title: Hypertension-induced remodeling of cardiac excitation-contraction coupling in ventricular myocytes occurs prior to hypertrophy development.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Kentucky College of Medicine, 741 S. Limestone Street, Lexington, KY 40536-0509, USA. yechen-izu@uky.edu
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: Stacey L
authors.initials: SL
authors.lastname: McCulle
authors.forename: Byron
authors.initials: B
authors.lastname: Norton
authors.forename: Steven M
authors.initials: SM
authors.lastname: Scharf
authors.forename: Anuj
authors.initials: A
authors.lastname: Agarwal
authors.forename: Abhijit
authors.initials: A
authors.lastname: Patwardhan
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
mesh_terms: 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