Submitted on March 2, 2007
Accepted on September 11, 2007
Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development
Ye Chen-Izu1*, Ling Chen2, Tamas Banyasz3, Stacey L McCulle2, Byron Norton1, Steven M. Scharf2, Anuj Agarwal4, Abhijit R. Patwardhan4, Leighton T Izu1, and C. William Balke5
1 Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States
2 Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
3 Physiology, University Medical School of Debrecen, Debrecen, Hungary; Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States
4 Center for Biomedical Engineering, University of Kentucky, Lexington, Kentucky, United States
5 Medicine/Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, United States
* To whom correspondence should be addressed. E-mail: YeChen-Izu{at}uky.edu.
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 which, in turn, induces hypertrophy. Here we test 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 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 of cardiac output following the onset of hypertension. (2) Studies in isolated ventricular myocytes show that the 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 Ca2+ 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 Ca2+ transient. Functionally, augmented Ca2+ transient causes enhancement of myocardial contraction which can partially compensate for the greater workload to maintain cardiac output. Increased Ca2+ signaling cascade as molecular mechanism linking hypertension to cardiac hypertrophy development is also discussed.
