Paradigm shift: new concepts for HCN4 function in cardiac pacemaking.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are the molecular correlate of the If current and are critically involved in controlling neuronal excitability and the autonomous rhythm of the heart. The HCN4 isoform is the main HCN channel subtype expressed in the sinoatrial node (SAN), a tissue composed of specialized pacemaker cells responsible for generating the intrinsic heartbeat. More than 40 years ago, the If current was first discovered in rabbit SAN tissue. Along with this discovery, a theory was proposed that cyclic adenosine monophosphate-dependent modulation of If mediates heart rate regulation by the autonomic nervous system-a process called chronotropic effect. However, up to the present day, this classical theory could not be reliably validated. Recently, new concepts emerged confirming that HCN4 channels indeed play an important role in heart rate regulation. However, the cellular mechanism by which HCN4 controls heart rate turned out to be completely different than originally postulated. Here, we review the latest findings regarding the physiological role of HCN4 in the SAN. We describe a newly discovered mechanism underlying heart rate regulation by HCN4 at the tissue and single cell levels, and we discuss these observations in the context of results from previously studied HCN4 mouse models.

Rad-GTPase contributes to heart rate via L-type calcium channel regulation.

Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of ß-adrenergic receptor signaling cascade (ß-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of ß-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in ß-adrenergic receptor directed modulation of LTCC. These studies have identified a conserved mechanism in which ß-AR stimulation results in PKA-dependent Rad phosphorylation: depletion of Rad from the LTCC complex, which is proposed to relieve the constitutive inhibition of CaV1.2 imposed by Rad association. Here, using a transgenic mouse model permitting conditional cardiomyocyte selective Rad ablation, we examine the contribution of Rad to the control of SANcm LTCC current (ICa,L) and sinus rhythm. Single cell analysis from a recent published database indicates that Rad is expressed in SANcm, and we show that SANcm ICa,L was significantly increased in dispersed SANcm following Rad silencing compared to those from CTRL hearts. Moreover, cRadKO SANcm ICa,L was not further increased with ß-AR agonists. We also evaluated heart rhythm in vivo using radiotelemetered ECG recordings in ambulating mice. In vivo, intrinsic HR is significantly elevated in cRadKO. During the sleep phase cRadKO also show elevated HR, and during the active phase there is no significant difference. Rad-deletion had no significant effect on heart rate variability. These results are consistent with Rad governing LTCC function under relatively low sympathetic drive conditions to contribute to slower HR during the diurnal sleep phase HR. In the absence of Rad, the tonic modulated SANcm ICa,L promotes elevated sinus HR. Future novel therapeutics for bradycardia targeting Rad - LTCC can thus elevate HR while retaining ßAR responsiveness.

Confinement, partial sleep deprivation and defined physical activity-influence on cardiorespiratory regulation and capacity.

INTRODUCTION: Adequate cardiorespiratory fitness is of utmost importance during spaceflight and should be assessable via moderate work rate intensities, e.g., using kinetics parameters. The combination of restricted sleep, and defined physical exercise during a 45-day simulated space mission is expected to slow heart rate (HR) kinetics without changes in oxygen uptake ([Formula: see text]) kinetics. METHODS: Overall, 14 crew members (9 males, 5 females, 37 ± 7 yrs, 23.4 ± 3.5 kg m-2) simulated a 45-d-mission to an asteroid. During the mission, the sleep schedule included 5 nights of 5 h and 2 nights of 8 h sleep. The crew members were tested on a cycle ergometer, using pseudo-random binary sequences, changing between 30 and 80 W on day 8 before (MD-8), day 22 (MD22) and 42 (MD42) after the beginning and day 4 (MD + 4) following the end of the mission. Kinetics information was assessed using the maxima of cross-correlation functions (CCFmax). Higher CCFmax indicates faster responses. RESULTS: CCFmax(HR) was significantly (p = 0.008) slower at MD-8 (0.30 ± 0.06) compared with MD22 (0.36 ± 0.06), MD42 (0.38 ± 0.06) and MD + 4 (0.35 ± 0.06). Mean HR values during the different work rate steps were higher at MD-8 and MD + 4 compared to MD22 and MD42 (p < 0.001). DISCUSSION: The physical training during the mission accelerated HR kinetics, but had no impact on mean HR values post mission. Thus, HR kinetics seem to be sensitive to changes in cardiorespiratory fitness and may be a valuable parameter to monitor fitness. Kinetics and capacities adapt independently in response to confinement in combination with defined physical activity and sleep.

G protein-gated IKACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block.

Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies "sick sinus" syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca(2+) channels (Cav1.3(-/-)) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K(+) channel (IKACh) could rescue SSS and heart block in Cav1.3(-/-) mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3(-/-) mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3(-/-) mice or following selective inhibition of Cav1.3-mediated L-type Ca(2+) (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

Dive heart rate in harbour porpoises is influenced by exercise and expectations.

The dive response, a decrease in heart rate (fH) and peripheral vasoconstriction, is the key mechanism allowing breath-hold divers to perform long-duration dives. This pronounced cardiovascular response to diving has been investigated intensely in pinnipeds, but comparatively little is known for cetaceans, in particular in ecologically relevant settings. Here, we studied the dive fH response in one of the smallest cetaceans, the harbour porpoise (Phocoena phocoena). We used a novel multi-sensor data logger to record dive behaviour, fH, ventilations and feeding events in three trained porpoises, providing the first evaluation of cetacean fH regulation while performing a variety of natural behaviours, including prey capture. We predicted that tagged harbour porpoises would exhibit a decrease in fH in all dives, but the degree of bradycardia would be influenced by dive duration and activity, i.e. the dive fH response would be exercise modulated. In all dives, fH decreased compared with surface rates by at least 50% (mean maximum surface fH=173 beats min-1, mean minimum dive fH=50 beats min-1); however, dive fH was approximately 10 beats min-1 higher in active dives as a result of a slower decrease in fH and more variable fH during pursuit of prey. We show that porpoises exhibit the typical breath-hold diver bradycardia during aerobic dives and that the fH response is modulated by exercise and dive duration; however, other variables such as expectations and individual differences are equally important in determining diving fH.

Small functional If current in sinoatrial pacemaker cells of the brown trout (Salmo trutta fario) heart despite strong expression of HCN channel transcripts.

Funny current (If), formed by hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), is supposed to be crucial for the membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout (Salmo trutta fario) sinoatrial (SA) pacemaker cells and their putative role in heart rate (fH) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3, and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4.0 and 4.9 times higher in SA pacemaker tissue than in atrium and ventricle, respectively. In the SA pacemaker, HCN3 and HCN4 were the main isoforms representing 35.8 ± 2.7 and 25.0 ± 1.5%, respectively, of the total HCN transcripts. Only a small If with a mean current density of -1.2 ± 0.37 pA/pF at -140 mV was found in 4 pacemaker cells out of 16 spontaneously beating cells examined, despite the optimization of recording conditions for If activity. If was not found in any of the 24 atrial myocytes and 21 ventricular myocytes examined. HCN4 coexpressed with the MinK-related peptide 1 (MiRP1) ß-subunit in CHO cells generated large If currents. In contrast, HCN3 (+MiRP1) failed to produce If in the same expression system. Cs+ (2 mM), which blocked 84 ± 12% of the native If, reversibly reduced fH 19.2 ± 3.6% of the excised multicellular pacemaker tissue from 53 ± 5 to 44 ± 5 beats/min (P < 0.05). However, this effect was probably due to the reduction of IKr, which was also inhibited (63.5 ± 4.6%) by Cs+ These results strongly suggest that fH regulation in the brown trout heart is largely independent on If.

ß1 -Adrenoceptor, but not ß2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo.

NEW FINDINGS: What is the central question of the study? The sympathetic system regulates heart rate via ß-adrenoceptors; this is impaired during diabetes. However, the specific ß-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the ß1 -adrenoceptor subtype, and not the ß2 -adrenoceptor, regulated the lower resting heart rate and increased ß-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. ß-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of ß1 - and ß2 -adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (ß1 - and ß2 -adrenoceptor agonist, 0.1-300 µg kg-1 ) in the presence of atenolol (ß1 -adrenoceptor antagonist, 2000 µg kg-1 ) or nadolol (ß1 - and ß2 -adrenoceptor agonist, 4000 µg kg-1 ) to determine the chronotropic contributions of the ß-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min-1 non-diabetic versus diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall ß-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 ± 66 versus 205 ± 28 beats min-1 , non-diabetic versus diabetic, P < 0.05), a difference that diminished after ß1 -adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 ± 37 versus 195 ± 22 beats min-1 , non-diabetic versus diabetic, P < 0.05). In conclusion, the ß1 -adrenoceptor is the main subtype to modulate chronotropic ß-adrenoceptor responses in healthy and diabetic rats. This study provides new insights into the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting diabetic chronotropic incompetence.

Effects of Parent-Delivered Traditional Thai Massage on Gait and Heart Rate Variability in Children with Autism: A Randomized Controlled Trial.

Aim: To examine the effects of parent-delivered traditional Thai massage (TTM) intervention on heart rate variability (HRV) and gait in children with autism. Methods: This was a two-armed, randomized controlled trial conducted at the Haikou Special Education School in Haikou Province, China, between October 2021 and March 2022. A total of 48 children with autism, aged between 7 and 12 years, were selected from the school and randomly divided into either the parent-delivered TTM group or the control group (no intervention) in a 1:1 ratio. In addition to their regular daily school routines, the TTM group received 16 TTM interventions (twice a week), with each session lasting ∼50 min. HRV and gait parameters were measured at baseline, completion of the 8-week intervention, and 2 months follow-up. Results: The results of this study showed that the TTM intervention had a notable positive effect on HRV, with a significant reduction in low-frequency value (p = 0.001), and increased high-frequency value (p = 0.001), compared with the controls, and the advantages persisted during the follow-up period. However, only the stride length in the TTM group was significantly longer than that in the control group at the post-test (p = 0.039) and follow-up test (p = 0.043), while none of the other parameters of gait comparison showed statistical significance. Conclusions: Parent-delivered Thai massage increased HRV levels and stride length in comparison to the control group, and some effects of the intervention were maintained over the follow-up period. Clinical Trials Registry Identifier ChiCTR2100051355; September 21, 2021.

Typical everyday movements cause specific patterns in heart rate.

Physical inactivity and sedentary behaviour are important risk factors for cardiovascular disease. Knowledge about the impact of everyday movements on cardiac autonomic regulation is sparse. This study aims to provide evidence that typical everyday movements show a clear impact on heart rate regulation. 40 healthy participants performed two everyday movements: (1) calmly kneeling down ("tie one's shoes") and standing up again and (2) raising the arms to the horizontal ("expressive yawning"). Both movements elicited reproducible pattern in the sequence of heart periods. Local minima and local maxima appeared in the transient period of approx. 30 s. The regulatory response for ergometer cycling, which was used as control, did not show a pattern formation. Calmly performed everyday movements are able to elicit rich cardiac regulatory responses including specific patterns in heart rate. These newly described patterns have multiple implications for clinical and rehabilitative medicine, basic research, digital health data processing, and public health. If carried out regularly these regulatory responses may help to mitigate the burden of physical inactivity and enrich cardiovascular regulation.

Beyond pacemaking: HCN channels in sinoatrial node function.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key proteins involved in the initiation and regulation of the heartbeat. Pacemaker cells within the sinoatrial node generate the electrical impulse that underlies the contraction of all atrial and ventricular cardiomyocytes. To generate a stable heart rhythm, it is necessary that the spontaneous activity of pacemaker cells is synchronized. Entrainment processes in the sinoatrial node create synchrony and also mediate heart rate regulation. In the past years it has become clear that the role of HCN channels goes beyond just pacemaking and that the channels play pivotal roles in these entrainment processes that coordinate and balance sinoatrial node network activity. Here, we review the role of HCN channels in the central pacemaker process and highlight new aspects of the contribution of HCN channels to stabilizing the electrical activity of the sinoatrial node network, especially during heart rate regulation by the autonomic nervous system.

Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function.

The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for generating the intrinsic heartbeat. Within the SAN, spontaneously active pacemaker cells initiate the electrical activity that causes the contraction of all cardiomyocytes. The firing rate of pacemaker cells depends on the slow diastolic depolarization (SDD) and determines the intrinsic heart rate (HR). To adapt cardiac output to varying physical demands, HR is regulated by the autonomic nervous system (ANS). The sympathetic and parasympathetic branches of the ANS innervate the SAN and regulate the firing rate of pacemaker cells by accelerating or decelerating SDD-a process well-known as the chronotropic effect. Although this process is of fundamental physiological relevance, it is still incompletely understood how it is mediated at the subcellular level. Over the past 20 years, most of the work to resolve the underlying cellular mechanisms has made use of genetically engineered mouse models. In this review, we focus on the findings from these mouse studies regarding the cellular mechanisms involved in the generation and regulation of the heartbeat, with particular focus on the highly debated role of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 in mediating the chronotropic effect. By focusing on experimental data obtained in mice and humans, but not in other species, we outline how findings obtained in mice relate to human physiology and pathophysiology and provide specific information on how dysfunction or loss of HCN4 channels leads to human SAN disease.

Heart rate regulation during cycle-ergometer exercise via event-driven biofeedback.

This paper is devoted to the problem of regulating the heart rate response along a predetermined reference profile, for cycle-ergometer exercises designed for training or cardio-respiratory rehabilitation. The controller designed in this study is a non-conventional, non-model-based, proportional, integral and derivative (PID) controller. The PID controller commands can be transmitted as biofeedback auditory commands, which can be heard and interpreted by the exercising subject to increase or reduce exercise intensity. However, in such a case, for the purposes of effectively communicating to the exercising subject a change in the required exercise intensity, the timing of this feedback signal relative to the position of the pedals becomes critical. A feedback signal delivered when the pedals are not in a suitable position to efficiently exert force may be ineffective and this may, in turn, lead to the cognitive disengagement of the user from the feedback controller. This note examines a novel form of control system which has been expressly designed for this project. The system is called an "actuator-based event-driven control system". The proposed control system was experimentally verified using 24 healthy male subjects who were randomly divided into two separate groups, along with cross-validation scheme. A statistical analysis was employed to test the generalisation of the PID tunes, derived based on the average transfer functions of the two groups, and it revealed that there were no significant differences between the mean values of root mean square of the tracking error of two groups (3.9 vs. 3.7 bpm, [Formula: see text]). Furthermore, the results of a second statistical hypothesis test showed that the proposed PID controller with novel synchronised biofeedback mechanism has better performance compared to a conventional PID controller with a fixed-rate biofeedback mechanism (Group 1: 3.9 vs. 5.0 bpm, Group 2: 3.7 vs. 4.4 bpm, [Formula: see text]).

Advanced portable remote monitoring system for the regulation of treadmill running exercises.

OBJECTIVE: This study aims to develop an advanced portable remote monitoring system to supervise high intensity treadmill exercises. MATERIALS AND METHODS: The supervisory level of the developed hierarchical system is implemented on a portable monitoring device (iPhone/iPad) as a client application, while the real-time control of treadmill exercises is accomplished by using an on-line adaptive neural network control scheme in a local computer system. During training or rehabilitation exercises, the intensity (measured by heart rate) is regulated by simultaneously manipulating both treadmill speed and gradient. In order to achieve adaptive tracking performance, a neural network controller has been designed and implemented. RESULTS: Six real-time experiments have been conducted to test the performance of the developed monitoring system. Experimental results obtained in real-time with heart-rate set-point varying from 145 bpm to 180 bmp, demonstrate that the proposed system can quickly and accurately regulate exercise intensity of treadmill running exercises with desired performance (no overshoot, settling time Ts ≤ 100 s). Subjects aged from 29 to 38 years old participated in different set-point experiments to confirm the system's adaptability to inter- and intra-model uncertainty. The desired system performance under external disturbances has also been confirmed in a final real-time experiment demonstrating a user carrying the 10 kg bag then removing it during the exercise. CONCLUSION: In contrast with conventional control approaches, the proposed adaptive controller achieves better heart rate tracking performance under inter- and intra-model uncertainty and external disturbances. The developed system can automatically adapt to various individual exercisers and a range of exercise intensity.