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BackgroundReduced heart rate (HR) increase (HRI), recovery (HRR), and higher resting HR are associated with cardiovascular (CV) disease, but causal inferences have not been deduced. We investigated causal effects of HRI, HRR, and resting HR on CV risk, all-cause mortality (ACM), atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke (IS) using Mendelian Randomization.Methods11 variants for HRI, 11 for HRR, and two sets of 46 and 414 variants for resting HR were obtained from four genome-wide association studies (GWASs) on UK Biobank. We performed a lookup on GWASs for CV risk and ACM in UK Biobank (N = 375,367, 5.4% cases and N = 393,165, 4.4% cases, respectively). For CAD, AF, and IS, we used publicly available summary statistics. We used a random-effects inverse-variance weighted (IVW) method and sensitivity analyses to estimate causality.ResultsIVW showed a nominally significant effect of HRI on CV events (odds ratio [OR] = 1.0012, P = 4.11 × 10–2) and on CAD and AF. Regarding HRR, IVW was not significant for any outcome. The IVW method indicated statistically significant associations of resting HR with AF (OR = 0.9825, P = 9.8 × 10–6), supported by all sensitivity analyses, and a nominally significant association with IS (OR = 0.9926, P = 9.82 × 10–3).ConclusionOur findings suggest no strong evidence of an association between HRI and HRR and any outcome and confirm prior work reporting a highly significant effect of resting HR on AF. Future research is required to explore HRI and HRR associations further using more powerful predictors, when available.

Singing and chanting are ubiquitous across World cultures. It has been theorized that such practices are an adaptive advantage for humans because they facilitate bonding and cohesion between group members. Investigations into the effects of singing together have so far focused on the physiological effects, such as the synchronization of heart rate variability (HRV), of experienced choir singers. Here, we study whether HRV synchronizes for pairs of non-experts in different vocalizing conditions. Using time-frequency coherence (TFC) analysis, we find that HRV becomes more coupled when people make long (> 10 s) sounds synchronously compared to short sounds (< 1 s) and baseline measurements (p < 0.01). Furthermore, we find that, although most of the effect can be attributed to respiratory sinus arrhythmia, some HRV synchronization persists when the effect of respiration is removed: long notes show higher partial TFC than baseline and breathing (p < 0.05). In addition, we observe that, for most dyads, the frequency of the vocalization onsets matches that of the peaks in the TFC spectra, even though these frequencies are above the typical range of 0.04–0.4 Hz. A clear correspondence between high HRV coupling and the subjective experience of “togetherness" was not found. These results suggest that since autonomic physiological entrainment is observed for non-expert singing, it may be exploited as part of interventions in music therapy or social prescription programs for the general population.

BackgroundRecent clinical, experimental and modeling studies link oscillations of ventricular repolarization in the low frequency (LF) (approx. 0.1 Hz) to arrhythmogenesis. Sympathetic provocation has been shown to enhance both LF oscillations of action potential duration (APD) and beat-to-beat variability (BVR) in humans. We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked.Methods and ResultsTwelve patients with normal ventricles were studied during routine electrophysiological procedures. Activation-recovery intervals (ARI) as a conventional surrogate for APD were recorded from 10 left and 10 right ventricular endocardial sites before and after acute beta-adrenergic adrenergic blockade. Cycle length was maintained constant with right ventricular pacing. Oscillatory behavior of ARI was quantified by spectral analysis and BVR as the short-term variability. Beta-adrenergic blockade reduced LF ARI oscillations (8.6 ± 4.5 ms2 vs. 5.5 ± 3.5 ms2, p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI (rs = 0.62, p = 0.037) such that when initial values are high the effect is greater. A similar relationship was also seen in the beat-to beat variability of ARI (rs = 0.74, p = 0.008). There was a significant correlation between the beta-adrenergic blockade induced reduction in LF power of ARI and the witnessed reduction of beat-to-beat variability of ARI (rs = 0.74, p = 0.01). These clinical results accord with recent computational modeling studies which provide mechanistic insight into the interactions of LF oscillations and beat-to-beat variability of APD at the cellular level.ConclusionBeta-adrenergic blockade reduces LF oscillatory behavior of APD (ARI) in humans in vivo. Our results support the importance of LF oscillations in modulating the response of BVR to beta-adrenergic blockers, suggesting that LF oscillations may play role in modulating beta-adrenergic mechanisms underlying BVR.

BackgroundEmotions can affect cardiac activity, but their impact on ventricular repolarization variability, an important parameter providing information about cardiac risk and autonomic nervous system activity, is unknown. The beat-to-beat variability of the QT interval (QTV) from the body surface ECG is a non-invasive marker of repolarization variability, which can be decomposed into QTV related to RR variability (QTVrRRV) and QTV unrelated to RRV (QTVuRRV), with the latter thought to be a marker of intrinsic repolarization variability.AimTo determine the effect of emotional valence (pleasant and unpleasant) on repolarization variability in healthy volunteers by means of QTV analysis.Methods75 individuals (24.5 ± 3.2 years, 36 females) without a history of cardiovascular disease listened to music-excerpts that were either felt as pleasant (n = 6) or unpleasant (n = 6). Excerpts lasted about 90 s and were presented in a random order along with silent intervals (n = 6). QTV and RRV were derived from the ECG and the time-frequency spectrum of RRV, QTV, QTVuRRV and QTVrRRV as well as time-frequency coherence between QTV and RRV were estimated. Analysis was performed in low-frequency (LF), high frequency (HF) and total spectral bands.ResultsThe heart rate-corrected QTV showed a small but significant increase from silence (median 347/interquartile range 31 ms) to listening to music felt as unpleasant (351/30 ms) and pleasant (355/32 ms). The dynamic response of QTV to emotional valence showed a transient phase lasting about 20 s after the onset of each musical excerpt. QTV and RRV were highly correlated in both HF and LF (mean coherence ranging 0.76–0.85). QTV and QTVrRRV decreased during listening to music felt as pleasant and unpleasant with respect to silence and further decreased during listening to music felt as pleasant. QTVuRRV was small and not affected by emotional valence.ConclusionEmotional valence, as evoked by music, has a small but significant effect on QTV and QTVrRRV, but not on QTVuRRV. This suggests that the interaction between emotional valence and ventricular repolarization variability is mediated by cycle length dynamics and not due to intrinsic repolarization variability.

Novel methods for assessing baroreflex sensitivity (BRS) using only pulse photoplethysmography (PPG) signals are presented. Proposed methods were evaluated with a data set containing electrocardiogram (ECG), blood pressure (BP), and PPG signals from 17 healthy subjects during a tilt table test. The methods are based on a surrogate of α index, which is defined as the power ratio of RR interval variability (RRV) and that of systolic arterial pressure series variability (SAPV). The proposed α index surrogates use pulse-to-pulse interval series variability (PPV) as a surrogate of RRV, and different morphological features of the PPG pulse which have been hypothesized to be related to BP, as series surrogates of SAPV. A time-frequency technique was used to assess BRS, taking into account the non-stationarity of the protocol. This technique identifies two time-varying frequency bands where RRV and SAPV (or their surrogates) are expected to be coupled: the low frequency (LF, inside 0.04–0.15 Hz range), and the high frequency (HF, inside 0.15–0.4 Hz range) bands. Furthermore, time-frequency coherence is used to identify the time intervals when the RRV and SAPV (or their surrogates) are coupled. Conventional α index based on RRV and SAPV was used as Gold Standard. Spearman correlation coefficients between conventional α index and its PPG-based surrogates were computed and the paired Wilcoxon statistical test was applied in order to assess whether the indices can find significant differences (p < 0.05) between different stages of the protocol. The highest correlations with the conventional α index were obtained by the α-index-surrogate based on PPV and pulse up-slope (PUS), with 0.74 for LF band, and 0.81 for HF band. Furthermore, this index found significant differences between rest stages and tilt stage in both LF and HF bands according to the paired Wilcoxon test, as the conventional α index also did. These results suggest that BRS changes induced by the tilt test can be assessed with high correlation by only a PPG signal using PPV as RRV surrogate, and PPG morphological features as SAPV surrogates, being PUS the most convenient SAPV surrogate among the studied ones.

Background: The temporal pattern of ventricular repolarization is of critical importance in arrhythmogenesis. Enhanced beat-to-beat variability (BBV) of ventricular action potential duration (APD) is pro-arrhythmic and is increased during sympathetic provocation. Since sympathetic nerve activity characteristically exhibits burst patterning in the low frequency range, we hypothesized that physiologically enhanced sympathetic activity may not only increase BBV of left ventricular APD but also impose a low frequency oscillation which further increases repolarization instability in humans.Methods and Results: Heart failure patients with cardiac resynchronization therapy defibrillator devices (n = 11) had activation recovery intervals (ARI, surrogate for APD) recorded from left ventricular epicardial electrodes alongside simultaneous non-invasive blood pressure and respiratory recordings. Fixed cycle length was achieved by right ventricular pacing. Recordings took place during resting conditions and following an autonomic stimulus (Valsalva). The variability of ARI and the normalized variability of ARI showed significant increases post Valsalva when compared to control (p = 0.019 and p = 0.032, respectively). The oscillatory behavior was quantified by spectral analysis. Significant increases in low frequency (LF) power (p = 0.002) and normalized LF power (p = 0.019) of ARI were seen following Valsalva. The Valsalva did not induce changes in conduction variability nor the LF oscillatory behavior of conduction. However, increases in the LF power of ARI were accompanied by increases in the LF power of systolic blood pressure (SBP) and the rate of systolic pressure increase (dP/dtmax). Positive correlations were found between LF-SBP and LF-dP/dtmax (rs = 0.933, p < 0.001), LF-ARI and LF-SBP (rs = 0.681, p = 0.001) and between LF-ARI and LF-dP/dtmax (rs = 0.623, p = 0.004). There was a strong positive correlation between the variability of ARI and LF power of ARI (rs = 0.679, p < 0.001).Conclusions: In heart failure patients, physiological sympathetic provocation induced low frequency oscillation (~0.1 Hz) of left ventricular APD with a strong positive correlation between the LF power of APD and the BBV of APD. These findings may be of importance in mechanisms underlying stability/instability of repolarization and arrhythmogenesis in humans.

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.