Risultati per: Long COVID: principali risultati, meccanismi e raccomandazioni

Circulation, Volume 150, Issue Suppl_1, Page A4136584-A4136584, November 12, 2024. Introduction:Niacin is a non-statin lipid-lowering therapy that has been shown to lower triglycerides and improve other risk factors for cardiovascular diseases. However, previous studies have reported inconsistent effects of niacin on mortality, and its effect on long-term prognosis has not been well studied.Goals:The aim of this study is to examine the association of niacin therapy with long-term all-cause mortality.Methods:In a nationwide historical cohort of 1,139,630 US Veterans with normal baseline kidney function, we examined the association of de novo niacin prescription from 2004 to 2006 with all-cause mortality during a 14-year follow-up. Associations were examined in Cox proportional hazard models adjusted for demographics, major comorbidities, and laboratory measurements. Prescription time-distribution matching was used to control for survival bias.Results:We identified 133,450 new users of niacin. Overall, patients had a mean (standard deviation) age of 60 (13) years, with 6% female, 78% White, 16% Black, and 6% Hispanic. Niacin users were more likely to be male, White, current, or former smokers and had higher frequencies of comorbidities. Niacin use (vs. non-use) was associated with a lower risk of death (Hazard ratio: 0.89, 95% confidential interval: 0.88-0.90) in the fully adjusted model (Model 4, Figure).Conclusion:In a large national cohort of US Veterans, niacin use was associated with a lower risk of death. Further studies are needed to corroborate the potential benefits of niacin on survival.

Circulation, Volume 150, Issue Suppl_1, Page A4141937-A4141937, November 12, 2024. Background:Although sucrose non-fermenting 1-related kinase (SNRK) in endothelial cells (EC) has a critical role in anti-inflammation and anti-fibrosis in the kidney, whether SNRK controls EC senescence and vascular aging, and how SNRK is regulated have never been studied. Long noncoding RNAs (lncRNAs) are involved in endothelial function and are altered during aging and in response to various senescence stimuli. However, whether lncRNA controls SNRK protein levels, which regulate EC senescence and cardiovascular diseases (CVD), is still poorly understood.Methods:Immunohistochemistry was performed on mouse aortic samples. RNA fluorescence in situ hybridization (RNA-FISH) staining was taken with young and aged arteries. Young and senescent primary human ECs were used for molecular signaling analysis, and SNRK expression was manipulated using plasmid overexpression and depletion. Senescence-associated β-galactosidase (SA-β-gal) staining was performedin vitro andin vivo.Results:Analyzing the expression of senescence-associated lncRNAs by qRT-PCR in human endothelial cells, we identified a long noncoding antisense (AS) transcript of SNRK, SNRKAS, which was upregulated by forkhead box A2 (FOXA2) activation in senescent human ECin vitroand EC from aged human vesselsin vivo. SNRKAS, acting in a cis-regulatory manner, downregulated SNRK expression via RNA-mRNA interaction in EC. The passaging of primary EC and X-ray irradiation (XRI) substantially decreased SNRK protein levels, while elevating SNRKAS levels; SNRK overexpression reversed XRI-induced protein and mRNA upregulation of p16, a cellular senescence marker. Furthermore, SNRK was required for the expression of lamin B1, while negatively regulating the stimulator of interferon genes (STING) signaling in EC. Finally, endothelial SNRK deficiency in mice promoted endothelial senescence, aortic stiffness, and atherogenesisin vivo.Conclusions:We conclude that lncRNA SNRKAS acts as a negative regulator of endothelial senescence via downregulation of SNRK.

Circulation, Volume 150, Issue Suppl_1, Page A4144299-A4144299, November 12, 2024. Introduction:Sleep and physical activity (PA) are essential components of ideal health. However, epidemiological data assessing PA and sleep have been limited by short measurement periods, small samples, or recall bias. We assess the relationship between objective measures of long-term PA and sleep across the human phenome.Methods:We included 9399 individuals in the All of Us cohort with >6 months of wearable (Fitbit) data and linked electronic health records. Fitbit data included daily total sleep duration (TSD) and moderate and vigorous physical activity (MVPA) over a median time of 1103 days. We used Cox regression to model the association of MVPA and TSD across 1711 phecodes (Cox pheWAS), adjusting for age, sex, and race. Top associations were investigated individually using restricted spline curves to quantify the change in hazard ratio (HR) of disease per minute of sleep or MVPA. Individual phenotype associations were further adjusted for smoking status, alcohol intake, education level, and BMI. We performed interaction analyses to assess whether TSD modifies the effect of MVPA on disease. We accounted for multiple hypothesis testing with Bonferroni correction.Results:TSD and MVPA levels were uncorrelated (r2: 0.004) and independently associated with several cardiometabolic and non-cardiometabolic diseases, including obesity (MVPA: HR 0.97, p 4e-14; TSD: HR 0.99, p 2e-16), hypertension (TSD: HR 0.99, p 4e-5), major depressive disorder (MVPA: HR 0.98, p 2e-7; TSD: HR 0.99, p 3e-3), and chronic migraine (MVPA: HR 0.97, p 3e-5) (Fig.1). The association between MVPA and chronic disease often demonstrated a linear or curvilinear dose-response curve. By contrast, the association of TSD and chronic disease was often sigmoidal, with increasing benefit of longer sleep between ~5hr20min and 6hr40min of sleep/day, but relatively constant health benefits/risks for longer/shorter sleep durations.Conclusion:In All of Us participants, TSD and MVPA are independently and inversely associated with chronic disease based on objective, long-term measures. These data highlight the importance ofbothsleep and MVPA in maintaining ideal health, and will help inform personalized, disease-specific sleep and PA recommendations.

Circulation, Volume 150, Issue Suppl_1, Page A4146803-A4146803, November 12, 2024. Introduction/Background:Patients admitted with sepsis are at risk of developing septic cardiomyopathy (SCM), which may elevate their risk of short-term mortality. However, the effect of SCM on long-term outcomes after sepsis is poorly understood. This study explores whether patients with sepsis and SCM have worse long-term outcomes compared to those without SCM.Research Questions/Hypothesis:What are the long-term major adverse cardiovascular events, including death, stroke, and myocardial infarction (MACE) 36 months after ICU discharge for septic patients with abnormal global left ventricular strain (LV GLS)?Methods:We conducted a retrospective study of 396 sepsis patients from August 2018 to September 2022, approved by the Mayo Clinic IRB. Patient demographics, comorbidities, echo parameters, and outcomes were collected. Due to the expected non-linear relation between LV GLS and Hazard Ratio (HR) of MACE we employed Cox regression analysis with Restricted Cubic Splines. Secondly, we divided the population into 2 groups, patients with and without normal LV GLS (between -23 and -16). The effect of non-normal LV GLS on MACE was evaluated using Cox regression weight by inverse probability weighting (IPWT) analysis after propensity score assessment, adjusting for diabetes, hypertension, BMI, history of stroke or myocardial infarction, chronic kidney disease, age, and sex.Results:Demographic variables did not differ significantly based on normal versus abnormal LV GLS. In the restricted cox regression with cubic spline models, we observed that patients with normal values had HR lower than one compared with patients without normal values (Figure 1). Secondly, we found that the HR of MACE in patients with normal LV GLS was significantly lower in the crude analysis (HR 0.66 [CI 95% 0.5, 0.86]; p

Circulation, Volume 150, Issue Suppl_1, Page A4141946-A4141946, November 12, 2024. INTRODUCTION:Mechanisms contributing to the post-acute sequelae of SARS-CoV-2 (PASC, aka Long COVID) and associated functional limitations are unclear.RESEARCH QUESTION:Determine cardiovascular, autonomic and exercise physiology among patients with Long COVID.METHODS:Twenty-one Long COVID patients (16 females, 41±12yrs) underwent cardiovascular assessment during head-up tilt at supine, 30oand 60o, a 10-minute upright standing orthostatic challenge and cardiopulmonary exercise testing (CPET). Baroreceptor sensitivity was determined with Valsalva maneuver. Heart rate (HR) and blood pressure (BP) were monitored continuously. Plasma norepinephrine (NE) was monitored during tilt.RESULTS:During tilt, HR increased with transition from supine to 30oand 60o(72±12 v. 80±14 v. 90±15bpm, P

Circulation, Volume 150, Issue Suppl_1, Page A4136632-A4136632, November 12, 2024. Background:The impact of postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) on long-term clinical outcomes has not been adequately evaluated yet.Methods:Among consecutive 14927 patients who underwent their first coronary revascularization in the CREDO-Kyoto PCI/CABG Registry Cohort-3 (2011-2013), the study population consisted of 1483 patients who underwent CABG after excluding those with prior AF. POAF was defined as newly documented AF during hospitalization for CABG. The primary outcome measure was all-cause death after discharge. The median clinical follow-up was 5.7 (interquartile range, 4.4-6.6) years.Results:POAF was observed in 337 patients (23%). Multivariable logistic regression analysis indicated that age >=75 years (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.24-2.10; P

Circulation, Volume 150, Issue Suppl_1, Page A4144997-A4144997, November 12, 2024. Introduction:Myocardial injury in patients hospitalized with acute on chronic heart failure concurrent with index SARS-CoV-2 (CoV-2) infection is well described, though studies incorporating pre- and post-acute COVID-19 (PAC) are lacking. We address this gap by estimating intensity of acutely decompensated heart failure (ADHF) using time-series pro-BNP levels across hospitalizations pre- vs. respectively index and initial readmission (PAC1).Hypothesis:Case time series analysis will reveal association (p

Circulation, Volume 150, Issue Suppl_1, Page A4141165-A4141165, November 12, 2024. Background:Current evidence supports the use of the Ross procedure (pulmonary autograft) in adults with aortic valve disease.Aims:To examine the ten-year clinical and echocardiographic outcomes following the Ross procedure using a tailored approach.Methods:This prospective cohort included 455 consecutive adults (333 male [73.1%]) with a median age of 50.0 years (IQR, 40.0-57.0) undergoing a Ross procedure at a single center. Patients with aortic aneurysms (37.4%), previous cardiac surgery (15.2%) and active endocarditis (5.7%) were included. The predominant lesion was aortic stenosis (AS) in 379 patients (83.3%) and aortic insufficiency (AI) in 76 patients (16.7%). The study period ranged from February 1, 2011, to December 31, 2019. Primary endpoints were cumulative incidence of any, autograft, or homograft reintervention, and time-related valve function (AI grades 0-4). The secondary endpoint was ten-year survival among Ross patients compared with that in the age- and sex-matched Canadian population. Median clinical follow-up was 6.0 years (maximum 13 years). Follow-up was 90% complete for clinical and 87% complete for echo follow-up.Results:Operative mortality was 0.4% (n=2). Both patients were operated among the first 100 cases. At 10 years, cumulative incidence of any aortic and/or pulmonary reintervention was 5.0% (95% CI, 2.3-9.4%); autograft reintervention 1.5% (0.5-3.4%); and homograft reintervention 3.4% (1.9-5.7%). In patients with preoperative AS, cumulative incidence of autograft reintervention was 1.8% at 10 years (0.6-4.1%), versus 0% in patients with preoperative AI (p=0.6) (Figure 1). At 10 years, cumulative incidence of AI grade >2 was 2.0% (0.9-4.2%), and did not differ between patients with preoperative AS or AI (p=0.9) (Figure 1). Ten-year survival was 96.5% (95% CI, 94.7-98.7%), translating to a relative survival of 100% (99.4-100%) compared to the matched general population.Conclusion:This study demonstrates that using a tailored surgical approach and contemporary perioperative management strategies, the Ross procedure is associated with excellent long-term valve function and freedom from reintervention in an all-comer adult patient population. Moreover, it translates into restored late survival, mimicking the general population. These results further support the notion that, in reference centers, the Ross procedure should be considered in adults needing valve replacement.

Circulation, Volume 150, Issue Suppl_1, Page A4143504-A4143504, November 12, 2024. Background:Beige adipocytes, express UCP1 and have thermogenic capability, making them a promising target for obesity treatments. However, beige adipocytes quickly transition into white adipocytes upon removal of stimuli. Our research identifies the cyclin-dependent kinase inhibitor 2A (Cdkn2a) as a crucial regulator of this transition. Ablation ofCdkn2aprolongs beige adipocyte lifespan, enhances energy expenditure, and improves glucose tolerance by inhibiting BECN1-mediated autophagy. These findings offer a potential therapeutic strategy to maintain beige adipocytes and combat obesity and related diseases.Methods:We used Ucp1-CreERT2mice with a Rosa26RRFPindelible labeling reporter andCdkn2afloxed mice. All mice were maintained on a mixed C57BL6/J-129SV background. To induce Cre recombination, mice received tamoxifen for 2 days. For in vitro induction, cells were treated with 2 µM 4-hydroxy-tamoxifen. In our in vitro study, we isolated stromal vascular fraction (SVF) cells from the inguinal white adipose tissue (IGW) or brown adipose tissue (BAT) of 6-week-old male mice for seeding. For the in vivo study, we used cold exposure, metabolic cages, and glucose tolerance tests.Results:Cdkn2aplays a pivotal role in the beige-to-white transition. Its absence prolongs the lifespan of beige adipocytes and in male mice, confers long-term metabolic protection against diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically,Cdkn2apromotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced byCdkn2aablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Hence, blockingCdkn2a-mediated BECN1 activity holds therapeutic potential in treating obesity and related metabolic diseases.Conclusion:Cdkn2adepletion extends beige adipocyte lifespan, providing long-term metabolic benefits against diet-induced obesity in male mice.Cdkn2aboosts BECN1 expression, triggering the beige-to-white transition by directly interacting with BECN1 mRNA and its negative regulator BCL2L1, activating autophagy. TargetingCdkn2a-mediated BECN1 activity holds promise as a therapeutic approach for treating obesity.

Circulation, Volume 150, Issue Suppl_1, Page A4146939-A4146939, November 12, 2024. Background:New onset AF during acute illness has a high rate of AF recurrence within 5-yr. However, little is known about AF progression in patients with new onset AF during COVID illness. It is also unknown whether the time of COVID diagnosis (early vs late) impacts AF progression. More specifically, did the potentially different immune and inflammatory responses during early vs late COVID produce structural and electrical cardiac remodeling that would increase the likelihood of AF progression.Objective:We sought to compare AF progression in patients with new onset AF during early vs late COVID and hypothesized that early COVID was associated with increased AF progression compared to late COVID.Methods:From Apr 2020 to Feb 2024, patients receiving a SARS-2-CoV test without a history of AF with new onset AF and at least 3-mo of follow up were included (N=11,767). Patients were subdivided based on pos vs neg SARS-2-CoV test and time of diagnosis. Early COVID diagnosis (n=3052) included Apr 2020-Aug 2021 and late COVID (n=8715) included Sep 2021-Feb 2024. AF progression endpoints at 3-, 6- and 12-mo included AF hospitalization, AF emergency department (ED) visit, cardioversion and AF ablation.Results:Patients with late COVID were more likely females with hypertension, coronary artery disease and hyperlipidemia compared to early COVID patients. At 3- and 6-mo follow-up there was no difference in AF progression between the early and late COVID groups for any endpoint. In contrast, at 12-mo follow up there was in increase in late diagnosis group AF ED visits (11% vs 7.6%,p

Circulation, Volume 150, Issue Suppl_1, Page ASa807-ASa807, November 12, 2024. Background:Despite the lack of evidence supporting the use of chest compression-only cardiopulmonary resuscitation (CO-CPR) emphasizing the importance of rescue breathing for pediatric out-of-hospital cardiac arrest (OHCA), prehospital CO-CPR is increasing. The COVID-19 pandemic may have led more bystanders to perform CO-CPR, even for pediatric OHCA. However, studies on the dissemination of CO-CPR and outcomes in pediatric OHCA are limited.Hypothesis:Spread of CO-CPR led to increased mortality in pediatric OHCA.Aims:Investigate the mortality of nationwide pediatric OHCA patients with the dissemination of CO-CPR pre- and post-COVID-19.Methods:We conducted a retrospective study using a Utstein-Style population cohort database (Japanese National Registry). Pediatric OHCA patients (≤17 years old) with bystander resuscitation attempts registered between the pre-COVID-19 era (2017-2019) and the post-COVID-19 era (2020-2021) were included. The primary outcome was 30-day mortality after OHCA. The secondary outcome was 30-day poor neurological outcomes, defined as Cerebral Performance Category scores of 3, 4, or 5. We used Poisson regression with robust variance to estimate adjusted risk ratio (aRR) with 95% confidence interval (CI) and the population attributable fraction (PAF, %) with a focus on the post-COVID-19 period.Results:A total of 3,352 pediatric OHCA, 2,023 pre-COVID-19, and 1,329 post-COVID-19 patients received bystander CPR and were registered in the database. CO-CPR was more common than CPR with rescue breathing (RB-CPR) during the pre- and post-COVID-19 periods [pre-COVID-19: 1,356 (67.0%) vs. 667 (33.0%), post-COVID-19: 1,048 (78.9%) vs. 281 (21.1%)]. Comparison of CO-CPR vs. RB-CPR showed increased 30-day mortality in both periods [pre-COVID-19: 1,081/1,356 (79.7%) vs. 420/667 (63.0%), post-COVID-19: 841/1,048 (80.2%) vs. 181/281 (64.4%)]. In the overall cohort, mortality increased with CO-CPR (aRR: 1.16, 95% CI: 1.09-1.23, PAF:1.60%). Due to the increased number of patients receiving CO-CPR, we estimated 21.2 excess deaths over the two-year post-COVID-19 period. Similar results were observed for poor neurological outcome (aRR: 1.10, 95% CI: 1.05-1.16, PAF: 1.10%, excess poor outcome: 14.6]).Conclusion:With the spread of CO-CPR for pediatric OHCA, an estimated 10.6 excess deaths per year attributed to CO-CPR may have occurred in the post-COVID-19 period compared to the pre-COVID-19 period in Japan.

Circulation, Volume 150, Issue Suppl_1, Page A4139852-A4139852, November 12, 2024. Despite current modestly effective triglyceride (TG) lowering therapies, the availability of more effective agents for persistently lowering elevated TGs and risk of acute pancreatitis remains a continuing need. More recently identified triglyceride-rich lipoproteins (TRLs), specifically remnant cholesterol (RC)-rich particles, are important drivers of ASCVD risk independent of LDL-C, driving development of more effective TG-directed therapies. Apolipoprotein C3 (APOC3) raises TGs by inhibiting lipoprotein lipase (LPL) dependent and -independent pathways. Plozasiran, a RNAi agent targeting APOC3 mRNA in hepatocytes, demonstrated large reductions in circulating APOC3, TGs, TRL-RC with a good safety profile in placebo-controlled trials.Here we report extension data to characterize long term safety and efficacy of plozasiran in subjects with elevated TGs.Plozasiran was studied in subjects with mixed hyperlipidemia (entry TGs 150-499 mg/dl) and severe hypertriglyceridemia (entry TGs >500-4000 mg/dl) in separate Phase 2 trials (MUIR and SHASTA-2). Subjects completing double-blind, placebo-controlled treatment could enter this open-label extension. Endpoints included changes in fasting TG levels, other lipid and lipoprotein parameters and safety assessments for up to 24 months. Data cut-off was 5/16/24 for this analysis, (up to 15 months of follow up) in the ongoing study.251 and 165 subjects from MUIR and SHASTA-2 entered the extension in which all received plozasiran 25 mg SQ dosed quarterly. 10, 25 or 50 mg of plozasiran under blinded conditions produced mean reductions in TGs of -52 to -64% (MUIR) and -69 to -74% (SHASTA-2), 12 weeks (trough) after the second dose. Corresponding trough reductions in the extension ranged from -44 to -73% (MUIR) and -62 to -86% (SHASTA-2) through 15 months follow-up. Common reported AEs were consistent with the index studies and patient populations and mean HbA1c did not increase, providing further evidence that long-term safety remains favorable with repeated dosing and longer observation periods.Extended open-label treatment with plozasiran in subjects with moderate to severely elevated TGs continue to show reductions of TG levels and safety consistent with the blinded index studies, demonstrating incidence rate and severity of TEAEs remain favorable with repeated dosing and longer observation. Results of additional lipid and lipoprotein parameters are also consistent with the blinded index data and will also be reported.

Circulation, Volume 150, Issue Suppl_1, Page A4144056-A4144056, November 12, 2024. Background:COVID-19 infections have been associated with cardiovascular autonomic dysfunction (AD). Clinical findings include fatigue, cognitive impairment, and postural intolerance. However, quantitative post-COVID AD assessments are lacking.Objective:Compare autonomic testing measures of post-COVID-19 subjects to controls and those with pure autonomic failure (PAF).Methods:Autonomic testing included 1) change in heart rate (HR) and blood pressure (BP) with active standing (AS) and tilt table testing (TT), 2) time to BP nadir and recovery during AS and TT, 3) Valsalva ratio (VR), and 4) respiratory sinus arrhythmia (RSA). Comparisons between two groups were made using t-tests, Kruskal-Wallis, or chi-square tests. Multivariable linear regression was used to adjust findings for age and sex. A p-value of

Circulation, Volume 150, Issue Suppl_1, Page A4143806-A4143806, November 12, 2024. Background:The American Heart Association Predicting Risk of Cardiovascular Disease Events (PREVENT) equations were recently developed to estimate risk of cardiovascular disease (CVD). Long-term risks of cardiovascular disease based on the PREVENT equations in the U.S. population are unknown.Methods:Using data on adults aged 30-79 years from the National Health and Nutrition Examination Survey between 2011 and 2020, we determined long-term risks of total CVD (atherosclerotic cardiovascular disease or heart failure) based on the PREVENT equations. Age-standardized and survey-weighted risk prevalence was determined with further stratification by age group, sex, race and ethnicity.Results:The study population included 14,256 participants representing 160.6 million U.S. adults (mean [SD] age 51.9 [11.2] years, 49.2% women, 66.4% non-Hispanic white, 9.8% non-Hispanic black, 5.7% non-Hispanic Asian and 14.8% Hispanic). Among adults aged 30-79 years, 9.6% had existing CVD and 20.2% were CVD-free but had intermediate or high (≥7.5%) 10-year risk of CVD. The prevalence of CVD-free US adults with low or borderline (

Circulation, Volume 150, Issue Suppl_1, Page A4126581-A4126581, November 12, 2024. Background:Coronavirus Disease-19 (COVID-19) pandemic had a significant impact on emergent and elective treatment strategies in patients with cardiovascular disease. We aimed to examine the impact of COVID-19 on septal reduction therapy (SRT) in hypertrophic cardiomyopathy (HCM).Methods:National Inpatient Sample 2019-2021 was queried to identify patients with HCM and SRT using appropriate ICD codes. Temporal trends for SRT were obtained before and after COVID-19 outset.Results:There was a significant decline in the number of SRT from 2019 to 2020 (1505 vs. 1180, p

Circulation, Volume 150, Issue Suppl_1, Page ASa906-ASa906, November 12, 2024. Aims:The aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) inKCNH2in patients with long QT syndrome (LQTS) and to explore the relationships between genotypes and phenotypes.Methods:Information onKCNH2variants in LQTS patients was retrospectively obtained from the HGMD, ClinVar and PubMed databases through October 2022. SNV pathogenicity was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired t tests and Fisher’s exact tests were used to analyze the SNV distributions across structural and functional domains, and their correlations with clinical phenotypes.Results:A total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were non-synonymous SNVs (nsSNVs) associated with LQTS. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched in the Cyto2, S5, S6, H5, and Extra3. In addition, 759 nsSNVs were enriched in the Per-Arnt-Sim (PAS) and selectivity filter (SF) functional domain. The P and LP nsSNVs remained enriched in the PAS, SF, and cyclic nucleotide binding domain (cNBD). Clinical data showed that patients with nsSNVs located at S5-H5-S6, PAS and SF regions were associated with increased risk of life-threatening cardiac events, including Torsade de Pointes and sudden cardiac death, and were predominantly female. Furthermore, nsSNVs enriched in N-terminus region, S5-H5-S6 region and PAS domain were associated with an increased risk of syncope.Conclusion:TheKCNH2nsSNVs located at the S5-H5-S6 region, and the PAS and SF domains are associated with increased risk of life-threatening cardiac events.