Reduced Basal Heart Rate Variability in a Calcineurin Aβ Deficient Mouse

Abstract

PurposeHeart rate and heart rhythm, quantified by heart rate variability (HRV) in vivo, are both determined by intrinsic pacemaker activity of sinoatrial node (SAN) pacemaker cells (SANC), and input to SAN from the autonomic nervous system (ANS). The spontaneous action potential (AP) firing rate and rhythm of SANC are governed, at least in part, by phosphorylation of proteins that regulate their intracellular calcium cycling and ion channel functions. Calcineurin Aβ (CnAβ), the catalytic subunit of a calcium‐activated serine/threonine phosphatase, influences SANC function protein phosphorylation. Increased calcium cycling and ion channel phosphorylation leads to an increase in SANC AP firing rate and reduced AP firing interval variability. CnAβ likely impacts SANC AP firing rate and AP interval variability, making CnAβ a prime candidate of in vivo HR and HRV regulation. Thus, we hypothesized the role of CnAβ in CnAβ−/− mice, in which cardiac Cn activity is decreased by 80%, would manifest an increased in vivo HR and reduced HRV.MethodsElectrocardiograms (EKG) were measured (via telemetry) in awake, unrestrained, 3‐month‐old male CnAβ−/− mice (n = 9) and wildtype littermates (n = 9). Four 1.5‐hour basal recordings were obtained at least 24 hours apart. A segment of at least 2048 beats with minimal noise were selected for each EKG time series recording and analyzed for different types of HRV parameters (LabChart). HRV parameters in the time domain quantify variance of unordered beat‐to‐beat intervals, frequency domain parameters measure how variance of ordered beat‐to‐beat intervals embedded within an EKG time series distribute as a function of frequency, and non‐linear domain parameters detect variation in fractals buried within the heart rhythm. Statistical analyses were performed using a linear mixed effect model (R) accounting for the four repeated measures.ResultsC.F. table. Mean basal HR was substantially higher in CnAβ−/− than in WT, and time, non‐linear, and most frequency domain HRV descriptors were markedly reduced in CnAβ−/− than WT.ConclusionBecause CnAβ regulates intrinsic SANC function to enable increased calcium cycling and ion channel phosphorylation, our results suggest intrinsic SANC function is a factor that contributes to HR and HRV in vivo. Whether the altered HR and HRV in the CnAβ−/− heart are driven solely by CnAβ dependent mechanisms intrinsic to SANC or, in addition, reflect changes in ANS input to the heart require further studies.Support or Funding InformationFunded by the National Institute of Health/National Institute on Aging Intramural Research Program. Average^ Basal HRV Values in CnAβ−/− vs WT Mice Parameter WT CnAβ−/− Mean HR (bpm) 460 ± 10.8 507 ± 9.6* TIME DOMAIN SD NN (ms) 9.87 ±0.8 5.39 ± 0.4** Range NN (ms) 47.77 ± 3.7 26.68 ± 2.4** Coefficient of Variance (%) 7.22 ± 0.5 4.34 ± 0.3** FREQUENCY DOMAIN Total Power (Power Spectral Density) 284.93 ± 23.5 184.21 ± 19.0* High Frequency (PSD) 70.28 ± 6.2 66.42 ± 9.5 Low Frequency (PSD) 62.58 ± 5.2 40.09 ± 4.7* Very Low Frequency (PSD) 152.07 ± 19.8 77.70 ± 10.5* NON‐LINEAR DOMAIN Beta Slope −2.15 ± 0.1 −2.84 ± 0.1** SDl(ms) 5.72 ± 0.4 2.80 ± 0.7* SD2 (ms) 12.57 ± 0.9 7.00 ± 0.6** Multiscale Entropy 1.57 ± 0.1 0.93 ± 0.1** Values are mean ± SE p<0.05 p<0.01 Average of 4 basal recordings over separate days This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.