Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy

Alessandro Di Toro; Mario Urtis; Nupoor Narula; Lorenzo Giuliani; Maurizia Grasso; Michele Pasotti; Carlo Pellegrini; Alessandra Serio; Andrea Pilotto; Elena Antoniazzi; Teresa Rampino; Lorenzo Magrassi; Adele Valentini; Anna Cavallini; Laura Scelsi; Stefano Ghio; Massimo Abelli; Iacopo Olivotto; Maurizio Porcu; Antonello Gavazzi; Takahide Kodama; Eloisa Arbustini

doi:10.1016/j.jacc.2022.04.067

Impediments to Heart Transplantation in Adults With MELAS^{MT-TL1:m.3243A>G} Cardiomyopathy

J Am Coll Cardiol. 2022 Oct 11;80(15):1431-1443. doi: 10.1016/j.jacc.2022.04.067.

Authors

Alessandro Di Toro¹, Mario Urtis², Nupoor Narula³, Lorenzo Giuliani¹, Maurizia Grasso¹, Michele Pasotti⁴, Carlo Pellegrini⁵, Alessandra Serio¹, Andrea Pilotto¹, Elena Antoniazzi⁶, Teresa Rampino⁷, Lorenzo Magrassi⁸, Adele Valentini⁹, Anna Cavallini¹⁰, Laura Scelsi¹¹, Stefano Ghio¹¹, Massimo Abelli¹², Iacopo Olivotto¹³, Maurizio Porcu¹⁴, Antonello Gavazzi¹⁵, Takahide Kodama¹⁶, Eloisa Arbustini¹⁷

Affiliations

¹ Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
² Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
³ Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
⁴ Department of Cardiology, Ospedale Civile di Voghera, Voghera, Italy.
⁵ Cardiac Surgery Division, Department of Intensive Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
⁶ Ophthalmology Division, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
⁷ Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
⁸ Neurosurgery Division, Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
⁹ Radiology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹⁰ Stroke Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹¹ Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹² Renal Transplantation Division, Department of Surgery, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
¹³ Cardiomyopathy Unit, University of Florence, Florence, Italy.
¹⁴ Cardiology Service, Mater Olbia Hospital, Olbia, Italy.
¹⁵ FROM Research Foundation, Bergamo, Italy.
¹⁶ Department of Cardiovascular Center, Toranomon Hospital, Tokyo, Japan.
¹⁷ Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: e.arbustini@smatteo.pv.it.

PMID: 36202533
DOI: 10.1016/j.jacc.2022.04.067

Abstract

Background: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results.

Objectives: We analyzed factors preventing HTx in consecutive adult patients with MELAS^{MT-TL1:m.3243A>G} cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center.

Methods: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives.

Results: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis.

Conclusions: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELAS^{MT-TL1:m.3243A>G} patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

Keywords: MELAS; MT-TL1:m.3243A>G; heart transplantation; mitochondrial cardiomyopathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathies* / complications
Cardiomyopathies* / genetics
Cardiomyopathies* / surgery
DNA, Mitochondrial / genetics
Heart Transplantation*
Humans
MELAS Syndrome* / diagnosis
MELAS Syndrome* / genetics
MELAS Syndrome* / pathology
Muscular Diseases*
Mutation
Renal Insufficiency, Chronic* / complications

Substances

DNA, Mitochondrial