Cardiomyopathy with Mitochondrial Damage Associated with Nucleoside Reverse-Transcriptase Inhibitors

Frerichs, Fenneke C.P.; Dingemans, K. P.; Brinkman, Kees

doi:10.1056/nejm200212053472320

Cited by 54 publications

(21 citation statements)

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“…Myelin figures are indicative of mitochondrial damage 10 when found in human HF samples, but it was not very clear at which point in time they occur during the progression of disease. Our extensive study in the hypertrophic murine model, starting from initiation and progression through transition from hypertrophy to HF, documented that these structures start to appear only at the end stage, and also, the formation of myelin body is a sequential phenomenon rather than a sudden mitochondrial alteration.…”

Section: Myofibril Structural Changesmentioning

confidence: 99%

“…7 End-stage human HF is characterized by fibrosis as well as impairment of myocyte degeneration, [7][8][9] apoptotic cell death, 9 and HF markers such as myeloid structures. [10][11][12] In recent years, many cardiomyopathies have been linked to mutations in either sarcomeric or cytoskeletal proteins, resulting in cardiovascular diseases, and several mouse models have been generated to study the structural and functional changes and elucidate the pathophysiology of the disease. In the cardiac hypertrophic mouse model involving Smad4, electron microscopic observations revealed abnormal mitochondria and disruption of Z-lines.…”

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confidence: 99%

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Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure

Gupta

Young

et al. 2010

Laboratory Investigation

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Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice. However, as the disease progresses, cardiomyocytes show deterioration in some mitochondrial as well as myofibril features, evidenced by swelling of mitochondria, misalignment of myofibril structure, and blurring as well as breakage of Z-lines. At 36 weeks of age, Tg mice (the group in transition from hypertrophy to HF) show significant degenerative changes in cardiomyocytes, including swelling of mitochondria, disruption of the nuclear membrane, and absence of myofibril structure. Besides these, formation of myelin bodies was also observed, a feature typically found in human hearts with HF. Changes in Z-line architecture were further confirmed by alteration in the gene expression profile of desmin and tubulin, the two main cytoskeletal proteins. We thus conclude that Tg mice overexpressing myotrophin show no visible changes in the initiation phase (4 weeks); however, as the disease progresses, alterations in the cytoskeleton are found during the transition phase from hypertrophy to HF (36 weeks onward). Our data suggest that treatment for prevention/reversal of hypertrophy should start at the early stage of hypertrophy to prevent its transition to HF.

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Section: Myofibril Structural Changesmentioning

confidence: 99%

mentioning

confidence: 99%

Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure

Gupta

Young

et al. 2010

Laboratory Investigation

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“…Although the use of highly active anti-retroviral therapy (HAART) is associated with virological suppression and immunological recovery in people living with HIV infection, HIV and HAART, especially protease inhibitors, induce disorders of lipid metabolism,7,8 such as diabetes and dyslipidaemia, which are implicated in the increased incidence of cardiovascular disease in this patient population 9,10…”

Section: Introductionmentioning

confidence: 99%

Electrocardiographic findings in a cross-sectional study of human immunodeficiency virus (HIV) patients in Enugu, south-east Nigeria

Njoku¹,

Ejim²,

Anisiuba³

et al. 2016

CVJA

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SummaryBackgroundElectrocardiographic (ECG) abnormalities are prevalent in subjects with human immunodeficiency virus (HIV) infection. In this study, three groups of subjects were investigated and the prevalence of ECG abnormalities was analysed.MethodsA cross-sectional study was carried out on adults between November 2010 and November 2011 at the University of Nigeria Teaching Hospital, Enugu, Nigeria. One hundred HIV-infected patients on highly active anti-retroviral therapy (HAART), 100 HIV-infected HAART-naïve patients and 100 HIV-negative controls were recruited. Twelve-lead electrocardiograms were done on all subjects. Data were analysed using the chi-squared, Student’s t-, one-way ANOVA and Duncan post hoc tests.ResultsLeft-axis deviation was seen in 15 (16%) of the HIV-positive subjects on HAART, 10 (13.7%) of the HAART-naïve subjects and eight (21%) of the controls (p = 0.265). Eight (11%) subjects with left ventricular hypertrophy (p <0.001) and two (2.7%) with ST-segment elevation were found among the HIV-positive HAART-naïve subjects (p = 0.134). Prolonged QTc interval was seen in 17 (18.2%) of the HIV-positive patients on HAART, 12 (16.4%) of the HIV-positive HAART-naïve patients and four (10.5%) of the controls (p = 0.012).ConclusionThe prevalence of ECG abnormalities was higher in the HIV-positive patients on HAART (93%) and the HIV-positive HAART-naïve patients (73%) compared to the controls.

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“…25 Drug-related cardiotoxicities may also play a role in some cases. 1,26,27 Simian immunodeficiency viruses (SIV) are lentiviruses that are genetically closely related to HIV and represent the original sources from which both HIV-1 and HIV-2 derived. 28,29 SIV infection of Asian macaque species produces a fatal immunodeficiency syndrome with properties of disease progression very similar to those seen in humans with HIV infection.…”

Section: Introductionmentioning

confidence: 99%

SIV-Associated Myocarditis: Viral and Cellular Correlates of Inflammation Severity

Yearley

Pearson

Carville

et al. 2006

AIDS Research and Human Retroviruses

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Myocarditis is a common finding in HIV-infected people. Cardiac inflammatory lesions and functional abnormalities similar to those documented in HIV infection are frequently seen in SIV infection of rhesus monkeys, suggesting a shared disease mechanism. A retrospective analysis of cardiac tissue collected at necropsy was performed to assess correlates of myocardial inflammation in SIV-infected rhesus monkeys. Intramyocardial SIV-infected cells were identified in 7 of 21 hearts from SIV-infected animals, with viral protein consistently colocalizing with the macrophage marker HAM 56. Productively infected cells occurred in low numbers, and did not correlate with the presence or quantity of inflammation or necrosis. Intramyocardial CMV was identified in 6 of 21 hearts from SIV+ animals, but also did not correlate with the presence or quantity of inflammation or necrosis. In contrast, T cell infiltration correlated inversely with DC-SIGN+ cell numbers, which occurred in significantly higher numbers in SIV+ animals with histologically normal myocardium than in SIV+ animals with active or borderline myocarditis or in uninfected controls (p < 0.001), suggesting an important immunoregulatory role for this population within the myocardium.

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Cardiomyopathy with Mitochondrial Damage Associated with Nucleoside Reverse-Transcriptase Inhibitors

Cited by 54 publications

References 3 publications

Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure

Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure

Electrocardiographic findings in a cross-sectional study of human immunodeficiency virus (HIV) patients in Enugu, south-east Nigeria

SIV-Associated Myocarditis: Viral and Cellular Correlates of Inflammation Severity

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