Abstract
BackgroundDiastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease’s complex pathology. The cause of the association is unknown and has no approved therapy strategies as of yet. However significant advances in this area may come from studies on suitable animal models.MethodsA total of 25 male rhesus monkeys (12-16 years, 9-13 kg) were enrolled. Fifteen of them were diagnosed as spontaneous type 2 diabetes mellitus (T2DM, FPG ≥ 104 mg/dl, HbA1c: 4.7-5.5 %, diabetes duration: 1-4 years). The other 10 monkeys were non-diabetic (ND, FPG < 90 mg/dl). Echocardiography and cardiac magnetic resonance were used for evaluating the cardiac structure and function. One T2DM monkey with impaired diastolic function and another ND monkey were both sacrificed to gain the necessary pathology and protein expression studies displayed here.ResultsSix out of 15 T2DM rhesus monkeys were diagnosed with diastolic dysfunction (DD) by echocardiography. Additionally, no abnormalities were found in the group which we determined as the ND monkeys. The six DD monkeys all showed low e’ velocity and decreased e’/a’ ratio, among which three of them showing decreased E/A ratio and the other 3 having elevated E/A ratio, this appears to be similar to the impaired relaxation pattern and pseudonormal pattern found in human patients respectively. The EF and FS of monkeys with pseudonormal pattern decreased significantly compared with ND subjects. A CMR study showed that LVID at end systole of 5 DD monkeys is significantly longer than that of 3 ND monkeys. Of great interest, myocardium lesions and mitochondria impairments and increased expression of AGEs and caspase-3 were found in a sacrificed DD subject.ConclusionThe changes in the imaging and physiological markers of spontaneous T2DM rhesus monkeys are similar to those key markers found in human type 2 diabetes and diastolic dysfunction. This monkey model could help the medical community and us to understand the pathology of this debilitating disease and serve as a beginning to explore important measures to prevent and treat diabetic cardiomyopathy.
Highlights
Diastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease’s complex pathology
Gravimetry and metabolic profile Hyperglycemia and elevated Hemoglobin A1c (HbA1c) percentage were confirmed in all spontaneous T2DM monkeys enrolled (Table 1)
Obesity was observed in all T2DM monkeys, whose BMI average body weight was larger than that of ND group (38.0 ± 2.8 vs 28.8 ± 2.8, kg/m2, p < 0.05), while there was no significance in body weight (11.3 ± 1.2 vs 9.2 ± 1.9, kg)
Summary
Diastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease’s complex pathology. DCM is marked by diastolic dysfunction (DD) early on the disease’s progression [5,6,7] that leads to the loss of contractile (systolic) function as time passes by [7,8,9]. The pathogenesis of this ventricular dysfunction remains unknown, but several hypotheses have been proposed, including autonomic dysfunction, metabolic derangements, abnormalities in ion homeostasis, alteration in structural proteins and the presence of interstitial fibrosis
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