Did you mean: sinoatrial node
-
Annual Review of Physiology Feb 2020A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness,... (Review)
Review
A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work.
Topics: Aging; Animals; Biological Clocks; Female; Heart; Heart Rate; Humans; Male; Sinoatrial Node
PubMed: 31756134
DOI: 10.1146/annurev-physiol-021119-034453 -
Circulation Jan 2022The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate...
BACKGROUND
The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown.
METHODS
Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created.
RESULTS
Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca clock" (spontaneous Ca release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function.
CONCLUSIONS
Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.
Topics: Animals; Heart Failure; Humans; Rats; Sinoatrial Node; Stroke Volume
PubMed: 34905696
DOI: 10.1161/CIRCULATIONAHA.121.054976 -
Annual Review of Pharmacology and... Jan 2021The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the... (Review)
Review
The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.
Topics: Heart Conduction System; Humans; Sick Sinus Syndrome; Sinoatrial Node
PubMed: 33017571
DOI: 10.1146/annurev-pharmtox-031120-115815 -
Disease Models & Mechanisms May 2023The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output... (Review)
Review
The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output meets physiological demand. SAN dysfunction (SND) can cause complex cardiac arrhythmias that can manifest as severe sinus bradycardia, sinus arrest, chronotropic incompetence and increased susceptibility to atrial fibrillation, among other cardiac conditions. SND has a complex aetiology, with both pre-existing disease and heritable genetic variation predisposing individuals to this pathology. In this Review, we summarize the current understanding of the genetic contributions to SND and the insights that they provide into this disorder's underlying molecular mechanisms. With an improved understanding of these molecular mechanisms, we can improve treatment options for SND patients and develop new therapeutics.
Topics: Animals; Humans; Sinoatrial Node; Heart Rate; Atrial Fibrillation; Mammals
PubMed: 37194974
DOI: 10.1242/dmm.050101 -
Fa Yi Xue Za Zhi Apr 2021Human heart rhythm is mainly regulated and controlled by the sinoatrial node. Fibrosis plays an important regulating role in adjusting the structural and functional... (Review)
Review
Human heart rhythm is mainly regulated and controlled by the sinoatrial node. Fibrosis plays an important regulating role in adjusting the structural and functional integrity of the sinoatrial node pacemaker complex. In physiological state, the fibrosis degree of sinoatrial node is negatively correlated with heart rate, positively correlated with age and heart size, and can maintain a relatively stable heart rate. Pathological fibrosis of sinoatrial node can induce various types of arrhythmias which can result in sudden death. Determination of the mechanisms related to sinoatrial node pathological fibrosis could provide a target for clinical treatment of sinoatrial node fibrosis and diagnosis basis for forensic pathologists. This paper reviews the main mechanism of sinoatrial node pathological fibrosis, including abnormal activation of cardiac fibroblast cells in sinoatrial node, hyperplasia of epicardial adipose tissue, calcium clock disorder, artery stenosis, etc., introduces the test methods, diagnostic criteria as well as its role in sudden cardiac death and discusses the potential application, to provide reference for relevant research and application.
Topics: Arrhythmias, Cardiac; Fibrosis; Heart Rate; Humans; Sinoatrial Node
PubMed: 34142485
DOI: 10.12116/j.issn.1004-5619.2020.400820 -
Progress in Biophysics and Molecular... Nov 2021Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key proteins involved in the initiation and regulation of the heartbeat. Pacemaker cells within... (Review)
Review
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.
Topics: Heart Rate; Heart Ventricles; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Myocytes, Cardiac; Sinoatrial Node
PubMed: 33753086
DOI: 10.1016/j.pbiomolbio.2021.03.004 -
Circulation Journal : Official Journal... Jan 2019Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF).... (Review)
Review
Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the I current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of I inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.
Topics: Cardiovascular Diseases; Heart Rate; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ivabradine; Sinoatrial Node
PubMed: 30606942
DOI: 10.1253/circj.CJ-18-1184 -
Journal of Veterinary Cardiology : the... Apr 2019The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure... (Review)
Review
The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.
Topics: Animals; Arrhythmias, Cardiac; Dog Diseases; Dogs; Heart Conduction System; Humans; Sinoatrial Node
PubMed: 30559056
DOI: 10.1016/j.jvc.2018.10.004 -
Journal of the American College of... Feb 2013Inappropriate sinus tachycardia (IST) is a syndrome in which the sinus heart rate is inexplicably faster than expected and associated symptoms are present. The heart... (Review)
Review
Inappropriate sinus tachycardia (IST) is a syndrome in which the sinus heart rate is inexplicably faster than expected and associated symptoms are present. The heart rate at rest, even in a supine position, can exceed 100 beats/min; minimal activity accelerates the rate rapidly and substantially. Patients with IST may require restriction from physical activity. Mechanisms responsible for IST are understood incompletely. It is important to distinguish IST from so-called appropriate sinus tachycardia and from postural orthostatic tachycardia syndrome, with which overlap may occur. Because the long-term outcome seems to be benign, treatment may be unnecessary or may be as simple as physical training. However, for patients with intolerable symptoms, therapeutic measures are warranted. Even at high doses, β-adrenergic blockers, the first-line therapy, often are ineffective; the same is true for most other medical therapies. In rare instances, catheter- or surgically- based right atrial or sinus node modification may be helpful, but even this is fraught with limited efficacy and potential complications. Overtreatment, in an attempt to reduce symptoms, can be difficult to avoid, but is discouraged.
Topics: Adrenergic beta-Antagonists; Biological Clocks; Catheter Ablation; Depression, Chemical; Disease Management; Electrocardiography; Electrophysiologic Techniques, Cardiac; Heart Rate; Humans; Neurotransmitter Agents; Sinoatrial Node; Tachycardia, Sinus; Vagus Nerve
PubMed: 23265330
DOI: 10.1016/j.jacc.2012.07.074 -
Philosophical Transactions of the Royal... Jun 2023Even before the sinoatrial node (SAN) was discovered, cardiovascular science was engaged in an active investigation of when and why the heart would beat. After the... (Review)
Review
Even before the sinoatrial node (SAN) was discovered, cardiovascular science was engaged in an active investigation of when and why the heart would beat. After the electrochemical theory of bioelectric membrane potentials was formulated and the first action potentials were measured in contracting muscle cells, the field became divided: some investigators studied electrophysiology and ion channels, others studied muscle contraction. It later became known that changes in intracellular Ca cause contraction. The pacemaking field was reunited by the coupled-clock theory of pacemaker cell function, which integrated intracellular Ca cycling and transmembrane voltage into one rhythmogenic system. In this review, we will discuss recent discoveries that contextualize the coupled-clock system, first described in isolated SAN cells, into the complex world of SAN tissue: heterogeneous local Ca releases, generated within SAN pacemaker cells and regulated by the other cell types within the SAN cytoarchitecture, variably co-localize and synchronize to give rise to relatively rhythmic impulses that emanate from the SAN to excite the heart. We will ultimately conceptualize the SAN as a brain-like structure, composed of intercommunicating meshworks of multiple types of pacemaker cells and interstitial cells, intertwined networks of nerves and glial cells and more. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Sinoatrial Node; Myocytes, Cardiac; Action Potentials; Calcium
PubMed: 37122227
DOI: 10.1098/rstb.2022.0180