Increased Plasma Catecholamines in Patients with Friedreich’s Ataxia

SUMMARY:We studied free plasma catecholamines in 23 patients with Friedreich’s ataxia, having a mean age of 22 ± 9.6 (SD) years. Conjugated catecholamines were also studied in 10 patients. Mean plasma norepinephrine and epinephrine were significantly higher than controls both in the supine and standing positions. In total 15 out of 23 patients (65%) had increased free and/or conjugated plasma catecholamines. The increase in plasma catecholamines was more marked in patients with severe neuromotor impairment. Among the patients with left ventricular concentric hypertrophy (wall thickness >12 mm), only 3 had no demonstrable sympathetic hyperfunction.Since the high local concentrations of norepinephrine at the site of release from sympathetic nerve terminals may serve as a trigger for the hypertrophic response of the myocardial cell, it is suggested that early pharmacological intervention could prevent or limit the cardiomyopathic process or its clinical consequences.

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Plasma Catecholamines in Friedreich’s Ataxia Assayed using High Performance Liquid Chromatography with Electrochemical Detection

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100043973 ◽

1982 ◽

Vol 9 (2) ◽

pp. 205-208 ◽

Cited By ~ 7

Author(s):

A.D. Merkel ◽

A. Barbeau

Keyword(s):

High Performance Liquid Chromatography ◽

Electrochemical Detection ◽

Present Method ◽

High Performance ◽

Plasma Catecholamines ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Assay Method ◽

Plasma Norepinephrine ◽

Routine Assay

ABSTRACT:Resting levels of plasma norepinephrine, epinephrine and dopamine were determined in 9 patients diagnosed as having Friedreich’s Ataxia using a relatively new assay method, HPLC with electrochemical detection. Levels of norepinephrine and dopamine were found to be significantly elevated in patients as compared to controls while epinephrine, though increased, was not significantly higher. These results confirm in most parts previous findings of Pasternak et al. of increased plasma catecholamines and demonstrate the sensitivity and utility of the present method for the routine assay of plasma catecholamines.

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Echocardiographic Findings in Friedreich's Ataxia

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100025543 ◽

1976 ◽

Vol 3 (4) ◽

pp. 329-332 ◽

Cited By ~ 25

Author(s):

H.F. Gattiker ◽

A. Davignon ◽

A. Bozio ◽

J. Batlle-Diaz ◽

G. Geoffroy ◽

...

Keyword(s):

Friedreich’S Ataxia ◽

Left Ventricular ◽

Friedreich's Ataxia ◽

Ventricular Free Wall ◽

Slight Reduction ◽

Free Wall ◽

Left Ventricular Free Wall ◽

Echocardiographic Examination ◽

Septal Hypertrophy ◽

Echocardiographic Findings

SUMMARY:Echocardiographic examination of 21 patients with Friedreich's ataxia (age 7 to 28 years) showed cardiac abnormalities in 90% of the cases. They were characterized by varying degrees of septal hypertrophy in 81%, left ventricular free wall hypertrophy in 61%, and a slight reduction of left ventricular internal dimension in 57% of the cases. Asymmetric septal hypertrophy (ASH) with a septal/left ventricular free wall ratio of over 1.3 was found in 29% of the cases, and systolic anterior motion (SAM) of the mitral valve in three patients. Two other patients showed evidence of a different type of cardiomyopathy with marked symmetric left ventricular hypertrophy and marked left ventricular enlargement.

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

Circulation ◽

10.1161/circ.138.suppl_1.17263 ◽

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.

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Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study

American Journal of Cardiovascular Drugs ◽

10.1007/s40256-019-00375-z ◽

2019 ◽

Vol 20 (2) ◽

pp. 209-216 ◽

Cited By ~ 1

Author(s):

Lise Legrand ◽

Abdourahmane Diallo ◽

Marie-Lorraine Monin ◽

Claire Ewenczyk ◽

Perrine Charles ◽

...

Keyword(s):

Observational Study ◽

Left Ventricular Dysfunction ◽

Ventricular Dysfunction ◽

Friedreich’S Ataxia ◽

Left Ventricular ◽

Friedreich's Ataxia

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May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich's ataxia?

Clinical Cardiology ◽

10.1002/clc.4960200211 ◽

1997 ◽

Vol 20 (2) ◽

pp. 141-145 ◽

Cited By ~ 11

Author(s):

Stefania Maione ◽

Anna Giunta ◽

Letizia Spinelli ◽

Giovanni Antonio Liucci ◽

Mario Condorelli ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Friedreich’S Ataxia ◽

Left Ventricular ◽

Friedreich's Ataxia

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

Archives of Disease in Childhood ◽

10.1136/archdischild-2021-322455 ◽

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.

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Abstract 2954: Short-term Effects of High Dose Idebenone on Left Ventricular Mass and Function in a Pediatric Cohort with Friedreich’s Ataxia

Circulation ◽

10.1161/circ.118.suppl_18.s_799-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jonathan F Plehn ◽

Keren Hasbani ◽

Ken Horton ◽

Inez Ernst ◽

Andrew E Arai ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Left Ventricular Mass ◽

Friedreich’S Ataxia ◽

Left Ventricular ◽

Friedreich's Ataxia ◽

High Dose ◽

Short Term ◽

Short Term Treatment ◽

Tissue Velocity ◽

Ventricular Mass

Background: Early mortality in Friedreich’s Ataxia (FA) is believed to commonly result from an underlying hypertrophic cardiomyopathy which may be caused by increases in reactive oxygen species. Antioxidant therapy could result in slowing of disease progression or regression of left ventricular mass (LVM). Methods: We tested the hypothesis that high dose idebenone could lead to regression of LVM and LV functional improvement in 48 pediatric subjects with genetically-confirmed FA (23 females, 25 males, mean age=13.4 years) randomly assigned to weight-stratified low (4 – 8 mg/kg), medium (10–20 mg/kg) or high (30–50 mg/kg) doses of idebenone or placebo. Cardiac magnetic resonance imaging (MRI) and echocardiographic (echo) two-dimensional and Doppler analysis blinded to treatment assignment were performed at baseline and after 6 months of therapy. Results: At baseline, increased LVM indexed by height 2.7 was observed in 44%, LV concentric remodeling (relative wall thickness >0.39) in 83% and impaired early relaxation by Doppler tissue velocity (E’) in 88% of subjects as determined by age-adjusted, normative echo data. MRI-determined LVM (n=45 subjects) was inversely related to measures of LV relaxation including E’ (p<0.0001), color Doppler flow propagation (p<0.007) and isovolumic relaxation time (p<0.005) but not mitral deceleration time. LVM also correlated with peak lateral systolic tissue velocity (p=0.002) but not LV ejection fraction. At 6 months combined, idebenone-assigned subjects demonstrated a 1.3 ± 1.6 % reduction of LVM vs. baseline which compared to an 8.9 ± 4.0% LVM increase in placebo subjects (p=.007). By Fisher’s test, LVM regression was observed only in the high and intermediate dose groups (p≤0.05 and p≤0.01) with a trend toward regression in the low dose group (p=0.056). No effects on diastolic relaxation or systolic functional parameters were observed after 6 months of idebenone treatment. Conclusions: Hypertrophic cardiomyopathy and associated diastolic functional impairment is highly prevalent in pediatric FA patients with moderate neurologic impairment. Short term treatment with high dose idebenone appears to result primarily in blunting of LV mass progression but not to detectable improvements in LV function.

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Effects of sodium–glucose cotransporter-2 inhibitors on cardiac structural and electrical remodeling: from myocardial cytology to cardiodiabetology

Current Vascular Pharmacology ◽

10.2174/1570161120666211227125033 ◽

2021 ◽

Vol 20 ◽

Author(s):

Maria Marketou ◽

Joanna Kontaraki ◽

Spyros Maragkoudakis ◽

Christos Danelatos ◽

Sofia Papadaki ◽

...

Keyword(s):

Ventricular Arrhythmias ◽

Ventricular Hypertrophy ◽

Myocardial Cell ◽

Left Ventricular ◽

Antiarrhythmic Action ◽

Matrix Remodeling ◽

Beneficial Effects ◽

Concentric Hypertrophy ◽

Sodium Glucose Cotransporter ◽

Pleiotropic Actions

Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have changed the clinical landscape of diabetes mellitus (DM) therapy through their favourable effects on cardiovascular outcomes. Notably, the use of SGLT2i has been linked to cardiovascular benefits regardless of DM status, while their pleiotropic actions remain to be fully elucidated. What we do know is that SGLT2i exert beneficial effects even at the level of the myocardial cell, and that these are linked to an improvement in the energy substrate, resulting in less inflammation and fibrosis. SGLT2i ameliorate myocardial extracellular matrix remodeling, cardiomyocyte stiffness and concentric hypertrophy, achieving beneficial remodeling of the left ventricle with significant implications for the pathogenesis and outcome of heart failure. Most studies show a significant improvement in markers of diastolic dysfunction along with a reduction in left ventricular hypertrophy. In addition to these effects there is electrophysiological remodeling, which explains initial data suggesting that SGLT2i have an antiarrhythmic action against both atrial and ventricular arrhythmias. However, future studies need to clarify not only the exact mechanisms of this beneficial functional, structural, and electrophysiological cardiac remodeling, but also its magnitude, and to determine whether this is a class or a drug effect.

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