Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome

Raman, Subha V.; Phatak, Kavita; Hoyle, J. Chad; Pennell, Michael L.; McCarthy, Beth; Tran, Tam; Prior, Thomas W.; Olesik, John W.; Lutton, Anthony; Rankin, Chelsea; Kissel, John T.; al-Dahhak, Roula

doi:10.1093/eurheartj/ehq443

Cited by 73 publications

(80 citation statements)

References 37 publications

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“…1). As in our previous cohort, 6 increased triplet expansion correlated with greater RWT (r=0.37, P <0.05) (Table II) (Figs. 2 and 3).…”

Section: Picp Levels and Baseline Measures Of Left Ventricular Structsupporting

confidence: 83%

“…5 Our group has previously shown that myocardial fibrosis can occur in FA patients who do not have overt cardiomyopathy. 6 As a measurement criterion for collagen production, PICP holds potential appeal; however, its usefulness in FA cardiomyopathy had not previously been evaluated. In our study, we have identif ied PICP as a marker of progressive LV dilation.…”

Section: Discussionmentioning

confidence: 99%

“…All had been referred for cardiac evaluation from 2007 through 2011 at a single academic medical center, including 26 subjects enrolled from a previously completed prospective study of subclinical myocardial disease. 6 One subject was excluded after CMR examination revealed advanced LV dysfunction (LV ejection fraction, 0.15) and extensive scarring. In 27 patients, FA had been diagnosed by means of genetic testing: 25 had GAA triplet expansions (minimum GAA repeat length was recorded), and 2 had point mutations.…”

Section: Methodsmentioning

confidence: 99%

“…1,4,5 Cardiac magnetic resonance (CMR) affords direct, in vivo evaluation of LV remodeling and fibrosis that can develop before cardiomyopathy in FA becomes clinically apparent. 6 The myocardial extracellular matrix plays a key role in determining myocardial architecture. The matrix's constitution depends on the balance between the production and degradation of collagen; disequilibrium leads to cardiac remodeling.…”

Section: Serum Versus Imaging Biomarkers In Friedreich Ataxiamentioning

confidence: 99%

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Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Mehta¹,

Chacko²,

Jin³

et al. 2016

Texas Heart Institute Journal

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Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months. Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P <0.001); severity of genetic abnormality did not indicate severity of PICP elevation. Higher PICP levels corresponded to greater LV concentric remodeling only at baseline (r=0.37, P <0.05). Higher baseline PICP strongly indicated subsequent increases in LV end-diastolic volume (r=0.52, P=0.02). The PICP levels did not distinguish between 14 patients with evident myocardial fibrosis identified through positive late gadolinium enhancement and 15 who had no enhancement (1,067 ± 125 vs 1,030 ± 98 ng/mL; P=0.82). At 12 months, cardiac events had occurred in 3 of 14 fibrosis-positive and none of 15 fibrosis-negative patients (P=0.1); their baseline PICP levels were similar. We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.

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“…1). As in our previous cohort, 6 increased triplet expansion correlated with greater RWT (r=0.37, P <0.05) (Table II) (Figs. 2 and 3).…”

Section: Picp Levels and Baseline Measures Of Left Ventricular Structsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Serum Versus Imaging Biomarkers In Friedreich Ataxiamentioning

confidence: 99%

See 2 more Smart Citations

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Mehta¹,

Chacko²,

Jin³

et al. 2016

Texas Heart Institute Journal

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“…The deficit in transcription of FXN in FRDA patients is often characterized by mitochondrial damage and the ensuing energy dysregulation (17,41). The central pathological outcomes of FRDA on the heart include hypertrophic cardiomyopathy, myocardial fibrosis, and myocardial infarction, which often progress the heart to congestive heart failure (38,39,53).…”

Section: New and Noteworthymentioning

confidence: 99%

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Mouli

Nanayakkara

AlAlasmari

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

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A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia

et al. 2015

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IMPORTANCE Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival. OBJECTIVE To assess FRDA survival and cardiac outcome to adapt future therapeutic trials. DESIGN, SETTING, AND PARTICIPANTS In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013. The setting was the French National . In total, 138 patients with FRDA were followed up. Among 133 patients homozygous for expanded GAA repeats, the mean (SD) age was 31 (10) years (age range, 11-62 years), with a mean (SD) age at disease onset of 16 (8) years (age range, 3-50 years) and a mean (SD) age at first wheelchair use of 26 (9) years (age range, 11-64 years). Cardiac hypertrophy was present in 57.9% (77 of 133), and electrocardiography was normal in 6.8% (9 of 133). MAIN OUTCOMES AND MEASURES Long-term cardiac outcome and predictors of survival in FRDA.RESULTS After a mean (SD) follow-up of 10.5 (5.5) years (range, 0.6-23.0 years), the 10-year survival rate was 88.5%. In 80.0% of patients (12 of 15), death was due to cardiac causes. Predictors of survival were a shorter GAA repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.69), left ventricular ejection fraction (HR, 0.42; 95% CI, 0.20-0.89), and left ventricular mass index (HR, 1.19; 95% CI, 1.04-1.36). Two cardiac evolutions were distinguished with a group-based trajectory model, including a low-risk cardiac group (78.6% [81 of 103] with normal ejection fraction at baseline that declined slightly over time but remained within the normal range) and a high-risk cardiac group (21.4% [22 of 103] in which the ejection fraction progressively declined during follow-up). The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time.CONCLUSIONS AND RELEVANCE Survival in FRDA is determined by cardiac complications, which are dependent on the mutation (ie, the size of the expanded GAA repeat). Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications. GanauA, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension.

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Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome

Cited by 73 publications

References 37 publications

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia

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