Atrial Fibrillation Is Poorly Tolerated by Patients with Hypertrophic Concentric Cardiomyopathy Caused by Mitochondrial tRNALeu (UUR) Mutations

Abstract

Knowledge on the molecular background of mitochondrial disorders has accumulated during the past two decades, but clinical and molecular features of mitochondrial cardiomyopathies (CMPs) are only starting to be characterized. We studied the detailed cardiologic phenotype of patients with adult-onset CMPs associated with mitochondrial DNA (mtDNA) mutations and their relatives, from three families. We identified a pathogenic T3258C point mutation of mtDNA tRNA^Leu(UUR) in an adult patient with mitochondrial myopathy and CMP, with acute manifestation of dyspnea and elevated plasma N-terminal pro-B-type natriuretic peptide concentration. Two other families with maternally segregated CMP, fatal in three patients, had the A3243G mutation in tRNA^Leu(UUR) of mtDNA. Many of the mutation carriers, even if oligosymptomatic, had concentric, non-obstructive hypertrophic CMP with diastolic dysfunction or restrictive hemodynamics, or depression of systolic function especially at times when patients had lactic acidosis. Atrial fibrillation led to manifest heart failure in four patients, fatal in one. In conclusion, tRNA^Leu(UUR) mutations in mtDNA may underlie mitochondrial non-obstructive, sometimes fatal, hypertrophic CMPs of adult age. Such CMPs are characterized by left ventricular hypertrophy and poor tolerance of atrial arrhythmias, often leading to rapidly deteriorating systolic function and heart failure. These patients benefit of rapid intervention of tachyarrhythmias. These patients may not have neurological symptoms, and may therefore remain underdiagnosed. Our observations emphasize that patients with tRNA^Leu(UUR) mutations need cardiologic evaluation and follow- up. tRNA^Leu(UUR) mutations should be screened of patients with hypertrophic CMP and metabolic acidosis, especially if atrial arrhythmia provoked cardiac decompensation

mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

“…Our echocardiographic analysis showed that rapa treatment decreased left ventricular mass in both WT and Deletors, but did not affect the functional parameters (Figure S3F). Deletors showed a tendency to slight hypertrophy of the interventricular septum in both systole and diastole, a typical sign in some mitochondrial disease patients, increasing their risk of arrhythmia complications (Heliö et al, 2013). Rapa cured this septum hypertrophy (Figure S3F).…”

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

“…Our findings support the hypotheses that a high mtDNA mutation load alone is not sufficient to trigger clinical heart disease in mtDNA disease patients; but, other adaptative metabolic pathways, either expose or protect the patient from cardiac manifestations. Currently, due to the severity of the heart symptoms, regular cardiac follow-ups are recommended for all m.3243A>G patients [ 37 ]. Understanding these additional factors would aid in early identification of those patients that will develop heart defects.…”