Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished ß-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post-myocardial infarction (MI), causing regional hypoinnervation that is associated with supersensitivity of ß-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypoinnervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord, and ß-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct region of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct versus remote region. Action potential duration (APD) dispersion and tendency for induction of ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI but not sham hearts. SNS decreased APD at 80% repolarization (APD80) in MI but not sham hearts, whereas isoproterenol decreased APD80 in both groups. Isoproterenol also shortened Ca2+ transient duration at 80% repolarization in both groups but to a greater extent in MI hearts. Our data suggest that sympathetic remodeling post-MI is similar between rodents and rabbits, with CSPGs associated with sympathetic hypoinnervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated ß-adrenergic responsiveness, which may underlie increased APD dispersion and tendency for VT/VF.NEW & NOTEWORTHY Here, we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypoinnervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between rodents and rabbits, with hypoinnervation likely associated with enhanced ß-adrenergic sensitivity.

Atrial Fibrillation and Chronic Kidney Disease: Aetiology and Management.

Chronic kidney disease (CKD) and atrial fibrillation (AF) are associated with significant cardiovascular morbidity and mortality. Recent studies have highlighted an increased prevalence and incidence of AF in patients with CKD. This article aims to provide a comprehensive review of current management strategies and considerations of treating atrial fibrillation with concomitant CKD. Potential electrophysiological mechanisms between AF and CKD are explored. Current evidence and literature focusing on pharmacological rate and rhythm control along with procedural intervention is reviewed and presented. The management of AF and CKD together is complex, but particularly pertinent when considering the close cyclical relationship in the progression of both diseases.

The validity and reliability of the Arabic version of the EQ-5D in atrial fibrillation patients in a conflict country: a study from Syria.

BACKGROUND: The EQ-5D is one of the most commonly used tools to establish health-related quality of life (QoL). EQ-5D data in atrial fibrillation (AF) patients in the Middle East are lacking. OBJECTIVES: This study aims to evaluate the reliability and validity of the Arabic version of the EQ-5D in AF inpatients in Syria. METHODS: The study involved patients admitted to the emergency department of Tishreen's University Hospital in Latakia with AF as the primary diagnosis between the 1st of June 2021 and the 1st of June 2023. Arabic versions of the EQ-5D, EQ-VAS and SF36 questionnaires were administered to patients. Validation was done using convergent, discriminant, and known-groups validity, while reliability was conducted using EQ-5D retesting within 2-4 weeks. RESULTS: 432 participants were included in the study with a mean ± standard deviation of 63 ± 15. Males represented 242 (56%) of the participants. All hypotheses relating EQ-5D responses to external variables were satisfied. All three validation hypotheses demonstrated that the EQ-5D had the convergent, discriminant and known group validity to assess QoL in this cohort. The intraclass correlation coefficient (ICC) for test-retest reliability ranged between 0.74 and 0.88, while Cohen's κ ranged between 0.72 and 0.86. Cronbach's α value for internal consistency was 0.73. CONCLUSION: The Arabic version of EQ-5D was valid and reliable in measuring QoL in AF inpatients in Syria. This validation opens the door for more widespread use of the EQ-5D in Arabic-speaking regions, facilitating better-informed healthcare decisions and improving patient care strategies in Syria and other Middle Eastern countries.

Incidence, outcomes, and predictors of new heart failure in syrian conflict-affected population following hospitalization for atrial fibrillation: A retrospective cohort study.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia worldwide. Data regarding readmission for new congestive heart failure (CHF) following index admission for AF in the developing world are poorly described. OBJECTIVES: The study aimed to assess the rate, predictors, and outcomes of 120-day CHF readmission after index admission for AF in Syria. METHODS: This retrospective cohort study collected all adult patients without known CHF who had an index admission with AF to Latakia's tertiary center between June 2021-December 2023. Data were taken from patients' medical notes. The primary outcome included readmission with incident CHF within 120 of index discharge, and secondary outcomes included predictors and outcomes of these CHF readmissions. RESULTS: A total of 660 patients were included in the final analysis, of which 69 (11.7%) were readmitted with new CHF within 120 days of index discharge. Readmitted patients had higher median age (58 vs 70 years, p < .001). Factors that independently increased 120-day CHF incidence were age ≥60 years (HR: 9.8, 95% CI: 4.8-23.6, p < .001), diabetes mellitus (DM) (HR:2.9, 95% CI:1.7-4.9, p < .001), valvular heart disease (VHD) (HR:1.7, 95% CI:1.04-2.78, p = .047), and hypertension (HR:2.5, 95% CI:1.5-4, p < .001). Inpatient mortality occurred in six readmitted patients (9%). LVEF <40% (HR:6.7, 95% CI: 24.31, p = .01) and DM (HR:7.2, 95% CI: 1.9-33, p = .004) were independently associated with inpatient mortality. CONCLUSION: Hospitalization for new CHF was common in Syrian patients discharged with AF. The clinical predictors of incident CHF emphasize the importance of integrated management of lifestyle risk factors and common comorbidities in AF patients to optimize outcomes in resource-depleted communities.

Atrial fibrillation inpatient management patterns and clinical outcomes during the conflict in Syria: An observational cohort study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide. However, there is no data on AF inpatient management strategies and clinical outcomes in Syria. OBJECTIVES: The study aims were to review the inpatient management of patients with AF and assess cardiovascular (CV) mortality in a tertiary cardiology centre in Latakia, Syria. METHODS: A single-centre retrospective observational cohort study was conducted at Tishreen's University Hospital, Latakia, Syria, from June 2021 to June 2023. Patients ≥16 years of age presenting and being treated for AF as the primary diagnosis with or without a thromboembolic event were included. Medical records were examined for patients' demographics, laboratory results, treatment plans and inpatient details. Studied outcomes include inpatient all-cause and CV mortality, ischemic and bleeding events, and conversion to sinus rhythm (SR). RESULTS: The study included 596 patients. The median age was 58, and 61% were males. 121 patients (20.3%) were known to have AF. A rhythm control strategy was pursued in 39% of patients. Ischemic and bleeding events occurred in 62 (11%) and 12 (2%), respectively. CV and all-cause mortality occurred in 28 (4.7%) and 31 patients (5%), respectively. The presence of valvular heart disease (VHD) (adjusted odds ratio (aOR) = 9.1, 95% confidence interval (CI): 1.7 to 55.1, p < .001), thyroid disease (aOR: 9.7, 95% CI = 1.2 to 91.6, p < .001) and chronic obstructive pulmonary disease (COPD) (aOR: 82, 95% CI: 12.7 to 71, p < .001) were independent risk factors of increased CV inpatient mortality. CONCLUSION: Syrian inpatients admitted with AF in Latakia are relatively younger than those in other countries. Active thyroid disease, COPD and VHD were independent risk factors of inpatient CV mortality with AF.

Compressed Deep Learning Models for Wearable Atrial Fibrillation Detection through Attention.

Deep learning (DL) models have shown promise for the accurate detection of atrial fibrillation (AF) from electrocardiogram/photoplethysmography (ECG/PPG) data, yet deploying these on resource-constrained wearable devices remains challenging. This study proposes integrating a customized channel attention mechanism to compress DL neural networks for AF detection, allowing the model to focus only on the most salient time-series features. The results demonstrate that applying compression through channel attention significantly reduces the total number of model parameters and file size while minimizing loss in detection accuracy. Notably, after compression, performance increases for certain model variants in key AF databases (ADB and C2017DB). Moreover, analyzing the learned channel attention distributions after training enhances the explainability of the AF detection models by highlighting the salient temporal ECG/PPG features most important for its diagnosis. Overall, this research establishes that integrating attention mechanisms is an effective strategy for compressing large DL models, making them deployable on low-power wearable devices. We show that this approach yields compressed, accurate, and explainable AF detectors ideal for wearables. Incorporating channel attention enables simpler yet more accurate algorithms that have the potential to provide clinicians with valuable insights into the salient temporal biomarkers of AF. Our findings highlight that the use of attention is an important direction for the future development of efficient, high-performing, and interpretable AF screening tools for wearable technology.

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

BACKGROUND: Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. METHODS: In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated. RESULTS: In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups. CONCLUSIONS: Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).

Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial.

AIMS: Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control. METHODS AND RESULTS: This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19). CONCLUSION: The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).

Correction: Mäkynen et al. Wearable Devices Combined with Artificial Intelligence-A Future Technology for Atrial Fibrillation Detection? Sensors 2022, 22, 8588.

The authors wish to add two authors to the original paper [...].

Machine learning in sudden cardiac death risk prediction: a systematic review.

AIMS: Most patients who receive implantable cardioverter defibrillators (ICDs) for primary prevention do not receive therapy during the lifespan of the ICD, whilst up to 50% of sudden cardiac death (SCD) occur in individuals who are considered low risk by conventional criteria. Machine learning offers a novel approach to risk stratification for ICD assignment. METHODS AND RESULTS: Systematic search was performed in MEDLINE, Embase, Emcare, CINAHL, Cochrane Library, OpenGrey, MedrXiv, arXiv, Scopus, and Web of Science. Studies modelling SCD risk prediction within days to years using machine learning were eligible for inclusion. Transparency and quality of reporting (TRIPOD) and risk of bias (PROBAST) were assessed. A total of 4356 studies were screened with 11 meeting the inclusion criteria with heterogeneous populations, methods, and outcome measures preventing meta-analysis. The study size ranged from 122 to 124 097 participants. Input data sources included demographic, clinical, electrocardiogram, electrophysiological, imaging, and genetic data ranging from 4 to 72 variables per model. The most common outcome metric reported was the area under the receiver operator characteristic (n = 7) ranging between 0.71 and 0.96. In six studies comparing machine learning models and regression, machine learning improved performance in five. No studies adhered to a reporting standard. Five of the papers were at high risk of bias. CONCLUSION: Machine learning for SCD prediction has been under-applied and incorrectly implemented but is ripe for future investigation. It may have some incremental utility in predicting SCD over traditional models. The development of reporting standards for machine learning is required to improve the quality of evidence reporting in the field.

Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial.

AIMS: Treatment patterns were compared between randomized groups in EAST-AFNET 4 to assess whether differences in anticoagulation, therapy of concomitant diseases, or intensity of care can explain the clinical benefit achieved with early rhythm control in EAST-AFNET 4. METHODS AND RESULTS: Cardiovascular treatment patterns and number of visits were compared between randomized groups in EAST-AFNET 4. Oral anticoagulation was used in >90% of patients during follow-up without differences between randomized groups. There were no differences in treatment of concomitant conditions between groups. The type of rhythm control varied by country and centre. Over time, antiarrhythmic drugs were given to 1171/1395 (84%) patients in early therapy, and to 202/1394 (14%) in usual care. Atrial fibrillation (AF) ablation was performed in 340/1395 (24%) patients randomized to early therapy, and in 168/1394 (12%) patients randomized to usual care. 97% of rhythm control therapies were within class I and class III recommendations of AF guidelines. Patients randomized to early therapy transmitted 297 166 telemetric electrocardiograms (ECGs) to a core lab. In total, 97 978 abnormal ECGs were sent to study sites. The resulting difference between study visits was low (0.06 visits/patient/year), with slightly more visits in early therapy (usual care 0.39 visits/patient/year; early rhythm control 0.45 visits/patient/year, P < 0.001), mainly due to visits for symptomatic AF recurrences or recurrent AF on telemetric ECGs. CONCLUSION: The clinical benefit of early, systematic rhythm control therapy was achieved using variable treatment patterns of antiarrhythmic drugs and AF ablation, applied within guideline recommendations.

Wearable Devices Combined with Artificial Intelligence-A Future Technology for Atrial Fibrillation Detection?

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. The arrhythmia and methods developed to cure it have been studied for several decades. However, professionals worldwide are still working to improve treatment quality. One novel technology that can be useful is a wearable device. The two most used recordings from these devices are photoplethysmogram (PPG) and electrocardiogram (ECG) signals. As the price lowers, these devices will become significant technology to increase sensitivity, for monitoring and for treatment quality support. This is important as AF can be challenging to detect in advance, especially during home monitoring. Modern artificial intelligence (AI) has the potential to respond to this challenge. AI has already achieved state of the art results in many applications, including bioengineering. In this perspective, we discuss wearable devices combined with AI for AF detection, an approach that enables a new era of possibilities for the future.

Application of two novel electrical restitution-based ECG markers of ventricular arrhythmia to patients with nonischemic cardiomyopathy.

INTRODUCTION: Sudden cardiac death (SCD) risk assessment is limited, particularly in patients with nonischemic cardiomyopathies. This is the first application, in patients with cardiomyopathies, of two novel risk markers, regional restitution instability index (R2I2) and peak electrocardiogram restitution slope (PERS), which have been shown to be predictive of ventricular arrhythmias (VA) or death in ischemic heart disease patients. METHODS: Blinded retrospective study of 50 patients: 33 dilated cardiomyopathy and 17 other; undergoing electrophysiological study (EPS) for SCD risk stratification, and 29 controls with structurally normal hearts undergoing EPS. R2I2 was calculated from an EPS using electrocardiogram surrogates for action potential duration and diastolic interval. Cut-offs for high and low R2I2/PERS were predefined. RESULTS: R2I2 was significantly higher in study than control patients (0.99 ± 0.05 vs. 0.63 ± 0.04, p < .001). PERS showed a trend to higher values in the study group (1.18[0.63] vs. 1.09[0.54], p = .07). During median follow up of 5.6 years [interquartile range 1.9 years], nine study patients reached the endpoint of VA/death. Patients who experienced VA/death showed trends to higher mean R2I2 (1.14 ± 0.07 vs.0.95 ± 0.05, p = .12) and PERS (1.46[0.49] vs. 1.13[0.62], p = .22). A Cox proportional hazards model using grouped markers: R2I2 < 1.03 + PERS < 1.21/either R2I2 ≥ 1.03 or PERS ≥ 1.21/R2I2 ≥ 1.03 + PERS ≥ 1.21; significantly predicted VA/death (p = .02) with a hazard ratio per positive component of 3.2 (95% confidence interval 1.2-8.8). CONCLUSION: R2I2≥ 1.03 + PERS ≥ 1.21 may predict VA/death in patients with cardiomyopathies. R2I2 ≥ 1.03 + PERS ≥ 1.21 have the potential to play an important role in SCD risk stratification in cardiomyopathies but their validity should be confirmed in a larger study.

Effects of sympatho-vagal interaction on ventricular electrophysiology and their modulation during beta-blockade.

AIMS: The effects of sympatho-vagal interaction on heart rate (HR) changes are characterized by vagal dominance resulting in accentuated antagonism. Complex autonomic modulation of ventricular electrophysiology may exert prognostic arrhythmic impact. We examined the effects of concurrent sympathetic (SNS) and vagus (VNS) nerve stimulation on ventricular fibrillation threshold (VFT) and standard restitution (RT) in an isolated rabbit heart preparation with intact dual autonomic innervation, with and without beta-blockade. METHODS AND RESULTS: Monophasic action potentials were recorded from left ventricular epicardial surface of dual-innervated isolated heart preparations from New Zealand white rabbits (n = 18). HR, VFT and RT were measured during different stimulation protocols (Protocol 1: VNS-SNS; Protocol 2: SNS-VNS) involving low- and high-frequency stimulations. A sub-study of Protocol 2 was performed in the presence of metoprolol tartrate. In both protocols, HR changes were characterized by vagal-dominant bradycardic component, affirming accentuated antagonism. During concurrent high-frequency VNS (HV), SNS prevails in lowering VFT in a frequency-sensitive manner during low (LS) or high (HS)-frequency stimulations (HV-LS: -2.8 ± 0.8 mA; HV-HS: -4.0 ± 0.9 mA, p < .05 vs. HV), with accompanying steepening of relative RT slope gradients (HV-LS: 223.54 ± 37.41%; HV-HS: 295.20 ± 60.86%, p < .05 vs. HV). In protocol 2, low (LV) and high (HV) vagal stimulations during concurrent HS raised VFT (HS-LV: 1.0 ± 0.4 mA; HS-HV: 3.0 ± 0.6 mA, p < .05 vs HS) with associated flattening of RT slopes (HS-LV: 32.40 ± 4.97%;HS-HV: 38.07 ± 6.37%; p < .05 vs HS). Metoprolol abolished accentuated antagonism in HR changes, reduced VFT and flattened RT globally during SNS-VNS. CONCLUSIONS: Accentuated antagonism is absent in ventricular electrophysiological changes during sympatho-vagal interaction with sympathetic effect prevailing, suggesting a different mechanism at the ventricular level from heart rate effects. Metoprolol nullified accentuated antagonism with additional anti-fibrillatory effect beyond adrenergic blockade during sympatho-vagal stimulations.

Cabins, castles, and constant hearts: rhythm control therapy in patients with atrial fibrillation.

Recent innovations have the potential to improve rhythm control therapy in patients with atrial fibrillation (AF). Controlled trials provide new evidence on the effectiveness and safety of rhythm control therapy, particularly in patients with AF and heart failure. This review summarizes evidence supporting the use of rhythm control therapy in patients with AF for different outcomes, discusses implications for indications, and highlights remaining clinical gaps in evidence. Rhythm control therapy improves symptoms and quality of life in patients with symptomatic AF and can be safely delivered in elderly patients with comorbidities (mean age 70 years, 3-7% complications at 1 year). Atrial fibrillation ablation maintains sinus rhythm more effectively than antiarrhythmic drug therapy, but recurrent AF remains common, highlighting the need for better patient selection (precision medicine). Antiarrhythmic drugs remain effective after AF ablation, underpinning the synergistic mechanisms of action of AF ablation and antiarrhythmic drugs. Atrial fibrillation ablation appears to improve left ventricular function in a subset of patients with AF and heart failure. Data on the prognostic effect of rhythm control therapy are heterogeneous without a clear signal for either benefit or harm. Rhythm control therapy has acceptable safety and improves quality of life in patients with symptomatic AF, including in elderly populations with stroke risk factors. There is a clinical need to better stratify patients for rhythm control therapy. Further studies are needed to determine whether rhythm control therapy, and particularly AF ablation, improves left ventricular function and reduces AF-related complications.

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts.

KEY POINTS: Cardiac electrophysiology and Ca2+ handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca2+ transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca2+ handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca2+ handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses. ABSTRACT: Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca2+ -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P < 0.05) followed by shortening (46.5 ± 9.1 ms at t = 60 s, P = NS vs. t = 0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by ß-adrenergic activation. Simulations with species-specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight-or-flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.

Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation.

KEY POINTS: Ageing results in changes to cardiac electrophysiology, Ca2+ handling, and ß-adrenergic responsiveness. Sympathetic neurodegeneration also occurs with age, yet detailed action potential and Ca2+ handling responses to physiological sympathetic nerve stimulation (SNS) in the aged heart have not been assessed. Optical mapping in mouse hearts with intact sympathetic innervation revealed reduced responsiveness to SNS in the aged atria (assessed by heart rate) and aged ventricles (assessed by action potentials and Ca2+ transients). Sympathetic nerve density and noradrenaline content were reduced in aged ventricles, but noradrenaline content was preserved in aged atria. These results demonstrate that reduced responsiveness to SNS in the atria may be primarily due to decreased ß-adrenergic receptor responsiveness, whereas reduced responsiveness to SNS in the ventricles may be primarily due to neurodegeneration. ABSTRACT: The objective of this study was to determine how age-related changes in sympathetic structure and function impact cardiac electrophysiology and intracellular Ca2+ handling. Innervated hearts from young (3-4 months, YWT, n = 10) and aged (20-24 months, AGED, n = 11) female mice (C57Bl6) were optically mapped using the voltage (Vm ,)- and calcium (Ca2+ )-sensitive indicators Rh237 and Rhod2-AM. Sympathetic nerve stimulation (SNS) was performed at the spinal cord (T1-T3). ß-Adrenergic responsiveness was assessed with isoproterenol (1 µM, ISO). Sympathetic nerve density and noradrenaline content were also quantified. Stimulation thresholds necessary to produce a defined increase in heart rate (HR) with SNS were higher in AGED vs. YWT hearts (5.4 ± 0.4 vs. 3.8 ± 0.4 Hz, P < 0.05). Maximal HR with SNS was lower in AGED vs. YWT (20.5 ± 3.41% vs. 73.0 ± 7.63% increase, P < 0.05). ß-Adrenergic responsiveness of the atria (measured as percentage increase in HR with ISO) was decreased in AGED vs. YWT hearts (75.3 ± 22.5% vs. 148.5 ± 19.8%, P < 0.05). SNS significantly increased action potential duration (APD) in YWT but not AGED. Ca2+ transient durations and rise times were unchanged by SNS, yet AGED hearts had an increased susceptibility to Ca2+ alternans and ventricular arrhythmias. ß-Adrenergic responsiveness of all ventricular parameters were similar between AGED and YWT. Sympathetic nerve density and noradrenaline content were decreased in the AGED ventricle, but not atria, compared to YWT. These data suggest that decreased responsiveness to SNS in the aged atria may be primarily due to decreased ß-adrenergic responsiveness, whereas decreased responsiveness to SNS in the aged ventricles may be primarily due to nerve degeneration.

Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?

Homeostasis around vascular endothelium is a function of the equilibrium between the bioavailability of nitric oxide (NO) and oxidizing reactive oxygen species (ROS). Within the vascular endothelium, NO enhances vasodilatation, reduces platelet aggression and adhesion (anti-thrombotic), prevents smooth muscle proliferation, inhibits adhesion of leukocytes and expression of pro-inflammatory cytokines genes (anti-inflammatory), and counters the oxidation of low density lipoprotein (LDL) cholesterol. A shift in the equilibrium that favours NO deficiency and ROS formation leads to endothelial dysfunction and cardiovascular disease. The synthesis of NO is catalysed by nitric oxide synthase and co-factored by tetrahydrobiopterin (BH4), nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN). The focus of this review is on endothelial nitric oxide synthase (eNOS), although we recognize that the other nitric oxide synthases may contribute as well. Levels of homocysteine and the active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF), play a determining role in circulating levels of nitric oxide. We review endothelial nitric oxide bioavailabilty in relation to endothelial dysfunction as well as the therapeutic strategies involving the nitric oxide synthesis pathway. Although folate supplementation improves endothelial function, results from large clinical trials and meta-analyses on palpable clinical endpoints have been inconsistent. There are however, encouraging results from animal and clinical studies of supplementation with the co-factor for nitric oxide synthesis, BH4, though its tendency to be oxidized to dihydrobiopterin (BH2) remains problematic. Understanding how to maintain a high ratio of BH4 to BH2 appears to be the key that will likely unlock the therapeutic potential of nitric oxide synthesis pathway.

Association of hypoglycaemia and risk of cardiac arrhythmia in patients with diabetes mellitus: A systematic review and meta-analysis.

AIMS: Hypoglycaemia is associated with increased cardiovascular risk among individuals with diabetes mellitus. It has been hypothesized that hypoglycaemia may trigger autonomic changes leading to increased cardiac arrhythmia risk. We conducted a systematic review and meta-analysis to explore this association. MATERIALS AND METHODS: Ovid Medline, Embase, Scopus, Web of Science and Cochrane were searched from inception to October 10, 2017. We included studies of adults with diabetes (Type 1 or Type 2) that compared acute electrocardiogram (ECG) changes during episodes of hypoglycaemia and euglycaemia. RESULTS: Our search resulted in 4625 citations, among which 20 studies met the predefined inclusion criteria. Finally, 12 studies were included in the descriptive analysis and 15 in the meta-analysis. Overall hypoglycaemia was associated with a reduction in heart rate variability and an increase in arrhythmia occurrence. QTc interval length was more significantly prolonged during hypoglycaemia compared to euglycaemia (pooled mean difference [95% confidence intervals] [0.64 (0.27-1.01], P = ·001). Subgroup analysis based on diabetes type showed that QTc prolongation occurred in individuals with Type 1 and Type 2 diabetes; however, the change between euglycaemia reached statistical significance only among individuals with Type 1 diabetes. CONCLUSION: Our findings suggest that hypoglycaemia results in ECG alterations that are associated with increased risk of cardiac arrhythmia, which is associated with increased cardiovascular events and mortality. More clinical studies are needed to determine the cardiac risks of hypoglycaemia in individuals with diabetes, especially in Type 2 diabetes.