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IMPORTANCE: Risk stratification strategies in primary prevention of coronary events lack precision.

OBJECTIVE: To determine whether prediction of first coronary events is improved by adding information on coronary atherosclerosis from coronary computed tomography angiography (CCTA) to a model using the pooled cohort equation (PCE) risk score tool and the coronary artery calcification score (CACS).

DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study including individuals aged 50 to 64 years randomly recruited from the general population and examined at 6 university hospitals in Sweden from 2013 to 2018, with a median follow-up of 7.8 years. A sample of 30 154 individuals underwent cardiopulmonary imaging, physical examinations, routine laboratory tests, questionnaires, and/or functional tests. This study included 24 791 individuals without previous cardiovascular disease for whom high-quality CCTA images were available. Events were followed up via registers until September 2024.

EXPOSURES: The information used from the CCTA images was the extent of coronary atherosclerosis (segment involvement score), presence of noncalcified atherosclerosis, and presence of coronary obstructive disease (stenosis ≥50%).

MAIN OUTCOMES AND MEASURES: The outcome was a composite of first occurrence of nonfatal myocardial infarction or death from coronary heart disease.

RESULTS: During follow-up, 304 coronary events occurred. Segment involvement scores of 3 to 4 and greater than 4 and presence of noncalcified atherosclerosis were associated with hazard ratios of 2.71 (95% CI, 1.34-5.44), 5.27 (95% CI, 2.50-11.07), and 1.66 (95% CI, 1.23-2.22), respectively. In a model based on the PCE and CACS, CCTA-derived data improved risk discrimination (C statistic improved from 0.764 to 0.779; P = .004) and risk reclassification (net reclassification improvement of 0.133 [95% CI, 0.031-0.165]), conferred a net correct upward reclassification of 14.2% in those with events and incorrectly classified 1.6% of participants not experiencing an event into a higher-risk category. Because of the low event rate in the cohort, reclassification mainly occurred in the group classified as at low risk (<5%) according to the PCE.

CONCLUSIONS AND RELEVANCE: Information on coronary atherosclerosis from CCTA modestly improved risk prediction beyond traditional risk factors and CACS in identifying individuals at risk of coronary events and in need of primary prevention.

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.

Given the complex relationship between cardiovascular disease (CVD) and chronic kidney disease (CKD), CVD-related markers may serve as CKD biomarkers. We examined associations of three major CVD-markers [mid-regional pro-adrenomedullin (MR-proADM), MR-pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)] with CKD. Cross-sectional analyses included up to 61,830 participants, and longitudinal analyses (NT-proBNP only) 4205 individuals. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using creatinine, cystatin C, or both (eGFRcr-cys). Markers were categorized into four groups. Cross-sectional analyses found that higher levels of all three markers were consistently associated with lower eGFR and higher CKD prevalence. For example, per 1 standard deviation (SD) increase in log-transformed NT-proBNP, corresponding to a 2.71-fold increase in the original concentration, was associated with -2.35 (-2.49, -2.21) ml/min/1.73m2 lower eGFRcr-cys, and the highest NT-proBNP group had a 5.72-fold higher odds of CKDcr-cys (eGFRcr-cys < 60 ml/min/1.73m2) compared with the lowest. Associations with eGFR were stronger among participants with CVD and diabetes. In longitudinal analyses, participants with higher baseline NT-proBNP had faster declines in eGFR, with a 10-year decline of -1.37 (-1.77, -0.98) ml/min/1.73m2 eGFRcr-cys per 1 SD increase, and higher CKD incidence. These findings suggest MR-proADM, MR-proANP, and NT-proBNP as CKD biomarkers.

INTRODUCTION: Upfront combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5i) is guideline-recommended for low- or intermediate-risk pulmonary arterial hypertension (PAH). This study compared time to all-cause mortality for macitentan+PDE5i combination and each monotherapy.

METHODS: Long-term patient-level data (planned follow-up ≥1 year) were pooled from four clinical trials and three observational registries. All-cause mortality data were available from adults with incident PAH initiated on macitentan 10 mg or PDE5i monotherapy, or macitentan+PDE5i. Propensity-score (PS) methods balanced key demographic and disease characteristics across cohorts. Hazard ratios (HRs) were computed from a Cox-regression model that included PS-calculated weights. Weighted Kaplan–Meier estimates with 95% confidence intervals (CI) were computed 6-monthly.

RESULTS: 2201 patients were included: 754 received macitentan+PDE5i (421 tadalafil, 324 sildenafil, 9 other), 654 macitentan, and 793 PDE5i (301 tadalafil, 490 sildenafil, 2 other). After weighting, characteristics were similar across cohorts. Upfront macitentan+PDE5i was associated with a 39% risk reduction of all-cause mortality versus PDE5i (HR 0.61 [95% CI 0.46–0.82]) and 32% versus macitentan (HR 0.68 [95% CI 0.37–0.95]). Reduction in all-cause mortality was 49% for macitentan+tadalafil vs tadalafil (HR 0.51 [95% CI 0.30–0.85]), 43% for macitentan+tadalafil vs macitentan (HR 0.57 [95% CI 0.37–0.88]), 31% for macitentan+sildenafil vs sildenafil (HR 0.69 [95% CI 0.45–1.0]) and 26% for macitentan+sildenafil vs macitentan (HR 0.74 [95% CI 0.46–1.17]).

CONCLUSION: This large, pooled analysis suggests an observed statistical association indicating a potential survival benefit for early macitentan+PDE5i versus either monotherapy in newly diagnosed PAH.

Background: Treatment strategies for pulmonary arterial hypertension (PAH) depend on patients’ 1-year mortality risk; however, real-world practices and outcomes remain inadequately described.

Objective: We aimed to investigate real-world experience with selexipag, an oral selective prostacyclin I2 receptor agonist used to treat PAH.

Methods: This analysis of two large, prospective, observational studies: SPHERE (NCT03278002; USA; completed) and EXPOSURE (EUPAS19085; Europe and Canada; ongoing, data cutoff November 2021) included adults newly initiating selexipag with follow-up available.

Results: Of 1366 selexipag users, 894 met eligibility criteria. At selexipag initiation, the median (Q1–Q3) age was 61 (48–70) years and the time since diagnosis was 2.7 (0.8–7.4) years. Most patients initiated selexipag within triple oral combination therapy (67%) with WHO-FC III symptoms (61%). During a median 10.8 (Q1–Q3: 3.3–18.6) months of selexipag exposure, 388 (43%) patients discontinued selexipag, mostly as a result of tolerability (n = 173, 19%) and death (n = 69, 8%). The median individualised dose was 800 μg twice-daily (n = 742). One-year mortality risk at selexipag initiation (assessable for 591 patients using a four-strata method): 22% were low-risk, 40% intermediate–low, 29% intermediate–high, and 9% high-risk. From low to high risk: 86%, 73%, 57% and 45% were free from all-cause hospitalisation at 1 year, and 1-year survival was 100%, 96%, 91%, and 59%, respectively.

Conclusions: Despite current guidelines, over half of patients started selexipag almost 3 years after diagnosis, and 38% were already intermediate–high or high risk of 1-year mortality. Lower hospitalisation rates and better survival were observed for selexipag-treated patients in the low and intermediate–low risk groups versus higher risk groups.

Background: Aortic valve calcification (AVC) is a disease process driven by inflammation and lipid infiltration, serving as a precursor to aortic stenosis. While male sex has been implicated as a risk factor for AVC, sex-specific differences, particularly among younger individuals in the general population, are not well characterised.

Methods: The Swedish CArdioPulmonary BioImage Study was used, comprising 30154 individuals between 50 and 64 years, randomly selected from the general population. Study participants were part of a prospective cohort and underwent laboratory tests, clinical examinations, comprehensive questionnaires and cardiac CT. Cardiac CT was used for determining presence of AVC. Logistic regression analysis was performed to assess associations between traditional cardiovascular risk factors and AVC.

Results: In total, 29160 participants were included and AVC was found in 1291 men (9%) and 730women (5%). Male sex was an independent predictor of AVC (OR 1.91; 95%CI 1.71 to 2.13). Characteristics associated with AVC were similar between the sexes. In the adjusted analyses, lipoprotein(a), hyperlipidaemia, hypertension and smoking were strongly associated with AVC, whereas low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, diabetes, glycated haemoglobin and estimated glomerular filtration rate showed no significant associations with AVC. Higher body mass index (BMI) was associated with AVC in men but not women.

Conclusions: Male sex was independently associated with AVC, and the prevalence of AVC was nearly twice as high in men as in women. Traditional cardiovascular risk factors, including lipoprotein(a), hyperlipidaemia, hypertension and smoking, were associated with AVC, with similar associations between sexes, except for BMI, which was associated with AVC in men but not in women.

Inter-arm blood pressure differences (IABPDs) can be caused by atherosclerosis. We investigated 29 921 men and women aged 50-64 years from the nationwide population-based Swedish CArdio Pulmonary bioImage Study (SCAPIS) to evaluate if IABPD is related to risk factors for atherosclerosis and can be used as a marker of atherosclerosis as evaluated by coronary artery calcium score, arterial segment involvement score on computed tomography, carotid ultrasound, and ankle-brachial index (ABI).

The overall prevalence of systolic IABPD at least 10 mmHg was 2110/29 921 (7.1%). Individuals with IABPD at least 10 mmHg were significantly ( P  < 0.001) older, more often women, had higher BMI, nonhigh-density lipoprotein cholesterol, triglycerides, SBP and DBPs, and were more likely to have diabetes. In unadjusted analyses, IABPD at least 10 mmHg was associated with presence of coronary atherosclerosis, with more carotid arteries with plaque, and with pathological ABI. These associations were largely attenuated after adjustment for cardiovascular risk factors (age, sex, nonhigh-density lipoprotein cholesterol, systolic BP, smoking, diabetes, and the use of BP lowering drugs). Only ABI retained significance after these adjustments.

In conclusion, a systolic IABPD of at least 10 mmHg in middle aged men and women is common in the general population, and can be used as a screening tool for subclinical atherosclerotic changes in coronary, carotid, and lower extremity arteries. However, these relationships were largely explained by correlations between IABPD and traditional cardiovascular risk factors.

Imaging-defined atherosclerosis represents an intermediate phenotype of atherosclerotic cardiovascular disease (ASCVD). Genome-wide association studies (GWAS) on directly measured coronary plaques using coronary computed tomography angiography (CCTA) are scarce. In the so far largest population-based cohort with CCTA data, we performed a GWAS on coronary plaque burden as determined by the segment involvement score (SIS) in 24,811 European individuals. We identified 20 significant independent genetic markers for SIS, three of which were found in loci not implicated in ASCVD before. Further GWAS on coronary artery calcification showed similar results to that of SIS, whereas a GWAS on ultrasound-assessed carotid plaques identified both shared and non-shared loci with SIS. In two-sample Mendelian randomization studies using SIS-associated markers in UK Biobank and CARDIoGRAMplusC4D, one extra coronary segment with atherosclerosis corresponded to 1.8-fold increased odds of myocardial infarction. This GWAS data can aid future studies of causal pathways in ASCVD.

Aims: Endotypes integrate individual clinical and molecular data and can be used to formulate molecular subclassifications of diseases. We previously derived four endotypes of subclinical carotid atherosclerosis in a large European cohort, c-IMT and c-IMT Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE), identifying individuals with a specific cardiovascular (CV) risk, ranging from low (endotype 1) to very high (endotype 4). Here, we investigate the mechanisms underlying the differences in CV risk observed across these four endotypes.

Methods and results: We validated the four endotypes in SCAPIS (n = 5050) and UK Biobank (n = 50 396) using carotid plaque and carotid intima-media thickness (c-IMT) as subclinical atherosclerosis measures. Endotype 4 associated with a larger number of carotid plaques and increased c-IMT measures as compared to endotype 1. We performed a meta-analysis of individual genome wide association studies in IMPROVE (n = 3711), SCAPIS and UK Biobank, and identified 12 SNPs associated with endotypes. We investigated if they regulated gene expression and circulating protein levels. We found that rs2228145A/C at Interleukin-6 Receptor (IL6R), associated with endotype 4, regulated IL6R expression and circulating levels of OncoStatin M Receptor (OSMR), Complement Factor B (CFB) and Fibrinogen Chain A (FGA). We used rs2228145A/C as an instrument in two-sample Mendelian randomization analyses and showed that a decreasing IL6R expression, associated with increasing CFB, FGA, and OSMR circulating levels. Endotype 4, IL6R, CFB, FGA, and OSMR co-localized within 250 kb surrounding rs2228145A/C. However, only OSMR was up-regulated in advanced carotid atherosclerotic plaques in the presence of the A allele and in aortic region exposed to low wall shear stress. In the UK Biobank, we observed that each additional A allele at rs2228145 increased by 1.28-times the risk of myocardial infarction (MI) in endotype 4.

Conclusion: Rs2228145A/C associated with endotype 4 clinical and molecular characteristics and amplified the MI risk in individuals assigned to endotype 4. These effects appeared to be mediated by a crosstalk with OSMR.

Background: Aortic valve calcification (AVC) is an underlying pathophysiological mechanism in aortic stenosis, which shares many risk factors with diabetes. However, the association between dysglycemia and early stages of AVC remains unclear. The aim was to examine the associations between stages of dysglycemia and signs of AVC among middle-aged individuals from the general population.

Methods: This was a cross-sectional study from the Swedish CArdioPulmonary bioImage Study (SCAPIS) randomly enrolling 30,154 middle-aged men and women from six study sites in Sweden between 2013 and 2018. Glycemic status was based on the World Health Organization criteria (fasting blood glucose and/or HbA1c) and questionnaire-based answers on previous diseases and categorized as normoglycemia, prediabetes, newly detected diabetes and known diabetes. AVC was assessed on cardiac computed tomography (CT) and defined as evident or not.

Results: Of 29,331 individuals with data on glycemic status and AVC available, mean age was 57.5 years and normoglycemia was present in 76%, prediabetes in 16%, newly detected diabetes in 3% and known diabetes in 5%. The prevalence of AVC increased progressively across glycemic categories, particularly in males (8%, 11%, 14% and 17%; P < 0.01) compared to females (5%, 6%, 8% and 9%; P < 0.01). There was an association with AVC already in the early stages of dysglycemia; prediabetes (OR 1.16, 95% CI 1.02–1.31), newly detected diabetes (1.34 [1.05–1.71]) and known diabetes (1.61 [1.34–1.93]) after adjusting for age, sex, smoking, study site, low density lipoprotein-cholesterol and hypertension.

Conclusions: In this large, contemporary, and randomly selected population of middle-aged individuals, prediabetes, newly detected diabetes and known diabetes were all associated with CT-detected AVC. Further studies are warranted to investigate if managing dysglycemia, even in its early stages, may help slow down AVC progression.