Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia

Raman, Subha V.; Dickerson, Jennifer A.; al-Dahhak, Roula

doi:10.1186/1532-429x-10-15

Cited by 12 publications

(9 citation statements)

References 8 publications

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“…However, some histopathologic studies suggest that there is also an increased risk for coronary artery disease. Although one study found no occlusive coronary disease in postmortem patients[21], another study of three postmortem patients identified potential occlusive coronary disease in the microvasculature of the coronary arteries[20]. Fibrotic replacement of the coronary intima has also been identified, and it has been proposed that the coronary arteries of FRDA patients are susceptible to fibromuscular dysplasia.…”

Section: Coronary Artery Diseasementioning

confidence: 99%

Heart disease in Friedreich’s ataxia

Hanson

Sheldon

Pacheco

et al. 2019

WJC

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Friedreich’s ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.

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Section: Coronary Artery Diseasementioning

confidence: 99%

Heart disease in Friedreich’s ataxia

Hanson

Sheldon

Pacheco

et al. 2019

WJC

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“…54 Thus, patients with Friedreich ataxia may experience chest pain or symptoms of decreased coronary reserve in the absence of epicardial coronary disease. 55 Arrhythmias are also common in patients with Friedreich ataxia, particularly atrial arrhythmias, and contribute to mortality. 51 The electrocardiogram is abnormal in more than 90% of cases and most often demonstrates T-wave abnormalities, such as inversion or flattening, in the left chest leads (Figure 3).…”

Section: Clinical Findingsmentioning

confidence: 99%

Cardiomyopathy in Friedreich Ataxia

Payne

Wagner

2012

J Child Neurol

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Friedreich ataxia is the most common human ataxia and results from inadequate production of the frataxin protein, most often due to a triplet expansion in the nuclear FXN gene. The gene cannot be transcribed to generate the messenger RNA for frataxin. Frataxin is an iron-binding protein targeted to the mitochondrial matrix. In its absence, multiple iron-sulfur-dependent proteins in mitochondria and the cytosol lack proper assembly, destroying mitochondrial and nuclear function. Mitochondrial oxidant stress may also participate in ongoing cellular injury. Although progressive and debilitative ataxia is the most prominent clinical finding, hypertrophic cardiomyopathy with heart failure is the most common cause of early death in this disease. There is no cure. In this review we cover recent basic and clinical findings regarding the heart in Friedreich ataxia, offer recommendations for clinical management of the cardiomyopathy in this disease, and point out new research directions to advance the field.

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“…FRDA also involves cardiac disturbances such as increased LV wall thickness, reduced chamber size and finally hypertrophic cardiomyopathy leading to heart failure with preserved ejection fraction (HFpEF; Peverill, Donelan, Corben, & Delatycki, 2018). Impaired myocardial perfusion in an FRDA patient was described to be the result of microvascular abnormality without epicardial coronary artery disease (Raman, Dickerson, & Al-Dahhak, 2008). The occurrence of atrial fibrillation and ventricular tachyarrhythmias is also common, which eventually increases cardiac mortality (Zipse & Aleong, 2016).…”

Section: Santos Et Al Validated the Chronic Neurodegeneration In Dormentioning

confidence: 99%

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options

Bencsik

Gömöri

Szabados

et al. 2020

British J Pharmacology

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During the last decades, mortality from acute myocardial infarction has been dramatically reduced. However, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischaemic conditioning had been discovered more than three decades ago. Its clinical translation, however, is still an unmet need. This is mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors, co-morbidities and the medication being taken. Sensory neuropathy is one of the co-morbidities that has been shown to interfere with cardioprotection. In the present review, we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which these neuropathies may interfere with ischaemic heart disease and cardioprotective signalling. Finally, we suggest future therapeutic options targeting both ischaemic heart and sensory neuropathy simultaneously.

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Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia

Cited by 12 publications

References 8 publications

Heart disease in Friedreich’s ataxia

Heart disease in Friedreich’s ataxia

Cardiomyopathy in Friedreich Ataxia

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options

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