Conduction Remodeling in Human End-Stage Nonischemic Left Ventricular Cardiomyopathy

Abstract

Background Several arrhythmogenic mechanisms have been inferred from animal heart failure (HF) models. However, the translation of these hypotheses is difficult due to lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage non-ischemic cardiomyopathy. Methods and Results We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage non-ischemic cardiomyopathy (HF, n=10) and non-failing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. HF produced heterogeneous prolongation of action potential duration (APD) resulting in the decrease of transmural APD dispersion (64±12 ms vs 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 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 wavebreaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in HF 16.4±7.7 versus 9.9±1.4% in NF, P=0.02). Conclusions 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 non-ischemic cardiomyopathy.

Relationships Between Clinical Characteristics and Decreased Plakoglobin and Connexin 43 Expressions in Myocardial Biopsies From Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

“…15) Recently, it has been reported that down regulation of connexin 43 expression, reduction of connexin 43 phosphorylation, and increased fibrosis cause a conduction disorder that is likely to be a crucial component of arrhythmogenicity in human nonischemic cardiomyopathy. 16) In the present study, a decrease in expression of connexin 43 similar to that in ARVC was observed in controls, ie, HCM and DCM. However, there was no patient with sustained VT in the control group.…”

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

“…Connexin-43 downregulation and lateralization, along with increased fibrous tissue content, are typical of end-stage heart failure in man and cause significant conduction abnormalities. 20 One interesting aspect of the phenotype we noticed was the regional distribution of tissue fibrosis, which was restricted to the basal regions of the heart, where it was marked ( Figure 2B). This basal localization of fibrosis has not, to our knowledge, been previously reported in other animal models of cardiomyopathy.…”

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

“…Translocation of connexin-43 to the lateral cardiomyocyte membrane was detected only in septic patients and only in a subset of these patients. Lateralization of connexin-43 is additional evidence of myocyte injury (32)(33)(34)(35). Thus, sepsis does not induce significant cardiomyocyte cell death but does induce changes consistent with mitochondrial injury and cardiomyocyte uncoupling.…”

“…Newly characterized markers of cell injury have also contributed to defining pathologic processes that mediate cell injury. Connexin-43, a critical gap junction protein that regulates cell-cell interaction and forms electrical synapses between adjacent myocytes, is involved in cellular stress responses in heart (32)(33)(34)(35). Kidney injury molecule 1 (Kim-1), a transmembrane protein expressed in damaged proximal tubular epithelial cells, is a sensitive biomarker of kidney injury (36,37).…”