Differences in underlying cardiac substrate among S-ICD recipients and its impact on long-term device-related outcomes: Real-world insights from the iSUSI registry.

BACKGROUND: Outcome comparisons among subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with nonischemic cardiomyopathies are scarce. OBJECTIVE: The aim of this study was to evaluate differences in device-related outcomes among S-ICD recipients with different structural substrates. METHODS: Patients enrolled in the i-SUSI (International SUbcutaneouS Implantable cardioverter defibrillator registry) project were grouped according to the underlying substrate (ischemic vs nonischemic) and subgrouped into dilated cardiomyopathy, hypertrophic cardiomyopathy, Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC). The main outcome of our study was to compare the rates of appropriate and inappropriate shocks and device-related complications. RESULTS: Among 1698 patients, the most common underlying substrate was ischemic (31.7%), followed by dilated cardiomyopathy (20.5%), BrS (10.8%), hypertrophic cardiomyopathy (8.5%), and ARVC (4.4%). S-ICD for primary prevention was more common in the nonischemic cohort (70.9% vs 65.4%; P = .037). Over a median (interquartile range) follow-up of 26.5 (12.6-42.8) months, no differences were observed in appropriate shocks between ischemic and nonischemic patients (4.8%/y vs 3.9%/y; log-rank, P = .282). ARVC (9.0%/y; hazard ratio [HR] 2.492; P = .001) and BrS (1.8%/y; HR 0.396; P = .008) constituted the groups with the highest and lowest rates of appropriate shocks, respectively. Device-related complications did not differ between groups (ischemic: 6.4%/y vs nonischemic: 6.1%/y; log-rank, P = .666), nor among underlying substrates (log-rank, P = .089). Nonischemic patients experienced higher rates of inappropriate shocks than did ischemic S-ICD recipients (4.4%/y vs 3.0%/y; log-rank, P = .043), with patients with ARVC (9.9%/y; P = .001) having the highest risk, even after controlling for confounders (adjusted HR 2.243; confidence interval 1.338-4.267; P = .002). CONCLUSION: Most S-ICD recipients were primary prevention nonischemic cardiomyopathy patients. Among those, patients with ARVC tend to receive the most frequent appropriate and inappropriate shocks and patients with BrS the least frequent appropriate shocks.

Atrial Fibrillation Ablation in a Patient With SV ASD and PAPVR Preceding Transcatheter Septal Closure.

Atrial fibrillation (AF) is common in adults with unrepaired atrial septal defects (ASDs). Sinus venosus (SV) ASDs associated with partial anomalous pulmonary venous return (PAPVR) are traditionally managed surgically. We report the first AF catheter ablation in a patient with SV ASD and PAPVR preceding transcatheter ASD repair with a covered stent. (Level of Difficulty: Advanced.).

Sex-based differences in safety and efficacy of catheter ablation for atrial fibrillation.

BACKGROUND: Studies have identified significant sex-based differences and disparities in the clinical presentation and treatment of atrial fibrillation (AF). Studies have shown women are less likely to be referred for catheter ablation, are older at the time of ablation, and are more likely to have recurrence after ablation. However, in most studies investigating AF ablation outcomes, the female cohorts were relatively small. The impact of sex on the outcome and safety of ablation procedures is still unclear. OBJECTIVE: To investigate sex-based differences in outcomes and complications after AF catheter ablation, with a significant female cohort METHOD: In this retrospective study, patients undergoing AF ablation from January 1, 2014, to March 31, 2021, were included. We investigated clinical characteristics, duration and progression of AF, number of EP appointments from diagnosis to ablation, procedural data, and procedure complications. RESULTS: Total of 1346 patients underwent first catheter ablation for AF during this period, including 896 (66.5%) male and 450 (33.4%) female patients. Female patients were older at the time of ablation (66.2 vs. 62.4 years; p < .001). Women had higher CHA2 DS2 -VASc (congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, sex category) scores (3 vs. 2; p < .001) than men, expectedly, as the female sex warrants an additional point. 25.3% female patients had PersAF at the time of diagnosis versus 35.3% male patients (p < .001). At the time of ablation, 31.8% female patients had PersAF as compared to 43.1% male patients (p < .001), indicating progression of PAF to PersAF in both sexes. Women tried more AADs than men before ablation (1.13 vs. 0.98; p = .002). Male and female patients had no statistically significant difference in (a) arrhythmia recurrence at 1-year post ablation (27.7% vs. 30%; p = .38) or (b) procedural complication rate (1.8% vs. 3.1%; p = .56). CONCLUSION: Female patients were older and had higher CHA2 DS2 -VASc scores compared to males at the time of AF ablation. Women tried more AADs than men before ablation. One-year arrhythmia recurrence rates and procedural complications were similar in both sexes. No sex-based differences were observed in safety and efficacy of ablation.

Relationship between amiodarone response prior to ablation and 1-year outcomes of catheter ablation for atrial fibrillation.

INTRODUCTION: Catheter ablation for atrial fibrillation (AF) is a common therapeutic strategy for patients with either paroxysmal AF (PAF) or persistent AF (persAF), but long-term ablation success rates are imperfect. Maintenance of sinus rhythm immediately before ablation with antiarrhythmic drug (AAD) therapy has been associated with improved outcomes in patients undergoing ablation. Amiodarone has superior efficacy relative to other AADs. Whether failure of amiodarone to maintain sinus rhythm before ablation for either PAF or persAF is associated with poor outcomes is unknown. METHODS: A total of 307 patients who received amiodarone in a 1-year window before undergoing catheter ablation for AF were included. Patients were divided into amiodarone success (n = 183) and amiodarone failure (n = 124) groups based on the response to pre-ablation amiodarone treatment. Analysis of procedural outcomes as a function of response to amiodarone therapy was performed. Patients were followed for at least 12 months postablation, to assess outcomes (adverse events and arrhythmia recurrence). Procedural success was defined by the absence of documented arrhythmia (>30 s) without any antiarrhythmic agents beyond a 90-day blanking period. RESULTS: Following ablation for either PAF or persAF, freedom from any recurrent atrial arrhythmia at 1 year was 57.7% for the entire cohort. One-year freedom from recurrent arrhythmia in the amiodarone success group was comparable to that in the amiodarone failure group (55.7% vs. 60.5%; p = .54). Success rates following ablation did not vary by the response to amiodarone when analyzed for PAF or persAF subgroups. CONCLUSION: Failure to restore and maintain sinus rhythm with amiodarone before ablation for either PAF or persAF is not a predictor of ablation procedural failure. Amiodarone failure alone should not deter practitioners from considering ablation therapy for patients with AF.

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis.

Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the renin-angiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 renin-secreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant "renin recruitment" as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.

Endothelial Pannexin 1 Channels Control Inflammation by Regulating Intracellular Calcium.

The proinflammatory cytokine IL-1ß is a significant risk factor in cardiovascular disease that can be targeted to reduce major cardiovascular events. IL-1ß expression and release are tightly controlled by changes in intracellular Ca2+ ([Ca2+]i), which has been associated with ATP release and purinergic signaling. Despite this, the mechanisms that regulate these changes have not been identified. The pannexin 1 (Panx1) channels have canonically been implicated in ATP release, especially during inflammation. We examined Panx1 in human umbilical vein endothelial cells following treatment with the proinflammatory cytokine TNF-α. Analysis by whole transcriptome sequencing and immunoblot identified a dramatic increase in Panx1 mRNA and protein expression that is regulated in an NF-κB-dependent manner. Furthermore, genetic inhibition of Panx1 reduced the expression and release of IL-1ß. We initially hypothesized that increased Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. However, our data demonstrate that IL-1ß expression was not altered after direct ATP stimulation in human umbilical vein endothelial cells. Because Panx1 forms a large pore channel, we hypothesized it may permit Ca2+ diffusion into the cell to regulate IL-1ß. High-throughput flow cytometric analysis demonstrated that TNF-α treatments lead to elevated [Ca2+]i, corresponding with Panx1 membrane localization. Genetic or pharmacological inhibition of Panx1 reduced TNF-α-associated increases in [Ca2+]i, blocked phosphorylation of the NF-κB-p65 protein, and reduced IL-1ß transcription. Taken together, the data in our study provide the first evidence, to our knowledge, that [Ca2+]i regulation via the Panx1 channel induces a feed-forward effect on NF-κB to regulate IL-1ß synthesis and release in endothelium during inflammation.

Endothelial calreticulin deletion impairs endothelial function in aged mice.

Discrete calcium signals within the vascular endothelium decrease with age and contribute to impaired endothelial-dependent vasodilation. Calreticulin (Calr), a multifunctional calcium binding protein and endoplasmic reticulum (ER) chaperone, can mediate calcium signals and vascular function within the endothelial cells (ECs) of small resistance arteries. We found Calr protein expression significantly decreases with age in mesenteric arteries and examined the functional role of EC Calr in vasodilation and calcium mobilization in the context of aging. Third-order mesenteric arteries from mice with or without EC Calr knockdown were examined for calcium signals and constriction to phenylephrine (PE) or vasodilation to carbachol (CCh) after 75 wk of age. PE constriction in aged mice with or without EC Calr was unchanged. However, calcium signals and vasodilation to endothelial-dependent agonist carbachol were significantly impaired in aged EC Calr knockdown mice. Ex vivo incubation of arteries with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) significantly improved vasodilation in mice lacking EC Calr. Our data suggests diminished vascular Calr expression with age can contribute to the detrimental effects of aging on endothelial calcium regulation and vasodilation.NEW & NOTEWORTHY Calreticulin (Calr) is responsible for key physiological processes in endoplasmic reticulum, especially in aging tissue. In particular, endothelial Calr is crucial to vascular function. In this study, we deleted Calr from the endothelium and aged the mice up to 75 wk to examine changes in vascular function. We found two key differences: 1) calcium events in endothelium were severely diminished after muscarinic stimulation, which 2) corresponded with a dramatic decrease in muscarinic vasodilation. Remarkably, we were able to rescue the effect of Calr deletion on endothelial-dependent vasodilatory function using tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum stress that is currently in clinical trials.