Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract

Background: The ability to increase heart rate (HR) during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiologic HR response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. Methods: Dahl salt-sensitive rats fed with a high-salt diet and C57Bl6 mice fed with high fat and an inhibitor of constitutive nitric oxide synthase (L-NAME, 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction (HFrEF). Rats and mice fed with a normal diet or having 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 electrophysiological 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 HFrEF rats. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca 2+ clock" (spontaneous Ca 2+ release events). The physiological impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. Conclusions: Thus, 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.

Cellular Heterogeneity of the Heart

“…In a rat model of heart failure with preserved ejection fraction, scRNAseq transcriptome analyses of the sinoatrial node revealed significant alterations in both the “membrane clock” (ion channels) and the “calcium clock” (spontaneous calcium release events) which—when probed in functional experiments—further validated RNA-seq data ( 117 ).…”

Non-invasive assessment of HFpEF in mouse models: current gaps and future directions

“…LV, left ventricle; bpm, beats per minute (See figure on next page.) exercise (chronotropic incompetence) and a functional limitation to further sinus node activation during exercise (sinoatrial node dysfunction) would explain at least in part this impaired exercise capability [57,58]. These features have also been recently observed in preclinical models of HF [57].…”

“…exercise (chronotropic incompetence) and a functional limitation to further sinus node activation during exercise (sinoatrial node dysfunction) would explain at least in part this impaired exercise capability [57,58]. These features have also been recently observed in preclinical models of HF [57]. To assess the degree of heart rate increase following stimulation in mice, the β-adrenergic agonist isoproterenol is injected intraperitoneally (1-2 mg/kg body weight) during ECG acquisition [56].…”

MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18

“…Whole-cell electrophysiology recordings were performed as we previously described 43 Experiments were carried out using standard microelectrode amphotericin B-perforated whole-cell patch-clamp with an Axopatch 200B amplifier (Molecular Devices) with a sampling rate of 20 kHz and low-pass filtered at 5 kHz. Experiments were performed at 36 ± 1°C with cells perfused with an extracellular Tyrode’s solution containing (mM): 140 NaCl, 5 KCl, 1.8 CaCl2, 1 MgCl2, 10 glucose, and 10 HEPES, pH 7.4 NaOH.…”