Brain Natriuretic Peptide and HIV-Related Cardiomyopathy

January 9, 2003

Case Report

Rodolfo Carrillo-Jimenez, MD, L. Treadwell, MD, Harvey Goldfine, MD, Alvaro Buenano, MD, Gervasio A. Lamas, MD, H. Hennekens, MD, DrPHAIDS Read 12(11):501-508, 2002. © 2002 Cliggott Publishing, Division of SCP Communications

Posted 12/20/2002

Abstract and Introduction

AbstractThe brain natriuretic peptide (BNP) assay is a new, relatively inexpensive, and simple test that has the potential to be an early, cost-effective, and reliable marker for HIV-related cardiomyopathy. We report 1 case of HIV-related cardiomyopathy and 10 cases of HIV infection with unknown heart disease in which we measured BNP levels and performed echocardiography. We found a significant inverse relationship between BNP and left ventricular function in these patients. Further basic and epidemiologic research on BNP measurement for the detection of HIV-related cardiomyopathy is needed to support these findings, which if confirmed could have important clinical and public health implications.IntroductionBrain natriuretic peptide (BNP) is a cardiac neurohormone secreted from the ventricles of the heart in response to ventricular volume expansion and pressure overload.[1] Elevated BNP levels have been reported in patients who have left ventricular dysfunction from different causes, including ischemic and idiopathic dilated cardiomyopathy.[1,2] As a diagnostic test, the BNP assay has high sensitivity, specificity, and predictive value for left ventricular dysfunction.[3-6]Perhaps as a consequence of treatment with protease inhibitors and/or increased survival of patients infected with HIV, cardiovascular complications are becoming more common.[7-11] Severe global left ventricular dysfunction (cardiomyopathy) is the most common and life-threatening cardiovascular complication of HIV infection.[12,13] At present, there is no single, cost-effective, and reliable method of screening for this highly prevalent HIV- related cardiomyopathy.

Case Summary

A 43-year-old man with a 7-year history of HIV infection presented to an outpatient clinic with a 3-week history of exertional dyspnea and a dry cough. He also reported asthenia, dizziness, and a low-grade fever. An upper respiratory tract infection had been diagnosed in the emergency department the day before. He had a history of nonadherence to antiretroviral medications including zidovudine. His current medications included trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis. He denied any history of smoking or alcohol abuse. There was no personal or family history of coronary heart disease. The patient's physical examination revealed an afebrile, moderately dyspneic, chronically ill-appearing man with a blood pressure of 80/50 mm Hg, pulse rate of 120 beats per minute, and a respiratory rate of 28 breaths per minute. Cardiac examination revealed both S3 and S4; no murmurs were heard. An examination of the lungs revealed bilateral basilar rales. No jugular venous pressure elevation, peripheral edema, or cyanosis was found. The remainder of the examination was unremarkable.Results of a chest roentgenogram showed cardiomegaly and mild interstitial abnormalities. Complete blood cell count showed a hemoglobin level of 9.6 g/dL and platelet count of 128 3 103/mL. Liver function test results and serum electrolyte levels were within normal limits. His CD4+ cell count was less than 20/µL, and his HIV RNA level was 750,000 copies/mL. A standard 12-lead ECG showed sinus tachycardia, left axis deviation, and symmetric T-wave inversion in anterolateral leads. A 2-D echocardiogram showed severe biventricular dilatation, global hypokinesis with a left ventricular ejection fraction (LVEF) of 10% (calculated by modified Simpson rule). A moderate pericardial effusion was noted.The patient was admitted to the hospital and treated with intravenous furosemide, digoxin, and lisinopril. After clinical improvement, the patient was discharged with a diagnosis of HIV-related cardiomyopathy. Oral digoxin and lisinopril were prescribed. Because we had previously reported the potential utility of BNP as a marker of HIV- related cardiomyopathy,[14] we were interested in the association between cardiac function and BNP levels in this case.MethodsAt the 1-month follow-up visit, the patient was asymptomatic, and a 5-mL sample of venous blood was collected in a tube containing potassium EDTA (1 mg/mL of blood). The BNP level was measured with the B-type natriuretic peptide assay (Triage BNP Test, Biosite Diagnostics, San Diego) within 1 hour of the sample collection.To determine an expected value for BNP, we evaluated the BNP levels in 10 (7 men, 3 women) consecutive asymptomatic HIV-infected patients with no known heart disease and normal echocardiograms. The possible relationship between BNP level and different patient characteristics was assessed.ResultsIn the control group, the clinical characteristics were age, 32 to 52 years (mean, 41.5 years); duration of known HIV infection, 1 to 10 years (mean, 3 years); CD4+ cell count, 8 to 325/µL (mean, 182.6/µL); HIV RNA level, 15,000 to 2,300,000 copies/mL (mean, 433,364 copies/mL) (Table 1).In the patient with asymptomatic HIV-related cardiomyopathy, the BNP level was 136 pg/mL. In the 10 control patients, the BNP levels ranged from 0.3 to 48.4 pg/mL (mean, 14.4 pg/mL), and the LVEF ranged from 43.4% to 62.9% (mean, 55.9%).There was a statistically significant inverse relationship between BNP level and LVEF (Pearson r = 20.934; P < .001) (Figure 1) among this group of HIV-infected patients with and without cardiomyopathy. In contrast, there were no significant associations of BNP levels between the case patient and controls with any other potential confounding variables, including age (P = .65), duration of HIV infection (P = .19), CD4+ cell count (P = .08), and viral load (P = .74). Although zidovudine, protease inhibitors, and alcohol are postulated to play a role in HIV- related cardiomyopathy, there were no significant associations between BNP levels and the use of zidovudine (P = .69), protease inhibitors (P = .52), or alcohol (P = .66).

Figure 1. Inverse relationship of brain natriuretic peptide (BNP) level and left ventricular ejection fraction (LVEF) between the control group and the patient with HIV-related cardiomyopathy (Pearson r = -0.934; P < .001).

Discussion

The prevalence of cardiac involvement in patients with HIV infection ranges from 28% to 73%.[8-11] More than 6% of patients infected with HIV may have symptomatic heart disease.[12] A prospective echocardiographic study found dilated cardiomyopathy in 8% of asymptomatic HIV-infected patients, with a mean annual incidence rate of 15.9 cases per 1000 patients.[15] This condition may well represent a paradigm of virus-related heart muscle disease. HIV-related cardiomyopathy does not appear to be limited to any HIV risk group or to patients with major cardiac risk factors, such as hypertension or diabetes.[16] Furthermore, there is no clear association with any opportunistic infection.[15-17] Thus, this condition likely represents a form of idiopathic cardiomyopathy.This case illustrates an important clinical point. Specifically, when left ventricular dysfunction and heart failure develop in HIV-infected patients, the symptoms and signs may be misinterpreted as being the result of pulmonary or other organ diseases.[18-20] Unnecessary and preventable morbidity and mortality may result from delays in the diagnosis and treatment of HIV-related cardiomyopathy. Echocardiography has a high sensitivity and predictive value, and it is considered to be the gold standard for the diagnosis of ventricular dysfunction.[10] However, the widespread use of echocardiography for all HIV-infected patients would be costly and time-consuming.At present, plasma levels of BNP are useful for screening patients without HIV disease who are at risk for ventricular dysfunction and for identifying the preclinical stage of ischemic heart disease and idiopathic dilated cardiomyopathy.[1] BNP screening has the potential to detect patients in whom HIV-related cardiomyopathy develops, even though the origins of cardiomyopathy in coronary disease and HIV infection are different. In coronary heart disease, ventricular dysfunction derives from ischemia and infarction leading to cell death and scar formation. In contrast, HIV-related cardiomyopathy is believed to originate from factors other than coronary disease.[11-15] It is unknown whether these factors affect BNP production in the ventricular myocardium of HIV-infected patients.Dilated cardiomyopathy has been described in a nonhuman primate model of simian AIDS[21,22] and in AIDS transgenic mice,[23] where myocardial pathology includes lymphocytic myocarditis and necrosis. Of note, BNP also has been shown to be a marker of systolic dysfunction in hamsters with genetic cardiomyopathy.[24] To our knowledge, however, there are no previous reports on the use of BNP measurements in HIV-infected patients or in animal models of AIDS with cardiomyopathy and ventricular dysfunction.Our findings indicate a significant inverse relationship between BNP levels and HIV-related cardiomyopathy. We hypothesize that had BNP been measured in this affected patient during the emergency department visit 1 month earlier, the diagnosis of HIV-related cardiomyopathy could have been made and treatment initiated. We are not aware of any other data concerning BNP and HIV-related cardiomyopathy.Measurement of BNP is a relatively inexpensive and simple test that may turn out to be useful in identifying patients with HIV-related cardiomyopathy. Further research is required to test this hypothesis, including basic scientific studies to understand mechanisms, observational epidemiologic studies (case-control and cohort studies) if the effect size ranges from moderate to large, and large-scale randomized trials if the effect size ranges from small to moderate for the early detection and treatment of HIV-related cardiomyopathy.[25] If true, this hypothesis would have important clinical and public health implications.

Tables

Table 1. BNP Levels and Characteristics of a Patient With HIV-Related Cardiomyopathy and 10 HIV-Infected Patients Without Known Heart Disease

GenderAgeDuration of known infection (y)CD4+ cell count (/µL)Viral load (HIV RNA copies/mL)ZDV useAlcohol usePI useBNP level (pg/mL)LVEF (%)

CaseM43713750,000+0+13610

Controls

1F442167400,0000++8.252.7

2F44320020,000+0+17.662.7

3M3531152,300,000+0+1359.7

4M35131815,0000000.362.5

5M465325400,000+0+4.355.7

6M32221626,00000+48.443.4

7M363242400,000+0+5.957

8M42215636,000+0+4.752.1

9M490.57920,00000+18.951

10F52108400,000+0+2362.9

BNP, brain natriuretic peptide; ZDV, zidovudine; PI, protease inhibitor; LVEF, left ventricular ejection fraction.

References

Valli N, Gobinet A, Bordenave L. Review of 10 years of the clinical use of brain natriuretic peptide in cardiology. J Lab Clin Med. 1999;134:437-444.

Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet. 1997;350:1349-1353.

Yamamoto K, Burnett JC Jr, Bermudez EA, et al. Clinical criteria and biochemical markers for the detection of systolic dysfunction. J Card Fail. 2000;6:194-200.

Suzuki T, Yamaoki K, Nakajima O, et al. Screening for cardiac dysfunction in asymptomatic patients by measuring B-type natriuretic peptide levels. Jpn Heart J. 2000;41:205-214.

McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351:9-13.

Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37:379-385.

DeCastro S, Migliau G, Silvestri A, et al. Heart involvement in AIDS: a prospective study during various stages of the disease. Eur Heart J. 1992;13:1452-1459.

Rerkpattanapipat P, Wongpraparut N, s LE, Kotler MN. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med. 2000; 160:602-608.

Yunis NA, Stone VE. Cardiac manifestations of HIV/AIDS: a review of disease spectrum and clinical management. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:145-154.

s AD, Lederman RJ, MacGregor JS, Cheitlin MD. Cardiovascular involvement in AIDS. Curr Probl Cardiol. 1997;22:111-148.

Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Cardiac involvement in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologicodei pazienti affetti da AIDS Investigators. AIDS Res Hum Retroviruses. 1998;14:1071-1077.

W. Cardiomyopathy in AIDS: a pathophysiological perspective. Prog Cardiovasc Dis. 2000; 43:151-170.

Herskowitz A. Cardiomyopathy and other symptomatic heart diseases associated with HIV infection. Curr Opin Cardiol. 1996;11:325-331.

Carrillo-Jimenez R, Lamas GA, Hennekens CH. Plasma markers of brain natriuretic peptide: a potential marker for HIV-related cardiomyopathy. J Cardiovasc Pharmacol Ther. 2002;7:135-137.

Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. N Engl J Med. 1998;339:1093-1099.

Herskowitz A, Vlahov D, Willoughby S, et al. Prevalence and incidence of left ventricular dysfunction in patients with human immunodeficiency virus infection. Am J Cardiol. 1993;71:955-958.

Segal BH, Factor SM. Myocardial risk factors other than human immunodeficiency virus infection may contribute to histologic cardiomyopathic changes in acquired immune deficiency syndrome. Mod Pathol. 1993;6:560-564.

son LW. The limited availability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261:884-888.

Akhras F, Durbey S, Gazzard B, Noble MI. Emerging patterns of heart disease in HIV infected homosexual subjects with and without opportunistic infections; a prospective color flow Doppler echocardiographic study. Eur Heart J. 1994;15:68-75.

Corallo S, Mutinelli MR, Moroni M, et al. Echocardiography detects myocardial damage in AIDS: prospective study in 102 patients. Eur Heart J. 1988; 9:887-892.

RP, Simon MA, Mathier MA, et al. Dilated cardiomyopathy associated with simian AIDS in nonhuman primates. Circulation. 2000;101:185-193.

RP. SIV cardiomyopathy in non-human primates. Trends Cardiovasc Med. 2001;11:242-246.

W, Grupp IL, Grupp G, et al. Cardiac dysfunction occurs in the HIV-1 transgenic mouse treated with zidovudine. Lab Invest. 2000;80:187-197.

Carnio EC, Jankowski M, Mukaddam-Daher S, et al. Elevated levels of natriuretic peptides in lungs of hamsters with genetic cardiomyopathy. Regul Pept. 1997;70:67-73.

Hennekens CH, Buring J, Mayrent SL, eds. Epidemiology in Medicine. Boston: Little Brown & Co Inc; 1987.

Acknowledgements

The authors thank Kathy Anastas, RN, for assistance provided during this research study.

Funding Information

The study of brain natriuretic peptide levels stemming from the case reported here was partially supported by Biosite Diagnostics, Inc (San Diego).

Rodolfo Carrillo-Jimenez, MD, Alvaro Buenano, MD, Mount Sinai Medical Center, Miami Beach, Fla; L. Treadwell, MD, Harvey Goldfine, MD, MetroWest Medical Center, Framingham, Mass; Gervasio A. Lamas, MD, University of Miami School of Medicine, Coral Gables, Fla, and, Mount Sinai Medical Center, Miami Beach; H. Hennekens, MD, DrPH, University of Miami School of Medicine, Coral Gables, and Mount Sinai Medical Center, Miami Beach.