Myocardial mechanics and titin in experimental insulin-resistant rats

We investigated the intrinsic cardiac mechanics of myocardium and changes in titin in insulin-resistant rats. Microsonometry and micromanometry were used to evaluate the maximal elastance (Emax) and myocardial stiffness constant (Km) of the left ventricle, in addition to the traditional systolic and diastolic cardiac function, with an isolated working heart preparation. Thirty 150 g Wistar rats were divided into three groups of 10. Group A was fed rat chow, while groups B and C were fed a 66% fructose diet for 7-8 months. Group C also received clonidine. Group B rats developed insulin resistance, as well as elevated plasma glucose and blood pressure. Group C rats also had insulin resistance and elevated plasma glucose, but not higher blood pressure. Group B rats had decreased Emax, decreased peak-dp/dt, prolonged Tau and increased Km compared to normal control rats. Group C rats, which mimicked the clinical condition of diabetic cardiomyopathy, maintained normal global left ventricular function as revealed by cardiac output, peak + dp/dt, peak-dp/dt and Tau of relaxation. However, they had a lower Emax slope (355 +/- 51 vs 535 +/- 56 mmHg.mm than group A rats, p < 0.05) and increased Km (81.6 +/- 9.9 vs 25.5 +/- 4.8 in group A, p < 0.001), even though the extent of elevation of plasma glucose was only mild (71.3 +/- 2.0 to 108.9 +/- 4.4 mg/dl, p < 0.001). Their left ventricular mass, myocyte size, interstitial fibrosis and vascular picture did not change. However, the content of myocardial titin decreased significantly (intensity ratio of titin/actin was 0.23 +/- 0.01 and 0.29 +/- 0.02 in group C and group A rats respectively, p < 0.05). These findings suggest that changes in titin play a role in the change in myocardial functional characteristics and may be one of the causes of diabetic cardiomyopathy.