Ideal Cardiovascular Health and Incident Cardiovascular Disease: Heterogeneity Across Event Subtypes and Mediating Effect of Blood Biomarkers: The PRIME Study.

BACKGROUND: The aim of this study was to investigate whether the association between baseline cardiovascular health (CVH) and incident cardiovascular disease differs according to coronary heart disease (CHD) and stroke subtypes, and to assess the mediating effect of inflammatory and hemostatic blood biomarkers. METHODS AND RESULTS: The association of ideal CVH with outcomes was derived in 9312 middle-aged men from Northern Ireland and France (whole cohort) in multivariable Cox proportional hazards regression analysis. The mediating effect of baseline inflammatory and hemostatic blood biomarkers was evaluated in a case-control study nested within the cohort after 10 years of follow-up. After a median follow-up of 10 years, 614 first CHD events and 117 first stroke events were adjudicated. Compared with those with poor CVH, those with an ideal CVH profile at baseline had a 72% lower risk of CHD (hazard ratio=0.28; 95% confidence interval, 0.17; 0.46) and a 76% lower risk of stroke (hazard ratio =0.24; 95% confidence interval, 0.06; 0.98). The magnitude of the risk reductions was similar for incident angina and myocardial infarction, but was lower for ischemic stroke. In the controls, the mean concentrations of high-sensitivity C-reactive protein, IL-6, and fibrinogen decreased with higher CVH status. Furthermore, the association of behavioral CVH with incident CHD was partly mediated by high-sensitivity C-reactive protein (16.69%), IL-6 (8.52%), and fibrinogen (7.30%) CONCLUSIONS: Our study shows no clear heterogeneity in the association of baseline CVH with the main subtypes of cardiovascular disease. This supports a universal promotion of ideal CVH for all cardiovascular disease subtypes. Furthermore, our mediation analysis suggests that the lower risk of CHD associated with ideal CVH is partly mediated by lower inflammatory and hemostatic blood biomarkers.

Changes over time in the prevalence and treatment of cardiovascular risk factors, and contributions to time trends in coronary mortality over 25 years in the Lille urban area (northern France).

BACKGROUND: The long-term collection of population-based data should improve our knowledge of the contribution of trend in cardiovascular risk factors to the steady fall in mortality associated with coronary heart disease in high-income countries. AIMS: To assess long-term time trends in the prevalence of cardiovascular risk factors, estimated coronary heart disease risk and mortality between 1986 and 2013 in the Lille urban area (northern France). METHODS: We studied representative samples of inhabitants of the Lille urban area (aged 40-64 years) in 1986-1988 (n=860), 1995-1996 (n=1021), 2005-2007 (n=1021) and 2011-2013 (n=1636), together with data from the Lille MONICA registry. RESULTS: In men, the age-standardized prevalence fell between 1986 and 2013 from 70.5% to 42.5% for hypertension, from 71.1% to 58.3% for dyslipidaemia and from 44.1% to 24.7% for smoking (all P<0.001). The prevalence of being overweight increased from 59.6% to 65.1% (P<0.05). In women, the prevalences decreased from 56.6% to 34.3% for hypertension and from 60.9% to 42.2% for dyslipidaemia (both P<0.001). The prevalences of smoking (17%) and being overweight (50%) were stable. The mean 10-year (95% confidence interval) predicted risk of fatal coronary heart disease (estimated with the Systematic Coronary Risk Evaluation equation) decreased by 2.02% (1.78-2.25%) per year for men and by 1.55% (1.32-1.78%) for women. The observed coronary mortality rate fell by 2.6% (2.2-3.0%) in men and 2.8% (1.9-3.6%) in women. CONCLUSIONS: Prevalences of main risk factors and estimated coronary mortality risk decreased concomitantly with the observed coronary mortality - indicating that primary prevention made a major contribution to the decrease in mortality.

Lipoprotein(a) plasma levels and the risk of cancer: the PRIME study.

Although experimental studies have shown lipoprotein(a) antiangiogenic and antitumoral effects, the association of lipoprotein(a) levels with cancer in population studies remains elusive and poorly documented. The aim of this study was to analyse the relationship between lipoprotein(a) plasma levels and the incidence of cancer over 10 years of follow-up. Data from two French centres of the PRIME cohort were used, representing 5237 men aged 50-59 years and free from a history of cancer at baseline. Data on medical history, socioeconomic and lifestyle factors were obtained by questionnaire. Lipoprotein(a) plasma levels were analysed from fasting blood samples collected at baseline. The relationship between lipoprotein(a) levels and first incident cancer was studied using the multivariate Cox proportional hazards models for all-site and the main-site-specific cancers, adjusted for various potential confounders including age, centre, smoking status and alcohol consumption. During follow-up, 456 new cancers were identified. No significant association was found between lipoprotein(a) and the all-site or main-site-specific cancers (hazard ratios for quartiles 2-4 vs. 1, respectively: 1.24, 1.11, 1.29, P=0.23). However, a higher risk seemed to be observed for highest lipoprotein(a) levels in all sites, lung, colorectal or tobacco/alcohol-related cancers. For prostate cancer, the lowest risk was observed for the highest levels of lipoprotein(a) (P=0.12). In conclusion, no evident association was found between the lipoprotein(a) levels and the incidence of cancer. Nevertheless, a higher cancer risk seemed to be observed for the highest lipoprotein(a) levels. Further research focusing on the lipoprotein(a) qualitative structure, that is, apolipoprotein(a) polymorphism could help clarify this highly complex relation.

Measures of abdominal adiposity and the risk of stroke: the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study.

BACKGROUND AND PURPOSE: Excess fat accumulates in the subcutaneous and visceral adipose tissue compartments. We tested the hypothesis that indicators of visceral adiposity, namely, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), are better predictors of stroke risk than body mass index (BMI). METHODS: The association of BMI, WC, WHR, and WHtR with stroke was assessed in 31,201 men and 23,516 women, free of vascular disease at baseline, from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. During a mean follow-up of 11 years, 1130 strokes were recorded. Relative risks (95% CI) were calculated by Cox regression after stratification for center and adjustment for age, smoking, educational level, alcohol consumption, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, and BMI and model fit was assessed using log-likelihoods. RESULTS: BMI, WC, WHR, and WHtR were associated with the risk of stroke in men. After full adjustment including BMI, the relative risks for stroke remained significant for WC (1.19 [1.02 to 1.34] per 1 SD increase in WC), WHR (1.14 [1.03 to 1.26]), and WHtR (1.50 [1.28 to 1.77]). Among women, the extent of the associations with stroke risk was similar for WHtR (1.31 [1.04 to 1.65]), WC (1.19 [0.96 to 1.47]), and WHR (1.08 [0.97 to 1.22]). Further analyses by World Health Organization obesity categories showed that WC, WHR, and WHtR were associated with the risk of stroke also in lean men and women (BMI<25 kg/m2), independently of confounders, cardiovascular risk factors, and BMI. CONCLUSIONS: Indicators of abdominal adiposity, especially WHtR, are more strongly associated with stroke risk than BMI. These results emphasize the importance of measuring abdominal adiposity, especially in lean subjects.

Association between a thyroid hormone receptor-α gene polymorphism and blood pressure but not with coronary heart disease risk.

BACKGROUND: Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-ß whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk. METHODS: We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls). RESULTS: Individuals carrying the rs939348 T allele had higher systolic BP (~+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected. CONCLUSIONS: For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings.

Gender differences in the implementation of cardiovascular prevention measures after an acute coronary event.

OBJECTIVE: To compare gender-related lifestyle changes and risk factor management after hospitalisation for a coronary event or revascularisation intervention in Europe. METHOD: The EUROASPIRE III survey was carried out in 22 European countries in 2006-2007. Consecutive patients having had a coronary event or revascularisation before the age of 80 were identified. A total of 8966 patients (25.3% women) were interviewed and underwent clinical and biochemical tests at least 6 months after hospital admission. Trends in cardiovascular risk management were assessed on the basis of the 1994-1995, 1999-2000 and 2006-2007 EUROASPIRE surveys. RESULTS: Female survey participants were generally older and had a lower educational level than male participants (p<0.0001). The prevalences of obesity (p<0.0001), high blood pressure (BP) (p=0.001), elevated low-density lipoprotein (LDL)-cholesterol (p<0.0001) and diabetes (p<0.0001) were significantly higher in women than in men, whereas current smoking (p<0.0001) was significantly more common in men. The use of antihypertensive and antidiabetic drugs (but not that of other drugs) was more common in women than in men. However, BP (p<0.0001), LDL-cholesterol (p<0.0001) and HbA1c (p<0.0001) targets were less often achieved in women than in men. Between 1994 and 2007, cholesterol control improved less in women than in men (interaction: p=0.009), whereas trends in BP control (p=0.32) and glycaemia (p=0.36) were similar for both genders. CONCLUSION: The EUROASPIRE III results show that despite similarities in medication exposure, women are less likely than men to achieve BP, LDL-cholesterol and HbA1c targets after a coronary event. This gap did not appear to narrow between 1994 and 2007.

C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the PRIME study.

OBJECTIVE: To examine prospectively the association of high-sensitivity C-reactive protein, interleukin 6, and fibrinogen with sudden death in asymptomatic European men. METHODS AND RESULTS: Among the 9771 men from the Etude PRospective de l'Infarctus du Myocarde (PRIME) Study, 664 had a first coronary heart disease over 10 years, including 50 sudden deaths, 34 nonsudden coronary deaths, and 580 nonfatal coronary heart disease events. For each outcome, 2 matched controls, who were free of coronary heart disease at the index date, were randomly selected from the initial cohort (nested case control study design). There was a 3-fold increased risk (95% CI, 1.20 to 7.81) of sudden death between the upper and the lower third of interleukin 6 after adjustment for baseline confounders in conditional logistic regression analysis. Neither high-sensitivity C-reactive protein (hazard ratio(third versus first tertile)=1.27; 95% CI, 0.51 to 3.17) nor fibrinogen (hazard ratio(third versus first tertile)=1.90; 95% CI, 0.76 to 4.75) was associated with sudden death. For comparison, there was a 6-fold increased risk of nonsudden coronary death from the highest compared with the lowest tertile of fibrinogen and a trend toward an association with higher C-reactive protein and higher interleukin 6. All 3 inflammatory biomarkers were moderately, but significantly, associated with nonfatal coronary heart disease. CONCLUSIONS: Interleukin 6, but not high-sensitivity C-reactive protein or fibrinogen, is an independent predictor of sudden death in asymptomatic European men.

Respective contribution of conventional risk factors and antihypertensive treatment to stable angina pectoris and acute coronary syndrome as the first presentation of coronary heart disease: the PRIME Study.

OBJECTIVE: To test whether conventional risk factors and antihypertensive treatment were more predictive of stable angina (SA) than acute coronary syndrome (ACS) as the first presentation of coronary heart disease (CHD). DESIGN: We used data from the PRIME Study (Prospective Epidemiological Study of Myocardial Infarction), a prospective cohort of 9758 asymptomatic middle-aged men recruited from WHO MONICA centers in Northern Ireland and France between 1991 and 1993. SA and ACS events were registered during 5 years of follow-up. METHODS: Hazard ratios (HRs) of each risk factor measured at baseline for SA and ACS events were assessed using separate Cox proportional hazard models. Difference between HRs was estimated by the bootstrap method. RESULTS: After 5 years of follow-up, there were 114 SA and 178 ACS as the first presentation of CHD. Diastolic blood pressure [adjusted HRs for 1 standard deviation increase = 1.34; 95% confidence interval (CI): 1.17-1.54 vs. 1.04; 95% CI: 0.87-1.25; P for comparison between HRs = 0.012], and possibly cigarette smoking over or equal to 20 pack-years (adjusted HR = 2.07; 95% CI: 1.43-2.99 vs. 1.29; 95% CI: 0.83-2.01; P for comparison between HRs = 0.062) were more predictive of ACS than SA, whereas this was the opposite for antihypertensive treatment (adjusted HR = 2.18; 95% CI: 1.39-3.41 for SA vs. 1.28; 95% CI: 0.85-1.93 for ACS, P for comparison between HRs = 0.049). CONCLUSION: The present data support that SA and ACS, as the first presentation of CHD, may not share exactly the same determinants.

Contribution of cardiovascular risk factors to coronary risk in patients with intermittent claudication in the PRIME Cohort Study of European men.

BACKGROUND: Intermittent claudication (IC) is associated with an increased cardiovascular morbidity. The goal of the present study was to assess the contribution of conventional cardiovascular risk factors (CVRFs) to this increased risk. METHOD: The PRIME Study is a multicenter Prospective Cohort Study of 10 602 men recruited in 1991-1993, aged 50-59 at baseline and followed over 10 years. At baseline, a questionnaire on socio demographic data was self-administered and CVRFs were measured. Composite outcome consisted of incident MI, effort angina, unstable angina and coronary death. The standardized questionnaire of the London School of hygiene was used to identify claudicants. Data were analyzed using multivariate Cox models. RESULTS: Probable and possible cases of IC were reported by 1.4% (135) and 4.6% (442) of subjects, respectively. Compared to subjects with no claudication, the probable cases demonstrated higher rates of CVRFs. The incidence of CAD events was 7.23/1000 person-year. Compared to non claudicants, probable claudicants had an increased age and country adjusted risk of coronary events (HR (95% CI), 2.4 (1.5-3.7), p<0.0001). After further adjustments for school duration, family history of early myocardial infarction, tobacco consumption, alcohol consumption, BMI, systolic blood pressure, antihypertensive treatment, diabetes, total cholesterol, HDL-cholesterol, triglycerides and lipid-lowering treatment, participants with probable claudication had an increased risk of coronary events but this was no longer significant (HR (95% CI), 1.3 (0.8-2.1), p=0.23). CONCLUSION: IC is associated with an increased risk of developing coronary events. This association is largely explained by the coexistence of CVRFs.

Lack of association between serological evidence of past Coxiella burnetii infection and incident ischaemic heart disease: nested case-control study.

BACKGROUND: Coxiella burnetii causes the common worldwide zoonotic infection, Q fever. It has been previously suggested that patients who had recovered from acute Q fever (whether symptomatic or otherwise) may be at increased risk of ischaemic heart disease. We undertook this study to determine if past infection with Coxiella burnetii, the aetiological agent of Q fever, is a risk factor for the subsequent development of ischaemic heart disease. METHODS: A nested case-control study within the Prospective Epidemiological Study of Myocardial Infarction (PRIME). The PRIME study is a cohort study of 10,593 middle-aged men undertaken in France and Northern Ireland in the 1990s. A total of 335 incident cases of ischaemic heart disease (IHD) were identified and each case was matched to 2 IHD free controls. Q fever seropositivity was determined using a commercial IgG ELISA method. RESULTS: Seroprevalence of Q fever in the controls from Northern Ireland and France were 7.8% and 9.0% respectively. No association was seen between seropositivity and age, smoking, lipid levels, or inflammatory markers. The unadjusted odds ratio (95% CI) for Q fever seropositivity in cases compared to controls was 0.95 (0.59, 1.57). The relationship was substantially unaltered following adjustment for cardiovascular risk factors and potential confounders. CONCLUSION: Serological evidence of past infection with C. burnetii was not found to be associated with an increased risk of IHD.

Residual coronary risk in men aged 50-59 years treated for hypertension and hyperlipidaemia in the population: the PRIME study.

OBJECTIVE: Since the proportion of subjects taking antihypertensive and lipid-lowering drugs is currently increasing in industrialized countries, it is important to evaluate, at the population level, coronary risk of treated individuals, while taking into account the achieved level of their risk factors (i.e. their 'residual coronary risk'). DESIGN AND METHODS: We used the data from the Prospective Study of Myocardial Infarction (PRIME), which involved populations from France (three centres) and Northern Ireland (one centre) (in each centre, 2500 men, aged 50-59 years, free of coronary heart disease, with a 5-year follow-up), to analyse the relationships between cardiovascular drug use and subsequent coronary risk. RESULTS: Antihypertensive drug use was significantly positively associated (relative risk = 1.60; 95% confidence interval, 1.18-2.16) with total coronary risk, but not lipid-lowering drug use (relative risk = 1.15; 95% confidence interval, 0.77-1.73), while adjusting on classical risk factor levels (age, smoking, total cholesterol, high-density lipoprotein-cholesterol and systolic blood pressure). Subgroup analysis showed that these results applied to beta-blockers and calcium channel antagonists, but not to diuretics and angiotensin-converting enzyme inhibitors, to both angina pectoris and hard coronary event risk, but in the French population only and not in Belfast. Although the PRIME study was not designed to test the ability of different drugs to prevent coronary heart disease, this analysis raises the hypothesis that antihypertensive drugs could be associated with a sizeable residual coronary risk in middle-aged men. CONCLUSION: Treatment with antihypertensive agents, beta-blockers and calcium channel antagonists in particular, was associated with a sizeable residual coronary risk. It seems, therefore, important to consider antihypertensive treatment in the cardiovascular risk assessment of individuals.

Fish consumption is associated with lower heart rates.

BACKGROUND: Fish consumption decreases risk of sudden death. The goal of the present study was to assess the relationship between fish consumption and heart rate. METHODS AND RESULTS: A cross-sectional analysis was conducted of 9758 men, age 50 to 59 years, without coronary heart disease (CHD) who were recruited in France and Belfast, Ireland, from 1991 to 1993. Heart rate and CHD risk factors were compared among 4 categories of fish consumption, as follows: (1) less than once per week (n=2662), (2) once per week (n=4576), (3) twice per week (n=1964), and (4) more than twice per week (n=556). Fatty acid profiles of erythrocyte phospholipids were determined in a random subsample of 407 subjects. In erythrocyte phospholipids, eicosapentaenoic acid (P<0.0005), docosahexaenoic acid (P<0.0001), and total n-3 fatty acid (P<0.0008) increased across the categories of fish intake. Triglycerides (P<0.0001), systolic blood pressure (P<0.006), and diastolic blood pressure (P<0.0001) were lower and HDL cholesterol levels (P<0.004) were higher in fish consumers than in nonconsumers. Similarly, heart rate decreased across the categories of fish intake (P<0.0001). After adjustment for age, center, education level, physical activity, smoking habit, alcohol consumption, body mass index, and antiarrhythmic medications, heart rate remained statistically lower among fish consumers than among nonconsumers (P for trend <0.0001). Docosahexaenoic acid content of erythrocyte phospholipids was inversely correlated with heart rate (P<0.03). CONCLUSIONS: Fish consumption is associated with decreased heart rate in men. Because heart rate is positively associated with risk of sudden death, this association may explain, at least in part, the lower risk of sudden death among fish consumers.