Biochemistry of cardiomyopathy in the mitochondrial disease Friedreich's ataxia

2013 ◽  
Vol 453 (3) ◽  
pp. 321-336 ◽  
Author(s):  
Darius J. R. Lane ◽  
Michael Li-Hsuan Huang ◽  
Samantha Ting ◽  
Sutharshani Sivagurunathan ◽  
Des R. Richardson
Keyword(s):  
Heart Failure ◽  
Stress Response ◽  
Mitochondrial Disease ◽  
Mitochondrial Disorder ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Comprehensive Understanding ◽  
Disease Pathogenesis ◽  
Common Cause ◽  
Biochemical Mechanisms

FRDA (Friedreich's ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression. Additionally, recent data suggest that low frataxin expression in heart muscle of conditional frataxin knockout mice activates an integrated stress response that contributes to and/or exacerbates cardiac hypertrophy and the loss of cardiomyocytes. The elucidation of these potential mechanisms will lead to a more comprehensive understanding of the pathogenesis of FRDA, and will contribute to the development of better treatments and therapeutics.

Abstract 17263: Pre-Clinical Left Ventricular Myocardial Remodeling in Patients With Friedreich’s Ataxia: A Cardiac MRI Study

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Karen A Takazaki1 ◽  
Thiago Quinaglia A. C. Silva ◽  
Alberto Martinez ◽  
Tomas Neilan ◽  
Ravi SHAH ◽  
...  
Keyword(s):  
Heart Failure ◽  
Volume Fraction ◽  
Extracellular Volume ◽  
Extracellular Volume Fraction ◽  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia ◽  
Intracellular Water ◽  
Lv Mass ◽  
Burn Out

Background: Heart Failure (HF) is the most common cause of death in Friedreich’s ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis is a well-documented histopathological feature among FRDA patients with HF. Objectives: In this study we will investigate the myocardial extracellular volume fraction (ECV) and intracellular water lifetime (τ ic ), using T1-weighted CMR imaging, in a cohort of patients with FRDA without signs of heart failure. We will also investigate whether myocardial tissue phenotyping by CMR can highlight particular characteristics of LV remodeling in FRDA’s cardiomyopathy, beyond those currently assessed with imaging-based classification of disease severity. Methods: Twenty-six FRDA’s patients (age 26.6±9.3 years, 15 women) without signs of HF, and 10 healthy controls (32.6±7.3 years, 5 women) underwent cardiac magnetic resonance (CMR) studies for assessment of left ventricular (LV) function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τ ic ) as marker of cardiomyocyte size. Neurological decline was determined using the FRDA rating scale (FARS 3). Results: FRDA patients had normal LV ejection fraction (LVEF: 67.66±11.4 vs. 63.9±9.0, P=0.311), larger LV mass index (LVMASSi: 61.03±22.1 vs. 45±4.2g/m 2 , P<0.001), and decreased LV end-diastolic volume index (LVEDVi 53.42±12 vs. 75.7±16.1, P=0.002), compared with controls. ECV and τ ic , were increased in FRDA patients (ECV: 0.36±0.05 vs. 0.25±0.02, P<0.0001; τ ic : 0.13±0.07 vs. 0.06±0.03, P=0.001). ECV was positively associated with LV mass-to-volume ratio (r=0.628, P<0.001). FARS 3 correlated positively with disease duration (r=0.669, P<0.001), and negatively with τ ic , (r=0.478, P=0.039). LVMASSi and cardiomyocyte mass-index [(1–ECV)LVMASSi] declined with age, indicating that LV hypertrophy may transition to a “burn-out” phase with LV atrophy. Conclusions: LV hypertrophy in FRDA reflects an expansion of the myocardial interstitium and an increase in cardiomyocyte size. In contrast, the neurological decline was more likely with decreasing cardiomyocyte size, possibly an early sign of myocardial “burn-out” in FRDA.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

2005 ◽  
Vol 233 (1-2) ◽  
pp. 145-162 ◽  
Author(s):  
Vittorio Calabrese ◽  
Raffaele Lodi ◽  
Caterina Tonon ◽  
Velia D'Agata ◽  
Maria Sapienza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Cellular Stress ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cellular Stress Response

Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients?

2011 ◽  
Vol 26 (5) ◽  
pp. 769-771 ◽  
Author(s):  
José L. García-Giménez ◽  
Fabián Sanchis-Gomar ◽  
Federico V. Pallardó
Keyword(s):  
Heart Failure ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia

scholarly journals Friedreich’s ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

2021 ◽  
pp. archdischild-2021-322455
Author(s):  
Gabrielle Norrish ◽  
Thomas Rance ◽  
Elena Montanes ◽  
Ella Field ◽  
Elspeth Brown ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cohort Study ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiac Death ◽  
Friedreich’S Ataxia ◽  
Left Ventricular ◽  
Friedreich's Ataxia ◽  
Atrial Arrhythmia ◽  
Primary Study

ObjectiveHypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich’s ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM.Design and settingRetrospective, longitudinal cohort study of children with FA-HCM from the UK.Patients78 children (<18 years) with FA-HCM diagnosed over four decades.InterventionAnonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up.Main outcome measuresThe primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation.ResultsThe mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4–7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8).ConclusionsThis is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

scholarly journals P1602 An adult with mitochondrial cardiomyopathy

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
A Kandil ◽  
J Daniel ◽  
R Nata ◽  
P Felix
Keyword(s):  
Heart Failure ◽  
Mitochondrial Disease ◽  
Systolic Function ◽  
Mitochondrial Disorder ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Inherited Disorders ◽  
Flow Acceleration ◽  
Mitochondrial Cardiomyopathy ◽  
Normal Systolic Function

Abstract Introduction Mitochondrial diseases are a group of rare inherited disorders with diverse phenotypes that are caused by mutation in nuclear or mitochondrial DNA. The prevalence of mitochondrial disease is estimated to be one in 5000 livebirths. The heart depends mainly on the energy produced through aerobic respiration and hence cardiac involvement is common, progressive and its presence is an independent predictor of mortality in patients with mitochondrial disease and may occur as the principal clinical manifestation or part of a multisystem disease. Case report We present a 31 years old lady who was referred to our hospital with a newly diagnosed hypertension and non-specific ECG changes. The patient had no shortness of breath, no palpitation and no chest pain. She was overweight and had short stature. Her blood pressure was elevated 155/90. There was no signs of heart failure and no murmurs on auscultation of the heart and lung. Her ECG showed sinus bradycardia 55-60 b/min, ST segment elevation in the anterior chest leads with non-specific widespread t wave inversion. An Echocardiogram was done and showed concentric left ventricular hypertrophy (LVH) at 1.5 cm with speckling and granite-like appearance of the myocardium with no LV out flow tract (LVOT) obstruction and with normal systolic function and no significant valvular disease. A cardiac MRI was done and showed mildly dilated LV with normal geometry, normal systolic function, concentric LV hypertrophy with papillary muscles hypertrophy, relative sparing of the apical segments and with no LVOT flow acceleration and no late gadolinium enhancement. Our patient had mild hearing loss which is maternally inherited with her mother and her maternal uncle had cochlear implants. She also had borderline diabetes mellitus and she was also found to have the m.3243 &gt; G mutation suggesting a mitochondrial disorder . A diagnosis of mitochondrial cardiomyopathy was made and the patient was started on an antihypertensive and planned to have regular cardiology clinic follow up. Conclusion Hypertrophic remodelling is the dominant pattern of cardiomyopathy in all forms of mitochondrial disease; occurring in up to 40% of patients and its presence is associated with higher mortality. The severity can vary from asymptomatic as in our patient to severe heart failure with acute decompensation that can occur with metabolic disorders or general illnesses. Treatment of mitochondrial disorders is mainly symptomatic with no curative therapy available. We aimed at increasing awareness of this rare disease. Abstract P1602 Figure.

Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich's Ataxia Patients and Their Association with Disease Pathology

2017 ◽  
Vol 49 (01) ◽  
pp. 035-043 ◽  
Author(s):  
Subrahamanyam Dantham ◽  
Achal Srivastava ◽  
Sheffali Gulati ◽  
Moganty Rajeswari
Keyword(s):  
Microarray Platform ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Therapeutic Interventions ◽  
Healthy Controls ◽  
Disease Pathogenesis ◽  
Multisystem Disease ◽  
Mirna Microarray ◽  
Thermo Fisher Scientific ◽  
Fisher Scientific

AbstractFriedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.

scholarly journals Electrocardiographic and Vectocardiographic Findings in Friedreich's Ataxia

1976 ◽  
Vol 3 (4) ◽  
pp. 323-328 ◽  
Author(s):  
S. Malo ◽  
Y. Latour ◽  
M. Cote ◽  
G. Geoffroy ◽  
B. Lemieux ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Right Ventricular ◽  
Neurological Disorder ◽  
Ventricular Hypertrophy ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Right Ventricular Hypertrophy ◽  
Serial Examination

SUMMARY:Electrocardiographic and vectocardiographic changes are frequent in Friedreich's ataxia. In one of 35 patients both tests were normal. The vectocardiogram is more explicit in demonstrating the severity of the QRS changes with a right ventricular hypertrophy pattern present in 60% of cases. Serial examination and ECG tracings are recommended to monitor the cardiomyopathy in this progressive neurological disorder, in order to detect the onset of congestive heart failure, significant tachyarrythmias, or obstructive cardiomypathy.

Re-purposing small-molecule drugs to treat the mitochondrial disease Friedreich's ataxia

Mitochondrion ◽  
2012 ◽  
Vol 12 (5) ◽  
pp. 571-572
Author(s):  
Sunil Sahdeo ◽  
Mark Pook ◽  
Marek Napierala ◽  
Joe Sarsero ◽  
Gino Cortopassi
Keyword(s):  
Small Molecule ◽  
Mitochondrial Disease ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Small Molecule Drugs
Sign in / Sign up

Export Citation Format

Share Document