The SIDECAR project: S-IcD registry in European paediatriC and young Adult patients with congenital heaRt defects.

AIMS: Subcutaneous-implantable cardiac defibrillators (S-ICDs) are used increasingly to prevent sudden cardiac death in young patients. This study was set up to gain insight in the indications for S-ICD, possible complications, and their predictors and follow-up results. METHODS AND RESULTS: A multicentre, observational, retrospective, non-randomized, standard-of-care registry on S-ICD outcome in young patients with congenital heart diseases (CHDs), inherited arrhythmias (IAs), idiopathic ventricular fibrillation (IVF), and cardiomyopathies (CMPs). Anthropometry was registered as well as implantation technique, mid-term device-related complications, and incidence of appropriate/inappropriate shocks (IASs). Data are reported as median (interquartile range) or mean ± standard deviation. Eighty-one patients (47% CMPs, 20% CHD, 21% IVF, and 12% IA), aged 15 (14-17) years, with body mass index (BMI) 21.8 ± 3.8 kg/m2, underwent S-ICD implantation (primary prevention in 59%). This was performed with two-incision technique in 81% and with a subcutaneous pocket in 59%. Shock and conditional zones were programmed at 250 (200-250) and 210 (180-240) b.p.m., respectively. No intraoperative complications occurred. Follow up was 19 (6-35) months: no defibrillation failure occurred, 17% of patients received appropriate shocks, 13% of patients received IAS (supraventricular tachycardias 40%, T-wave oversensing 40%, and non-cardiac oversensing 20%). Reprogramming, proper drug therapy, and surgical revision avoided further IAS. Complications requiring surgical revision occurred in 9% of patients, with higher risks in patients with three-incision procedures [hazard ratio (HR) 4.3, 95% confidence interval (95% CI) 0.5-34, P = 0.038] and BMI < 20 (HR 5.1, 95% CI 1-24, P = 0.031). CONCLUSION: This multicentre European paediatric registry showed good S-ICD efficacy and safety in young patients. Newer implantation techniques and BMI > 20 showed better outcome.

Role of KCNQ channels in skeletal muscle arteries and periadventitial vascular dysfunction.

KCNQ channels have been identified in arterial smooth muscle. However, their role in vasoregulation and chronic vascular diseases remains elusive. We tested the hypothesis that KCNQ channels contribute to periadventitial vasoregulation in peripheral skeletal muscle arteries by perivascular adipose tissue and that they represent novel targets to rescue periadventitial vascular dysfunction. Two models, spontaneously hypertensive rats and New Zealand obese mice, were studied using quantitative polymerase chain reaction, the patch-clamp technique, membrane potential measurements, myography of isolated vessels, and blood pressure telemetry. In rat Gracilis muscle arteries, anticontractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine but not by other selective K(+) channel inhibitors. Accordingly, XE991 and linopirdine blocked noninactivating K(+) currents in freshly isolated Gracilis artery smooth muscle cells. mRNAs of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In spontaneously hypertensive rats, the anticontractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared with Wistar rats. However, the vasodilator effects of KCNQ channel openers and mRNA expression of KCNQ channels were normal. Furthermore, KCNQ channel openers restored the diminished anticontractile effects of perivascular fat in spontaneously hypertensive rats. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independent of ganglionic blockade. Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries, and KCNQ channel opening may be an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.

Cigarette smoke elicits relaxation of renal arteries.

BACKGROUND: Epidemiological studies suggest that cigarette smoking - probably by eliciting hyperperfusion - increases glomerular filtration rate; thus, we hypothesized that cigarette smoke affects the vasomotor tone of renal arteries. MATERIALS AND METHODS: Acute changes in the resistance index of a segmental renal artery were measured in healthy individuals during smoking. In addition, the effects of water-soluble components of cigarette smoke on the isometric tension of isolated rat renal arteries were investigated in various conditions. RESULTS: In humans, cigarette smoking transiently reduced the resistance index of the renal artery segments (83·25 ± 5·67% of the baseline, P < 0·05). In the experimental model, water-soluble components of cigarette smoke (wCS) - either nicotinic or nicotine-free - elicited dose-dependent relaxations of rat isolated renal arteries (1% solution of nicotinic wCS: 41·18 ± 14·86% relaxation, 5% nicotinic wCS: 79·28 ± 8·91% relaxation, 10% nicotinic wCS 90·3 ± 6·1% relaxation, P < 0·05), which were not affected by removal of the endothelium, or by the soluble guanylate cyclase inhibitor oxadiazolo-quinoxalin-1, or the non specific potassium channel blocker tetraethylammonium, or the K(ATP) channel blocker glibenclamide. However, relaxations were reduced by catalase (1000 U mL⁻¹ catalase + 5% nicotinic wCS: 49·71 ± 18·4%, P < 0·05) and enhanced by superoxide dismutase (200 U mL⁻¹ SOD + 5% nicotinic wCS: 95·7 ± 2·3%, P < 0·05). CONCLUSIONS: On the basis of these findings, we propose that cigarette smoking could contribute to the increased glomerular filtration rate observed in healthy smokers. In addition, cigarette smoke via hydrogen peroxide mediation reduces vasomotor tone of renal arteries, which could lead to hyperperfusion of kidneys.

Amplification of EDHF-type vasodilatations in TRPC1-deficient mice.

BACKGROUND AND PURPOSE: TRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca(2+) handling. However, little is known about their role in endothelium-dependent vasodilatations including endothelium-derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca(2+) -activated K(+) channels (K(Ca)). To provide molecular information on the role of TRPC1 for K(Ca) function and the EDHF signalling complex, we examined endothelium-dependent and independent vasodilatations, K(Ca) currents and smooth muscle contractility in TRPC1-deficient mice (TRPC1-/-). EXPERIMENTAL APPROACH: Vascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca(2+) imaging for studying K(Ca) channel functions and Ca(2+) sparks. KEY RESULTS: TRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM-34- and UCL1684-sensitive EDHF-type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO-mediated vasodilatations were unchanged. TRPC1-/- exhibited enhanced EDHF-type vasodilatations in resistance-sized arterioles in vivo associated with reduced spontaneous tone. Endothelial IK(Ca) /SK(Ca)-type K(Ca) currents, smooth muscle cell Ca(2+) sparks and associated BK(Ca)-mediated spontaneous transient outward currents were unchanged in TRPC1-/-. Smooth muscle contractility induced by receptor-operated Ca(2+) influx or Ca(2+) release and endothelium-independent vasodilatations were unaltered in TRPC1-/-. TRPC1-/- exhibited lower systolic blood pressure as determined by tail-cuff blood pressure measurements. CONCLUSIONS AND IMPLICATIONS: Our data demonstrate that TRPC1 acts as a negative regulator of endothelial K(Ca) channel-dependent EDHF-type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF-K(Ca) signalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure.

Adiponectin is a novel humoral vasodilator.

OBJECTIVES: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor(s) (ADRF) that opens K(v) channels in rat arteries. Visceral fat accumulation causes adipocyte dysfunction, including hyposecretion of adiponectin. We tested the hypothesis that ADRF might be adiponectin and that adiponectin plays a role in the paracrine control of vascular tone by perivascular adipose tissue. METHODS AND RESULTS: We studied Sprague-Dawley rats, wild-type and adiponectin gene-deficient (Apn 1-/-) mice, and New Zealand obese (NZO) mice. In rat aortas, recombinant adiponectin at serum levels (2-5 microg/ml) inhibited serotonin-induced contractions. The effects were abolished by K(v) channel inhibition with 4-aminopyridine (4-AP, 2 mM). Similar effects were observed in NZO mouse mesenteric arteries. To study vascular function in Apn 1-/- mice, the mesenteric vascular bed was isolated, cannulated, and perfused at a constant 4-5-ml/min flow in the absence and presence of serotonin. 4-AP (2 mM) induced a similar increase in perfusion pressure in the Apn 1-/- perfused isolated mesenteric vascular bed, compared to wild-type mice. Removal of perivascular fat increased the vasoconstrictor responses, but abolished the 4-AP effects. The anti-contractile effects of perivascular fat were similar in mesenteric artery and aortic rings from Apn 1-/- and wild-type mice. Despite high adiponectin levels, the anti-contractile effects of perivascular fat were diminished in mesenteric arteries of NZO mice with age. CONCLUSION: Adiponectin is a novel humoral vasodilator that relaxes aortic and mesenteric rings by opening K(v) channels. Similar to the rat, perivascular adipose tissue of the mouse harbors an ADRF, which is malfunctional in NZO mice and is not adiponectin.

Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12.

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.