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Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

Introduction: In aortic valve disease, several interventions are available. In young people who are still growing, or considering the risks of long-term anticoagulation, the Ross procedure remains an alternative for aortic valve replacement. This procedure entails the transposition of the patient’s pulmonary valve to the aortic position, with placement of a homograft in the pulmonary position. However, long-term prognosis remains largely unknown.

Methods: The Swedish national registry of congenital heart disease was searched for adult patients with a history of Ross operation.

Results: 82 patients (mean age 40.4±15.8 years) were identified, with a mean age at the time of the Ross procedure of 23.6±14.7 years. After a mean follow-up of 16.8±5.5 years, 24.4% of patients underwent a first reoperation involving either the neoaortic valve or the pulmonary homograft, at a mean age of 32.0±13.9 years. The cumulative incidence of reoperation was approximately 15% at 10 years and 30% at 20 years post-Ross procedure. Among the 20 reinterventions, 17 (85.0%) involved the pulmonary valve and 8 the neoaortic valve; five patients underwent procedures on both valves. Two patients (2.3%) died during follow-up.

Forty-eight patients in the cohort had undergone primary Ross surgery. This subgroup was older at the time of data extraction (mean age 46.7±15.7 years) compared with those who underwent secondary Ross surgery (mean age 31.3±10.7 years), that is, typically following previous interventions. The secondary Ross group demonstrated better left ventricular function, with ejection fraction >50% in 91.7% of cases, compared with 69.8% in the primary group (p=0.041).

Conclusion: One in four patients undergoing the Ross procedure requires a reintervention, commonly involving the pulmonary valve. Long-term mortality was low. In selected patients, the Ross procedure remains a viable option; however, late morbidity must be considered. Our findings suggest that secondary Ross surgery is associated with better long-term outcomes, particularly regarding left ventricular function, although the underlying mechanisms remain unclear.

Background: Impaired muscle function, aerobic capacity, and fatigue are common in individuals with Fontan circulation. Knowledge regarding the effects of strength training in this population is limited. Therefore, the study aimed to investigate the effects of strength training on dynamic muscle function, aerobic capacity, and fatigue in adults with Fontan circulation compared to matched controls.

Methods: In this pilot non-randomised controlled trial, nine patients with Fontan circulation (median age 28.9 years [IQR: 23.4-35.0], 44.4% women) and nine age- and sex-matched controls completed a 10-week strength training intervention. Dynamic muscle function was assessed through shoulder flexion, heel rise, elbow flexion, and knee extension tests. Aerobic capacity was evaluated using cardiopulmonary exercise testing, and fatigue using the questionnaire Multidimensional Fatigue Inventory. All assessments were conducted pre- and post-intervention. Within-group changes were analysed using the Wilcoxon signed rank test and between-group differences using the Mann-Whitney U test.

Results: Patients showed improvements in all muscle function tests post-intervention (shoulder flexions 39.3% [IQR: 18.9-69.7], p = 0.008; heel rise 26.7% [IQR:17.5-58.1], p = 0.008; elbow flexions 57.1% [IQR: 50.0-173.8], p = 0.007; knee extensions 66.7% [24.3-92.9], p = 0.008). The improvements were at comparable levels to controls. Only controls reported reduced fatigue (-19.4% [IQR: -28.7, -10.5], p = 0.01), while patients showed no change (-5.9% [IQR: -25.5, 3.2], p = 0.1). Aerobic capacity remained unchanged. No severe adverse events occurred.

Conclusion: Strength training is safe and improves dynamic muscle function in patients with Fontan circulation, with changes comparable to those of healthy controls. However, the effect of strength training on fatigue and aerobic capacity requires further investigation. ClinicalTrials.gov, ID: NCT05454254, https://clinicaltrials.gov.

Background: In congenital aortic stenosis (CAS), commissurotomy is an option in patients not suitable to receive a valve prosthesis. However, there is often a need for future additional interventions on the aortic valve. The fate of the aortic valve is, however, essentially unknown. This study reports the need for reinterventions after surgical commissurotomy, based on a national register.

Materials and methods: The national register on congenital heart diseases (CHDs) was searched for patients with CAS, simple or associated with other CHD and an index commissurotomy with later data from follow-up.

Results: 300 patients with CAS and an index commissurotomy (mean age at the operation 7.4±7.8 years, 72.4% males) were identified. After an observation time of 27.4±10.0 years, 54.7% of the patients had a reintervention that occurred 14.2±10.1 years after the index operation. The cumulative incidence of reintervention was approximately 25% 10 years after and 60% 30 years after the index intervention. The prevalence of left ventricular hypertrophy (LVH) was higher among those that needed reintervention (41.3 vs 26.8%, p=0.023). Furthermore, eight patients died with a cumulative incidence of 7% 30 years after the index intervention, where most were (7/8) without reintervention (p=0.025). There were no additional important differences between patients with and without reintervention. The prevalence of left ventricular dysfunction and New York Heart Association class >1 was low.

Conclusion: Most (54.7%) patients with a commissurotomy, more than half of them within 30 years and eventually all will need a reintervention. This is important information to patients, especially for women in childbearing age. The higher prevalence of LVH in the group with reintervention needs attention during follow-up. Furthermore, those without reintervention, for unknown reasons, had a higher mortality. Our data strengthen the arguments for close outpatient follow-up among patients with a previous commissurotomy.

Aims: Men are more likely to suffer a myocardial infarction than women, but population-based studies on sex differences in imaging-detected atherosclerosis are lacking. The aims were to assess sex differences in the prevalence of imaging-detected coronary and carotid atherosclerosis, as well as multivariable adjusted associations between sex and atherosclerosis.

Methods and results: Participants aged 50-65, recruited from the general population to the Swedish Cardiopulmonary bioImage Study (SCAPIS), were included in this population-based cross-sectional study. Comprehensive diagnostics, including coronary computed tomography angiography and carotid ultrasound, were performed. The image findings were any coronary atherosclerosis, coronary stenosis >= 50%, segment involvement score (SIS) >= 4, coronary artery calcium score (CACS) > 100, and any ultrasound-detected carotid plaque. In 25 580 participants (50% women), men had more hypertension (20.3% vs. 17.0%), hyperlipidaemia (9.0% vs. 5.5%), and diabetes (8.5% vs. 4.7%). The prevalence was 56.2% vs. 29.5% for any coronary atherosclerosis (P < 0.01), 9.0% vs. 2.3% for coronary stenosis >= 50% (P < 0.01), 20.2% vs. 5.3% for SIS >= 4 (P < 0.01), 18.2% vs. 5.6% for CACS > 100 (P < 0.01), and 60.9% vs. 48.7% for carotid plaque (P < 0.01), in men vs. women, respectively. Multivariable adjustment only marginally changed these associations: odds ratios (ORs) (95% confidence interval): 2.75 (2.53-2.99) for coronary atherosclerosis, 2.88 (2.40-3.45) for coronary stenosis >= 50%, 3.99 (3.50-4.55) for SIS >= 4, 3.29 (2.88-3.75) for CACS > 100, and 1.57 (1.45-1.70) for carotid plaque.

Conclusion: Men had higher prevalence of imaging-detected carotid and coronary atherosclerosis with prevalence in women aged 65 corresponding to men 11-13 years younger. The associations remained after extensive multivariable adjustment.

Objectives: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR).

Design: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents.

Results: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92–1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08–1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82–1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64–0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI).

Conclusions: The adipokine leptin may promote the development of AS.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

OBJECTIVES: Surgery of ascending aortic aneurysms is performed prophylactically or acute. The expected survival after surgery is uncertain. The goal of this study was to compare mortality in people with aortic surgery with matched controls.

METHODS: All patients undergoing ascending aortic surgery at Umeå University Hospital from 1988 to 2012, who previously participated in 1 of 3 population-based health surveys, were matched to 2 randomly selected controls from the same health survey and followed until death or until censoring on 24 August 2017, whichever came first. Mortality was calculated using the Kaplan-Meier method and the log-rank test. Cox regression analyses were made for all-cause mortality, adjusted for traditional cardiovascular risk factors. Deaths during the first 90 days after surgery and at >90 days postoperatively were studied separately.

RESULTS: The median follow-up time was 9.2 years. A total of 61 of 189 patients and 51 of 370 controls died [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.91-4.01]. Mortality was increased during the first 90 days post-surgery (HR 43.4, 95% CI 5.83-323), as well as after the first 90 days (HR 1.90, 95% CI 1.25-2.88) and after acute surgery (HR 6.05, 95% CI 2.92-12.56) as well as after elective surgery (HR 2.10, 95% CI 1.35-3.27). Among 57 surgical patients with information about cause of death, 23 (40%) died of aortic disease.

CONCLUSIONS: During follow-up, more patients died than matched controls. Findings were consistent when adjusting for traditional cardiovascular risk factors and across subgroups. Both short-term and long-term postoperative deaths were increased as well.

Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.

Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.

Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.

Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.

Objective: To identify novel genetic loci and pathways associated with AS.

Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019.

Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples.

Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography.

Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]).

Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.