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

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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Røe ÅT,Ruud M,Espe EK,Manfra O,Longobardi S,Aronsen JM,Nordén ES,Husebye T,Kolstad TRS,Cataliotti A,Christensen G,Sejersted OM,Niederer SA,Andersen GØ,Sjaastad I,Louch WE

doi

10.1093/cvr/cvy257

subject

Has Abstract

pub_date

2019-03-15 00:00:00

pages

752-764

issue

4

eissn

0008-6363

issn

1755-3245

pii

5142689

journal_volume

115

pub_type

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