title: Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease.
abstract: Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement.
  
  
  
  Twenty-five MD patients (aged 46 ± 3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P < 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P < 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO2/kg) than controls (P < 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO2/kg (both P < 0.001), and several indicators of autonomic imbalance (P < 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P < 0.05).
  
  
  
  Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation.
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Giannoni
authors.affiliation: Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Aimo
authors.affiliation: Neurology Clinic, University of Pisa, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Mancuso
authors.affiliation: Heart Failure Unit, Cardiac Department, Guglielmo da Saliceto Hospital, Piacenza, Italy.
authors.forename: Massimo Francesco
authors.initials: MF
authors.lastname: Piepoli
authors.affiliation: Neurology Clinic, University of Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Orsucci
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Giovanni Donato
authors.initials: GD
authors.lastname: Aquaro
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barison
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: De Marchi
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Taddei
authors.affiliation: Department of Cardiovascular Diseases, University of Siena, Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cameli
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Raglianti
authors.affiliation: Neurology Clinic, University of Pisa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.|Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Passino
authors.affiliation: Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.|Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Emdin
mesh_terms: D000328:Adult; D001341:Autonomic Nervous System / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002628:Chemoreceptor Cells / Q000378:metabolism; D016552:Ergometry; D005080:Exercise Test; D017079:Exercise Tolerance / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000502:physiology*; D012018:Reflex / Q000502:physiology*; D012189:Retrospective Studies
keywords: Autonomic balance; Dyspnoea; Exercise; Mitochondrial disease; Myopathy