Carotid Plaque Composition and Prediction of Incident Atherosclerotic Cardiovascular Disease.

BACKGROUND: Whether information on carotid plaque composition contributes to prediction of incident atherosclerotic cardiovascular disease (ASCVD) remains to be investigated. We determined the sex-specific added value of carotid plaque components for predicting incident ASCVD events, beyond traditional cardiovascular risk factors. METHODS: Between 2007 and 2012, participants from the population-based Rotterdam Study with asymptomatic carotid wall thickening >2.5 mm on ultrasonography were invited for carotid magnetic resonance imaging. Among 1349 participants (mean age: 72 years [SD±9.3], 49.5% women) without cardiovascular disease, we assessed plaque thickness, luminal stenosis (>30%), presence of intraplaque hemorrhage, lipid-rich necrotic core, and calcification. Follow-up for ASCVD was complete until January 1, 2015. Using Cox proportional hazards models, we fitted sex-specific prediction models including traditional cardiovascular risk factors (base model). We extended the base model by single and simultaneous additions of plaque characteristics and calculated improvement of model performance by the C statistics. RESULTS: During a median follow-up of 4.8 years, 60 men and 48 women developed ASCVD. In women, presence of intraplaque hemorrhage was associated with incident ASCVD (adjusted hazard ratio, 3.37 [95% CI, 1.81-6.25]). The C statistic (95% CI) improved from 0.73 (0.66-0.79) to 0.76 (0.70-0.83) after single addition of intraplaque hemorrhage to the base model. Simultaneous addition of plaque components, plaque thickness, and stenosis did not change the results. In men, only carotid stenosis was statistically significantly associated with incident ASCVD (adjusted hazard ratio, 1.75 [95% CI, 1.00-3.08]); yet, the association diminished after the addition of other plaque characteristics, and no improvements were observed in C statistics. CONCLUSIONS: Presence of intraplaque hemorrhage contributes to the prediction of incident ASCVD in women, beyond traditional cardiovascular risk factors, other plaque components, plaque size, and stenosis.

Cardiac abnormalities in athletes after SARS-CoV-2 infection: a systematic review.

OBJECTIVES: Quantification of pericardial/myocardial involvement and risks of sudden cardiac arrest/sudden cardiac death (SCA/SCD) after SARS-CoV-2 infection in athletes who return to sports. DESIGN: Systematic review on post-SARS-CoV-2 infection pericardial/myocardial manifestations in athletes. DATA SOURCES: Combinations of key terms in Medline, Embase and Scopus (through 2 June 2021). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Inclusion: athletes, with cardiovascular magnetic resonance (CMR) or echocardiography after recovery from SARS-CoV-2 infection, including arrhythmia outcomes. Exclusion: study population ≥1 individual comorbidity and mean age <18 or >64 years. Quality assessment was performed using Joanna Briggs Institute Critical Appraisal tools checklists. RESULTS: In total, 12 manuscripts (1650 papers reviewed) comprising 3131 athletes (2198 college/student athletes, 879 professional athletes and 54 elite athletes) were included. The prevalence of myocarditis on echocardiography and/or CMR was 0%-15%, pericardial effusion 0%-58% and late gadolinium enhancement (LGE) 0%-46%. Weighted means of diagnosed myocarditis were 2.1% in college/student athletes and 0% in elite athletes. The prevalence of LGE was markedly lower in studies with high-quality assessment scores (3%-4%) versus low scores (38%-42%). A single study reported reversibility of myocardial involvement in 40.7%. No important arrhythmias were reported. Ten studies (n=4171) reporting postrecovery troponin T/I found no clear relationship with cardiac abnormalities. SUMMARY/CONCLUSION: Athletes have an overall low risk of SARS-CoV-2 pericardial/myocardial involvement, arrhythmias and SCA/SCD. Rates of pericardial/myocardial abnormalities in athletes are highly variable and dependent on study quality. Troponin screenings seem unreliable to identify athletes at risk for myocardial involvement. Prospective athlete studies, with pre-SARS-CoV-2 imaging (CMR), including structured follow-up and arrhythmia monitoring, are urgently needed.

Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces.

BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP (WASL) locus is associated with carotid-femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Expression and gene variation studies deny association of human HSD3B1 gene with aldosterone production or blood pressure.

BACKGROUND: Recent evidence suggests that the type I 3ß-hydroxysteroid dehydrogenase, a steroidogenic enzyme encoded by the HSD3B1 gene, could be involved in aldosterone production and that genetic variation in HSD3B1 is associated with blood pressure. These findings challenge the long-standing hypothesis that all adrenocortical steroidogenesis is executed by the type II iso-enzyme, encoded by HSD3B2. METHODS: To verify these findings, the adrenal presence of HSD3B1 and its effect on aldosterone synthesis and blood pressure were studied in expression and genetic association analyses, respectively. Expression of HSD3B1 and HSD3B2 was investigated in various adrenocortical tissues (n = 15) and in primary adrenal cell cultures (n = 5) after stimulation with adrenocorticotropin and angiotensin II. Six tagging single nucleotide polymorphisms within the HSD3B1 gene were studied for association with blood pressure and hypertension in a meta-analysis of 4 Dutch cohorts (n = 11,192). RESULTS: HSD3B1 expression was minimal or absent in adrenocortical tissues, including 6 aldosterone-producing adenomas. In contrast with the ubiquitously expressed HSD3B2 mRNA, HSD3B1 levels were not stimulated by adrenocorticotropin or angiotensin II. No variants in the HSD3B1 gene were associated with blood pressure or the occurrence of hypertension. CONCLUSIONS: We found no evidence to support confirmation that HSD3B1 is involved in aldosterone synthesis in the human adrenal cortex or that genetic variation in HSD3B1 affects blood pressure or hypertension, favoring the hypothesis that all adrenocortical steroidogenesis is primarily dependent on the type II 3ß-hydroxysteroid dehydrogenase.

Association of renal function with vascular stiffness in older adults: the Rotterdam study.

BACKGROUND: arterial stiffening is a marker of vascular ageing and an independent risk factor for cardiovascular disease. A potential mechanism linking cardiovascular disease to chronic kidney disease might be the change in arterial elasticity. We aim to determine the association between renal function and arterial stiffness in older subjects. DESIGN: cross-sectional study. SETTING: Rotterdam study, a population-based cohort study. SUBJECTS: we included 3,279 subjects from 1997 to 1999 with a mean age of 71.9 years. METHODS: estimation of glomerular filtration rate (eGFR) was used to assess renal function. Aortic pulse wave velocity (PWV) and carotid distensibility coefficient were used as measures of arterial stiffness. RESULTS: each standard deviation increase in eGFR, adjusting for age and sex, was associated with 0.14 m/s lower PWV [95% confidence interval (CI): -0.23, -0.05]. Further adjustments for socio-demographic and cardiovascular risk factors did not change the association (ß: -0.16 m/s; 95% CI: -0.26, -0.06). There was a linear association between mean values of PWV and quartiles of glomerular filtration rate (P for trend = 0.006). There was no association between decreased renal function and carotid distensibility. There was no statistical difference in the strength of the association between renal function and PWV in subgroups of participants with and without cardiovascular risk factors. CONCLUSIONS: in this large population-based study of elderly subjects, our findings suggest that renal impairment is associated with aortic stiffness. This association is independent of cardiovascular risk factors.

Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

BACKGROUND: Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. METHODS AND RESULTS: We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36×10(-12)), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54×10(-13)) and rs2957717 (P=4.24×10(-8)). Reflection index was independently associated with rs11042717 (P<10(-4)) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression. CONCLUSIONS: These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study.

OBJECTIVE: We studied whether arterial stiffness measured as aortic pulse wave velocity (aPWV) and carotid distensibility was associated with different subtypes of hypertension in a large population of untreated middle-aged and elderly men and women. METHODS: The study was conducted within the framework of the population-based Rotterdam Study. We included 4088 individuals with information on aPWV, with 3554 individuals with carotid distensibility measurements without use of antihypertensive medication. Isolated systolic hypertension (ISH) was defined as SBP at least 140 mmHg and DBP less than 90 mmHg. Combined systolic and diastolic hypertension (Sys/Dia hypertension) was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Analysis of covariance was used to compare means of arterial stiffness for the different subtypes of hypertension. Multinomial logistic regression analysis was performed to investigate the association of arterial stiffness and the subtypes of hypertension in models adjusted for age, sex, mean arterial pressure, heart rate and cardiovascular risk factors. RESULTS: The mean age of the individuals was 68 years: 45.3% were men, 1597 individuals had ISH and 441 individuals had Sys/Dia hypertension. aPWV was higher (13.2 vs. 12.9 m/s; P = 0.008) in individuals with ISH compared to those with Sys/Dia hypertension. Multivariate odds ratios and corresponding 95% confidence interval of aPWV for ISH were 1.53 (1.38-1.71) and 1.28 (1.09-1.53) for Sys/Dia hypertension. Corresponding odds ratios associated with carotid distensibility were 0.84 (0.75-0.94) and 0.66 (0.54-0.81), respectively. Age significantly modified the association of aPWV with subtypes of hypertension (P < 0.001). CONCLUSION: In a large untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared to individuals with Sys/Dia hypertension, a difference that was most pronounced at older age. The results suggest that aortic stiffness contributes to ISH in older individuals without treatment for hypertension.

Arterial stiffness is associated with carotid intraplaque hemorrhage in the general population: the Rotterdam study.

OBJECTIVE: The relation between arterial stiffness and atherosclerosis, and specifically the influence of arterial stiffness on plaque composition, is largely unknown. In a population-based study, we investigated the association between arterial stiffness and the presence and composition of carotid atherosclerotic plaques. APPROACH AND RESULTS: Arterial stiffness was measured in 6527 participants (67.0±8.6 years) using aortic pulse wave velocity (PWV). Presence of carotid atherosclerotic plaques was assessed with ultrasound. Subsequently, 1059 subjects with carotid plaques (>2.5 mm) underwent MRI to assess plaque composition (presence of intraplaque hemorrhage, lipid, and calcification). Generalized estimation equation analyses adjusted for age, sex, mean arterial pressure, heart rate, carotid wall thickening, pulse pressure, and traditional cardiovascular risk factors were used to study the association between PWV and the presence and composition of carotid atherosclerotic plaques. In multivariable analysis, higher PWV was independently related to higher prevalence of carotid atherosclerotic plaque on ultrasound (odds ratio for highest quartile of PWV compared with lowest quartile, 1.24 [95% confidence interval, 1.02-1.51]). Furthermore, higher PWV was associated with intraplaque hemorrhage (age- and sex-adjusted odds ratio per SD increase in PWV, 1.20 [1.04-1.38] and calcification, 1.18 [1.03-1.35]), but not with lipid. After adjustment for cardiovascular risk factors, PWV remained significantly associated with intraplaque hemorrhage (1.20 [1.01-1.43]). Additional adjustment for pulse pressure did not materially affect the effect estimate (1.19 [1.00-1.42]). CONCLUSIONS: Higher PWV is associated with presence and composition of carotid atherosclerotic plaques, in particular with intraplaque hemorrhage. These findings provide further clues for understanding the development of vulnerable atherosclerotic plaque.