Multicenter Study

. 2022 Oct 11;80(15):1421-1430.

doi: 10.1016/j.jacc.2022.08.716.

Cardiac Outcomes in Adults With Mitochondrial Diseases

Konstantinos Savvatis¹, Christoffer Rasmus Vissing², Lori Klouvi³, Anca Florian⁴, Mehjabin Rahman⁵, Anthony Béhin⁶, Abdallah Fayssoil⁷, Marion Masingue⁶, Tanya Stojkovic⁶, Henri Marc Bécane⁶, Nawal Berber⁶, Fanny Mochel⁸, Denis Duboc⁹, Bertrand Fontaine¹⁰, Bjørg Krett¹¹, Caroline Stalens³, Julie Lejeune³, Robert D S Pitceathly¹², Luis Lopes¹³, Malika Saadi¹⁴, Thomas Gossios¹⁵, Vincent Procaccio¹⁶, Marco Spinazzi¹⁷, Céline Tard¹⁸, Pascal De Groote¹⁹, Claire-Marie Dhaenens²⁰, Claire Douillard²¹, Andoni Echaniz-Laguna²², Ros Quinlivan¹², Michael G Hanna¹², Ali Yilmaz⁴, John Vissing¹¹, Pascal Laforêt²³, Perry Elliott¹³, Karim Wahbi²⁴

Affiliations

¹ Inherited Cardiac Conditions Unit, Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; William Harvey Research Institute, Queen Mary University London, London, United Kingdom; Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
² Copenhagen Neuromuscular Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; The Capital Region's Unit for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³ AFM Telethon, Evry, France.
⁴ Department of Cardiology I, Division of Cardiovascular Imaging, University Hospital Münster, Münster, Germany.
⁵ Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
⁶ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France.
⁷ AP-HP, Raymond Poincare University Hospital, Garches, France; Université de Versailles-Saint Quentin, Boulogne-Billancourt, France.
⁸ AP-HP, Pitié-Salpêtrière Hospital, Genetics Department, Inserm UMR S975, CNRS UMR7225, ICM, Paris, France; Pierre et Marie Curie-Paris 6 University, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France.
⁹ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France; AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France; Université de Paris, Paris, France.
¹⁰ Sorbonne-Université, INSERM, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de Recherche en Myologie-UMR 974, Service de Neuro-Myologie, Institut de Myologie, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
¹¹ Copenhagen Neuromuscular Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹² Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom.
¹³ Inherited Cardiac Conditions Unit, Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
¹⁴ AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France.
¹⁵ Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece.
¹⁶ Equipe Mitolab, Unité Mixte de Recherche MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France; Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
¹⁷ Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France; Neuromuscular Reference Center, Department of Neurology, CHU Angers, Angers, France.
¹⁸ Université de Lille, INSERMU1172, Lille, France; Centre de Référence des Maladies Neuromusculaires Nord Est Ile de France, CHU de Lille, Lille, France.
¹⁹ Service de Cardiologie, Pôle Cardio-vasculaire et Pulmonaire, CHRU de Lille, Lille, France; Inserm U1167, Institut Pasteur de Lille, Université de Lille 2, Lille, France.
²⁰ Université de Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience and Cognition, Lille, France.
²¹ CHU de Lille, Département d'Endocrinologie et Métabolisme, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Huriez, Lille, France.
²² Department of Neurology, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, France; French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin-Bicêtre, France; INSERM U1195, Paris-Saclay University, Le Kremlin-Bicêtre, France.
²³ Inserm U1167, Institut Pasteur de Lille, Université de Lille 2, Lille, France; Nord/Est/Île-de-France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Teaching Hospital, AP-HP, Garches, France; INSERM U1179, END-ICAP, Versailles-Saint-Quentin-en-Yvelines University, Université Paris Saclay, Montigny-le-Bretonneux, France.
²⁴ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France; AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France; Université de Paris, Paris, France; Paris Cardiovascular Research Center (PARCC), INSERM Unit 970, Paris, France. Electronic address: karim.wahbi@cch.aphp.fr.

PMID: 36202532
DOI: 10.1016/j.jacc.2022.08.716

Free article

Multicenter Study

Cardiac Outcomes in Adults With Mitochondrial Diseases

Konstantinos Savvatis et al. J Am Coll Cardiol. 2022.

Free article

. 2022 Oct 11;80(15):1421-1430.

doi: 10.1016/j.jacc.2022.08.716.

Authors

Affiliations

¹ Inherited Cardiac Conditions Unit, Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; William Harvey Research Institute, Queen Mary University London, London, United Kingdom; Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
² Copenhagen Neuromuscular Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; The Capital Region's Unit for Inherited Cardiac Diseases, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³ AFM Telethon, Evry, France.
⁴ Department of Cardiology I, Division of Cardiovascular Imaging, University Hospital Münster, Münster, Germany.
⁵ Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
⁶ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France.
⁷ AP-HP, Raymond Poincare University Hospital, Garches, France; Université de Versailles-Saint Quentin, Boulogne-Billancourt, France.
⁸ AP-HP, Pitié-Salpêtrière Hospital, Genetics Department, Inserm UMR S975, CNRS UMR7225, ICM, Paris, France; Pierre et Marie Curie-Paris 6 University, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France.
⁹ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France; AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France; Université de Paris, Paris, France.
¹⁰ Sorbonne-Université, INSERM, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de Recherche en Myologie-UMR 974, Service de Neuro-Myologie, Institut de Myologie, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
¹¹ Copenhagen Neuromuscular Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹² Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom.
¹³ Inherited Cardiac Conditions Unit, Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Centre for Heart Muscle Disease, Institute for Cardiovascular Science, University College London, London, United Kingdom.
¹⁴ AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France.
¹⁵ Cardiomyopathies Laboratory, 1st Aristotle University of Thessaloniki Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece.
¹⁶ Equipe Mitolab, Unité Mixte de Recherche MITOVASC, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France; Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.
¹⁷ Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France; Neuromuscular Reference Center, Department of Neurology, CHU Angers, Angers, France.
¹⁸ Université de Lille, INSERMU1172, Lille, France; Centre de Référence des Maladies Neuromusculaires Nord Est Ile de France, CHU de Lille, Lille, France.
¹⁹ Service de Cardiologie, Pôle Cardio-vasculaire et Pulmonaire, CHRU de Lille, Lille, France; Inserm U1167, Institut Pasteur de Lille, Université de Lille 2, Lille, France.
²⁰ Université de Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience and Cognition, Lille, France.
²¹ CHU de Lille, Département d'Endocrinologie et Métabolisme, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Huriez, Lille, France.
²² Department of Neurology, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, France; French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin-Bicêtre, France; INSERM U1195, Paris-Saclay University, Le Kremlin-Bicêtre, France.
²³ Inserm U1167, Institut Pasteur de Lille, Université de Lille 2, Lille, France; Nord/Est/Île-de-France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Teaching Hospital, AP-HP, Garches, France; INSERM U1179, END-ICAP, Versailles-Saint-Quentin-en-Yvelines University, Université Paris Saclay, Montigny-le-Bretonneux, France.
²⁴ AP-HP, Pitié-Salpêtrière Hospital, Reference Center for Muscle Diseases Paris-Est, Myology Institute, Paris, France; AP-HP, Cochin Hospital, Cardiology Department, Paris Cedex, France; Université de Paris, Paris, France; Paris Cardiovascular Research Center (PARCC), INSERM Unit 970, Paris, France. Electronic address: karim.wahbi@cch.aphp.fr.

PMID: 36202532
DOI: 10.1016/j.jacc.2022.08.716

Abstract

Background: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE).

Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population.

Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases.

Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively.

Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments.

Keywords: conduction disease; heart failure; m3243A>G; mitochondrial diseases; single large-scale deletions; sudden death.

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Conflict of interest statement

Funding Support and Author Disclosures This study was funded by grants from the Association Française contre les Myopathies (French Alliance against Myopathies), which was not involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review or approval of the manuscript; nor in the decision to submit the manuscript for publication. Dr Pitceathly is supported by a Medical Research Council (United Kingdom) Clinician Scientist Fellowship (MR/S002065/1). Drs Pitceathly and Hanna receive funding from a Medical Research Council (United Kingdom) strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1). Dr Lopes is supported by a Medical Research Council (United Kingdom) clinical academic partnership (CARP) award. Dr Quinlivan was funded by National Institute for Health and Care Research Biomedical Research Centre, University College Hospitals Foundation Trust. The University College London Hospitals/University College London Queen Square Institute of Neurology sequencing facility receives a proportion of funding from the Department of Health's National Institute for Health and Care Research Biomedical Research Centre’s funding scheme. The clinical and diagnostic “Rare Mitochondrial Disorders” Service in London is funded by the U.K. NHS Highly Specialised Commissioners. Dr Elliott has received consultancy fees from Pfizer, Sanofi, Sarepta, DinaQor, Freeline, Novo Nordisk, and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Comment in

Cardiac Disease in Patients With Mitochondrial Defects: 2 Steps Forward and 1 Step Back.
Ware SM. Ware SM. J Am Coll Cardiol. 2022 Oct 11;80(15):1444-1446. doi: 10.1016/j.jacc.2022.08.719. J Am Coll Cardiol. 2022. PMID: 36202534 No abstract available.

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Cardiac Outcomes in Adults With Mitochondrial Diseases

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Cardiac Outcomes in Adults With Mitochondrial Diseases

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