Format

Send to

Choose Destination
Cardiovasc Res. 2017 Aug 1;113(10):1161-1172. doi: 10.1093/cvr/cvx087.

Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy.

Author information

1
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, NO-0407 Oslo, Norway.
2
Bjørknes College, Oslo, Norway.
3
Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
4
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
5
Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
6
Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.

Abstract

Aims:

Concentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload.

Methods and results:

Rats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e' values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+].

Conclusion:

In the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis.

KEYWORDS:

Ca2+ homeostasis; Collagen; Concentric hypertrophy; Diastolic dysfunction; Titin

PMID:
28472418
PMCID:
PMC5852536
DOI:
10.1093/cvr/cvx087
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center