ABSTRACT
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.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Carotid Stenosis , Plaque, Atherosclerotic , Aged , Atherosclerosis/pathology , Cardiovascular Diseases/complications , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/epidemiology , Carotid Arteries/diagnostic imaging , Carotid Arteries/pathology , Carotid Stenosis/complications , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/epidemiology , Constriction, Pathologic/complications , Constriction, Pathologic/pathology , Female , Hemorrhage/diagnostic imaging , Hemorrhage/epidemiology , Humans , Magnetic Resonance Imaging/methods , Male , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/epidemiology , Risk FactorsABSTRACT
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.
ABSTRACT
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.
Subject(s)
Aging , Aorta, Thoracic/physiopathology , Cytoskeletal Proteins/genetics , Hypertension/physiopathology , Muscle, Smooth, Vascular/physiopathology , Polymorphism, Single Nucleotide , Vascular Stiffness/physiology , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Blood Pressure , Cells, Cultured , Cytoskeletal Proteins/metabolism , DNA/genetics , Genome-Wide Association Study/methods , Humans , Hypertension/genetics , Hypertension/pathology , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/pathology , Pulse Wave AnalysisABSTRACT
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.
ABSTRACT
BACKGROUND: Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. METHODS AND RESULTS: Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5'-C-phosphate-G-3' methylation site) during prepuberty (P=2.86×10(-8)) and rs872256 during puberty (P=8.67×10(-9)). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10(-3). Using a P value threshold of <5×10(-3), we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. CONCLUSIONS: Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.
Subject(s)
Blood Pressure/genetics , Genetic Loci , Hypertension/genetics , Integrin alpha Chains/genetics , Adolescent , Age Factors , Child , Child, Preschool , Female , Genetic Markers , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Hypertension/diagnosis , Hypertension/ethnology , Hypertension/physiopathology , Male , Molecular Epidemiology , Phenotype , Polymorphism, Single Nucleotide , Risk Assessment , Risk Factors , White People/genetics , Young AdultABSTRACT
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.
Subject(s)
Adrenal Cortex/enzymology , Aldosterone/biosynthesis , Blood Pressure/genetics , Hypertension/genetics , Multienzyme Complexes/genetics , Polymorphism, Single Nucleotide , Progesterone Reductase/genetics , Steroid Isomerases/genetics , Aged , Cells, Cultured , Female , Gene Expression Regulation, Enzymologic , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Hypertension/enzymology , Hypertension/physiopathology , Male , Middle Aged , Netherlands , Phenotype , RNA, Messenger/metabolism , Risk FactorsABSTRACT
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.
Subject(s)
Cardiovascular Diseases/physiopathology , Carotid Arteries/physiopathology , Glomerular Filtration Rate , Kidney Diseases/physiopathology , Kidney/physiopathology , Vascular Stiffness , Age Factors , Aged , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cross-Sectional Studies , Female , Humans , Kidney Diseases/diagnosis , Kidney Diseases/epidemiology , Linear Models , Male , Middle Aged , Multivariate Analysis , Netherlands , Pulse Wave Analysis , Risk FactorsABSTRACT
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.
Subject(s)
Adrenomedullin/blood , Adrenomedullin/metabolism , Protein Precursors/blood , Vascular Stiffness/genetics , Adult , Aged , Atherosclerosis/blood , Atherosclerosis/genetics , Carotid Arteries/diagnostic imaging , Carotid Intima-Media Thickness , Cohort Studies , Female , Gene Expression Profiling , Gene Expression Regulation , Genetic Variation , Genome-Wide Association Study , Genotype , Humans , Linear Models , Male , Middle Aged , Monocytes/cytology , Polymorphism, Single Nucleotide , Transcription, Genetic , TranscriptomeABSTRACT
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 140âmmHg and DBP less than 90âmmHg. Combined systolic and diastolic hypertension (Sys/Dia hypertension) was defined as SBP at least 140âmmHg and DBP at least 90âmmHg. 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. 12.9âm/s; Pâ=â0.008) 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 (Pâ<â0.001). 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.
Subject(s)
Hypertension/physiopathology , Vascular Stiffness , Aged , Carotid Arteries/physiopathology , Diastole/physiology , Female , Humans , Male , Middle Aged , Pulse Wave Analysis , Systole/physiologyABSTRACT
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.
Subject(s)
Age Factors , Blood Pressure/genetics , Adolescent , Adult , Aged , Cohort Studies , Humans , Middle Aged , Young AdultABSTRACT
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.
Subject(s)
Carotid Artery Diseases/physiopathology , Hemorrhage/physiopathology , Plaque, Atherosclerotic , Vascular Stiffness , Aged , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/epidemiology , Disease Progression , Female , Hemorrhage/epidemiology , Humans , Logistic Models , Magnetic Resonance Angiography , Male , Middle Aged , Multivariate Analysis , Netherlands/epidemiology , Odds Ratio , Prevalence , Prospective Studies , Pulse Wave Analysis , Risk Factors , Rupture, Spontaneous , Ultrasonography , Vascular Calcification/epidemiology , Vascular Calcification/physiopathologyABSTRACT
BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5×10(-4) (0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs. OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. RESULTS: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 ×10(-10)) and diastolic (P = 1.6 ×10(-14)) blood pressure and coronary artery disease (P = 2.2 ×10(-6)), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 ×10(-07) and P = 7.05 ×10(-08)). LIMITATIONS: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. CONCLUSIONS: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
Subject(s)
Cardiovascular Diseases/genetics , Polymorphism, Single Nucleotide , Renal Insufficiency, Chronic/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Blood Pressure/genetics , Carotid Intima-Media Thickness , Female , Genome-Wide Association Study , Glomerular Filtration Rate/genetics , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Proteins/geneticsABSTRACT
BACKGROUND: Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear. METHODS AND RESULTS: We identified 8 loss-of-function (LOF) mutations in LIPG in individuals with high-density lipoprotein cholesterol. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF, whereas 2 more common mutations N396S and R476W reduce activity by ≈50%, indicating partial LOF and implying ≈50% and ≈75% remaining endothelial lipase function in heterozygous complete LOF and partial LOF mutation carriers, respectively. complete LOF mutation carriers had significantly higher plasma high-density lipoprotein cholesterol levels compared with partial LOF mutation carriers. Apolipoprotein B-depleted serum from complete LOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in partial LOF carriers. Carriers of LIPG mutations exhibited trends toward reduced coronary artery disease in 4 independent cohorts (meta-analysis odds ratio, 0.7; P=0.04). CONCLUSIONS: Our data suggest that the impact of LIPG mutations is directly related to their effect on endothelial lipase function and support that antagonism of endothelial lipase function improves cardioprotection.
Subject(s)
Cholesterol, HDL/blood , Coronary Artery Disease/enzymology , Coronary Artery Disease/genetics , Lipase/genetics , Mutation, Missense , Cohort Studies , Coronary Artery Disease/metabolism , Heterozygote , Humans , Lipase/metabolismABSTRACT
Intraplaque hemorrhage (IPH) is a characteristic of the vulnerable atherosclerotic plaque that has been associated with ischemic stroke. Not much is known about determinants of IPH. We studied whether blood pressure parameters are associated with presence of IPH. Within the framework of a prospective population-based cohort study, The Rotterdam Study, the carotid arteries of 1006 healthy participants ≥45 years and with intima-media thickening (≥2.5 mm) on ultrasound were imaged with a 1.5-T magnetic resonance imaging scanner. IPH was defined as a hyperintense signal on a 3D-T1w-GRE magnetic resonance sequence. Generalized estimation equation analysis, adjusted for age, sex, carotid wall thickness, and cardiovascular risk factors, was used to assess the association between blood pressure parameters and IPH. Magnetic resonance imaging of the carotid arteries revealed presence of IPH in 444 of 1860 plaques (24%). Systolic blood pressure and pulse pressure (PP) were significantly associated with IPH after adjustment for age and sex. In multivariate analysis, PP yielded the strongest association, with an odds ratio per SD increase in PP of 1.22 (95% CI, 1.07-1.40). The odds ratio per SD for systolic blood pressure was 1.13 (0.99-1.28). Only PP remained significant after additional adjustment for other blood pressure components. The combination of smoking and isolated systolic hypertension was associated with 2.5 times increased risk of IPH (1.2-5.2). In conclusion, PP was the strongest determinant of IPH independent of cardiovascular risk factors and other blood pressure components. The association between pulsatile flow and IPH may provide novel insights in the development of the vulnerable plaque.
Subject(s)
Blood Pressure/physiology , Carotid Arteries/pathology , Hemorrhage/pathology , Hypertension/pathology , Magnetic Resonance Imaging , Plaque, Atherosclerotic/pathology , Aged , Aged, 80 and over , Carotid Arteries/physiopathology , Carotid Intima-Media Thickness , Female , Hemorrhage/complications , Hemorrhage/physiopathology , Humans , Hypertension/complications , Hypertension/physiopathology , Male , Middle Aged , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/physiopathology , Prospective Studies , Risk FactorsABSTRACT
BACKGROUND AND PURPOSE: Aging and vascular risk factors contribute to arterial stiffening. Increased arterial stiffness exposes the small vessels in the brain to abnormal flow pulsations and, as such, may contribute to the pathogenesis of cerebral small vessel disease. In a population-based study, we investigated the association between arterial stiffness, as measured by aortic pulse wave velocity (aPWV), and small vessel disease. METHODS: Overall, 1460 participants (mean age, 58.2 years) underwent aPWV measurement and brain MRI scanning. We calculated aPWV by measuring time differences and distances between pulse waves in the carotid and femoral arteries. Using automated MRI analysis, we obtained white matter lesion volumes. Infarcts and microbleeds were rated visually. We used linear and logistic regression models to associate aPWV with small vessel disease, adjusting for age, sex, mean arterial pressure, and heart rate and additionally for cardiovascular risk factors. Subsequently, we explored associations in strata of hypertension. RESULTS: In the study group, higher aPWV was associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.07; 95% CI, 0.02-0.12) but not with lacunar infarcts or microbleeds. In persons with uncontrolled hypertension, higher aPWV was significantly associated with larger white matter lesion volume (difference in volume per SD increase in aPWV 0.09; 95% CI, 0.00-0.18), deep or infratentorial microbleeds (OR, 2.13; 95% CI, 1.16-3.91), and to a lesser extent also with lacunar infarcts (OR, 1.63; 95% CI, 0.98-2.70). No such associations were present in persons with controlled hypertension or without hypertension. CONCLUSIONS: In our study, increased arterial stiffness is associated with a larger volume of white matter lesions.
Subject(s)
Cerebral Small Vessel Diseases/etiology , Cerebral Small Vessel Diseases/physiopathology , Cerebrovascular Circulation/physiology , Regional Blood Flow/physiology , Vascular Stiffness/physiology , Aged , Arterial Pressure/physiology , Blood Pressure/physiology , Cerebral Small Vessel Diseases/pathology , Cohort Studies , Cross-Sectional Studies , Female , Humans , Logistic Models , Magnetic Resonance Imaging , Male , Middle Aged , Netherlands , Pulse Wave AnalysisABSTRACT
BACKGROUND: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. METHODS AND RESULTS: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. CONCLUSIONS: Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
Subject(s)
Aging/physiology , Cellular Senescence/physiology , DNA Repair/physiology , Endothelium, Vascular/physiopathology , Genomic Instability/physiology , Vascular Stiffness/physiology , Animals , Blood Pressure/physiology , Carotid Arteries/physiopathology , Cells, Cultured , DNA-Binding Proteins/genetics , Endonucleases/genetics , Endothelium, Vascular/pathology , Femoral Artery/physiopathology , Humans , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Models, Animal , Polymorphism, Single Nucleotide/genetics , Xeroderma Pigmentosum Group D Protein/geneticsABSTRACT
AIMS: Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. METHODS AND RESULTS: A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥ 20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85-0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75-0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87-0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02-1.24; P = 0.02, rs198358: 1.10, 1.01-1.20; P = 0.04, and rs5068: 1.22, 1.04-1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04). CONCLUSION: The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
Subject(s)
Blood Pressure/genetics , Hypotension, Orthostatic/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Antihypertensive Agents/therapeutic use , Atherosclerosis/genetics , Atherosclerosis/physiopathology , Epidemiologic Methods , Female , Gene Frequency , Heterozygote , Homozygote , Humans , Hypotension, Orthostatic/drug therapy , Hypotension, Orthostatic/physiopathology , Male , Middle AgedABSTRACT
BACKGROUND: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. OBJECTIVE: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. DESIGN: Prospective population-based study. SETTING: The Rotterdam Study, Rotterdam, the Netherlands. PARTICIPANTS: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). MEASUREMENTS: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima-media thickness, peripheral arterial disease, and pulse wave velocity). RESULTS: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal. LIMITATION: The findings may not be generalizable to younger or nonwhite populations. CONCLUSION: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and health systems. PRIMARY FUNDING SOURCE: Netherlands Organization for Health Research and Development (ZonMw).
Subject(s)
Biomarkers/blood , Coronary Artery Disease/blood , Coronary Artery Disease/epidemiology , Risk Assessment , Aged , Coronary Artery Disease/diagnosis , Coronary Vessels/metabolism , Female , Humans , Incidence , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Prospective Studies , Risk Factors , Vascular Calcification/bloodABSTRACT
AIM: Non-invasive measures of atherosclerosis, such as carotid intima-media thickness (cIMT), may improve global cardiovascular risk prediction. The aim of this study was to determine whether common carotid IMT in addition to traditional risk factors improves risk classification in a general population of older people. METHODS AND RESULTS: A group of 3580 non-diabetic people aged 55-75 years and free of cardiovascular disease at baseline were followed for a median time of 12.2 years. Compared to models based on Framingham risk factors, we studied the ability of common cIMT measurement to better classify people into categories of low (<10%), intermediate (10-20%) and high (>20%) 10-year risk of hard coronary heart disease (CHD) and stroke. In older men, addition of cIMT to Framingham risk factors did not improve prediction of hard CHD or stroke. In older women, addition of cIMT to Framingham risk factors significantly improved risk classification. cIMT improved the C-statistic of the model for hard CHD from 0.711 to 0.719 and for stroke from 0.712 to 0.721, at good calibration. Reclassification was least in the majority of women classified as low risk (4% (n = 76) for hard CHD and 3% (n = 62) for stroke) and most substantial in women at intermediate risk (43% (n = 70) for hard CHD and 28% (n = 76) for stroke). The net reclassification improvement in women was 8.2% (p = 0.03) for hard CHD and 8.0% (p = 0.06) for stroke. CONCLUSION: cIMT had some additional value beyond traditional risk factors in the cardiovascular risk stratification of older women, but not of older men.