Sarcoplasmic reticulum Ca2+ load in human heart failure

Basic Res Cardiol. 2002:97 Suppl 1:I63-71. doi: 10.1007/s003950200032.

Abstract

Excitation-contraction coupling and intracellular Ca2+ homeostasis are altered in heart failure. We tested the hypothesis that these changes are related to disturbed Ca2+ handling of the sarcoplasmic reticulum (SR). Isolated, electrically stimulated trabeculae were obtained from end-stage failing (NYHA IV) and nonfailing human hearts. Isometric twitch tension, intracellular Ca2+ transients (aequorin method) and SR Ca2+ content (rapid cooling contractures) were assessed under basal conditions (1 Hz, 37 degrees C) as well as after stepwise increasing rest intervals from 2-240 s (post-rest contractions). Protein expression of SERCA2a and phospholamban (Western blot) was assessed in a subset of failing trabeculae. In addition, the effects of SERCA1 overexpression on contractile function of isolated myocytes was tested. On average, post-rest twitch tension continuously increased with increasing rest intervals in nonfailing, but declined with rest intervals longer than 15 s in failing myocardium. The rest-dependent contractile changes were accompanied by parallel changes in intracellular Ca2+ transients. Failing trabeculae (n = 40) were grouped (group A: post-rest potentiation (force of contraction > pre-rest twitch force) after 120 s rest interval; group B: post-rest decay (force of contraction < pre-rest twitch force) after 120 s rest interval), and post-rest contractile function was related to SERCA2a and PLB expression. While PLB protein expression was not different, SERCA2a protein expression as well as SERCA2a/PLB ratio was significantly higher in group A vs. group B. Transfection of SERCA1 increased shortening amplitude and enhanced relaxation kinetics in failing human myocytes. In conclusion, SR Ca2+ handling is severely altered in human heart failure. Reduced SR Ca2+ release is due to diminished SR Ca2+ content directly related to a depressed expression of SERCA2a protein. Enhancing SERCA function or expression may improve SR Ca2+ handling in failing human myocardium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium-Binding Proteins / metabolism
  • Calcium-Transporting ATPases / metabolism
  • Cardiac Output, Low / metabolism*
  • Cardiac Output, Low / physiopathology
  • Heart / physiology
  • Heart / physiopathology
  • Humans
  • In Vitro Techniques
  • Myocardial Contraction / physiology
  • Reference Values
  • Rest
  • Sarcoplasmic Reticulum / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases

Substances

  • Calcium-Binding Proteins
  • phospholamban
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A1 protein, human
  • Calcium-Transporting ATPases
  • Calcium