Dikilitas, Ozan

Background: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization–phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA—odds ratio and 95% CI for coronary heart disease 1.28 (1.16–1.41); cerebrovascular disease 1.14 (1.07–1.21); peripheral artery disease 1.22 (1.11–1.34); abdominal aortic aneurysm 1.28 (1.17–1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99–1.24) and cerebrovascular disease 1.06 (0.99–1.14) but similar for peripheral artery disease 1.16 (1.01–1.33) and abdominal aortic aneurysm 1.34 (1.11–1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10–1.62), mitral valve disorders 1.18 (1.09–1.27), congestive heart failure 1.12 (1.05–1.19), and chronic kidney disease 1.07 (1.01–1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94–1.25), mitral valve disorders 1.02 (0.89–1.16), congestive heart failure 1.02 (0.95–1.10), or chronic kidney disease 1.05 (0.99–1.12). Mendelian randomization–phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.

Background: Atrial fibrillation (AF) ablation targets improvement in quality of life (QoL). Data is scarce on predictors of QoL improvement following ablation. We aimed to investigate the clinical characteristics underlying differential response in QoL after AF ablation (with or without arrhythmia recurrence). Methods: All patients undergoing AF ablation (2013–2016) at our center were prospectively enrolled in a fully automated patient-reported outcomes registry. A large number of variables were collected including AF symptom severity scale and AF burden (as indicated by AF frequency and duration scores). Patients were divided into 3 groups based on self-report of QoL improvement: remarkable (super responders), mild/moderate, and unchanged or worse (nonresponders). Univariable and multivariable logistic regression models assessed clinical characteristics and QoL outcomes. Results: A total of 956 patients were included (25% females, mean age 63.9). Most patients (≈80%) were super responders (n=761), 138 (14.4%) had mild/moderate improvement, and 57 (5.9%) were nonresponders. The strongest predictors of remarkable QoL improvement were freedom of arrhythmia recurrence (OR, 2.42 [95% CI, 1.27–4.59], P =0.007) and lower AF burden at 12 months. Similarly, higher AF burden was significantly associated with clinical nonresponse. In patients with observed clinical recurrence-QoL mismatch, changes in AF burden at 12 months were the main predictors of QoL outcome, with lower burden predicting higher improvement in QoL and vice versa. Conclusions: Most patients derive significant QoL benefit from AF ablation. Freedom from arrhythmia recurrence and lower AF burden predict remarkable QoL improvement following ablation.

Introduction: Current risk equations for coronary heart disease (CHD) do not take into account family history or cumulative exposure to LDL-C. We modified CHD risk equations for use in familial hypercholesterolemia (FH) patients and developed a decision aid (DA) for FH to facilitate shared decision making (SDM). Methods: Literature review, evidence synthesis and expert input were used to adapt the 30-year Framingham Risk Score (FRS) and 10-year ACC/AHA pooled cohort equations to calculate the CHD risk in individuals with FH aged 20-39 years and ≥40 years, respectively. Based on published data, estimated risk was multiplied by 2 for family history of early CHD or 3 in the presence of a pathogenic variant. Treatment benefit of lipid lowering was estimated based on the ‘cumulative exposure to LDL-C’ model ( JACC 2012; 60 ) using the following equations: Post-treatment 30-yr risk in those aged 20-39 years = Baseline Risk (FRS) x 0.54 delta LDL-C (mmol/L) Post-treatment 10-yr risk in those aged ≥40 years = Baseline Risk (ACC/AHA Pooled Cohort) x 0.72 delta LDL-C (mmol/L) To convey CHD risk and treatment benefit, we developed a DA using an iterative, patient-centered design process for use in FH encounters. Results: Using the DA, providers can discuss baseline CHD risk estimates, lipid lowering drug (LLD) options and the expected post-treatment risk reduction with FH patients. The estimated % LDL-C reduction for each LLD and the predicted risk reduction per mmol/L of LDL-C lowered were obtained from literature review. Lowering LDL-C by 1 mmol/L (39 mg/dL) was associated with a 28% CHD risk reduction over 10 years and a 46% reduction over 30 years ( Eur Heart J 2017; 38 ). We describe 2 examples of estimating CHD risk and treatment benefit in FH cases in Table 1 . Conclusion: We adapted CHD risk prediction equations to account for family history of CHD and presence of a pathogenic FH variant and designed a DA to convey personalized CHD risk estimates and treatment benefit to facilitate SDM with FH patients.

Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.

Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency <1%) in KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.

Abstract Objective: Fibromuscular dysplasia (FMD) is an arteriopathy that presents mainly by hypertension, stroke or dissection. Diagnosis is often made in middle-aged women with few cardiovascular risk factors. We aim at identifying common genetic variants associated to FMD. Design and method: We tested ∼6.5 million common genetic variants (MAF > 0.01) in 1962 cases and 7100 controls from 6 studies using variants and gene-based association analyses. Participants were of European ancestry, with similar characteristics (91% multifocal, 88% women), diagnosis methods and inclusion/exclusion criteria. Transcriptome-wide association (TWAS), eQTL, gene expression by sex and colocalization analyses used expression data in arteries from GTEx and/or FMD patients and matched controls. Open chromatin regions were defined using ATAC-Seq on primary human fibroblasts, smooth muscle and endothelial cells. Genetic correlations were assessed using summary statistics from UKBiobank and/or published studies by linkage disequilibrium score regression and multi-trait-based conditional and joint analyses (mtCOJO). Results: We confirmed the previously identified PHACTR1 locus and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. TWAS in arteries identified one additional locus (SLC24A3). Through integration of annotation datasets, we provided prioritization of variants and genes. These are consistently and specifically expressed in fibroblasts, smooth muscle cells, and arterial tissues. PHACTR1 and SLC24A3 showed sex differences in gene expressions consistent with the direction of effects of FMD risk alleles. FMD genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, two mechanisms central to vascular contraction. We found significant genetic overlaps between FMD and blood pressure traits, for the associated loci and globally at the genome level, but demonstrated that hypertension is not driving the genetic association with FMD. We also found positive genetic correlations with migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independently from the genetics of blood pressure. Conclusions: We describe robustly associated loci and genes with FMD and provide several new leads toward understanding biological mechanisms of stenosis and dissection in young women in the absence of atherosclerosis, which shares part of its genetic basis with more common cardiovascular and neurovascular diseases.

Introduction: Several clinical trials evaluating the efficacy of a carotid revascularization procedure excluded patients above age 80. In the current study, we sought to assess the differences in characteristics of octogenarians undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS) for carotid stenosis using “real-world” data from a national surgical quality registry. Methods: The National Surgical Quality Improvement Program (NSQIP) targeted datasets for CEA and CAS were queried for patients aged ≥80 years between 2012-2018. Results: We identified 5,814 patients undergoing CEA and 189 patients undergoing CAS. Patients in the CAS group were more likely to be ≥90 years (p=0.004), diabetic (p=0.04), had a history of CHF (p=0.012) and a bleeding-disorder (p<0.001). Patients in the CAS group were also more likely to have high risk anatomy (p<0.001), high-risk-physiology (p=0.028). Ninety-nine (52.4%) patients in the CAS group and 2,775 (47.7%) in the CEA group were symptomatic, with most patients in both groups presenting with an ipsilateral stroke. Among asymptomatic patients, 64 (74%) in the CAS group and 2222 (72.7%) in the CEA group had severe/total stenosis (>80%-100%) of the ipsilateral carotid, while 13(14.5%) in the CAS group and 302 (11%) in the CEA group had severe or total stenosis of contralateral carotid. Among symptomatic patients, 58(61.7%) in the CAS group and 1527 (57.5%) in the CEA group were found to have severe/total stenosis of the ipsilateral-carotid, while 12(12.8%) in the CAS group and 208(7.8%) in the CEA group were found to have severe/total occlusion of the contralateral carotid. In the carotid endarterectomy group, 12.2% (n=711) underwent CEA-alone, 44.3% (n=2,575) CEA with angioplasty, 29.9% (n=1,737) CEA with angioplasty and shunt, 2.9% (n=166) CEA with shunt and 10.7%(n=166) eversion CEA. In the CAS group, 52.4%(n=99) underwent CAS with a single tapered stent, 29.1%(n=55) CAS with single tapered stent with CPD, 11.1%(n=21) single straight stent with CPD and 1.6%(n=3) a single straight stent alone. Conclusion: These analyses from real-world data show that there may be some differences in demographic and comorbid characteristics between octogenarians undergoing CAS and CEA.

Introduction: Due to their exclusion from most clinical trials, outcomes of carotid revascularization via a carotid endarterectomy (CEA) or carotid artery stenting (CAS) among octogenarians are not well studied. Herein, we present analysis of thirty-day stroke and mortality of patients aged ≥ 80 using real-world data from a national surgical quality registry. Methods: The National Surgical Quality Improvement Program (NSQIP) targeted dataset for CEA and CAS was queried for patients aged ≥ 80 undergoing CEA and CAS between 2012-2018. Results: A total of 94 and 2,656 patients aged ≥ 80 with symptomatic carotid stenosis undergoing CAS and CEA (respectively) were identified. Patients in the CAS group were more likely to be over 90 (p=0.006). Patients in the CAS group were more likely to have high-risk anatomy (p<0.001) and more likely to be on aspirin preoperatively (p=0.02) but less likely to have higher ASA (p<0.001). Most patients in the group presented with an ipsilateral stroke (CAS: 43.6% and CEA: 41.7%). The rate of thirty-day composite outcome (stroke or death) was found to be 5.3% in the CAS group and 4.5% in the CEA group (p=0.714) (stroke: 2.1% for CAS and 3.2% for CEA; death: 4.3% for CAS and 1.7% for CEA). Upon multivariable analysis, procedure type (CAS vs CEA) was not found to be associated with the composite-outcome (OR 1.1, 95%CI 0.43-2.82,p=0.836). Symptom presentation other than ipsilateral stroke was found to be associated with significantly decreased odds of 30-day composite outcome (amaurosis-fugax/transient monocular blindness: OR 0.42,95%CI 0.21-0.86, p=0.02; TIA: OR 0.62, 95%CI 0.42-0.93,p=0.02), while higher age was found to be associated with significantly increased odds (OR 1.512, 95%CI 1.01-2.24, p=0.02). Conclusion: Real world analysis from a surgical quality registry show that both CAS and CEA are associated with optimal 30-day outcomes among octogenarians with symptomatic carotid stenosis.

Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.