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Background: Age-related differences on leadless pacemaker (LP) are poorly described. Aim of this study was to compare clinical indications, periprocedural and mid-term device-associated outcomes in a large real-world cohort of LP patients, stratified by age at implantation. Methods: Two cohorts of younger and older patients (≤50 and > 50 years old) were retrieved from the iLEAPER registry. The primary outcome was to compare the underlying indication why a LP was preferred over a transvenous PM across the two cohorts. Rates of peri-procedural and mid-term follow-up major complications as well as LP electrical performance were deemed secondary outcomes. Results: 1154 patients were enrolled, with younger patients representing 6.2% of the entire cohort. Infective and vascular concerns were the most frequent characteristics that led to a LP implantation in the older cohort (45.8% vs 67.7%, p < 0.001; 4.2% vs 16.4%, p = 0.006), while patient preference was the leading cause to choose a LP in the younger (47.2% vs 5.6%, p < 0.001). Median overall procedural (52 [40–70] vs 50 [40–65] mins) and fluoroscopy time were similar in both groups. 4.3% of patients experienced periprocedural complications, without differences among groups. Threshold values were higher in the younger, both at discharge and at last follow-up (0.63 [0.5–0.9] vs 0.5 [0.38–0-7] V, p = 0.004). Conclusion: When considering LP indications, patient preference was more common in younger, while infective and vascular concerns were more frequent in the older cohort. Rates of device-related complications did not differ significantly. Younger patients tended to have a slightly higher pacing threshold at mid-term follow-up.

BACKGROUND: Limited data on the real-world safety and efficacy of leadless pacemakers (LPMs) post-transvenous lead extraction (TLE) are available. OBJECTIVE: The purpose of this study was to assess the long-term safety and effectiveness of LPMs following TLE in comparison with LPMs de novo implantation. METHODS: Consecutive patients who underwent LPM implantation in 12 European centers joining the International LEAdless PacemakEr Registry were enrolled. The primary end point was the comparison of LPM-related complication rate at implantation and during follow-up (FU) between groups. Differences in electrical performance were deemed secondary outcomes. RESULTS: Of the 1179 patients enrolled, 15.6% underwent a previous TLE. During a median FU of 33 (interquartile range 24-47) months, LPM-related major complications and all-cause mortality did not differ between groups (TLE group: 1.6% and 5.4% vs de novo group: 2.2% and 7.8%; P = .785 and P = .288, respectively). Pacing threshold (PT) was higher in the TLE group at implantation and during FU, with very high PT (>2 V@0.24 ms) patients being more represented than in the de novo implantation group (5.4% vs 1.6 %; P = .004). When the LPM was deployed at a different right ventricular (RV) location than the one where the previous transvenous RV lead was extracted, a lower proportion of high PT (>1-2 V@0.24 ms) patients at implantation, 1-month FU, and 12-month FU (5.9% vs 18.2%, P = .012; 3.4% vs 12.9%, P = .026; and 4.3% vs 14.5%, P = .037, respectively) was found. CONCLUSION: LPMs showed a satisfactory safety and efficacy profile after TLE. Better electrical parameters were obtained when LPMs were implanted at a different RV location than the one where the previous transvenous RV lead was extracted.

This study aimed at investigating whether tissue Doppler imaging (TDI) is associated with adverse events in arrhythmogenic right ventricular cardiomyopathy (ARVC).Transthoracic echocardiography was performed in 72 patients with definite (n = 63) or borderline (n = 9) ARVC diagnosed according to the 2010 Task Force Criteria and included in the prospective Zurich ARVC registry. Myocardial peak systolic tissue velocity (S') was measured by TDI at lateral tricuspid (tricuspid S'), medial mitral (septal S'), and lateral mitral annulus (lateral S'). Association of echocardiographic parameters with outcome was assessed by univariable Cox regression. During a median follow-up of 4.9 ± 2.6 years, 6 (8.3%) patients died of cardiovascular cause or received heart transplantation and 21 (29.2%) patients developed sustained ventricular arrhythmia. Tricuspid, septal, and lateral S' were lower in patients who died (p = 0.001; p lt; 0.001; p = 0.008; respectively), while tricuspid and septal S' were lower in those with ventricular arrhythmia (p = 0.001; p = 0.008; respectively). There was a significant association of tricuspid, septal, and lateral S' with mortality (HR = 1.61, p = 0.011; HR = 2.15, p = 0.007; HR = 1.67, p = 0.017; respectively), while tricuspid and septal S' were associated with ventricular arrhythmia (HR = 1.20, p = 0.022; HR = 1.37, p = 0.004; respectively). Kaplan-Meier analyses demonstrated a higher freedom from mortality with tricuspid S'gt;8 cm/s (p = 0.001) and from ventricular arrhythmia with S'gt;10.5 cm/s (p = 0.021).This study demonstrates that TDI provides information on the ARVC phenotype, is associated with adverse events in ARVC patients, and differentiates between patients with and without adverse events.

The present study tested outcomes of the Transdiagnostic Sleep and Circadian Intervention (TranS-C) among midlife and older adults with serious mental illness (SMI). Further, we tested predictors-credibility, expectancy, usefulness, and utilization-that may affect TranS-C outcomes. Midlife and older participants from a community setting (49 years, 62.3% female, 37.7% African American or Black) with sleep and circadian problems and SMI were randomized to receive TranS-C plus usual care (TranS-C+UC, n = 27) or usual care followed by delayed treatment with TranS-C (UC-DT, n = 26). Immediate and delayed TranS-C data were combined to increase power (combined n = 52). Outcomes were assessed at pretreatment, posttreatment, and 6-month follow-up. Credibility and expectancy were assessed during the second session. Usefulness and utilization of TranS-C skills were assessed at posttreatment and 6-month follow-up. TranS-C+UC, relative to UC-DT, was associated with improvements in depression symptoms, sleep disturbance, overall sleep health, and select sleep/wake outcomes, though not all improvements were sustained at 6-month follow-up. Lower usefulness of TranS-C skills predicted more severe sleep disturbance at posttreatment and daytime sleep-related impairment at posttreatment and 6-month follow-up. Lower utilization predicted more severe psychiatric symptoms at posttreatment, sleep disturbance at posttreatment and 6-month follow-up, and overall impairment and daytime sleep-related impairment at 6-month follow-up. Higher credibility and expectancy predicted greater usefulness of TranS-C skills at posttreatment and 6-month follow-up and greater utilization at 6-month follow-up. Together, findings highlight benefits of TranS-C for midlife and older adults with SMI. However, boosting credibility, expectancy, utilization, and usefulness may meaningfully improve TranS-C outcomes.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC. P.J. is supported by the Daniel Bravo Foundation grant and Spanish Society of Cardiology Magda Heras mobility grant, A.G. by the Wilton W. Webster Fellow of Heart Rhythm Society, The Johns Hopkins ARVD/C Programme by the Leonie-Wild Foundation, Leyla Erkan Family Fund for ARVD Research, The Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center, Dr Francis P. Chiramonte Private Foundation, Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, Bogle Foundation, Campanella Family, Patrick J. Harrison Family, Peter French Memorial Foundation, and Wilmerding Endowments, H.K.J. by grants from Novo Nordisk Foundation, Denmark (NNF18OC0031258 and NNF20OC0065151), S.A.L. by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007, R.T. by the Canada Research Chairs programme, J.C.T. by the Philippa and Marvin Carsley Cardiology Research Chair. S.G.P. receives support from Ricerca Corrente funding scheme of the Italian Ministry of Health and Italian Ministry of Research and University Dipartimenti di Eccellenza 2018 to 2022 grant to the Molecular Medicine Department (University of Pavia). Sí

Funding Acknowledgements Type of funding sources: None. Background The recent PARTITA trial showed a net clinical benefit of early ventricular tachycardia (VT) ablation in patients with implantable cardioverter defibrillator (ICD) experiencing appropriate shocks. The PARTITA trial analysis, however, was performed in transvenous ICD recipients and data regarding its generalizability in subcutaneous ICD (S-ICD) recipients are lacking. Purpose To test whether VT ablation after an ICD shock or a hospitalization for slow VT impacts long-term clinical outcomes in S-ICD recipients. Methods All patients experiencing an ICD shock or a hospitalization for slow VT (index event) in the multicenter, international, physician-initiated, real-world iSUSI (International SubcutaneouS Implantable Cardioverter Defibrillator) registry were included in the study. Time zero was set as time of first ICD shock / slow VT hospitalization. Patients were stratified based on performance of VT ablation after the index event (VTA+ vs VTA- cohorts). The primary outcome was a combination of device-related appropriate shocks, slow VTs, and cardiovascular mortality during follow-up. Secondary outcomes were device-related appropriate shocks, slow VTs and cardiovascular mortality, taken individually. Results Among 1701 patients enrolled in the iSUSI registry, n=211 were included in this study (n=178 experiencing appropriate shocks; n=33 with slow VTs). After the index event, n=58 (27.5%) underwent VT ablation (VTA+ cohort). No significant differences regarding baseline characteristics between VTA+ and VTA- cohorts were observed: mean age 47.3±16.0 years (VTA+) vs 47.9±17.0 years (VTA-), p=0.799; males 82.8% (VTA+) vs 82.4% (VTA-), p=0.945; mean LVEF 43.8±13.2% (VTA+) vs 42.3±15.5% (VTA-), p=0.530; underlying ischemic cardiomyopathy 31.0% (VTA+) vs 32.7% (VTA-), p=0.8.19; primary prevention implant 36.2% (VTA+) vs 43.4% (VTA-), p=0.434; median number of shocks at index time n=2 [1-4] (VTA+) vs n=2 [1-3] (VTA-), p=0.590. Over a median follow-up of 17.3 [10.4–34.8] months, the combined primary outcome was experienced by 46 (21.8%) patients (Figure 1). VT ablation performance was associated with significantly lower event rates (8.6% vs 26.8%; HR 0.215 [CI 0.100–0.637]; p=0.004), although only a trend towards significance of cardiovascular mortality was observed (HR 0.168 [CI 0.020–1.252]; p=0.081). Among VT ablation, LVEF and ischemic cardiomyopathy, which resulted significantly associated with the primary combined outcome at univariate analysis, only VT ablation remained significantly associated with the outcome of interest at multivariate analysis (HR 0.264 [CI 0.104-0.672], p=0.005) (Figure 1). Survival analysis plotted using Kaplan Meier curves has been reported in Figure 2. Conclusions In a real world registry of S-ICD recipients, VT ablation post ICD shocks or hospitalizations for slow VTs was associated with a combined improved arrhythmic and mortality outcome at long-term follow-up.

Funding Acknowledgements Type of funding sources: None. Introduction Invasive three-dimensional electroanatomical mapping (EAM) can be helpful to diagnose arrhythmogenic right ventricular cardiomyopathy (ARVC). Contact force sensing catheters (CFSC) represent the gold standard to verify adequate tissue contact during EAM. However, normal reference values for right ventricular (RV) EAM as well as substrate characterization in patients with ARVC using CFSC have not been systematically investigated, which was the aim of this prospective study. Methods EAM of the RV during sinus rhythm was performed with the Thermocool SmartTouch catheter via a long sheath in the CARTO3 system in 11 patients with definite ARVC and 5 age- and gender-matched control subjects without structural heart disease. Only points with a mean contact force of ≥4G were analyzed. To account for differences due to RV anatomy, it was divided into 5 segments: RV outflow tract (RVOT), septum, free wall, sub-tricuspid region and apex. Endocardial bipolar and unipolar voltages, signal characteristics and signal duration were analyzed. The impact of catheter orientation on endocardial signals was also assessed. Results A median of 227 (IQR:120-364) endocardial RV points were analyzed. Median bipolar voltage in healthy controls was 3.8mV (range 3.6-4.6, IQR 2.7-5.4), with lower values in the RVOT and higher values in the RV septum. ARVC patients showed significantly lower bipolar voltages as compared to controls (repeated measures ANOVA; between-subjects effect: F=6.443,p=0.024), showing significantly lower bipolar voltage values in the sub-tricuspid region (1.8±1.9vs.4.6±2.9mV,p=0.031) and in the RV apex (2.9±1.4vs.7.2±5.2mV,p=0.024), Figure 1c. Bipolar voltage values in all RV regions yielded a high sensitivity and specificity for ARVC diagnosis (AUC62-78%,p Conclusions For the first time a systematic analysis of RV endocardial low voltage areas in ARVC patients as compared to controls by using CFSC was performed, and confirmed that RV voltages are generally lower in ARVC as compared to controls, with the sub-tricuspid area showing the lowest values and highest discriminatory power vs controls.

Funding Acknowledgements Type of funding sources: None. Introduction Exercise capacity and ventilatory efficiency are often altered in hypertrophic cardiomyopathy (HCM) and several factors have been advocated as possible causes. Aim This study investigates the determinants of cardiopulmonary exercise test (CPET) prognostic markers for HCM (VO2Peak, VE/VCO2 Slope and PETCO2 apex), by considering echocardiographic and cardiac magnetic resonance (CMR) parameters. Secondly, it scopes if myocardial fibrosis at CMR leads to clinical and functional differences. Methods 64 patients with HCM underwent a clinical assessment, including maximal CPET, echocardiography, and CMR. Exclusion criteria were the corrective surgery for cardiac hypertrophy and heart failure stage. Results The study included 66% males, age 40±17 years, NYHA class I or II 91%. Mean left ventricle (LV) ejection fraction was 63,8±7,7%, with a mean LV maximal wall thickness (MVT) of 20,2±5,6 mm; LVOT gradient was >30mmHg in 14% of patients. Late gadolinium enhancement (LGE) was described in 70,3% of cases with a mean LGE extension on bullseye plot of 11%. 39% of patients had a VO2 peak At the stepwise multivariate analysis, age (β=-0,33; p=0,00), BMI (β=-0,80; p=0,002), systolic blood pressure increase (β=0,22; p=0,02), left atrial volume (β=-0,15; p=0,02) and BB therapy (β=-0,45; p=0,00) were independently associated with VO2 peak (R2-adjusted index 0,95). Concerning ventilatory efficiency, sex (β=-0,41; p=0,03), left atrial volume (β=0,46; p=0,01) and LGE extension (β=0,33; p=0,01) were independently associated with VE/VCO2 Slope (R2-adjusted index 0,46). Similar data, with reversed correlations, emerged for PETCO2 apex. Patients with LGE had a LV mass index (mean 104,6 vs 82,7 g/m2, p=0,04), MWT (mean 21,8 vs 16,2 mm, p=0,00) and diastolic function (mean E/e’ 13,4 vs 10,0, p=0,01) worse that the counterpart. No differences were found in sex, age, therapy, CPET parameters and arrhythmic burden. BB+ patients were older, had more LV hypertrophy, worse diastolic parameters, and functional capacity while ventilatory efficiency was similar. Conclusions This study supports previous data about VO2 peak determinants. The correlation between the extension of the LGE and ventilatory efficiency in patients with HCM is an original finding. It confirms the pathophysiological explanation of a lung ventilation/perfusion mismatch due to the increased left atrium pressure that is secondary to a more severe LV diastolic disfunction in patients with LGE. The reduced VO2 in BB+ compared to BB- patients is not inferable given the different age and severity of disease. Moreover, the negative chronotropic effect of BB during exercise prolongs the diastolic filling time, thus, improving stroke volume and alleviating the LV filling pressures, thus normalising, in the less advanced stages of pathology, the ventilatory efficiency in HCM patients.

Funding Acknowledgements Type of funding sources: None. Background transvenous (TV) pacemakers are negatively associated with local and systemic device-related infections, often requiring transvenous lead extraction (TLE). Moreover, patients reimplanted with a TV device following TLE, exhibit substantial mortality and reinfection rates during the subsequent follow-up (FU). In this setting, leadless pacemakers (LPMs) are appealing as a first choice for TLE patients requiring a pacemaker reimplantation. To date, limited data on real-world safety and efficacy of LPMs in patients who underwent TLE are available. Purpose The present study aims to assess long-term safety and efficacy of LPM implantation in patients who previously underwent TLE of a transvenous pacemaker, compared to LPM de novo implant patients. Methods Consecutive patients who underwent LPM implantation in 12 centers joining the International LEAdless PacemakEr (i-LEAPER) registry were enrolled. Patients receiving LPM following TLE (n=184) were compared with patients with de novo implant (n=995). The primary endpoint was LPM-related major complications rate at implant and during FU. Additionally, differences in electrical performance were assessed between the two groups. Completion of 12-months FU was obtained in all patients. Results 1179 patients were enrolled in this study and followed for a median of 12 [IQR 11-14] months. Baseline clinical characteristics resulted balanced among the two groups, apart from a higher prevalence of heart failure among recipients of LPM following TLE (16.8% vs. 9.4%, p=0.013). As reported in the Table, LPM related major complications and all-cause mortality did not differ among the two groups (1.6% TLE group vs. 2.2% de novo group, p=0.785, and 5.4% TLE group vs. 7.8% de novo group, p=0.288, respectively). Pacing threshold (PT) resulted higher in the TLE group throughout the FU (Figure-Panel A). Higher PTs were recorded in LPMs implanted at same location from where the previous transvenous lead was removed, as far as 12-months postimplant (Figure-Panel B), with a higher proportion of patients with high PT (>1 to 2V @0.24ms) in the first group at implant, 1-month, and 12-month FU (Figure-Panel C). Conclusion In this real-world registry, LPMs showed a satisfactory safety and efficacy profile after TLE. In the post-TLE cohort, better electrical parameters were obtained when LPMs were implanted at a different location from where the previous transvenous lead was extracted.

Funding Acknowledgements Type of funding sources: None. Background Implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT) are widely used in patients with life-threatening cardiac arrhythmias or systolic heart failure. Real world data regarding gender impact on ICD and CRT implantation and outcome is scarce. Purpose To investigate the impact of gender-specific differences on cardiac devices implantation and outcomes. Methods The German DEVICE registry is a nationwide prospective multicentre database of ICD and CRT devices implantation. A total of 5451 patients were prospectively enrolled in 44 centres between March 2007 and February 2014 and were monitored for a median of 17 months. Results A minority of patients in this registry was female 1050 (19.3%; mean age 64.4 ± 14.6 years; median BMI 27.2) while men represented 80.7% (mean age 65.5 ± 12.4 years; median BMI 26.8). Female patients were less likely to have a LVEF 55% (13.3% vs. 6.6%; p Similar rates of primary and secondary prevention indication were noted for female and male patients (p=0.9717). There was no difference between the groups regarding the need of postprocedural system revision (p=0.7884), as well as in-hospital death, cardiac death, or sudden cardiac death. The non-fatal complications during follow-up were comparable for men and women. Moreover, similar rates and durations of all cause and cardiac rehospitalizations were found (p=0.1644 and p= 0.1816). Conclusion In this real-life patient cohort only a minority of female patients were enrolled. Female patients were more likely to undergo CRT implantation and had a higher risk for acute major periprocedural complications and in-hospital complications but a lower overall mortality in 1-year follow-up. However, the differences in baseline characteristics should be considered as potential confounders.

Funding Acknowledgements Type of funding sources: None. Background Congenital heart disease (CHD) affects approximately 0.5-1% of the general population. Thanks to the improvement of medical and surgical techniques, in developed countries 90% of individuals with CHD reach adulthood and, consequently, the demand for participation in sporting activities also increases. Recently, the European Society of Cardiology have given recommendations on participation in recreational and competitive sports (ESC 2020) based on a clinical and functional algorithm. Purpose To show the prevalence of the eligibility for competitive sports proposed by ESC 2020 in a real CHD population and the prevalence of real engagement in physical activity (both competitive and non-competitive). Also, to evaluate the difference in cardiorespiratory fitness (CRF) and the impact of training among different sport eligibility classes. Methods Retrospective study of 401 patients with surgically corrected CHD and followed up with cardiopulmonary exercise test (CPET) performed on treadmill or cycle ergometer until patients’ exhaustion. Subjects were divided in 4 classes according with ESC 2020 guidelines and corresponding to the eligibility for all competitive sport (A), all except endurance specialties (B), only for skill disciplines (C) or not eligible (D). Results Median (IQR) age was 18.0(13.0; 21.5) years; 266 patients (66.3%) were males. 34% were in class D, 13% in class B, 25% in class C and 28% in class A. Within the entire population, 179 subjects (44.6%) carried out structured exercise training, corresponding to 60.7% of subjects in class A, 45.1% of those in class B, 41.7% of those in class C and 41.1% of those in class D. VO2peak/Kg was similar between class A [39.2 (33.6-44.4) mL/Kg/min] and B [37.9 (30.6-42.6) mL/Kg/min], but significantly different between class A vs. class C [33.3 (28.3-41.4) mL/Kg/min p Conclusions Subjects in class A had better functional capacity than those in C and D classes, but exercise training (competitive or non-competitive) can have a significant impact on CRF level. Figure 1 shows that trained people in D class had higher CRF than untrained in A class, supporting that functional evaluation and an individualized exercise prescription may recruit functional "reserve" by improving the VO2peak as key prognostic component.

Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats.Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response.Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors.Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

Background: Clinical guidelines recommend regular screening for arrhythmogenic right ventricular cardiomyopathy (ARVC) to monitor at-risk relatives, resulting in a significant burden on clinical resources. Prioritizing relatives on their probability of developing definite ARVC may provide more efficient patient care. Objectives: The aim of this study was to determine the predictors and probability of ARVC development over time among at-risk relatives. Methods: A total of 136 relatives (46% men, median age 25.5 years [IQR: 15.8-44.4 years]) from the Netherlands Arrhythmogenic Cardiomyopathy Registry without definite ARVC by 2010 task force criteria were included. Phenotype was ascertained using electrocardiography, Holter monitoring, and cardiac imaging. Subjects were divided into groups with “possible ARVC” (only genetic or familial predisposition) and “borderline ARVC” (1 minor task force criterion plus genetic or familial predisposition). Cox regression was performed to determine predictors and multistate modeling to assess the probability of ARVC development. Results were replicated in an unrelated Italian cohort (57% men, median age 37.0 years [IQR: 25.4-50.4 years]). Results: At baseline, 93 subjects (68%) had possible ARVC, and 43 (32%) had borderline ARVC. Follow-up was available for 123 relatives (90%). After 8.1 years (IQR: 4.2-11.4 years), 41 (33%) had developed definite ARVC. Independent of baseline phenotype, symptomatic subjects (P = 0.014) and those 20 to 30 years of age (P = 0.002) had a higher hazard of developing definite ARVC. Furthermore, patients with borderline ARVC had a higher probability of developing definite ARVC compared with those with possible ARVC (1-year probability 13% vs 0.6%, 3-year probability 35% vs 5%; P < 0.01). External replication showed comparable results (P > 0.05). Conclusions: Symptomatic relatives, those 20 to 30 years of age, and those with borderline ARVC have a higher probability of developing definite ARVC. These patients may benefit from more frequent follow-up, while others may be monitored less often.

(1) Background: Leadless (LL) stimulation is perceived to lower surgical, vascular, and lead-related complications compared to transvenous (TV) pacemakers, yet controlled studies are lacking and real-life experience is non-conclusive. (2) Aim: To prospectively analyse survival and complication rates in leadless versus transvenous VVIR pacemakers. (3) Methods: Prospective analysis of mortality and complications in 344 consecutive VVIR TV and LL pacemaker recipients between June 2015 and May 2021. Indications for VVIR pacing were “slow” AF, atrio-ventricular block in AF or in sinus rhythm in bedridden cognitively impaired patients. LL indication was based on individualised clinical judgement. (4) Results: 72 patients received LL and 272 TV VVIR pacemakers. LL pacemaker indications included ongoing/expected chronic haemodialysis, superior venous access issues, active lifestyle with low pacing percentage expected, frailty causing high bleeding/infectious risk, previous valvular endocarditis, or device infection requiring extraction. No significant difference in the overall acute and long-term complication rate was observed between LL and TV cohorts, with greater mortality occurring in TV due to selection of older patients. (5) Conclusions: Given the low complication rate and life expectancy in this contemporary VVIR cohort, extending LL indications to all VVIR candidates is unlikely to provide clear-cut benefits. Considering the higher costs of LL technology, careful patient selection is mandatory for LL PMs to become advantageous, i.e., in the presence of vascular access issues, high bleeding/infectious risk, and long life expectancy, rendering lead-related issues and repeated surgery relevant in the long-term perspective.

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibro-fatty infiltration of the myocardium and associated with adverse cardiovascular (CV) events. This study aims to examine right atrial (RA) deformation in ARVC and understand its association with CV outcomes. Methods and results RA strain was determined in 50 patients with definite ARVC, compared with a matched control group of 50 healthy individuals, and analysed for outcome association over a median follow-up duration of 5 years. A subgroup of 30 ARVC patients with normal RA volume (ARVC-N group) was compared with 30 matched controls (Control-N), and the outcome was analysed separately. RA reservoir, conduit, and pump strain were significantly impaired in ARVC vs. control. Similar observations were made in the N-ARVC subgroup. Reservoir strain was associated with an increased risk of atrial arrhythmia (AA) [hazard ratio (HR) 0.88, P Conclusion ARVC patients display impaired RA strain even when RA volume is normal. Reservoir and pump strain are associated with an increased risk of CV events. Reservoir strain improved model fitness for the association of RVGLS and other echocardiographic parameters with CV events.

This study evaluates whether the Transdiagnostic Sleep and Circadian Intervention for Youth (TranS-C) improves objective sleep and rest-activity rhythms in a sample of youth with an evening circadian preference (ECP).Youth with an ECP aged 10-18 years were randomized to receive 6 sessions of TranS-C (n = 60) or Psychoeducation (PE; n = 58). For one week prior to beginning treatment and within 2 weeks of completing treatment, participants wore an actiwatch to assess objective sleep and rest-activity rhythms.Among TranS-C participants, there were significant pre-post improvements in weeknight total sleep time (TST), weekend TST, and weeknight-weekend discrepancy in TST and sleep offset time. These changes were not significant in PE. There was no significant treatment by time interactions for the sleep or rest-activity outcomes.For youth with an ECP, TranS-C improves select objective sleep but not rest-activity outcomes, though compared to PE, these benefits did not reach statistical significance.

While looking for a “magic bullet” to treat COVID-19, the massive off-label use of several of drugs in COVID-19, including repurposed antimalarial drugs, immunosuppressive agents, anti-virals and antibacterial agents, have generated concerns in the early phase of the pandemic due a possible arrhythmogenic effects in relation to QTc interval prolongation. Indeed, some of these drugs have been historically associated to QT prolongation and Torsade de Point, a potentially lethal ventricular arrhythmia, and their first-time use on a very large scale has raised several concerns in the scientific community. The aim of this work is to summarize the underlying arrhythmogenic mechanisms related to the use of potentially QT prolonging drugs used during the pandemic to treat COVID-19.

COVID-19 threatens to slow progress on the implementation of peace agreements, and reverse hard-won gains of women peacebuilders’ work towards holistic, gender-equal peace, rooted in human security. Through an analysis of in-depth interviews from a purposive sample of women peacebuilders in Colombia, South Sudan, the Philippines, and Ukraine, this article contributes to a greater understanding of the pandemic’s impact on women’s peace activism, as these peacebuilders adapted to emerging realities and became first responders. We argue that the pandemic has deepened the marginalization of women peacebuilders from formal peace processes, possibly to detriment of both immediate recovery and long-term peacebuilding.

Background limited data on real-world safety and efficacy of leadless pacemakers (LPMs) in patients who underwent transvenous lead extraction (TLE) are currently available. The present study aims to assess long-term safety and efficacy of LPMs implantation following TLE, compared with LPM de novo implant patients. Methods consecutive patients who underwent LPM implantation in 12 centers joining the International LEAdless PacemakEr (i-LEAPER) registry were enrolled end retrospectively considered. Patients receiving LPM following TLE (n=184) were compared with patients with de novo implant (n=995). The primary endpoint was LPM-related complications rate at implant and during follow-up (FU). Additionally, differences in electrical performance were assessed between the two groups. Results 1179 patients were enrolled in this study and followed for a median of 33 months. LPM related major complications and all-cause mortality did not differ among the two groups (1.6% TLE group vs. 2.2% de novo group, p=0.785, and 5.4% TLE group vs. 7.8% de novo group, p=0.288, respectively). Pacing threshold (PT) resulted higher in the TLE group throughout the whole follow-up (FU) (Figure 1). Higher PTs were recorded in LPMs implanted at same location from where the previous transvenous lead was removed, as far as 24-months postimplant (Figure 2), with a higher proportion of patients with high PT (>1 to 2V @0.24ms) in the first group at implant, 1-month, and 12-month FU (Figure 3). Conclusion In this real-world registry, LPMs showed a satisfactory safety and efficacy profile after TLE. In the post-TLE cohort, better electrical parameters were obtained when LPMs were implanted at a different location from where the previous transvenous lead was extracted.

While facing potentially high morbidity from COVID-19 without known effective therapies, the off-label use of several non-specific drugs has been advocated, including re-purposed anti- viral (e.g., remdesivir or the lopinavir/ritonavir combination), biologic agents (e.g., tocilizumab), and antimalarial drugs such as chloroquine and hydroxychloroquine, in association with or without azithromycin. Data regarding the effectiveness of these drugs in treating COVID-19 has been shown in some trials and clinical settings, but further randomised controlled trials are still being carried out. One of the main concerns regarding their widespread use, however, is their possible effects on the QT interval and arrhythmogenic potential. Some of these drugs have been associated with QT prolongation and Torsades de Point, a potentially lethal ventricular arrhythmia. The review aims to highlight the magnitude of this problem, to quickly refresh clinically impacting cornerstones of QT interval and TdP pathophysiology, to summarize the available evidence regarding the QT and arrhythmia impact of drugs used in different clinical settings in COVID-19 patients, and to help the physicians dealing with the knowledge needed in the everyday clinical duties in case of doubts regarding QT-induced arrhythmias in this time of emergency.

OBJECTIVE: The goal of this study was to develop rat models of partial body irradiation with bone-marrow sparing (leg-out PBI), to test medical countermeasures (MCM) of both acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE) under the FDA animal rule. METHODS: The leg-out PBI models were developed in female and male WAG/RijCmcr rats at doses of 12.5–14.5 Gy. Rats received supportive care consisting of fluids and antibiotics. Gastrointestinal ARS (GI-ARS) was assessed by lethality to day 7 and diarrhea scoring to day 10. Differential blood counts were analyzed between days 1–42 for the natural history of hematopoietic ARS (H-ARS). Lethality and breathing intervals (BI) were measured between days 28–110 to assess delayed injury to the lung (L-DEARE). Kidney injury (K-DEARE) was evaluated by measuring elevation of blood urea nitrogen (BUN) between days 90–180. RESULTS: The LD(50/30), including both lethality from GI-ARS and H-ARS, for female and male rats is 14.0 Gy and 13.5 Gy respectively, while the LD(50/7) for only GI-ARS is 14.3 Gy and 13.6 Gy respectively. The all-cause mortality, including ARS and L-DEARE, through 120 days (LD(50/120)) is 13.5 Gy and 12.9 Gy respectively. Secondary end points confirmed occurrence of 4 distinct sequelae representing GI, hematopoietic, lung and kidney toxicities after leg-out PBI. CONCLUSION: Adult rat models of leg-out PBI developed showed the acute and long-term sequelae of radiation damage that has been reported in human radiation exposure case studies. Sex-specific differences were observed in the DRR between females and males. These rat models are among the most useful for the development and approval of countermeasures for mitigation of radiation injuries under the FDA animal rule.

STUDY OBJECTIVES: This study sought to examine the relationship between internet use, sleep, and internalizing disorder symptoms in adolescents with an evening circadian preference. METHODS: One hundred seventy-two adolescents aged 10–18 years with an evening circadian preference completed a week of sleep diaries and questionnaires about internet use and internalizing disorder symptoms. RESULTS: Adolescents reported internet use for 3.81 hours on weekdays and 5.44 hours on weekends, with > 90% having access to both a computer with internet and a personal cell phone. A majority of adolescents used the internet from 4–8 pm (71%) and from 9–11 pm (62%). Common online activities included listening to music (77%), watching videos (64%), communicating with others (64%), and doing homework (58%). Late-night internet use (9–11 pm) was associated with more internalizing disorder symptoms. Middle-of-the-night internet use (midnight–5 am) was associated with a later bedtime, shorter total sleep time, and more internalizing disorder symptoms. Adolescents used the internet to fulfill social needs, to avoid or combat boredom, or for maladaptive activities. Using the internet for social interaction or avoidance/boredom was associated with higher internalizing disorder symptoms. Using the internet for maladaptive reasons was associated with more late-night and middle-of-the-night use. CONCLUSIONS: Adolescent internet use late at night and in the middle of the night is common. Internet use may be motivated by desires for social connection, by boredom/avoidance, or for maladaptive behaviors. Because middle-of-the-night internet use was associated with higher internalizing disorder symptoms and worse sleep, it presents as a potential target for intervention. CITATION: Asarnow LD, Gasperetti CE, Gumport NB, Harvey AG. Internet use and its impact on internalizing disorder symptoms and sleep in adolescents with an evening circadian preference. J Clin Sleep Med. 2021;17(10):2019–2027.

Cardiac magnetic resonance (CMR) findings suggesting a suspected left-dominant arrhythmogenic cardiomyopathy (LDAC) may be difficult to distinguish from those related to previous myocarditis; however, especially in patients with ventricular arrhythmias (VA) with ECG morphology consistent with a left ventricle (LV) origin differential diagnosis is fundamental. Aim of the study was to identify potential imaging features at CMR specific for LDAC diagnosis. Between January 2011 and December 2019, we enrolled 15 consecutive stable patients with a recent diagnosis of significant VA and ECG morphology consistent with a LV origin, detection of potential LV arrhythmic substrate at CMR and undergoing a clinically-indicated LV endomyocardial biopsy showing tissue abnormalities consistent with the diagnosis of LDAC. From the same CMR-endomyocardial biopsy registry, a second group of 30 consecutive patients who underwent CMR and biopsy with a histological diagnosis of previous myocarditis were identified. (1) Subepicardial LGE at the level of the posterolateral wall of the LV was detected in 13 cases of LDAC vs. 21 cases of myocarditis; (2) fat infiltration, and particularly subepicardial posterolateral fat infiltration, was found in almost all LDAC patients vs. one myocarditis only (p

Leadless pacemakers have become a major breakthrough in the management of bradyarrhythmia as an attractive alternative to the standard transvenous pacemakers, but safety and long-term outcomes of the new Micra-AV, which is capable guarantee atrioventricular (AV) synchrony, have been poorly described. Hence, we describe how we managed a 57-year-old patient who developed pacemaker syndrome due to significant Micra-AV dyssynchrony. This case emphasizes how leadless pacemaker AV synchrony could be overestimated, thereby requiring a stepwise process leading to adequate device reprogramming. Holter-ECG monitoring and exercise test resulted to be valuable tools for an early detection of inadequate AV synchrony, integrating and completing device reports.

Objectives This study aimed to assess the long-term outcomes of minimally fluoroscopic approach (MFA) compared with conventional fluoroscopic ablation (ConvA) in terms of recurrences of arrhythmia and long-term complications. Background Catheter ablation (CA) of supraventricular tachycardia (SVT) with an MFA, under the guidance of electroanatomic mapping (EAM) systems, results in a significant reduction in exposure to ionizing radiations without impairing acute procedural success and complication rate. However, data regarding long-term outcomes of MFA compared with ConvA are lacking. Methods This is a retrospective observational study. All patients undergoing MFA CA of SVT (atrioventricular nodal re-entrant tachycardia and atrioventricular re-entrant tachycardia) between 2010 and 2015 were enrolled and were compared with matched subjects (1 MFA: 2 ConvA) undergoing ConvA during the same period. The 2 co-primary outcomes were recurrence of arrhythmias and long-term complications. Results A total of 618 patients (mean age 38 ± 15 years, 60% female) were enrolled. MFA included 206 patients, whereas 412 were treated with ConvA. Acute success (99% vs. 97%; p = 0.10) and acute complications (2.4% vs. 5.3%; p = 0.14) were similar in the 2 groups. During a median follow-up of 4.4 years, 5.9% of patients experienced recurrence of arrhythmias. At multivariate analysis, ConvA (hazard ratio [HR]: 3.03) and procedural success (HR: 0.10) were independently associated with recurrence of arrhythmias. Late complications (i.e., advance atrioventricular block and need for pacemaker implantation) occurred more frequently in ConvA (3.4% vs. 0.5%; p = 0.03) compared with MFA. Conclusions CA guided by EAM systems with MFA provided better long-term results and reduced risk of complications compared with ConvA.

Arrhythmogenic right ventricular cardiomyopathy is an inherited desmosomal myopathy characterized by progressive fibrofatty replacement of the myocardium, right ventricular enlargement, and malignant ventricular arrhythmias. Ventricular tachycardias is one of the most common initial presentation of ARVC. This manuscript addresses invasive VT ablation options for the managmenet of VT in patients with ARVC.

Background: Bariatric surgery is the most effective procedure for obesity management, with a greater body weight loss and the remission of several diseases. The aim of this study was to analyze the relationships between the anthropometric profile and postural control outcomes in a group of obese adult women, and the effect of bariatric surgery on postural control. Methods: eighty-eight women candidates for bariatric surgery were recruited. Static balance was measured with the ARGO stabilometric platform under two conditions: open eyes (OE) and closed eyes (CE). Results: Multiple linear regression indicated BMI as the first predictor for postural control in all parameters, except for APO in open eyes, predicted mainly by height. Changes in body weight and BMI showed no statistically significant correlations with modification of postural control parameters (OE), while they appeared to exert an influence under closed eyes conditions. Conclusions: Before surgery, obese patients with a higher BMI showed a better postural control. After surgery, the sway path and antero-posterior oscillation improved under open eyes conditions, while the magnitude of weight loss was negatively correlated with differences in postural control.

This item has been withdrawn due to a press embargo and will be reinstated once the embargo has lifted. For further information please contact info@openaccess.cam.ac.uk, National Science Foundation (NSF): Christopher B. Ruff BCS-0642297 National Science Foundation (NSF): Christopher B. Ruff BCS-0642710

Introduction Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease characterized by progressive fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular (BiV) involvement may lead to heart failure. This study aimed to investigate characteristic proteomic patterns in plasma of ACM patients, and correlated them with clinical outcome as well as physical exercise, to assess if key soluble molecules may serve as specific biomarkers for ACM, and whether mechanical stress induced by physical exercise may alter proteomic patterns in ACM patients. Methods In 38 ACM patients clinical parameters and major adverse cardiovascular events (MACE defined as presence of sustained ventricular tachycardia, ventricular fibrillation, appropriate therapy from implantable cardioverter defibrillator, sudden cardiac death, death related to end-stage heart failure or cardiac transplant) were obtained prospectively during a mean follow-up period of 36 months. All patients received genetic testing using next generation DNA sequencing. Plasma protein expression was analysed using the Proximity Extension Assay (PEA) technology, where a pair of oligonucleotide-labelled antibody probe binds to each targeted protein. In a subgroup of 11 patients blood was drawn immediately before and 3 hours after standardised bicycle exercise testing, and plasma protein expression was compared. Results 12 patients had ACM with BiV involvement, and 26 patients had isolated right ventricular (RV) involvement. During the follow-up period, 34 patients had a MACE (30% with RV and 14% with BiV). Over 360 proteins were assessed in all ACM patients and compared to 24 healthy controls. The proteomic signature of ACM patients differed significantly compared to controls, and 32 proteins were upregulated in ACM (Figure 1). The proteomic profiles of patients with RV involvement also differed from those with BiV involvement. Most importantly, after exercise, over 40 proteins were upregulated specifically in ACM patients compared to controls, including key pro-inflammatory, adipogenic molecules and also markers of cardiac fibrosis. Conclusion Our study shows that ACM patients with RV and BiV involvement have different plasma proteomic profiles compared to healthy controls. Furthermore we were able to demonstrate that, specifically in ACM patients, several pro-inflammatory pathways are upregulated after exercise compared to healthy controls, further elucidating the molecular pathways associated with arrhythmogenicity and disease progression and highlighting the key role of physical stress. Our results may enable the identification of potential future biomarkers for diagnosis and risk stratification and may pave the way for personalized patient specific treatments. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Baugarten Foundation ZurichSwiss National Foundation

Background Transvenous (TV) pacemakers are a well established treatment of bradyarrhythmias yet their complications, namely bleeding, infection and pneumothorax, still pose challenges to modern cardiology. This applies particularly to the older patient subgroup requiring single-chamber pacing due to comorbid atrial fibrillation (AF). Furthermore, conditions such as superior venous access issues, high infectious, or bleeding risk may complicate or preclude transvenous lead implantation. While VVIR leadless (LL) pacemakers aim to tackle these shortcomings, a comparison with contemporary single-chamber TV cohorts is currently lacking thus hindering a clear definition of the scope of LL pacing in clinical practice. Purpose To prospectively analyse survival and complication rates in leadless versus transvenous single-chamber pacemaker recipients. Methods This is a prospective analysis of 344 consecutive patients who received single-chamber TV or LL pacemakers between June 2015 and May 2021 in two tertiary cardiology centres. Indications for single-chamber pacing were “slow” AF, atrio-ventricular block with comorbid AF (either permanent or accepted as “destination rhythm”) or with sinus rhythm in bedridden cognitively impaired patients. LL indications were ongoing or expected chronic haemodialysis (6.9%), superior venous access issues such as occlusion (11.1%) or need for its preservation (9.7%), active lifestyle with low amount of pacing expected (22.2%), frailty causing high bleeding and infectious risk (23.6%), as well as recent valvular endocarditis (2.8%) or implantable electronic device infection requiring extraction (5.6%). Results 72 patients (20.9%) received LL and 272 (79.1%) TV single-chamber pacemakers. In keeping with LL indications, diabetes and ongoing haemodialysis were more prevalent in the LL population. No significant difference in overall complication rate was observed between LL and TV patients (5.6% vs. 5.1%, p=0.33) apart from haematomas, which occurred more frequently in the LL population. Only 1 haematoma in the TV group required surgical reintervention. TV recipients survival was lower with greater cardiovascular mortality, likely due to selection of significantly older patients. Conclusions Given the limited complication rate observed in this contemporary single-chamber TV cohort and low life expectancy of this particular population, extending LL indications to all VVIR candidates is unlikely to provide a clearcut survival advantage. Considering the higher costs of LL technology, these data prompt a careful selection of those cases where LL approach does indeed provide an advantage. In addition to the setting of vascular access issues and high bleeding or infectious risk, these may include patients with sufficient life expectancy where lead-related risks may indeed adversely affect prognosis. Based on our patient selection criteria, LL might account for approximately 20% of VVIR pacing recipients. Funding Acknowledgement Type of funding sources: None.

Introduction: Obesity is associated with a higher risk of cardiac arrhythmias. Sleeve Gastrectomy (SG) is a common bariatric surgery with beneficial effects on weight loss and comorbidities. The study aimed to investigate the prevalence of arrhythmias during maximal exercise testing in patients with moderate-severe obesity and to evaluate the impact of SG on these arrhythmic events. Methods: All patients with moderate or severe obesity who were considered suitable candidates for SG between June 2015 and September 2020 were recruited. Each patient underwent three incremental, maximal, ECG-monitored cardiopulmonary exercise test one month before and six and twelve months after SG; the frequency and complexity of ventricular premature beats (VPBs) and atrial premature beats (APBs) have been evaluated during rest, exercise and recovery phases. Results: 50 patients with severe obesity (BMI 46.39 ±7.89 kg/m2) were included in the study. After SG, patients presented a decreased BMI (34.15 ± 6.25 kg/m2 at six months post-SG and 31.87 ± 5.99 kg/m2 at twelve months post-SG). At six months post-SG, an increase in VPBs, mainly during the recovery phase, was observed. At twelve months post-SG, a reduction in VPBs compared with the six months evaluation was showed. Conclusion: Although in the early post-surgical phase the risk of exercise-induced arrhythmias may be higher, SG does not seem to increase the occurrence of arrhythmias in the long-term. No life-threating arrhythmias were found during post-SG evaluations.

Aims The aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings. Methods and results COVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36–72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9–16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting. Conclusion HCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.

Coronary artery anomalies (CAAs) are a heterogeneous group of rare congenital diseases whose features and pathophysiological mechanisms are extremely variable, ranging from silent anomalies to sudden cardiac death (SCD) in the most severe cases. Although rare, congenital CAAs confer a high risk of myocardial ischemia and SCD, especially in young, previously “healthy” athletes during or immediately after vigorous exertion. Although some high-risk features that may lead to SCD have been identified, specific pathophysiological mechanisms related to SCD still remain poorly understood. When a CAA is incidentally diagnosed, optimal SCD risk stratification remains challenging, particularly in cases of anomalous aortic origin of a coronary artery arising from the opposite aortic sinus of Valsalva (ACAOS). In recent times, invasive imaging with intravascular ultrasound has gained a role in further identifying high-risk anatomic features; it has been integrated with traditional, non-invasive anatomic imaging evaluations, typically high-quality echocardiography, and cardiac magnetic resonance. Multidisciplinary programs and specific SCD risk scores should be developed in an endeavor to choose the right therapeutic approach, either clinical or interventional/surgical. Intravascular ultrasound is an extremely useful tool to evaluate vessel stenosis, even if prospective studies are still required to further validate this diagnostic strategy. In the present review, we aimed to analyze the pathophysiology and the clinical impact of ACAOS. We also summarized the predominant mechanisms for interference with normal coronary artery function, which might contribute to the onset of life-threatening arrhythmias and SCD.