NS1643 interacts around L529 of hERG to alter voltage sensor movement on the path to activation.

Activators of hERG1 such as NS1643 are being developed for congenital/acquired long QT syndrome. Previous studies identify the neighborhood of L529 around the voltage-sensor as a putative interacting site for NS1643. With NS1643, the V1/2 of activation of L529I (-34 ± 4 mV) is similar to wild-type (WT) (-37 ± 3 mV; P > 0.

Auto-entrainment risk assessment in heart failure.

Background: Risk assessment studies use a suite of nominally independent noninvasive heart rate metrics, often brought together in a statistical model to compute a risk score. The ongoing need to noninvasively identify the higher risk patients requiring more invasive investigations/interventions drives the search for better noninvasive predictive metrics, with increased sensitivity. Many varieties of autoregulatory malfunction occur within the cardiovascular system; thus, it seems a daunting challenge to build predictive models that account for all potential modes of failure.

Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca(2+) release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.

Effects of ovarian hormones and aging on respiratory sinus arrhythmia and breathing patterns in women.

We investigated the effect of ovarian hormones and aging on breathing pattern [pulmonary minute ventilation (V(E))], tidal volume (V(T)), breathing frequency (F(b)), and respiratory sinus arrhythmia (RSA) in women. Recordings of V(E) and electrocardiogram (ECG) were obtained from 23 healthy women (10 premenopausal, 13 postmenopausal) under resting, isocapnic hypoxia (IH), and euoxic hypercapnia (EH) conditions. Premenopausal women were tested on three different days, each day corresponding to a specific phase of the menstrual cycle (follicular, mid-cycle, and luteal); postmenopausal women (PMW) were tested on 1 day only.

Mechanism of hypotensive transients associated with abrupt bradycardias in conscious rabbits.

Background: Transient bradycardic hypotensive events occur in resting rabbits. If the hypotension is due to vasodepression, these events may be a model for vasovagal syncope.

Objectives: To determine whether these events are responses to brief stimuli and whether the hypotensive episodes are solely due to rapid-onset bradycardia.

Role of hypotension in heart rate turbulence physiology.

Background: Heart rate turbulence is a recently described cardiac prognostic marker that may be mediated by arterial baroreceptor sensitivity, suggesting it is induced by a brief initial hypotension.

Objectives: The purpose of this study was to assess whether heart rate turbulence could be noninvasively induced through a previously implanted defibrillator and whether hypotension modulates turbulence physiology.

Methods: Premature ventricular paced beats was delivered during continuous ECG and blood pressure monitoring in patients with implanted defibrillators.

Activity-responsive pacing produces long-term heart rate variability.

Introduction: Long-term heart rate variability (HRV) measures, including the standard deviation of means of successive 5-minute epochs of R-R interval intervals (SDANN) and the power law slope (beta), are important prognostic measures, yet their physiologic basis is unknown. We tested the hypothesis that long-term HRV arises from physical activity in a randomized cross-over study in patients with rate-responsive pacemakers.

Methods And Results: Ten patients with complete heart block and dual-chamber pacemakers underwent 24-hour periods of ambulatory ECG in each of three pacing modes: atrially tracked, fixed-rate, and rate-responsive pacing.