NS5806 Induces Electromechanically Discordant Alternans and Arrhythmogenic Voltage-Calcium Dynamics in the Isolated Intact Rabbit Heart

Background: NS5806 activates the transient outward potassium current I to, and has been claimed to reproduce Brugada Syndrome (BrS) in ventricular wedge preparations. I to modulates excitation-contraction coupling, which is critical in alternans dynamics. We explored NS5806-arrhythmogenic effects in the intact whole heart and its impact on alternans. Methods: Langendorff-perfused rabbit hearts (n = 20) underwent optical AP and Ca mapping during pacing at decremental cycle lengths (CL). Spontaneous arrhythmias and pacing-induced alternans was characterized at baseline (BL), after perfusing with NS5806, before and after adding verapamil (VP), and SEA0400 (SEA, n = 5 each), to modulate Ca-current and Na-Ca exchange, the main AP-Ca coupling mechanisms. Results: NS5806 induced BrS-like ECG features in 6 out of 20 hearts. NS5806 prolonged steady-state (3 Hz) action potential duration (APD) by 16.8%, Ca decay constant by 34%, and decreased conduction velocity (CV) by 52.6%. After NS5806 infusion, spontaneous ventricular ectopy (VE) and AP/Ca alternans occurred. Pacing-induced alternans during NS5806 infusion occurred at longer CL and were AP/Ca discordant from its onset. Spatially discordant alternans after NS5806 infusion had non-propagation-driven nodal line distribution. No spontaneous phase-2 reentry occurred. Under NS5806 + VP, alternans became AP/Ca concordant and only induced in two out of five; NS5806 + SEA did not affect alternans but suppressed spontaneous ectopy. Conclusions: NS5806 disrupts AP-Ca coupling and leads to Ca-driven, AP/Ca-discordant alternans and VE. Despite BrS-like ECG features, no spontaneous sustained arrhythmias or phase-2 reentry occurred. NS5806 does not fully reproduce BrS in the intact rabbit heart

Cardiac Afferent Denervation Abolishes Ganglionated Plexi and Sympathetic Responses to Apnea: Implications for Atrial Fibrillation

Background: The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20+/-31.3 ms to 90.6+/-29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7+/-26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF

A prospective study of the clinical outcomes and prognosis associated with comorbid COPD in the atrial fibrillation population

Background: Patients with COPD are at higher risk of presenting with atrial fibrillation (AF). Information about clinical outcomes and optimal medical treatment of AF in the setting of COPD remains missing. We aimed to describe the prevalence of COPD in a sizeable cohort of real-world AF patients belonging to the same healthcare area and to examine the relationship between comorbid COPD and AF prognosis. Methods: Prospective analysis performed in a specific healthcare area. Data were obtained from several sources within the "data warehouse of the Galician Healthcare Service" using multiple analytical tools. Statistical analyses were completed using SPSS 19 and STATA 14.0. Results: A total of 7,990 (2.08%) patients with AF were registered throughout 2013 in our healthcare area (n=348,985). Mean age was 76.83+/-10.51 years and 937 (11.7%) presented with COPD. COPD patients had a higher mean CHA2DS2-VASc (4.21 vs 3.46; P=0.02) and received less beta-blocker and more digoxin therapy than those without COPD. During a mean follow-up of 707+/-103 days, 1,361 patients (17%) died. All-cause mortality was close to two fold higher in the COPD group (28.3% vs 15.5%; P<0.001). Independent predictive factors for all-cause mortality were age, heart failure, diabetes, previous thromboembolic event, dementia, COPD, and oral anticoagulation (OA). There were nonsignificant differences in thromboembolic events (1.7% vs 1.5%; P=0.7), but the rate of hemorrhagic events was significantly higher in the COPD group (3.3% vs 1.9%; P=0.004). Age, valvular AF, OA, and COPD were independent predictive factors for hemorrhagic events. In COPD patients, age, heart failure, vasculopathy, lack of OA, and lack of beta-blocker use were independent predictive factors for all-cause mortality. Conclusion: AF patients with COPD have a higher incidence of adverse events with significantly increased rates of all-cause mortality and hemorrhagic events than AF patients without COPD. However, comorbid COPD was not associated with differences in cardiovascular death or stroke rate. OA and beta-blocker treatment presented a risk reduction in mortality while digoxin use exerted a neutral effect

Clinical impact of mineralocorticoid receptor antagonists treatment after acute coronary syndrome in the real world: A propensity score matching analysis

BACKGROUND: Recent studies suggest that the benefit of mineralocorticoid receptor antagonists in the acute coronary syndrome setting is controversial. The aim of this study was to examine the current long-term prognostic benefit of mineralocorticoid receptor antagonists in patients with acute coronary syndrome. MATERIAL AND METHODS: We conducted a retrospective cohort study of 8318 consecutive acute coronary syndrome patients. Baseline patient characteristics were examined and a follow-up period was established for registry of death, major cardiovascular adverse events and heart failure re-hospitalization. We performed a propensity-matching analysis to draw up two groups of patients paired according to whether or not they had been treated with mineralocorticoid receptor antagonists. The prognostic value of mineralocorticoid receptor antagonists to predict events during follow-up was analysed using Cox regression. RESULTS: Among the study participants, only 524 patients (6.3%) were discharged on mineralocorticoid receptor antagonists. Patients on mineralocorticoid receptor antagonists had a different clinical and pharmacological profile. These differences disappeared after the propensity score analysis. The median follow-up was 40.7 months. After the propensity score analysis, the cardiovascular mortality and heart failure readmission rates were similar between patients who were discharged on mineralocorticoid receptor antagonists and those whose not. The use of mineralocorticoid receptor antagonists was only associated with a reduction in major cardiovascular adverse events (hazard ratio=0.83, 95% confidence interval 0.69-0.97, p=0.001). CONCLUSIONS: Our results do not corroborate the long-term benefit of mineralocorticoid receptor antagonists to improve survival after acute coronary syndrome in a large cohort of patients with heart failure or reduced left ventricular ejection fraction and diabetes. Their prescription was associated with a significantly lower incidence of major cardiovascular adverse events during the long-term follow-up without effect on heart failure development