Personalized pulmonary vein isolation with very high-power short-duration lesions guided by left atrial wall thickness: the QDOT-by-LAWT randomized trial.

AIMS: Pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) using very high-power short-duration (vHPSD) radiofrequency (RF) ablation proved to be safe and effective. However, vHPSD applications result in shallower lesions that might not be always transmural. Multidetector computed tomography-derived left atrial wall thickness (LAWT) maps could enable a thickness-guided switching from vHPSD to the standard-power ablation mode. The aim of this randomized trial was to compare the safety, the efficacy, and the efficiency of a LAWT-guided vHPSD PVI approach with those of the CLOSE protocol for PAF ablation (NCT04298177). METHODS AND RESULTS: Consecutive patients referred for first-time PAF ablation were randomized on a 1:1 basis. In the QDOT-by-LAWT arm, for LAWT ≤2.5 mm, vHPSD ablation was performed; for points with LAWT > 2.5 mm, standard-power RF ablation titrating ablation index (AI) according to the local LAWT was performed. In the CLOSE arm, LAWT information was not available to the operator; ablation was performed according to the CLOSE study settings: AI ≥400 at the posterior wall and ≥550 at the anterior wall. A total of 162 patients were included. In the QDOT-by-LAWT group, a significant reduction in procedure time (40 vs. 70 min; P < 0.001) and RF time (6.6 vs. 25.7 min; P < 0.001) was observed. No difference was observed between the groups regarding complication rate (P = 0.99) and first-pass isolation (P = 0.99). At 12-month follow-up, no significant differences occurred in atrial arrhythmia-free survival between groups (P = 0.88). CONCLUSION: LAWT-guided PVI combining vHPSD and standard-power ablation is not inferior to the CLOSE protocol in terms of 1-year atrial arrhythmia-free survival and demonstrated a reduction in procedural and RF times.

Scar architecture affects the electrophysiological characteristics of induced ventricular arrhythmias in hypertrophic cardiomyopathy.

AIMS: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) detects myocardial scarring, a risk factor for ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy (HCM). The LGE-CMR distinguishes core, borderzone (BZ) fibrosis, and BZ channels, crucial components of re-entry circuits. We studied how scar architecture affects inducibility and electrophysiological traits of VA in HCM. METHODS AND RESULTS: We correlated scar composition with programmed ventricular stimulation-inducible VA features using LGE intensity maps. Thirty consecutive patients were enrolled. Thirteen (43%) were non-inducible, 6 (20%) had inducible non-sustained, and 11 (37%) had inducible sustained mono (MMVT)- or polymorphic VT/VF (PVT/VF). Of 17 induced VA, 13 (76%) were MMVT that either ended spontaneously, persisted as sustained monomorphic, or degenerated into PVT/VF. Twenty-seven patients (90%) had LGE. Of these, 17 (57%) had non-sustained or sustained inducible VA. Scar mass significantly increased (P = 0.002) from non-inducible to inducible non-sustained and sustained VA patients in both the BZ and core components. Borderzone channels were found in 23%, 67%, and 91% of non-inducible, inducible non-sustained, and inducible sustained VA patients (P = 0.003). All 13 patients induced with MMVT or monomorphic-initiated PVT/VF had LGE. The origin of 10/13 of these VTs matched scar location, with 8/10 of these LGE regions showing BZ channels. During follow-up (20 months, interquartile range: 7-37), one patient with BZ channels and inducible PVT had an ICD shock for VF. CONCLUSION: Scar architecture determines inducibility and electrophysiological traits of VA in HCM. Larger studies should explore the role of complex LGE patterns in refining risk assessment in HCM patients.

Long-term clinical outcomes of patients with drug-induced type 1 Brugada electrocardiographic pattern: A nationwide cohort registry study.

BACKGROUND: There are limited real-world data on the extended prognosis of patients with drug-induced type 1 Brugada electrocardiogram (ECG). OBJECTIVE: We assessed the clinical outcomes and predictors of life-threatening arrhythmias in patients with drug-induced type 1 Brugada ECG. METHODS: This multicenter retrospective study, conducted at 21 Italian and Swiss hospitals from July 1997 to May 2021, included consecutive patients with drug-induced type 1 ECG. The primary outcome, a composite of appropriate ICD therapies and sudden cardiac death, was assessed along with the clinical predictors of these events. RESULTS: A total of 606 patients (mean age 49.7 ± 14.7 years; 423 [69.8%] men) were followed for a median of 60.3 months (interquartile range 23.0-122.4 months). Nineteen patients (3.1%) experienced life-threatening arrhythmias, with a median annual event rate of 0.5% over 5 years and 0.25% over 10 years. The SCN5A mutation was the only predictor of the primary outcome (hazard ratio 4.54; P = .002), whereas a trend was observed for unexplained syncope (hazard ratio 3.85; P = .05). In patients who were asymptomatic at presentation, the median annual rate of life-threatening arrhythmias is 0.24% over 5 years and increases to 1.2% if they have inducible ventricular fibrillation during programmed ventricular stimulation. CONCLUSION: In patients with drug-induced type 1 Brugada ECG, the annual risk of life-threatening arrhythmias is low, with the SCN5A mutation as the only independent predictor. Unexplained syncope correlated with worse clinical outcomes. Ventricular fibrillation inducibility at programmed ventricular stimulation significantly increases the median annual rate of life-threatening arrhythmias from 0.24% to 1.2% over 5 years.

Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: Role of age and heart failure phenotypes.

BACKGROUND: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes. METHODS: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments. RESULTS: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001). CONCLUSIONS: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes.

Assessing left atrial intramyocardial fat infiltration from computerized tomography angiography in patients with atrial fibrillation.

AIMS: Epicardial adipose tissue might promote atrial fibrillation (AF) in several ways, including infiltrating the underlying atrial myocardium. However, the role of this potential mechanism has been poorly investigated. The aim of this study is to evaluate the presence of left atrial (LA) infiltrated adipose tissue (inFAT) by analysing multi-detector computer tomography (MDCT)-derived three-dimensional (3D) fat infiltration maps and to compare the extent of LA inFAT between patients without AF history, with paroxysmal, and with persistent AF. METHODS AND RESULTS: Sixty consecutive patients with AF diagnosis (30 persistent and 30 paroxysmal) were enrolled and compared with 20 age-matched control; MDCT-derived images were post-processed to obtain 3D LA inFAT maps for all patients. Volume (mL) and mean signal intensities [(Hounsfield Units (HU)] of inFAT (HU -194; -5), dense inFAT (HU -194; -50), and fat-myocardial admixture (HU -50; -5) were automatically computed by the software. inFAT volume was significantly different across the three groups (P = 0.009), with post-hoc pairwise comparisons showing a significant increase in inFAT volume in persistent AF compared to controls (P = 0.006). Dense inFAT retained a significant difference also after correcting for body mass index (P = 0.028). In addition, more negative inFAT radiodensity values were found in AF patients. Regional distribution analysis showed a significantly higher regional distribution of LA inFAT at left and right superior pulmonary vein antra in AF patients. CONCLUSION: Persistent forms of AF are associated with greater degree of LA intramyocardial adipose infiltration, independently of body mass index. Compared to controls, AF patients present higher LA inFAT volume at left and right superior pulmonary vein antra.

Clinical course of hypertrophic cardiomyopathy patients implanted with a transvenous or subcutaneous defibrillator.

AIMS: The implantable cardioverter-defibrillator (ICD) is a life-saving therapy in patients with hypertrophic cardiomyopathy (HCM) at risk of sudden cardiac death. Implantable cardioverter-defibrillator complications are of concern. The subcutaneous ICD (S-ICD) does not use transvenous leads and is expected to reduce complications. However, it does not provide bradycardia and anti-tachycardia pacing (ATP). The aim of this study was to compare appropriate and inappropriate ICD interventions, complications, disease-related adverse events and mortality between HCM patients implanted with a S- or transvenous (TV)-ICD. METHODS AND RESULTS: Consecutive HCM patients implanted with a S- (n = 216) or TV-ICD (n = 211) were enrolled. Propensity-adjusted cumulative Kaplan-Meier curves and multivariate Cox proportional hazard ratios were used to compare 5-year event-free survival and the risk of events. The S-ICD patients had lower 5-year risk of appropriate (HR: 0.32; 95%CI: 0.15-0.65; P = 0.002) and inappropriate (HR: 0.44; 95%CI: 0.20-0.95; P = 0.038) ICD interventions, driven by a high incidence of ATP therapy in the TV-ICD group. The S- and TV-ICD patients experienced similar 5-year rate of device-related complications, albeit the risk of major lead-related complications was lower in S-ICD patients (HR: 0.17; 95%CI: 0.038-0.79; P = 0.023). The TV- and S-ICD patients displayed similar risk of disease-related complications (HR: 0.64; 95%CI: 0.27-1.52; P = 0.309) and mortality (HR: 0.74; 95%CI: 0.29-1.87; P = 0.521). CONCLUSION: Hypertrophic cardiomyopathy patients implanted with a S-ICD had lower 5-year risk of appropriate and inappropriate ICD therapies as well as of major lead-related complications as compared to those implanted with a TV-ICD. Long-term comparative follow-up studies will clarify whether the lower incidence of major lead-related complications will translate into a morbidity or survival benefit.

Modern subcutaneous implantable defibrillator therapy in patients with cardiomyopathies and channelopathies: data from a large multicentre registry.

AIMS: Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they have nearly normal life expectancy thanks to the protection against sudden cardiac death provided by the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) is an effective alternative to the transvenous ICD and has evolved over the years. This study aimed to evaluate the rate of inappropriate shocks (IS), appropriate therapies, and device-related complications in patients with cardiomyopathies and channelopathies who underwent modern S-ICD implantation. METHODS AND RESULTS: We enrolled consecutive patients with cardiomyopathies and channelopathies who had undergone implantation of a modern S-ICD from January 2016 to December 2020 and who were followed up until December 2022. A total of 1338 S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies. The rate of IS at 12 months was 4.6% [95% confidence interval (CI): 2.8-6.9] in patients with cardiomyopathies and 1.1% (95% CI: 0.1-3.8) in patients with channelopathies (P = 0.032). No significant differences were noted over a median follow-up of 43 months [hazard ratio (HR): 0.76; 95% CI: 0.45-1.31; P = 0.351]. The rate of appropriate shocks at 12 months was 2.3% (95% CI: 1.1-4.1) in patients with cardiomyopathies and 2.1% (95% CI: 0.6-5.3) in patients with channelopathies (P = 1.0). The rate of device-related complications was 0.9% (95% CI: 0.3-2.3) and 3.2% (95% CI: 1.2-6.8), respectively (P = 0.074). No significant differences were noted over the entire follow-up. The need for pacing was low, occurring in 0.8% of patients. CONCLUSION: Modern S-ICDs may be a valuable alternative to transvenous ICDs in patients with cardiomyopathies and channelopathies. Our findings suggest that modern S-ICD therapy carries a low rate of IS. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/Identifier: NCT02275637.

Clinical impact of aging on outcomes of cardioneuroablation for reflex syncope or functional bradycardia: Results from the cardionEuroabLation: patiEnt selection, imaGe integrAtioN and outComEs-The ELEGANCE multicenter study.

BACKGROUND: Cardioneuroablation (CNA) is a novel treatment for reflex syncope. The effect of aging on CNA efficacy is not fully understood. OBJECTIVE: The purpose of this study was to assess the impact of aging on candidacy and efficacy of CNA for treating vasovagal syncope (VVS), carotid sinus syndrome (CSS), and functional bradyarrhythmia. METHODS: The ELEGANCE (cardionEuroabLation: patiEnt selection, imaGe integrAtioN and outComEs) multicenter study assessed CNA in patients with reflex syncope or severe functional bradyarrhythmia. Patients underwent pre-CNA Holter electrocardiography (ECG), head-up tilt testing (HUT), and electrophysiological study. CNA candidacy and efficacy was assessed in 14 young (18-40 years), 26 middle-aged (41-60 years), and 20 older (>60 years) patients. RESULTS: Sixty patients (37 men; mean age 51 ± 16 years) underwent CNA. The majority (80%) had VVS, 8% had CSS, and 12% had functional bradycardia/atrioventricular block. Pre-CNA Holter ECG, HUT, and electrophysiological findings did not differ across age groups. Acute CNA success was 93%, without differences between age groups (P = .42). Post-CNA HUT response was negative in 53%, vasodepressor in 38%, cardioinhibitory in 7%, and mixed in 2%, without differences across age groups (P = .59). At follow-up (8 months, interquartile range 4-15), 53 patients (88%) were free of symptoms. Kaplan-Meier curves did not show differences in event-free survival between age groups (P = .29). The negative predictive value of a negative HUT was 91.7%. CONCLUSION: CNA is a viable treatment for reflex syncope and functional bradyarrhythmia in all ages, and is highly effective in mixed VVS. HUT is a key step in postablation clinical assessment.

Procedure, management, and outcome of subcutaneous implantable cardioverter-defibrillator extraction in clinical practice.

AIMS: Subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy is expanding rapidly. However, there are few data on the S-ICD extraction procedure and subsequent patient management. The aim of this analysis was to describe the procedure, management, and outcome of S-ICD extractions in clinical practice. METHODS AND RESULTS: We enrolled consecutive patients who required complete S-ICD extraction at 66 Italian centres. From 2013 to 2022, 2718 patients undergoing de novo implantation of an S-ICD were enrolled. Of these, 71 required complete S-ICD system extraction (17 owing to infection). The S-ICD system was successfully extracted in all patients, and no complications were reported; the median procedure duration was 40 (25th-75th percentile: 20-55) min. Simple manual traction was sufficient to remove the lead in 59 (84%) patients, in whom lead-dwelling time was shorter [20 (9-32) months vs. 30 (22-41) months; P = 0.032]. Hospitalization time was short in the case of both non-infectious [2 (1-2) days] and infectious indications [3 (1-6) days]. In the case of infection, no patients required post-extraction intravenous antibiotics, the median duration of any antibiotic therapy was 10 (10-14) days, and the re-implantation was performed during the same procedure in 29% of cases. No complications arose over a median of 21 months. CONCLUSION: The S-ICD extraction was safe and easy to perform, with no complications. Simple traction of the lead was successful in most patients, but specific tools could be needed for systems implanted for a longer time. The peri- and post-procedural management of S-ICD extraction was free from complications and not burdensome for patients and healthcare system. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/Identifier: NCT02275637.

Personalized pulmonary vein antrum isolation guided by left atrial wall thickness for persistent atrial fibrillation.

AIMS: Pulmonary vein (PV) antrum isolation proved to be effective for treating persistent atrial fibrillation (PeAF). We sought to investigate the results of a personalized approach aimed at adapting the ablation index (AI) to the local left atrial wall thickness (LAWT) in a cohort of consecutive patients with PeAF. METHODS AND RESULTS: Consecutive patients referred for PeAF first ablation were prospectively enrolled. The LAWT three-dimensional maps were obtained from pre-procedure multidetector computed tomography and integrated into the navigation system. Ablation index was titrated according to the local LAWT, and the ablation line was personalized to avoid the thickest regions while encircling the PV antrum. A total of 121 patients (69.4% male, age 64.5 ± 9.5 years) were included. Procedure time was 57 min (IQR 50-67), fluoroscopy time was 43 s (IQR 20-71), and radiofrequency (RF) time was 16.5 min (IQR 14.3-18.4). The median AI tailored to the local LAWT was 387 (IQR 360-410) for the anterior wall and 335 (IQR 300-375) for the posterior wall. First-pass PV antrum isolation was obtained in 103 (85%) of the right PVs and 103 (85%) of the left PVs. Median LAWT values were higher for PVs without first-pass isolation as compared to the whole cohort (P = 0.02 for left PVs and P = 0.03 for right PVs). Recurrence-free survival was 79% at 12 month follow-up. CONCLUSION: In this prospective study, LAWT-guided PV antrum isolation for PeAF was effective and efficient, requiring low procedure, fluoroscopy, and RF time. A randomized trial comparing the LAWT-guided ablation with the standard of practice is in progress (ClinicalTrials.gov, NCT05396534).

Old and new therapeutic solutions in the treatment of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium that is relatively common in the general population, with an autosomal dominant inheritance as a genetic basis. Clinical and natural history pathways can be very different among patients with HCM. Treatment strategies have made very important advances in the last two decades, especially reducing cases of sudden death through effective risk stratification and the use of implantable defibrillators. Heart failure has become the predominant cause of morbidity and mortality in patients with HCM, being responsible for as many as 60% of disease-related deaths. HCM is most often characterized by the presence of left ventricular outflow tract (LVOT) obstruction, and this obstruction is the most frequent cause of impaired exercise tolerance in HCM and a strong independent predictor of heart failure progression and mortality. The different treatment strategies of LVOT obstruction in HCM are discussed below: surgical, invasive, and the more recent pharmacological.

New insertable cardiac monitors show high diagnostic yield and good safety profile in real-world clinical practice: results from the international prospective observational SMART Registry.

AIMS: Insertable cardiac monitors (ICMs) are indicated for long-term monitoring of unexplained syncope or palpitations, and for detection of bradycardia, ventricular tachycardia, and/or atrial fibrillation (AF). The aim of our study was to evaluate the safety and clinical value associated with a new generation ICM (Confirm Rx™, Abbott, Illinois, USA), featuring a new remote monitoring system based on smartphone patient applications. METHODS AND RESULTS: The SMART Registry is an international prospective observational study. The main endpoints were ICM safety (incidence of serious adverse device and procedure-related events (SADEs) at 1 month), ICM clinical value (incidence of device-detected true arrhythmias and of clinical diagnoses and interventions), and patient-reported experience measurements (PREMs). A total of 1400 subjects were enrolled. ICM indications included syncope (49.1%), AF (18.8%), unexplained palpitations (13.6%), risk of ventricular arrhythmia (6.6%), and cryptogenic stroke (6.0%). Freedom from SADEs at 1 month was 99.4% (95% Confidence Interval: 98.8-99.7%). In the 6-month monitoring period, the ICM detected true cardiac arrhythmias in 45.7% of patients and led to clinical interventions in a relevant proportion of patients; in particular, a pacemaker implant was performed after bradycardia detection in 8.9% of subjects who received an ICM for syncope and oral anticoagulation therapy was indicated after AF detection in 15.7% of subjects with cryptogenic stroke. PREMs showed that 78.2% of subjects were satisfied with the remote monitoring patient app. CONCLUSION: The evaluated ICM is associated with an excellent safety profile and high diagnostic yield. Patients reported positive experiences associated with the use of their smartphone for the device remote monitoring.

Reduction in inappropriate therapies through device programming in subcutaneous implantable defibrillator patients: data from clinical practice.

AIMS: In subcutaneous implantable cardioverter defibrillator (S-ICD) recipients, the UNTOUCHED study demonstrated a very low inappropriate shock rate on programming a conditional zone between 200 and 250 bpm and a shock zone for arrhythmias >250 bpm. The extent to which this programming approach is adopted in clinical practice is still unknown, as is its impact on the rates of inappropriate and appropriate therapies. METHODS AND RESULTS: We assessed ICD programming on implantation and during follow-up in a cohort of 1468 consecutive S-ICD recipients in 56 Italian centres. We also measured the occurrence of inappropriate and appropriate shocks during follow-up. On implantation, the median programmed conditional zone cut-off was set to 200 bpm (IQR: 200-220) and the shock zone cut-off was 230 bpm (IQR: 210-250). During follow-up, the conditional zone cut-off rate was not significantly changed, while the shock zone cut-off was changed in 622 (42%) patients and the median value increased to 250 bpm (IQR: 230-250) (P < 0.001). UNTOUCHED-like programming of detection cut-offs was adopted in 426 (29%) patients immediately after device implantation, and in 714 (49%, P < 0.001) at the last follow-up. UNTOUCHED-like programming was independently associated with fewer inappropriate shocks (hazard ratio 0.50, 95%CI 0.25-0.98, P = 0.044), and had no impact on appropriate and ineffective shocks. CONCLUSIONS: In recent years, S-ICD implanting centres have increasingly programmed high arrhythmia detection cut-off rates, at the time of implantation in the case of new S-ICD recipients, and during follow-up in the case of pre-existing implants. This has contributed significantly to reducing the incidence of inappropriate shocks in clinical practice. Rordorf: Programming of the S-ICD. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/Identifier: NCT02275637.

Outcomes of cavotricuspid isthmus-dependent flutter ablation: randomized study comparing single vs. multiple catheter procedures-the SIMPLE study.

BACKGROUND: Catheter ablation is recommended as first-line therapy for patients with symptomatic typical AFl. Although the conventional multi-catheter approach is the standard of care for cavotricuspid isthmus (CTI) ablation, a single-catheter approach was recently described as a feasible alternative. The present study sought to compare safety, efficacy, and efficiency of single vs. multi-catheter approach for atrial flutter (AFl) ablation. METHODS: In this randomized multi-center study, consecutive patients referred for AFl ablation (n = 253) were enrolled and randomized to multiple vs. single-catheter approach for CTI ablation. In the single-catheter arm, PR interval (PRI) on the surface ECG was used to prove CTI block. Procedural and follow-up data were collected and compared between the two arms. RESULTS: 128 and 125 patients were assigned to the single-catheter and to the multi-catheter arms, respectively. In the single-catheter arm, procedure time was significantly shorter (37 ± 25 vs. 48 ± 27 minutes, p = 0.002) and required less fluoroscopy time (430 ± 461 vs. 712 ± 628 seconds, p < 0.001) and less radiofrequency time (428 ± 316 vs. 643 ± 519 seconds, p < 0.001), achieving a higher first-pass CTI block rate (55 (45%) vs. 37 (31%), p = 0.044), compared with the multi-catheter arm. After a median follow-up of 12 months, 11 (4%) patients experienced AFl recurrences (5 (4%) in the single-catheter arm and 6 (5%) in the multi-catheter arm, p = 0.99). No differences were found in arrhythmia-free survival between arms (log-rank = 0.71). CONCLUSIONS: The single-catheter approach for typical AFl ablation is not inferior to the conventional multiple-catheter approach, reducing procedure, fluoroscopy, and radiofrequency time.

Intermuscular technique for implantation of the subcutaneous implantable defibrillator: a propensity-matched case-control study.

AIMS: A previous randomized study demonstrated that the subcutaneous implantable cardioverter defibrillator (S-ICD) was noninferior to transvenous ICD with respect to device-related complications and inappropriate shocks. However, that was performed prior to the widespread adoption of pulse generator implantation in the intermuscular (IM) space instead of the traditional subcutaneous (SC) pocket. The aim of this analysis was to compare survival from device-related complications and inappropriate shocks between patients who underwent S-ICD implantation with the generator positioned in an IM position in comparison with an SC pocket. METHODS AND RESULTS: We analysed 1577 consecutive patients who had undergone S-ICD implantation from 2013 to 2021 and were followed up until December 2021. Subcutaneous patients (n = 290) were propensity matched with patients of the IM group (n = 290), and their outcomes were compared. : During a median follow-up of 28 months, device-related complications were reported in 28 (4.8%) patients and inappropriate shocks were reported in 37 (6.4%) patients. The risk of complication was lower in the matched IM group than in the SC group [hazard ratio 0.41, 95% confidence interval (CI) 0.17-0.99, P = 0.041], as well as the composite of complications and inappropriate shocks (hazard ratio 0.50, 95% CI 0.30-0.86, P = 0.013). The risk of appropriate shocks was similar between groups (hazard ratio 0.90, 95% CI 0.50-1.61, P = 0.721). There was no significant interaction between generator positioning and variables such as gender, age, body mass index, and ejection fraction. CONCLUSION: Our data showed the superiority of the IM S-ICD generator positioning in reducing device-related complications and inappropriate shocks. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: ClinicalTrials.gov; NCT02275637.