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Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

ABSTRACT: Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling.Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 ?m and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca(2+)] (pCa ?6.5) in HTN patients. Analysis of protein phosphorylation revealed ?25% reduction in phosphorylation of troponin I in HTN patients (P<0.05).Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca(2+)] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

SUBMITTER: Donaldson C

PROVIDER: S-EPMC3505876 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

Donaldson Cameron C Palmer Bradley M BM Zile Michael M Maughan David W DW Ikonomidis John S JS Granzier Henk H Meyer Markus M VanBuren Peter P LeWinter Martin M MM

Circulation. Heart failure 20120926 6

<h4>Background</h4>Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling.<h4>Methods and results</h4>Intraoperative myocardial biopsies w ...[more]

PMID: 23014131

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Project description:The purpose of the present article is to identify intrinsic genes across general hypertension (HT), hypertension with left ventricular remodeling (HT-LVR), and uncontrolled hypertension (UN-HT). In total, four microarray datasets (GSE24752, GSE75360, GSE74144, and GSE71994) were downloaded from the GEO database and were used to identify differentially expressed genes (DEGs), respectively. Furthermore, gene set enrichment analysis (GSEA) was utilized to screen for significantly enriched biological pathways across the four datasets above, respectively. Furthermore, weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were applied to screen out gene modules of interest and potential biological functions, respectively. Finally, a Metascape-based multiple gene list meta-analysis was used to investigate intrinsic genes at different stages of the progression of hypertension. A total of 75 DEGs (63 upregulated genes and 12 downregulated genes, GSE24752) and 23 DEGs (2 upregulated genes and 21 downregulated genes, GSE74144) were identified. However, there were few DEGs identified in GSE75360, GSE71994, and part of the GSE74144 datasets. GSEA and functional enrichment of gene module of interest have indicated that "Heme metabolism," "TNF alpha/NFkB," and "interferon alpha response signaling," and MYC target v1/v2 were enriched significantly in different stages of hypertension progression. Significantly, findings from the multiple gene list meta-analysis suggested that FBXW4 and other 13 genes were unique to the hypertension group, and TRIM11 and other 40 genes were mainly involved in hypertension with the left ventricular remodeling group, while the other 18 genes including F13A1 significantly enriched in uncontrolled hypertension. Collectively, the precise switch of the "immune-metabolic-inflammatory" loop pathway was the most significant hallmark across different stages of hypertension, thereby providing a potential therapeutic target for uncontrolled hypertension treatment.

Project description:Background This study compared left ventricular (LV) characteristics between patients with type-A and type-B aortic dissection (AD) and evaluated the ability of LV remodeling phenotypes (hypertrophy, concentricity, or geometric patterns) to predict mortality in both AD types. Methods and Results We evaluated 236 patients with type A and 120 patients with type B who had echocardiograms within 60 days before or after AD diagnosis (median [25th, 75th percentiles] time difference between echocardiogram and AD diagnosis=1 [0, 6] days) from 3 centers. Patients were stratified according to LV phenotypes, and early (90-day) and late (1-year) mortality after AD diagnosis were assessed. In adjusted logistic regression analysis, patients with type A had higher and lower odds of concentric and eccentric hypertrophy (odds ratio [OR], 2.56; 95% CI, 1.50-4.36; P<0.001; and OR, 0.55; 95% CI, 0.31-0.97; P=0.039, respectively) than those with type B. Results of multivariable Cox-regression analysis showed that LV remodeling phenotypes were not related to mortality in patients with type B. By contrast, LV concentricity was associated with greater early and late mortality (hazard ratio [HR], 2.22; 95% CI, 1.24-3.96; P=0.007 and HR, 2.06; 95% CI, 1.20-3.54; P=0.009, respectively) in type A. In further analysis considering normal LV geometry as reference, LV concentric remodeling and concentric hypertrophy were associated with early mortality (HR, 7.78; 95% CI, 2.35-25.78; P<0.001 and HR, 4.38; 95% CI, 1.47-13.11; P=0.008, respectively), whereas concentric remodeling was associated with late mortality (HR, 5.40; 95% CI, 1.91-15.26; P<0.001) among patients with type A. Assessment of LV geometric patterns and concentricity provided incremental prognostic value in predicting early and late mortality beyond clinical variables in patients with type A based on net reclassification improvement and integrated discrimination improvement. Conclusions LV geometric patterns derived from LV concentricity were associated with greater mortality among patients with type A and may be markers of adverse prognosis in this population.

Dataset Information

Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

Publications

Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

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