Sudden cardiac death due to ventricular arrhythmia in diabetes mellitus: A bench to bedside review.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. Diabetes mellitus induces adverse structural, electrophysiological, and autonomic cardiac remodeling which can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiology of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. Based on this pathophysiological framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this high-risk patient population.

Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

OBJECTIVES: Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. METHODS: A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50 y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. CONCLUSIONS: We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.

Robust Artificial Intelligence Tool for Atrial Fibrillation Diagnosis: Novel Development Approach Incorporating Both Atrial Electrograms and Surface ECG and Evaluation by Head-to-Head Comparison With Hospital-Based Physician ECG Readers.

BACKGROUND: Atrial fibrillation (AF) increases risk of embolic stroke, and in postoperative patients, increases cost of care. Consequently, ECG screening for AF in high-risk patients is important but labor-intensive. Artificial intelligence (AI) may reduce AF detection workload, but AI development presents challenges. METHODS AND RESULTS: We used a novel approach to AI development for AF detection using both surface ECG recordings and atrial epicardial electrograms obtained in postoperative cardiac patients. Atrial electrograms were used only to facilitate establishing true AF for AI development; this permitted the establishment of an AI-based tool for subsequent AF detection using ECG records alone. A total of 5 million 30-second epochs from 329 patients were annotated as AF or non-AF by expert ECG readers for AI training and validation, while 5 million 30-second epochs from 330 different patients were used for AI testing. AI performance was assessed at the epoch level as well as AF burden at the patient level. AI achieved an area under the receiver operating characteristic curve of 0.932 on validation and 0.953 on testing. At the epoch level, testing results showed means of AF detection sensitivity, specificity, negative predictive value, positive predictive value, and F1 (harmonic mean of positive predictive value and sensitivity) as 0.970, 0.814, 0.976, 0.776, and 0.862, respectively, while the intraclass correlation coefficient for AF burden detection was 0.952. At the patient level, AF burden sensitivity and positive predictivity were 96.2% and 94.5%, respectively. CONCLUSIONS: Use of both atrial electrograms and surface ECG permitted development of a robust AI-based approach to postoperative AF recognition and AF burden assessment. This novel tool may enhance detection and management of AF, particularly in patients following operative cardiac surgery.

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.

Pseudo-vagal Responses Elicited by Cryoballoon Ablation.

Pulmonary vein isolation via cryoballoon (CB) ablation is the cornerstone ablation strategy for the treatment of atrial fibrillation (AF). Acute intraprocedural hypotensive and/or bradycardic responses have been reported in patients undergoing CB ablation for AF. However, it remains unclear as to whether these are due to a true vagal response (VR), which can be used to predict long-term outcomes of CB ablation. We analyzed 139 freezes across 17 patients who received CB ablation for paroxysmal AF, measuring vital signs and freeze characteristics. Only one freeze was associated with both hypotension and bradycardia, constituting a true VR. Several freezes were associated with hypotension only that did not respond to atropine administration, suggesting that these responses are not associated with a VR. Hypotensive responses were significantly associated with ice bubble bursts during CB deflation. Unlike the true VR reported in patients undergoing conscious sedation, the presence of acute hypotension shortly after CB deflation cannot be used as a predictor for long-term ablation outcomes.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

PURPOSE: Acute decompensated heart failure (ADHF) is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown whether neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level tragus stimulation on inflammation and oxidative stress in ADHF. METHODS: Nineteen patients with ejection fraction < 40% were randomized to neuromodulation 4 h twice daily (6-10 a.m. and 6-10 p.m.) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using a dihydrodichlorofluorescein probe test (expressed as fluorescein units). RESULTS: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum interleukin-6 levels (-78% vs. -9%; p = 0.012). Similarly, neuromodulation led to a reduction of endothelial cell oxidative stress in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant differences in heart rate, blood pressure, or renal function were noted between the two groups. CONCLUSION: In this proof-of-concept pilot study, in acute decompensated heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of coronary endothelial cellular oxidative stress. CLINICAL TRIAL REGISTRATION: NCT02898181.

Transcutaneous electrical vagus nerve stimulation to suppress premature ventricular complexes (TREAT PVC): study protocol for a multi-center, double-blind, randomized controlled trial.

BACKGROUND: The autonomic nervous system can be responsible for the initiation and maintenance of arrhythmias. Low-level tragus stimulation (LLTS), a noninvasive form of autonomic neuromodulation, has been shown to be effective in treating atrial fibrillation. We intended to treat frequent premature ventricular complexes (PVCs) with LLTS. METHODS AND DESIGN: The present study will be a prospective multicenter, double-blind, randomized, controlled trial to assess the antiarrhythmic effects of LLTS on frequent PVCs in patients without structured heart disease (SHD). A total of 100 patients with PVC burden > 10% will be randomly assigned to the active or sham LLTS in 1:1 fashion and receive the proposed intervention for 6 months. The primary outcome is PVC burden at 6 months as assessed by 10 days of continuous ambulatory electrocardiographic monitoring. Secondary outcomes include heart rate variability (HRV), quality of life, skin sympathetic nerve activity, and inflammatory markers. Adverse events will also be recorded. DISCUSSION: The present trial will be the first to evaluate the effect of LLTS on frequent PVCs on patients without SHD. LLTS may serve as a low-cost, minimal-risk, and non-invasive alternative to conventional antiarrhythmic therapy. TRIAL REGISTRATION: ClinicalTrial.gov NCT04909528. Registered on 17 June 2021. World health organization trial registration data set was shown in Supplementary Table 1.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

Purpose: Acute decompensated heart failure is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown if neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level Tragus stimulation on inflammation and oxidative stress in ADHF. Methods: 19 patients with ejection fraction < 40% were randomized to neuromodulation- 4 hours twice daily (6 AM-10 AM and 6 PM-10 PM) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using dihydrodichlorofluorescein probe test (expressed as fluorescein units). Results: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum Interleukin-6 levels (-78% vs -9%; p = 0.012). Similarly, neuromodulation led to reduction of endothelial cell oxidative stress, in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant difference in heart rate, blood pressure or renal function were noted between the two groups. Conclusion: In this proof-of-concept pilot study, in acute systolic heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of cellular oxidative stress. Clinical trial: NCT02898181.

The effect of weight loss on recurrence of atrial fibrillation after catheter ablation: A systematic review and meta-analysis.

BACKGROUND: Obesity is associated with an increased risk of developing recurrent atrial fibrillation (AF) after catheter ablation (CA). However, the current data on weight loss interventions show inconsistent results in preventing the recurrence of AF after CA. METHODS: We conducted a systematic search in MEDLINE and EMBASE to identify studies that reported the outcome of recurrence of AF after CA in obese patients undergoing weight interventions. The subgroup analysis included: (1) Weight loss versus no weight loss, (2) >10% weight loss versus <10% weight loss, (3) <10% weight loss versus no weight loss, (4) Follow-up <12 months, and (5) Follow-up >12 months after CA. Mantel-Haenszel risk ratios with a 95% confidence interval (CI) were calculated using a random effects model and for heterogeneity, I2 statistics were reported. RESULTS: A total of 10 studies (one randomized controlled trial and nine observational studies) comprising 1851 patients were included. The recurrence of AF was numerically reduced in the weight loss group (34.5%) versus no weight loss group (58.2%), but no statistically significant difference was observed (risk ratio [RR] = 0.76; 95% CI: 0.49-1.18, p = .22). However, there was a statistically significant reduction in recurrence of AF with weight loss versus no weight loss at follow-up >12 months after CA (RR = 0.47; 95% CI: 0.32-0.68, p < .0001). At follow-up >12 months after CA, both >10% weight loss versus <10% weight loss (RR = 0.49; 95% CI: 0.31-0.80, p = .004) and <10% weight loss versus no weight loss (RR = 0.39; 95% CI: 0.31-0.49, p < .00001) were associated with a statistically significant reduction in recurrent AF. CONCLUSION: In patients with AF undergoing CA, weight loss is associated with reducing recurrent AF at > 12 months after ablation and these benefits are consistently seen with both >10% and <10% weight loss. The benefits of weight loss in preventing recurrent AF after CA should be examined in larger studies with extended follow-up duration.

Protein kinase A: A potential marker of sympathovagal imbalance in heart failure.

Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification of a biomarker for the quantification of sympathovagal balance, the potential target of 'neuromodulation' strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF.

The neurometabolic axis: A novel therapeutic target in heart failure.

Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger and maintain the mechanical dysfunction and electrical, and structural abnormalities of the ventricle. A dysregulated cardiac autonomic tone characterized by sympathetic overdrive with blunted parasympathetic activation is another pathophysiological hallmark of HF. Emerging evidence suggests a link between autonomic nervous system activity and cardiac metabolism. Chronic ß-adrenergic activation promotes maladaptive metabolic remodeling whereas cholinergic activation attenuates the metabolic aberrations through favorable modulation of key metabolic regulatory molecules. Restoration of sympathovagal balance by neuromodulation strategies is emerging as a novel nonpharmacological treatment strategy in HF. The current review attempts to evaluate the 'neuro-metabolic axis' in HFrEF and whether neuromodulation can mitigate the adverse metabolic remodeling in HFrEF.

Psychosocial risk factors and outcomes in patients undergoing catheter ablation for atrial fibrillation.

The association of psychosocial risk factors with cardiovascular disease is well-established, and there is a growing recognition of their influence on atrial fibrillation (AF) . A recent National Heart, Lung, and Blood Institute workshop called for transforming AF research to integrate social determinants of health. There is limited data examining the impact of psychosocial risk factors (PSRFs) on outcomes in patients with an established diagnosis of AF. Catheter ablation for AF has been shown to improve arrhythmia burden and quality of life compared with medical treatment alone. It is unknown how PSRFs affect clinical outcomes in patients undergoing AF ablation. It is important to understand this relationship, especially given the increasing adoption of catheter ablation in clinical practice.

Cardioneuroablation for Treating Vasovagal Syncope: Current Status and Future Directions.

Syncope is defined by transient and spontaneous loss of consciousness with rapid recovery. Vasovagal syncope (VVS) is the most common form of syncope and is strongly associated with hypervagotonia. There is, however, a lack of effective therapies for VVS. Cardioneuroablation (CNA) is an emerging and promising intervention for VVS with favourable outcomes. CNA has been shown to suppress excessive excitation of vagal activity through ablating the cardiac ganglionated plexi. CNA in the management of VVS requires more structured and comprehensive studies and several issues concerning patient selection, selection of ablation targets, ablation endpoints and the long-term effect of CNA are yet to be determined. This review describes its clinical applications and future directions based on current research data and the authors' own experiences.

Safety and efficacy of colchicine for the prevention of post-operative atrial fibrillation in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colchicine is an anti-inflammatory drug that may prevent post-operative atrial fibrillation (POAF). The effect of this drug has been inconsistently shown in previous clinical trials. We aimed to compare the efficacy and safety of colchicine vs. placebo to prevent POAF in patients undergoing cardiac surgery. METHODS AND RESULTS: A systematic search of EMBASE, MEDLINE, SCOPUS, ClinicalTrials.gov, and the Cochrane Library for randomized controlled trials (RCTs) was conducted from inception till April 2023. The primary outcome was the incidence of POAF after any cardiac surgery. The secondary outcome was the rate of drug discontinuation due to adverse events and adverse gastrointestinal events. Risk ratios (RR) were reported using the Mantel Haenszel method. A total of eight RCTs comprising 1885 patients were included. There was a statistically significant lower risk of developing POAF with colchicine vs. placebo (RR: 0.70; 95% CI: 0.59-0.82; P < 0.01, I2 = 0%), and this effect persisted across different subgroups. There was a significantly higher risk of adverse gastrointestinal events (RR: 2.20; 95% CI: 1.38-3.51; P < 0.01, I2 = 55%) with no difference in the risk of drug discontinuation in patients receiving colchicine vs. placebo (RR: 1.33; 95% CI: 0.93-1.89; P = 0.11, I2 = 0%). CONCLUSION: This meta-analysis of eight RCTs shows that colchicine is effective at preventing POAF, with a significantly higher risk of adverse gastrointestinal events but no difference in the rate of drug discontinuation. Future studies are required to define the optimal duration and dose of colchicine for the prevention of POAF.

Same-day discharge for left atrial appendage occlusion procedure: A systematic review and meta-analysis.

INTRODUCTION: Most patients undergoing a left atrial appendage occlusion (LAAO) procedure are admitted for overnight observation. A same-day discharge strategy offers the opportunity to improve resource utilization without compromising patient safety. We compared the patient safety outcomes and post-discharge complications between same-day discharge versus hospital admission (HA) (>1 day) in patients undergoing LAAO procedure. METHODS: A systematic search of MEDLINE and Embase was conducted. Outcomes of interest included peri-procedural complications, re-admissions, discharge complications including major bleeding and vascular complications, ischemic stroke, all-cause mortality, and peri-device leak >5 mm. Mantel-Haenszel risk ratios (RRs) with 95% CIs were calculated. RESULTS: A total of seven observational studies met the inclusion criteria. There was no statistically significant difference between same-day discharge versus HA regarding readmission (RR: 0.61; 95% confidence interval [CI]: [0.29-1.31]; p = .21), ischemic stroke after discharge (RR: 1.16; 95% CI: [0.49-2.73]), peri-device leak >5 mm (RR: 1.27; 95% CI: [0.42-3.85], and all-cause mortality (RR: 0.60; 95% CI: [0.36-1.02]). The same-day discharge study group had significantly lower major bleeding or vascular complications (RR: 0.71; 95% CI: [0.54-0.94]). CONCLUSIONS: This meta-analysis of seven observational studies showed no significant difference in patient safety outcomes and post-discharge complications between same-day discharge versus HA. These findings provide a solid basis to perform a randomized control trial to eliminate any potential confounders.

Autonomic Nervous System and Cardiac Metabolism: Links Between Autonomic and Metabolic Remodeling in Atrial Fibrillation.

Simultaneous activation of the sympathetic and parasympathetic nervous systems is crucial for the initiation of paroxysmal atrial fibrillation (AF). However, unbalanced activation of the sympathetic system is characteristic of autonomic remodeling in long-standing persistent AF. Moreover, the adrenergic activation-induced metabolic derangements provide a milieu for acute AF and promote the transition from the paroxysmal to the persistent phase of AF. On the other hand, cholinergic activation ameliorates the maladaptive metabolic remodeling in the face of metabolic challenges. Selective inhibition of the sympathetic system and restoration of the balance of the cholinergic system by neuromodulation is emerging as a novel nonpharmacologic strategy for managing AF. This review explores the link between cardiac autonomic and metabolic remodeling and the potential roles of different autonomic modulation strategies on atrial metabolic aberrations in AF.