DNA methylation biomarkers of myocardial infarction and cardiovascular disease

Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identifed biomarkers is still limited. We aimed to identify diferentially methylated loci associ‑ ated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infnium MethylationEPIC BeadChip. We performed a fxed efects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n~1800 and n~2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infnium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic infuence and therefore the results were not conclusive. Conclusions: We have identifed 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metab‑ olism, and infammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive informatio

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

Abstract 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 ban's 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 CH

Do individuals with autoimmune disease have increased risk of subclinical carotid atherosclerosis and stiffness?

To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 1:5) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. Mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval): 0.058 (0.009; 0.108); p-value=0.022] and the percentage having IMT ≥ percentile 75 [1.012 (0.145; 1.880); p-value=0.022]. Women without autoimmune disease were more likely to have IMT ≥ percentile 75 [-2.181 (-4.214; -0.149); p-value=0.035] but analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was higher in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases

Validation of the Regicor Short Physical Activity Questionnaire for the Adult Population

OBJECTIVE: To develop and validate a short questionnaire to estimate physical activity (PA) practice and sedentary behavior for the adult population. METHODS: The short questionnaire was developed using data from a cross-sectional population-based survey (n = 6352) that included the Minnesota leisure-time PA questionnaire. Activities that explained a significant proportion of the variability of population PA practice were identified. Validation of the short questionnaire included a cross-sectional component to assess validity with respect to the data collected by accelerometers and a longitudinal component to assess reliability and sensitivity to detect changes (n = 114, aged 35 to 74 years). RESULTS: Six types of activities that accounted for 87% of population variability in PA estimated with the Minnesota questionnaire were selected. The short questionnaire estimates energy expenditure in total PA and by intensity (light, moderate, vigorous), and includes 2 questions about sedentary behavior and a question about occupational PA. The short questionnaire showed high reliability, with intraclass correlation coefficients ranging between 0.79 to 0.95. The Spearman correlation coefficients between estimated energy expenditure obtained with the questionnaire and the number of steps detected by the accelerometer were as follows: 0.36 for total PA, 0.40 for moderate intensity, and 0.26 for vigorous intensity. The questionnaire was sensitive to detect changes in moderate and vigorous PA (correlation coefficients ranging from 0.26 to 0.34). CONCLUSION: The REGICOR short questionnaire is reliable, valid, and sensitive to detect changes in moderate and vigorous PA. This questionnaire could be used in daily clinical practice and epidemiological studies

Interaction between cardiovascular risk factors and body mass index and 10-year incidence of cardiovascular disease, cancer death, and overall mortality

The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI-associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54-20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations

Early mortality in bone marrow transplantation for acute lymphocytic leukaemia a multivariate analysis of risk factors

Objectives: bone marrow transplantation is still associated with a high case-fatality rate. This study was conducted to identify the risk factors for early mortality in acute lymphocytic leukaemia patients treated with bone marrow transplantation. Methods: prospectively collected data on 76 acute lymphocytic leukaemia patients, treated with 60 mg/kg cyclophosphamide for two consecutive days, before (32 patients) or after (44 patients) total body irradiation who received an allogeneic (56 patients) or autologous (20 patients) bone marrow transplantation were considered in the multivariate analysis including fifteen potentially prognostic variables for early mortality. Results: in the entire group, patients older than 20 years had a relative risk for early mortality of 3.96 (95% confidence interval (CI): 1.33-11.76) and those with a Karnofsky Index lower than 90% had a relative risk of 5.56 (95% CI: 1.29-25). In the subgroup of allogeneic patients, those over 20 years had a relative risk of 5.17 (95% CI: 1.30-20.6); the relative risk for patients with a Karnofsky index < 90% was 10.55 (95% CI: 1.55-71.43) and 8.04 (95% CI: 43-45.07) for acute severe graft-versus-host disease. Among radiation therapy variables only dose-rate showed a trend towards better prognosis in patients treated with less than 5 cGy/min. Conclusions: in our patients and within the range of treatment variables studied, age, Karnofsky index, and graft-versus-host disease are the most important factors related with early mortality

Early mortality in bone marrow transplantation for acute lymphocytic leukaemia a multivariate analysis of risk factors

Objectives: bone marrow transplantation is still associated with a high case-fatality rate. This study was conducted to identify the risk factors for early mortality in acute lymphocytic leukaemia patients treated with bone marrow transplantation. Methods: prospectively collected data on 76 acute lymphocytic leukaemia patients, treated with 60 mg/kg cyclophosphamide for two consecutive days, before (32 patients) or after (44 patients) total body irradiation who received an allogeneic (56 patients) or autologous (20 patients) bone marrow transplantation were considered in the multivariate analysis including fifteen potentially prognostic variables for early mortality. Results: in the entire group, patients older than 20 years had a relative risk for early mortality of 3.96 (95% confidence interval (CI): 1.33-11.76) and those with a Karnofsky Index lower than 90% had a relative risk of 5.56 (95% CI: 1.29-25). In the subgroup of allogeneic patients, those over 20 years had a relative risk of 5.17 (95% CI: 1.30-20.6); the relative risk for patients with a Karnofsky index < 90% was 10.55 (95% CI: 1.55-71.43) and 8.04 (95% CI: 43-45.07) for acute severe graft-versus-host disease. Among radiation therapy variables only dose-rate showed a trend towards better prognosis in patients treated with less than 5 cGy/min. Conclusions: in our patients and within the range of treatment variables studied, age, Karnofsky index, and graft-versus-host disease are the most important factors related with early mortality

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

Abstract 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 ban's 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 CH

Validation of the Regicor Short Physical Activity Questionnaire for the Adult Population

OBJECTIVE: To develop and validate a short questionnaire to estimate physical activity (PA) practice and sedentary behavior for the adult population. METHODS: The short questionnaire was developed using data from a cross-sectional population-based survey (n = 6352) that included the Minnesota leisure-time PA questionnaire. Activities that explained a significant proportion of the variability of population PA practice were identified. Validation of the short questionnaire included a cross-sectional component to assess validity with respect to the data collected by accelerometers and a longitudinal component to assess reliability and sensitivity to detect changes (n = 114, aged 35 to 74 years). RESULTS: Six types of activities that accounted for 87% of population variability in PA estimated with the Minnesota questionnaire were selected. The short questionnaire estimates energy expenditure in total PA and by intensity (light, moderate, vigorous), and includes 2 questions about sedentary behavior and a question about occupational PA. The short questionnaire showed high reliability, with intraclass correlation coefficients ranging between 0.79 to 0.95. The Spearman correlation coefficients between estimated energy expenditure obtained with the questionnaire and the number of steps detected by the accelerometer were as follows: 0.36 for total PA, 0.40 for moderate intensity, and 0.26 for vigorous intensity. The questionnaire was sensitive to detect changes in moderate and vigorous PA (correlation coefficients ranging from 0.26 to 0.34). CONCLUSION: The REGICOR short questionnaire is reliable, valid, and sensitive to detect changes in moderate and vigorous PA. This questionnaire could be used in daily clinical practice and epidemiological studies

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 Gironi del Cor (REGICOR) investigators in Spain.#N##N#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.#N##N#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&lt;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&lt;0.001).#N##N#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