Myocardial glucose uptake in patients with the m.3243A > G mutation in mitochondrial DNA

Abstract

Mitochondrial mutations impair glucose oxidation and increase glucose uptake in cell cultures and lead to cardiomyopathy in patients. Here we characterize cardiac glucose uptake in 14 patients with the m.3243A > G mutation in mitochondrial DNA. The 14 patients with m.3243A > G and 13 controls were similar in age, physical activity and body mass index. Ten patients had diabetes. Left ventricular glucose uptake per tissue mass (LVGU) was measured with 2-[(18) F]fluoro-2-deoxyglucose positron emission tomography during euglycemic hyperinsulinemia. Cardiac morphology and function were assessed with magnetic resonance imaging. We found that the LVGU was 25% lower in the patients than that in the controls (P = 0.029). LVGU was inversely correlated with mutation heteroplasmy, glycated haemoglobin and fasting lactate in patients. The seven patients with mutation heteroplasmy ≥ 49% had 44% lower LVGU than the seven patients with heteroplasmy < 49%. This difference remained significant after adjustment for concurrent free fatty acid concentration or glycated haemoglobin or glucose uptake in skeletal muscle or all (p < 0.048 [All]). Patients with m.3243A > G had a lower stroke volume and a higher heart rate than the controls, whereas cardiac output and work were similar. Myocardial glucose uptake is not increased but decreased with a threshold effect pattern in patients with the m.3243A > G mutation. The glucose hypometabolism adds to the impaired cardiac energetics and likely contributes to the progression of the mitochondrial cardiomyopathy.

Systematic review and meta-analysis of cardiac involvement in mitochondrial myopathy

“…13,14 The available evidence shows similar diagnostic yield of CMRI in comparison with echo; however, the data are very heterogeneous and from a limited number of patients. In studies including m.3243A>G and/or MELAS patients, 2 studies 15,16 reported no CMRI abnormalities, and 1 study 17 reported CMRI abnormalities in nearly all patients. This discrepancy can hopefully be addressed in future research.…”

“…One study of CMRI in 14 participants showed no structural abnormalities, but an overall reduction of myocardial glucose uptake, which may be a biomarker of interest for future study. 16 Only a single study included CMRI data from a pediatric participant. 10 Overall, CMRI has thus far had very limited study in MM, and further investigation will be required to understand the advantages and limitations of this modality in patients with MM.…”

“…In our study, 10 articles described patients with MM with diabetes. 9,11,12,15–17,21–24 Of the 122 patients with diabetes, 47 of them were diagnosed with MELAS. Given that diabetes is a major risk factor for cardiac dysfunction, it might be expected that patients with MELAS have greater cardiac risk as a consequence.…”

Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders

“…Fatty acid oxidation provides reducing equivalents directly to the mitochondrial respiratory chain, as well as acetyl-CoA for the Krebs cycle, which in turn generates additional reducing equivalents to maintain energy homeostasis. In an otherwise normal heart, the respiratory chain is compromised in cardiac failure, leading to an increase in the NADH/NAD + ratio and a decrease in pyruvate oxidation for gluconeogenesis [26]. This metabolic state decreases the utility of glucose as a backup energy source in the failing heart.…”

Mitochondrial mutation m.3243A>G associates with insulin resistance in non-diabetic carriers

“…The elevated lactate level in the m.3243A>G was an expected finding and could be a contributing cause of the insulin resistance as fasting lactate levels have been shown to be inversely correlated with glucose uptake in the left ventricle of the heart during an euglycemic hyperinsulinemic clamp in m.3243A>G carriers (39).…”