Intrinsic Heart Rate Research Articles

Coupled-Clock Pacemaker System becomes Dysfunctional with Aging

An age-associated reduction in heart rate (HR) acceleration governed by the sinoatrial node (SAN) in response to stress is a major factor underlying the age-associated decline in cardiovascular reserve. SAN automaticity involves an oscillatory coupled-clock system within its cells: the sarcoplasmic reticulum (SR) Ca2+-clock and the sarcolemmal membrane clock. Ca2+-activated-calmodulin-AC/CamKII-cAMP/PKA-Ca2+-signaling regulated by PDE/phosphatase activities drives SAN automaticity. The rate and rhythm of action potential (AP) firing are determined by that of the local calcium releases (LCRs) generated by the Ca2+-clock. These then activate NCX in the membrane clock, which in turn initiates AP-firing and myocardial contraction. We hypothesize that dysfunctions in SAN cells (SANC) that accumulate with aging involve changes in the expression and function of SANC coupled-clock Ca2+-cycling proteins.We found that an age-dependent reduction in the intrinsic HR in vivo (22%) in 24- vs 3-mo mice is accompanied by a 29% reduction in single SANC AP-firing rate. These are associated with a number of changes stemming from compromised SR Ca2+-function, including reduced Ca2+-cycling and diminished response to pharmacologic SR stress. These changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SERCA2 and RyR2, and also NCX1. Aged SANC were also found to have reduced SR Ca2+-load compared to young, as well as a reduced size, number and duration of spontaneous LCRs. Finally, the sensitivity to PDE inhibition-associated increase in PLB-phosphorylation, LCR size, amplitude and number were reduced in 24- vs 3-mo SANC. Thus, a deterioration in intrinsic Ca2+-clock kinetics in aged SANC due to deficits in intrinsic SR Ca2+-cycling and its response to a PDE stress appears to be involved in age-associated reduction in intrinsic resting AP-firing rate, and intrinsic HR in vivo, and may also underlie the age-associated reduction in the acceleration of HR in response to stress.

Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in "intrinsic heart rate" (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that age-dependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L- and T-type Ca(2+) currents and the "funny current" (If), and a hyperpolarizing shift in the voltage dependence of If. The age-dependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L- and T-type Ca(2+) currents, and If. Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging.

Oxyntomodulin increases intrinsic heart rate through the glucagon receptor

Two hormones from the gastrointestinal tract, glucagon and oxyntomodulin (OXM), vigorously elevate the intrinsic heart rate (IHR) of mice. We have previously shown that OXM influences murine heart rate (HR) independent of the glucagon-like peptide 1 (GLP-1) receptor. Here, we demonstrate using radiotelemetry in mice deficient in the glucagon receptor (Gcgr −/−) that both OXM and glucagon require the glucagon receptor for their chronotropic effects on the heart. Furthermore, we found that other hormones associated with hunger and satiety (ghrelin, leptin, and PYY3-36) had no effect on IHR, while cholecystokinin moderately elevated the IHR. Finally, the resting HR of Gcgr −/− mice was higher than in control mice (Gcgr +/+ and Gcgr +/−) at thermal neutral temperature (30°C). Using atropine, we demonstrated that Gcgr −/− mice have diminished parasympathetic (PNS) influence of the heart at this temperature. Gcgr −/− mice displayed a normal bradycardia as compared to controls in response to administration of either methacholine (to activate the muscarinic acetylcholine receptor) or methoxamine (to activate the baroreflex through agonism of the α1 adrenergic receptor agonist) suggesting that vagal pathways are intact in the Gcgr −/− mice. As OXM is an agonist of the GLP-1 receptor and Gcgr with antidiabetic activity, we suggest OXM may be an alternative to glucagon in the treatment of overdose of beta-blockers to elevate HR in clinical conditions.

Short-term reduction in intrinsic heart rate during biventricular pacing after cardiac surgery: A substudy of a randomized clinical trial

The Biventricular Pacing After Cardiac Surgery trial investigates hemodynamics of temporary pacing in selected patients at risk of left ventricular dysfunction. This trial demonstrates improved hemodynamics during optimized biventricular pacing compared with atrial pacing at the same heart rate 1 and 2 hours after bypass and reduced vasoactive-inotropic score over the first 4 hours after bypass. However, this advantage of biventricular versus atrial pacing disappears 12 to 24 hours later. We hypothesized that changes in intrinsic heart rate can explain variable effects of atrial pacing in this setting. Heart rate, mean arterial pressure, cardiac output, and medications depressing heart rate were analyzed in patients randomized to continuous biventricular pacing (n=16) or standard of care (n=18). During 30-second testing periods without pacing, intrinsic heart rate was lower in the paced group 12 to 24 hours after bypass (76.5 ± 17.5 vs 91.7 ± 13.0 beats per minute; P=.040) but not 1 or 2 hours after bypass. Cardiac output (4.4 ± 1.2 vs 3.6 ± 1.9 L/min; P=.054) and stroke volume (53 ± 2 vs 42 ± 2 mL; P=.051) increased overnight in the paced group. Vasoactive medication doses were not different between groups, whereas dexmedetomidine administration was prolonged over postoperative hours 12 to 24 in the paced group (793 ± 528 vs 478 ± 295 minutes; P=.013). These observations suggest that hemodynamic benefits of biventricular pacing 12 to 24 hours after cardiopulmonary bypass lead to withdrawal of sympathetic drive and decreased intrinsic heart rate. Depression of intrinsic rate increases the apparent benefit of atrial pacing in the chronically paced group but not in the control group. Additional study is needed to define clinical benefits of these effects.

Swimming training prevents fat deposition and decreases angiotensin II-induced coronary vasoconstriction in ovariectomized rats

We investigated the effects of chronic swimming training (ST) on the deposition of abdominal fat and vasoconstriction in response to angiotensin II (ANG II) in the coronary arterial bed of estrogen deficient rats. Twenty-eight 3-month old Wistar female rats were divided into 4 groups: sedentary sham (SS), sedentary-ovariectomized (SO), swimming-trained sham (STS) and swimming-trained ovariectomized (STO). ST protocol consisted of a continuous 60-min session, with a 5% BW load attached to the tail, completed 5 days/week for 8-weeks. The retroperitoneal, parametrial, perirenal and inguinal fat pads were measured. The intrinsic heart rate (IHR), coronary perfusion pressure (CPP) and a concentration–response curve to ANG II in the coronary bed was constructed using the Langendorff preparation. Ovariectomy (OVX) significantly reduced 17-β-estradiol plasma levels in SO and STO groups (p<0.05). The STO group had a significantly reduced retroperitoneal and parametrial fat pad compared with the SO group (p<0.05). IHR values were similar in all groups; however, baseline CPP was significantly reduced in the SO, STS and STO groups compared with the SS group (p<0.05). ANG II caused vasoconstriction in the coronary bed in a concentration-dependent manner. The SO group had an increased response to ANG II when compared with all other experimental groups (p<0.05), which was prevented by 8-weeks of ST in the STO group (p<0.05). OVX increased ANG II-induced vasoconstriction in the coronary vascular bed and abdominal fat pad deposition. Eight weeks of swimming training improved these vasoconstrictor effects and decreased abdominal fat deposition in ovariectomized rats.

Athlete's bradycardia may be a multifactorial mechanism

to the editor: Boyett et al. ([1][1]) provides interesting evidences, arguing that endurance training-induced bradycardia seems mostly related to a remodeling of the sinoatrial node. However, we would like to add four complementary elements to extend this paper. #### About intrinsic heart rate. In

Noninvasive Assessment of Autonomic Cardiovascular Activity in Patients With Inappropriate Sinus Tachycardia

Inappropriate sinus tachycardia (IST) is a clinical syndrome characterized by excessive resting heart rate (HR) or disproportional HR increase during exercise. The etiology of IST has not been fully elucidated and remains controversial. The aim of the present study was to assess autonomic function by means of noninvasive tests and commonly available electrocardiographic methods in a series of consecutive patients with symptomatic IST. Twenty-four patients (37 ± 12 years; 20 women) with IST were enrolled. Six cardiovascular reflex tests were performed: (1) HR variation during slow deep breathing, (2) 30-to-15 ratio during active standing, (3) blood pressure response to standing, (4) cold face test, (5) Valsalva maneuver, and (6) blood pressure response to sustained handgrip. Intrinsic HR was calculated and compared with HR after pharmacologic denervation. Additionally, spontaneous baroreflex sensitivity and 24-hour HR variability indices were analyzed. In IST patients, intrinsic HR was significantly higher compared with control subjects. Most cardiovascular autonomic tests revealed abnormal or borderline results, particularly those reflecting mainly parasympathetic function. The spontaneous baroreflex gain was significantly reduced in IST patients. After controlled orthostatic stress and during Valsalva maneuver, impaired baroreflex function was observed. The sympathovagal balance from HR variability was preserved, but altered activity in both bands of frequency domain analysis was recorded. In conclusion, IST is a heterogenic syndrome with enhanced sinus node automaticity modulated by complex alterations of autonomic tone.

Predictors of Pacemaker Dependence and Pacemaker Dependence as a Predictor of Mortality in Patients with Implantable Cardioverter Defibrillator

The prevalence, predictors, and survival for the development of pacemaker dependence (PD) in patients implanted with an implantable cardioverter defibrillator (ICD) are unknown. This was a retrospective analysis of 1,550 consecutive patients with ICD implantation at a single center from 1996 to 2008 with a mean of 4.2 ± 3.4 years. Patients with implant intrinsic heart rates less than 40 beats/min (n = 48) and cardiac resynchronization therapy (n = 444) were excluded leaving 1,058 patients in this study. PD was defined as an intrinsic rhythm <40 beats/min after inhibiting the pacemaker, <50 beats/min with transient symptoms of dizziness relieved by resumption of pacing and right ventricle pacing despite algorithms to promote intrinsic conduction at the 3 monthly follow-up ICD clinic visits. Multivariate regression and Cox proportional hazard models were used for analysis. The mean age was 64 ± 13 years; 79% were male with a primary indication for the ICD in 57%. PD occurred in 142 (13.4%) of patients, with a mean time to PD of 2.6 ± 1.9 years. PD was associated with a 48% increased odds for mortality versus non-PD ICD patients during the mean follow-up time of 4.2 ± 3.4 years (adjusted odds ratio = 1.48 [95% confidence interval 1.080-2.042]; P = 0.015). Older age, a history of atrial fibrillation, amiodarone use, and secondary prevention were the strongest predictors for the development of PD. In this single-center ICD cohort, the development of PD was not uncommon and was associated with decreased survival.

Commentaries on Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

Commentaries on Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

Cardiovascular Determinants Involved in Pacing Under Heat Stress

I read with interest the review by Roelands et al. [1] regarding the ‘‘Neurophysiological Determinants of Theoretical Concepts and Mechanisms Involved in Pacing.’’ The manuscript explains much of the recently published literature pertaining to the novel mechanisms suggested to regulate or influence pacing and pacing strategy during time-trial exercise. As the authors highlight, the regulation of prolonged self-paced exercise is multifactorial and as such is influenced by a variety of factors, including the development of hyperthermia, brain neurotransmitters, the perception of effort, neuromuscular function, and metabolism. However, a particular mechanism that is conspicuously absent from the discussion, particularly when referring to prolonged efforts in the heat, is that of cardiovascular limitations. The first goal of the manuscript was to review the existing literature on pacing strategies in different climatic conditions [1]. Rightly, it is underscored that during exercise in the heat, a redistribution of blood from the core to the skin may decrease available blood flow to the exercising muscle. Yet, this potential influence on performance is not further discussed. Rather, the authors conclude that ‘‘recent literature showed that during exercise in the heat, a reduction in power output and muscle activation occurs before a critical core temperature is reached, indicating that subjects can anticipate the exercise intensity and heat stress they will be exposed to; thereby preventing catastrophic outcomes’’ [1]. Although the concept of cardiovascular limitations during prolonged exercise in the heat dates from the early work of Rowell [2–4], it is in itself not dated. The premise of this mechanism lies with the redistribution of blood flow from the central to the peripheral circulation for the purposes of thermoregulation. During exercise in the heat, core and skin temperature increase. This increase narrows the core-to-skin temperature gradient, which in turn increases the skin blood flow requirement for heat dissipation [5]. The rise in cutaneous blood volume and a temperature-mediated increase in intrinsic heart rate result in a decrease in cardiac filling, which ultimately leads to the reduction in stroke volume [3, 6–9]. Consequently, when exercise is performed in the heat, maximum cardiac output decreases [10, 11] and the cardiovascular system is forced toward a functional limit at submaximal workloads and oxygen uptake (i.e., maximal aerobic capacity is reduced) [12–15]. This reduction in cardiovascular reserve is purported to be the primary factor limiting constant rate aerobic exercise in the heat, and is manifested as an increase in relative exercise intensity [% maximum oxygen uptake (%VO2max)] and perceived exertion [10, 11, 16]. While the previous observations pertain to constant-rate exercise and have been reported outside the literature search range (2004–2012) defined by the authors, two selfpaced studies that fall within the literature search parameters were not included. Indeed, Ely et al. [17] examined well-trained runners performing an 8-km time trial in warm (*30 C) and cool (*17 C) environments. As with most studies, it was observed that time to completion was longer in warm conditions. However, the authors provided evidence against both the attainment of a critical core temperature and changes in heat storage regulating pacing in Please link with doi:10.1007/s40279-013-0051-z, the reply to this letter.

The effect of pentobarbital anesthesia on “intrinsic” heart rate.

While it is well established that pentobarbital alters cardiac autonomic regulation, the effects of this anesthetic agent on intrinsic heart rate (HRi) remain to be determined. Therefore, HRi, was measured in purpose‐bred mixed breed dogs (n = 11, 22.2 ± 0.9 kg, age 1–3 y) by means of combined adrenergic (propranolol HCl 1.0 mg/kg, i.v.) and muscarinic (atropine sulfate 50 ug/kg iv.) receptor inhibition before (Control, Con) and, at least one week later, during pentobarbital anesthesia (Pen, 30–40 mg/kg, i.v). Pentobarbital significantly (ANOVA, P&lt;0.01) depressed the high frequency component (0.24 – 1.04 Hz, an index of cardiac parasympathetic regulation) of heart rate variability (Con, 7.2 ± 0.4 vs. Pen, 1.0 ± 0.4 ln ms2) and increased baseline heart rate (Con, 105.9 ± 8.7 vs. Pen, 139.1 ± 6.8 beats/min) but decreased HRi (Con, 148.7 ± 6.7 vs. Pen, 128.9 ± 5.3 beats/min). The nonselective adenosine antagonist aminophylline (10 mg/kg, i.v.) did not alter heart rate variability (0.4 ± 0.3 ln ms2) but restored HRi to control (i.e., without pentobarbital) values (141.5 ± 6.7 beats/min). These data suggest that pentobarbital both alters cardiac autonomic regulation and depresses intrinsic heart rate. These data further indicate that the activation of adenosine receptors may play an important role in this apparent depression of cardiac pacemaker rate.

Environmentally‐Induced Phenotypic Plasticity in Embryonic Reptiles

In response to chronic developmental stress, embryonic reptiles exhibit phenotypic plasticity resulting in morphological and physiological modifications. Utilizing chronic hypoxia, we investigated plasticity of cardiovascular regulatory maturation in two species, American alligator and common snapping turtle. Both exhibit phenotypic plasticity, resulting in increased relative heart mass and depressed heart rate. However, they differ in their capacity to modify the timing of cardioregulatory ability and the strength of each regulatory mechanism during development. We also determined that the cardiovascular system appeared most susceptible to environmentally‐induced phenotypic change during the last third of embryonic development. Relocation of chronically hypoxic‐incubated (10% O2) American alligator embryos to normoxia (H to N) at 70% of incubation returned heart mass to control values measured at 90% of development; the opposite manipulation (N to H) did not increase heart mass. Physiological phenotype was also altered, resulting in a reduced intrinsic heart rate in the N to H shift group compared to the H to N group. These data indicate that the degree of cardiovascular developmental phenotypic plasticity is species dependent and may require exposure during finite (‘critical’) windows of development to produce a given response. NSF CAREER IBN IOS‐0845741 to DAC

Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported ([7][1]). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The

Effect of training on intrinsic and resting heart rate and plasma volume in young and old horses

The chronic bradycardia seen in several species after intense exercise training may be due to autonomic mechanisms, non-autonomic mechanisms, such as increased pre-load, or a combination of the two. Thirteen, healthy, unfit Standardbred mares were split into two groups: young (age 12±1 yr; mean ± standard error, n=8) and old (age 22±1 yr, n=5) to test the hypothesis that there would be age and training related differences in resting heart rate (RHR), intrinsic heart rate (IHR), maximal heart rate (HRmax) and plasma volume (PV). Mares were trained 3 d/wk at 60% HRmax for 20 min and gradually increased to exercising 5 d/wk at 70% HRmax for 30 min and RHR, IHR, HRmax, and PV were measured prior to and after the 8 wk training period. There were no age related differences (P≯0.05) between young and old mares before (41±2 vs. 42±2 beats per minute (bpm); 86±5 vs. 80±4 bpm) or after training (35±1 vs. 34±1 bpm; 81±6 vs. 78±2 bpm) for RHR and IHR respectively. RHR was decreased (P&lt;0.05) following training in both the young (41±2 vs. 35±1 bpm) and old mares (42±2 vs. 34±2 bpm). Training decreased IHR (P&lt;0.05) in the young mares (86±5 vs. 81±6 bpm), but not (P≯0.05) the old mares (80±4 vs. 78±2 bpm). The young horses had a higher HRmax than the old horses (P&lt;0.05) both before (216±5 vs. 200±4 bpm) and after training (218±3 vs. 197±5 bpm). Maximal heart rate was not altered after training (P≯0.05) in either young (216±5 vs. 218±3 bpm) or old (200±4 vs. 197±5 bpm) mares. The PV of the young mares was 15% higher before training and 32% higher after training when compared to the old mares (P&lt;0.05). Training caused an increase in PV in young mares (+9%; P&lt;0.05), but did not alter PV in old mares (-5%; P≯0.05). Training improved RHR in the young but not the old horses. The decrease in measured parameters in the young horses appears to be related to enhanced pre-load associated with a training-induced hypervolemia as well as changes in autonomic function.

Is cold acclimation of benefit to hibernating rodents?

The thermal challenge associated with cold acclimation (CA) and hibernation requires effective cardio-respiratory function over a large range of temperatures. We examined the impact of acute cooling in a cold-naïve hibernator to quantify the presumed improvement in cardio-respiratory dysfunction triggered by CA, and estimate the role of the autonomic nervous system in optimising cardiac and respiratory function. Golden hamsters (Mesocricetus auratus) were held at a 12 h:12 h light:dark photoperiod and room temperature (21°C euthermic control) or exposed to simulated onset of winter in an environmental chamber, by progression to 1 h:23 h light:dark and 4°C over 4 weeks. In vivo acute cooling (core temperature Tb=25°C) in euthermic controls led to a hypotension and bradycardia, but preserved cardiac output. CA induced a hypertension at normothermia (Tb=37°C) but on cooling led to decreases in diastolic pressure below euthermic controls and a decrease in cardiac output, despite an increase in left ventricular conductance. Power spectral analysis of heart rate variability suggested a decline in vagal tone on cooling euthermic hamsters (Tb=25°C). Following CA, vagal tone was increased at Tb=37°C, but declined more quickly on cooling (Tb=25°C) to preserve vagal tone at levels similar to euthermic controls at Tb=37°C. For the isolated heart, CA led to concentric hypertrophy with decreased end-diastolic volume, but with no change in intrinsic heart rate at either 37 or 25°C. Mechanical impairment was noted at 37°C following CA, with peak developed pressure decreased by 50% and peak rate-pressure product decreased by 65%; this difference was preserved at 25°C. For euthermic hearts, coronary flow showed thermal sensitivity, decreasing by 65% on cooling (T=25°C). By contrast, CA hearts had low coronary flow compared with euthermic controls, but with a loss of thermal sensitivity. Together, these observations suggest that CA induced a functional impairment in the myocardium that limits performance of the cardiovascular system at euthermia, despite increased autonomic input to preserve cardiac function. On acute cooling this autonomic control was lost and cardiac performance declined further than for cold-naïve hamsters, suggesting that CA may compromise elements of cardiovascular function to facilitate preservation of those more critical for subsequent rewarming.

Reduced Excitability and Ca2+ Current Density in Sinoatrial Myocytes from Aged Mice

Cardiac pacemaking results from the generation of spontaneous action potentials (APs) by specialized myocytes in the sinoatrial node (sinoatrial myocytes, SAMs). These APs are produced by the coordinated activity of a number of different ion channels, including hyperpolarization-activated cyclic nucleotide-sensitive (HCN) channels and voltage-gated Ca2+ channels. Across all mammalian species, the maximum heart rate that can be elicited by stress or exercise decreases with age. However, little is known about age-related changes in the intrinsic excitability of SAMs. In this study, we examined differences in heart rate in young (<3 mo) versus old (>32 mo) mice, and the corresponding differences in spontaneous AP firing rate and ionic currents in isolated SAMs from young versus old animals. ECG measurements in vivo confirmed previous observations of age-related reductions in maximum heart rate and intrinsic heart rate (i.e., in the absence of autonomic input). Current clamp recordings from acutely isolated SAMs revealed age-related deficits in spontaneous AP firing rate that mirrored the age-related changes in heart rate; the basal AP firing rate was significantly slower in SAMs from elderly animals, and maximal stimulation with 1 μM isoproterenol (Iso, a β adrenergic agonist) resulted in a slower average maximum firing rate in SAMs from old mice. To explore the mechanistic bases of these age-related deficiencies in sinoatrial AP generation, we have recently begun voltage-clamp recordings of hyperpolarization-activated currents and voltage-gated calcium currents from isolated SAMs from young and old mice. To date, we have found significant reductions in Ca2+ current density in cells from older animals. These studies may provide mechanistic information about fundamental processes that limit the physical capability of the elderly.

TTX Converts Polymorphic VT to Monomorphic VT in Transgenic Rabbit Model of LQT1

Long QT syndrome Type 1 (LQT1) is a congenital disease defined by loss of function mutations in KCNQ1, and associated with syncope and sudden death preceded by polymorphic ventricular tachycardia (pVT). We hypothesized that inhibition of sodium channel function suppresses pVT formation. using a transgenic rabbit model of LQT1 (n=4), we simultaneously mapped activation patterns from a voltage sensitive dye and microelectrode. The AV node was ablated to slow intrinsic heart rate, isoproterenol (140nM) was injected to mimic sympathetic stimulation, and pVTs were subsequently observed (avg = 3-10 s). The associated activation patterns revealed multifocal activities and complex waveform propagation varying in spatial origin and direction. Subsequent perfusion of a sodium channel blocker, TTX (2 μM), notably converted pVTs toward monomorphic activation patterns. We also report evidence of fully rotating spiral waves, and their role in maintaining monomorphic VTs. Taken together, these results strongly suggest that 1) early afterdepolarizations (EADs) play an important role in maintaining pVTs complexity, 2) sodium currents significantly influence EAD regeneration by their continuous firing during pVTs, 3) sodium channel inhibition by TTX reduces EAD generation and stabilizes reentry into monomorphic VTs.View Large Image | View Hi-Res Image | Download PowerPoint Slide

The treatment with pyridostigmine improves the cardiocirculatory function in rats with chronic heart failure

Sympathetic hyperactivity and its outcome in heart failure have been thoroughly investigated to determine the focus of pharmacologic approaches targeting the sympathetic nervous system in the treatment of this pathophysiological condition. On the other hand, therapeutic approaches aiming to protect the reduced cardiac parasympathetic function have not received much attention. The present study evaluated rats with chronic heart failure (six to seven weeks after coronary artery ligation) and the effects of an increased parasympathetic function by pyridostigmine (an acetylcholinesterase inhibitor) on the following aspects: arterial pressure (AP), heart rate (HR), baroreceptor and Bezold-Jarisch reflex, pulse interval (PI) and AP variability, cardiac sympathetic and parasympathetic tonus, intrinsic heart rate (i-HR) and cardiac function. Conscious rats with heart failure exhibited no change in HR, Bezold-Jarisch reflex, PI variability and cardiac sympathetic tonus. On the other hand, these animals presented hypotension and reduced baroreflex sensitivity, power in the low frequency (LF) band of the systolic AP spectrum, cardiac parasympathetic tonus and i-HR, while anesthetized rats exhibited reduced cardiac performance. Pyridostigmine prevented the attenuation of all the parameters examined, except basal AP and cardiac performance. In conclusion, the blockade of acetylcholinesterase with pyridostigmine was revealed to be an important pharmacological approach, which could be used to increase parasympathetic function and to improve a number of cardiocirculatory parameters in rats with heart failure.

Aerobic physical training has little effect on cardiovascular autonomic control in aging rats subjected to early menopause

We investigated and compared the effects of physiological menopause (PM) and early menopause (EM) and the adaptations promoted by physical training on the cardiovascular autonomic control of aged rats. Female Wistar rats (N=72) were assigned to 3 groups: control (22weeks old rats, undergoing sham surgery in the 10th week of life), PM (82weeks old rats, undergoing sham surgery in the 10th week of life) and EM (82weeks old rats, undergoing ovariectomy in the 10th week of life). In each group, half of the rats were subjected to swimming training over a period of 10weeks. Sedentary PM and EM groups had higher basal mean arterial pressure (MAP) and heart rate (HR) and lower intrinsic HR compared to the sedentary control group. Physical training reduced MAP in PM group. All trained groups had lower basal HR; however, only control and PM-trained groups showed decreased intrinsic HR. The assessment of cardiac autonomic balance showed that PM and EM sedentary groups exhibited sympathetic predominance compared to control group. After physical training, only EM group presented sympathetic predominance. HR variability (pulse interval) was similar among all sedentary groups. However, control and PM-trained groups showed lower power in low frequency band (LF; 0.2–0.75Hz) and higher power in high frequency band (HF; 0.75–3.0Hz). The analysis of systolic arterial pressure variability revealed that PM and EM sedentary groups had higher LF power. However, PM group showed lower LF power following physical training. Finally, PM and EM groups had a reduction in spontaneous baroreflex sensitivity, that was attenuated by physical training. The overall results suggest that PM or EM promotes similar negative effects on MAP, HR and cardiovascular autonomic control. However, unlike the PM group, physical training was not able to mitigate all negative effects of EM on cardiovascular autonomic control.

Pharmacoresistant Cav2·3 (E‐type/R‐type) voltage‐gated calcium channels influence heart rate dynamics and may contribute to cardiac impulse conduction

Voltage-gated Ca(2+) channels regulate cardiac automaticity, rhythmicity and excitation-contraction coupling. Whereas L-type (Cav 1·2, Cav 1·3) and T-type (Cav 3·1, Cav 3·2) channels are widely accepted for their functional relevance in the heart, the role of Cav 2·3 Ca(2+) channels expressing R-type currents remains to be elucidated. We have investigated heart rate dynamics in control and Cav 2·3-deficient mice using implantable electrocardiogram radiotelemetry and pharmacological injection experiments. Autonomic block revealed that the intrinsic heart rate does not differ between both genotypes. Systemic administration of isoproterenol resulted in a significant reduction in interbeat interval in both genotypes. It remained unaffected after administering propranolol in Cav 2·3(-|-) mice. Heart rate from isolated hearts as well as atrioventricular conduction for both genotypes differed significantly. Additionally, we identified and analysed the developmental expression of two splice variants, i.e. Cav 2·3c and Cav 2·3e. Using patch clamp technology, R-type currents could be detected in isolated prenatal cardiomyocytes and be related to R-type Ca(2+) channels. Our results indicate that on the systemic level, the pharmacologically inducible heart rate range and heart rate reserve are impaired in Cav 2·3 (-|-) mice. In addition, experiments on Langendorff perfused hearts elucidate differences in basic properties between both genotypes. Thus, Cav 2·3 does not only contribute to the cardiac autonomous nervous system but also to intrinsic rhythm propagation.