Dataset Information

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

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.

SUBMITTER: Roe AT

PROVIDER: S-EPMC5852536 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Røe Åsmund T ÅT Aronsen Jan Magnus JM Skårdal Kristine K Hamdani Nazha N Linke Wolfgang A WA Danielsen Håvard E HE Sejersted Ole M OM Sjaastad Ivar I Louch William E WE

Cardiovascular research 20170801 10

<h4>Aims</h4>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 act ...[more]

PMID: 28472418

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Project description:ImportanceCompared with white individuals, black individuals have increased electrocardiographic voltage and an increased prevalence of concentric left ventricular (LV) hypertrophy. Whether environmental or genetic factors lead to these racial differences is unknown.ObjectiveTo determine whether proportion of genetically determined African ancestry among self-reported black individuals is associated with increased electrocardiographic voltage and concentric LV hypertrophy (LVH).Design, setting, and participantsThe Dallas Heart Study is a probability-based cohort study of English- or Spanish-speaking Dallas County, Texas, residents, with deliberate oversampling of black individuals. Participants underwent extensive phenotyping, which included electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), and dual-energy radiography absorptiometry (DEXA) at a single center. Participants aged 18 to 65 years who enrolled in the Dallas Heart Study between July 2000 and December 2002, self-identified as black (n = 1251) or white (n = 826), and had ECG, CMR, and DEXA data were included in this analysis. Data were analyzed from June 2017 to September 2018.ExposuresProportion of African ancestry.Main outcomes and measuresElectrocardiographic voltage (12-lead and 9-lead) and markers of concentric LVH as assessed by CMR (LV concentricity0.67 [LV mass/end-diastolic volume0.67], LV wall thickness [LVWT], and prevalent LVH [defined by LV mass/height2.7]).ResultsOf the 2077 participants included in the study, 1138 (54.8%) were women, and the mean (SD) age was 45.2 (9.9) years. Black race and African ancestry were individually associated with increased ECG voltage, LV concentricity0.67, LVWT, and prevalent LVH in multivariable analyses adjusting for age, sex, systolic blood pressure, antihypertensive medication use, and body composition. When African ancestry and black race were entered together into multivariable models, African ancestry but not black race remained associated with ECG voltage, LVWT, LV concentricity0.67, and prevalent LVH. Among black participants, African ancestry remained associated with these 4 phenotypes (12-lead voltage: β, 0.05; P = .04; LVWT: β, 0.05; P = .02; LV concentricty0.67: β, 0.05; P = .045; prevalent LVH: odds ratio, 1.2; 95% CI, 1.03-1.4; P = .02).Conclusions and relevanceGenetically determined African ancestry was associated with electrocardiographic voltage, measures of concentric LV remodeling, and prevalent LVH. These data support a genetic basis related to African ancestry for the increased prevalence of these cardiovascular traits in black individuals.

Dataset Information

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

Aims

Methods and results

Conclusion

Publications

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

Similar Datasets

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