Avaliação do metabolismo dos fosfatos de alta energia em pacientes com doença de Chagas

Leme, Ana Maria Betim Paes; Salemi, Vera Maria Cury; Parga, José R.; Ianni, Bárbara Maria; Mady, Charles; Weiss, Robert G.; Kalil‐Filho, Roberto

doi:10.1590/s0066-782x2010005000099

Cited by 13 publications

(7 citation statements)

References 30 publications

(38 reference statements)

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“…A reduction of high-energy phosphates, indicative of reduced ATP production, has been observed in vivo in CCC heart tissue. 34 In agreement, mitochondrial DNA content was found to be reduced in CCC heart tissue as compared to healthy or DCM patients. 35 Comparatively, CCC exhibited heightened nitro-oxidative stress in contrast to DCM, further indicating that mitochondrial function is especially disturbed in CCC.…”

Section: Mitochondria In the Pathogenesis Of CCCsupporting

confidence: 59%

Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

Nunes,

Roda,

Andrieux

et al. 2023

Exp Biol Med (Maywood)

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Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies, which may be linked to a Th1-T cell rich myocarditis with abundant interferon (IFN)-γ and tumor necrosis factor (TNF)-α, selectively lower levels of mitochondrial energy metabolism enzymes in the heart, and reduced levels of high-energy phosphate, indicating poor adenosine triphosphate (ATP) production. IFN-γ and TNF-α signaling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function in cardiomyocytes, recapitulating findings in CCC heart tissue. Genetic studies such as whole-exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. In this minireview, we summarized studies showing how IFN-γ and TNF-α affect cell energy generation, mitochondrial health, and redox homeostasis in cardiomyocytes, in addition to human CD and mitochondria. We hypothesize that cytokine-induced mitochondrial dysfunction in genetically predisposed patients may be the underlying cause of CCC severity and we believe this mechanism may have a bearing on other inflammatory cardiomyopathies.

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Section: Mitochondria In the Pathogenesis Of CCCsupporting

confidence: 59%

Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

Nunes,

Roda,

Andrieux

et al. 2023

Exp Biol Med (Maywood)

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“…Variant calls with Variant quality (QUAL) ≤60, depth of coverage (DP) <20, and mapping quality (MQ) ≤40 were filtered out. We also assessed an available Brazilian exome database of 609 elderly individuals from the city of Sao Paulo [ 18 ]. Only exonic nonsynonymous damaging variants were kept for downstream genetic analyses.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, CCC myocardium displays signs of reduced mitochondrial activity and energy production. Decreased mitochondrial rRNA [ 10 ], rDNA [ 38 ], and in vivo ATP production [ 18 ] were observed in the CCC myocardium. Myocardial levels and activity of mitochondrial energy metabolism enzymes ATP synthase and creatine kinase are even lower than in CCC than other cardiomyopathies [ 17 ], which might contribute to the worse prognosis of CCC.…”

Section: Discussionmentioning

confidence: 99%

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Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

et al. 2021

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Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

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“…The decreased PCr/ATP ratio improved 2 min after cessation of exercise and did not recur in those that had subsequent revascularization [ 105 ]. The technique was further validated by Yabe et al as a sensitive method to detect myocardial ischaemia in those with reversible defects on 201 T1 MPS-SPECT [ 127 ] and subsequently used to demonstrate decreased PCr/ATP ratios on exercise in cardiac transplant patients [ 128 ] and patients with Chagas heart disease [ 129 ].…”

Section: Exercise Cmr Spectroscopymentioning

confidence: 99%

Exercise cardiovascular magnetic resonance: development, current utility and future applications

Craven

Tsao

Gerche

et al. 2020

Journal of Cardiovascular Magnetic Resonance

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Stress cardiac imaging is the current first line investigation for coronary artery disease diagnosis and decision making and an adjunctive tool in a range of non-ischaemic cardiovascular diseases. Exercise cardiovascular magnetic resonance (Ex-CMR) has developed over the past 25 years to combine the superior image qualities of CMR with the preferred method of exercise stress. Presently, numerous exercise methods exist, from performing stress on an adjacent CMR compatible treadmill to in-scanner exercise, most commonly on a supine cycle ergometer. Cardiac conditions studied by Ex-CMR are broad, commonly investigating ischaemic heart disease and congenital heart disease but extending to pulmonary hypertension and diabetic heart disease. This review presents an in-depth assessment of the various Ex-CMR stress methods and the varied pulse sequence approaches, including those specially designed for Ex-CMR. Current and future developments in image acquisition are highlighted, and will likely lead to a much greater clinical use of Ex-CMR across a range of cardiovascular conditions.

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Avaliação do metabolismo dos fosfatos de alta energia em pacientes com doença de Chagas

Abstract: Background: Abnormalities in myocardial metabolism have been observed in patients with heart failure of different etiologies. Magnetic resonance spectroscopy (MRS) with phosphorus-31 is a noninvasive technique that allows detection of myocardial metabolic changes.

Cited by 13 publications

References 30 publications

Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

Inflammation and mitochondria in the pathogenesis of chronic Chagas disease cardiomyopathy

Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

Exercise cardiovascular magnetic resonance: development, current utility and future applications

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