Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management

Abstract

Mitochondrial disease refers to a heterogenous group of genetic disorders that result from dysfunction of the final common pathway of energy metabolism. Mitochondrial DNA mutations affect key components of the respiratory chain and account for the majority of mitochondrial disease in adults. Owing to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. Recent advances in our understanding of the clinical spectrum and genetic aetiology of cardiac involvement in mitochondrial DNA disease have important implications for cardiologists in terms of the investigation and multi-disciplinary management of patients.

Figure 1

Clinical features of mitochondrial DNA disease. Diverse organ systems can be affected in mitochondrial DNA disease either within an individual or a family. Patterns of distant organ involvement (e.g. diabetes and deafness) or a relevant family history may prompt consideration of a mitochondrial aetiology.

Figure 2

Mitochondrial DNA mutations and patterns of cellular respiratory function. (A) In normal individuals, all cardiomyocytes contain multiple copies of wild-type mitochondrial DNA (black circles, upper panel), with sequential cytochrome c oxidase/succinate dehydrogenase histochemistry showing all cardiomyocytes as cytochrome c oxidase-positive (brown, lower panel). (B) In patients with heteroplasmic mitochondrial DNA mutations, different proportions of wild-type (black) and mutated mitochondrial DNA (red) are present in individual cardiomyocytes (upper panel); cytochrome c oxidase/succinate dehydrogenase histochemistry reveals a mosaic pattern of cytochrome c oxidase-deficient and cytochrome c oxidase-positive cardiomyocytes, with cellular respiratory deficiency only apparent when a threshold proportion of mutated mitochondrial DNA is reached (lower panel). (C) In patients with homoplasmic mitochondrial DNA mutations, all cardiomyocytes contain multiple copies of mutated mitochondrial DNA (red, upper panel), with the majority of cells displaying cytochrome c oxidase deficiency (blue, lower panel).

Figure 3

Algorithm for investigation of mitochondrial DNA disease. Ideally, mitochondrial disease should be assessed in the most affected tissue. However, this is often not possible and skeletal muscle biopsy can serve as an alternative even without clinical myopathy. Histochemical analysis, although not always possible due to tissue availability, can direct genetic investigation but it may be necessary to perform biochemical or molecular genetic analysis directly (dashed arrows). mtDNA, mitochondrial DNA; PCR, polymerase chain reaction.

Figure 4

Histological, histochemical, and ultrastructural features of mitochondrial DNA-related cardiomyopathy. (A) Histological examination of explanted left ventricular tissue from a patient with a homoplasmic mt-tRNA^Ile mutation reveals enlarged cardiomyocytes with prominent cytoplasmic vacuolization (H&E, 20×). (B) Vacuoles contain lipid droplets that stain with Oil Red O (40×). (C) Sequential cytochrome c oxidase/succinate dehydrogenase histochemistry shows several cytochrome c oxidase-deficient cardiomyocytes (blue) with scattered cytochrome c oxidase-positive cells (brown, 40×). (D) Ultrastructural analysis reveals proliferation of polymorphic mitochondria and displacement of sarcomeres (uracyl acetate lead citrate, 3150×).

Figure 5

Clinical algorithm for cardiac screening and management in mitochondrial DNA disease. International guidelines support early intervention for conduction disease in patients with mitochondrial DNA disease.^, ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AV, atrio-ventricular; CPEO, chronic progressive external ophthalmoplegia; DCM, dilated cardiomyopathy; EPS, electrophysiological study; HCM, hypertrophic cardiomyopathy; KSS, Kearns-Sayre syndrome; LVH, left ventricular hypertrophy; LVOTO, left ventricular outflow tract obstruction; mtDNA, mitochondrial DNA; PPM, permanent pacemaker; *many experienced centres regard rapid progression of conduction disease, severe surface ECG abnormalities, and/or HV interval >70 ms as high-risk features for progression to AV block.^,