Sympathetic toggled paroxysmal atrial fibrillation and recurrent premature atrial contractions in ambulatory patients.

BACKGROUND: Autonomic nerve activity is important in the mechanisms of paroxysmal atrial fibrillation (PAF). OBJECTIVE: To test the hypothesis that a single burst of skin sympathetic nerve activity (SKNA) can toggle on and off PAF or premature atrial contraction (PAC) clusters. METHODS: We performed neuECG recording over 7 days in patients with PAF. RESULTS: In Study 1, we found 8 patients (7 men, 1 woman, 62±8 years) had 124 episodes of PAF. An SKNA burst toggled both on and off PAF in 8 (6.5%) episodes (Type 1), toggled on but not off in 12 (9.7%) episodes (Type 2), and toggled on a PAC cluster, followed by PAF in 4 (3.2%) episodes (Type 3). The duration of these PAF episodes was < 10 min. The remaining 100 (80.6%) episodes were associated with active SKNA bursts throughout PAF (Type 4) and lasted longer than Type 1 (p=0.0185) and Type 2 (p=0.0027) PAF. There were 47 PAC clusters. Among them, 24 (51.1%) were toggled on and off, and 23 (48.9%) were toggled on but not off by an SKNA burst. In Study 2, we found 17 patients (9 men, 8 women, 58±12 years) with < 10 min PAF (4, 8, 0, and 31 of Types 1-4, respectively). There were significant circadian variations of all types of PAF. CONCLUSIONS: A single SKNA burst can toggle short-duration PAF and PAC cluster episodes on and off. The absence of continued SKNA after the onset might have affected the maintenance of these arrhythmias.

Deep learning evaluation of echocardiograms to identify occult atrial fibrillation.

Atrial fibrillation (AF) often escapes detection, given its frequent paroxysmal and asymptomatic presentation. Deep learning of transthoracic echocardiograms (TTEs), which have structural information, could help identify occult AF. We created a two-stage deep learning algorithm using a video-based convolutional neural network model that (1) distinguished whether TTEs were in sinus rhythm or AF and then (2) predicted which of the TTEs in sinus rhythm were in patients who had experienced AF within 90 days. Our model, trained on 111,319 TTE videos, distinguished TTEs in AF from those in sinus rhythm with high accuracy in a held-out test cohort (AUC 0.96 (0.95-0.96), AUPRC 0.91 (0.90-0.92)). Among TTEs in sinus rhythm, the model predicted the presence of concurrent paroxysmal AF (AUC 0.74 (0.71-0.77), AUPRC 0.19 (0.16-0.23)). Model discrimination remained similar in an external cohort of 10,203 TTEs (AUC of 0.69 (0.67-0.70), AUPRC 0.34 (0.31-0.36)). Performance held across patients who were women (AUC 0.76 (0.72-0.81)), older than 65 years (0.73 (0.69-0.76)), or had a CHA2DS2VASc ≥2 (0.73 (0.79-0.77)). The model performed better than using clinical risk factors (AUC 0.64 (0.62-0.67)), TTE measurements (0.64 (0.62-0.67)), left atrial size (0.63 (0.62-0.64)), or CHA2DS2VASc (0.61 (0.60-0.62)). An ensemble model in a cohort subset combining the TTE model with an electrocardiogram (ECGs) deep learning model performed better than using the ECG model alone (AUC 0.81 vs. 0.79, p = 0.01). Deep learning using TTEs can predict patients with active or occult AF and could be used for opportunistic AF screening that could lead to earlier treatment.

Postural orthostatic tachycardia syndrome after COVID-19 vaccination.

BACKGROUND: There is an association between coronavirus disease 2019 (COVID-19) mRNA vaccination and the incidence or exacerbation of postural orthostatic tachycardia syndrome (POTS). OBJECTIVE: The purpose of this study was to characterize patients reporting new or exacerbated POTS after receiving the mRNA COVID-19 vaccine. METHODS: We prospectively collected data from sequential patients in a POTS clinic between July 2021 and June 2022 reporting new or exacerbated POTS symptoms after COVID-19 vaccination. Heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) were compared against those of 24 healthy controls. RESULTS: Ten patients (6 women and 4 men; age 41.5 ± 7.9 years) met inclusion criteria. Four patients had standing norepinephrine levels > 600 pg/mL. All patients had conditions that could raise POTS risk, including previous COVID-19 infection (N = 4), hypermobile Ehlers-Danlos syndrome (N = 6), mast cell activation syndrome (N = 6), and autoimmune (N = 7), cardiac (N = 7), neurological (N = 6), or gastrointestinal conditions (N = 4). HRV analysis indicated a lower ambulatory root mean square of successive differences (46.19 ±24 ms; P = .042) vs control (72.49 ± 40.8 ms). SKNA showed a reduced mean amplitude (0.97 ± 0.052 µV; P = .011) vs control (1.2 ± 0.31 µV) and burst amplitude (1.67 ± 0.16 µV; P = .018) vs control (4. 3 ± 4.3 µV). After 417.2 ± 131.4 days of follow-up, all patients reported improvement with the usual POTS care, although 2 with COVID-19 reinfection and 1 with small fiber neuropathy did have relapses of POTS symptoms. CONCLUSION: All patients with postvaccination POTS had pre-existing conditions. There was no evidence of myocardial injuries or echocardiographic abnormalities. The decreased HRV suggests a sympathetic dominant state. Although all patients improved with guideline-directed care, there is a risk of relapse.

Blood pressure variability supersedes heart rate variability as a real-world measure of dementia risk.

Blood pressure variability (BPV) and heart rate variability (HRV) have been associated with Alzheimer's Disease and Related Dementias (ADRD) in rigorously controlled studies. However, the extent to which BPV and HRV may offer predictive information in real-world, routine clinical care is unclear. In a retrospective cohort study of 48,204 adults (age 54.9 ± 17.5 years, 60% female) receiving continuous care at a single center, we derived BPV and HRV from routinely collected clinical data. We use multivariable Cox models to evaluate the association of BPV and HRV, separately and in combination, with incident ADRD. Over a median 3 [2.4, 3.0] years, there were 443 cases of new-onset ADRD. We found that clinically derived measures of BPV, but not HRV, were consistently associated with incident ADRD. In combined analyses, only patients in both the highest quartile of BPV and lowest quartile of HRV had increased ADRD risk (HR 2.34, 95% CI 1.44-3.81). These results indicate that clinically derived BPV, rather than HRV, offers a consistent and readily available metric for ADRD risk assessment in a real-world patient care setting. Thus, implementation of BPV as a widely accessible tool could allow clinical providers to efficiently identify patients most likely to benefit from comprehensive ADRD screening.

Potential consequences of cardioneuroablation for vasovagal syncope: A call for appropriately designed, sham-controlled clinical trials.

Cardioneuroablation (CNA) is being increasingly used to treat patients with vasovagal syncope (VVS). Bradycardia, in the cardioinhibitory subtype of VVS, results from transient parasympathetic overactivity leading to sinus bradycardia and/or atrioventricular block. By mitigating parasympathetic overactivity, CNA has been shown to improve VVS symptoms in clinical studies with relatively small sample sizes and short follow-up periods (<5 years) at selected centers. However, CNA may potentially tip the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity. A higher heart rate is associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases. Chronic sympathovagal imbalance may also affect the pathophysiology of spectra of cardiovascular disorders including atrial and ventricular arrhythmias. This review addresses potential long-term pathophysiological consequences of CNA for VVS.

Autonomic Modulation of Atrial Fibrillation.

The autonomic nervous system plays a vital role in cardiac arrhythmias, including atrial fibrillation (AF). Therefore, reducing the sympathetic tone via neuromodulation methods may be helpful in AF control. Myocardial ischemia is associated with increased sympathetic tone and incidence of AF. It is an excellent disease model to understand the neural mechanisms of AF and the effects of neuromodulation. This review summarizes the relationship between autonomic nervous system and AF and reviews methods and mechanisms of neuromodulation. This review proposes that noninvasive or minimally invasive neuromodulation methods will be most useful in the future management of AF.

Skin sympathetic nerve activity and nocturnal blood pressure nondipping in patients with postural orthostatic tachycardia syndrome.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS. METHOD: We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ±â€Š11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring. RESULTS: Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group ( P  = 0.016, P  = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ±â€Š0.103 vs. 0.095 ±â€Š0.099 µV, P  = 0.021, and Δmean BP 15.0 ±â€Š5.2 vs. 4.9 ±â€Š4.2 mmHg, P  < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P  = 0.013) and the differences between standing and supine NE levels ( r  = 0.411, P  = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ±â€Š0.081 and 0.936 ±â€Š0.080 µV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ±â€Š0.087 µV, P  < 0.001 for both) in the same patient. CONCLUSION: POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.

Sympathetic toggled sinus rate acceleration as a mechanism of sustained sinus tachycardia in chronic orthostatic intolerance syndrome.

BACKGROUND: The role of sympathetic nerve activity to maintain sinus rate acceleration remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that sustained (>30 seconds) sinus rate acceleration can be associated with either a sympathetic driven or a sympathetic toggled mechanism. METHODS: We used a patch monitor to record skin sympathetic nerve activity (SKNA) and electrocardiogram over 24 hours. Study 1 included chronic orthostatic intolerance (OI) (n = 18), atrial fibrillation (n = 7), and asymptomatic normal control (n = 19) groups. Study 2 included 17 participants with chronic OI not treated with ivabradine, pyridostigmine, or ß-blockers. RESULTS: While a majority of sinus rate acceleration was driven by persistent SKNA in study 1, some episodes were toggled on and off by SKNA bursts without persistent SKNA elevation. The sympathetic toggled sinus rate acceleration episodes were found in 7 of 18 participants with chronic OI (39%), 2 of 7 participants with atrial fibrillation (29%), and 6 of 19 normal control participants (32%) (P = .847) and were faster and longer in the chronic OI group than in other groups. In study 2, there were a total of 11 episodes of sinus rate acceleration that persisted for >200 seconds. Among these episodes, 6 (35%) were toggled on and off by SKNA bursts. CONCLUSION: Sustained sinus rate acceleration (may be toggled on or off) is associated with SKNA bursts in participants with chronic OI, participants with atrial fibrillation, and normal controls. Patients with OI had more frequent and longer episodes than did other groups.

Testosterone does not shorten action potential duration in Langendorff-perfused rabbit ventricles.

BACKGROUND: Women have longer baseline QT intervals than men. Because previous studies showed that testosterone and 5α-dihydrotestosterone shorten the ventricular action potential duration (APD) in animal models, differential testosterone concentrations may account for the sex differences in QT interval. OBJECTIVE: The purpose of this study was to test the hypothesis that testosterone shortens the APD in Langendorff-perfused rabbit ventricles. METHODS: We performed optical mapping studies in hearts with or without testosterone administration. Acute studies included 26 hearts using 2 different protocols, including 17 without and 9 with atrioventricular (AV) block. For chronic studies, we implanted testosterone pellets subcutaneously in 7 female rabbits for 2-3 weeks before optical mapping studies during complete AV block. Six rabbits without pellet implantation served as controls. RESULTS: The hearts in the acute studies were paced with a pacing cycle length (PCL) of 200-300 ms and mapped at baseline and after administration of 1 nM, 10 nM, 100 nM, and 3 µM of testosterone. There was no shortening of APD80 at any PCL. Instead, a lengthening of APD80 was noted at higher concentrations. There were no sex differences in testosterone responses. In chronic studies, heart rates were 136 ± 5 bpm before and 148 ± 9 bpm after (P = .10) while QTc intervals were 314 ± 9 ms before and 317 ± 99 ms after (P = .69) testosterone pellet implantation, respectively. Overall, ventricular APD80 in the pellet group was longer than in the control group at 300- to 700-ms PCL. CONCLUSION: Testosterone does not shorten ventricular repolarization in rabbit hearts.

Skin sympathetic nerve activity and ventricular arrhythmias in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) is major cause of ventricular arrhythmias (VAs) and sudden death. neuECG is a noninvasive method to simultaneously record skin sympathetic nerve activity (SKNA) and electrocardiogram. OBJECTIVE: The purpose of this study was to test the hypotheses that (1) ACS increases average SKNA (aSKNA), (2) the magnitude of aSKNA elevation is associated with VAs during ACS, and (3) there is a gender difference in aSKNA between patients without and with ACS. METHODS: We prospectively studied 128 ACS and 165 control participants. The neuECG was recorded with electrodes at Lead I configuration at baseline, during mental math stress, and during recovery (5 minutes for each phase). All recordings were done in the morning. RESULTS: In the control group, women have higher aSKNA than do men at baseline (0.82 ± 0.25 µV vs 0.73 ± 0.20 µV; P = .009) but not during mental stress (1.21 ± 0.36 µV vs 1.16 ± 0.36 µV; P = .394), suggesting women had lower sympathetic reserve. In comparison, ACS is associated with equally elevated aSKNA in women vs men at baseline (1.14 ± 0.33 µV vs 1.04 ± 0.35 µV; P = .531), during mental stress (1.46 ± 0.32 µV vs 1.33 ± 0.37 µV; P = .113), and during recovery (1.30 ± 0.33 µV vs 1.11 ± 0.30 µV; P = .075). After adjusting for age and gender, the adjusted odds ratio for VAs including ventricular tachycardia and ventricular fibrillation is 1.23 (95% confidence interval 1.05-1.44) for each 0.1 µV aSKNA elevation. aSKNA is positively correlated with plasma norepinephrine level. CONCLUSION: ACS is associated with elevated aSKNA, and the magnitude of aSKNA elevation is associated with the occurrence of VAs. Women have higher aSKNA and lower SKNA reserve than do men among controls but not among patients with ACS.

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation. However, more recent evidence indicates that PVCs also can arise from the T wave itself. In the latter case, the PVC initiating reentry is not a separate event from the T wave but rather is causally generated from the repolarization gradient that manifests as the T wave. We call the former an "R-to-T" mechanism and the latter an "R-from-T" mechanism, which are initiation mechanisms distinct from each other. Both are important components of the R-on-T phenomenon and need to be taken into account when designing antiarrhythmic strategies. Strategies targeting suppression of triggers alone or vulnerable substrate alone may be appropriate in some instances but not in others. Preventing R-from-T arrhythmias requires suppressing the underlying dynamic tissue instabilities responsible for producing both triggers and substrate vulnerability simultaneously. The same principles are likely to apply to supraventricular arrhythmias.

Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop.

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

Skin sympathetic nerve activity in patients with chronic orthostatic intolerance.

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by the development of tachycardia and other symptoms when assuming an upright body position. OBJECTIVE: The purpose of this study was to test the hypothesis that skin sympathetic nerve activity (SKNA) bursts are specific symptomatic biomarkers in patients with chronic OI. METHODS: We used an electrocardiogram monitor with a built-in triaxial accelerometer to simultaneously record SKNA and posture in ambulatory participants. Study 1 compared chronic OI (14 women and 2 men; mean age 35 ± 10 years) with reference control participants (14 women; mean age 31 ± 6 years). Study 2 included 17 participants with chronic OI (15 women and 2 men; mean age 39 ± 12 years) not yet treated with ivabradine, pyridostigmine, or ß-blockers. RESULTS: In study 1, there were 124 episodes (8 ± 4 per participant) of postural changes, with 11 episodes (8.9%) associated with symptoms. In comparison, 0 of 104 postural changes (7 ± 3 per participant) in controls were symptomatic (P = .0011). In participants with chronic OI, the SKNA bursts associated with symptoms had higher burst frequencies, longer burst durations, and larger mean burst areas than did bursts during asymptomatic periods. However, SKNA bursts and tachycardia were asymptomatic in controls. We analyzed 110 symptomatic episodes in study 2 (6 ± 5 per participant). Among them, 98 (89.1%) followed at least 1 SKNA burst. In comparison, only 41 (37.3%) had heart rate exceed 100 beats/min 1 minute before symptom onset (P < .0001). CONCLUSION: SKNA bursts are a highly specific, albeit insensitive, symptomatic biomarker for chronic OI.