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BACKGROUND: A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3as a cause of SQTS or sudden cardiac death remains unknown.OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants using gene panels including SLC4A3.METHODS: In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was validated in a zebrafish embryo heart model.RESULTS: Potentially disease-causing variants were identified in 26% of patients and were mainly (15%) located in SLC4A3: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett interval) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutant AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting the pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes.CONCLUSION: In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3in the genetic screening of patients with SQTS or sudden cardiac death.

Aims Atrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology. Methods and results We identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7–46.2 years]. After a median follow-up of 9.8 years (IQR 5.7–14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9–5.1; P, Graphical Abstract Atrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. CI, confidence interval.

Background: Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive CAD. Methods: In this prespecified diagnostic substudy of the Dan-NICAD trial (Danish study of Non-Invasive testing in Coronary Artery Disease), we included 1617 consecutive patients with stable chest symptoms and no history of CAD referred for coronary computed tomography angiography. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped, and their PRSs were calculated. All patients underwent coronary computed tomography angiography. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography with fractional flow reserve. A combined end point of obstructive CAD was defined as a visual invasive coronary angiography stenosis >90%, fractional flow reserve 50% if fractional flow reserve measurements were not feasible. Results: The PRS was associated with obstructive CAD independent of CRFs (adjusted odds ratio, 1.8 [95% CI, 1.5–2.2] per SD). The PRS had an area under the curve of 0.63 (0.59–0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with area under the curve of 0.75 (0.71–0.79), which was 0.04 more than the CRF model ( P =0.0029). By using pretest probability (pretest probability) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% ( P =3.1×10 −4 ) was obtained, with a down-classification of risk in 24% of patients (211 of 862) in whom the pretest probability was 5% to 15% based on CRFs alone. Conclusions: Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02264717.

BACKGROUND: Genome-wide association studies of patients with coronary artery disease (CAD) suggest that several risk loci increase the risk of CAD and myocardial infarction (MI) equally. In contrast, the ABO locus is stronger associated with MI than with CAD, but the underlying mechanisms are unknown.PURPOSE: To investigate the association between the ABO risk variant and platelet activation and aggregation. Moreover, to explore the effects of other CAD-associated risk variants.METHODS: We included 879 stable CAD patients receiving low-dose aspirin. All patients were genotyped for 45 genome-wide significant CAD risk variants, including rs495828 at the ABO locus. A genetic risk score (GRS) was calculated to assess the combined risk of all genetic variants. Serum soluble P-selectin (sP-selectin) and thromboxane B2 were used as measures of platelet activation, and platelet aggregation was assessed by multiple electrode aggregometry (MEA) using arachidonic acid and collagen as agonists and VerifyNow.RESULTS: The rs495828 CAD risk allele was associated with higher MEA platelet aggregation; arachidonic acid: 14.9% (6.7-23.7%, p = 0.0002) higher AUC (Area Under aggregation Curve) per risk allele, and collagen: 13.1% (5.8%-20.9%, p = 0.0003). Conversely, sP-selectin levels were 7.5% (3.1%-11.7%, p = 0.001) lower per risk allele. Rs495828 genotypes were not associated with aggregation assessed by VerifyNow (p = 0.30) or S-thromboxane B2 levels (p = 0.98). None of the remaining variants or the GRS were associated with platelet activation or aggregation.CONCLUSIONS: The ABO risk allele was associated with increased platelet aggregation as assessed by MEA. This finding may contribute to explain the increased MI risk in ABO risk variant carriers.

OBJECTIVE: An association between bulimia nervosa (BN) and prolonged corrected QT interval (QTc) in the electrocardiogram has been suggested, but results of previous studies are conflicting, and the risk of cardiac events in patients with BN has yet to be investigated.METHOD: We estimated mean QTc interval and relative risk of borderline (QTc >440 ms) and prolonged QTc (QTc >460 ms) between adult women with BN (N = 531) and healthy controls (N = 123). In follow-up analyses, we investigated the risk of a primary endpoint (syncope, ventricular tachycardia, and cardiac arrest) and all-cause mortality in patients with BN (N = 702) compared with a population-based cohort derived from the Danish Civil Register (N = 7,020).RESULTS: Mean QTc did not differ between patients with BN and controls. Relative risk of borderline prolonged QTc was 2.3 (p = 0.28). The number of patients and controls with prolonged QTc was small, and the risk did not differ between patients with BN and controls. Median follow-up was 10.6 years. Although there appeared to be increased risks after 5 years of follow-up, long-term risks of the primary endpoint (Hazard ratio [HR] = 1.4, p = 0.37) and all-cause mortality (HR = 1.7, p = .28), respectively, were not increased in patients with BN compared to a population-based cohort.DISCUSSION: Mean QTc did not differ between patients with BN and healthy controls, and the risk of prolonged QTc was not increased in patients with BN. There was no difference in the long-term risk of cardiac events, and long-term all-cause mortality did not differ significantly between patients with BN and a population-based cohort.

Aims Women with arrhythmogenic right ventricular cardiomyopathy (ARVC) are at relatively lower risk of ventricular arrhythmias (VAs) than men, but the physical burden associated with pregnancy on VA risk remains insufficiently studied. We aimed to assess the risk of VA in relation to pregnancies in women with ARVC. Methods and results We included 199 females with definite ARVC (n = 121) and mutation-positive family members without ascertained ARVC diagnosis (n = 78), of whom 120 had at least one childbirth. Ventricular arrhythmia-free survival after the latest childbirth was compared between women with one (n = 20), two (n = 67), and three or more (n = 37) childbirths. Cumulative probability of VA for each pregnancy (n = 261) was assessed from conception through 2 years after childbirth and compared between those pregnancies that occurred before (n = 191) or after (n = 19) ARVC diagnosis and in mutation-positive family members (n = 51). The nulliparous women had lower median age at ARVC diagnosis (38 vs. 42 years, P Conclusion In women with ARVC, pregnancy was uneventful for the overwhelming majority and the number of prior completed pregnancies was not associated with VA risk. Pregnancy-related VA was primarily related to the phenotypical severity rather than pregnancy itself.

Background The ABO locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the ABO risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants. Methods We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the ABO locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential. Results The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 − 1.09], p = 0.01) but not with clot lysis time (p = 0.97). The rs12936587 (p = 0.04), rs4773144 (p = 0.02), and rs501120 (p = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (p-values > 0.05). Conclusion The ABO risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in ABO risk variant carriers.

Catheter ablation may reduce ventricular tachycardia (VT) burden in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, little is known about factors predicting need for ablation. Therefore, we sought to investigate predictors and use of VT ablation and to evaluate the postprocedural outcome in ARVC patients. We studied 435 patients from the Nordic ARVC registry including 220 probands with definite ARVC according to the 2010 task force criteria and 215 mutation-carrying relatives identified through cascade screening. Patients were followed until first-time VT ablation, death, heart transplantation, or January 1st 2018. Additionally, patients undergoing VT ablation were further followed from the time of ablation for recurrent ventricular arrhythmias. The cumulative use of VT ablation was 4% (95% confidence interval [CI] 3% to 6%) and 11% (95% CI 8% to 15%) after 1 and 10 years. All procedures were performed in probands in whom cumulative use was 8% (95% CI 5% to 12%) and 20% (95% CI 15% to 26%). In adjusted analyses among probands, only young age predicted ablation. In patients undergoing ablation, risk of recurrent arrhythmias was 59% (95% CI 44% to 71%) and 74% (95% CI 59% to 84%) 1 and 5 years after the procedure. Despite high recurrence rates, the burden of ventricular arrhythmias was reduced after ablation (p = 0.0042). Young age, use of several antiarrhythmic drugs and inducibility to VT after ablation were associated with an unfavorable outcome. In conclusion, twenty percent of ARVC probands developed a clinical indication for VT ablation within 10 years whereas mutation-carrying relatives were without such need. Although the burden of ventricular arrhythmias decreased after ablation, risk of recurrence was substantial.

Background Polygenic risk scores ( PRS s) based on risk variants from genome‐wide association studies predict coronary artery disease ( CAD ) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics. Methods and Results We consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18‐segment model and characterized by stenosis severity and composition (soft [0%‐19% calcified], mixed‐soft [20%‐49% calcified], mixed‐calcified [50%‐79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS , coronary artery calcium score increased by 78% ( P =4.1e‐26) and segment stenosis score increased by 16% ( P =2.4e‐29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [ OR ] : 1.78, P =5.6e‐16), calcified ( OR : 1.69, P =6.5e‐17), mixed‐calcified ( OR : 1.67, P =7.3e‐9), mixed‐soft ( OR : 1.45, P =1.6e‐6), and soft plaques ( OR : 1.49, P =2.5e‐6), and a higher prevalence of plaque in each coronary vessel (all P PRS was not associated with stenosis severity, plaque composition, or localization (all P >0.05). Conclusions Our results suggest that polygenic risk based on large genome‐wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02264717.

BACKGROUND: Recent studies in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have drawn attention to atrial fibrillation (AF) as an arrhythmic manifestation of ARVC and as an indicator of atrial involvement in the disease progression. We aimed to assess the prevalence of AF in the Scandinavian cohort of ARVC patients and to evaluate its association with disease clinical manifestations. METHODS: Study sample comprised of 293 definite ARVC patients by 2010 Task Force criteria (TFC2010) and 141 genotype-positive family members (total n = 434, 43% females, median age at ARVC diagnosis 41 years [interquartile range (IQR) 28-52 years]). ARVC diagnostic score was calculated as the sum of major (2 points) and minor (1 point) criteria in all categories of the TFC2010. RESULTS: AF was diagnosed in 42 patients (10%): in 41 patients with definite ARVC diagnosis (14%) vs in one genotype-positive family member (1%), p BACKGROUND: Recent studies in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have drawn attention to atrial fibrillation (AF) as an arrhythmic manifestation of ARVC and as an indicator of atrial involvement in the disease progression. We aimed to assess the prevalence of AF in the Scandinavian cohort of ARVC patients and to evaluate its association with disease clinical manifestations.METHODS: Study sample comprised of 293 definite ARVC patients by 2010 Task Force criteria (TFC2010) and 141 genotype-positive family members (total n = 434, 43% females, median age at ARVC diagnosis 41 years [interquartile range (IQR) 28-52 years]). ARVC diagnostic score was calculated as the sum of major (2 points) and minor (1 point) criteria in all categories of the TFC2010.RESULTS: AF was diagnosed in 42 patients (10%): in 41 patients with definite ARVC diagnosis (14%) vs in one genotype-positive family member (1%), p CONCLUSION: AF is seen in 14% of definite ARVC patients and is related to the severity of disease phenotype thus suggesting AF being an arrhythmic manifestation of this cardiomyopathy indicating atrial myocardial involvement in the disease progression.

OBJECTIVES: This study characterized and quantified subclinical atherosclerosis by coronary computed tomography angiography (CTA) in first-degree relatives of patients with early onset coronary artery disease (CAD).BACKGROUND: A strong family history of CAD is an important risk factor for adverse cardiovascular events. Whether predisposed individuals suffer an increased burden of coronary atherosclerosis and adverse plaque features is not known.METHODS: We included 88 healthy middle-aged first-degree relatives from 59 families with early onset CAD. Participants were matched by age and sex with 88 control patients with atypical angina or nonanginal chest pain and no family history of CAD, referred for coronary CTA. A blinded analysis of plaque burden and composition was performed using semiautomated plaque quantification software. The relative differences between the median volumes or the odds ratios (OR) were compared between groups, using a mixed model.RESULTS: First-degree relatives had significantly more affected coronary segments than controls (0 segments: 30% vs. 49%, respectively; 1 to 2 segments: 27% vs. 32%, respectively; 3 to 4 segments: 18% vs. 6%, respectively; and ≥5 segments: 25% vs. 14%, respectively; p = 0.001). In a multivariate model, the relative differences of total plaque, total calcified plaque (CP), total noncalcified plaque (NCP), and total low-density NCP (LD-NCP) were 5.8 (95% confidence interval [CI]: 2.8 to 11.9), 2.6 (95% CI: 1.5 to 4.5), 5.8 (95% CI: 2.9 to 12.0), and 3.6 (95% CI: 2.1 to 6.1), respectively. The adjusted OR of any positive remodeling plaque or any LD-NCP plaque was 4.2 (95% CI: 1.2 to 14) and 4.2 (95% CI: 1.9 to 9.5), respectively.CONCLUSIONS: Healthy first-degree relatives of patients with early onset CAD have an increased coronary plaque burden compared with symptomatic patients. The plaques display characteristics associated with myocardial ischemia and adverse coronary events.

BACKGROUND: Genetic risk scores (GRSs) may predict cardiovascular risk in community-based populations. However, studies investigating the association with recurrent cardiovascular events in patients with established coronary artery disease (CAD) are conflicting.METHODS: We genotyped 879 patients with high-risk stable CAD and created a GRS based on 45 single nucleotide polymorphisms previously reported to be associated with CAD in genome-wide association studies. Patients were categorised into high or low GRS according to the median GRS and followed for recurrent cardiovascular events using national Danish registries. The primary endpoint was a composite of myocardial infarction, coronary revascularisation, and cardiovascular death.RESULTS: Median (interquartile range) follow-up time was 2.8 (2.4-3.8)years. The cumulative incidence proportions of the primary endpoint at 1 and 3years were 6.4% and 11.5% in high-GRS patients vs. 2.5% and 7.3% in low-GRS patients. The corresponding relative risks were 2.56 (95% confidence interval (CI) 1.29-5.07), and 1.57 (95% CI 1.02-2.44). The adjusted hazard ratio (HR) of the primary endpoint was 1.50 (95% CI 1.00-2.25). The most pronounced effect of a high GRS was observed on coronary revascularisations (adjusted HR 2.10 [95% CI 1.08-4.07]). Risks of cardiovascular death (adjusted HR 1.07 [95% CI 0.46-2.48]) and all-cause death (adjusted HR 1.15 [95% CI 0.65-2.03]) were unaffected.CONCLUSIONS: A GRS predicts recurrent cardiovascular events in high-risk stable CAD patients. The observed effect was mainly driven by coronary revascularisations.

BACKGROUND AND AIMS: Common genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD.METHODS: 134 early-onset CAD patients (55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering.RESULTS: Early-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1-2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4-3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9-1.9]).CONCLUSIONS: The GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.

Background Catheter ablation may reduce ventricular tachycardia (VT) burden in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, little is known about factors predicting need for ablation and various outcomes have been reported. Purpose We sought to investigate predictors and use of VT ablation and to evaluate the post-procedural outcome in ARVC patients. Methods We studied 435 patients from the Nordic ARVC registry including 220 probands with definite ARVC according to the 2010 task force criteria and 215 mutation-carrying relatives identified through cascade screening. Patients were followed until first-time VT ablation, death, heart transplantation, or January 1st 2018. Additionally, patients undergoing VT ablation were further followed from the time of ablation for recurrent ventricular arrhythmias. Results Cumulative use of VT ablation was 4% (95% CI 3%-6%) and 11% (95% CI 8%-15%) after 1 and 10 years. All procedures were performed in probands in whom the cumulative use was 8% (95% CI 5%-12%) and 20% (95% CI 15%-26%). In adjusted analyses restricted to probands, only young age predicted need for ablation. In patients undergoing ablation, risk of recurrent arrhythmias was 59% (95% CI 44%-71%) and 74% (95% CI 59%-84%) 1 and 5 years after the procedure. Despite high recurrence rates, the burden of ventricular arrhythmias was reduced after ablation (p=0.0042). Young age, use of several antiarrhythmic drugs and inducibility to VT immediately after ablation were associated with an unfavorable outcome. Conclusions Twenty percent of ARVC probands developed a clinical indication for VT ablation within 10 years after diagnosis whereas mutation-carrying relatives were without such need. Although the burden of ventricular arrhythmias decreased after ablation, risk of recurrence was substantial.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of ventricular arrhythmias (VA) and sudden cardiac death (SCD). Even though female patients with ARVC are considered to be at lower risk of VA, the impact of pregnancy and child birth on the arrhythmic risk and development of arrhythmic substrate in the context of ARVC remains insufficiently studied. Objective To assess the risk of VA in relation to childbirth in women with ARVC and the impact of multiple pregnancies on progression of arrhythmic manifestations of the disease. Methods The study included 186 females with definite ARVC (n=107, 70 probands) or unaffected mutation-carriers (n=79) with median age at the end of follow up of 48 (IQR 34–60) years. Seventeen women had 1, 59 had 2 and 29 had ≥3 child births by the age of 40 years. VA was defined as ventricular tachycardia, appropriate ICD therapy, aborted cardiac arrest or SCD. Proportions of patients who experienced VA by the age of 40 years were compared between nulliparous women (n=81) and those with reported child births (n=105). VA-free survival after accomplished pregnancies was assessed for women ≥40 years of age (n=119). Cumulative probability of VA for each pregnancy (n=230) was assessed from conception through 2 years after child birth and compared between those that occurred before ARVC diagnosis (Pre-Ds, n=164), after it (Post-Ds, n=11) and in unaffected mutation carriers (No-Ds, n=55). Results The nulliparous women had lower age at ARVC diagnosis (37 vs 44, p=0.023) and more often had VA before the age of 40 (31% vs 13%, p=0.003) while the number of child births was not related to the prevalence of VA (18% among women with 1 childbirth, 12% in those with 2 and 14% in those with 3 or more, ns). Three women suffered SCD before the age of 40. VA-free survival after 40 years did not differ between nulliparous and those who gave birth (Figure A). Only four pregnancy-related events were documented (Figure B): 1 in the Post-Ds group and three in the Pre-Ds group. No pregnancy-related events were reported in the unaffected mutation carriers. Conclusion In this Scandinavian cohort of women with ARVC we observed no indication of an increased VA risk either associated with pregnancies or during long-term follow up after the last child birth.

Background Genetic risk scores (GRSs), based on variants identified in genome-wide association studies (GWAS), have been shown to predict risk of coronary artery disease (CAD). However, the clinical potential remains unknown. Purpose To investigate whether a GRS improves discrimination of hemodynamically obstructive CAD beyond the CAD Consortium scores and coronary artery calcium score (CACS) in patients referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing CACS scoring and coronary CTA on a suspicion of CAD. Using LDPred, a recently validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Patients with a ≥50% stenosis on CTA further underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). Hemodynamically obstructive CAD was defined as a visual ICA stenosis >90%, FFR 50% if FFR was not feasible. Discrimination was evaluated by receiver-operating characteristics. Results Median age was 57 (interquartile range 50–64) years and 799 (49%) were males. Hemodynamically obstructive CAD was present in 14 (4%) with a low GRS (80th percentile) (p0.05). Conclusion A GRS improves discrimination of hemodynamically obstructive CAD beyond CAD consortium scores, particularly in young women. However, the additive discriminative value is attenuated in models including CACS.

Background Genetic risk scores (GRSs) based on risk variants identified from genome-wide association studies (GWASs) predict coronary artery disease (CAD) risk. However, it is unknown whether the GRS is associated with coronary plaque burden or specific high-risk plaque features responsible for the clinical disease onset. Purpose To investigate if a GRS is associated with coronary plaque burden and specific plaque characteristics, in patients with suspected stable CAD referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing coronary CTA. Using LDPred, a previously validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Plaques were evaluated using an 18-segment model and characterized by stenosis severity (0%, 1–49%, 50–69%, 70–100%) and composition (calcified (>80% calcified), mixed-calcified (50–80% calcified), mixed-soft (20–50% calcified), or soft ( Results For each SD increase in the GRS, the segment stenosis score increased with 49% (p=8.6e-27) and CACS increased with 110% (p=2.3e-24). The GRS was associated with a higher risk of plaque stenosis >50% (OR: 1.74, p=3.2e-15), calcified (OR: 1.65, p=3.0e-16), mixed-calcified (OR: 1.64, p=1.5e-8), mixed-soft (OR: 1.44, p=1.6e-6), and soft plaques (OR: 1.40, p=3.0e-6), and all coronary vessels were more often affected with plaques (all p-values When analyzing the plaque characteristics (3007 plaques in 849 patients), the GRS was associated with stenosis severity (OR per severity category: 1.15 (p=0.005), but not with extent of calcification, proximal location, or presence in any of the major coronary vessels (all p-values >0.05). GRS and Plaque burden Conclusion The GRS was strongly associated with the extent and severity of CAD at coronary CTA, but not any specific plaque characteristics per se. The results may suggest that polygenic risk based on large CAD-GWAS increases CAD risk through increased coronary plaque burden rather than specific plaque features.

Background Genetic risk scores (GRSs), based on variants identified in genome-wide association studies (GWAS), have been shown to predict risk of coronary artery disease (CAD). However, the clinical potential remains unknown. Purpose To investigate whether a GRS improves discrimination of hemodynamically obstructive CAD beyond the CAD Consortium scores and coronary artery calcium score (CACS) in patients referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing CACS scoring and coronary CTA on a suspicion of CAD. Using LDPred, a recently validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Patients with a ≥50% stenosis on CTA further underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). Hemodynamically obstructive CAD was defined as a visual ICA stenosis >90%, FFR 50% if FFR was not feasible. Discrimination was evaluated by receiver-operating characteristics. Results Median age was 57 (interquartile range 50-64) years and 799 (49%) were males. Hemodynamically obstructive CAD was present in 14 (4%) with a low GRS (80th percentile) (p0.05). Conclusion A GRS improves discrimination of hemodynamically obstructive CAD beyond CAD consortium scores, particularly in young women. However, the additive discriminative value is attenuated in models including CACS.

Aims To describe aetiologies and temporal trends in young patients with atrioventricular block (AVB). Methods and results We identified all patients in Denmark, receiving their first pacemaker because of AVB before the age of 50 years between 1996 and 2015. Medical records were reviewed and clinical information and diagnostic work-up results were obtained to evaluate the aetiology. We used Poisson regression testing for temporal trends. One thousand and twenty-seven patients were identified, median age at time of implantation was 38 (interquartile range 25–45) years, 584 (56.9%) were male. The aetiologies were complications to cardiac surgery [n = 157 (15.3%)], congenital AVB [n = 93 (9.0%)], cardioinhibitory reflex [n = 52 (5.0%)], congenital heart disease [n = 43 (4.2%)], complication to radiofrequency ablation [n = 35 (3.4%)], cardiomyopathy [n = 31 (3.0%)], endocarditis [n = 18 (1.7%)], muscular dystrophy [n = 14 (1.4%)], ischaemic heart disease [n = 14 (1.4%)], sarcoidosis [n = 11 (1.1%)], borreliosis [n = 9 (0.9%)], hereditary [n = 6 (0.6%)], side-effect to antiarrhythmics [n = 6 (0.6%)], planned His-ablation [n = 5 (0.5%)], complication to alcohol septal ablation [n = 5 (0.5%)], and other known aetiologies [n = 11 (1.1%)]. The aetiology remained unknown in 517 (50.3%) cases. While the number of patients with unknown aetiology increased during the study period (P Conclusion In a nationwide cohort, the aetiology of AVB was identified in only half the patients younger than 50 years referred for first-time pacemaker implantation. The number of patients with unknown aetiology increased during the study period. These findings indicate need for better insight into aetiologies of AVB and improved diagnostic work-up guidelines.

Aims: To quantify appropriate and inappropriate therapy and complications related to implantable cardioverter-defibrillator (ICD) treatment in young patients receiving an ICD for a hereditary cardiomyopathy or channelopathy.Methods and results: This was a retrospective study including 117 consecutive patients who had received an ICD at Aarhus University Hospital, Denmark from 1 January 1999 to 31 December 2015. Patients were followed from the date of ICD implantation until migration, death, heart transplantation, or end of follow-up on 1 February 2017. Mean age at implantation was 30.5 ± 12.8 years, and the patients were followed for a mean period of 7.1 ± 4.4 years. The cumulative incidence at 1, 5, and 10 years was 17%, 29%, and 48% for appropriate ICD therapy, 6%, 13%, and 20% for inappropriate ICD therapy, and 7%, 18%, and 33% for device-related complications, respectively. Patients with an ICD implanted for secondary prevention had a higher risk of appropriate therapy compared with patients implanted for primary prevention [adjusted hazard ratio (HR) 5.18, 95% confidence interval (CI) 2.22-12.09; P Conclusion: We observed high absolute risk estimates for appropriate ICD therapy in young patients with an ICD indicated by a hereditary cardiomyopathy or channelopathy. Also risks for inappropriate ICD therapy and device-related complications were significant.

Background: The literature contains several cases of anorexia nervosa (AN) patients with prolonged QTc interval. However, the risk of prolonged QTc interval is controversial and the risk of cardiac events in AN patients has yet to be investigated. Methods: We estimated the difference in mean QTc interval and relative risk of borderline prolonged QTc (>440 ms) and prolonged QTc (>460 ms) between 430 adult women AN patients and 123 healthy controls using 3 correction formulas. In a follow-up study, we estimated the risk of a primary end point (a composite of ventricular tachycardia, aborted cardiac arrest, and cardiac arrest) in AN patients compared with a population-based cohort derived from the Danish Civil Register. Results: Mean QTc for AN patients was 408 ms (Hodges), 402 ms (Fridericia), and 399 ms (Bazett). Hodges’ found a slightly increased mean QTc (6.8 ms, 95% confidence interval, 1.6–12.0; P =0.01) and percentage with QTc >440 ms in AN patients (relative risk, 3.7, 95% confidence interval, 1.4–10.3; P =0.01), not observed with Fridericia’s and Bazett’s formulas. There was no difference in the risk of QTc >460 ms between AN patients and healthy controls. During a median follow-up of 10.1 years, AN patients had an increased risk of the primary end point compared with the population-based cohort (hazard ratio, 10.4, 95% confidence interval, 2.6–41.6; P =0.001). However, absolute numbers were small with cumulative incidences of 0.5% and 0.07%, respectively, after 10 years. No events occurred in any AN patient with QTc >440 ms. All-cause mortality was also significantly increased in AN patients compared with the population-based cohort (hazard ratio, 11.2, 95% confidence interval, 5.1–24.5; P Conclusions: Overall, there was no difference in mean QTc interval or risk of prolonged QTc between AN patients and healthy controls. However, AN patients had a notably increased all-cause mortality, as well as an increased risk of cardiac events, which was not related to the baseline QTc interval.

BACKGROUND: International guidelines recommend clinical assessment of the surviving first-degree relatives of sudden cardiac death (SCD) victims to identify a probable cause of death and protect surviving relatives. Only few studies have reported the outcome of clinical management and follow-up of relatives to SCD victims.METHODS: We performed a retrospective cohort study of the clinical and genetic assessment of surviving relatives of SCD victims referred to the Clinic of Inherited Cardiac Diseases at Aarhus University Hospital, Denmark, between 1995 and 2016. We studied clinical and autopsy findings on all cases of SCD among children and adults. Relatives were followed for adverse cardiovascular events including cardiac hospitalization, new-onset heart failure, coronary heart disease, malignant syncope or documented malignant ventricular arrhythmias, and death.RESULTS: We included 292 relatives of 56 SCD victims. During a median (interquartile range) follow-up of 3.3 (1.6-4.7) years twelve relatives experienced an adverse cardiovascular event of which only five were related to the inherited cardiac disease in the family. One developed dilated cardiomyopathy and one tachycardia induced heart failure, five suffered from ventricular tachycardia or a malignant syncope and received a secondary prophylactic Implantable Cardioverter Defibrillator, three had a coronary heart disease event and two died from old age.CONCLUSION: Relatives of SCD victims have a low rate of adverse cardiac events when guideline-based assessment and care is applied.

A family history of coronary artery disease (CAD) is an important risk factor for adverse coronary events, in particular if the disease has an early onset. The risk of CAD is influenced by genetic and environmental factors with a greater genetic contribution earlier in life. Through recent years the advances in genetic techniques has led to an increased understanding of the genetic background of CAD, which may potentially be translated into clinical use. The studies of this thesis aimed to investigate the burden of conventional risk factors and control in early-onset CAD (i.e. < 40 years), and to characterize and quantify subclinical atherosclerosis in their relatives. Furthermore, the aim was to explore the impact of common genetic risk variants on the age of onset, familial clustering and disease severity. In study I, 143 patients with early-onset CAD were recruited from the Western Denmark Heart Registry and risk factor control was evaluated. The study revealed that risk factors are common in early-onset CAD and that a large room for risk factor improvement remains. In study II, we used coronary computed tomography angiography to compare the coronary plaque burden and characteristics between 88 first-degree relatives of patients with early-onset CAD and 88 controls with no familial predisposition. Relatives had a significantly increased coronary plaque burden, which displayed characteristics associated with myocardial ischemia and adverse coronary events. In study III, 134 patients with early-onset CAD, a cohort of 446 late-onset CAD patients (onset > 55/65 years in males/females), and 89 healthy controls were genotyped for 45 common genetic risk variants and a genetic risk score was calculated as a measure of the polygenetic burden. Early-onset CAD patients had a modestly increased genetic burden compared with late-onset CAD patients and healthy controls; however, the burden did not associate with familial clustering of CAD. Additionally, familial clustering seemed to be stronger associated with CAD disease severity than the polygenetic burden. Our findings emphasize the hereditary component of coronary atherosclerosis and underpin the need for risk factor optimization in early-onset CAD. Furthermore, our data support that yet identified common risk variants may have little clinical relevance in the clinical setting of early-onset CAD.

Background Heterozygous familial hypercholesterolemia increases the risk of adverse cardiovascular events. Whether affected relatives of probands are at increased risk remains unknown. We aimed to evaluate the long‐term cardiovascular risk in heterozygous familial hypercholesterolemia relatives with a low‐density lipoprotein receptor ( LDLR ) mutation who were all recommended statin therapy. Methods and Results Participants were identified by cascade screening at Aarhus University Hospital during 1992–1994. A comparison cohort from the Danish general population was matched 10:1 to relatives by birth year and sex. Using medical registries, participants were followed until the event of interest, migration, death, or end of follow‐up on December 31, 2014. The primary end point was all‐cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives. Median age was 37 years (interquartile range: 27–52 years) of which 118 (54%) had an LDLR mutation. By 2004, when prescription data became available, 89% of mutation‐carrying participants were taking statins during their follow‐up period. Despite frequent use of lipid‐lowering medication, the adjusted hazard ratio of the primary end point was 1.65 (95% confidence interval, 1.17–2.33) in mutation‐carrying relatives compared with the general population cohort. The risk in non–mutation‐carrying relatives was not different from that of the general population cohort (adjusted hazard ratio: 0.85; 95% confidence interval, 0.56–1.29). Comparing mutation‐carrying relatives with non–mutation‐carrying relatives, the adjusted hazard ratio was 1.94 (95% confidence interval, 1.14–3.31). Results were driven by nonfatal events. Conclusion Heterozygous familial hypercholesterolemia relatives with an LDLR mutation had an increased long‐term risk of adverse cardiovascular events.

INTRODUCTION: In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown.AIM: We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO).METHODS: We genotyped 45 genome-wide significant CAD/MI-markers in 879 stable CAD patients. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. Platelet indices were analysed using the Sysmex XE-2100 haematology analyser. TPO was measured by ELISA.RESULTS: Two variants were nominally associated with several indices; for rs10947789 (KCNK5), the adjusted geometric mean was 2% higher for MPV (95% confidence interval: 1-2%, p=0.002), 6% for IPC (0-12%, p=0.033), and 9% for IPF (3-16%, p=0.004) per CAD risk allele. Moreover, an 11% lower TPO (3-19%, p=0.010) was observed. Rs3184504 (SH2B3) was associated with a higher adjusted geometric mean of 3% (1-6%, p=0.003) per CAD risk allele for PC, and an 11% (5-17%, pCONCLUSION: As a novel finding, our study suggests a role for KCNK5 in the regulation of platelet size and maturity. Furthermore, our findings confirm an association between the SH2B3-locus and platelet count.

Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999-2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort. One third (24/80) of the study population had first-line genetic testing with a targeted next-generation sequencing (NGS) panel, and two-third (56/80) of the study population had second-line genetic testing with NGS where prior Sanger sequencing did not reveal a causative variant. Variants were assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We included 80 patients. Median age (IQR) was 38 (28-43) years, 54 (68%) were males. First-line genetic testing identified a genetic variant in 33% (8/24) of the cases and second-line genetic testing revealed a variant in 20% (11/56) of the cases. Eleven variants were considered pathogenic, three likely pathogenic and 10 were variants of unknown significance (VUS). Seventeen variants were very rare with a minor allele frequency (MAF) ≤0.02% in all population databases used in the study. Molecular genetic testing of patients with suspected inherited cardiac arrhythmias with NGS identifies a molecular-genetic cause in a significant proportion of patients. Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999-2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort. One third (24/80) of the study population had first-line genetic testing with a targeted next-generation sequencing (NGS) panel, and two-third (56/80) of the study population had second-line genetic testing with NGS where prior Sanger sequencing did not reveal a causative variant. Variants were assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We included 80 patients. Median age (IQR) was 38 (28-43) years, 54 (68%) were males. First-line genetic testing identified a genetic variant in 33% (8/24) of the cases and second-line genetic testing revealed a variant in 20% (11/56) of the cases. Eleven variants were considered pathogenic, three likely pathogenic and 10 were variants of unknown significance (VUS). Seventeen variants were very rare with a minor allele frequency (MAF) ≤0.02% in all population databases used in the study. Molecular genetic testing of patients with suspected inherited cardiac arrhythmias with NGS identifies a molecular-genetic cause in a significant proportion of patients.

Morten Krogh Christiansen, Jesper Møller Jensen, Anders Krogh Brøndberg, Hans Erik Bøtker, Henrik Kjærulf JensenDepartment of Cardiology, Aarhus University Hospital, Aarhus, DenmarkBackground: Control of cardiovascular risk factor is important in secondary prevention of coronary artery disease (CAD) but it is unknown whether treatment targets are achieved in young patients. We aimed to examine the prevalence and control of risk factors in this subset of patients.Methods: We performed a cross-sectional, single-center study on patients with documented CAD before age 40. All patients treated between 2002 and 2014 were invited to participate at least 6 months after the last coronary intervention. We included 143 patients and recorded the family history of cardiovascular disease, physical activity level, smoking status, body mass index, waist circumference, blood pressure, cholesterol levels, metabolic status, and current medical therapy. Risk factor control and treatment targets were evaluated according to the shared guidelines from the European Society of Cardiology.Results: The most common insufficiently controlled risk factors were overweight (113 [79.0%]), low-density lipoprotein cholesterol above target (77 [57.9%]), low physical activity level (78 [54.6%]), hypertriglyceridemia (67 [46.9%]), and current smoking (53 [37.1%]). Almost one-half of the patients fulfilled the criteria of metabolic syndrome. The median (interquartile range) number of uncontrolled modifiable risk factors was 2 (2;4) and only seven (4.9%) patients fulfilled all modifiable health measure targets.Conclusion: Among the youngest patients with CAD, there remains a potential to improve the cardiovascular risk profile.Keywords: coronary artery disease, cardiovascular diseases/prevention and control, health behavior, risk factors, young adult, middle aged

Familial hypercholesterolemia caused by low-density lipoprotein receptor mutations leads to an elevated long-term risk of adverse cardiovascular events despite statin treatment. It remains unclear whether this Is the case for the probands only. We hypothesized that mutation-carrying relatives Are

Recent research in genetics has revealed that PCSK9 - which codes for proprotein convertase subtilisin/kexin type 9 (PCSK9) - plays a major role in cholesterol regulatory pathways. Normal genetic variations in PCSK9 have a great impact on low-density lipoprotein cholesterol levels and hence the risk of cardio-vascular disease. This has led to huge efforts in inhibiting PCSK9. Recent clinical phase II trials with monoclonal antibodies against PCSK9 have shown great results for lowering low-density lipoprotein cholesterol levels making the inhibition of PCSK9 a promising target in the prevention of cardiovascular disease.

INTRODUCTION:Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers.METHODS:We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers.RESULTS:The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score.CONCLUSIONS:In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers. INTRODUCTION: Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers.METHODS: We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers.RESULTS: The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score.CONCLUSIONS: In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers.

Udgivelsesdato: 2009-May Sudden strenuous exercise increases the risk of ischemic cardiac events in patients with coronary artery disease. The exact mechanism behind this observation is unknown, but platelet activation induced by exercise may be of importance. We hypothesized that brief strenuous exercise would activate platelets in healthy men, assessed by the Platelet Function Analyzer 100 and light transmittance aggregometry. Nearly all participants exhibited increased platelet reactivity after exercise measured by the Platelet Function Analyzer 100, whereas only minor changes were detected by light transmittance aggregometry. A significant increase in plasma von Willebrand Factor was also found in response to exercise. In conclusion, platelet activation occurs during exercise in healthy individuals. This activation is not prevented by use of aspirin or clopidogrel, and may partly be explained by an increase in plasma von Willebrand Factor.

The long QT syndrome (LQTS) is a genetic disorder, typically characterized by a prolonged QT interval in the ECG due to abnormal cardiac repolarization. LQTS may lead to syncopal episodes and sudden cardiac death. Various parameters based on T-wave morphology, as well as the QT interval itself have been shown to be useful discriminators, but no single ECG parameter has been sufficient to solve the diagnostic problem. In this study we present a method for discrimination among persons with a normal genotype and those with mutations in the KCNQ1 (KvLQT1 or LQT1) and KCNH2 (HERG or LQT2) genes on the basis of parameters describing T-wave morphology in terms of duration, asymmetry, flatness and amplitude. Discriminant analyses based on 4 or 5 parameters both resulted in perfect discrimination in a learning set of 36 subjects. In both cases cross-validation of the resulting classifiers showed no misclassifications either.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of ventricular arrhythmias (VA) and sudden cardiac death (SCD). Even though female patients with ARVC are considered to be at lower risk of VA, the impact of pregnancy and child birth on the arrhythmic risk and development of arrhythmic substrate in the context of ARVC remains insufficiently studied.ObjectiveTo assess the risk of VA in relation to childbirth in women with ARVC and the impact of multiple pregnancies on progression of arrhythmic manifestations of the disease.MethodsThe study included 186 females with definite ARVC (n=107, 70 probands) or unaffected mutation-carriers (n=79) with median age at the end of follow up of 48 (IQR 34–60) years. Seventeen women had 1, 59 had 2 and 29 had ≥3 child births by the age of 40 years. VA was defined as ventricular tachycardia, appropriate ICD therapy, aborted cardiac arrest or SCD. Proportions of patients who experienced VA by the age of 40 years were compared between nulliparous women (n=81) and those with reported child births (n=105). VA-free survival after accomplished pregnancies was assessed for women ≥40 years of age (n=119). Cumulative probability of VA for each pregnancy (n=230) was assessed from conception through 2 years after child birth and compared between those that occurred before ARVC diagnosis (Pre-Ds, n=164), after it (Post-Ds, n=11) and in unaffected mutation carriers (No-Ds, n=55).ResultsThe nulliparous women had lower age at ARVC diagnosis (37 vs 44, p=0.023) and more often had VA before the age of 40 (31% vs 13%, p=0.003) while the number of child births was not related to the prevalence of VA (18% among women with 1 childbirth, 12% in those with 2 and 14% in those with 3 or more, ns). Three women suffered SCD before the age of 40. VA-free survival after 40 years did not differ between nulliparous and those who gave birth (Figure A). Only four pregnancy-related events were documented (Figure B): 1 in the Post-Ds group and three in the Pre-Ds group. No pregnancy-related events were reported in the unaffected mutation carriers.ConclusionIn this Scandinavian cohort of women with ARVC we observed no indication of an increased VA risk either associated with pregnancies or during long-term follow up after the last child birth.

Introduction: A family history of premature coronary artery disease (CAD) is a well-known risk factor for adverse coronary events with age of onset being inversely related to the degree of heritability.Hypothesis: We hypothesized that asymptomatic first degree relatives, of patients with premature CAD, suffer a high burden of subclinical coronary atherosclerosis.Methods: First degree relatives, aged 30-65 years, of patients with a documented coronary revascularization procedure before the age of 40 years, were invited to participate in the study. Participants were matched by age, sex and absence of a family history, with patients referred for coronary CT angiography (CTA) because of atypical angina or non-anginal chest pain. A pooled blinded analysis was performed.The main outcome measure was the number of plaque-affected coronary segments.Results: 88 relatives and 88 symptomatic controls underwent CTA. Treatment of hypertension and dyslipidemia tended to be more common among controls (p=0.06). 4 relatives reported vague symptoms of which none had angiographic signs of obstructive CAD (any luminal stenosis above 50%). The calculated SCORE risk among relatives was generally low (85% having a 10-year risk of ≤1%).Relatives had significantly (p=0.006) more affected segments than controls (0 segments: 29,6% vs. 48,9%, 1-2 segments: 27,3% vs. 31,8%, 3-5 segments: 23,9% vs. 11,4% and ≥6 segments: 19,3% vs. 8,0%). In a multivariable logistic regression analysis, the presence of any CAD (OR 3.16 (1.50;6.70)) as well as non-calcified plaques (OR 2.2 (1.14;4.26)), mixed plaques (OR 6.77 (2.7;16.98)) and calcified plaques (OR 2.34 (1.01;5.43)) were more frequent. Although increased, the presence of obstructive plaques, however, did not differ statistically significantly between relatives and controls (OR 2.58 (0.85;7.83)).Conclusions: Asymptomatic relatives of patients with premature CAD suffer a high coronary plaque burden even when compared with symptomatic patients with an a priori higher risk of CAD. Our results indicate a strong genetic component in the genesis of coronary atherosclerosis and, moreover, underline the limitations of current guidelines on prevention of CAD.

Background Genetic risk scores (GRSs) based on risk variants identified from genome-wide association studies (GWASs) predict coronary artery disease (CAD) risk. However, it is unknown whether the GRS is associated with coronary plaque burden or specific high-risk plaque features responsible for the clinical disease onset. Purpose To investigate if a GRS is associated with coronary plaque burden and specific plaque characteristics, in patients with suspected stable CAD referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing coronary CTA. Using LDPred, a previously validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Plaques were evaluated using an 18-segment model and characterized by stenosis severity (0%, 1-49%, 50-69%, 70-100%) and composition (calcified (>80% calcified), mixed-calcified (50-80% calcified), mixed-soft (20-50% calcified), or soft (50% (OR: 1.74, p=3.2e-15), calcified (OR: 1.65, p=3.0e-16), mixed-calcified (OR: 1.64, p=1.5e-8), mixed-soft (OR: 1.44, p=1.6e-6), and soft plaques (OR: 1.40, p=3.0e-6), and all coronary vessels were more often affected with plaques (all p-values 0.05). Conclusion The GRS was strongly associated with the extent and severity of CAD at coronary CTA, but not any specific plaque characteristics per se. The results may suggest that polygenic risk based on large CAD-GWAS increases CAD risk through increased coronary plaque burden rather than specific plaque features.