Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia
© Raman et al; licensee BioMed Central Ltd. 2008
Received: 13 March 2008
Accepted: 08 April 2008
Published: 08 April 2008
We present the first in vivo detection of microvascular abnormality in a patient with Friedreich's ataxia (FA) without epicardial coronary artery disease using cardiac magnetic resonance (CMR). The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.
This report describes myocardial perfusion reserve abnormality in Freidreich's ataxia (FA), a heritable disorder whose major manifestations are neurological and myocardial disease. In more than 90% of cases, this autosomal recessive condition results from excess of DNA triplet repeats (GAA) in the first intron at the end of exon 1 leading to suppression of FRDA (frataxin) gene expression. Around 5% of patients have a point mutation in the frataxin gene; both forms result in a deficiency of the protein frataxin that is located in the inner mitochondrial membrane. Frataxin deficiency results in mitochondrial iron accumulation in neurons, cardiomyocytes and other cell types. Historically, diagnosis of cardiac involvement in FA has relied on nonspecific electrocardiographic abnormalities and imaging-based detection of ventricular hypertrophy, neither of which yields significant insight into mechanisms of disease that would allow development of targeted therapies. We sought to test the utility of cardiac magnetic resonance (CMR) in identifying microvascular abnormalities in FA, a previously unexplored target for cardiotherapeutic intervention in this disorder.
2. Case presentation
In summary, we identified impaired microcirculatory reserve in FA using CMR that occurred in the absence of epicardial coronary artery disease. Friedreich's ataxia is a neurodegenerative condition frequently accompanied by cardiomyopathy due to a mutation in the gene frataxin, resulting in intra-mitochondrial accumulation of iron. The predilection for neuromuscular and myocardial involvement in FA reflects the high energy demands of both systems.
Prior magnetic resonance-based evaluation of FA cardiomyopathy has focused on cardiac magnetic resonance spectroscopy  or quantification of left ventricular mass; to date, CMR perfusion findings have not been reported. The absence of significant iron overload using T2* imaging is not unexpected, given the localization of iron particles in the mitochondria as opposed to the gross iron aggregates that occur in conditions such as hemochromatosis and the transfusion-related secondary iron overload of thalassemia and can produce T2*-shortening. The abnormal myocardial perfusion reserve demonstrated in this young FA patient occurred in the setting of normal epicardial coronary arteries and absence of metabolic syndrome or other known cause of microvascular disease. The only prior investigation of myocardial perfusion was done by Gregory et al. using positron emission tomography; their work suggested that compensation for impaired energetics in FA occurs by increasing myocardial oxygen consumption rather than myocardial blood flow, though this study was conducted under resting conditions only.
The detection of subendocardial perfusion abnormality afforded by adenosine CMR is similar to that described in other conditions such as syndrome X and coarctation of the aorta[6, 7], though the mechanism for abnormal myocardial perfusion reserve may vary among these disorders. Prospective studies of therapies proven to improve microvascular function, such as nitrates and calcium channel blockers, warrant investigation as methods to attenuate the morbidity and mortality due to cardiomyopathy in FA.
The authors wish to thank the patient for providing consent to publish her medical history.
- Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M: Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996, 271: 1423-1427. 10.1126/science.271.5254.1423.View ArticlePubMedGoogle Scholar
- Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA: Cardiac involvement in Friedreich's ataxia: a clinical study of 75 patients. J Am Coll Cardiol. 1986, 7: 1370-1378.View ArticlePubMedGoogle Scholar
- Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, Schapira AH: Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A. 1999, 96: 11492-11495. 10.1073/pnas.96.20.11492.PubMed CentralView ArticlePubMedGoogle Scholar
- Meyer C, Schmid G, Gorlitz S, Ernst M, Wilkens C, Wilhelms I, Kraus PH, Bauer P, Tomiuk J, Przuntek H, Mugge A, Schols L: Cardiomyopathy in Friedreich's ataxia-assessment by cardiac MRI. Mov Disord. 2007, 22: 1615-1622. 10.1002/mds.21590.View ArticlePubMedGoogle Scholar
- Gregory SA, MacRae CA, Aziz K, Sims KB, Schmahmann JD, Kardan A, Morss AM, Ellinor PT, Tawakol A, Fischman AJ, Gewirtz H: Myocardial blood flow and oxygen consumption in patients with Friedreich's ataxia prior to the onset of cardiomyopathy. Coron Artery Dis. 2007, 18: 15-22. 10.1097/01.mca.0000236289.02178.60.View ArticlePubMedGoogle Scholar
- Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P, Pennell DJ: Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002, 346: 1948-1953. 10.1056/NEJMoa012369.View ArticlePubMedGoogle Scholar
- Cook SC, Ferketich AK, Raman SV: Myocardial ischemia in asymptomatic adults with repaired aortic coarctation. Int J Cardiol. 2008Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.