Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development.
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.
Chen-Izu
Ye
Y
Department of Internal Medicine, University of Kentucky College of Medicine, 741 S. Limestone Street, Lexington, KY 40536-0509, USA. yechen-izu@uky.edu
Chen
Ling
L
Bányász
Tamás
T
McCulle
Stacey L
SL
Norton
Byron
B
Scharf
Steven M
SM
Agarwal
Anuj
A
Patwardhan
Abhijit
A
Izu
Leighton T
LT
Balke
C William
CW
D000200:Action Potentials; D000818:Animals; D020013:Calcium Signaling; D002302:Cardiac Output; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling