Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression

Cardiovasc Res. 2019 Mar 15;115(4):752-764. doi: 10.1093/cvr/cvy257.


Aims: Regional heterogeneities in contraction contribute to heart failure with reduced ejection fraction (HFrEF). We aimed to determine whether regional changes in myocardial relaxation similarly contribute to diastolic dysfunction in post-infarction HFrEF, and to elucidate the underlying mechanisms.

Methods and results: Using the magnetic resonance imaging phase-contrast technique, we examined local diastolic function in a rat model of post-infarction HFrEF. In comparison with sham-operated animals, post-infarction HFrEF rats exhibited reduced diastolic strain rate adjacent to the scar, but not in remote regions of the myocardium. Removal of Ca2+ within cardiomyocytes governs relaxation, and we indeed found that Ca2+ transients declined more slowly in cells isolated from the adjacent region. Resting Ca2+ levels in adjacent zone myocytes were also markedly elevated at high pacing rates. Impaired Ca2+ removal was attributed to a reduced rate of Ca2+ sequestration into the sarcoplasmic reticulum (SR), due to decreased local expression of the SR Ca2+ ATPase (SERCA). Wall stress was elevated in the adjacent region. Using ex vivo experiments with loaded papillary muscles, we demonstrated that high mechanical stress is directly linked to SERCA down-regulation and slowing of relaxation. Finally, we confirmed that regional diastolic dysfunction is also present in human HFrEF patients. Using echocardiographic speckle-tracking of patients enrolled in the LEAF trial, we found that in comparison with controls, post-infarction HFrEF subjects exhibited reduced diastolic train rate adjacent to the scar, but not in remote regions of the myocardium.

Conclusion: Our data indicate that relaxation varies across the heart in post-infarction HFrEF. Regional diastolic dysfunction in this condition is linked to elevated wall stress adjacent to the infarction, resulting in down-regulation of SERCA, disrupted diastolic Ca2+ handling, and local slowing of relaxation.

Keywords: Cardiomyocyte calcium cycling; Diastolic dysfunction; Heart failure; Post-infarction remodelling; Wall stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Calcium Signaling*
  • Computer Simulation
  • Diastole
  • Disease Models, Animal
  • Fibrosis
  • Heart Failure / etiology*
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Humans
  • Kinetics
  • Male
  • Middle Aged
  • Models, Cardiovascular
  • Myocardial Infarction / complications*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Randomized Controlled Trials as Topic
  • Rats, Wistar
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Ventricular Dysfunction, Left / etiology*
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left*
  • Ventricular Remodeling*


  • Sarcoplasmic Reticulum Calcium-Transporting ATPases