Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background A spontaneous type 1 Brugada (spT1-BrS) pattern is a recognised marker of arrhythmic risk. However, its fluctuations may underestimate the risk in subjects with concealed T1-BrS at presentation. Aim To investigate the yield of repeat resting and high-lead 12-lead ECG and the additional role of 12-lead 24-hour Holter monitoring with leads V1 and V2 in standard and high precordial ECG positions (12-HPL Holter), and evaluate the prognostic role of spT1-BrS in a large, single-centre, cohort of BrS patients. Methods Three-hundred and eighty-one subjects with BrS enrolled in our Registry from 2008 to December 2021 and with at least 3 months follow-up data were included in this study. Seventy-seven had spT1-BrS pattern at presentation (Group 1), and 304 did not (Group 2). All received lifestyle recommendations and had regular follow-up appointments with 12-lead ECG; the majority of them were also screened with 12-HPL Holter. Medical notes and tracings were reviewed to identify a dynamic spT1-BrS and events at f-up (SCD/appropriate ICD shock). Results The mean age at presentation was 44±15 years; 52% of participants were males. All had at least 2 resting ECGs recorded; in 281 subjects at least one 12-HPL Holter was available (total 643, median 2, range 1-8). Over a median follow-up of 66 months (IQR 75), 37 subjects in Group 2 showed a spT1-BrS at least once: 10 during a repeat resting ECG, 2 during/after exercise tolerance test, 25 at 12-HPL Holter. The average time at spT1 appearance during follow-up was 23 months (range 1- 225). Those with a newly detected spT1-BrS were more frequently males and less likely to have a familial history of sudden cardiac death (Table 1). Excluding subjects with previous aCA/documented VT, 6 events occurred at f-up, all in subjects with spT1 (Figure 1). Univariate models showed that the presence of a spT1-BrS pattern was consistently associated with increased risk of events (at presentation: HR 10, 95% C.I. 1.8-54; at follow-up: HR 5.3, 95% C.I. 1.6-17). Conclusions A spontaneous T1-BrS can be detected in up to 12% of subjects with concealed BrS at presentation using 12-HPL Holter monitoring. Its presence is consistently associated with arrhythmic risk at f-up up, regardless of the time at detection. Prolonged ambulatory ECG monitoring is fundamental for risk stratification in this population.
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.
genotypes of hemostatic system.One patient (2,3%) had unfavorable heterozygous genotypes according to 5 studied variants predisposing to the development of thrombophilia; 8 (18%) had heterozygous genotypes of 4 SNP, 14 (32%) had heterozygous genotypes of 3 SNP, 14 (32%) had 2 SNPs, 4 (9% ) -1 SNP; only three (7%) individuals did not have adverse heterozygous alleles.The frequency of registration of genotypes predisposing to thromboses shown in table.At the same time, data are available on the prevalence of alleles 5G and 4G polymorphic variant of the PAI-1 gene in healthy adolescents in Russia.In particular, heterozygous genotypes of homozygotes both at the 5G allele and 4G allele are less frequently detected in patients with NOCA, and 5G / 4G are more often detected. Conclusion:The proportion of patients with NOCA among patients with ACS in 2015-2016 was 4.8%.The frequency of adverse allelic variants hemostatic gene polymorphisms associated with risk of thrombophilia in patients with ACS and NOCA was 98%.
Background/Purpose: Perivascular adipose tissue (PVAT) releases factors which are vital in regulating vascular tone.Loss of function will lead to an increase in arterial tone, and may contribute to development of hypertension and type-II diabetes.In obesity, sympathetic nerves become pathologically overactive, which may lead to desensitisation and loss of PVAT function.Therefore, the purpose of this study was to examine sympathetic function within PVAT, and the potential for exercise in restoring PVAT function in obesity.Methods: Mouse mesenteric arteries (<250μm, +/-PVAT) were dissected from healthy, obese, and exercised obese mice.Electrical field stimulation (0.1-30Hz, 20V, 0.2ms pulse, 4s train) was used to activate sympathetic nerves, and contractility was characterised using wire myography.Pharmacological sympathetic denervation of healthy PVAT was achieved using the catecholamine toxin 6hydroxydopamine (2μM).The role of β3-adrenoceptors was investigated using the agonist CL-316,243 (10μM) and antagonist SR59203A (1μM).Immunohistochemistry was used to examine β3-adrenoceptor expression, and the inflammatory cytokine; tumour necrosis factor alpha (TNFα).The role of the adipokine, adiponectin, was examined using exogenous adiponectin (5μg/ml), and a blocking peptide for adiponectin receptor 1 (ABP, 5μg/ml).Results: High fat feeding in mice resulted in an obese, hypertensive, and diabetic phenotype.In obese mice subjected to forced swimming, hypertension and diabetes was reversed; independent of weight loss.In vitro, electrical activation of nerves within healthy PVAT elicited an anti-contractile effect on the arteries; which was abolished using sympathetic denervation.The PVAT anti-contractile effect was absent in obese arteries, and was restored in obese exercised mice.In healthy and obese exercised PVAT, the β3-adrenoceptor antagonist SR59203A reduced the anti-contractile effect; however in obesity the β3-adrenoceptor agonist CL-316,243 could not restore function.Using immunohistochemistry, β3adrenoceptor expression was reduced in obesity, and restored in exercise.TNFα was significantly increased in obese PVAT, and reduced in obese exercised PVAT.Exogenous application of adiponectin induced vasodilation of healthy and obese exercised arteries, and application of ABP reduced PVAT anti-contractile effect.However, in obese vessels exogenous adiponectin no longer exerted a vasodilator effect.Conclusions: Healthy PVAT sympathetic nerve stimulation activates adipocyte β3-adrenoreceptors, which triggers the release of adiponectin; exerting an anticontractile effect on the vessel.This effect was lost in obesity, which may contribute to development of hypertension and type-II diabetes.Healthy sympathetic hyperstimulation using exercise reduced inflammation of obese PVAT, and restored PVAT dysfunction in obesity.In addition, exercise normalised glucose, insulin, and blood pressure, independent of weight loss.
Abstract Introduction/Background The Care Quality Commission (CQC) has recently raised concerns around resuscitation decisions in the UK. In our hospital an early resuscitation decision is made on admission, often by junior doctors, and documented in electronic notes. Concerns have been raised about the veracity of these discussions in patients with implantable cardioverter-defibrillators (ICD's). We investigated resuscitation status as documented on the electronic record for our ICD population. Methods The ICD database was interrogated in 2020 for patients under current follow-up. Baseline demographics, hospital admissions over the past 5 years and ICD indications were documented from the electronic hospital records. All patients with an electronic do-not-resuscitate (DNR) flag on the electronic system were recorded, as were any documented resuscitation discussions and ICD deactivations between 2015 and 2020. Any patient deaths were recorded and correlated with resuscitation status and ICD status at the time of death. Results Six-hundred and thirty-six patients with ICD's (transvenous, subcutaneous and CRT defibrillators) were identified under follow-up for the study period. The mean age of the population was 68 years old. 251 had an ischaemic cardiomyopathy, 209 had dilated cardiomyopathy, 50 prior ventricular fibrillation or tachycardia, 40 hypertrophic cardiomyopathy, 26 ARVC and the rest a channelopathy, congenital heart disease, sarcoidosis or valvular heart disease. Thirty-seven of the 636 patients were flagged on the electronic record as being not for resuscitation (5.9%). They had a mean age of 79 and 54% had an ischaemic cardiomyopathy. Of these, only 15 (39%) had their ICD deactivated and only 12 of those at the time of the resuscitation decision (32%). 15 of the 37 (39%) patients made DNR have subsequently died. Six of these (40%) had an active ICD at the time of death. In the 257 patients who had had a hospital admission in the study period, 34 were made not for resuscitation during the admission (13%) of whom 11 had their ICD deactivated at the time of discussion (32%). Patients with a DNR flag and an “active” ICD were contacted about deactivation of their ICD and offered discussion with a cardiologist or specialist nurse about ICD deactivation. Of these 9/27 (33%) stated that they wanted resuscitation and the alert was removed and the ICD kept on, although 3 subsequently had the device deactivated. Conclusions In this study the majority of patients with ICD's who were made not for resuscitation on admission to hospital did not have their ICD therapies switched off, therefore putting them at risk of unnecessary ICD shocks. In addition, one third these patients subsequently chose to be for resuscitation after discussion. These complex decisions would be improved with the early involvement of cardiologists and specialist nurses. Funding Acknowledgement Type of funding sources: None.
Objective: Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure, and evidence suggests that sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of beta3-adrenoceptors. In obesity there is sympathetic over-activity, which may result in a loss of PVAT function and subsequent hypertension. Therefore we examined beta3-adrenoceptor function in obesity. Design and method: Electrical field stimulation (EFS) profiles of healthy and obese mouse mesenteric arteries (<200um, +/−PVAT) were characterised using wire myography (0.1–30 Hz, 20 V, 0.2ms pulse duration, 4 s train duration). To demonstrate the release of an anti-contractile factor in health, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT denuded vessel. Beta3-adrenoceptor function was investigated using the agonist CL-316,243 (10uM) and antagonist SR59203A (100 nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100uM), and NOS activator histamine (100uM). Results: During EFS healthy PVAT elicited an anti-contractile effect; which was lost in obesity. Solution transfer from stimulated healthy exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming that stimulated PVAT releases a transferable anti-contractile factor. Solution transfer from obese PVAT had no effect on contraction. Inhibition of beta3-adrenoceptors in healthy PVAT using SR59230A significantly reduced the anti-contractile effect, whereas activation of beta3-adrenoceptors in obese PVAT using CL-316,243 did not restore function. Using immunohistochemistry, expression of beta3-adrenoceptors is reduced in obesity. In healthy PVAT, inhibition of NOS using L-NMMA abolished the anti-contractile effect. In obese PVAT, activation of NOS using histamine was able to restore the anti-contractile function. Conclusions: These results demonstrate that in health PVAT releases an anti-contractile factor via activation of beta3-adrenoreceptors, which downstream triggers the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by beta3-activation, but is restored by activation of NOS. This reveals that in obesity beta3-adrenoreceptors are downregulated, leading to a loss of anti-contractile function, which may contribute to the development of hypertension. Targeting the NOS pathway may restore anti-contractile function, and treat the vascular complications of obesity.
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.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.PVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the β3 -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.We have shown that adipocyte-located β3 -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.
Abstract 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 β 3 -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 β 3 -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 β 3 -adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β 3 -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.
The Care Quality Commission (CQC) has recently raised concerns around resuscitation decisions in the UK. In our hospital an early resuscitation decision is made on admission, often by junior doctors, and documented in electronic notes. Concerns have been raised about the veracity of these discussions in patients with implantable cardioverter-defibrillators (ICD's). We investigated resuscitation status as documented on the electronic record for our ICD population.
Methods
The ICD database was interrogated in 2020 for patients under current follow-up. Baseline demographics, hospital admissions over the past 5 years and ICD indications were documented from the electronic hospital records. All patients with an electronic do-not-resuscitate (DNR) flag on the electronic system were recorded, as were any documented resuscitation discussions and ICD deactivations between 2015 and 2020. Any patient deaths were recorded and correlated with resuscitation status and ICD status at the time of death.
Results
Six-hundred and thirty-six patients with ICD's (transvenous, subcutaneous and CRT defibrillators) were identified under follow-up for the study period. The mean age of the population was 68 years old. 251 had an ischaemic cardiomyopathy, 209 had dilated cardiomyopathy, 50 prior ventricular fibrillation or tachycardia, 40 hypertrophic cardiomyopathy, 26 ARVC and the rest a channelopathy, congenital heart disease, sarcoidosis or valvular heart disease. Thirty-seven of the 636 patients were flagged on the electronic record as being not for resuscitation (5.9%). They had a mean age of 79 and 54% had an ischaemic cardiomyopathy. Of these, only 15 (39%) had their ICD deactivated and only 12 of those at the time of the resuscitation decision (32%). 15 of the 37 (39%) patients made DNR have subsequently died. Six of these (40%) had an active ICD at the time of death. In the 257 patients who had had a hospital admission in the study period, 34 were made not for resuscitation during the admission (13%) of whom 11 had their ICD deactivated at the time of discussion (32%). Patients with a DNR flag and an 'active' ICD were contacted about deactivation of their ICD and offered discussion with a cardiologist or specialist nurse about ICD deactivation. Of these 9/27 (33%) stated that they wanted resuscitation and the alert was removed and the ICD kept on, although 3 subsequently had the device deactivated.
Conclusions
In this study the majority of patients with ICD's who were made not for resuscitation on admission to hospital did not have their ICD therapies switched off, therefore putting them at risk of unnecessary ICD shocks. In addition, one third these patients subsequently chose to be for resuscitation after discussion. These complex decisions would be improved with the early involvement of cardiologists and specialist nurses.
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