Origins of the power of the low frequency heart rate variability bandwidth.

PURPOSE: We hypothesized that heart period (HP) variability in the low frequency (LF) band is due to transient fluctuations of about 10 s in HP sequences, associated with fluctuations in blood pressure. METHODS: 10 healthy subjects, mean age 36 y, had HP and blood pressure acquired for 10 min each. Nonrandom HP fluctuations (ripples) lasting 6.7-20 s were detected using time-scrambled surrogate sequences as controls. RESULTS: Ripples were 99 ±â€¯40 ms in amplitude, in concatenates 23.4 ±â€¯7.4 s long. They co-occurred with similar blood pressure ripples with amplitudes 5 ±â€¯5 mm Hg, correlating with them with r2 = 0.68 ±â€¯0.10, slope 23.9 ±â€¯10.8 ms/mm Hg, at an optimum lag of 2.16 ±â€¯0.63 beats. A second HP structure consisting of transient tachycardias of 140 ±â€¯53 ms lasting 15.1 ±â€¯6.1 occurred singly. Together the two structures contributed 84% ±â€¯8% of the total power in the LF band. CONCLUSION: The LF band is caused by two types of HP structures that occur at discrete times.

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.

The interpretation of polycrystalline coherent inelastic neutron scattering from aluminium.

A new approach to the interpretation and analysis of coherent inelastic neutron scattering from polycrystals (poly-CINS) is presented. This article describes a simulation of the one-phonon coherent inelastic scattering from a lattice model of an arbitrary crystal system. The one-phonon component is characterized by sharp features, determined, for example, by boundaries of the (Q, ω) regions where one-phonon scattering is allowed. These features may be identified with the same features apparent in the measured total coherent inelastic cross section, the other components of which (multiphonon or multiple scattering) show no sharp features. The parameters of the model can then be relaxed to improve the fit between model and experiment. This method is of particular interest where no single crystals are available. To test the approach, the poly-CINS has been measured for polycrystalline aluminium using the MARI spectrometer (ISIS), because both lattice dynamical models and measured dispersion curves are available for this material. The models used include a simple Lennard-Jones model fitted to the elastic constants of this material plus a number of embedded atom method force fields. The agreement obtained suggests that the method demonstrated should be effective in developing models for other materials where single-crystal dispersion curves are not available.

The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1ß.

Heart failure is associated with a low-grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac-specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger-sensing pathway required for processing the pro-inflammatory cytokine interleukin-1ß (IL-1ß), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild-type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro-caspase-1 to cleaved and activated forms, as well as markedly increased serum IL-1ß. Blockade of IL-1ß signalling via chronic IL-1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro-inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro-inflammatory IL-1ß. Blockade of IL-1ß signalling with the IL-1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.

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.

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.

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.

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.

Corporate responsibility: not-for-profits-prepare to be held accountable.

Compliance requires a systematic plan, accomplished in phases. The compliance effort should begin by focusing on the areas that pose the greatest compliance risk to the organization. Sections 302 and 404 are key sections of the legislation that should be tackled at the outset.

Dissection of long-range heart rate variability: controlled induction of prognostic measures by activity in the laboratory.

OBJECTIVES: We sought to determine whether the long-range measures of heart rate variability (HRV)--the standard deviation of sequential 5-min heart period mean values (SDANN) and the heart period spectral amplitude in the ultra-low frequency band <0.0033 Hz (ULF)--had their origins partly in physical activity. BACKGROUND: The SDANN and ULF are prognostic HRV factors whose physiologic origins are obscure. Their discontinuous presence throughout the day suggested that they arise from changes in heart period due to activity. METHODS: Heart period sequences were recorded from 14 patients with left ventricular dysfunction and 14 control subjects during an unrestricted 24-h day, 4-h supine rest, and 4-h epoch with scripted activities. RESULTS: The SDANN was higher during activity than during rest (74 +/- 23 ms vs. 43 +/- 17 ms, p < 0.0001), as were ULF magnitudes (p < 0.0001). The increase in SDANN was due to specific activities that contributed heavily (p < 0.0001 by analysis of variance); for example, a 10-min walk and 90-min rest each contributed 22% of total SDANN. Patients with heart disease had a lower SDANN and ULF and a higher mean heart rate than control subjects during all recordings. The proportional ranges in heart period were the same in the two groups during controlled, scripted activities but were wider in control subjects than in patients during ambulatory recordings, suggesting decreased activity by patients. CONCLUSIONS: Activity increases SDANN by increasing the range of heart periods. Patients with diminished ventricular function have a reduced SDANN on ambulatory electrocardiograms, possibly and partly because of a higher mean heart rate and reduced variations in physical activity.

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.

Similarity of spontaneous and induced heart rate and blood pressure turbulence.

BACKGROUND: Heart rate turbulence (HRT) is a transient tachycardia-bradycardia that follows premature ventricular complexes (PVCs). The physiology of turbulence is studied in the electrophysiology lab using induced premature ventricular stimuli but the reliability of this model for HRT is unknown. OBJECTIVES: To compare heart rate and blood pressure signatures of induced and spontaneous HRT. METHODS: Each patient received 10 ventricular extrastimuli at 1-min intervals. Electrocardiogram and continuous blood pressure results were digitized for 34 electrophysiology patients. RESULTS: Fifteen patients yielded at least one induced and one spontaneous analyzable PVC. Per subject, 3.6+/-2.2 spontaneous and 6.1+/-3.3 induced HRT sequences were detected. Spontaneous and inducible HRT were indistinguishable according to turbulence onset (median -1.7% versus -2.3%, P=0.09), turbulence slope (median 7.1 ms/beat versus 10.0 ms/beat, P=0.73), turbulence tachycardia (median 29 ms versus 22 ms, P=0.97) and turbulence bradycardia (45 ms versus 72 ms, P=0.60). Accompanying blood pressure signatures were indistinguishable according to initial hypotension (-0.5+/-5.9 mmHg versus 12.1+/-5.5 mmHg, P=0.19), hypertension time (7.7+/-3.6 s versus 7.8+/-1.9 s, P=0.93) and turbulence hypertension (13.5+/-5.7 mmHg versus 16.1+/-9.2 mmHg, P=0.19). Baroreflex sensitivities estimated by the spontaneous sequence method were similar for spontaneous and induced turbulence (median 7.5 ms/mmHg versus 7.2 ms/mmHg, P=0.89) and correlated with each other (r2=0.81). Heart rate and blood pressure turbulence induced in the electrophysiology laboratory were similar to those following spontaneous PVCs and induced turbulence was a valid model for study under controlled conditions.

Genetic control of NKT cell numbers maps to major diabetes and lupus loci.

Natural killer T cells are an immunoregulatory population of lymphocytes that plays a critical role in controlling the adaptive immune system and contributes to the regulation of autoimmune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the nonobese diabetic (NOD) mouse strain, a well-validated model of type 1 diabetes and systemic lupus erythematosus. In this study, we report the results of a genetic linkage analysis of the genes controlling NKT cell numbers in a first backcross (BC1) from C57BL/6 to NOD.Nkrp1(b) mice. The numbers of thymic NKT cells of 320 BC1 mice were determined by fluorescence-activated cell analysis using anti-TCR Ab and CD1/alpha-galactosylceramide tetramer. Tail DNA of 138 female BC1 mice was analyzed for PCR product length polymorphisms at 181 simple sequence repeats, providing greater than 90% coverage of the autosomal genome with an average marker separation of 8 cM. Two loci exhibiting significant linkage to NKT cell numbers were identified; the most significant (Nkt1) was on distal chromosome 1, in the same region as the NOD mouse lupus susceptibility gene Babs2/Bana3. The second most significant locus (Nkt2) mapped to the same region as Idd13, a NOD-derived diabetes susceptibility gene on chromosome 2.

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.

TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.

Host immunity to mycobacterial infection is dependent on the activation of T lymphocytes and their recruitment with monocytes to form granulomas. These discrete foci of activated macrophages and lymphocytes provide a microenvironment for containing the infection. The cytokine, TNF, is essential for the formation and maintenance of granulomas, but the mechanisms by which TNF regulates these processes are unclear. We have compared the responses of TNF-deficient (TNF(-/-)) and wild-type C57BL/6 mice to infection with Mycobacterium smegmatis, a potent inducer of TNF, and virulent Mycobacterium tuberculosis to delineate the TNF-dependent and -independent components of the process. The initial clearance of M. smegmatis was TNF independent, but TNF was required for the early expression of mRNA encoding C-C and C-X-C chemokines and the initial recruitment of CD11b(+) macrophages and CD4(+) T cells to the liver during the second week of infection. Late chemokine expression and cell recruitment developed in TNF(-/-) mice associated with enhanced Th1-like T cell responses and mycobacterial clearance, but recruited leukocytes did not form tight granulomas. Infection of TNF(-/-) mice with M. tuberculosis also resulted in an initial delay in chemokine induction and cellular recruitment to the liver. Subsequently, increased mRNA expression was evident in TNF(-/-) mice, but the loosely associated lymphocytes and macrophages failed to form granulomas and prevent progressive infection. Therefore, TNF orchestrates early induction of chemokines and initial leukocyte recruitment, but has an additional role in the aggregation of leukocytes into functional granulomas capable of controlling virulent mycobacterial infection.