Remodeling of gap junctional channel function in epicardial border zone of healing canine infarcts.
ABSTRACT The epicardial border zone (EBZ) of canine infarcts has increased anisotropy because of transverse conduction slowing. It remains unknown whether changes in gap junctional conductance (Gj) accompany the increased anisotropy. Ventricular cell pairs were isolated from EBZ and normal hearts (NZ). Dual patch clamp was used to quantify Gj. At a transjunctional voltage (Vj) of +10 mV, side-to-side Gj of EBZ pairs (9.2+/-3.4 nS, n=16) was reduced compared with NZ side-to-side Gj (109.4+/-23.6 nS, n=14, P<0.001). Gj of end-to-end coupled cells was not reduced in EBZ. Steady-state Gj of both NZ and EBZ showed voltage dependence, described by a two-way Boltzmann function. Half-maximal activation voltage in EBZ was shifted to higher Vj in positive and negative directions. Immunoconfocal planimetry and quantification showed no change in connexin43 per unit cell volume or surface area in EBZ. Decreased side-to-side coupling occurs in EBZ myocytes, independent of reduced connexin43 expression, and is hypothesized to contribute to increased anisotropy and reentrant arrhythmias.
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ABSTRACT: The extent of peri-infarct zone (PIZ) by contrast-enhanced cardiac magnetic resonance (ce-CMR) has been related to inducibility of ventricular arrhythmia in patients with ischemic cardiomyopathy. However, this relationship has not been established in postmyocardial infarction (post-MI) patients with relatively reserved left ventricular (LV) systolic function yet. In this study, we investigated myocardial scar size and characteristics and its relationship with ventricular arrhythmia inducibility in patients with relatively preserved LV systolic function. This study enrolled 28 post-MI patients with a left ventricular ejection fraction between 40% and 50% and nonsustained ventricular tachycardia who underwent programmed ventricular stimulation (PVS) for risk stratification. Cine and gadolinium-enhanced cardiac magnetic resonance imaging was performed before PVS. A computer-assisted algorithm quantified the total scar (TS) size and divided it into the dense scar (DS) and the PIZ based on signal intensity thresholds (>6 standard deviations [SDs] and 2 to 6 SDs above remote normal myocardium, respectively). Scar measurements were determined and compared among noninducible (n = 19) and inducible patients (n = 9). The groups had similar baseline clinical characteristics. The LV masses, volumes, and ejection fractions did not differ significantly between the groups. For the inducible versus noninducible patients, DS percent was similar (3.11 ± 1.02% vs 3.44 ± 0.79%, P = NS). PIZ percent (28.02 ± 7.49% vs 19.86 ± 7.82%, P = 0.01) and TS percent (31.14 ± 7.96% vs 23.31 ± 8.21%, P = 0.02) were associated with inducibility of monomorphic VT. Multivariate analysis demonstrated that PIZ percent (P = 0.021, OR [odds ratio] 1.18, 95% CI [confidence interval] 1.03-1.35), and TS percent (P = 0.03, OR 1.15, 95% CI 1.01-1.30) were independent predictors of inducibility. Higher PIZ percent and TS percent were correlated with increased ventricular inducibility. These data support the hypothesis that ce-CMR may be used to identify the substrate for ventricular arrhythmia in this cohort.Pacing and Clinical Electrophysiology 11/2013; · 1.75 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are now recognized as critical regulators of diverse physiological and pathological processes; however, studies of miRNAs and arrhythmogenesis remain sparse. Connexin43 (Cx43), a major cardiac gap junction protein, has elicited great interest in its role in arrhythmias. Additionally, Cx43 was a potential target for miR-130a as predicted by several computational algorithms. This study investigates the effect of miR-130a overexpression in the adult heart and its effect on cardiac rhythm. Using a cardiac-specific inducible system, transgenic mice demonstrated both atrial and ventricular arrhythmias. We performed ventricular-programmed electrical stimulation and found that the αMHC-miR130a mice developed sustained ventricular tachycardia beginning 6weeks after overexpression. Western blot analysis demonstrated a steady decline in Cx43 after 2weeks of overexpression with over a 90% reduction in Cx43 levels by 10weeks. Immunofluorescent staining confirmed a near complete loss of Cx43 throughout the heart. To validate Cx43 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts and HL-1 cardiomyocytes, both known to endogenously express miR-130a. Using a luciferase reporter fused to the 3'UTR of Cx43, we found a 52.9% reduction in luciferase activity in 3T3 cells (p<0.0001) and a 47.6% reduction in HL-1 cells (p=0.0056) compared to controls. Addition of an antisense miR-130a inhibitor resulted in a loss of inhibitory activity of the Cx43 3'UTR reporter. We have identified an unappreciated role for miR-130a as a direct regulator of Cx43. Overexpression of miR-130a may contribute importantly to gap junction remodeling and to the pathogenesis of atrial and ventricular arrhythmias.Journal of Molecular and Cellular Cardiology 05/2014; · 5.15 Impact Factor
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ABSTRACT: Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.PLoS Genetics 08/2014; 10(8):e1004550. · 8.52 Impact Factor