Daniel E. Roach

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 Ca2+ 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.

Letter regarding article by Adamson et al, "Continuous autonomic assessment in patients with symptomatic heart failure: prognostic value of heart rate variability measured by an implanted cardiac resynchronization device".

To the Editor: We read the article by Adamson et al with great interest.1 In a prospective manner, they have convincingly shown that (1) a measure of long-term heart rate variability (HRV), SDAAM, is a predictor of mortality and hospitalization in patients with congestive heart failure and (2) reductions in SDAAM precede clinical deterioration. Although we do not question the prognostic value of this measure, SDAAM is not simply a marker of the autonomic nervous system. The closest conventional HRV measure to SDAAM (the standard deviation of a 5-minute median atrial-atrial sensed interval) is SDANN (the standard deviation of a 5-minute mean normal RR interval).1 The spectral correlate of SDANN is the ultralow-frequency (ULF) power (<0.0033 Hz; the inverse of 5 minutes)2 and not the very-low-frequency band (VLF; 0.0033 to 0.04 Hz) suggested by the authors. Although VLF likely reflects both autonomic and neurohumoral influences, ULF and SDANN have not been shown to do so. Indeed, Bigger et al found these to be among …

Induction of Heart Rate and Blood Pressure Turbulence in the Electrophysiologic Laboratory

Heart rate turbulence (HRT) is a transient tachycardia and/or bradycardia that follows ventricular premature complexes (VPCs). Absent or blunted HRT is associated with a poor prognosis in patients with heart disease, but its physiology is unknown. We hypothesized that HRT might be mediated by baroreflexes following early depolarizations. We sought to induce and characterize HRT in the electrophysiologic laboratory by introducing 1 ventricular extrastimulus every 60 seconds in 23 patients who underwent invasive electrophysiologic studies. On average, HRT was characterized by an initial RR interval decrease of 38 ms occurring 3.4 seconds after early depolarization. This was followed by a transient RR interval increase of 88 ms occurring 5.4 seconds later. HRT was preceded by similar hypotensive and/or hypertensive blood pressure turbulence. Baroreflex sensitivity estimates from post-VPCs and sinus sequences were similar (12.3 +/- 10.3 vs 10.2 +/- 8.9 ms/mm Hg, p = 0.51). The failure to induce HRT was associated with a limited initial hypotensive phase of blood pressure turbulence (-7.9 vs -12.1 mm Hg, p = 0.037). Patients with structural heart disease had reduced turbulence onset and reduced turbulence slope relative to those with structurally normal hearts, although blood pressure response was similar in both groups. HRT is an inducible, transient tachycardia and/or bradycardia that likely arises from a baroreflex response to transient hypotension following VPCs. Patients with structural heart disease have blunted HRT.

Temporally localized contributions to measures of large-scale heart rate variability.

The purpose of this work was to determine the temporal origins of the standard deviation of successive 5-min mean heart period sequences (SDANN) and the power of the ultralow-frequency (ULF) spectral band (<0.0033 Hz). We hypothesized that SDANN and ULF might have their origins in changes in human activity rather than slow oscillatory rhythms. Heart period sequences were obtained from 24-h Holter electrocardiograms of 10 healthy ambulatory subjects. There was no evidence of any persistent oscillation within the ULF band. Using moving 4-h windows in short-time Fourier transforms, we showed that the amplitude of ULF fluctuated markedly, particularly during times bordering sleep. The local ULF amplitude correlated ( r = 0.59 ± 0.09) with large-scale changes in heart period quantified with 2- and 4-h wavelet transforms. Local SDANN also fluctuated, mainly around times of sleep. Although the 24-h SDANN and ULF values correlated highly, there was little correlation between their temporal distributions ( r = 0.10 ± 0.25). The temporal distributions of measures of long-range heart period variability suggest that they reflect changes in human activity levels.The purpose of this work was to determine the temporal origins of the standard deviation of successive 5-min mean heart period sequences (SDANN) and the power of the ultralow-frequency (ULF) spectral band (< 0.0033 Hz). We hypothesized that SDANN and ULF might have their origins in changes in human activity rather than slow oscillatory rhythms. Heart period sequences were obtained from 24-h Holter electrocardiograms of 10 healthy ambulatory subjects. There was no evidence of any persistent oscillation within the ULF band. Using moving 4-h windows in short-time Fourier transforms, we showed that the amplitude of ULF fluctuated markedly, particularly during times bordering sleep. The local ULF amplitude correlated (r = 0.59 +/- 0.09) with large-scale changes in heart period quantified with 2- and 4-h wavelet transforms. Local SDANN also fluctuated, mainly around times of sleep. Although the 24-h SDANN and ULF values correlated highly, there was little correlation between their temporal distributions (r = 0.10 +/- 0.25). The temporal distributions of measures of long-range heart period variability suggest that they reflect changes in human activity levels.

Information scaling properties of heart rate variability

Many chaos detection methods have proven inherently ambiguous in that they yield similar results for chaotic signals and correlated noise. The purpose of this work was to determine whether human resting heart period sequences have global properties characteristic of chaotic systems. We investigated the inherent global organization of heart period sequences by quantifying how the information content of the embedded sequences varied as a function of scale. We compared the information scaling characteristics of 60-min heart period sequences obtained from 10 healthy resting volunteers with those obtained from numerous periodic and chaotic control sequences. The information scaling properties of the heart period sequences were significantly different from those obtained for the controls, particularly at the coarsest scales (P = 0.0003 vs. low-dimensional periodic controls; P = 0.0005 vs. low-dimensional chaotic controls; P = 0.0003 vs. low-dimensional periodic and chaotic controls). We also showed that nondeterministic components, such as large tachycardic (or bradycardic) events or aperiodic fluctuations, can lead to scaling characteristics similar to those observed for the resting heart period sequences. This, in addition to previous evidence from spectral, nonlinear predictability and lexical studies, favors an events-based approach to understanding heart rate variability.Many chaos detection methods have proven inherently ambiguous in that they yield similar results for chaotic signals and correlated noise. The purpose of this work was to determine whether human resting heart period sequences have global properties characteristic of chaotic systems. We investigated the inherent global organization of heart period sequences by quantifying how the information content of the embedded sequences varied as a function of scale. We compared the information scaling characteristics of 60-min heart period sequences obtained from 10 healthy resting volunteers with those obtained from numerous periodic and chaotic control sequences. The information scaling properties of the heart period sequences were significantly different from those obtained for the controls, particularly at the coarsest scales ( P = 0.0003 vs. low-dimensional periodic controls; P = 0.0005 vs. low-dimensional chaotic controls; P = 0.0003 vs. low-dimensional periodic and chaotic controls). We also showed that nondeterministic components, such as large tachycardic (or bradycardic) events or aperiodic fluctuations, can lead to scaling characteristics similar to those observed for the resting heart period sequences. This, in addition to previous evidence from spectral, nonlinear predictability and lexical studies, favors an events-based approach to understanding heart rate variability.

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS(-/-) and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS(-/-) mice had improved systolic performance (P < 0.001) and less heart block (P < 0.0001); larger sodium current density and lower serum TNF-alpha levels (P < 0.03); and less apoptosis (P < 0.01) resulting in improved survival (P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS(-/-) mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.

Mechanism of loss of consciousness during vascular neck restraint

Vascular neck restraint (VNR) is a technique that police officers may employ to control combative individuals. As the mechanism of unconsciousness is not completely understood, we tested the hypothesis that VNR simply compresses the carotid arteries, thereby decreasing middle cerebral artery blood flow. Twenty-four healthy police officers (age 35 ± 4 yr) were studied. Heart rate (HR), arterial pressure, rate of change of pressure (dP/dt), and stroke volume (SV) were measured using infrared finger photoplethysmography. Bilateral mean middle cerebral artery flow velocity (MCAVmean) was measured by using transcranial Doppler ultrasound. Neck pressure was measured using flat, fluid-filled balloon transducers positioned over both carotid bifurcations. To detect ocular fixation, subjects were asked to focus on a pen that was moved from side to side. VNR was released 1-2 s after ocular fixation. Ocular fixation occurred in 16 subjects [time 9.5 ± 0.4 (SE) s]. Pressures over the right (R) and left (L) carotid arteries were 257 ± 22 and 146 ± 18 mmHg, respectively. VNR decreased MCAVmean (R 45 ± 3 to 8 ± 4 cm/s; L 53 ± 2 to 10 ± 3 cm/s) and SV (92 ± 4 to 75 ± 4 ml; P < 0.001). Mean arterial pressure (MAP), dP/dt, and HR did not change significantly. We conclude that the most important mechanism in loss of consciousness was decreased cerebral blood flow caused by carotid artery compression. The small decrease in CO (9.6 to 7.5 l/min) observed would not seem to be important as there was no change in MAP. In addition, with no significant change in HR, ventricular contractility, or MAP, the carotid sinus baroreceptor reflex appears to contribute little to the response to VNR.

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.

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