Search

Background Heart rate variability (HRV) is determined by intrinsic sinoatrial node (SAN) activity and the autonomic nervous system (ANS). HRV is reduced in aging; however, aging is heterogeneous. Frailty, which can be measured using a frailty index (FI), can quantify health status in aging separately from chronological age. Objective The purpose of this study was to investigate the impacts of age and frailty on HRV in mice. Methods Frailty was measured in aging mice between 10 and 130 weeks of age. HRV was assessed using time domain, frequency domain, and Poincare plot analyses in anesthetized mice at baseline and after ANS blockade, as well as in isolated atrial preparations. Results HRV was reduced in aged mice (90–130 weeks and 50–80 weeks old) compared to younger mice (10–30 weeks old); however, there was substantial variability within age groups. In contrast, HRV was strongly correlated with FI score regardless of chronological age. ANS blockade resulted in reductions in heart rate that were largest in 90- to 130-week-old mice and were correlated with FI score. HRV after ANS blockade or in isolated atrial preparations was increased in aged mice but again showed high variability among age groups. HRV was correlated with FI score after ANS blockade and in isolated atrial preparations. Conclusion HRV is reduced in aging mice in association with a shift in sympathovagal balance and increased intrinsic SAN beating variability; however, HRV is highly variable within age groups. HRV was strongly correlated with frailty, which was able to detect differences in HRV separately from chronological age.

Aims Heart rate (HR) is a critical indicator of cardiac performance that is determined by sinoatrial node (SAN) function and regulation. Natriuretic peptides, including C-type NP (CNP), have been shown to modulate ion channel function in the SAN when applied exogenously. CNP is the only NP that acts as a ligand for natriuretic peptide receptor-B (NPR-B). Despite these properties, the ability of CNP and NPR-B to regulate HR and intrinsic SAN automaticity in vivo, and the mechanisms by which it does so, are incompletely understood. Thus, the objective of this study was to determine the role of NPR-B signalling in regulating HR and SAN function. Methods and results We have used NPR-B deficient mice (NPR-B+/−) to study HR regulation and SAN function using telemetry in conscious mice, intracardiac electrophysiology in anaesthetized mice, high-resolution optical mapping in isolated SAN preparations, patch-clamping in isolated SAN myocytes, and molecular biology in isolated SAN tissue. These studies demonstrate that NPR-B+/− mice exhibit slow HR, increased corrected SAN recovery time, and slowed SAN conduction. Spontaneous AP firing frequency in isolated SAN myocytes was impaired in NPR-B+/− mice due to reductions in the hyperpolarization activated current (If) and L-type Ca2+ current (ICa,L). If and ICa,L were reduced due to lower cGMP levels and increased hydrolysis of cAMP by phosphodiesterase 3 (PDE3) in the SAN. Inhibiting PDE3 or restoring cGMP signalling via application of 8-Br-cGMP abolished the reductions in cAMP, AP firing, If, and ICa,L, and normalized SAN conduction, in the SAN in NPR-B+/− mice. NPR-B+/− mice did not exhibit changes in SAN fibrosis and showed no evidence of cardiac hypertrophy or changes in ventricular function. Conclusions NPR-B plays an essential physiological role in maintaining normal HR and SAN function by modulating ion channel function in SAN myocytes via a cGMP/PDE3/cAMP signalling mechanism.

Objective: To determine the test-retest reliability of quantitative and qualitative baroreflex sensitivity (BRS) parameters derived from the Valsalva maneuver (VM) in individuals with traumatic cervical SCI. Design: Test-retest reliability. Setting: Tertiary rehabilitation center. Participants: Fourteen participants with cervical SCI (ranging from C3-C8 neurological level). Outcome Measurements: Beat-to-beat systolic blood pressure (SBP) traces (finger photoplethysmography) were obtained during a 15-second forced expiration at two time points (7.6 ± 2.9 days between sessions) to assess VM reliability. Test-retest reliability of BRS metrics from derived from the VM (Valsalva ratio; VR, pressure recovery time; PRT, vagal baroreflex sensitivity; BRSv, adrenergic baroreflex sensitivity; BRSa(1), and total recovery; TR) were assessed by intra-class correlation coefficient (ICC, with 95% confidence interval; CI) and by qualitative reproducibility (V, N, or M pattern). Results: ICCs for quantitative parameters were (CI): VR = 0.894 (0.703–0.965), TR = 0.927 (0.789–0.976), BRSa(1) = 0.561 (0.149–0.911), PRT = 0.728 (0.343–0.904), BRSv = 0.243 (−0.309–0.673). Qualitatively, 12 subjects (85.7%) demonstrated reproducible VM patterns at both time points (3 “M” pattern, 8 “V” pattern and one “N” pattern). Conclusion: VR (a measure of cardiovagal function) and TR (a measure of sympathetic adrenergic function) are reliable quantitative parameters that can be derived from SBP response to VM in participants with SCI. Qualitative waveform analysis was reproducible in 12/14 participants. This provides the foundational evidence required to pursue further validity testing to establish a role for VM in the assessment of autonomic functions in SCI.

Cardiovagal baroreflex sensitivity (cvBRS) reflects the efficiency of modulating heart rate in response to changes in systolic blood pressure. International guidelines recommend that older adults achieve at least 150 min of moderate–vigorous physical activity per week. We tested the hypothesis that older adults who achieve these guidelines will exhibit greater cardiovagal baroreflex sensitivity versus those who do not. A cross-sectional comparison of older adults who did (active, 66 ± 5 years, 251 ± 79 min/week; n = 19) and who did not (inactive, 68 ± 7 years, 89 ± 32 min/week; n = 17) meet the activity guidelines. Beat-by-beat R–R intervals (electrocardiography) and systolic blood pressure (finger photoplethysmography) were recorded. Spontaneous cardiovagal baroreflex sensitivity was assessed using the sequence technique from 10 min of resting supine data. Cardiovagal baroreflex function was also measured during early phase II and phase IV of the Valsalva maneuver. Peak oxygen uptake was determined during maximal cycle ergometry. Moderate–vigorous intensity physical activity and time spent sedentary were assessed over 5 days using the PiezoRx and activPAL, respectively. Groups had similar peak oxygen uptake (active 25 ± 9 vs. inactive 22 ± 6 ml/kg/min; p = 0.218) and sedentary time (active 529 ± 60 vs. inactive 568 ± 88 min/day; p = 0.130). However, the active group had greater (all, p

Background Atrial fibrillation (AF) is highly prevalent in diabetes mellitus (DM), yet the basis for this finding is poorly understood. Type 2 DM may be associated with unique patterns of atrial electrical and structural remodeling; however, this has not been investigated in detail. Objective The purpose of this study was to investigate AF susceptibility and atrial electrical and structural remodeling in type 2 diabetic db/db mice. Methods AF susceptibility and atrial function were assessed in male and female db/db mice and age-matched wildtype littermates. Electrophysiological studies were conducted in vivo using intracardiac electrophysiology and programmed stimulation. Atrial electrophysiology was also investigated in isolated atrial preparations using high-resolution optical mapping and in isolated atrial myocytes using patch-clamping. Molecular biology studies were performed using quantitative polymerase chain reaction and western blotting. Atrial fibrosis was assessed using histology. Results db/db mice were highly susceptible to AF in association with reduced atrial conduction velocity, action potential duration prolongation, and increased heterogeneity in repolarization in left and right atria. In db/db mice, atrial K+ currents, including the transient outward current (Ito) and the ultrarapid delayed rectifier current (IKur), were reduced. The reduction in Ito occurred in association with reductions in Kcnd2 mRNA expression and KV4.2 protein levels. The reduction in IKur was not related to gene or protein expression changes. Interstitial atrial fibrosis was increased in db/db mice. Conclusion Our study demonstrates that increased susceptibility to AF in db/db mice occurs in association with impaired electrical conduction as well as electrical and structural remodeling of the atria.

Background Hypertensive heart disease is associated with sinoatrial node (SAN) dysfunction and reductions in heart rate variability (HRV). Alterations in HRV could occur in association with changes in autonomic nervous system (ANS) activity, changes in SAN function and responsiveness to ANS agonists, or both. These relationships are unclear. Objective The purpose of this study was to investigate the roles of ANS signaling, intrinsic SAN function, and changes in HRV in a mouse model of angiotensin II (AngII)–mediated hypertensive heart disease. Methods Mice were treated with saline or AngII (2.5 mg/(kg⋅d)) for 3 weeks. ANS activity was assessed through HRV analysis of electrocardiograms collected in vivo by telemetry as well as direct recordings of vagal nerve activity and renal sympathetic nerve activity from anesthetized mice. The effects of the ANS agonists isoproterenol and carbachol on SAN function and beating interval variability were assessed from electrogram recordings in intact isolated atrial preparations and from spontaneous action potential recordings in isolated SAN myocytes. Results Time and frequency domain analysis demonstrates that mice infused with AngII had reduced HRV. AngII-infused mice had elevated renal sympathetic nerve activity while resting vagal nerve activity was unchanged. AngII caused an increase in SAN beating interval variability in isolated atrial preparations and isolated SAN myocytes. Furthermore, isolated atrial preparations and SAN myocytes from AngII-infused mice had impaired responses to both isoproterenol and carbachol. Conclusion Reduced HRV in hypertension occurs in association with altered sympathovagal balance as well as intrinsic SAN dysfunction and reduced responsiveness of SAN myocytes to ANS agonists.

Long-term endurance training is associated with an increased risk of atrial arrhythmia in older adults (OA). We tested the hypothesis that Aerobically-Fit OA would have prolonged indices related to atrial arrhythmias (e.g. PR-intervals and P durations) compared to younger adults (YA) and Aerobically-Unfit OA. 10-minute stable supine electrocardiogram (ECG) recordings were collected at 1000 Hz in 15 YA (4F, 22 ± 2 years, 50.7 ± 8.5 ml/kg/min), 11 Aerobically-Unfit OA (6♀, 63 ± 7 years, 25.2 ± 2.3 ml/kg/min) and 10 Aerobically-Fit OA (4F, 64 ± 3 years, 45.5 ± 7.0 ml/kg/min) to assess ECG morphology and spectral indices of heart rate variability. In the pooled sample, age was a predictor of PR-interval (r = 0.75) and P wave duration (r = 0.80) (both, p 0.01). Regardless of age, aerobic fitness was positively associated with PR interval duration (r = 0.81; p 0.01). Aerobically-Fit OA had prolonged PR-intervals (187 ± 17 vs 161 ± 14 vs. 168 ± 20 ms) and P-wave durations (123 ± 9 vs. 97 ± 9 vs. 96 ± 9 ms) compared to YA and Aerobically-Unfit OA, respectively (all, p 0.05). In addition, Aerobically-Fit OA had greater normalized high-frequency (HF) power compared to Aerobically-Unfit OA (40.7 ± 4.5nu vs. 30.1 ± 14.2 ± nu; p = 0.03) suggestive of enhance parasympathetic tone. These data highlight that the combination of age-related electrical remodeling and enhanced vagal tone in OA with higher aerobic fitness may contribute to prolongation of atrial-related ECG indices. This is further supported by the correlation between HF power and PR-interval duration (r = 0.45; p = 0.02). These findings may help identify older individuals at risk for atrial arrhythmias who are otherwise free of cardiovascular disease.