Isaac Subirana

Validity of an adaptation of the Framingham cardiovascular risk function: the VERIFICA study

Background: To assess the reliability and accuracy of the Framingham coronary heart disease (CHD) risk function adapted by the Registre Gironí del Cor (REGICOR) investigators in Spain. Methods: A 5-year follow-up study was completed in 5732 participants aged 35–74 years. The adaptation consisted of using in the function the average population risk factor prevalence and the cumulative incidence observed in Spain instead of those from Framingham in a Cox proportional hazards model. Reliability and accuracy in estimating the observed cumulative incidence were tested with the area under the curve comparison and goodness-of-fit test, respectively. Results: The Kaplan–Meier CHD cumulative incidence during the follow-up was 4.0% in men and 1.7% in women. The original Framingham function and the REGICOR adapted estimates were 10.4% and 4.8%, and 3.6% and 2.0%, respectively. The REGICOR-adapted function’s estimate did not differ from the observed cumulated incidence (goodness of fit in men, p = 0.078, in women, p = 0.256), whereas all the original Framingham function estimates differed significantly (p<0.001). Reliabilities of the original Framingham function and of the best Cox model fit with the study data were similar in men (area under the receiver operator characteristic curve 0.68 and 0.69, respectively, p = 0.273), whereas the best Cox model fitted better in women (0.73 and 0.81, respectively, p<0.001). Conclusion: The Framingham function adapted to local population characteristics accurately and reliably predicted the 5-year CHD risk for patients aged 35–74 years, in contrast with the original function, which consistently overestimated the actual risk.

Trends in cardiovascular risk factor prevalence (1995-2000-2005) in northeastern Spain

Background High prevalence of cardiovascular risk factors has been observed in Spain along with low incidence of acute myocardial infarction. Our objective was to determine the trends of cardiovascular risk factor prevalence between 1995 and 2005 in the 35-74-year-old population of Gerona, Spain. Design Comparison of cross-sectional studies were conducted in random population samples in 1995, 2000, and 2005 at Gerona, Spain. Methods An electrocardiogram was obtained, along with standardized measurements of body mass index, lipid profile, systolic and diastolic blood pressure, glycaemia, energy expenditure in physical activity, smoking, use of lipid-lowering and antihypertensive medications, and cardiovascular risk. Prevalence of diabetes, hypertension, and obesity was calculated and standardized for age. Results A total of 7571 individuals (52.0% women) were included (response rate 72%). Low-density lipoprotein cholesterol > 3.4 mmol/l (130 mg/dl) (49.7%) and hypertension (39.1%) were the most prevalent cardiovascular risk factors. In 1995, 2000 and 2005, low-density lipoprotein cholesterol decreased in both men and women: 4.05-3.913.55 mmol/l (156-151-137 mg/dl) and 3.84-3.81-3.40 mmol/l (148-147-131 mg/dl), respectively. Increases were observed in lipid-lowering drug use (5.7-6.3-9.6% in men and 4.0-5.8-8.0% in women), controlled hypertension (14.8-35.4-37.7% in men and 21.3-36.9-45.0% in women); (all P-trends < 0.01), and obesity (greatest for men: 17.5-26.0-22.7%, P-trends = 0.020). Prevalence of myocardial infarction or possibly abnormal Q waves in electrocardiogram also increased significantly (3.9-4.7-6.4%, P-trends = 0.018). Conclusions The cardiovascular risk factor prevalence change in Gerona was marked in this decade by a shift of total cholesterol and low-density lipoprotein cholesterol distributions to the left, independent of the increase in lipid-lowering drug use, and better hypertension control with increased use of antihypertensive drugs. Eur J Cardiovasc Prev Rehabil 14:653-659

Polymorphisms in the NOS1AP Gene Modulate QT Interval Duration and Risk of Arrhythmias in the Long QT Syndrome

OBJECTIVES We investigated the role of nitric oxide 1 adaptor protein (NOS1AP) as a genetic modifier of long QT syndrome (LQTS). BACKGROUND LQTS risk stratification is complicated by the phenotype variability that limits prediction of life-threatening arrhythmic events based on available metrics. Thus, the identification of new markers is desirable. Recent studies have shown that NOS1AP variations in the gene modulate QT interval in healthy and 1 LQTS kindred, and occurrence of cardiac events in healthy subjects. METHODS The study included 901 patients enrolled in a prospective LQTS registry. Three NOS1AP marker SNPs (rs4657139, rs16847548, and rs10494366) were genotyped to assess the effect of variant alleles on QTc and on the incidence of cardiac events. We quantified the association between variant alleles, QTc, and outcomes to assess whether NOS1AP is a useful risk stratifier in LQTS. RESULTS Variant alleles tagged by SNPs rs4657139 and rs16847548 were associated with an average QTc prolongation of 7 and 8 ms, respectively (p < 0.05; p < 0.01); whereas rs4657139 and rs10494366 were associated with increased incidence of cardiac events (25.2% vs. 18.0%, p < 0.05 and 24.8% vs. 17.8% p < 0.05). Cox multivariate analysis identified rs10494366 minor allele as an independent prognostic marker among patients with QTc <500 ms (hazard ratio: 1.63; 95% confidence interval: 1.06 to 2.5; p < 0.05) but not in the entire cohort. CONCLUSIONS Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Prevalence of Symptomatic and Asymptomatic Peripheral Arterial Disease and the Value of the Ankle-brachial Index to Stratify Cardiovascular Risk

OBJECTIVES To determine the prevalence of ankle-brachial index (ABI)<0.9 and symptomatic peripheral arterial disease (PAD), association with cardiovascular risk factors (CVRF), and impact of adding ABI measurement to coronary heart disease (CHD) risk screening. DESIGN Population-based cross-sectional survey of 6262 participants aged 35-79 in Girona, Spain. METHODS Standardized measurements (CVRF, ABI, 10-year CHD risk) and history of intermittent claudication (IC), CHD, and stroke were recorded. ABI<0.9 was considered equivalent to moderate-to-high CHD risk (> or =10%). RESULTS ABI<0.9 prevalence was 4.5%. Only 0.62% presented low ABI and IC. Age, current smoker, cardiovascular disease, and uncontrolled hypertension independently associated with ABI<0.9 in both sexes; IC was also associated in men and diabetes in women. Among participants 35-74 free of cardiovascular disease, 6.1% showed moderate-to-high 10-year CHD risk; adding ABI measurement yielded 8.7%. Conversely, the risk function identified 16.8% of these participants as having 10-year CHD risk>10%. In participants 75-79 free of cardiovascular disease, the prevalence of ABI<0.9 (i.e., CHD risk> or =10%) was 11.9%. CONCLUSIONS ABI<0.9 is relatively frequent in those 35-79, particularly over 74. However, IC and CHD risk> or =10% indicators are often missing. Adding ABI measurement to CHD-risk screening better identifies moderate-to-high cardiovascular risk patients.

Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel

Aims To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies. Methods A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity. Results Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR =1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I2 =35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size <500 patients (HR =3.55; 95% CI 1.66 to 7.56) and lower among studies with a sample size ≥500 (HR =1.06; 95% CI 0.89 to 1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR =2.24; 95% CI 1.52 to 3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR =0.75; 95% CI 0.66 to 0.87) and a higher risk of major bleeding (HR =1.26; 95% CI 1.05 to 1.50). Conclusions Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding.

Validez relativa de la estimación del riesgo cardiovascular a 10 años en una cohorte poblacional del estudio REGICOR

INTRODUCTION AND OBJECTIVES Cardiovascular risk screening requires accurate risk functions. The relative validity of the Framingham-based REGICOR adapted function is analyzed and the population distribution of cardiovascular 10-year cardiovascular events is described by risk group. METHODS A population cohort of 3856 participants recruited between 1995 and 2000, aged 35 to 74 years from Girona without symptoms of cardiovascular diseases, was followed between 2006 and 2009. Standardized laboratory and blood pressure measurements, questionnaires, and case definitions were used. The follow-up combined cross-linkage of our databases with our regional mortality registry, reexamination, and telephone contact with participants. Coronary disease endpoints alone were considered. RESULTS A total of 27 487 person-years were obtained (mean follow-up 7.1 years), and the follow-up was achieved in 97% of participants (120 coronary disease events). Validity was good: the regression coefficients estimated with the cohort data did not differ from those obtained in the original Framingham function. Function calibration was good: the observed incidence of cardiovascular events in the decile groups of risk did not differ from the function prediction (P=.127 in women, and P=.054 in men). The C statistic (discrimination) was 0.82 (95% confidence interval, 0.76-0.88) in women, and 0.78 (95% confidence interval, 0.73-0.83) in men. More than 50% of cardiovascular events occurred in participants whose 10-year risk was 5% to 14.9%. CONCLUSIONS The studied function accurately predicts coronary disease events at 10 years. Risk stratification could be simplified in 4 groups: low (<5%), moderate (5%-9.9%), high (10%-14.9%) and very high (≥15%).

Impact of a partial smoke-free legislation on myocardial infarction incidence, mortality and case-fatality in a population-based registry: the REGICOR Study.

Background and Objective Coronary heart disease (CHD) is the leading cause of death, and smoking its strongest modifiable risk factor. Our aim was to determine the impact of the Spanish 2006 partial smoke-free legislation on acute myocardial infarction (AMI) incidence, hospitalization and mortality rates, and 28-day case-fatality in Girona, Spain. Methods Using a population-based registry (the REGICOR Study), we compared population incidence, hospitalization, and mortality rates, and 28-day case-fatality in the pre- and post-ban periods (2002–2005 and 2006–2008, respectively) by binomial regression analysis adjusted for confounding factors. We also analyzed the bans impact on the outcomes of interest using the AMI definitions of the American Heart Association (AHA)/European Society of Cardiology (ESC) and the World Health Organization (WHO)-Monitoring trends and determinants in cardiovascular diseases (MONICA). Results In the post-ban period, AMI incidence and mortality rates significantly decreased (relative risk [RR] = 0.89; 95% confidence interval [CI] = 0.81–0.97 and RR = 0.82; 95% CI = 0.71–0.94, respectively). Incidence and mortality rates decreased in both sexes, especially in women, and in people aged 65–74 years. Former and non-smokers (passive smokers) showed diminished incidence rates. Implementation of the ban was not associated with AMI case-fatality. Models tended to be more significant with the WHO-MONICA than with the AHA/ESC definition. Conclusions The 2006 Spanish partial smoke-free legislation was associated with a decrease in population AMI incidence and mortality, particularly in women, in people aged 65–74 years, and in passive smokers. These results clarify the association between AMI mortality and the enactment of a partial smoke-free legislation and reinforce the effectiveness of smoking regulations in preventing CHD.

Olive oil polyphenols enhance the expression of cholesterol efflux related genes in vivo in humans. A randomized controlled trial

Both oleic acid and polyphenols have been shown to increase high-density lipoprotein (HDL) cholesterol and to protect HDL from oxidation, a phenomenon associated with a low cholesterol efflux from cells. Our goal was to determine whether polyphenols from olive oil could exert an in vivo nutrigenomic effect on genes related to cholesterol efflux in humans. In a randomized, controlled, cross-over trial, 13 pre/hypertensive patients were assigned 30 ml of two similar olive oils with high (961 mg/kg) and moderate (289 mg/kg) polyphenol content. We found an increase in ATP binding cassette transporter-A1, scavenger receptor class B type 1, peroxisome proliferator-activated receptor (PPAR)BP, PPARα, PPARγ, PPARδ and CD36 gene expression in white blood cells at postprandial after high polyphenol olive oil when compared with moderate polyphenol olive oil intervention (P<.017), with COX-1 reaching borderline significance (P=.024). Linear regression analyses showed that changes in gene expression were related to a decrease in oxidized low-density lipoproteins and with an increase in oxygen radical absorbance capacity and olive oil polyphenols (P<.05). Our results indicate a significant role of olive oil polyphenols in the up-regulation of genes involved in the cholesterol efflux from cells to HDL in vivo in humans. These results are in agreement with previous ones concerning the fact that benefits associated with polyphenol-rich olive oil consumption on cardiovascular risk could be mediated through an in vivo nutrigenomic effect in humans.

Assessment of the value of a genetic risk score in improving the estimation of coronary risk

BACKGROUND The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.

Relation Between Renal Function and Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Real-World Data From the European Public Health Outcome Research and Indicators Collection Project

BACKGROUND Clinical trials provide limited information about the outcome of patients with acute coronary syndromes (ACSs) and kidney disease (KD) owing to underrepresentation of this population in most studies. METHODS To evaluate the outcome of patients with non-ST-segment elevation ACS (NSTE-ACS) and KD in a real-world setting, we compared the risk of in-hospital and 30-day mortality by the presence of KD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2)) in 13 141 patients with NSTE-ACS enrolled in 3 multinational ACS registries between 2000 and 2006 as part of the European Public Health Outcome Research and Indicators Collection Project. RESULTS Patients with KD (n = 4181) composed 31.8% of the study population and had significantly higher rates of in-hospital (5.4%) and 30-day (7.2%) case fatality compared with patients without KD (1.1% and 1.7%, respectively; P < .001 for both). In multivariate analysis, the presence of KD was independently associated with a significantly higher mortality risk (in-hospital: odds ratio [OR], 2.11; 95% confidence interval [CI], 1.48-3.00; 30-day: OR, 1.95; 95% CI, 1.46-2.61). Patients with KD who underwent coronary angiography experienced a 36% (P = .05) and 40% (P < .001) lower risk of in-hospital and 30-day mortality, respectively, but this high-risk population still exhibited significantly higher case-fatality rates during hospitalization (3.3%) and at 30 days (4.6%) compared with patients without KD who underwent coronary angiography (0.7% and 1.3%, respectively; P < .001 for all). CONCLUSIONS In a real-world setting, KD was present in approximately one-third of patients with NSTE-ACS and is a powerful independent predictor of subsequent mortality. Patients with NSTE-ACS and KD referred for coronary angiography have a significantly lower risk of death, but this high-risk population continues to exhibit increased mortality rates despite intervention procedures.