The Effects of Troponin T Heterogeneity on Reducing Myocardial Efficiency

Cardiac TnT variants with abnormal splicing in the N-terminal region have been found in avian and mammalian cases of dilated cardiomyopathy. Similar abnormality also occurs in myopathic and failing human hearts. These cardiac TnT variants may play a role in the pathogenesis and pathophysiology of cardiomyopathy and heart failure. Without losses of function, the cardiac TnT variants result in only minor differences in thin filament Ca2+ sensitivity. Therefore, we hypothesize that the heterogeneity resulting from the presence of two or more functionally distinct cardiac TnT variants in the normally uniform adult cardiac muscle thin filaments desynchronizes myofilament activation and decreases the contractile efficiency. We studied transgenic mouse hearts expressing one or two of the myopathy-related cardiac TnT variants together with the wild type adult cardiac TnT. The function of isolated working hearts was examined for pumping efficiency in the absence of neurohumoral influence. The results showed that at heart rate of 480 beat per minute and pressure load of 90 mmHg, contractile and relaxation velocities were lower in the transgenic mouse hearts than that in the wild type hearts. Left ventricular pumping efficiency calculated by the ratio of ejection integral to total systolic integral was also lower in the transgenic mouse hearts than that in wild type controls. When stressed by pacing at 600 beats per minute and giving 10 nM isoproterenol, the transgenic mouse hearts exhibited shorter ejection time and decreased cardiac efficiency than that of wild type hearts. These results indicate a chronic pathogenic mechanism that TnT heterogeneity leads to decreased myocardial efficiency due to desynchronized responses to intracellular Ca2+ transient.