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.

Right predominant electrical remodeling in a pure model of pulmonary hypertension promotes reentrant arrhythmias.

BACKGROUND: Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling. OBJECTIVE: The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities. METHODS: Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed in vivo, optical action potential (AP) mapping ex vivo, and molecular analyses in vitro. RESULTS: Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation. CONCLUSION: In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.

Heart Watch Study: protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Personal digital devices that provide health information, such as the Apple Watch, have developed an increasing array of cardiopulmonary tracking features which have received regulatory clearance and are directly marketed to consumers. Despite their widespread and increasing use, data about the impact of personal digital device use on patient-reported outcomes and healthcare utilisation are sparse. Among a population of patients with atrial fibrillation and/or atrial flutter undergoing cardioversion, our primary aim is to determine the impact of the heart rate measurement, irregular rhythm notification, and ECG features of the Apple Watch on quality of life and healthcare utilisation. METHODS AND ANALYSIS: We are conducting a prospective, open-label multicentre pragmatic randomised clinical trial, leveraging a unique patient-centred health data sharing platform for enrolment and follow-up. A total of 150 patients undergoing cardioversion for atrial fibrillation or atrial flutter will be randomised 1:1 to receive the Apple Watch Series 6 or Withings Move at the time of cardioversion. The primary outcome is the difference in the Atrial Fibrillation Effect on QualiTy-of-life global score at 6 months postcardioversion. Secondary outcomes include inpatient and outpatient healthcare utilisation. Additional secondary outcomes include a comparison of the Apple Watch ECG and pulse oximeter features with gold-standard data obtained in routine clinical care settings. ETHICS AND DISSEMINATION: The Institutional Review Boards at Yale University, Mayo Clinic, and Duke University Health System have approved the trial protocol. This trial will provide important data to policymakers, clinicians and patients about the impact of the heart rate, irregular rhythm notification, and ECG features of widely used personal digital devices on patient quality of life and healthcare utilisation. Findings will be disseminated to study participants, at professional society meetings and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04468321.

Catheter-related complications and mortality of atrial fibrillation ablation following introduction of contact force-sensing technology.

OBJECTIVES: Contact force-sensing catheters allow real-time catheter-tissue contact force monitoring during atrial fibrillation. These catheters were rapidly adopted into clinical practice following market introduction in 2014, but concerns have been raised regarding collateral damage such as esophageal injury. We sought to examine whether the introduction of force-sensing catheters was associated with a change in short-term and intermediate-term acute care use, complications and mortality following atrial fibrillation ablation. DESIGN: Retrospective cohort analysis. We used inverse probability treatment weight matching to account for the differences in baseline characteristics between groups. SETTING: We examined patients included in the OptumLabs Data Warehouse who underwent ablation for atrial fibrillation before (2011-2013) and after (2015-2017) the market introduction of contact force-sensing catheters. MAIN OUTCOME MEASURES: We examined 30-day and 90-day rates of all-cause acute care use, including hospitalizations and emergency department visits, as well as death and hospitalization for catheter-related complications, including atrioesophageal fistula, pericarditis, cardiac tamponade/perforation and stroke/transient ischemic attack. RESULTS: Our sample included 3470 and 5772 patients who underwent atrial fibrillation (AF) ablation before and after market introduction of contact force-sensing catheters, respectively. Complication rates were low and did not differ between the two periods (p>0.10 for each outcome). The 30-day and 90-day mortality was 0.1% and 0.3%, respectively after market introduction and unchanged from prior to 2014. The 90-day rates of all-cause acute care use decreased, from 27.0% in 2011-2013 to 23.9% in 2015-2017 (p<0.001). CONCLUSIONS: AF ablation-related catheter complications and mortality are low and there has been no significant change following the introduction of force-sensing catheters.

Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. OBJECTIVE: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. METHODS: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu-vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). RESULTS: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. CONCLUSIONS: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Recurrence quantification analysis of complex-fractionated electrograms differentiates active and passive sites during atrial fibrillation.

OBJECTIVES: To differentiate electrograms representing sites of active atrial fibrillation (AF) drivers from passive ones. BACKGROUND: Ablation of complex-fractionated atrial electrograms (CFAEs) is controversial due to difficulty in distinguishing CFAEs representing sites of active AF drivers from passive mechanisms. We hypothesized that active CFAE sites exhibit repetitive wavefront directionality, thereby inscribing an electrogram conformation (Egm-C) that is more recurrent compared with passive CFAE sites; and that can be differentiated from passive CFAEs using nonlinear recurrence quantification analysis (RQA). METHODS: We developed multiple computer models of active CFAE mechanisms (ie, rotors) and passive CFAE mechanisms (ie, wavebreak, slow conduction, and double potentials). CFAE signals were converted into discrete time-series representing Egm-C. The RQA algorithm was used to compare signals derived from active CFAE sites to those from passive CFAEs sites. The RQA algorithm was then applied to human CFAE signals collected during AF ablation (n = 17 patients). RESULTS: RQA was performed in silico on simulated bipolar CFAEs within active (n = 45) and passive (n = 60) areas. Recurrence of Egm-C was significantly higher in active compared with passive CFAE sites (31.8% ± 19.6% vs 0.3% ± 0.5%, respectively, P < .0001) despite no difference in mean cycle length (CL). Similarly, for human AF (n = 39 signals), Egm-C recurrence was higher in active vs passive CFAE areas despite similar CLs (%recurrence 13.6% ± 15.5% vs 0.1% ± 0.3%, P < .002; mean CL 102.5 ± 14.3 vs 106.6 ± 14.4, P = NS). CONCLUSION: Active CFAEs critical to AF maintenance exhibit higher Egm-C recurrence and can be differentiated from passive bystander CFAE sites using RQA.

Outcomes and costs of remote patient monitoring among patients with implanted cardiac defibrillators: An economic model based on the PREDICT RM database.

BACKGROUND: Remote monitoring of implantable cardioverter-defibrillators has been associated with reduced rates of all-cause rehospitalizations and mortality among device recipients, but long-term economic benefits have not been studied. METHODS AND RESULTS: An economic model was developed using the PREDICT RM database comparing outcomes with and without remote monitoring. The database included patients ages 65 to 89 who received a Boston Scientific device from 2006 to 2010. Parametric survival equations were derived for rehospitalization and mortality to predict outcomes over a maximum time horizon of 25 years. The analysis assessed rehospitalization, mortality, and the cost-effectiveness (expressed as the incremental cost per quality-adjusted life year) of remote monitoring versus no remote monitoring. Remote monitoring was associated with reduced mortality; average life expectancy and average quality-adjusted life years increased by 0.77 years and 0.64, respectively (6.85 life years and 5.65 quality-adjusted life years). When expressed per patient-year, remote monitoring patients had fewer subsequent rehospitalizations (by 0.08 per patient-year) and lower hospitalization costs (by $554 per patient year). With longer life expectancies, remote monitoring patients experienced an average of 0.64 additional subsequent rehospitalizations with increased average lifetime hospitalization costs of $2784. Total costs of outpatient and physician claims were higher with remote monitoring ($47 515 vs $42 792), but average per patient-year costs were lower ($6232 vs $6244). The base-case incremental cost-effectiveness ratio was $10 752 per quality-adjusted life year, making remote monitoring high-value care. CONCLUSION: Remote monitoring is a cost-effective approach for the lifetime management of patients with implantable cardioverter-defibrillators.

Physiologic and histopathologic effects of targeted lung denervation in an animal model.

Parasympathetic efferent innervation of the lung is the primary source of lung acetylcholine. Inhaled long-acting anticholinergics improve lung function and symptoms in patients with chronic obstructive pulmonary disease. Targeted lung denervation (TLD), a bronchoscopic procedure intended to disrupt pulmonary parasympathetic inputs, is an experimental treatment for chronic obstructive pulmonary disease. The physiologic and histologic effects of TLD have not previously been assessed. Eleven sheep and two dogs underwent circumferential ablation of the main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., Minneapolis, MN). Changes in pulmonary air flow resistance were monitored before and following TLD. Four animals were assessed for the presence or abolishment of the sensory axon-mediated Hering-Breuer reflex before and following TLD. Six sheep were histologically evaluated 30 days post-TLD for the extent of lung denervation (axonal staining) and effect on peribronchial structures near the treatment site. No adverse clinical effects were seen in any treated animals. TLD produced a ~30% reduction in pulmonary resistance and abolished the sensory-mediated Hering-Breuer reflex. Axonal staining was consistently decreased 60% at 30 days after TLD. All treated airways exhibited 100% epithelial integrity. Damage to other peribronchial structures was minimal. Tissue 1 cm proximal and distal to the treatment was normal, and the esophagus and periesophageal vagus nerve branches were unaffected. TLD treatment effectively denervates the lung while protecting the bronchial epithelium and minimizing effects on peribronchial structures. NEW & NOTEWORTHY The feasibility of targeted lung denervation, a new minimally invasive therapy for obstructive lung disease, has been demonstrated in humans with preliminary clinical studies demonstrating improvement in symptoms, pulmonary function, and exercise capacity in patients with chronic obstructive pulmonary disease. This preclinical animal study demonstrates the ability of targeted lung denervation to disrupt vagal inputs to the lung and details its physiologic and histopathologic effects.

Luminal esophageal temperature monitoring to reduce esophageal thermal injury during catheter ablation for atrial fibrillation: A review.

Over the past decade, catheter ablation for atrial fibrillation has emerged as an important rhythm control strategy. One of the most dreaded complications of this procedure is atrio-esophageal (AE) fistula formation, which is relatively rare but usually fatal. Esophageal tissue injury during ablation appears to be a precursor to the formation of AE fistulae. Luminal esophageal temperature (LET) monitoring is one of the most commonly utilized strategies to mitigate this risk, despite little evidence that it reduces esophageal injury. The incidence of AE fistulae appears to be on the rise, despite the widespread use of LET monitoring. This may be due to the advent of improved large lesion technology including force-sensing catheters and the use of high power, although AE fistulae have also been observed with the use of low power along the left atrial posterior wall. Currently available discrete sensors probes, whether single or multiple, do not appear to significantly reduce injury rates. The purpose of this manuscript is to systematically review the incidence of esophageal thermal injury with and without LET monitoring and review the factors that may be associated with increased risk of injury.

New skip parameter to facilitate recurrence quantification of signals comprised of multiple components.

Recurrence analyses are typically performed on discretized time series after applying proper embeddings, delays, and thresholds. In our study of atrial electrograms, we found limitations to this approach when sequential bipolar complexes were defined as the timings of the first two zero crosses following the initiation of each event. The reason for this is that each bipolar component consists of two points in odd-even pairings. Since recurrence analysis starts vectors on each sequential point, incorrect even-odd pairings occur for every other vector. To overcome this limitation, a new parameter SKIP is introduced such that recurrence vectors can skip 1 (or 2) points for signals with defined multiple components. To demonstrate the utility of parameter SKIP, we used the Courtemanche model to simulate the electrical activity in the human atrium on a square, two-dimensional plane with 800 × 800 nodes. Over this plane, a grid of 39 × 39 virtual unipoles was created. Neighboring unipoles formed 39 × 38 bipolar pairs, which were recorded as 1482 continuous and synchronous time series. At each unipolar site, the actual wavefront direction was determined by comparing the relative activation timings of the local intracellular potentials. Parameters were set such that the "tissue" exhibited both spiral waves (organized activity) and wave breakups (chaotic activity). For each bipolar complex in the continuous electrogram, discretized electrogram conformation was defined as the timing delays from the start of the complex to the first two zero-crosses. Long sequences of paired zero-cross timings were subjected to recurrence analysis using SKIP values of 0 (no skipping) and 1 (single skipping). Recurrence variables were computed and correlated with the absolute wavefront directions. The results showed that the introduction of the skipping window improved the correlations of some recurrence variables with absolute wavefront directions. This is critically important because such variables may be better markers for wavefront directions in human recordings when the absolute wavefront directions cannot be calculated directly.

Posterior Wall Isolation in Atrial Fibrillation Ablation.

Catheter ablation is widely utilized for the management of atrial fibrillation (AF), particularly in patients who are refractory to medical therapy. The left atrium appears to play a dominant role in the condition of most patients with AF and, in particular, the posterior wall and pulmonary veins frequently harbor sources of fibrillation. Currently, the role of posterior wall isolation during catheter ablation of AF is controversial. In this review, we will examine the mechanistic role of the posterior left atrium, discuss the technical challenges of ablating in the posterior wall and the evolution of strategies to achieve isolation with catheter approaches, and review the relevant literature to date.

Arrhythmias after left ventricular assist device implantation: Incidence and management.

The use of mechanical circulatory support has become an increasingly common practice in patients with heart failure, whether used as bridge to transplantation or as destination therapy. The last couple of decades has seen a drastic change in the functioning of the left ventricular assist devices (LVAD), changing from the first generation devices running on pulsatile flow to the current continuous flow devices. Atrial and ventricular arrhythmias are common among heart failure patients, and though the systematic circulation is well supported in patients on mechanical circulatory support, these arrhythmias can still be the cause of detrimental symptoms and lead to potentially fatal outcomes. Several studies have shown that mortality rates in LVAD recipients secondary to lethal arrhythmias are uncommon, and newer generation continuous flow devices particularly seem to support hemodynamic support well. While it is common practice to implant ICDs in patients with LVADs and a history of ventricular arrhythmias, the efficacy behind this practice at preventing sudden death in this population is unknown. In this review, we highlight what is already known about the complications, management and treatment of atrial and ventricular arrhythmias in patients with LVAD devices.

A method for quantifying recurrent patterns of local wavefront direction during atrial fibrillation.

INTRODUCTION: Spiral wave reentry is a potential mechanism of atrial fibrillation (AF), but is difficult to differentiate clinically from multiple wavelet breakup using standard bipolar recordings. We developed a new methodology using bipolar recordings to estimate the direction of local activation wavefronts during AF by calculating the electrogram conformation (Egm-C). We subsequently used recurrence quantification analysis (RQA) of Egm-C to differentiate regions of spiral wave reentry from wavelet breakup. METHODS: A 2D computer simulation was created with regions containing a stable spiral wave and also regions of wavebreak. A grid of 40 × 40 unipolar electrodes was superimposed. At each site, the actual wavefront direction (WD) was determined by comparing relative activation timings of the local intracellular recordings, and the estimated wavefront direction (Egm-C) was determined from the morphology of the local bipolar electrogram. RQA of Egm-C was compared to RQA of actual WD in order to differentiate AF mechanisms. RESULTS: RQA of actual WD and Egm-C both distinguished regions of spiral wave reentry from wavelet breakup with high correlation between the two methods (recurrence rate, r = 0.96; determinism, r = 0.61; line max, r = 0.95; entropy, r = 0.84; p < 0.001 for all). In areas of stable spiral wave reentry, the recurrence plots of both Egm-C and actual WD demonstrated stable, periodic dynamics, while regions of wavelet breakup demonstrated chaotic behavior largely devoid of repetitive activation patterns. CONCLUSION: Calculation of Egm-C allows RQA to be performed on bipolar electrograms during AF and differentiates regions of spiral wave reentry from multiple wavelet breakup.

Challenges and Outcomes of Posterior Wall Isolation for Ablation of Atrial Fibrillation.

BACKGROUND: The left atrial posterior wall (PW) often contains sites required for maintenance of atrial fibrillation (AF). Electrical isolation of the PW is an important feature of all open surgeries for AF. This study assessed the ability of current ablation techniques to achieve PW isolation (PWI) and its effect on recurrent AF. METHODS AND RESULTS: Fifty-seven consecutive patients with persistent or high-burden paroxysmal AF underwent catheter ablation, which was performed using an endocardial-only (30) or a hybrid endocardial-epicardial procedure (27). The catheter ablation lesion set included pulmonary vein antral isolation and a box lesion on the PW (roof and posterior lines). Success in creating the box lesion was assessed as electrical silence of the PW (voltage <0.1 mV) and exit block in the PW with electrical capture. Cox proportional hazards models were used for analysis of AF recurrence. PWI was achieved in 21 patients (36.8%), more often in patients undergoing hybrid ablation than endocardial ablation alone (51.9% versus 23.3%, P=0.05). Twelve patients underwent redo ablation. Five of 12 had a successful procedural PWI, but all had PW reconnection at the redo procedure. Over a median follow-up of 302 days, 56.1% of the patients were free of atrial arrhythmias. No parameter including procedural PWI was a statistically significant predictor of recurrent atrial arrhythmias. CONCLUSIONS: PWI during catheter ablation for AF is difficult to achieve, especially with endocardial ablation alone. Procedural achievement of PWI in this group of patients was not associated with a reduction in recurrent atrial arrhythmias, but reconnection of the PW was common.