Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

Yaniv, Yael; Lyashkov, Alexey E.; Sirenko, Syevda; Okamoto, Y.; Guiriba, Toni Rose; Ziman, Bruce D.; Morrell, Christopher H.; Lakatta, Edward G.

doi:10.1016/j.yjmcc.2014.09.008

Cited by 40 publications

(58 citation statements)

References 34 publications

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“…This simple model allows keeping the ANS modulation constant for different mean HR values, which is not possible in the reality. This simulation allowed assessing the nonlinear dependence of the standard deviation of normal beats on mean HR as it has been pointed out in previous studies (Zaza and Lombardi, 2001; Monfredi et al, 2014; Yaniv et al, 2014b; data not included in the manuscript). Two approaches have been proposed to attenuate the effect shown in the simulation study: regression formulas and interpolation.…”

Section: Discussionmentioning

confidence: 99%

“…The nonlinear relationship between temporal and complexity HRV indices with respect to HR has been addressed emphasizing the importance of attenuating this effect (Zaza and Lombardi, 2001; Platisa and Gal, 2006; Monfredi et al, 2014; Yaniv et al, 2014b). Furthermore, different mathematical models have demonstrated a relationship between HRV amplitude and HR correcting it (Chiu et al, 2003; Meste et al, 2005; Bailón et al, 2011; Sacha, 2014; Billman et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Influence of Heart Rate in Non-linear HRV Indices as a Sampling Rate Effect Evaluated on Supine and Standing

et al. 2016

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The purpose of this study is to characterize and attenuate the influence of mean heart rate (HR) on nonlinear heart rate variability (HRV) indices (correlation dimension, sample, and approximate entropy) as a consequence of being the HR the intrinsic sampling rate of HRV signal. This influence can notably alter nonlinear HRV indices and lead to biased information regarding autonomic nervous system (ANS) modulation. First, a simulation study was carried out to characterize the dependence of nonlinear HRV indices on HR assuming similar ANS modulation. Second, two HR-correction approaches were proposed: one based on regression formulas and another one based on interpolating RR time series. Finally, standard and HR-corrected HRV indices were studied in a body position change database. The simulation study showed the HR-dependence of non-linear indices as a sampling rate effect, as well as the ability of the proposed HR-corrections to attenuate mean HR influence. Analysis in a body position changes database shows that correlation dimension was reduced around 21% in median values in standing with respect to supine position (p < 0.05), concomitant with a 28% increase in mean HR (p < 0.05). After HR-correction, correlation dimension decreased around 18% in standing with respect to supine position, being the decrease still significant. Sample and approximate entropy showed similar trends. HR-corrected nonlinear HRV indices could represent an improvement in their applicability as markers of ANS modulation when mean HR changes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of Heart Rate in Non-linear HRV Indices as a Sampling Rate Effect Evaluated on Supine and Standing

et al. 2016

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“…Thus, ivabradine indirectly suppresses intracellular calcium cycling, which also contributes to the bradycardic effects of the drug, indicating once more the relevance of a coordinated cross talk between the two pacemaking “clocks” 45,46…”

Section: Ivabradine – Mode Of Action and Pharmacologymentioning

confidence: 99%

Advances in the management of heart failure: the role of ivabradine

Müller‐Werdan

Stöckl

Werdan

2016

VHRM

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A high resting heart rate (≥70–75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class “IIa” = weight of evidence/opinion is in favor of usefulness/efficacy: “should be considered”; level of evidence “B” = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5–7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication “HF with reduced EF” together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF.

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“…Two main mechanisms regulate the average BI and BIV: (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. β‐adrenergic receptors (β‐AR) or cholinergic receptors (CR)) within the sinoatrial node (SAN) (O'Brien et al ., ; Sloan et al ., ) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca 2+ ‐calmodulin adenylyl cyclase (AC) types 1 and 8 (Papaioannou et al ., ; Ben‐Ari et al ., ; Yaniv et al ., ,b), which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation (Mattick et al ., ; Younes et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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SummaryWe aimed to determine how age‐associated changes in mechanisms extrinsic and intrinsic to pacemaker cells relate to basal beating interval variability (BIV) reduction in vivo. Beating intervals (BIs) were measured in aged (23–25 months) and adult (3–4 months) C57BL/6 male mice (i) via ECG in vivo during light anesthesia in the basal state, or in the presence of 0.5 mg mL−1 atropine + 1 mg mL−1 propranolol (in vivo intrinsic conditions), and (ii) via a surface electrogram, in intact isolated pacemaker tissue. BIV was quantified in both time and frequency domains using linear and nonlinear indices. Although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad‐spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input.

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Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

Cited by 40 publications

References 34 publications

Influence of Heart Rate in Non-linear HRV Indices as a Sampling Rate Effect Evaluated on Supine and Standing

Influence of Heart Rate in Non-linear HRV Indices as a Sampling Rate Effect Evaluated on Supine and Standing

Advances in the management of heart failure: the role of ivabradine

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

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