Correspondence

Cardiomyopathy with Mitochondrial Damage Associated with Nucleoside Reverse-Transcriptase Inhibitors

N Engl J Med 2002; 347:1895-1896December 5, 2002

Article

To the Editor:

In July 2000, a 58-year-old man infected with the human immunodeficiency virus (HIV) began treatment with highly active antiretroviral therapy, which initially consisted of zidovudine, lamivudine, and ritonavir-boosted indinavir. After three months, a buffalo hump, anemia, and proximal muscle weakness developed, and the regimen was therefore switched to stavudine, lamivudine, and nevirapine. Because of pain in his legs, stavudine was replaced with abacavir three months later.

In February 2001, the patient was admitted to our hospital because of progressive exertional dyspnea and peripheral edema. At that time, his CD4 count had risen to 160 per cubic millimeter and plasma HIV RNA was undetectable (<50 copies per milliliter). At presentation, enlargement of the heart and a pleural effusion were seen on a chest radiograph. Echocardiography showed severe dilated cardiomyopathy. Left-sided catheterization showed normal coronary arteries, and a myocardial-biopsy specimen was obtained through right-sided catheterization, which was complicated by a tamponade due to an unusually thin cardiac wall. Histologic examination showed hypertrophic myocardial tissue without any signs of inflammation or infection. Electron microscopy showed striking accumulations of myelin figures in a considerable proportion of the mitochondria. In some fields, cytoplasmic areas were filled with mitochondria that were stuffed with large myelin figures (Figure 1AFigure 1Electron Micrograph of a Myocardial-Biopsy Specimen, Showing a Large Cluster of Mitochondria. and Figure 1B). Such changes are highly suggestive of selective mitochondrial damage. Since the nucleoside reverse-transcriptase inhibitors with the greatest mitochondrial toxicity (stavudine and zidovudine) had already been withdrawn shortly before admission, treatment with an angiotensin-converting–enzyme inhibitor, furosemide, and digoxin was started. The patient's condition improved slowly. The most recent echocardiographic study showed improvement in the cardiac dimensions.

Dilated cardiomyopathy is believed to be caused by a direct action of HIV on the myocardial tissue or an autoimmune process induced by HIV or possibly other cardiotropic viruses.1 In animal models, there is clear evidence of cardiomyopathy due to the use of zidovudine,2 but in humans, such an association has been described only in children.3 In general, nucleoside reverse-transcriptase inhibitors are not believed to cause cardiomyopathy. However, nucleoside reverse-transcriptase inhibitors — in particular, zalcitabine, didanosine, stavudine, and zidovudine — can have mitochondrial toxic effects in several other tissues.

This case demonstrates cardiomyopathy associated with severe mitochondrial damage in an HIV-infected patient after treatment with nucleoside reverse-transcriptase inhibitors that have mitochondrial toxicity, which improved after these drugs were stopped.

Fenneke C.P. Frerichs, M.D.
Onze Lieve Vrouwe Gasthuis, 1090 HM Amsterdam, the Netherlands

Koert P. Dingemans, Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands

Kees Brinkman, M.D., Ph.D.
Onze Lieve Vrouwe Gasthuis, 1090 HM Amsterdam, the Netherlands
k.brinkman@olvg.nl

3 References

1. 1

   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 | Medline

2. 2

   Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective. Prog Cardiovasc Dis 2000;43:151-170
   CrossRef | Web of Science | Medline

3. 3

   Domanski MJ, Sloas MM, Follmann DA, et al. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr 1995;127:137-146
   CrossRef | Web of Science | Medline

Citing Articles (16)

Citing Articles

1. 1

   Lungile Pepeta, Antoinette M. Cilliers. (2012) Impact of Highly Active Antiretroviral Therapy on paediatric Human Immunodeficiency Virus-associated left ventricular dysfunction within the Johannesburg teaching hospital complex. Cardiology in the Young1-10
   CrossRef

2. 2

   Patrick Yu-Wai-Man, Philip G. Griffiths, Patrick F. Chinnery. (2011) Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies. Progress in Retinal and Eye Research 30:2, 81-114
   CrossRef

3. 3

   K. E. Mondy, J. Gottdiener, E. T. Overton, K. Henry, T. Bush, L. Conley, J. Hammer, C. C. Carpenter, E. Kojic, P. Patel, J. T. Brooks, . (2011) High Prevalence of Echocardiographic Abnormalities among HIV-infected Persons in the Era of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 52:3, 378-386
   CrossRef

4. 4

   Kerstin Balcarek, Nils Venhoff, Catherine Deveaud, Bertrand Beauvoit, Jacques Bonnet, Janbernd Kirschner, Ana C Venhoff, Dirk Lebrecht, Ulrich A Walker. (2010) Role of Pyrimidine Depletion in the Mitochondrial Cardiotoxicity of Nucleoside Analogue Reverse Transcriptase Inhibitors. JAIDS Journal of Acquired Immune Deficiency Syndromes 55:5, 550-557
   CrossRef

5. 5

   James J. Kohler, William Lewis. 2010. Cardiovascular Toxicities of Life-Saving Drugs: Antiviral Therapy. , 313-332.
   CrossRef

6. 6

   Anasuya Gupta, Sudhiranjan Gupta, David Young, Biswajit Das, James McMahon, Subha Sen. (2010) Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure. Laboratory Investigation 90:4, 520-530
   CrossRef

7. 7

   Guillaume Montastruc, Sylvie Favreliere, Agnès Sommet, Atul Pathak, Maryse Lapeyre-Mestre, Marie-Christine Perault-Pochat, Jean-Louis Montastruc, . (2010) Drugs and dilated cardiomyopathies: a case/noncase study in the French PharmacoVigilance Database. British Journal of Clinical Pharmacology 69:3, 287-294
   CrossRef

8. 8

   , Till Neumann, Nico Reinsch, Kathrin Neuhaus, Norbert Brockmeyer, Anja Potthoff, Stefan Esser, Martin Hower, Anja Neumann, Sarah Mostardt, Götz Gelbrich, Raimund Erbel. (2009) Wertigkeit des Biomarkers BNP bei HIV-infizierten Patienten. Herz 34:8, 634-640
   CrossRef

9. 9

   Gilles J Thöni, Iris Schuster, Guillaume Walther, Stéphane Nottin, Agnès Vinet, Franck Boccara, Jean-Marc Mauboussin, Isabelle Rouanet, Stéphane Edérhy, Michel Dauzat, Patick Messner-Pellenc, Philippe Obert. (2008) Silent cardiac dysfunction and exercise intolerance in HIV+ men receiving combined antiretroviral therapies. AIDS 22:18, 2537-2540
   CrossRef

10. 10

    Iris Schuster, Gilles Jacques Thöni, Stéphane Edérhy, Guillaume Walther, Stéphane Nottin, Agnès Vinet, Franck Boccara, Mohamed Khireddine, Pierre-Marie Girard, Jean-Marc Mauboussin, Isabelle Rouanet, Michel Dauzat, Ariel Cohen, Patrick Messner-Pellenc, Philippe Obert. (2008) Subclinical Cardiac Abnormalities in Human Immunodeficiency Virus–Infected Men Receiving Antiretroviral Therapy. The American Journal of Cardiology 101:8, 1213-1217
    CrossRef

11. 11

    Jennifer H Yearley, Keith G Mansfield, Angela AL Carville, George G Sokos, Dongling Xia, Christine B Pearson, Richard P Shannon. (2008) Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFα. AIDS 22:5, 585-594
    CrossRef

12. 12

    Elisa Nemes, Enrico Lugli, Milena Nasi, Roberta Ferraresi, Marcello Pinti, Roberto Bugarini, Vanni Borghi, Francesca Prati, Roberto Esposito, Andrea Cossarizza, Cristina Mussini. (2006) Immunophenotype of HIV+ patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system. AIDS 20:16, 2021-2032
    CrossRef

13. 13

    Jennifer H. Yearley, Christine Pearson, Angela Carville, Richard P. Shannon, Keith G. Mansfield. (2006) SIV-Associated Myocarditis: Viral and Cellular Correlates of Inflammation Severity. AIDS Research and Human Retroviruses 22:6, 529-540
    CrossRef

14. 14

    Cristina Mussini, Marcello Pinti, Roberto Bugarini, Vanni Borghi, Milena Nasi, Elisa Nemes, Leonarda Troiano, Giovanni Guaraldi, Andrea Bedini, Caroline Sabin, Roberto Esposito, Andrea Cossarizza. (2005) Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study. AIDS 19:15, 1627-1633
    CrossRef

15. 15

    J. Tanuma, A. Ishizaki, H. Gatanaga, Y. Kikuchi, S. Kimura, M. Hiroe, S. Oka. (2003) Dilated Cardiomyopathy in an Adult Human Immunodeficiency Virus Type 1-Positive Patient Treated with a Zidovudine-Containing Antiretroviral Regime. Clinical Infectious Diseases 37:7, e109-e111
    CrossRef

16. 16

    &NA;. (2003) Stavudine/zidovudine. Reactions Weekly &amp;NA;:934, 11
    CrossRef