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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.

SUBMITTER: Roe AT

PROVIDER: S-EPMC6432054 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Røe Åsmund T ÅT Ruud Marianne M Espe Emil K EK Manfra Ornella O Longobardi Stefano S Aronsen Jan M JM Nordén Einar Sjaastad ES Husebye Trygve T Kolstad Terje R S TRS Cataliotti Alessandro A Christensen Geir G Sejersted Ole M OM Niederer Steven A SA Andersen Geir Øystein GØ Sjaastad Ivar I Louch William E WE

Cardiovascular research 20190301 4

<h4>Aims</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 30351410

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Project description:Aldosterone infusion results in left ventricular hypertrophy (LVH) and hypertension and may involve profibrotic and proinflammatory mechanisms. In turn, hypertension is the major cause of diastolic heart failure (HF). Adiponectin, an adipose-derived plasma protein, exerts antiinflammatory and anti-hypertrophic effects and is implicated in the development of hypertension and systolic HF. We thus tested the hypothesis that hypoadiponectinemia in aldosterone-induced hypertension exacerbated cardiac remodeling and diastolic HF. Wild-type (WT) or adiponectin-deficient (APNKO) mice underwent saline or aldosterone infusion and uninephrectomy and were fed 1% salt water for 4 wk. Blood pressure was increased in aldosterone-infused WT (132 +/- 2 vs. 109 +/- 3 mm Hg; P < 0.01) and further augmented in APNKO mice (140 +/- 3 mm Hg; P < 0.05 vs. aldosterone-infused WT). LVH was increased in aldosterone-infused WT vs. WT mice (LV/body weight ratio, 4.8 +/- 0.2 vs. 4.1 +/- 0.2 mg/g) and further increased in aldosterone-infused APNKO mice (LV/body weight ratio, 6.0 +/- 0.4 mg/g). Left ventricular ejection fraction was not decreased in either aldosterone-infused WT or APNKO hearts. Pulmonary congestion however was worse in APNKO mice (P < 0.01). The ratio of early ventricular filling over late ventricular filling (E/A) and the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e'), measures of diastolic function, were increased in aldosterone-infused WT hearts and further increased in APNKO hearts (P < 0.05 for both). Renal function and cardiac fibrosis were no different between both aldosterone-infused groups. Aldosterone increased matrix metalloproteinase-2 expression in WT hearts (P < 0.05 vs. WT and P < 0.01 vs. APNKO). Myocardial atrial natriuretic peptide, interferon-gamma, and TNF-alpha expression were increased in aldosterone-infused WT hearts. Expression of these proteins was further increased in aldosterone-infused APNKO hearts. Therefore, hypoadiponectinemia in hypertension-induced diastolic HF exacerbates LVH, diastolic dysfunction, and diastolic HF. Whether or not adiponectin replacement prevents the progression to diastolic HF will warrant further study.

Project description:Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures (DBP) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and DBP, defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. DBP levels were significantly related to WMHV differentially across regions (P for interaction<0.05). Relative to those with DBP 90+ mm?Hg, participants with DBP <80 mm?Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with DBP 80 to 89 mm?Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with DBP 90? mm?Hg. Post hoc pairwise t tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted P<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower DBP levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.

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Project description:A simple rule adopted for myofiber reorientation in the ventricles is pursued by taking the microscopic branching network of myocytes into account. The macroscopic active tension generated on the microscopic branching structure is modeled by a multidirectional active stress tensor, which is defined as a function of the strains in the branching directions. In our reorientation algorithm, the principal direction of the branching network is updated so that it turns in the direction of greater active tension in the isovolumetric systole. Updates are performed step-by-step after the mechanical equilibrium has been attained with the current fiber structure. Starting from a nearly flat distribution of the principal fiber orientation along the circumferential direction, the reoriented fiber helix angles range from 70 to 40° at epicardium and from 60 to 80° at endocardium, in agreement with experimental observations. The helical ventricular myocardial band of Torrent-Guasp's model and the apical spiral structure of Rushmer's model are also reconstructed by our algorithm. Applying our algorithm to the infarcted ventricle model, the fiber structure near the infarcted site is remodeled so that the helix angle becomes steeper with respect to the circumferential direction near the epicardial surface. Based on our numerical analysis, we draw the following conclusions. (i) The multidirectional active tension based on the microscopic branching network is potentially used to seek tighter connection with neighboring aggregates. (ii) The thickening and thinning transitions in response to active tension in each myocyte allow the macroscopic principal fiber orientation of the microscopic branching network to move toward the direction of greater active tension. (iii) The force-velocity relationship is the key factor in transferring the fiber shortening strain to the magnitude of active tensions used in the myofiber reorientation. (iv) The algorithm naturally leads to homogeneity in the macroscopic active tension and the fiber shortening strain, and results in near-optimal pumping performance. (v) However, the reorientation mechanism may degrade the pumping performance if there is severely inhomogeneous contractility resulting from infarction. Our goal is to provide a tool to predict the fiber architecture of various heart disease patients for numerical simulations of their treatment plans.

Dataset Information

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

Publications

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

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