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Clonal hematopoiesis affecting cardiovascular health
Cell senescence in atherosclerosis and vascular ageing
COMBINING POLYGENIC RISK SCORES TO PREDICT MYOCARDIAL INFARCTION IN THE CANADIAN LONGITUDINAL STUDY ON AGING
Abstract
Background and Aims
Estimating the risk of developing complex pathologies, such as coronary artery disease (CAD), is now possible by aggregating data from genome-wide association studies (GWAS) into polygenic risk scores (PRS). This study aims to evaluate the performance of PRS derived from CAD and blood lipids GWAS to predict myocardial infarction (MI).
Methods
Using publicly available GWAS data (CARDIoGRAMplusC4D consortium for CAD and UK Biobank for blood lipids concentration and number of lipoprotein particles, obtained from nuclear magnetic resonance), we derived multiple PRS in individuals of European ancestry aged between 45 and 86 years, in the Canadian Longitudinal Study on Aging cohort. These PRS included >1.12 million of genetic variants and were calculated using LDpred2. Odds ratios (OR) for prevalent MI (971 cases and 18,628 controls) and their 95% confidence interval are reported from adjusted logistic regressions (age, sex and 10 genetic principal components) for 1-SD increase of each PRS distribution.
Results
Among all models, CAD PRS showed the strongest association (OR=1.62 [1.51-1.73], p=1.89e-43), whereas PRS for total triglyceride (TG) and small LDL particles (sLDLp) reached respectively 1.21 ([1.13-1.29], p=1.43e-08) and 1.20 ([1.12-1.28], p=1.53e-07). Both apolipoprotein B and LDL-cholesterol PRS showed similar OR (respectively 1.19 [1.11-1.27], p=8.63e-07 and 1.19 [1.11-1.28], p=7.52e-07). Area under the ROC curve showed better performance for the model including common risk factors and the strongest independent PRS (CAD, TG and sLDLp) versus risk factors only.
Conclusions
The combination of several PRS derived from common genetic variants associated with CAD and blood lipids has the potential to improve the prediction of MI.
LIPOPROTEIN(A) IS A RESIDUAL CARDIOVASCULAR RISK FACTOR IN STATIN TREATED STROKE SURVIVORS: INSIGHTS FROM THE SPARCL TRIAL
Abstract
Background and Aims
The association between Lipoprotein(a) [Lp(a)] and cardiovascular risk in stroke survivors is unknown. We investigated the contribution of elevated Lp(a) to cardiovascular and cerebrovascular events in patients with previous stroke or TIA.
Methods
Lp(a) levels and apo(a) isoform size were determined by LC-MS/MS in plasma samples collected at baseline from 2814 patients from the SPARCL trial (1418 randomized to atorvastatin and 1396 to placebo). We compared patients in the highest quartile (> 84 nmol/L) with those in the lowest quartiles of plasma Lp(a) concentrations and patients in the lowest quartile (<25.9 KIV domains) with those in the highest quartiles of apo(a) isoform sizes distributions.
Results
In patients randomized to atorvastatin, elevated Lp(a) concentrations as well as short apo(a) isoforms were associated with an increased risk of coronary events [adjusted cox proportional HR (95% CI) of 1.607 (1.007-2.563) p=0.047 and 2.052 (1.303-3.232) p=0.002, respectively]. No such association was found in patients randomized to placebo [HR of 0.925(0.606-1.412) p=0.718, and 1.105(0.735-1.659) p=0.632]. In contrast, we did not observe any significant association between elevated Lp(a) concentrations or short apo(a) isoforms and the risk of recurrent cerebrovascular events in patients randomized to atorvastatin [HR of 0.794(0.586-1.076) p=0.138, and 1.114(0.760-1.352) p=0.926] or placebo [HR of 0.914(0.688-1.214) p=0.534, and 0.940(0.709-1.248) p=0.671].
Conclusions
Elevated Lp(a) is associated with the risk of subsequent coronary but not of recurrent cerebrovascular events in statin-treated stroke survivors. This underlines that elevated LDL is driving the global risk in these patients and that elevated Lp(a) is an important contributor to their residual risk.
CAROTID PLAQUE CHARACTERISTICS PREDICT RECURRENT ISCHEMIC STROKE: THE PLAQUE AT RISK (PARISK) STUDY
Abstract
Background and Aims
Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. Currently, treatment decisions for carotid revascularization mainly rely on degree of stenosis. However, other plaque characteristics might be better determinants of recurrent stroke, allowing more targeted intervention. The Plaque At RISK (PARISK)-study aimed to improve identification of patients at increased risk of recurrent stroke using multimodality carotid imaging.
Methods
We included 240 patients with symptomatic <70% ipsilateral carotid stenosis in a prospective multicenter cohort study. MRI (carotid and brain) and MDCTA (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or TIA. Cox-proportional hazard models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, we investigated the predictive performance of these imaging biomarkers by adding (combinations of) these markers to the ECST-risk score.
Results
During 5.1 years follow-up 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR=2.12, 95%CI: 1.02-4.44 for IPH; HR=1.07, 95%CI: 1.00-1.15 for total plaque volume per 100 mm3 increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST-risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78).
Conclusions
IPH and total plaque volume are independent risk factors of recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making.
CLONAL HEMATOPOIESIS ARE NOT ASSOCIATED WITH AN INCREASED SYSTEMIC INFLAMMATION, ATHEROSCLEROSIS NOR INCIDENCE OF ATHEROTHROMBOSIS : RESULTS FROM THE 3-CITY STUDY (CHIP-3C).
Abstract
Background and Aims
Clonal hematopoiesis of indeterminate Potential (CHIP) is defined by the detection of leukemia-associated mutations in the absence of hematological malignancy. This condition is associated with an increased mortality mainly driven by athero-thrombotic complications. Previous studies in mouse models demonstrated that CHIP increase atherosclerosis development. However the association between CHIP, atherosclerosis and athero-thrombosis remains poorly evaluated in patients.
Methods
The 3-city study is a population-based longitudinal study that enrolled individuals aged ≥65 years. In this cohort, we selected 322 persons who had no cardiovascular event before inclusion. Eighty five of them suffered from a myocardial infarction or stroke during the 12-year follow-up. We searched for CHIP by a targeted NGS strategy on DNA collected at inclusion. Anthropomorphic, cardiovascular (risk factors, diet, atherosclerosis) and biological (CRP level) data at inclusion as well as incidence of athero-thrombotic events were compared between patients with or without CHIP.
Results
A CHIP was detected in 41% of patients. As described, most patients presented mutations in DNMT3A (46%) and TET2 (30%). Patients with CHIP were slightly older than patients without CHIP (74.2 years VS 73 years, p=0.03). Neither the cardiovascular risk profile, nor the CRP levels (1.66 VS 1.75), nor the number of atheromatous plaques nor the intima-media thickness (0.67 VS 0.68) were different between patients with and without CHIP. The incidence of athero-thrombotic complications (myocardial infarction or stroke) was similar between patients with a CHIP and patients without.
Conclusions
In conclusion, CHIP, in particular involving DNMT3A mutations, are not strongly associated with systemic inflammation, atherosclerosis or athero-thrombotic events.
BODY MASS INDEX AND RISK OF DEMENTIA
Abstract
Background and Aims
Midlife obesity and underweight in the elderly have been associated with a high risk of dementia. However, the association between body mass (BMI) and risk of dementia depends on the type of dementia investigated. Whether there is a causal association between BMI and the vascular part of dementia called “non-Alzheimer dementia” remains unknown. We aimed to investigate the association between BMI and risk of “non-Alzheimer dementia”, Alzheimer’s disease, and all-cause dementia.
Methods
In a prospective cohort of the Danish general population including 95,000 individuals we investigated the observational and genetically determined association between BMI and risk of “non-Alzheimer dementia”, Alzheimer’s disease, and all-cause dementia. For the genetic analyses we created a weighted allele score and divided it into four groups from lowest to highest BMI.
Results
The observational association between BMI and risk of “non-Alzheimer dementia” and all-cause dementia was u-shaped with nadir at a BMI of 26 kg/m2. For Alzheimer’s disease the association was linear with low BMI associated with high risk. Comparing the group with the lowest genetically determined BMI to the group with the highest genetically determined BMI the hazard ratio (95% confidence interval) was 1.22 (1.01- 1.47) for “non-Alzheimer dementia”, 1.04 (0.90-1.20) for Alzheimer’s disease, and 1.10 (0.98-1.23) for all-cause dementia.
Conclusions
Genetically determined high BMI is associated with high risk of the vascular part of dementia in the general population. BMI is thus a potentially modifiable risk factor for dementia that could be targeted in the strive to prevent this devastating disease.