AimsThe totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transvenous ICD system to minimize intravascular lead complications. There are limited data describing the long-term performance of the S-ICD. This paper presents the first large international patient population collected as part of the EFFORTLESS S-ICD Registry.Methods and resultsThe EFFORTLESS S-ICD Registry is a non-randomized, standard of care, multicentre Registry designed to collect long-term, system-related, clinical, and patient reported outcome data from S-ICD implanted patients since June 2009. Follow-up data are systematically collected over 60-month post-implant including Quality of Life. The study population of 472 patients of which 241 (51%) were enrolled prospectively has a mean follow-up duration of 558 days (range 13–1342 days, median 498 days), 72% male, mean age of 49 ± 18 years (range 9–88 years), 42% mean left ventricular ejection fraction. Complication-free rates were 97 and 94%, at 30 and 360 days, respectively. Three hundred and seventeen spontaneous episodes were recorded in 85 patients during the follow-up period. Of these episodes, 169 (53%) received therapy, 93 being for Ventricular Tachycardia/Fibrillation (VT/VF). One patient died of recurrent VF and severe bradycardia. Regarding discrete VT/VF episodes, first shock conversion efficacy was 88% with 100% overall successful clinical conversion after a maximum of five shocks. The 360-day inappropriate shock rate was 7% with the vast majority occurring for oversensing (62/73 episodes), primarily of cardiac signals (94% of oversensed episodes).ConclusionThe first large cohort of real-world data from an International patient S-ICD population demonstrates appropriate system performance with clinical event rates and inappropriate shock rates comparable with those reported for conventional ICDs. Clinical trial registration URL: . Unique identifier NCT01085435.

Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca 2 ϩ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (E m ) or HPV. However, the Kv channels involved in E m and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1.

The cellular mechanisms that determine differences in reactivity of arteries of varying size and origin are unknown. We evaluated the hypothesis that there is diversity in the distribution of K+ channels between vascular smooth muscle (VSM) cells within a single segment of the pulmonary arteries (PAs) and that there are differences in the prevalence of these cell types between conduit and resistance arteries, which contribute to segmental differences in the vascular response to NO and hypoxia. Three types of VSM cells can be identified in rat PAs on the basis of their whole-cell electrophysiological properties- current density and the pharmacological dissection of whole-cell K+ current(I(K))-and morphology. Cells are referred to as "K(Ca), K(Dr), or mixed," acknowledging the type of K+ channel that dominates the IK: the Ca2+-sensitive (K(Ca)) channel, delayed rectifier (K(Dr)) channel, or a mixture of both. The three cell types were identified by light and electron microscopy. K(Ca) cells are large and elongated, and they have low current density and currents that are inhibited by tetraethylammonium (5 mmol/L) or charybdotoxin (100 nmol/L). K(Dr) cells are smaller, with a perinuclear bulge, but have high current density and currents that are inhibited by 4-aminopyridine (5 mmol/L). Conduit arteries contain significant numbers of K(Ca) cells, whereas resistance arteries have a majority of K(Dr) cells and few K(Ca) cells. NO rapidly and reversibly increases I(K) and hyperpolarizes K(Ca) cells because of an increase in open probability of a 170-pS K(Ca) channel. Hypoxia depolarizes K(Dr) cells by rapidly and reversibly inhibiting one or more of the tonically active K(Dr) channels (including a 37-pS channel) that control resting membrane potential. The effects of both hypoxia and NO on K+ channels are evident at negative membrane potentials, supporting their physiological relevance. The functional correlate of this electrophysiological diversity is that K(Dr)-enriched resistance vessels constrict to hypoxia, whereas conduit arteries have a biphasic response predominated by relaxation. Although effective in both segments, NO relaxes conduit more than resistance rings, in both cases by a cGMP-dependent mechanism. We conclude that regional electrophysiological diversity among smooth muscle cells is a major determinant of segmental differences in vascular reactivity.

The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O 2 -responsive K ؉ channels. K ؉ channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K ؉ channels are not themselves ''O 2 sensors'' but rather respond to the reduced redox state created by hypoxic inhibition of candidate O 2 sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O 2 . Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K ؉ channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K ؉ current but lack the specificity to identify the O 2 -sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O 2 -sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages > airways and veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O 2 species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K ؉ current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O 2 sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O 2 sensor in mice.The pulmonary circulation is a low-resistance vascular bed. Within seconds of onset of alveolar hypoxia (1, 2), the small, muscular pulmonary arteries (PAs) serving the hypoxic area constrict. This hypoxic pulmonary vasoconstriction (HPV) diverts blood flow to better-ventilated alveoli, thereby matching ventilation to perfusion and optimizing systemic PO 2 .