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 > 0.05). WT and L529I showed no difference in the slope factor in the absence of NS1643 (8 ± 0 vs. 9 ± 0) but showed a difference in the presence of NS1643 (9 ± 0.3 vs. 22 ± 1; P < 0.01). Voltage-clamp-fluorimetry studies also indicated that in L529I, NS1643 reduces the voltage-sensitivity of S4 movement. To further assess mechanism of NS1643 action, mutations were made in this neighborhood. NS1643 shifts the V1/2 of activation of both K525C and K525C/L529I to hyperpolarized potentials (-131 ± 4 mV for K525C and -120 ± 21 mV for K525C/L529I). Both K525C and K525C/K529I had similar slope factors in the absence of NS1643 (18 ± 2 vs. 34 ± 5, respectively) but with NS1643, the slope factor of K525C/L529I increased from 34 ± 5 to 71 ± 10 (P < 0.01) whereas for K525C the slope factor did not change (18 ± 2 at baseline and 16 ± 2 for NS1643). At baseline, K525R had a slope factor similar to WT (9 vs. 8) but in the presence of NS1643, the slope factor of K525R was increased to 24 ± 4 vs. 9 ± 0 mV for WT (P < 0.01). Molecular modeling indicates that L529I induces a kink in the S4 voltage-sensor helix, altering a salt-bridge involving K525. Moreover, docking studies indicate that NS1643 binds to the kinked structure induced by the mutation with a higher affinity. Combining biophysical, computational, and electrophysiological evidence, a mechanistic principle governing the action of some activators of hERG1 channels is proposed.

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. METHODS: Rabbits were instrumented with subcutaneous electrocardiogram leads, and cannulae were acutely inserted into an ear artery to obtain continuous arterial pressure measurements. Exposure to brief, low-level auditory stimuli at 5 kHz transiently increased the RR interval by approximately 70 ms and decreased mean arterial pressure by approximately 5 mmHg. RESULTS: These evoked bradycardic hypotensive events were almost identical to previously reported spontaneous bradycardic hypotensive events. Intra-aortic telemetric blood pressure monitoring was used to demonstrate that the evoked hypotension reflected prolonged diastole, rather than local ear arterial vasoconstriction. Furthermore, administration of the muscarinic blocker glycopyrrolate abolished not only bradycardia (RR interval 64+/-14 ms to 1+/-1 ms; P<0.0001), but also hypotension (--4.1+/-0.8 mmHg to --0.4+/-0.3 mmHg; P=0.0055). Finally, cardiac pacing abolished the inducible bradycardia (RR interval 51+/-10 ms to 2+/-1 ms; P=0.0006) and its associated hypotension (--4.1+/-0.7 mmHg to --1.2+/-0.3 mmHg; P=0.003). CONCLUSIONS: Brief auditory stimuli evoked a transient bradycardia mediated by cardiac muscarinic receptors and consequent hypotension. This is not a model for vasovagal syncope.

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. Heart rate turbulence parameters from paced beats were compared with those from spontaneous premature ventricular beats. Subsequently, turbulence hemodynamic parameters were compared in 11 subjects with turbulence induced by pacing trains of 1, 3, 5, and 8 beats at a cycle length of 400 ms. RESULTS: Heart rate turbulence was very similar whether it followed a spontaneous premature ventricular complex or a paced beat. Induced and spontaneous turbulence slopes correlated well (R(s) = 0.917, P = .001). With increasing pacing train length, the magnitude of hypotension, cumulative hypotension time from the last sinus beat, turbulence tachycardia magnitude, magnitude of hypertension in recovery, and turbulence onset (but not turbulence slope) all increased. The cumulative hypotension time, but not the magnitude of hypotension, was tightly correlated with the magnitude of tachycardia (R2 = 0.999, P = .003) and turbulence onset (R2 = 0.975, P = .01). CONCLUSION: Heart rate turbulence can be induced noninvasively through an implanted device. Turbulence parameters are physiologically modulated by the duration of the initial hypotension, suggesting a possible important role for arterial baroreceptors.

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. Auto-entrainment (AE) methodology was developed to help address this challenge. METHODS AND RESULTS: AE methodology tests intrinsic capacity to maintain a stable and coherent oscillatory dynamic of autoregulatory control via respiratory entrainment of the blood pressure and heart period. Using cardiovascular death (n=18) at follow-up (1.5 years) as the end point, analysis of AE measurements from 148 patients with heart failure revealed 2 parameters significantly predictive of death. Using logistic regression, the magnitude of systolic pulsus alternans measured during AE had predictive sensitivity of 90% (confidence interval, 62%-100% and specificity of 62% (confidence interval, 49%-74%). The capacity to maintain a stable oscillatory dynamic was measured by the fraction of the total RR-interval spectral power contained within the AE-band. This capacity had predictive sensitivity of 73% (confidence interval, 47%-99%) and specificity of 55% (confidence interval, 43%-66%). CONCLUSIONS: AE methodology provides a noninvasive platform to assess the integrity of cardiovascular autoregulatory control systems for risk assessment in heart failure patients.

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. On each test day, subjects were challenged with IH and EH. The order of the two tests was randomized and separated by at least 1 hour. Due to the low F (b) of several PMW, the band limits for RSA analysis had to be adjusted. The spectral coherence between respiratory flow and ECG RR-interval was used to determine the spectral band. Within the spectral band, there was a consistent phase relationship between the two variables where high values of spectral coherence indicate a well-defined phase relationship between respiratory flow and RR-interval variability. The main findings in this study for RSA are fourfold. First, RSA did not change with different levels of ovarian hormones (progesterone, serum 17beta-estradiol) during the menstrual cycle. Second, RSA was not influenced by hormone replacement therapy. Third, RSA did not change with age. Fourth, RSA did not change with IH and EH-induced changes in breathing patterns. Finally, high individual variability of average RR-interval change per breath was found.

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. SDANN, ultra low frequency (ULF; frequencies <0.0033 Hz), and beta slope were calculated; and high-frequency power and root mean square of consecutive normal R-R intervals (rMSSD) were calculated as measures of short-term HRV, which have autonomic origins. Long-term HRV measures were similar with atrially tracked and rate-responsive pacing and were much greater than in fixed-rate pacing (SDANN P = 0.0001; ULF P = 0.0001; beta slope P = 0.0002). Short-term HRV measures were similarly low in fixed-rate and rate-responsive pacing (P = NS) and were significantly lower than with atrially tracked pacing (P = 0.0034). CONCLUSION: Rate-responsive pacing reproduces long-term, but not short-term, measures of HRV, suggesting that they may be markers of heart rate responses to patient activity.