Correspondence
Dilated Cardiomyopathy in HIV-Infected Patients
N Engl J Med 1999; 340:732-735March 4, 1999
- Article
To the Editor:
In their study of dilated cardiomyopathy in patients with human immunodeficiency virus (HIV) infection, Barbaro et al. (Oct. 15 issue)1 did not ascertain whether nutritional abnormalities were present, as Lipshultz notes in his accompanying editorial.2 Causes of left ventricular dysfunction in patients with HIV infection include cardiomyopathies due to wasting and deficiencies of trace elements.2 Selenium deficiency is an independent factor associated with high mortality among HIV-infected patients.3 As a component of glutathione peroxidase, selenium is involved in the antioxidant response in cells and tissues. In patients with HIV infection, selenium deficiency may be due to the trapping of selenium by a selenoprotein encoded by the proviral genome.3 Congestive cardiomyopathy or skeletal-muscle disorders may develop in patients with selenium deficiency.4 Skeletal-muscle involvement in HIV-infected patients is associated with marked selenium deficiency.5
To determine whether antioxidant deficiencies may be implicated in the occurrence of cardiac involvement in patients with HIV infection, we measured selenium and vitamin E in eight HIV-infected patients with dilated cardiomyopathy (ejection fraction, <45 percent, and left ventricular end-diastolic diameter, >55 mm, as measured with a modification of Simpson's rule)1 who had no history of heart disease before HIV infection. We also studied a control group of eight HIV-infected patients with normal echocardiographic findings who were matched with the patients with cardiomyopathy according to sex, age, Karnofsky index, and CD4 count. Selenium was measured in plasma with the use of atomic-absorption spectrometry (normal value, >0.80 μM).5 Plasma vitamin E was measured with the use of high-performance liquid chromatography (normal value, >12 μM).5
Antioxidant deficiency was more frequent in the patients than in the matched controls (P<0.05 by Fisher's exact test). Seven of the eight patients with dilated cardiomyopathy had a deficiency of selenium (six patients) or vitamin E (three patients). Two of the eight controls had selenium deficiency; none had vitamin E deficiency. Selenium levels, but not vitamin E levels, were significantly lower in the patients than in the controls. The mean (±SD) selenium concentration was 0.67±0.21 μM in the patients with dilated cardiomyopathy and 0.86±0.12 μM in the controls (P<0.05 by Student's paired t-test). The mean vitamin E concentration was 14.5±4.6 μM in the patients with dilated cardiomyopathy and 18.3±4.2 μM in the controls (P=0.16).
Supplementation was evaluated in three patients with selenium deficiency, who were given oral selenium (200 μg daily) while their antiretroviral therapy remained unchanged. Two patients evaluated for more than three months had clinical and echocardiographic improvement as their selenium levels returned to normal. In the third patient, there was no substantial improvement. The reason for the inconsistent results may be related to the duration of antioxidant deficiency before supplementation, as has been suggested in the case of Keshan disease, an endemic cardiomyopathy related to selenium deficiency.4 We conclude that deficiency of selenium and vitamin E may be involved in the pathogenesis of some cases of dilated cardiomyopathy in HIV-infected patients. A controlled study of antioxidant supplementation in such patients would be helpful.
5 ReferencesPatrick Chariot, M.D.
Hôpital Henri Mondor, 94000 Créteil, FranceHervé Perchet, M.D.
Isabelle Monnet, M.D.
Centre Hospitalier Intercommunal, 94010 Créteil, France1
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
Full Text | Web of Science | Medline2
Lipshultz SE . Dilated cardiomyopathy in HIV-infected patients. N Engl J Med 1998;339:1153-1155
Full Text | Web of Science | Medline3
Baum MK ,Shor-Posner G ,Lai S , et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:370-374
CrossRef | Medline4
Dworkin BM . Selenium deficiency in HIV infection and the acquired immunodeficiency syndrome (AIDS). Chem Biol Interact 1994;91:181-186
CrossRef | Web of Science | Medline5
Chariot P ,Dubreuil-Lemaire ML ,Zhou JY , et al. Muscle involvement in human immunodeficiency virus-infected patients is associated with marked selenium deficiency. Muscle Nerve 1997;20:386-389
CrossRef | Web of Science | Medline
To the Editor:
We were surprised that in the report by Barbaro et al. no mention was made of the status of the coronary arteries. Coronary catheterization is often performed in patients with cardiomyopathy, in order to diagnose and treat obstructive coronary-artery lesions, especially if risk factors are present.1 Of the 76 patients in the study by Barbaro et al., only 36 (47 percent) had a histologic diagnosis of active myocarditis, and only 27 (36 percent) had a diagnosis of borderline myocarditis. Thus, there may have been other causes of dilated cardiomyopathy.
Coronary-artery lesions have been found in patients with HIV infection. One postmortem study2 showed severe atherosclerotic lesions (up to 80 to 90 percent obstruction of the arterial lumen) in eight patients with AIDS (mean age, 27 years). In addition, myocardial interstitial fibrosis was found, as it was in the 13 patients in the study by Barbaro et al. who did not have clear or borderline myocarditis. None of the eight patients in the postmortem study had associated cardiovascular risk factors.
The postmortem study was performed before the widespread use of current anti-HIV therapy. Protease inhibitors have been shown to be linked to severe premature coronary artery disease,3 perhaps connected to the associated hyperlipidemia. In the study by Barbaro et al., 71 of the 76 patients with dilated cardiomyopathy had a CD4 count of less than 400 cells per cubic millimeter. These were the patients who were most likely to receive antiretroviral medication.
In addition, there may be activation of cytomegalovirus infection in patients with AIDS.4 Cytomegalovirus infection has been linked to atherosclerosis and also to restenosis after angioplasty.5 No data are available on the incidence of activation of cytomegalovirus in the cohort of patients described by Barbaro et al.
In summary, dilated cardiomyopathy may be seen in patients with HIV infection. Myocarditis may cause some of these cases of cardiomyopathy, although other mechanisms, such as coronary artery disease and cytomegalovirus infection, need to be assessed.
5 ReferencesStephen Malnick, M.B., B.S.
Sorel Goland, M.D.
Kaplan Medical Center, Rehovot 76100, Israel1
Dec GW ,Fuster V . Idiopathic dilated cardiomyopathy. N Engl J Med 1994;331:1564-1575
Full Text | Web of Science | Medline2
Paton P ,Tabib A ,Loire R ,Tete R . Coronary artery lesions and human immunodeficiency virus infection. Res Virol 1993;144:225-231
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Henry K ,Melroe H ,Huebsch J , et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998;351:1328-1328
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Jacobson MA ,Mills J . Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS): clinical findings, diagnosis, and treatment. Ann Intern Med 1988;108:585-594
Web of Science | Medline5
Epstein SE ,Speir E ,Zhou YF ,Guetta E ,Leon M ,Finkel T . The role of infection in restenosis and atherosclerosis: focus on cytomegalovirus. Lancet 1996;348:Suppl 1:s13-s17
CrossRef | Web of Science | Medline
To the Editor:
Barbaro and colleagues present the results of their large, prospective study of the incidence of dilated cardiomyopathy in asymptomatic HIV-infected adults, correlating the development of dilated cardiomyopathy with immunologic and virologic data. During a five-year follow-up period, an echocardiographic diagnosis of dilated cardiomyopathy was made in 8 percent of the patients. The incidence of dilated cardiomyopathy was higher among patients with a CD4 count of less than 400 cells per cubic millimeter than among those with higher CD4 counts. These results are consistent with those of a previous study indicating that cardiac involvement usually occurs during the late stages of HIV infection, when the immunologic system is clearly compromised.1 However, Barbaro et al. excluded from their study patients who used illicit drugs. Such patients constitute the majority of HIV-infected patients in Italy, where the study was performed. This exclusion could have introduced a major bias in the assessment of the incidence of dilated cardiomyopathy, which was one of the objectives of the study.
We evaluated 53 HIV-infected patients from all groups at risk for HIV infection, using indium-111–labeled antimyosin scintigraphy, a sensitive means of detecting early myocardial damage,2 to determine whether subclinical myocardial damage had occurred early in the course of disease. Thirty-two patients (60 percent) had AIDS. None of the patients had any clinical condition suggestive of myocardial involvement. Seven patients (13 percent) had positive antimyosin scans. The other 46 patients had normal scans.
Of the seven patients with positive scans, two were classified as having stage A1 HIV infection, one as having stage B2 infection, and four as having stage C3 infection, according to the 1993 classification system of the Centers for Disease Control and Prevention. All the patients underwent echocardiographic examination. Six of the seven patients with positive scans had normal function; one patient had dilated cardiomyopathy with a left ventricular ejection fraction of 25 percent. Logistic-regression analysis was performed to identify predictors of myocardial damage among variables pertaining to HIV infection; only the duration of infection was a significant predictor of damage. Since our study included patients treated with highly active antiviral therapy, it is possible that the CD4 cell count was not a useful surrogate marker of myocardial damage in this population. Our results are similar to findings of Le Guludec et al. in their study of patients with AIDS.3
Thus, it is conceivable that myocardial involvement is not infrequent in patients with HIV infection, that it is correlated with the duration of infection, and that it can be detected early in the course of the disease with antimyosin scintigraphy, which may contribute substantially to patient care.
3 ReferencesAlbert Flotats, M.D.
Pere Domingo, M.D.
Ignasi Carrió, M.D.
Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain1
Herskowitz A ,Wu TC ,Willoughby SB , et al. Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus. J Am Coll Cardiol 1994;24:1025-1032
CrossRef | Web of Science | Medline2
Yasuda T ,Palacios IF ,Dec GW , et al. Indium 111-monoclonal antimyosin antibody imaging in the diagnosis of acute myocarditis. Circulation 1987;76:306-311
CrossRef | Web of Science | Medline3
Le Guludec D ,Weinmann P ,Namade M , et al. Prevalence of myocarditis in acquired immunodeficiency syndrome (AIDS): an indium-111-antimyosin scintigraphic study. Eur J Nucl Med 1992;19:671-671 abstract.
Author/Editor Response
The authors reply:
To the Editor: The role of selenium deficiency in the development of HIV-associated dilated cardiomyopathy is still controversial.1 The results reported by Chariot et al., although interesting, cannot be considered definitive because of the small sample. The relation between selenium deficiency and cardiomyopathy has also been studied in selenium-deficient mice, with contrasting results.2
Selenium deficiency may be involved in the increased production of free radicals in patients with HIV disease. In a previous study, we reported that asymptomatic HIV-positive subjects had an impairment of the cardiac vagal system (assessed by corrected coefficients of electrocardiographic RR intervals), which were significantly correlated with markers of lipoperoxidation.3
In the editorial accompanying our article, Lipshultz reports that HIV encephalopathy is one of the strongest predictors of cardiac involvement in patients with AIDS. We are currently studying the association between HIV encephalopathy and HIV-associated dilated cardiomyopathy. Interestingly, the preliminary results demonstrate that patients in whom encephalopathy develops have more severe left ventricular dysfunction and a higher rate of mortality from congestive heart failure than patients without encephalopathy (unpublished data). These data on HIV-infected adults confirm the previously reported observations in HIV-infected children.4 The impairment of the autonomic system may contribute to the progression of HIV-associated dilated cardiomyopathy, and increased lipoperoxidation may be involved in this impairment. However, the role of selenium deficiency in the lipoperoxidation process still has to be determined.
The assessment of the status of the coronary arteries was not one of the end points of our study. According to our experience with autopsy studies, the overall prevalence of coronary-artery lesions in patients with AIDS is low, and these lesions are not significantly associated with cytomegalovirus infection.5 The histologic finding of myocardial fibrosis may represent the final expression of a previous myocardial inflammatory process without specific involvement of the coronary arteries. It is our opinion that coronary artery disease should not be considered a specific causal factor in HIV-associated dilated cardiomyopathy.
Drug addicts have a high prevalence of endocarditis, and in several patients with previous infectious endocarditis, dilated cardiomyopathy related to chronic valvular regurgitation (tricuspid, mitral, or both) has developed.5 Cocaine abuse has been associated with myocarditis and dilated cardiomyopathy, even in HIV-negative subjects. For these reasons, we excluded drug addicts from our study. The diagnostic value of indium-111–labeled antimyosin scintigraphy, a sensitive method used by Flotats et al., further supports the role of the inflammatory process in dilated cardiomyopathy. However, the value of this technique in evaluating HIV-associated dilated cardiomyopathy requires confirmation in further controlled investigations.
5 ReferencesGiuseppe Barbaro, M.D.
University La Sapienza, 00161 Rome, ItalyGiorgio Barbarini, M.D.
University of Pavia, 27100 Pavia, Italy1
Kaul S ,Fishbein MC ,Siegel RJ . Cardiac manifestations of acquired immunodeficiency syndrome: a 1991 update. Am Heart J 1991;122:535-544
CrossRef | Web of Science | Medline2
Beck MA ,Kolbeck PC ,Shi Q ,Rohr LH ,Morris VC ,Levander OA . Increased virulence of a human enterovirus (coxsackievirus B3) in selenium-deficient mice. J Infect Dis 1994;170:351-357
CrossRef | Web of Science | Medline3
Barbaro G ,Di Lorenzo G ,Soldini M , et al. Vagal system impairment in human immunodeficiency virus-positive patients with chronic hepatitis C: does hepatic glutathione deficiency have a pathogenetic role? Scand J Gastroenterol 1997;32:1261-1266
CrossRef | Web of Science | Medline4
Lipshultz SE ,Easley KA ,Orav EJ , et al. Left ventricular structure and function in children infected with human immunodeficiency virus: the prospective P2C2 HIV Multicenter Study. Circulation 1998;97:1246-1256
Web of Science | Medline5
Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G, Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators
CrossRef | Web of Science | Medline
Author/Editor Response
Micronutrient deficiencies are common in HIV-infected patients, but they are not always related to weight loss. We agree with Chariot et al. that nutrition should be assessed as part of an overall evaluation of ventricular function in patients with HIV infection, since many clinical factors that can influence ventricular function, other than HIV infection, may be operating simultaneously. In particular, it is important to determine selenium, carnitine, and thiamine levels in patients with ventricular dysfunction, because each of these micronutrients alone can cause decreased ventricular function.1
We have examined the relation between nutrition and ventricular mass and function in HIV-infected children, in whom ventricular mass and function are preserved despite low weight and height.2 We have previously shown that selenium deficiency is common in HIV-infected children, with significant positive correlations of the selenium level with weight, the albumin level, and the CD4 count.3 In our study of 19 children, there were positive but nonsignificant relations between selenium levels and ventricular function.3 It is unclear what degree of selenium deficiency can cause ventricular dysfunction or whether there are other synergistic clinical effects. For example, low levels of selenium or other micronutrients have been reported to increase the ability of coxsackievirus to cause cardiac damage and to increase the toxic effects of zidovudine on skeletal muscle; both findings may be relevant to selenium-related ventricular dysfunction.
We have prospectively followed 64 HIV-infected children and 26 control children to determine alterations in serum micronutrient levels, as part of a large prospective study of nutrition and AIDS (the Nutrition for Healthy Living Study). On the basis of preliminary data, children with HIV infection have adequate intake of all major macronutrients and micronutrients, with the exception of zinc, vitamin E, and vitamin D (as measured in relation to recommended daily allowances for age). However, comparisons of the HIV-infected and control groups revealed differences in the intake of riboflavin, vitamin D, vitamin K, calcium, folate, niacin, and thiamine, regardless of nutritional status. These findings suggest that children with HIV infection are at risk for micronutrient deficiencies that are independent of nutritional status and that have the potential to affect other organ systems, such as the heart.
We concur that all factors influencing cardiac function in HIV-infected patients need to be evaluated in order to determine accurately the pathogenesis of heart disease in these patients. Our recommendations for the evaluation of HIV-infected patients with ventricular dysfunction include the assessment of micronutrient status, since a deficiency becomes a potentially treatable cause of cardiomyopathy.4 In the light of the new highly active antiretroviral therapies that have already proved to affect nutritional status, with the development of lipodystrophy, it is even more important that prospective studies, accounting for these clinical factors, be continued.
4 ReferencesTracie L. Miller, M.D.
Steven E. Lipshultz, M.D.
University of Rochester Medical Center, Rochester, NY 146421
Miller TL. Cardiac complications of nutritional disorders. In: Lipshultz SE, ed. Cardiology in AIDS. New York: Chapman & Hall, 1998:307-16.
2
Miller TL ,Orav EJ ,Colan SD ,Lipshultz SE . Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus. Am J Clin Nutr 1997;66:660-664
Web of Science | Medline3
Miller TL ,Orav EJ ,McIntosh K ,Lipshultz SE . Is selenium deficiency clinically significant in pediatric HIV infection? Gastroenterology 1993;104:Suppl:A746-A746 abstract.
Web of Science4
Moorthy LN, Lipshultz SE. Cardiovascular monitoring of HIV-infected patients. In: Lipshultz SE, ed. Cardiology in AIDS. New York: Chapman & Hall, 1998:345-86.
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Michel Lorgeril, Patricia Salen. (2006) Selenium and antioxidant defenses as major mediators in the development of chronic heart failure. Heart Failure Reviews 11:1, 13-17
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M. de Lorgeril, P. Salen. 2004. Diet and the prevention of coronary heart disease. , 21-55.
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Michel de Lorgeril, Patricia Salen. 2003. Dietary Prevention of CHD. .
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Patrick Chariot, Olivier Bignani. (2003) Skeletal muscle disorders associated with selenium deficiency in humans. Muscle & Nerve 27:6, 662-668
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GIUSEPPE BARBARO, STEVEN E. LIPSHULTZ. (2001) Pathogenesis of HIV-Associated Cardiomyopathy. Annals of the New York Academy of Sciences 946:1, 57-81
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Heloise Buys, Gregory Hussey. 2001. Micronutrients in the Case Management of Hiv Infection. , 201-217.
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