Dataset Information

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart.

ABSTRACT: Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, in vivo, there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the ex vivo CCS and key proteins that are involved in pacemaker mechanisms in TIDM. RR interval, PR interval and QRS complex duration were significantly increased in diabetic rats. The beating rate of the isolated sinoatrial node (SAN) preparation was significantly decreased in diabetic rats. The funny current density and cell capacitance were significantly decreased in diabetic nodal cells. Western blot showed that proteins involved in the function of the CCS were significantly decreased in diabetic rats, namely: HCN4, Cav1.3, Cav3.1, Cx45, and NCX1 in the SAN; RyR2 and NCX1 in the atrioventricular junction and Cx40, Cx43, Cx45, and RyR2 in the Purkinje network. We conclude that there are complex functional and cellular changes in the CCS in TIDM. The changes in the proteins involved in the function of this electrical system are expected to adversely affect action potential generation and propagation, and these changes are likely to be arrhythmogenic.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6628866 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart.

Zhang Yu Y Wang Yanwen Y Yanni Joseph J Qureshi Mohammed Anwar MA Logantha Sunil Jit R J SJRJ Kassab Sarah S Boyett Mark R MR Gardiner Natalie J NJ Sun Hong H Howarth Frank Christopher FC Dobrzynski Halina H

Frontiers in physiology 20190708

Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, <i>in vivo</i>, there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the <i>ex vivo</i> CCS and key proteins that are inv ...[more]

PMID: 31338036

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Project description:Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+?AP coupling and AP?Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue's susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.

Project description:With an estimated 64.3 million cases worldwide, heart failure (HF) imposes an enormous burden on healthcare systems. Sudden death from arrhythmia is the major cause of mortality in HF patients. Computational modeling of the failing heart provides insights into mechanisms of arrhythmogenesis, risk stratification of patients, and clinical treatment. However, the lack of a clinically informed approach to model cardiac tissues in HF hinders progress in developing patient-specific strategies. Here, we provide a microscopy-based foundation for modeling conduction in HF tissues. We acquired 2D images of left ventricular tissues from HF patients (n = 16) and donors (n = 5). The composition and heterogeneity of fibrosis were quantified at a sub-micrometer resolution over an area of 1 mm2. From the images, we constructed computational bidomain models of tissue electrophysiology. We computed local upstroke velocities of the membrane voltage and anisotropic conduction velocities (CV). The non-myocyte volume fraction was higher in HF than donors (39.68 ± 14.23 vs. 22.09 ± 2.72%, p < 0.01), and higher in ischemic (IC) than nonischemic (NIC) cardiomyopathy (47.2 ± 16.18 vs. 32.16 ± 6.55%, p < 0.05). The heterogeneity of fibrosis within each subject was highest for IC (27.1 ± 6.03%) and lowest for donors (7.47 ± 1.37%) with NIC (15.69 ± 5.76%) in between. K-means clustering of this heterogeneity discriminated IC and NIC with an accuracy of 81.25%. The heterogeneity in CV increased from donor to NIC to IC tissues. CV decreased with increasing fibrosis for longitudinal (R 2 = 0.28, p < 0.05) and transverse conduction (R 2 = 0.46, p < 0.01). The tilt angle of the CV vectors increased 2.1° for longitudinal and 0.91° for transverse conduction per 1% increase in fibrosis. Our study suggests that conduction fundamentally differs in the two etiologies due to the characteristics of fibrosis. Our study highlights the importance of the etiology-specific modeling of HF tissues and integration of medical history into electrophysiology models for personalized risk stratification and treatment planning.

Dataset Information

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart.

Publications

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart.

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