Association of atherosclerosis with expression of the LILRB1 receptor by human NK and T-cells supports the infectious burden hypothesis.

OBJECTIVE: The contribution of human cytomegalovirus (HCMV) to vascular disease may depend on features of the immune response not reflected by the detection of specific antibodies. Persistent HCMV infection in healthy blood donors has been associated with changes in the distribution of NK cell receptors (NKR). The putative relationship among HCMV infection, NKR distribution, subclinical atherosclerosis, and coronary heart disease was assessed. METHODS AND RESULTS: NKR expression was compared in acute myocardial infarction (AMI) patients (n=70) and a population-based control sample (n=209). The relationship between NKR expression and carotid intima-media thickness (CIMT) in controls (n=149) was also studied. HCMV infection was associated with higher proportions of NKG2C+ and LILRB1+ NK and T-cells. In contrast, only LILRB1+ NK and CD56+ T-cells were found to be increased in AMI patients, independent of age, sex, conventional vascular risk factors, and HCMV seropositivity. Remarkably, LILRB1 expression in NK and T-cells significantly correlated with CIMT in controls. CONCLUSIONS: The association of overt and subclinical atherosclerotic disease with LILRB1+ NK and T-cells likely reflects a relationship between the immune challenge by infections and cardiovascular disease risk, without attributing a dominant role for HCMV. Our findings may lead to the identification of novel biomarkers of vascular disease.

Trends in Q-wave acute myocardial infarction case fatality from 1978 to 2007 and analysis of the effectiveness of different treatments.

BACKGROUND: We sought to analyze the trends in first Q-wave acute myocardial infarction (AMI) case fatality from 1978 to 2007 in a population-based hospital register, to determine the variables related to these changes, and to assess the effectiveness of current AMI management. METHODS: Population-based hospital registry included patients with first Q-wave AMI aged 25 to 74 years admitted between 1978 and 2007. Sociodemographic and clinical characteristics, treatments, and procedures used during hospital stay, and 28-day case fatality were recorded. Logistic regression was used for multivariate analysis of six 5-year periods. RESULTS: The 30-year study included 3,982 patients. Mean 28-day case fatality was 8.96%, with a decreasing trend from 16.6% in the first 5-year period to 4.7% in the sixth (P for trend < .001). Study period was independently associated with case fatality. Case-fatality reduction attributable to pharmacologic treatments was 51% overall; in 24-hour survivors, pharmacologic treatments and broad use of invasive procedures explained 39% and 38%, respectively, of the difference between the observed case fatality in 2003-2007 and 1978-1982. CONCLUSION: A dramatic decrease in 28-day case fatality occurred during this 30-year period and was mainly related to the use of antiplatelet drugs, ß-blockers, thrombolysis, and invasive procedures. These data support the current guidelines for the management of acute coronary syndrome.

Partial ventricular septal defect (Pacman Heart).

Complete ventricular septal defects (VSD) can be congenital (estimated prevalence 0.5% in live births) (Roguin N, et al. High prevalence of muscular ventricular septal defect in neonates. J Am Coll Cardiol 1995;26:1545-1548) or may be a complication of acute myocardial infarction (estimated incidence in the era of thrombolysis 0.2%) [Crenshaw BS, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) Trial Investigators. Circulation 2000;101:27-32]. In this paper, we report two unique cases of partial VSD.

Antioxidant paraoxonase 1 activity in the metabolic syndrome.

Paraoxonase (PON1) is an antioxidant enzyme closely associated with high-density lipoproteins. Low PON1 has been shown in oxidative stress-associated processes such as dyslipidemia, diabetes mellitus, advancing age, and smoking. Indeed, oxidative stress is related to the degree of insulin resistance, a key component of the metabolic syndrome. Therefore, the possible relationship between PON1 activity and the metabolic syndrome was investigated. From 1364 randomly recruited subjects, 285 were found to have the metabolic syndrome, according to the guidelines published by the National Cholesterol Education Program, Adult Treatment Panel III. PON1 activity, lipid peroxides, and PON1 codon 192 genotypes, which strongly modulate PON1 activity, were determined. Serum PON1 activity levels were found to be significantly lower, and lipid peroxide concentrations significantly higher, in subjects with the metabolic syndrome compared with unaffected subjects (P = 0.033 and < 0.001, respectively). Study subjects showed a significant decreasing trend in PON1 activity levels and a significant increasing trend in lipid peroxide concentrations, with the increase in the number of metabolic disturbances. No differences in the prevalence of PON1 codon 192 genotypes were found among the categories of metabolic abnormalities. In conclusion, a greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity.

Oxidized low-density lipoprotein antibodies in myocardial infarction patients without classical risk factors.

AIM: To determine whether circulating antibodies against oxidized low-density lipoprotein (LDL; OLAB) levels are associated with acute myocardial infarction (AMI) in individuals without classical cardiovascular risk factors. METHODS: A case-control study including 34 first AMI patients without classical risk factors (smoking, dyslipidemia, hypertension or diabetes) and 45 population-based healthy controls. RESULTS: There were no differences in anthropometric variables between cases and controls. Oxidized LDL levels were similar in both groups. Total cholesterol, LDL cholesterol, apolipoprotein B and physical activity were lower in cases than in controls. OLAB levels were also lower in cases than controls (128 versus 447 U/l, P < 0.001). After adjusting for age, oxidized LDL and physical activity, participants with OLAB levels of 165 U/l or less had a higher risk of AMI (odds ratio, OR = 7.48, 95% confidence interval: 1.57-35.66). When the model was fitted with OLAB as a continuous variable, the natural logarithm (LnOLAB) levels were independently associated with AMI with an OR of 0.40 (95% confidence interval: 0.19-0.86). After adjusting the model by Framingham-risk-adapted score and oxidized LDL, the LnOLAB levels maintained their independent association (OR of 0.43, 95% confidence interval: 0.23-0.79). CONCLUSION: First AMI patients without classical risk factors had lower levels of OLAB compared with healthy controls. It is likely that the immunological reaction due to oxidized LDL participates as a preventive factor in the physiopathology of atherosclerosis.

Relationship of lipid oxidation with subclinical atherosclerosis and 10-year coronary events in general population.

OBJECTIVES: To assess 1) the association of lipid oxidation biomarkers with 10-year coronary artery disease (CAD) events and subclinical atherosclerosis, and 2) the reclassification capacity of these biomarkers over Framingham-derived CAD risk functions, in a general population. METHODS: Within the framework of the REGICOR study, 4782 individuals aged between 25 and 74 years were recruited in a population-based cohort study. Follow-up of the 4042 who met the eligibility criteria was carried out. Plasma, circulating oxidized low-density lipoprotein (oxLDL) and oxLDL antibodies (OLAB) were measured in a random sample of 2793 participants. End-points included fatal and non-fatal acute myocardial infarction (AMI) and angina. Carotid intima-media thickness (IMT) in the highest quintile and ankle-brachial index <0.9 were considered indicators of subclinical atherosclerosis. RESULTS: Mean age was 50.0 (13.4) years, and 52.4% were women. There were 103 CAD events (34 myocardial infarction, 43 angina, 26 coronary deaths), and 306 subclinical atherosclerosis cases. Oxidized LDL was independently associated with higher incidence of CAD events (HR = 1.70; 95% Confidence Interval: 1.02-2.84), but not with subclinical atherosclerosis. The net classification index of the Framingham-derived CAD risk function was significantly improved when ox-LDL was included (NRI = 14.67% [4.90; 24.45], P = 0.003). No associations were found between OLAB and clinical or subclinical events. The reference values for oxLDL and OLAB are also provided (percentiles). CONCLUSIONS: OxLDL was independently associated with 10-year CAD events but not subclinical atherosclerosis in a general population, and improved the reclassification capacity of Framingham-derived CAD risk functions.

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 (I(2) =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.

Effect of opening a new catheterization laboratory on 30-day and 2-year survival rates in myocardial infarction patients.

INTRODUCTION AND OBJECTIVES: To determine the effect of opening an on-site diagnostic catheterization facility on 30-day and 2-year mortality rates in patients with myocardial infarction (MI). METHODS: The study included 1539 consecutive MI patients aged 25-74 years who were recruited before and after the catheterization laboratory opened in 1998: during 1995-1997 and 1999-2003, respectively. RESULTS: The 641 consecutive MI patients recruited in 1995-1997 had worse 30-day mortality than the 898 recruited between 1999-2003 (11.2% versus 6.35%, respectively; P=.001). The number of coronary angiographies and percutaneous coronary interventions carried out was greater in the second period (19.4% versus 3.3%, and 54.8% versus 23.0%, respectively; P<.001). Two-year survival curves were significantly better in the second period for all-cause and cardiovascular death. The adjusted odds ratio for death at 30 days was 0.58 (95% confidence interval [CI] 0.36-0.95) for the second period compared with the first and the adjusted hazard ratio for cardiovascular death at 2 years for patients still alive at 30 days was 0.62 (95%CI 0.39-0.99). After adjustment for the prescription of statins, angiotensin-converting enzyme inhibitors, beta-blockers and antiplatelet drugs at discharge, the effect observed at 2 years was no longer significant. CONCLUSIONS: Opening a new on-site diagnostic catheterization unit significantly increased the 30-day survival of MI patients. However, the increase in 2-year survival of 30-day survivors observed was largely explained by the implementation of better secondary prevention.

Trends in the prevalence, awareness, treatment, and control of cardiovascular risk factors across educational level in the 1995-2005 period.

PURPOSE: To determine the differences and trends in the prevalence, awareness, treatment and control of cardiovascular risk factors and lifestyle variables across educational level in the 1995-2005 period in a country with a universal free health care system. METHODS: Data from three consecutive independent population-based surveys were used. Cardiovascular risk factors, lifestyle variables, and self-reported educational level were collected in 9646 individuals ages 35-74 years throughout the decade. RESULTS: The prevalence of hypertension and diabetes was inversely associated with education. An increase in the proportion of hypertension and dyslipidemia awareness, treatment, and control in all educational level groups was observed. This increase was greater among the lowest education group, reducing the disparities between groups. The prevalence of lifestyle-related risk factors decreased in the greatest but increased in the lowest education group, widening the disparities between groups. CONCLUSIONS: A universal free health care system is effective in avoiding inequalities in the diagnosis, treatment, and control of cardiovascular risk factors. However, other social determinants seem to explain the social inequalities in the prevalence of these risk factors and in the adoption of healthy lifestyles.

Derivation and validation of REASON: a risk score identifying candidates to screen for peripheral arterial disease using ankle brachial index.

BACKGROUND: The recommendation of screening with ankle brachial index (ABI) in asymptomatic individuals is controversial. The aims of the present study were to develop and validate a pre-screening test to select candidates for ABI measurement in the Spanish population 50-79 years old, and to compare its predictive capacity to current Inter-Society Consensus (ISC) screening criteria. METHODS AND RESULTS: Two population-based cross-sectional studies were used to develop (n = 4046) and validate (n = 3285) a regression model to predict ABI < 0.9. The validation dataset was also used to compare the model's predictive capacity to that of ISC screening criteria. The best model to predict ABI < 0.9 included age, sex, smoking, pulse pressure and diabetes. Assessment of discrimination and calibration in the validation dataset demonstrated a good fit (AUC: 0.76 [95% CI 0.73-0.79] and Hosmer-Lemeshow test: χ(2): 10.73 (df = 6), p-value = 0.097). Predictions (probability cut-off value of 4.1) presented better specificity and positive likelihood ratio than the ABI screening criteria of the ISC guidelines, and similar sensitivity. This resulted in fewer patients screened per diagnosis of ABI < 0.9 (10.6 vs. 8.75) and a lower proportion of the population aged 50-79 years candidate to ABI screening (63.3% vs. 55.0%). CONCLUSION: This model provides accurate ABI < 0.9 risk estimates for ages 50-79, with a better predictive capacity than that of ISC criteria. Its use could reduce possible harms and unnecessary work-ups of ABI screening as a risk stratification strategy in primary prevention of peripheral vascular disease.

Trends in in-hospital mortality and six-month outcomes in patients with a first acute myocardial infarction. Change over the last decade.

INTRODUCTION AND OBJECTIVES: Treatment of acute myocardial infarction (AMI) has changed considerably in recent years. The objective of this study was to investigate differences in in-hospital mortality and 6-month outcomes after a first AMI between patients who participated in two trials, in 1992-1994 and 2001-2003, respectively. METHODS: The study involved 1440 consecutive patients with a first AMI who were admitted to four university hospitals during 1992-1994 (the RESCATE-I trial) and 1288 with a first AMI who met the same diagnostic criteria and who were admitted to the same hospitals during 2001-2003 (the RESCATE-II trial). Patient management, in-hospital mortality and 6-month prognosis and outcomes were compared between the two trials. RESULTS: Reperfusion therapy was carried out in 60.7% of patients in the first trial and in 72.6% in the second (P< .001). In the RESCATE-II trial, the median door-to-needle time was shorter (41 min vs. 93 min; P< .001) and patients more frequently underwent coronary angiography (65.2% vs. 28.1%; P< .001) and revascularization (34.9% vs. 8.1%; P< .001). In addition, in-hospital mortality was lower in RESCATE-II (7.5% vs. 10.9%; P< .001). After adjustment for age, sex, comorbidity, AMI severity and reperfusion therapy, the odds ratio for in-hospital mortality in RESCATE-II compared with the first trial was 0.52 (95% confidence interval, 0.31-0.86). In addition, mortality (1.4% vs. 3.6%; P=.001) and readmissions at 6 months were also lower in RESCATE-II. CONCLUSIONS: Both in-hospital and 6-month mortality in patients with a first AMI decreased during the last decade, probably due to more frequent reperfusion and revascularization therapy and better medical treatment.

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: 4.05-3.91-3.55 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.

The paraoxonase-1 codon 192 polymorphism is associated with fasting total cholesterol and LDL-cholesterol concentrations only in postmenopausal women. The REGICOR study.

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-linked enzyme which appears to protect low-density lipoproteins (LDL) from oxidation. PON1 activity is associated with variation at the PON1 gene locus, specifically the common amino acid polymorphism at codon 192, for which the Q192 allele specifies low activity and the R192 allele specifies high activity. We investigated the association between the PON1 codon 192 polymorphism and fasting concentrations of glucose, lipids, lipoproteins and PON1 activity in 1380 subjects (724 men and 656 women). Several anthropometric and environmental factors were assessed in the present study. The PON1 Q192 allele frequency was 0.70 and 0.68 in men and women, respectively. In women, but not in men, significant associations were found between the PON1 codon 192 genotype and both total and LDL-cholesterol (p=0.004 and p=0.008, respectively), and subgroup analysis indicated that this relationship was predominant in postmenopausal women. Specifically, the Q192 allele was associated with increased total and LDL-cholesterol concentrations. Furthermore, these lipoprotein variables were higher among postmenopausal women with Q192/Q192 and Q192/R192 genotypes than in premenopausal women with the same genotypes (p<0.001). The findings suggest a gender-specific lipoprotein-genotype association with PON1 codon 192 genotypes in this study sample.