Comprehensive Analyses of Arrhythmogenic Substrates and Vulnerability to Ventricular Tachycardia in Left Ventricular Hypertrophy in Salt-Sensitive Hypertensive Rats

Abstract

ypertensive left ventricular hypertrophy (LVH) is associated with an enhanced incidence of ventricular arrhythmia and an increased risk of sudden cardiac death. [1][2][3] Although in vitro studies of hypetensive LVH have proposed various electrophysiological abnormalities (ie, impulse formation 4,5 and conduction, 6-8 and repolarization abnormalities 9 ) as arrhythmogenic substrates, it remains unclear how these factors directly relate to the vulnerability to ventricular tachyarrhythmia in the in vivo whole heart. In other words, it remains poorly understood just how these electrophysiological abnormalities develop and increase the vulnerability to ventricular tachyarrhythmia with progression of LVH. The arrhythmogenic potential in hypertensive LVH may be multifactorial, but susceptibility to ventricular tachycardia (VT) induction has not been simultaneously investigated in the same LVH preparations, and therefore the relationships between various underlying arrhythmogenic mechanisms and VT attack have not been clarified. A clear understanding of this pathophysiological linkage is essential for determining the therapeutic target for prevention of fatal ventricular tachyarrhythmia. To investigate this issue, we used Dahl salt-sensitive hypertensive rats in which concentric LVH develops in a relatively short period. 10 Our preliminary study using this LVH model revealed that polymorphic VT was induced by programmed electrical stimulation, as shown by Coste et al in their clinical report. 11 Thus, the objectives of this study were first, to quantify the vulnerability of VT to programmed extrastimuli, and the changes it undergoes during the development of hypertensive LVH; second, to clarify how this vulnerability of VT relates to arrhythmogenic substrates (ie, conduction disturbances defined by a decrease in conduction velocity and an increase in the fractionation of QRS complex, and repolarization abnormalities defined by increases in the absolute refractory period and monophasic action potential (MAP) duration); and third, to examine how cellular electrophysiological remodeling relates to conduction and repolarization abnormalities of the whole heart during the progress of LVH. For these purposes, we performed programmed electrical stimulation to induce VT at 3 different observation periods in Dahl salt-sensitive (S) rats and -resistant (R) rats, and compared the vulnerability to VT with the conduction velocity and the degree of inhomogeneous conduction evaluated by wavelet analysis, 12,13 duration of MAP, 14 and absolute refractory period. In addition, myocytes were isolated from the same hearts, and patch-clamp analysis was performed for evaluation of resting membrane potential (RMP) and action potential (AP), as well as sodium (INa), calcium (ICa), and transient outward potassium currents (Ito). Background The contribution of conduction disturbances to susceptibility to ventricular tachycardia (VT) has not been directly examined in the process of left ventricular hypertrophy (LVH). Methods and ResultsDahl salt...

Computer simulation of ECG manifestations of left ventricular electrical remodeling

“…The simulated slowing of conduction velocity was consistent with published data on electrical remodeling in LVH in animals and humans, [17][18][19][20][21][22] and we have shown that the conduction velocity slowing in the left ventricle by 30% in the Purkinje fiber net and by 50% in the working myocardium resulted in an increase in QRS amplitude in all simulated cases including the reference heart. 9 In this simulation study, 9 we also showed that anatomical types of hypertrophy and conduction slowing have different effect on ECG-LVH criteria.…”

Therapeutic Hypothermia (30.DEG.C) Enhances Arrhythmogenic Substrates, Including Spatially Discordant Alternans, and Facilitates Pacing-Induced Ventricular Fibrillation in Isolated Rabbit Hearts

“…11,18,24,34 We also observed that the enhancement of these proarrhythmic parameters during TH (30°C) was associated with an increased number of PSs (ie, wavebreaks) during S1 pacing and VF. These findings suggest that these accumulated proarrhythmic parameters during TH (30°C), either via a single dominant factor (such as SDA) or by a synergistic effect of multiple coexisting factors, contribute to the occurrence of wavebreaks during S1 pacing, leading to increased vulnerability to pacing-induced VF.…”

Clinical Diagnosis of Electrical Versus Anatomic Left Ventricular Hypertrophy

“…The exact nature of true electrical remodeling in LVH has been the subject of active investigation 43 , and is likely to largely explain the observed differences between electrical and anatomic LVH. These altered electrophysiological properties of the myocardium seem to be somewhat independent from the morphological transformations in LVH 29 , and may serve as a substrate for triggering and maintaining ventricular arrhythmias 44 . In some experimental models, reduced Cx43 expression has been associated with diminished QRS amplitudes 41, 45 , a phenomenon that along with extracardiac factors may partly explain the common “false negative” results of ECG in diagnosing anatomic LVH.…”