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

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

Author information

1
Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway.
2
KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.
3
Biomedical Engineering Department, The Rayne Institute, King's College, London, London, UK.
4
Bjørknes College, Oslo, Norway.
5
Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.

Abstract

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

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