular dilation. Human immunodeficiency virus (HIV) cardiomyopathy carries a poor prognosis, and the role of antiretroviral therapy in the reversal of heart failure is not very clear. We report two patients with HIV infection who presented with severe right ventricular (RV) dysfunction in the absence of pulmonary parenchymal, pulmonary arterial and left ventricular myocardial involvement. During the period of intensive antiretroviral therapy, the symptoms of right heart failure progressively and remarkably improved. This was accompanied by normalization of right ventricular size and RV function documented by repeat echocardiograms. Given that the serologic tests for opportunistic infections were negative, and the RV function improvement correlated with a decrement in the viral load, it is likely that the cardiomyopathy was due to direct infection by HIV. These cases illustrate that there can be isolated involvement of the right heart in the absence of lung, significant pulmonary vascular and left ventricular disease, and also that the antiretroviral therapy might reverse the cardiomyopathy.

Key Words: HIV, cardiomyopathy, antiretroviral therapy, right ventricle.

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Cardiomyopathy is noted in 10 to 20% of patients infected with human immunodeficiency virus (HIV), and accounts for approximately one-third of HIV-related deaths. (1) HIV cardiomyopathy is usually seen in patients with advanced disease and carries a very poor prognosis. (2) Patients often present with symptoms and signs of biventricular failure, and the final diagnosis is made by both noninvasive echocardiography and angiogram to rule out ischemic cardiac involvement. (3,4) Echocardiography typically demonstrates multichamber enlargement associated with global hypokinesia and decreased left ventricular fractional shortening. These findings correlate with postmortem findings of chamber dilation, increase in the weight of the heart, and a pale appearance to the myocardium. (4,5) Treatment is often symptomatic, similar to that of nonischemic dilated cardiomyopathy, and the outcome is dismal. (4)

We report two interesting HIV cardiomyopathy patients who presented with right ventricular involvement with no involvement of the left ventricle or lungs (parenchymal and significant pulmonary vascular). Symptoms of right heart failure improved progressively and remarkably following treatment with combination antiretroviral therapy.

Case Report

Human immunodeficiency virus-related cardiomyopathy is characterized by left ventricular dysfunction and the role of antiretroviral therapy in its treatment is not known. We report two unusual cases of HIV cardiomyopathy with isolated right ventricular dysfunction and its reversal following combination antiretroviral therapy.

Patient 1

A 68-year-old Caucasian male presented to his primary care physician with a 2-month history of easy fatigability and severe bilateral lower extremity edema. His past medical history included an 18-year history of adequately treated hypothyroidism. Review of systems revealed arthralgias, paresthesia, numbness, and unsteady gait. The patient denied smoking, alcohol or IV drug abuse. Physical examination was consistent with normal blood pressure, tachycardia (heart rate 120 beats per minute), raised jugular venous pressure, positive hepatojugular reflux, and severe bilateral pitting pedal edema. Precordial examination was unremarkable. The lungs were clear to auscultation. The neurologic examination was notable for absent ankle jerks and positive Romberg sign. Clinical diagnosis of right heart failure and peripheral neuropathy were made. Diagnostic testing showed mild pancytopenia (hemoglobin 11.6 g percent [normal range 13.5-17.5], WBC 4.3 [4.5-10.5 X [10.sup.3]] and platelet count 141 [150-400 X [10.sup.3]]) with a high ESR (90 mm at the end of one hour). Thyroid function test was normal. Chest x-ray was significant for cardiomegaly. EKG showed sinus tachycardia and a borderline right ventricular strain pattern.

Transthoracic 2-dimensional echocardiography showed dilation of the right ventricle and atrium associated with a plethoric inferior vena cava (Fig. 1). Estimated right ventricular systolic pressure (RVSP) and pulmonary artery systolic pressures were both 48 mm Hg. The pulmonary artery, including the main branches, was normal in size. The left ventricular (LV) size and function was normal. At the time of transthoracic echocardiography, the patient had tachycardia with a heart rate equaling the target rate during stress test. There were no wall motion abnormalities noted at target heart rate; hence, ischemic cardiomyopathy was considered unlikely. No further tests were performed to rule out coronary artery disease.

Lower limb nerve conduction study confirmed mixed polyneuropathy. In view of multisystem involvement (cardiac, hematologic, joints and neurologic) the possibility of connective tissue disorder and occult malignancy were investigated with computed tomography of the thorax and abdomen, which were also normal. Connective tissue workup, syphilis screen and viral markers for hepatitis were also negative. Symptoms of RV failure persisted despite treatment with an increased dose of diuretics. Since a unifying diagnosis could not be made, the patient's history was taken again, including the sexual history. The patient then confessed to homosexual activity during the preceding 10 years and an HIV test was ordered. The serology confirmed HIV infection with a viral load of 74,091 (HIV BDNA, quantitative assay) and a CD4 count of 183/[mm.sup.3]. Serum markers for opportunistic infections (cytomegalovirus [CMV]. Epstein-Barr virus [EBV], coxsackie, adenovirus, leptospira, toxoplasma, etc.) were negative. He was started on triple antiretroviral therapy with zidovudine, lamivudine and nevirapine.

Following antiretroviral therapy, there was a slow but steady reversal of the pancytopenia, improvement of the CD4 count and a decline in the viral load. These changes were associated with steady and sustained improvement of his symptoms of RV failure, including complete resolution of edema. During three years of follow-up, the HIV-RNA level was undetectable and the CD4 count improved from 183 to 604/[mm.sup.3] Sequential repeat transthoracic echocardiography confirmed significant regression in the size of the right atrium and right ventricle, and normalization of right sided pressures (right ventricular systolic pressure [RVSP] was 20 mm Hg) [Figure 2]. The left ventricular function remained unchanged. During the follow-up period, the patient remained free from other complications of HIV infection.

Patient 2

A 39-year-old white female with known HIV infection was diagnosed with metastatic breast cancer. The patient was on antiretroviral therapy and the HIV infection was in remission. Baseline workup before starting chemotherapy included transthoracic echocardiography (poor quality images), which showed normal biventricular size and function. Physical examination was unremarkable except for lymphadenopathy and a lump in the left breast. Antiretroviral treatment was withheld to avoid interaction with an experimental chemotherapy regimen. Two months following discontinuation of antiretroviral therapy, the patient complained of increased swelling of the legs and easy fatigability. Further investigation showed only mild pancytopenia. Repeat transthoracic echocardiography showed enlarged right ventricle and right atrium associated with plethoric inferior vena cava. The LV size and functions (systolic and diastolic) were normal. Estimated right ventricular systolic pressure was 45 mm Hg. A computed tomography of the thorax confirmed dilated RV. Symptoms of RV failure improved partially with diuretics. The serology confirmed a worsening viral load and CD4 count. Serum markers for opportunistic infections were negative. The patient was restarted on antiretroviral therapy with zidovudine, lamivudine and nevirapine, following which a slow but steady improvement of her CD4 count and decline in the viral load was noted. These changes were associated with improvement of her symptoms and RV function on follow-up transthoracic echocardiography.

[FIGURE 1 OMITTED]

Discussion

Cardiomyopathy related to HIV/AIDS was first described in 1986. (6) It is reported to affect 10 to 20% patients with HIV infection. (4) Human immunodeficiency virus is the underlying cause of cardiomyopathy in 4% of patients with idiopathic dilated nonischemic cardiomyopathies. (4) HIV cardiomyopathy is associated with poor prognosis, with a median survival of 101 days as opposed to 472 days in those without cardiomyopathy. (7) Congestive heart failure due to cardiomyopathy has become the leading noninfectious cause of death in pediatric patients infected with HIV. (8)

The pathogenesis of cardiomyopathy remains unknown. Attributed causes include direct infection by HIV-1 with or without myocarditis, effects of circulating or systemic toxins (tumor necrosis factor alpha, endothelian-1 and transforming growth factor [TGF]), infection of the heart by opportunistic pathogens (CMV, EBV, coxsackie, adenovirus, leptospira and toxoplasmosis etc.), toxicity due to antiretroviral therapy (zidovudine), illicit drugs, self-prescribed pharmaceuticals or homemade remedies, and nutritional disorders (L-carnitine and selenium deficiency). In addition, more than one factor may be present in a single patient. (9) Patients with HIV infection and encephalopathy are more likely to die from congestive heart failure than those without. (8) It is possible that the virus in the myocardium and cerebral cortex persists even after the treatment, and the reservoir cells may continue to release cytotoxic cytokines contributing to progressive and late tissue damage in both systems, independent of antiretroviral therapy. (8)

[FIGURE 2 OMITTED]

Diagnosis of cardiomyopathy is usually made by two-dimensional transthoracic echocardiography which commonly demonstrates dilation of all the cardiac chambers, global LV hypokinesia and dysfunction. (5) Computed tomography or magnetic resonance imaging may be useful to rule out metastatic involvement of the heart or to exclude parenchymal lung disease. (4) Catheterization may be required to rule out coronary artery disease. Although myocardial biopsy has been reported to be useful in identifying myocarditis, its role is controversial due to low sensitivity and significant risks associated with the procedure. (4)

Pulmonary arterial hypertension (PAH) occurs with increased frequency among patients with HIV infection and may present with right heart failure similar to our patients. (10) HIV-infected patients are 1,000 times more likely to develop PAH than the general population. Until December 2004, 279 cases of HIV-related PAH had been described in the literature. (10) The pathogenesis of HIV-related PAH is not clear. In vivo and in vitro studies show that HIV does not infect lung endothelial cells and neither HIV RNA nor p24 antigen could be detected in the pulmonary vessels. The most likely mechanisms include increased production of inflammatory cytokines and chemokines by infected lymphocytes and alveolar macrophages leading to endothelial dysfunction, elevated levels of endothelian-1 and increased pulmonary vascular resistance. (11,14,15) Also, the role of antiretroviral therapy on HIV-related PAH is not clear; only a case report and a small cohort study showed survival benefit. (12,13) Our patients had mild to moderate PAH (RVSP; 45-48 mm Hg); although it is possible that this might have contributed to the RV dysfunction, it is very unlikely to be the sole cause of RV dysfunction, considering their severity.

Our patients differed from those typically described with HIV cardiomyopathy. Both had normal left ventricular size and function and no discernable pulmonary vascular or parenchymal involvement. It is possible that the isolated right ventricular involvement in our patients was just part of the spectrum of HIV-related cardiomyopathy and our patients were diagnosed before LV involvement became evident.

Treatment of HIV-associated cardiomyopathy is mostly symptomatic and similar to that of nonischemic dilated cardiomyopathy. (4) However, one has to be careful in adjusting medication dosages, as these patients are susceptible to hemodynamic stress from opportunistic infections, diarrhea and dehydration. (4) Patients with myocarditis have enhanced sensitivity to digoxin, and anticoagulation therapy may present special risks to patients with cerebral vasculopathy and possible aneurysm formation. (4)

Literature showing reversal of cardiomyopathy in HIV infection is scant. A retrospective study by Pugliese et al (16) reported a decrease in the incidence of cardiac complications of HIV infection with HAART as compared with nucleoside reverse transcriptase analogues. In a small study in children with HIV cardiomyopathy, IV immunoglobins were shown to improve myocardial contractility by 10%. (17)

Wilkins et al, (18) in the earliest report, demonstrated reversal of myocarditis following 3 months of therapy with AZT. However, although the patient improved clinically, there was only slight improvement in the cardiac index (from 2.3-2.6 L/min/[m.sup.2]) and a detailed echocardiography report was not available. Recently described reports (19-22) included patients who are young, relatively asymptomatic, had higher CD4 counts and a very low to undetectable viral load. Most of these reports, however, fail to mention pre- and post-treatment echocardiographic detail.

Our cases are unique for several reasons. Both patients had isolated RV dysfunction and a normal LV function with antiretroviral treatment, both patients showed reversal of symptoms of RV failure and improvement of RV function by echocardiogram. In both patients the improvement coincided with the decline in viral load and improvement in the CD4 count. Finally, both patients lacked any other cardiac history or diagnosis, and in both patients improvement occurred without any heart-specific treatment.

Conclusions

The clinical course of these cases demonstrate that there can be isolated right heart involvement in patients with HIV infection and this may represent an early part of the spectrum of myocardial involvement in this disease. Treatment with antiretroviral therapy may reverse cardiomyopathy even in patients with fairly advanced right ventricular dysfunction. The reversible nature of the isolated right ventricular dysfunction warrants careful screening of HIV patients for cardiac involvement. Early diagnosis and treatment may reduce cardiomyopathy-related morbidity and mortality in patients with HIV infection. Finally, while our report as well as earlier publications present a role of HAART in the management of HIV-related cardiac complications, without a randomized controlled trial it may be too early to make a definitive recommendation in this regard.

Limitations

Neither patient underwent a cardiac stress test or cardiac catheterization to evaluate for coronary artery disease (CAD) and ischemic cardiomyopathy could not be conclusively ruled out. However, the clinical course of our patients precluded hemodynamically significant CAD. Our second patient also received chemotherapy, and cardiac toxicity due to chemotherapeutic agents is also possible. Cardiac toxicity of such drugs is usually associated with LV dysfunction and isolated RV dysfunction due to drug toxicity is unlikely.

Pre- and post-treatment endomyocardial biopsy would have provided more objective findings, but was unnecessary and unethical as myocardial biopsy is not risk free, and both patients improved clinically.

References

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Umamahesh C. Rangasetty, MD, Atiar M. Rahman, MD, and Nasir Hussain, MD

From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX and the Division of Cardiology, University of Texas, MD Anderson Cancer Center, Houston, TX.

Reprint requests to Nasir Hussain, Associate Professor of Medicine, Department of Internal Medicine, 4.174 John Sealy Annex, 301 University Boulevard, Galveston, TX 77555. Email: [e-mail]

Accepted October 20, 2005.

RELATED ARTICLE: Key Points

* Isolated right heart failure can occur in patients with HIV infection due to cardiomyopathy.

* Reviewing the patient's history is very important in the diagnostic evaluation of patients.

* Treatment with antiretroviral therapy might reverse human immunodeficiency virus-associated cardiomyopathy.