Background: The Subcutaneous ICD (S-ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, less left ventricular dysfunction and received more inappropriate shocks (IAS) than in typical transvenous (TV)-ICD trials. The UNTOUCHED trial was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms. Methods: Primary prevention patients with left ventricular ejection fraction (LVEF) ≤ 35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥ 250 beats per minute (bpm) and morphology discrimination for rates ≥200 and < 250 bpm. Patients were followed for 18 months. The primary endpoint was the IAS free rate compared to a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study. Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of endpoints. Results: S-ICD implant was attempted in 1116 patients and 1111 patients were included in post-implant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% women, 23.4% black race, 53.5% with ischemic heart disease, 87.7% with symptomatic heart failure and a mean LVEF of 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (Lower confidence limit LCL 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the three-incision technique, no history of atrial fibrillation, and ischemic etiology. The 18-month all cause shock free rate was 90.6% (LCL 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication free rate at 18 months was 92.7%. Conclusions: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of co-morbidities in comparison to earlier S-ICD trials. The inappropriate shock rate (3.1% at one year) is the lowest reported for the S-ICD and lower than many TV ICD studies using contemporary programming to reduce IAS. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02433379

Abstract-In the vasculature, ATP-sensitive potassium channels (K ATP ) channels regulate vascular tone. Mice with targeted gene disruptions of K ATP subunits expressed in vascular smooth muscle develop spontaneous coronary vascular spasm and sudden death. From these models, it was hypothesized that the loss of K ATP channel activity in arterial vascular smooth muscle was responsible for coronary artery spasm. We now tested this hypothesis using a transgenic strategy where the full-length sulfonylurea receptor containing exon 40 was expressed under the control of a smooth muscle-specific SM22␣ promoter. Two transgenic founder lines were generated and independently bred to sulfonylurea receptor 2 (SUR2) null mice to generate mice that restored expression of K ATP channels in vascular smooth muscle. Transgenic expression of the sulfonylurea receptor in vascular smooth muscle cells was confirmed by detecting mRNA and protein from the transgene. Functional restoration was determined by recording pinacidil-based K ATP current by whole cell voltage clamping of isolated aortic vascular smooth muscle cells isolated from the transgenic restored mice. Despite successful restoration of K ATP channels in vascular smooth muscle, transgene-restored SUR2 null mice continued to display frequent episodes of spontaneous ST segment elevation, identical to the phenotype seen in SUR2 null mice. As in SUR2 null mice, ST segment elevation was frequently followed by atrioventricular heart block. ST segment elevation and coronary perfusion pressure in the restored mice did not differ significantly between transgene-negative and transgene-positive SUR2 null mice. We conclude that spontaneous coronary vasospasm and sudden death in SUR2 null mice arises from a coronary artery vascular smooth muscle-extrinsic process.

Adenosine triphosphate sensitive potassium (K ATP ) channels are thought to mediate stress response by sensing intracellular ATP concentration. Cardiomyocyte K ATP channels are composed of the poreforming Kir6.2 subunit and the regulatory sulfonylurea receptor 2 (SUR2). We studied the response to acute isoproterenol in SUR2 null mice as a model of acute adrenergic stress and found that the episodic coronary vasospasm observed at baseline in SUR2 null mice was alleviated. Similar results were observed following administration of a nitric oxide donor consistent with a vasodilatory role. Langendorff-perfused hearts were subjected to global ischemia, and hearts from SUR2 null mice exhibited significantly reduced infarct size (54±4 vs 30±3%) and improved cardiac function compared to control mice. SUR2 null mice have hypertension and develop cardiac hypertrophy. However, despite longstanding hypertension, fibrosis was absent in SUR2 null mice. SUR2 null mice were administered nifedipine to block baseline coronary vasospasm, and hearts from nifedipinetreated SUR2 null mice exhibited increased infarct size compared to untreated SUR2 null mice (42 ±3 % vs 54±3%). We conclude that conventional sarcolemmal cardiomyocyte K ATP channels containing full length SUR2 are not required for mediating the response to acute cardiovascular stress.

Polyurethane (PU55D) and copolymer materials have low thermal stability and are highly susceptible to thermal damage during cautery. Implanting physicians should be aware of the lead insulation materials being used during implant procedures and their properties. The use of direct contact cautery on transvenous leads should be minimized to avoid damage to the lead, especially on leads with polyurethane or copolymer outer insulations.

A radiofrequency powered transseptal needle can be used to perform TSP safely and successfully without the need for significant mechanical force, even in patients who have undergone TSP previously. Additional studies are needed to determine whether a powered transseptal needle should be used routinely.