Takashi Kusayama

Substantial interindividual variability exists in orthostatic sympathetic and blood pressure (BP) responses among patients with hypertension. We investigated whether resting skin sympathetic nerve activity (SKNA) spectral characteristics are associated with this variability and with exaggerated orthostatic pressor responses (EPR). In 108 patients with hypertension, BP and SKNA were recorded in the supine and active standing positions. SKNA amplitude (average SKNA [aSKNA]) and frequency-domain parameters (low-frequency [LF] and high-frequency [HF] components, LF/HF ratio) were analyzed. Patients were stratified into low-LF/HF and high-LF/HF groups based on the median supine SKNA-derived LF/HF ratio. EPR was defined as a systolic BP increase of ≥ 20 mmHg at 3 min of active standing. Active standing significantly increased aSKNA ( P < 0.001), whereas the overall SKNA-derived LF/HF ratio showed no significant change ( P = 0.081). Upon standing, the low-LF/HF group exhibited a significant increase in LF/HF ( P = 0.004), whereas the high-LF/HF group exhibited a decrease ( P < 0.001), with an attenuation of the between-group difference during standing ( P = 0.162). EPR occurred exclusively in the low-LF/HF group (13.0% vs. 0%, P = 0.013). In a receiver operating characteristic analysis, the supine LF/HF ratio discriminated EPR with an area under the curve of 0.863 (95% confidence interval, 0.775–0.950). Resting SKNA spectral characteristics may characterize interindividual variability in orthostatic sympathetic responses and be associated with EPR, offering a non-invasive approach for sympathetic phenotyping in hypertension

Pulmonary vein isolation (PVI) is an established treatment for atrial fibrillation (AF). While it is known to affect the autonomic nervous system, the relationship between left atrial (LA) remodeling and PVI-mediated neuromodulation remains unclear. We aimed to assess the neuromodulatory effects of PVI using skin sympathetic nerve activity (SKNA). SKNA was recorded one day before and 2–3 days after PVI in 28 paroxysmal AF (PAF) and 33 persistent AF (PerAF) groups. Baseline low frequency to high frequency (LF/HF) ratio was higher in the PAF group (1.23 [interquartile range {IQR}: 0.79–1.76] vs. 0.74 [IQR: 0.49–1.38], p = 0.017). After PVI, the PAF group demonstrated significant reductions in burst amplitude (1.46 [IQR: 1.04–2.84] vs. 1.09 [IQR: 0.78–2.17] μV, p = 0.015) and LF/HF ratio (0.91 [IQR: 0.73–1.52] vs. 0.71 [IQR: 0.48–1.21], p = 0.012), whereas the PerAF group exhibited no such changes. A weak positive correlation was observed between the percentage change in LF/HF ratio and LA volume index in the PAF group (r = 0.572, p = 0.002). PVI significantly decreased SKNA in PAF patients but not in PerAF. LA remodeling may hinder the effectiveness of PVI-mediated neuromodulation.

While autonomic dysregulation and repolarization abnormalities are observed in subarachnoid hemorrhage (SAH), their relationship remains unclear. We aimed to measure skin sympathetic nerve activity (SKNA), a novel method to estimate stellate ganglion nerve activity, and investigate its association with electrocardiogram (ECG) alterations after SAH. We recorded a total of 179 SKNA data from SAH patients at three distinct phases and compared them with 20 data from controls. Compared with control data, in the acute phase data (days 1–3 of SAH), T peak‐to‐end (Tp‐e) interval was significantly prolonged (81 [interquartile range {IQR}: 71–93] vs. 58 [IQR: 54–64] ms, p < 0.001), non‐burst amplitude of SKNA was significantly increased (2.4 [IQR: 1.3–4.1] vs. 0.7 [IQR: 0.5–1.7] μV, p < 0.001), and the ratio of low frequency to high frequency (HF) was significantly decreased (0.8 [IQR: 0.5–1.1] vs. 1.1 [IQR: 0.7–1.3], p = 0.028). Linear mixed model revealed a relationship between Tp‐e interval and SKNA. Although these abnormalities gradually normalized, delayed cerebral ischemia episodes were associated with increased HF oscillation. Transient sympathetic dysregulation contributes to repolarization impairment after SAH. SKNA may have the potential to monitor adverse outcomes.

This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney’s pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.

Background: An epicardial connection (EC) through the intercaval bundle (EC‐ICB) between the right pulmonary vein (RPV) and right atrium (RA) is one of the reasons for the need for carina ablation for PV isolation and may reduce the acute and chronic success of PV isolation. We evaluated the intra‐atrial activation sequence during RPV pacing after failure of ipsilateral RPV isolation and sought to identify specific conduction patterns in the presence of EC‐ICB. Methods and Results: This study included 223 consecutive patients who underwent initial catheter ablation of atrial fibrillation. If the RPV was not isolated using circumferential ablation or reconnected during the waiting period, an exit map was created during mid‐RPV carina pacing. If the earliest site on the exit map was the RA, the patient was classified into the EC‐ICB group. The exit map, intra‐atrial activation sequence, and RPV‐high RA time were evaluated. First‐pass isolation of the RPV was not achieved in 36 patients (16.1%), and 22 patients (9.9%) showed reconnection. Twelve and 28 patients were classified into the EC‐ICB and non‐EC‐ICB groups, respectively, after excluding those with multiple ablation lesion sets or incomplete mapping. The intra‐atrial activation sequence showed different patterns between the 2 groups. The RPV‐high RA time was significantly shorter in the EC‐ICB than in the non‐EC‐ICB group (69.2±15.2 versus 148.6±51.2 ms; P <0.001), and RPV‐high RA time<89.0 ms was highly predictive of the existence of an EC‐ICB (sensitivity, 91.7%; specificity, 89.3%). Conclusions: An EC‐ICB can be effectively detected by intra‐atrial sequencing during RPV pacing, and an RPV‐high RA time of <89.0 ms was highly predictive.

Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

NeuECG, the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity (SKNA), directly records sympathetic nerve activity over a long period of time. It can be used to measure sympathetic tone in healthy subjects and in subjects with non-cardiovascular diseases. The electrical activity that can be measured on the surface of the skin originates from the heart, the muscle or nerve structures. Because the frequency content of nerve activity falls in a higher frequency range than that of the ECG and myopotential, it is possible to use high-pass or band-pass filtering to specifically isolate the SKNA. neuECG is voltage calibrated and does not require invasive procedures to impale electrodes in nerves and thus has advantages over microneurography. Here, we present a protocol that takes <10 min to set up. The neuECG can be continuously recorded over a 24-h period or longer. We also describe methods to efficiently analyze neuECG from humans using commercially available hardware and software to facilitate adoption of this technology in clinical research.