Dataset Information

Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

ABSTRACT: Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 ± 12 ms versus 129 ± 15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39 ± 3 cm/s versus 49 ± 2 cm/s in NF, P=0.008) to the epicardium (28 ± 3 cm/s versus 40 ± 2 cm/s in NF, P=0.008). Conduction slowing was likely due to connexin 43 (Cx43) downregulation, decreased colocalization of Cx43 with N-cadherin (40 ± 2% versus 52 ± 5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 16.4 ± 7.7 versus 9.9 ± 1.4% in NF, P=0.02).Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with nonischemic cardiomyopathy.

SUBMITTER: Glukhov AV

PROVIDER: S-EPMC3351089 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

Glukhov Alexey V AV Fedorov Vadim V VV Kalish Paul W PW Ravikumar Vinod K VK Lou Qing Q Janks Deborah D Schuessler Richard B RB Moazami Nader N Efimov Igor R IR

Circulation 20120312 15

<h4>Background</h4>Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.<h4>Methods and results</h4>We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (hea ...[more]

PMID: 22412072

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Project description:Nonischemic cardiomyopathy is a common cause of left ventricular (LV) dysfunction and myocardial fibrosis. The purpose of this study was to noninvasively evaluate changes in segmental LV extracellular volume (ECV) fraction, LV velocities, myocardial scar, and wall motion in nonischemic cardiomyopathy patients.Cardiac MRI including pre- and postcontrast myocardial T1 mapping and velocity quantification (tissue phase mapping) of the LV (basal, midventricular, and apical short axis) was applied in 31 patients with nonischemic cardiomyopathy (50±18 years). Analysis based on the 16-segment American Heart Association model was used to evaluate the segmental distribution of ECV, peak systolic and diastolic myocardial velocities, scar determined by late gadolinium enhancement, and wall motion abnormalities. LV segments with scar or impaired wall motion were significantly associated with elevated ECV (rs =0.26; P<0.001) and reduced peak systolic radial velocities (r=-0.43; P<0.001). Regional myocardial velocities and ECV were similar for patients with reduced (n=12; ECV=0.28±0.06) and preserved left ventricular ejection fraction (n=19; ECV=0.30±0.09). Patients with preserved left ventricular ejection fraction showed significant relationships between increasing ECV and reduced systolic (r=-0.19; r=-0.30) and diastolic (r=0.34; r=0.26) radial and long-axis peak velocities (P<0.001). Even after excluding myocardial segments with late gadolinium enhancement, significant relationships between ECV and segmental LV velocities were maintained indicating the potential of elevated ECV to identify regional diffuse fibrosis not visible by late gadolinium enhancement, which was associated with impaired regional LV function.Regionally elevated ECV negatively affected myocardial velocities. The association of elevated regional ECV with reduced myocardial velocities independent of left ventricular ejection fraction suggests a structure-function relationship between altered ECV and segmental myocardial function in nonischemic cardiomyopathy.

Project description:Background Heart failure ( HF ) with "recovered" ejection fraction ( HF rec EF ) is an emerging phenotype, but no tools exist to predict ejection fraction ( EF ) recovery in acute HF . We hypothesized that indices of baseline cardiac structure and function predict HF rec EF in nonischemic cardiomyopathy and reduced EF . Methods and Results We identified a nonischemic cardiomyopathy cohort with EF <40% during the first HF hospitalization (n=166). We performed speckle-tracking echocardiography to measure longitudinal, circumferential, and radial strain, and the average of these measures (myocardial systolic performance). HF rec EF was defined as follow-up EF ≥40% and ≥10% improvement from baseline EF . Fifty-nine patients (36%) achieved HF rec EF (baseline EF 26±7%; follow-up EF 51±7%) within a median of 135 (interquartile range 58-239) days after the first HF hospitalization. Baseline demographics, biomarker profiles, and comorbid conditions (except lower chronic kidney disease in HF rec EF ) were similar between HF rec EF and persistent reduced- EF groups. HF rec EF patients had smaller baseline left ventricular end-systolic dimension (3.6 versus 4.8 cm; P<0.01), higher baseline myocardial systolic performance (9.2% versus 8.1%; P=0.02), and improved survival (adjusted hazard ratio 0.27, 95% confidence interval 0.11, 0.62). We found a significant interaction between baseline left ventricular end-systolic dimension and absolute longitudinal strain. Among patients with left ventricular end-systolic dimension >4.35 cm, higher absolute longitudinal strain (≥8%) was associated with HF rec EF (unadjusted odds ratio=3.9, 95% CI )confidence interval 1.2, 12.8). Incorporation of baseline indices of cardiac mechanics with clinical variables resulted in a predictive model for HF rec EF with c-statistic=0.85. Conclusions Factors associated with achieving HF rec EF were specific to cardiac structure and indices of cardiac mechanics. Higher baseline absolute longitudinal strain is associated with HF rec EF among nonischemic cardiomyopathy patients with reduced EF and larger left ventricular dimensions.

Dataset Information

Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

Publications

Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

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