The Fractal-like Complexity of Heart Rate Variability beyond Neurotransmitters and Autonomic Receptors: Signaling Intrinsic to Sinoatrial Node Pacemaker Cells

Aim. To evaluate the peripheral autonomic effects of isosorbide mononitrate on sinoatrial node pacemaker activity using wave structure analysis by rhythmocardiography. Methods. The study included 162 patients with III and IV functional classes of stable angina, among them 122 - with hypertension. The control group consisted of 42 healthy volunteers. In addition to standard techniques (electrocardiography, echocardiography, bicycle ergometry, electrocardiogram daily monitoring), high-resolution rhythmocardiography using a KAP-RK-01-«Mikor» diagnostic complex with time and spectral analysis of the sinus rhythm wave structure was performed. The method is based on the evaluation of peripheral autonomic regulation in the sinoatrial pacemaker and influence of humoral and metabolic environment on it. Results. In all patients with III and IV functional classes of stable angina regardless of the concomitant arterial hypertension heart rate variability, as well as Valsalva maneuver response increased in a number of patients taking isosorbide mononitrate. Negative events related to isosorbide mononitrate intake were reduced parasympathetic fluctuations in a number of cases, humoral-metabolic regulation growth, and increase of sympathetic regulation role in patients with concomitant arterial hypertension. Rhythmocardiography allowed to access the influence of isosorbide mononitrate on heart rate variability in patients with ischemic heart disease. Conclusion. Both positive (increased heart rate variability) and negative (spectral features redistribution with humoral, metabolic and sympathetic components increase and parasympathetic component decrease) effects were associated with isosorbide mononitrate intake with lesser sinoatrial node dysregulation in patients with concomitant arterial hypertension.

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Abstract 16515: Differential Functions of HCN1 and HCN4 Pacemaker Channels Within the Sinoatrial Node for the Stable and Precise Beating of the Heart

Circulation ◽

10.1161/circ.130.suppl_2.16515 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Stefanie Fenske ◽

Vanessa Marks ◽

Stefanie Koenigsbauer ◽

Sami I Hassan ◽

Tilman Ziegler ◽

...

Keyword(s):

Heart Rate ◽

Mouse Models ◽

Sinoatrial Node ◽

Critical Role ◽

Functional Characterization ◽

Heart Beat ◽

Fine Tuning ◽

Hcn Channels ◽

Pacemaker Cells

The heart beat is initiated by the generation of spontaneous action potentials in pacemaker cells of the sinoatrial node (SAN) region. The maintenance of a stable heart beat requires mechanisms which protect the SAN pacemaker cells from potential perturbing influences which arise from inside and outside the sinoatrial network. Our previous work suggests that the hyperpolarization-activated cyclic nucleotide gated channel subtype 1 (HCN1) protects against such perturbations and thereby increases the stability, the precision and the safety of the sinoatrial network. Here, we investigate the role of HCN4 channels within this context. Using genetic mouse models deficient for HCN channels as well as mouse models expressing engineered HCN channels, we performed a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparations, with telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology. We provide evidence that HCN4 has a critical role in counteracting and balancing potentially destabilizing effects of the autonomic nervous system on the regulation of the heart rate. Specifically, HCN4 channels smooth the transition of the heart rate to a new equilibrium. Furthermore, we provide evidence that the cAMP- dependent fine tuning of HCN4 channel activity could provide the exact dosage of current to balance and counteract overshooting responses of the heart rate to autonomic regulation. In the absence of such a protecting effect, mice display a brady- tachy syndrome.

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Altered heart rate variability in angiotensin II–mediated hypertension is associated with impaired autonomic nervous system signaling and intrinsic sinoatrial node dysfunction

Heart Rhythm ◽

10.1016/j.hrthm.2020.03.014 ◽

2020 ◽

Vol 17 (8) ◽

pp. 1360-1370 ◽

Cited By ~ 1

Author(s):

Tristan W. Dorey ◽

Motahareh Moghtadaei ◽

Robert A. Rose

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Nervous System ◽

Autonomic Nervous System ◽

Angiotensin Ii ◽

Sinoatrial Node ◽

Autonomic Nervous ◽

Sinoatrial Node Dysfunction

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Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age‐associated alterations in heart rate variability in vivo

Aging Cell ◽

10.1111/acel.12483 ◽

2016 ◽

Vol 15 (4) ◽

pp. 716-724 ◽

Cited By ~ 17

Author(s):

Yael Yaniv ◽

Ismayil Ahmet ◽

Kenta Tsutsui ◽

Joachim Behar ◽

Jack M. Moen ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Receptor Signaling ◽

Pacemaker Cells ◽

Neuronal Receptor

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Beating Rate Variability of Isolated Mammal Sinoatrial Node Tissue: Insight Into Its Contribution to Heart Rate Variability

Frontiers in Neuroscience ◽

10.3389/fnins.2020.614141 ◽

2021 ◽

Vol 14 ◽

Author(s):

Ori Shemla ◽

Kenta Tsutsui ◽

Joachim A. Behar ◽

Yael Yaniv

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Frequency Band ◽

Sinoatrial Node ◽

Low Frequency ◽

Relative Increase ◽

Test Mouse ◽

Beating Rate

BackgroundBecause of the complexity of the interaction between the internal pacemaker mechanisms, cell interconnected signals, and interaction with other body systems, study of the role of individual systems must be performed under in vivo and in situ conditions. The in situ approach is valuable when exploring the mechanisms that govern the beating rate and rhythm of the sinoatrial node (SAN), the heart’s primary pacemaker. SAN beating rate changes on a beat-to-beat basis. However, to date, there are no standard methods and tools for beating rate variability (BRV) analysis from electrograms (EGMs) collected from different mammals, and there is no centralized public database with such recordings.MethodsWe used EGM recordings obtained from control SAN tissues of rabbits (n = 9) and mice (n = 30) and from mouse SAN tissues (n = 6) that were exposed to drug intervention. The data were harnessed to develop a beat detector to derive the beat-to-beat interval time series from EGM recordings. We adapted BRV measures from heart rate variability and reported their range for rabbit and mouse.ResultsThe beat detector algorithm performed with 99% accuracy, sensitivity, and positive predictive value on the test (mouse) and validation (rabbit and mouse) sets. Differences in the frequency band cutoff were found between BRV of SAN tissue vs. heart rate variability (HRV) of in vivo recordings. A significant reduction in power spectrum density existed in the high frequency band, and a relative increase was seen in the low and very low frequency bands. In isolated SAN, the larger animal had a slower beating rate but with lower BRV, which contrasted the phenomena reported for in vivo analysis. Thus, the non-linear inverse relationship between the average HR and HRV is not maintained under in situ conditions. The beat detector, BRV measures, and databases were contributed to the open-source PhysioZoo software (available at: https://physiozoo.com/).ConclusionOur approach will enable standardization and reproducibility of BRV analysis in mammals. Different trends were found between beating rate and BRV or HRV in isolated SAN tissue vs. recordings collected under in vivo conditions, respectively, implying a complex interaction between the SAN and the autonomic nervous system in determining HRV in vivo.

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From beat rate variability in induced pluripotent stem cell–derived pacemaker cells to heart rate variability in human subjects

Heart Rhythm ◽

10.1016/j.hrthm.2014.05.037 ◽

2014 ◽

Vol 11 (10) ◽

pp. 1808-1818 ◽

Cited By ~ 24

Author(s):

Meital Ben-Ari ◽

Revital Schick ◽

Lili Barad ◽

Atara Novak ◽

Erez Ben-Ari ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Stem Cell ◽

Pluripotent Stem Cell ◽

Human Subjects ◽

Induced Pluripotent Stem Cell ◽

Pacemaker Cells ◽

Beat Rate ◽

Induced Pluripotent

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cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

Nature Communications ◽

10.1038/s41467-020-19304-9 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Stefanie Fenske ◽

Konstantin Hennis ◽

René D. Rötzer ◽

Verena F. Brox ◽

Elvir Becirovic ◽

...

Keyword(s):

Heart Rate ◽

Sinoatrial Node ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Mouse Line ◽

Pacemaker Cells ◽

Heart Rate Regulation ◽

Cardiac Phenotype ◽

Pacemaker Channel ◽

Central Pacemaker

Abstract It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

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