George Thanassoulis

Genetic Associations with Valvular Calcification and Aortic Stenosis

BACKGROUND Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Outcomes in Adults With Bicuspid Aortic Valves

CONTEXT Bicuspid aortic valve is the most common congenital cardiac anomaly in the adult population. Cardiac outcomes in a contemporary population of adults with bicuspid aortic valve have not been systematically determined. OBJECTIVE To determine the frequency and predictors of cardiac outcomes in a large consecutive series of adults with bicuspid aortic valve. DESIGN, SETTING, AND PARTICIPANTS Cohort study examining cardiac outcomes in 642 consecutive ambulatory adults (mean [SD] age, 35 [16] years; 68% male) with bicuspid aortic valve presenting to a Canadian congenital cardiac center from 1994 through 2001 and followed up for a mean (SD) period of 9 (5) years. Frequency and predictors of major cardiac events were determined by multivariate analysis. Mortality rate in the study group was compared with age- and sex-matched population estimates. MAIN OUTCOME MEASURES Mortality and cause of death were determined. Primary cardiac events were defined as the occurrence of any of the following complications: cardiac death, intervention on the aortic valve or ascending aorta, aortic dissection or aneurysm, or congestive heart failure requiring hospital admission during the follow-up period. RESULTS During the follow-up period, there were 28 deaths (mean [SD], 4% [1%]). One or more primary cardiac events occurred in 161 patients (mean [SD], 25% [2%]), which included cardiac death in 17 patients (mean [SD], 3% [1%]), intervention on aortic valve or ascending aorta in 142 patients (mean [SD], 22% [2%]), aortic dissection or aneurysm in 11 patients (mean [SD], 2% [1%]), or congestive heart failure requiring hospital admission in 16 patients (mean [SD], 2% [1%]). Independent predictors of primary cardiac events were age older than 30 years (hazard ratio [HR], 3.01; 95% confidence interval [CI], 2.15-4.19; P<.001), moderate or severe aortic stenosis (HR, 5.67; 95% CI, 4.16-7.80; P<.001), and moderate or severe aortic regurgitation (HR, 2.68; 95% CI, 1.93-3.76; P<.001). The 10-year survival rate of the study group (mean [SD], 96% [1%]) was not significantly different from population estimates (mean [SD], 97% [1%]; P = .71). At last follow-up, 280 patients (mean [SD], 45% [2%]) had dilated aortic sinus and/or ascending aorta. CONCLUSIONS In this study population of young adults with bicuspid aortic valve, age, severity of aortic stenosis, and severity of aortic regurgitation were independently associated with primary cardiac events. Over the mean follow-up duration of 9 years, survival rates were not lower than for the general population.

Pericardial Fat is Associated with Prevalent Atrial Fibrillation: The Framingham Heart Study

Background—Obesity represents an important risk factor for atrial fibrillation (AF). We tested the hypothesis that pericardial fat, a unique fat deposit in close anatomic proximity to cardiac structures and autonomic fibers, is associated with prevalent AF. Methods and Results—Participants from the Framingham Heart Study underwent multidetector computed tomography from 2002 to 2005. We estimated the association between quantitative pericardial, intrathoracic and visceral adipose tissue volumes (per standard deviation of volume) with prevalent AF adjusting for established AF risk factors (age, sex, systolic blood pressure, blood pressure treatment, PR interval, and clinically significant valvular disease). Of the 3217 eligible participants (mean age, 50.6±10.1 years; 48% women), 54 had a confirmed diagnosis of AF. Pericardial fat but not intrathoracic or visceral abdominal fat was associated with prevalent AF in multivariable-adjusted models (odds ratio per standard deviation of pericardial fat volume, 1.28; 95% confidence intervals, 1.03 to 1.58). Further adjustments for body mass index, heart failure, myocardial infarction, and intrathoracic fat volume did not materially change the association between pericardial fat and AF. Conclusions—Pericardial fat was associated with prevalent AF even after adjustment for AF risk factors, including body mass index. If this association is replicated, further investigations into the mechanisms linking pericardial fat to AF are merited.

A Genetic Risk Score Is Associated With Incident Cardiovascular Disease and Coronary Artery Calcium The Framingham Heart Study

Background— Limited data exist regarding the use of a genetic risk score (GRS) for predicting risk of incident cardiovascular disease (CVD) in US-based samples. Methods and Results— By using findings from recent genome-wide association studies, we constructed GRSs composed of 13 genetic variants associated with myocardial infarction or other manifestations of coronary heart disease (CHD) and 102 genetic variants associated with CHD or its major risk factors. We also updated the 13 single-nucleotide polymorphism (SNP) GRSs with 16 SNPs recently discovered by genome-wide association studies. We estimated the association, discrimination, and risk reclassification of each GRS for incident cardiovascular events and prevalent coronary artery calcium (CAC). In analyses adjusted for age, sex, CVD risk factors, and parental history of CVD, the 13 SNP GRSs were significantly associated with incident hard CHD (hazard ratio, 1.07; 95% CI, 1.00–1.15; P=0.04), CVD (hazard ratio per allele, 1.05; 95% CI, 1.01–1.09; P=0.03), and high CAC (defined as >75th age- and sex-specific percentile; odds ratio per allele, 1.18; 95% CI, 1.11–1.26; P=3.4×10−7). The GRS did not improve discrimination for incident CHD or CVD but led to modest improvements in risk reclassification. However, significant improvements in discrimination and risk reclassification were observed for the prediction of high CAC. The addition of 16 newly discovered SNPs to the 13 SNP GRSs did not significantly modify these results. Conclusions— A GRS composed of 13 SNPs associated with coronary disease is an independent predictor of cardiovascular events and of high CAC, modestly improves risk reclassification for incident CHD, and significantly improves discrimination for high CAC. The addition of recently discovered SNPs did not significantly improve the performance of this GRS.

Relations of Change in Plasma Levels of LDL-C, Non-HDL-C and apoB With Risk Reduction From Statin Therapy: A Meta-Analysis of Randomized Trials

Background Identifying the best markers to judge the adequacy of lipid‐lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid‐lowering therapies are in development. Reductions in LDL‐C, non‐HDL‐C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. Methods and Results We performed a random‐effects frequentist and Bayesian meta‐analysis of 7 placebo‐controlled statin trials in which LDL‐C, non‐HDL‐C, and apoB values were available at baseline and at 1‐year follow‐up. Summary level data for change in LDL‐C, non‐HDL‐C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta‐analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL‐C; 20.0% (15.2%, 24.7%) for non‐HDL‐C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL‐C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non‐HDL‐C (P<0.001). Similarly, in Bayesian meta‐analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL‐C or non‐HDL‐C (BFs ranging from 484 to 2380). Conclusions Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo‐controlled statin trials was more closely related to reductions in apoB than to reductions in either non‐HDL‐C or LDL‐C.

2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult

Since the publication of the 2012 guidelines new literature has emerged to inform decision-making. The 2016 guidelines primary panel selected a number of clinically relevant questions and has produced updated recommendations, on the basis of important new findings. In subjects with clinical atherosclerosis, abdominal aortic aneurysm, most subjects with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy is recommended. For all others, there is an emphasis on risk assessment linked to lipid determination to optimize decision-making. We have recommended nonfasting lipid determination as a suitable alternative to fasting levels. Risk assessment and lipid determination should be considered in individuals older than 40 years of age or in those at increased risk regardless of age. Pharmacotherapy is generally not indicated for those at low Framingham Risk Score (FRS; <10%). A wider range of patients are now eligible for statin therapy in the FRS intermediate risk category (10%-19%) and in those with a high FRS (> 20%). Despite the controversy, we continue to advocate for low-density lipoprotein cholesterol targets for subjects who start therapy. Detailed recommendations are also presented for health behaviour modification that is indicated in all subjects. Finally, recommendation for the use of nonstatin medications is provided. Shared decision-making is vital because there are many areas in which clinical trials do not fully inform practice. The guidelines are meant to be a platform for meaningful conversation between patient and care provider so that individual decisions can be made for risk screening, assessment, and treatment.

Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Background Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. Methods and Findings We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10−10 to 2 × 10−109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10−12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7–2.5; p = 7.7 × 10−12; I 2 = 63%, 95% CI: 0%–88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3–2.2; p = 2.3 × 10−5; I 2 = 47%, 95% CI: 0%–85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6–2.6, p = 1 × 10−9; ORmetabolism = 1.9, 95% CI: 1.3–2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. Conclusions A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves

Background Aortic dilatation is common among adults with bicuspid aortic valves (BAV). Predictors of risk and progression of aortic dilatation are not well described in this setting.Methods We analyzed retrospective data on the presence of dilation in several aortic segments in 156 adult patients with BAV who had serial echocardiograms performed at least 1 year apart. Various risk factors for the presence and progression of aortic dilatation were identified.Results Mean echocardiographic follow-up was 3.8 ± 1.4 years, yielding a total of 582 patient-years. Independent predictors of having a dilated aorta at baseline were age (odds ratio [OR] 1.06, 95% CI 1.03–1.09), body surface area (OR 8.78, 95% CI 1.08–71.70) and moderate to severe aortic regurgitation (OR 6.38, 95% CI 2.51–16.20). During echocardiographic follow-up, 16 (15.2%) patients developed dilatation (incidence 4 cases per 100 patientyears). Mean annual rates of progression were estimated at 0.37 mm (95% CI 0.17–0.57), 0.18 mm (95% CI 0.05–0.31), 0.17 mm (95% CI 0.06–0.29) and 0.18 mm (95% CI 0.05–0.31) for the ascending aorta, sinotubular junction, aortic sinus and aortic annulus, respectively. Fusion of the right and left valve leaflets was associated with rapid aortic dilatation (OR 2.92, 95% CI 1.15– 7.41) whereas prior coarctation repair was associated with protection from rapid aortic dilatation (OR 0.13, 95% CI 0.04–0.40).Conclusions Patients with BAV and increased age, high body surface area and moderate to severe aortic regurgitation are more likely to have a dilated aorta. Patients with right-to-left leaflet fusion are at increased risk of rapid aortic dilatation.

Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study

Background— Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension, and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community. Methods and Results— Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry, and brachial artery flow-mediated dilation testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol–to–high-density cholesterol ratio (P⩽0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (P=0.02), central pulse pressure (P<0.0001), mean arterial pressure (P=0.04), and baseline brachial flow (P=0.002) were positively associated with exercise systolic BP, whereas flow-mediated dilation was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (P<0.0001), whereas mean arterial pressure was positively related (P<0.0001). Conclusions— Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.

Gout, Allopurinol Use, and Heart Failure Outcomes

BACKGROUND Hyperuricemia is associated with reduced survival among patients with heart failure (HF), but the effect of gout on HF outcomes is unknown. A recent randomized trial suggested that allopurinol may reduce adverse outcomes among patients with hyperuricemia and HF. Our objective was to determine whether gout and allopurinol use are associated with HF outcomes. METHODS Time-matched, nested case-control analysis of a retrospective cohort of patients with HF who were 66 years or older using health care databases in Quebec, Canada. The primary outcome measure was a composite measure of HF readmission and all-cause mortality. The secondary outcome measure was all-cause mortality. Rate ratios were calculated using conditional logistic regression and adjusted for known prognostic factors. RESULTS Of the 25,090 patients in this cohort, 14,327 experienced the primary outcome. Both a remote history of gout and an acute episode of gout (within 60 days of the event date) were associated with an increased risk of HF readmission or death (adjusted rate ratio, 1.63; 95% confidence interval, 1.48-1.80; P<.001 and 2.06; 1.39-3.06; P<.001, respectively). Continuous allopurinol use (>30 days of continuous use) was not associated with the primary outcome among the overall population with HF (adjusted rate ratio, 1.02; 95% confidence interval, 0.95-1.10; P=.55) but was associated with reduced HF readmissions or death (0.69; 0.60-0.79; P<.001) and all-cause mortality (0.74; 0.61-0.90; P<.001) among patients with a history of gout. CONCLUSIONS Patients with HF and a history of gout represent a high-risk population. Among such patients, the use of allopurinol is associated with improved outcomes.