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Interaction between autonomic tone and the negative chronotropic effect of adenosine in humans.

Prior studies have demonstrated that sympathetic tone may influence the effects of adenosine on His-Purkinje automaticity, and that enhanced vagal tone may influence its effects on the sinus node. However, the interaction between autonomic tone and the effects of adenosine on the sinus node in humans remains unknown. Therefore, this study was designed to investigate the interaction between different states of autonomic tone and the bradycardiac response of the sinus node to adenosine. In 11 patients without structural heart disease who underwent a clinically indicated electrophysiology procedure, the sinus cycle length was measured before and after a 12-mg bolus of adenosine in the baseline state, during an infusion of 2 mcg/min of isoproterenol, after the administration of 0.2 mg/kg of propranolol, and again after the administration of 0.04 mg/kg of atropine. Adenosine significantly lengthened the sinus cycle length in the baseline state (760 +/- 165 vs 909 +/- 188 ms, P < 0.05), during isoproterenol infusion (516 +/- 67 vs 766 +/- 146 ms, P < 0.05), after propranolol (850 +/- 153 vs 914 +/- 143 ms, P < 0.05) and after the combination of propranolol and atropine (662 +/- 76 vs 801 +/- 121 ms, P < 0.05). The degree of lengthening in sinus cycle length was significantly greater (P < 0.05) during isoproterenol infusion (253 +/- 157 ms, or 51% +/- 40%) than in the baseline state (149 +/- 85 ms, or 20% +/- 12%), after propranolol (68 +/- 53 ms, or 8% +/- 8%), and after propranolol and atropine (140 +/- 110 ms, or 21% +/- 18%). The negative chronotropic effect of adenosine is influenced by autonomic tone. The effect of adenosine on the sinus node is accentuated by beta-adrenergic stimulation and unaffected by beta-adrenergic blockade or combined beta-adrenergic and cholinergic blockade.

Adenosine↗

Altered autonomic cardiac control predicts restenosis after percutaneous coronary intervention.

BACKGROUND: Early and late restenosis in up to 30% remains a major problem for long-term success after percutaneous coronary intervention (PCI). Compared to bare metal stents, the use of drug-eluting stents reduces restenosis below 10%, but implant coasts have to be considered. In restenosis noninvasive testing lacks diagnostic power. We applied a new approach to identify patients with a high risk for restenosis after PCI by combining heart rate (HR) and blood pressure variability (BPV) analyses. METHODS: In 52 patients with clinical suspicion of restenosis and history of PCI, we investigated patterns of cardiovagal autonomic regulation prior to cardiac catheterization. The patients were separated in (i) patients with restenosis (CAD+R) and (ii) patients without restenosis (CAD-R), where restenosis is defined as a stenosis greater than 75% of luminal diameter in at least one main vessel. The following parameters/methods were evaluated: Canadian Cardiovascular Society grade (CCS-grade), vessel disease score (CAD-level), left ventricular ejection fraction (LVEF), heart rate variability (HRV), BPV, baroreflex sensitivity (BRS), as well as HR turbulence and blood pressure (BP) potentiation caused by premature ventricular complexes. RESULTS: Whereas age, LVEF, CAD-level, CCS-grade, and mean BP did not differ between CAD+R and CAD-R, significant differences were found in (i) BPV: diastolic LF/P, systolic, and diastolic UVLF, (ii) in BRS: slope of tachycardic sequences, and (iii) in extrasystolic parameters: heart rate turbulence onset (HRTO) and potentiation of systolic BP (SBPP). Standard HRV parameters did not show significant differences between the groups. Using the two parameters diastolic LF/P (threshold >0.2) and HRTO (threshold >0) restenosis were predicted in 83.4%. CONCLUSIONS: These results demonstrate that indicators of sympathetic activation or vagal depression identify restenosis in patients after PCI, thus opening a perspective for a new noninvasive monitoring.

Angioplasty, Balloon, Coronary↗

Menstrual cycle and ST height.

BACKGROUND: Sex hormones and menstrual cycle effects on ST height have not yet been clearly identified. METHODS: Twenty-two young, healthy women (aged 22-32 years) were included in this study. Twelve-lead ECGs were registered during menses, follicular and luteal phase of the menstrual cycle at baseline, and after double autonomic blockade (DAB). Chest leads V2-V4 and limb leads I and II were chosen for analysis. ST height was measured manually at J-Point and 40 ms after the J-Point, and values were corrected for QRS amplitude (J-Point/QRS, 40 ms/QRS). Repeated measure ANOVA was used to analyze differences in ST height among the three phases of the menstrual cycle. A P-value < 0.05 was considered as significant. RESULTS: At baseline, ST height, QTc, and T wave amplitude were not significantly different among the three phases of the menstrual cycle. After double autonomic blockade, ST height at 40 ms, J-Point/QRS, and 40 ms/QRS was significantly higher during follicular versus luteal phase (0.152 +/- 0.413 mm versus -0.007 +/- 0.427 mm, P = 0.0059 at 40 ms; -0.001 +/- 0.030 versus -0.015 +/- 0.032, P = 0.0039 at J-Point/QRS; 0.013 +/- 0.031 versus -0.004 +/- 0.032, P = 0.0005 at 40 ms/QRS) as was the QTc. ST height differences at J-Point were not significantly different (-0.046 +/- 0.395 mm follicular, -0.167 +/- 0.448 mm luteal, and -0.083 +/- 0.492 mm menses, P = 0.1014). CONCLUSION: ST height and QTc varied among the three phases of the menstrual cycle, predominantly after double autonomic blockade. Female sex hormones that vary throughout the menstrual cycle may modulate measures of repolarization.

Adult↗

Cardiac autonomic modulation by estrogen in female mice undergoing ambulatory monitoring and in vivo electrophysiologic testing.

INTRODUCTION: Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice. METHODS: Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring. RESULTS: With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups). CONCLUSION: Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women.

Animals↗

Is baseline autonomic tone associated with new onset atrial fibrillation?: Insights from the framingham heart study.

BACKGROUND: Recent reports have indicated that autonomic tone fluctuations measured by heart rate variability (HRV) precede episodes of paroxysmal atrial fibrillation (AF). Little is known about the impact of baseline autonomic tone and the development of new onset AF in a population-based cohort. The purpose of this study was to assess the role of HRV as a predictor of new onset AF. METHOD: Ambulatory ECG recordings obtained from the Framingham Heart Study subjects attending a routine examination were processed for HRV. The HRV variables analyzed included standard deviation of normal R-R intervals (SDNN), low frequency power (LF), high frequency power (HF), and LF/HF ratio. There were 1434 women and 1142 men (54 +/- 14.1 years) eligible for the study. RESULTS: In 12 years of follow-up, 65 women and 67 men had new onset AF. The study had 80% power to detect a hazard ratio (HR) of 1.3 per standard deviation (SD) decrement in HRV. A one SD decrement in log LF/HF was associated with increased risk of developing AF (HR = 1.23; 95% confidence intervals (CI) = 1.06-1.44) in age- and sex-adjusted models; the association was no longer significant (HR = 1.15; 95% CI = 0.98-1.35) after adjusting for potential confounders. CONCLUSION: Autonomic dysregulation at baseline, as reflected by an altered HRV is associated with risk of AF; however, this association does not persist after adjusting for potential confounders. Much of the apparent association between HRV and AF is mediated by traditional risk factors.

Adult↗

Effects of physical conditioning on cardiac autonomic function in healthy middle-aged women.

The purpose of this study was to determine whether moderate exercise training affects heart rate variability (HRV) and spontaneous baroreflex (SBR) function in healthy middle-aged women. Thirty-two sedentary women aged 40-59 yr were divided into four groups depending on reproductive state (premenopausal, PrM or postmenopausal, PoM, and training group (exercise or sedentary control group). The electrocardiographic R-R interval and systolic blood pressure (finger plethysmograph) were measured at rest during paced breathing at 16 breaths/min in the left lateral decubitus, sitting, and free standing postures, and during upright cycling at 40% maximal heart rate reserve (MHRR). After initial testing, the exercise groups underwent a 12 week walking program. After training, both exercise groups (PrM and PoM) had a longer R-R interval in all conditions, a higher SBR slope in the sitting and standing posture and lower sympathetic modulation in the standing posture, than the control groups and pre-training levels. During exercise, vagal modulation was higher and sympathetic modulation was lower in both exercise groups compared to pre-training values. Vagal modulation is increased following moderate intensity aerobic conditioning in middle-aged women.

Adult↗

"Physiological genomics": mutant screens in zebrafish.

Large-scale mutagenesis screens have proved essential in the search for genes that are important to development in the fly, worm, and yeast. Here we present the power of large-scale screening in a vertebrate, the zebrafish Danio rerio, and propose the use of this genetic system to address fundamental questions of vertebrate developmental physiology. As an example, we focus on zebrafish mutations that reveal single genes essential for normal development of the cardiovascular system. These single gene mutations disrupt specific aspects of rate, rhythm, conduction, or contractility of the developing heart.

Animals↗

Orthostatic intolerance and motion sickness after parabolic flight.

Because it is not clear that the induction of orthostatic intolerance in returning astronauts always requires prolonged exposure to microgravity, we investigated orthostatic tolerance and autonomic cardiovascular function in 16 healthy subjects before and after the brief micro- and hypergravity of parabolic flight. Concomitantly, we investigated the effect of parabolic flight-induced vomiting on orthostatic tolerance, R-wave-R-wave interval and arterial pressure power spectra, and carotid-cardiac baroreflex and Valsalva responses. After parabolic flight 1) 8 of 16 subjects could not tolerate 30 min of upright tilt (compared to 2 of 16 before flight); 2) 6 of 16 subjects vomited; 3) new intolerance to upright tilt was associated with exaggerated falls in total peripheral resistance, whereas vomiting was associated with increased R-wave-R-wave interval variability and carotid-cardiac baroreflex responsiveness; and 4) the proximate mode of new orthostatic failure differed in subjects who did and did not vomit, with vomiters experiencing comparatively isolated upright hypocapnia and cerebral vasoconstriction and nonvomiters experiencing signs and symptoms reminiscent of the clinical postural tachycardia syndrome. Results suggest, first, that syndromes of orthostatic intolerance resembling those developing after space flight can develop after a brief (i.e., 2-h) parabolic flight and, second, that recent vomiting can influence the results of tests of autonomic cardiovascular function commonly utilized in returning astronauts.

Adult↗

Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction.

BACKGROUND: Myocardial conduction depends on intercellular transfer of current at gap junctions. Atrial myocytes express three different gap junction channel proteins-connexin43 (Cx43), connexin45 (Cx45), and connexin40 (Cx40)-- whereas ventricular myocytes express only Cx43 and Cx45. However, the physiological roles of individual connexins are unknown. We have previously shown that mice heterozygous for a null mutation in the gene encoding Cx43 (Cx43(+/-) mice) express 50% of the normal amount of Cx43 in ventricular myocardium and exhibit marked slowing of ventricular conduction. METHODS AND RESULTS: To determine whether atrial conduction is affected in Cx43(+/-) mice, we measured atrial conduction velocity in isolated hearts, performed detailed ECG and electrophysiological studies in intact animals, and determined the amount of cardiac connexins in atrial and ventricular tissue. Ventricular conduction velocity was reduced by 38% in Cx43(+/-) mice compared with wild-types, but atrial conduction velocity in the same hearts was normal. QRS duration was significantly greater in Cx43(+/-) mice than in wild-types, but P-wave duration and amplitude did not differ. Atrial expression of Cx43 was reduced by 50%. CONCLUSIONS: These results indicate that Cx43 is a principal conductor of intercellular current in the ventricle because ventricular conduction is significantly slowed when Cx43 content is reduced by only 50%. In contrast, a similar reduction in Cx43 content in atrial muscle has no effect on atrial conduction, suggesting that Cx40 (which is expressed in atrial but not ventricular myocytes) is a major electrical coupling protein in atrial muscle. Thus, Cx43 and Cx40 may be chamber-specific determinants of myocardial conduction.

Animals↗

Modulation of cardiac autonomic neurotransmission by epicardial superfusion. Effects of hexamethonium and tetrodotoxin.

The heart contains superficial cardiac nerves whose effects may be modulated by pericardial fluid bathing the epicardium. We tested this hypothesis in open-chest dogs anesthetized with secobarbital. Oxygenated normal Tyrode's solution (NT) or NT containing hexamethonium, a ganglionic blocker (500 microM), or tetrodotoxin, a blocker of axonal neurotransmission (5 microM, TTX), was instilled into the pericardial cavity to superfuse the epicardium of the whole heart. During each superfusion, effective refractory period (ERP) was determined in deep intramyocardium (greater than or equal to 4 mm in depth from the epicardium) of anterior and posterior left ventricle and in the subendocardium of the right ventricle in the baseline state and during bilateral cervical vagal stimulation (VS) or ansae subclaviae stimulation (SS). Lengthening of ERP induced by VS during superfusion with NT (6.9 +/- 0.3 msec, mean +/- SEM, n = 36) was eliminated during subsequent superfusion with hexamethonium (0.9 +/- 0.5 msec, p less than 0.001). Hexamethonium also prevented sinus arrest induced by VS but did not affect shortening of ERP induced by SS (17.3 +/- 1.3 to 16.6 +/- 1.0 msec, n = 26). TTX suppressed VS-induced changes in ERP (6.3 +/- 0.3 to 1.5 +/- 0.5 msec, n = 32, p less than 0.001) and SS-induced changes in ERP (18.8 +/- 1.6 to 6.0 +/- 0.9 msec, n = 23, p less than 0.001) but did not affect changes in ERP induced by intravenous administration of norepinephrine or methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Changes in cardiac autonomic activities in patients with syndrome X. A study of spectral analysis of heart rate variability.

The present study was designed to assess cardiac autonomic activities, coronary microvascular function, and their relationship in patients with syndrome X. Control of coronary blood flow is complex, and impaired coronary flow reserve has been attributed as the cause of myocardial ischemia in patients with syndrome X. It is unknown whether cardiac autonomic activities are altered in the presence of coronary microvascular dysfunction in patients with syndrome X. Eighteen patients with syndrome X were studied. Great cardiac vein flow was measured by the thermodilution method and the coronary flow reserve was determined by intravenous dipyridamole (0.56 mg/kg) infusion. Twenty-four-hour ambulatory electrocardiograms were obtained in a drug-free state. Another 14 age- and sex-matched normal subjects served as a control group. The amplitude (in ms) of ultralow (ULF), very-low (VLF), low (LF), and high (HF) frequency bands and total spectra of heart rate variability were measured for twenty-four-hour and every four-hour interval of the day.

Adult↗

Effects of midazolam on heart rate variability during surgery under spinal anaesthesia.

Effects of midazolam on the cardiac autonomic nervous system were studied by power spectral analysis of electrocardiographic R-R intervals in patients undergoing elective lower abdominal surgery under spinal anaesthesia. Patients were randomly assigned into two groups: 10 patients in group A received spinal anaesthesia only and 10 in group S received spinal anaesthesia and midazolam of 0.05 mg/kg when surgery started. In the frequency domain power spectra, low (Lo; 0.04-0.15 Hz) and high (Hi; 0.15-0.40 Hz) frequency components were integrated to ascertain sympathetic and parasympathetic activity, respectively. There was no intergroup difference in starting time of surgery, ventilatory frequency, arterial pressure, heart rate, mean and variance of R-R interval, and cephalad level of analgesia. In spectral component, Lo decreased (P < 0.05) and Hi/Lo ratio increased (P < 0.05) relative to their baselines in group S. These were also different from group A (P < 0.05). We concluded that intravenous midazolam depressed sympathetic activity to produce a vagotonic cardiac autonomic nervous system under spinal anaesthesia.

Abdomen↗

Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system.

Gonadal hormones may affect homeostatic mechanisms regulating the cardiovascular system. We investigated this relationship at five different crucial hormonal time points along the menstrual cycle. Eight eumenorrheic healthy subjects underwent a battery of autonomic tests, hemodynamics, and volume-regulatory hormone measurements. Fluid-regulatory hormones, plasma renin activity, and aldosterone increased along the luteal phase (P = 0.003 and 0.02, respectively), whereas rest supine-corrected hematocrit declined in the course of the menstrual cycle (P = 0.001). Plasma norepinephrine decreased from 1.4 +/- 0.2 to 0.95 +/- 0.1 nmol/liter (P < 0.02) [early follicular (EF) to late follicular]. Thereafter, concentrations gradually returned to EF levels. Lf to Hf domain ratio (spectral analysis of electrocardiogram) showed a difference from that of norepinephrine. The cardiovagal baroreflex sensitivity increased significantly along the luteal phase (P = 0.04). The dose of isoproterenol required to increase heart rate (HR) 15 beats per minute was 0.19 +/- 0.04 microg during the EF time point, and it increased to 0.39 +/- 0.06 microg during the late luteal time point (P = 0.05). However, blood pressure, HR, and their responses to orthostatic stress remained unchanged. Fluctuations in the ovarian hormones along the menstrual cycle are associated with unchanged blood pressure and HR, despite the significant variations in the different homeostatic mechanisms regulating the cardiovascular system.

Adrenergic beta-Agonists↗

The phase of supernormal excitation in relation to the strength of subthreshold stimuli.

The presence of supernormal excitation was confirmed repeatedly in all 10 cases following cardiac surgery. By the stimulation of minimum subthreshold impulses capable of originating ventricular responses, the supernormal excitation was limited only at the descending limb of T wave. The duration lasted only 0.02 sec at the minimum subthreshold stimuli. But the higher subthreshold stimuli produced the longer duration of supernormal excitation phase. The duration of the excitation phase prolonged towards the following R wave, hardly extending towards the preceding R wave, with the increase of subthreshold stimuli.

Action Potentials↗