Myocardial Contractile Dysfunction is Associated with Impaired Mitochondrial Function and Dynamics in Type 2 Diabetic but not in Obese Patients
Background—Obesity and diabetes mellitus (DM) are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance and DM on intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy.
Methods and Results—Right atrial myocardium was obtained from 141 consecutive patients, presenting no sign of cardiomyopathy. We investigated (i) ex vivo isometric contraction (ii) mitochondrial respiration and calcium retention capacity (iii) respiratory chain complex activities and oxidative stress status. DM was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction and increased myocardial oxidative stress, irrespective of weight status. By contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated haemoglobin (HbA1C), but neither body mass index nor the insulin resistance index HOMA-IR, was independently associated with cardiac mitochondrial function. Furthermore, DM was associated with cardiac mitochondrial network fragmentation and significant decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to HbA1C.
Conclusions—Worsening of intrinsic myocardial contraction in the transition from obesity to DM is likely related to worsening of cardiac mitochondrial function, since impaired mitochondrial function and dynamics, as well as contractile dysfunction are observed in diabetic patients but not in "metabolically healthy" obese patients at early stage in insulin resistance.
- Received December 28, 2013.
- Revision received May 13, 2014.
- Accepted June 6, 2014.