Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers

Abstract

Aims: Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement.

Methods and results: Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = -0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE.

Conclusion: Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.

Keywords: Cardiac tagging; Cardiomyopathy; Magnetic resonance imaging; Magnetic resonance spectroscopy; Mitochondrial disease.

Figure 1

Cardiac tagging analysis. (A) Cine imaging (top panels) and tagging (bottom) at end-diastole (left panels) and end-systole (right). A rectangular grid of nulled myocardium applied in the diastole enables tracking of myocardial deformation. (B) Tagging of two parallel short-axis slices allows the calculation of torsion, the longitudinal-circumferential sheer angle (θ) as shown.

Figure 2

LVMI and clinical markers. LVMI correlated positively with both (A) urinary mutation load and (B) NMDAS score, while peak endocardial circumferential strain correlated negatively with (C) urinary mutation load and (D) NMDAS score. LVMI, left ventricular mass index; NMDAS, Newcastle Mitochondrial Disease Adult Scale.

Figure 3

³¹P magnetic resonance spectroscopy. Representative spectra from (A) a patient carrying m.3243A>G, with the PCr/ATP ratio of 1.23, and (B) a matched control subject, with the PCr/ATP ratio of 2.10, showing a difference in the PCr concentration. Spectra are presented as acquired before correction for heart rate, flip angle and blood content. (C) A box plot of range and quartiles of the PCr/ATP ratio in patient and control groups. 2,3DPG, 2,3-disphosphoglycerate; PDE, phosphodiesters; PCr, phosphocreatine; ATP, adenosine triphosphate; ppm, parts per million; *P < 0.001 compared with controls.