The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study.

AIMS: Brugada syndrome (BrS) diagnosis and risk stratification rely on the presence of a spontaneous type 1 (spT1) electrocardiogram (ECG) pattern; however, its spontaneous fluctuations may lead to misdiagnosis and risk underestimation. This study aims to assess the role for repeat high precordial lead (HPL) resting and ambulatory ECG monitoring in identifying a spT1, and evaluate its prognostic role. METHODS AND RESULTS: HPL resting and ambulatory monitoring ECGs of BrS subjects were reviewed retrospectively, and the presence of a spT1 associated with ventricular dysrhythmias and sudden cardiac death (SCD). Three-hundred and fifty-eight subjects (77 with spT1 pattern at presentation, Group 1, and 281 without, Group 2) were included. In total, 1651 resting HPL resting and 621 ambulatory monitoring ECGs were available for review, or adequately described. Over a median follow-up of 72 months (interquartile range - IQR - 75), 42/77 (55%) subjects in Group 1 showed a spT1 in at least one ECG. In Group 2, 36/281 subjects (13%) had a newly detected spT1 (1.9 per 100 person-year) and 23 on an HPL ambulatory recording (8%). Seven previously asymptomatic subjects, five of whom had a spT1 (four at presentation and one at follow-up), experienced arrhythmic events; survival analysis indicated that a spT1, either at presentation or during lifetime, was associated with events. Univariate models showed that a spT1 was consistently associated with increased risk [spT1 at presentation: hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.4-28, P = 0.016; spT1 at follow-up: HR 3.1, 95% CI 1.3-7.2, P = 0.008]. CONCLUSION: Repeated ECG evaluation and HPL ambulatory monitoring are vital in identifying transient spT1 Brugada pattern and its associated risk.

Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise.

PURPOSE: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and ß3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function. METHODS: Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of ß3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT. RESULTS: High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via ß3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing ß3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored. CONCLUSION: Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Role of Sympathetic Nerves and Adipocyte Catecholamine Uptake in the Vasorelaxant Function of Perivascular Adipose Tissue.

OBJECTIVE: Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on resistance arteries which is vital in regulating arterial tone. Activation of ß3-adrenoceptors by sympathetic nerve-derived NA (noradrenaline) may be implicated in this effect and may stimulate the release of the vasodilator adiponectin from adipocytes. Understanding the mechanisms responsible is vital for determining how PVAT may modify vascular resistance in vivo. APPROACH AND RESULTS: Electrical field stimulation profiles of healthy C57BL/6J mouse mesenteric resistance arteries were characterized using wire myography. During electrical field stimulation, PVAT elicits a reproducible anticontractile effect, which is endothelium independent. To demonstrate the release of an anticontractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT-denuded vessel. Post-transfer contractility was significantly reduced confirming that stimulated PVAT releases a transferable anticontractile factor. Sympathetic denervation of PVAT using tetrodotoxin or 6-hydroxydopamine completely abolished the anticontractile effect. ß3-adrenoceptor antagonist SR59203A reduced the anticontractile effect, although the PVAT remained overall anticontractile. When the antagonist was used in combination with an OCT3 (organic cation transporter 3) inhibitor, corticosterone, the anticontractile effect was completely abolished. Application of an adiponectin receptor-1 blocking peptide significantly reduced the anticontractile effect in +PVAT arteries. When used in combination with the ß3-adrenoceptor antagonist, there was no further reduction. In adiponectin knockout mice, the anticontractile effect is absent. CONCLUSIONS: The roles of PVAT are 2-fold. First, sympathetic stimulation in PVAT triggers the release of adiponectin via ß3-adrenoceptor activation. Second, PVAT acts as a reservoir for NA, preventing it from reaching the vessel and causing contraction.

Obesity-Related Perivascular Adipose Tissue Damage Is Reversed by Sustained Weight Loss in the Rat.

OBJECTIVE: Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists, and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterized after weight loss induced by caloric restriction, which is often the first line treatment for obesity. APPROACH AND RESULTS: Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local tumor necrosis factor-α and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced tumor necrosis factor-α, and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalization of plasma adipokine levels, including leptin and insulin. CONCLUSIONS: We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly endothelial nitric oxide synthase, as potential targets for the treatment of PVAT dysfunction associated with obesity and metabolic syndrome.

MIRACLE2 Score Compared With Downtime and Current Selection Criterion for Invasive Cardiovascular Therapies After OHCA.

BACKGROUND: The MIRACLE2 score is the only risk score that does not incorporate and can be used for selection of therapies after out-of-hospital cardiac arrest (OHCA). OBJECTIVES: This study sought to compare the discrimination performance of the MIRACLE2 score, downtime, and current randomized controlled trial (RCT) recruitment criteria in predicting poor neurologic outcome after out-of-hospital cardiac arrest (OHCA). METHODS: We used the EUCAR (European Cardiac Arrest Registry), a retrospective cohort from 6 centers (May 2012-September 2022). The primary outcome was poor neurologic outcome on hospital discharge (cerebral performance category 3-5). RESULTS: A total of 1,259 patients (total downtime = 25 minutes; IQR: 15-36 minutes) were included in the study. Poor outcome occurred in 41.8% with downtime <30 minutes and in 79.3% for those with downtime >30 minutes. In a multivariable logistic regression analysis, MIRACLE2 had a stronger association with outcome (OR: 2.23; 95% CI: 1.98-2.51; P < 0.0001) than zero flow (OR: 1.07; 95% CI: 1.01-1.13; P = 0.013), low flow (OR: 1.04; 95% CI: 0.99-1.09; P = 0.054), and total downtime (OR: 0.99; 95% CI: 0.95-1.03; P = 0.52). MIRACLE2 had substantially superior discrimination for the primary endpoint (AUC: 0.877; 95% CI: 0.854-0.897) than zero flow (AUC: 0.610; 95% CI: 0.577-0.642), low flow (AUC: 0.725; 95% CI: 0.695-0.754), and total downtime (AUC: 0.732; 95% CI: 0.701-0.760). For those modeled for exclusion from study recruitment, the positive predictive value of MIRACLE2 ≥5 for poor outcome was significantly higher (0.92) than the CULPRIT-SHOCK (Culprit lesion only PCI Versus Multivessel PCI in Cardiogenic Shock) (0.80), EUROSHOCK (Testing the value of Novel Strategy and Its Cost Efficacy In Order to Improve the Poor Outcomes in Cardiogenic Shock) (0.74) and ECLS-SHOCK (Extra-corporeal life support in Cardiogenic shock) criteria (0.81) (P < 0.001). CONCLUSIONS: The MIRACLE2 score has superior prediction of outcome after OHCA than downtime and higher discrimination of poor outcome than the current RCT recruitment criteria. The potential for the MIRACLE2 score to improve the selection of OHCA patients should be evaluated formally in future RCTs.

ß3 -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries.

BACKGROUND AND PURPOSE: In response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline-induced PVAT anticontractile effect. EXPERIMENTAL APPROACH: In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer. KEY RESULTS: PVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the ß3 -adrenoceptor agonist, CL-316243, reduced the vasoconstrictor effect of phenylephrine but not noradrenaline. Kv 7 channel inhibition using XE 991 reversed the noradrenaline-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with noradrenaline and CL-316243, but not phenylephrine, was associated with increased adipocyte-derived NO production, and the contractile response to noradrenaline was augmented following incubation of exogenous PVAT with L-NMMA. PVAT from eNOS-/- mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with noradrenaline stimulation implicating Gαs signalling in this process. CONCLUSIONS AND IMPLICATIONS: We have shown that adipocyte-located ß3 -adrenoceptor stimulation leads to activation of Gαs signalling pathways with increased cAMP and the release of adipocyte-derived NO. This process is dependent upon Kv 7 channel function. We conclude that adipocyte-derived NO plays a central role in anticontractile activity when rodent PVAT is stimulated by noradrenaline.