Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development

1 Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky; 2 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; 3 Department of Physiology, University Medical School of Debrecen, Debrecen, Hungary; and 4 Center for Biomedical Engineering, University of Kentucky and 5 Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky Submitted 2 March 2007 ; accepted in final form 11 September 2007 Hypertension is a major risk factor for developing cardiac hypertrophy and heart failure. Previous studies show that hypertrophied and failing hearts display alterations in excitation-contraction (E-C) coupling. However, it is unclear whether remodeling of the E-C coupling system occurs before or after heart disease development. We hypothesized that hypertension might cause changes in the E-C coupling system that, in turn, induce hypertrophy. Here we tested this hypothesis by utilizing the progressive development of hypertensive heart disease in the spontaneously hypertensive rat (SHR) to identify a window period when SHR had just developed hypertension but had not yet developed hypertrophy. We found the following major changes in cardiac E-C coupling during this window period. 1 ) Using echocardiography and hemodynamics measurements, we found a decrease of left ventricular ejection fraction and cardiac output after the onset of hypertension. 2 ) Studies in isolated ventricular myocytes showed that myocardial contraction was also enhanced at the same time. 3 ) The action potential became prolonged. 4 ) The E-C coupling gain was increased. 5 ) The systolic Ca 2+ transient was augmented. These data show that profound changes in E-C coupling already occur at the onset of hypertension and precede hypertrophy development. Prolonged action potential and increased E-C coupling gain synergistically increase the Ca 2+ transient. Functionally, augmented Ca 2+ transient causes enhancement of myocardial contraction that can partially compensate for the greater workload to maintain cardiac output. The increased Ca 2+ signaling cascade as a molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed. heart failure; action potential; L-type Ca 2+ channel; ryanodine receptor Address for reprint requests and other correspondence: Y. Chen-Izu, Dept. of Internal Medicine, Univ. of Kentucky Coll. of Medicine, BBSRB, Rm. B255, 741 S. Limestone St., Le