Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects

Recent studies indicate that the enzyme paraoxonase may be an important modulator of cardiovascular disease risk because of its ability to protect LDL from oxidation. We tested for association between two functional variants of the paraoxonase gene (Met-55/Leu and Gln-192/Arg) and both all-cause mortality and fatal cardiovascular disease. This was done within a population-based study among subjects aged 85 years and over in a cross-sectional and a prospective design. In the cross-sectional analysis, the distribution of both paraoxonase genotypes was found to be similar in the subset of 364 elderly subjects who were born in Leiden, The Netherlands, as compared with 250 young subjects whose families originated from the same geographical region. The polymorphisms were in strong linkage disequilibrium (P<0.00001) and the frequency of the haplotype carrying both risk alleles was not lower in the elderly than in the young (0.313 vs. 0.284). The complete cohort of 666 elderly subjects was followed over 10 years. The risk of all-cause and cardiovascular mortality was not increased in elderly subjects with the paraoxonase Leu/Leu (RR, 1.1 [95% CI, 0.9-1.5] and 1.3 [95% CI, 0.8-2.0], respectively) or the Arg/Arg genotype (RR, 0. 9 [95% CI, 0.7-1.2] and 0.7 [95% CI, 0.4-1.3], respectively). In a subset of patients with diabetes, the all-cause mortality risk was elevated in Arg/Arg carriers (RR, 2.1 [95% CI, 0.8-5.8]) but this did not reach statistical significance. Analysis of genotype combinations did not yield significant associations with mortality. The paraoxonase gene variants, previously associated with coronary artery disease, are thus not likely to have a major effect on the risk of fatal cardiovascular disease in the population at large. Adverse effects of the gene variants might be observed in subjects exposed to factors that enhance oxidative stress such as diabetes.     

Plasminogen activator inhibitor-1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D gene polymorphisms and fibrinolytic activity in patients with essential hypertension and dyslipidemia

Essential arterial hypertension often predisposes patients to prothrombotic state and increased risk of vascular and organ complications. Vital role in regulation of hemostatic processes is played by genetic factors, renin-angiotensin system and disorders of lipid metabolism. Prime genetic factors involved in the process are 4G/5G polymorphism of promoter region coding tissue plasminogen activator inhibitor-1 (PAI-1) and I/D polymorphism for angiotensin converting enzyme (ACE) gene. The aim of work was the evaluation of alterations within fibrinolysis system (estimation of t-PA and PAI-1 levels), fibrinogen concentration (Fb) and ACE activity with regard to co-existent dyslipidemia and features of left ventricle hypertrophy (LVH). Moreover the analysis of influence of 4G/5G PAI and I/D ACE gene polymorphism on intensification of aforementioned alterations among hypertensive patients was performed. Research was carried out in 170 subjects under 40 years old, in two study groups, HT-- hypertensive group--125 patients with previously untreated hypertension without clinical features of ischaemic heart disease and NT--45 normotensive, healthy subjects. HT group has been further divided into four subgroups: DLP (dyslipidemic, n = 51), NLP (normolipidemic n = 74), LVH+ (with features of left ventricle hypertrophy, n = 35), LVH (-) (without features of left ventricle hypertrophy, n = 90). In a whole HT group significantly higher levels of PAI-1, t-PA and Fb were noted in comparison to NT group, considerably more pronounced within DLP rather than NLP subgroups. Moreover, pronounced increase in ACE activity was recorded in DLP and LVH+ subgroups. It has been proved that 4G/4G homozygous subjects of 4G/5G PAI-1 gene polymorphism from HT group tend to present higher levels of PAI-1 and t-PA if contrasted to 4G/4G genotype of NT group, with more distinct effect within DLP subgroup. Carriers of D allele (genotypes I/D, D/D) of I/D ACE gene polymorphism from HT group characterise with significantly higher activity of ACE in contrast to I/I genotype of HT group, with particularly marked effect in DLP and LVH+ subgroups. Basing on above mentioned results it may be concluded that essential hypertension (especially if complicated with dyslipidemia) impairs fibrinolysis, what might be related to renin-angiotensin system activation in lipid metabolism disorders. Deletion alleles of 4G/5G polymorphism (4G allele) and I/D polymorphism (D allele) in patients with hypertension independently modify fibrinolysis towards prothrombotic state with more distinct effect in dyslipidemia. Increased activity of ACE in D allele carriers may predispose to left ventricle hypertrophy.     

Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies

Objective

Serum uric acid (SUA) levels have been used to predict cardiovascular and all-cause mortality event, but the data have yielded conflicting results. We investigated whether SUA was an independent predictor for cardiovascular or all-cause mortality with prospective studies by meta-analysis.

Methods

Pubmed and Embase were searched without language restrictions for publications available till April 2013. Only prospective studies on cardiovascular or all-cause mortality related to SUA levels were included. Pooled adjust relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated separately for the highest vs. lowest category or the lowest vs. middle category.

Results

For the highest SUA, eleven studies with 172,123 participants were identified and analyzed. Elevated SUA increased risk of all-cause mortality (RR 1.24; 95% CI 1.09–1.42) and cardiovascular mortality (RR 1.37; 95% CI 1.19–1.57). Subgroup analyses showed that elevated SUA significantly increase the risk of all-cause mortality among men (RR 1.23; 95% CI 1.08–1.42), but not in women (RR 1.05; 95% CI 0.79–1.39). Risk of cardiovascular mortality appeared to be more pronounced among women (RR 1.35; 95% CI 1.06–1.72). The association between extremely low SUA and mortality was reported in three studies; we did not perform a pooled analysis because of high degree of heterogeneity in these studies.

Conclusions

Baseline SUA level is an independent predictor for future cardiovascular mortality. Elevated SUA appears to significantly increase the risk of all-cause mortality in men, but not in women. Whether low SUA levels are predictors of mortality is still inconclusive.     

A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study

PURPOSE: To describe the effect of atrial fibrillation on long-term morbidity and mortality. SUBJECTS AND METHODS: The Renfrew/Paisley Study surveyed 7052 men and 8354 women aged 45-64 years between 1972 and 1976. All hospitalizations and deaths occurring during the subsequent 20 years were analyzed by the presence or absence of atrial fibrillation at baseline. Lone atrial fibrillation was defined in the absence of other cardiovascular signs or symptoms. Cox proportional hazards models were used to adjust for age and cardiovascular conditions. RESULTS: After 20 years, 42 (89%) of the 47 women with atrial fibrillation had a cardiovascular event (death or hospitalization), compared with 2276 (27%) of the 8307 women without this arrhythmia. Among men, 35 (66%) of 53 with atrial fibrillation had an event, compared with 3151 (45%) of 6999 without atrial fibrillation. In women, atrial fibrillation was an independent predictor of cardiovascular events (rate ratio [RR] = 3.0; 95% confidence interval [CI]: 2.1-4.2), fatal or nonfatal strokes (RR = 3.2; 95% CI: 1.0-5.0), and heart failure (RR = 3.4; 95% CI: 1.9-6.2). The rate ratios among men were 1.8 (95% CI: 1.3-2.5) for cardiovascular events, 2.5 (95% CI: 1.3-4.8) for strokes, and 3.4 (95% CI: 1.7-6.8) for heart failure. Atrial fibrillation was an independent predictor of all-cause mortality in women (RR = 2.2; 95% CI: 1.5-3.2) and men (RR = 1.5; 95% CI: 1.2-2.2). However, lone atrial fibrillation (which occurred in 15 subjects) was not associated with a statistically significant increase in either cardiovascular events (RR = 1.5; 95% CI: 0.6-3.6) or mortality (RR = 1.8; 95% CI: 0.9-3.8). CONCLUSIONS: Atrial fibrillation is associated with an increased long-term risk of stroke, heart failure, and all-cause mortality, especially in women.     

Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients

PURPOSE: Aspiration due to an age-related reduction in cough is a major cause of pneumonia in elderly persons. Because the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE) has been associated with the cough reflex, we studied whether this genetic polymorphism was also associated with the risk of pneumonia. SUBJECTS AND METHODS: We studied 1011 elderly inpatients (221 men and 790 women, mean [+/- SD] age of 82 +/- 7 years) in a long-term care hospital. The association between the ACE I/D polymorphism and the incidence of pneumonia (defined using specific criteria that included radiographic abnormalities) was assessed during an 8-month period that excluded the winter. Data were analyzed using proportional hazards models, with adjustment for age, sex, and other potential confounders. RESULTS: During follow-up, 87 cases (9%) of pneumonia occurred, 38 of which were fatal. The ACE DD allele (vs. ID + II) was associated with an increased risk of pneumonia (relative risk [RR] = 2.9; 95% confidence interval [CI]: 1.7 to 4.8, P < 0.001) and fatal pneumonia [RR = 4.4; 95% CI: 2.1 to 9.0; P < 0.0001). CONCLUSIONS: The ACE D allele is an independent risk factor for pneumonia in elderly persons.     

Association Between Plasminogen Activator Inhibitor-1-675 4G/5G Insertion/Deletion Polymorphism and Chronic Obstructive Pulmonary Disease

Molecular pathology of chronic obstructive pulmonary disease (COPD) is still being investigated to discover relationships with disease pathogenesis. Evidence of plasminogen activator inhibitor-1 (PAI-1) overexpression in the sputum and the blood of COPD patients is growing. We aimed to investigate the potential relation between PAI-1 promoter 4G/5G insertion/deletion polymorphism and COPD development. In a case-control study, we genotyped 117 COPD patients and 160 control subjects for PAI-1 promoter 4G/5G polymorphism by an allele-specific polymerase chain reaction analysis. All subjects were male smokers. In the co-dominant model, there was a significant difference in the distribution of 5G/5G, 4G/5G and 4G/4G genotypes between COPD patients and controls (p = 0.002). In the recessive model, carriers of 4G/4G genotype were significantly higher in COPD patients than controls (p = 0.01). Carriers of 4G/4G genotype were at higher risk to develop COPD than those carrying 5G/5G or 4G/5G genotypes (crude odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.19–3.73, adjusted OR = 2.5, 95% CI = 1.22–3.99). In conclusion, PAI-1 4G/5G genetic variations are associated with COPD development in males.     

The association between circulating white blood cell count, triglyceride level and cardiovascular and all-cause mortality: population-based cohort study

OBJECTIVES: To examine the individual and combined relationship between elevated white blood cell count (WBC), triglyceride level and cardiovascular and all-cause mortality among older Australians. DESIGN: Prospective population-based cohort study. SETTING: Community in Blue Mountains region, Australia. PARTICIPANTS: 2904 individuals, aged 49-84 years, free of cardiovascular disease and cancer at the baseline examination. MAIN OUTCOME MEASURES: Cardiovascular (n=242) and all-cause mortality (n=575). RESULTS: Elevated WBC count and triglyceride level were found to be associated with cardiovascular and all-cause mortality, independent of several important confounders. Multivariable relative risk [RR] (95% confidence interval [CI]) comparing fourth (6.8 x 10(9) cells/L and above) versus first quartile (4.8 x 10(9) cells/L and below) of WBC count was 2.01 (1.40-2.90) for cardiovascular mortality and 1.68 (1.35-2.09) for all-cause mortality. Multivariable RR (95% CI) comparing fourth (1.98 mmol/L and above) versus first quartile (0.95 mmol/L and below) of triglyceride level was 1.58 (1.08-2.30) for cardiovascular mortality and 1.40 (1.11-1.77) for all-cause mortality. Furthermore, a combined exposure to the fourth quartiles of both WBC count and triglyceride level was found to be related to more than three-fold risk of cardiovascular mortality (RR [95% CI]: 3.15 [2.17-4.57], p-interaction=0.01), independent of traditional risk factors. CONCLUSIONS: Elevated WBC count and triglyceride level were associated with cardiovascular and all-cause mortality among older Australians. These data provide new epidemiological evidence regarding cardiovascular risk stratification using simple, inexpensive, and routinely available measures, suggesting that a combined exposure to both high WBC count and triglyceride level is related to more than three-fold risk of cardiovascular mortality, independent of traditional risk factors.     

The role of red blood cell distribution width in mortality and cardiovascular risk among patients with coronary artery diseases: a systematic review and meta-analysis

Background

Red cell distribution width (RDW) might be a novel biomarker that reflects multiple physiological impairments related to atherosclerosis and coronary artery diseases (CAD). We conducted this systematic review and meta-analysis to evaluate the association of RDW between all-cause mortality and fatal/non-fatal cardiovascular disease (CVD) events in CAD patients.

Methods

Relevant studies were searched and identified in the MEDLINE and EMBASE databases. English-language prospective studies that reported risk estimates for RDW and mortality/CVD events were included. Data were extracted regarding the characteristics and clinical outcomes, and a quality assessment was conducted. Results were extracted for the highest versus lowest RDW level, and meta-analyses were carried out using random effects models.

Results

We identified 22 studies enrolling 80,216 participants. The study duration ranged between 1 month and 23 years. Of the 15 studies that were included in the meta-analysis, higher RDW indicated a significant increased risk for all-cause mortality in CAD patients: pooled risk ratio (RR) 2.20 (95% CI, 1.42-3.39; P<0.0004). The results for fatal, non-fatal and fatal/non-fatal events were: pooled RR 1.80 (95% CI, 1.35-2.41; P<0.0001), RR 1.86 (95% CI, 1.50-2.31; P<0.00001) and RR 2.13 (95% CI, 1.20-3.77; P=0.01). Heterogeneity was moderately present; however, sensitivity analyses for follow-up duration, CAD subtype, or RDW as dichotomous values showed similar results.

Conclusions

The meta-analysis indicates that higher RDW levels are associated with increased risk of mortality and CVD events in patients with established CAD.     

Why cardiovascular mortality is higher in treated hypertensives versus subjects of the same age,in the general population

OBJECTIVE: The aim of the present study was to assess whether increased cardiovascular mortality in treated hypertensives could be explained by high blood pressure levels, or by the presence of associated risk factors and/or associated diseases. DESIGN: The study sample consisted of 8893 treated hypertensive men and women from the Investigations Préventives et Cliniques cohort, and 25880 gender-matched and age-matched untreated subjects from the same cohort. Vital status was obtained for an 8-12 year period. RESULTS: Treated hypertensive subjects had higher systolic blood pressure (SBP) (+ 15 mmHg) and higher diastolic blood pressure (+ 9 mmHg), and a higher prevalence of associated risk factors and diseases. Treated hypertensives compared with untreated subjects presented a two-fold increase in the risk ratio (RR) for cardiovascular mortality [RR, 1.96; 95% confidence interval (CI), 1.74-2.22] and coronary mortality (RR, 1.99; 95% CI, 1.63-2.44). Adjustment for unmodifiable risk factors decreased the excess cardiovascular risk observed in treated subjects only slightly: RR, 1.77; 95% CI, 1.56-2.00 for cardiovascular mortality; and RR, 1.76; 95% CI, 1.44-2.16 for coronary mortality. After additional adjustment for modifiable associated risk factors, the increased mortality in treated subjects persisted: RR, 1.52; 95% CI, 1.33-1.74 for cardiovascular mortality; and RR, 1.49; 95% CI, 1.19-1.86 for coronary mortality. Only after additional adjustment for SBP were cardiovascular mortality and coronary mortality similar in the two groups of subjects: RR, 1.06; 95% CI, 0.92-1.23; and RR, 1.06; 95% CI, 0.85-1.35, respectively. CONCLUSIONS: The increased cardiovascular mortality in treated hypertensive subjects as compared with untreated subjects is mainly due to high SBP levels under treatment. This result suggests that the excess risk found in treated hypertensives may be drastically reduced if SBP were brought under control.     

The D allele of the angiotensin-converting enzyme insertion/ deletion (I/D) polymorphism is a risk factor for type 2 diabetes in a population-based Japanese sample

The association of the ACE gene I/D polymorphism with type 2 diabetes (DM) was examined in a population-based Japanese sample. A total of 902 individuals (490 females and 412 males, age 58.8 +/- 12.2 yr) from a cohort population (n = 3,706) of the Funagata diabetes study were divided into three groups according to genotype: D/D (n = 104), I/D (n = 436) and I/I (n = 362). Chi-square test and ANOVA were used for association studies and to assess the differences in the traits' values, respectively. More individuals with the genotypes D/D and I/D were diabetic (8.7% and 4.1%, respectively) than those with the genotype I/I (2.8%, p = 0.008 and p = 0.032, respectively). The genotype D/D was a risk factor for DM (relative risk (RR) 3.13, 95% CI 1.31-7.51), and also for DM and IGT (RR 1.78, 95% CI 14-2.76). Multiple logistic regression analysis also showed that the genotypes with the D allele were risk factors for DM and IGT even when adjusting for age, sex, hypertension and serum total cholesterol levels (odds ratio 1.49, 95% CI 1.01-2.21). The D allele of the ACE gene I/D polymorphism is a risk factor for DM.     

Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis.

OBJECTIVES: This study was designed to determine whether statins reduce all-cause mortality in elderly patients with coronary heart disease. BACKGROUND: Statins continue to be underutilized in elderly patients because evidence has not consistently shown that they reduce mortality. METHODS: We searched 5 electronic databases, the Internet, and conference proceedings to identify relevant trials. In addition, we obtained unpublished data for the elderly patient subgroups from 4 trials and for the secondary prevention subgroup from the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial. Inclusion criteria were randomized allocation to statin or placebo, documented coronary heart disease, > or =50 elderly patients (defined as age > or =65 years), and > or =6 months of follow-up. Data were analyzed with hierarchical Bayesian modeling. RESULTS: We included 9 trials encompassing 19,569 patients with an age range of 65 to 82 years. Pooled rates of all-cause mortality were 15.6% with statins and 18.7% with placebo. We estimated a relative risk reduction of 22% over 5 years (relative risk [RR] 0.78; 95% credible interval [CI] 0.65 to 0.89). Furthermore, statins reduced coronary heart disease mortality by 30% (RR 0.70; 95% CI 0.53 to 0.83), nonfatal myocardial infarction by 26% (RR 0.74; 95% CI 0.60 to 0.89), need for revascularization by 30% (RR 0.70; 95% CI 0.53 to 0.83), and stroke by 25% (RR 0.75; 95% CI 0.56 to 0.94). The posterior median estimate of the number needed to treat to save 1 life was 28 (95% CI 15 to 56). CONCLUSIONS: Statins reduce all-cause mortality in elderly patients and the magnitude of this effect is substantially larger than had been previously estimated.     

A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women

We examined the relationship of maturity-onset clinical diabetes mellitus with the subsequent incidence of coronary heart disease, stroke, total cardiovascular mortality, and all-cause mortality in a cohort of 116,177 US women who were 30 to 55 years of age and free of known coronary heart disease, stroke, and cancer in 1976. During 8 years of follow-up (889 255 person-years), we identified 338 nonfatal myocardial infarctions, 111 coronary deaths, 259 strokes, 238 cardiovascular deaths, and 1349 deaths from all causes. Diabetes was associated with a markedly increased risk of nonfatal myocardial infarction and fatal coronary heart disease (age-adjusted relative risk [RR] = 6.7; 95% confidence interval [CI], 5.3 to 8.4), ischemic stroke (RR = 5.4; 95% CI, 3.3 to 9.0), total cardiovascular mortality (RR = 6.3; 95% CI, 4.6 to 8.6), and all-cause mortality (RR = 3.0; 95% CI, 2.5 to 3.7). A major independent effect of diabetes persisted in multivariate analyses after simultaneous control for other known coronary risk factors (for these end points, RR [95% CI] = 3.1 [2.3 to 4.2], 3.0 [1.6 to 5.7], 3.0 [1.9 to 4.8], and 1.9 [1.4 to 2.4], respectively). The absolute excess coronary risk due to diabetes was greater in the presence of other risk factors, including cigarette smoking, hypertension, and obesity. These prospective data indicate that maturity-onset clinical diabetes is a strong determinant of coronary heart disease, ischemic stroke, and cardiovascular mortality among middle-aged women. The adverse effect of diabetes is amplified in the presence of other cardiovascular risk factors, many of which are modifiable.     

Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting

BACKGROUND: Observations with intravascular ultrasound demonstrated that neointimal hyperplasia is the predominant factor responsible for in-stent restenosis. Experimental data suggest that angiotensin I converting enzyme (ACE) plays a role in the thickening of neointima after balloon denudation. Insertion/deletion (I/D) polymorphism of the ACE gene is significantly associated with plasma level of ACE and subjects with D/D genotype have significantly higher plasma levels of ACE than normal. OBJECTIVE: To investigate whether this polymorphism influences the risk of restenosis after coronary stenting. METHODS: We genotyped 158 patients who had undergone single-vessel coronary stenting for the ACE I/D polymorphism. RESULTS: Of the 158 patients, 56 (35%) had the D/D genotype, 71 (45%) had the I/D genotype and 31 (20%) had the I/I genotype. Prevalences of genotypes were compatible with Hardy-Weinberg equilibrium and distributions of ACE genotype among patients and 132 healthy controls from the same geographic area did not differ. At follow-up (after a median duration of 5.4 months), overall rates of angiographic restenosis and of revascularization of target lesion (RTL) were 32.3 and 22.8%, respectively. Of 51 patients with angiographic restenosis, 31 (60.8%) had focal and 20 (39.2%) had diffuse patterns of restenosis. Diffuse in-stent restenosis was significantly more prevalent among patients with D/D genotype (P = 0.016). Multiple stepwise logistic regression analysis identified ACE I/D polymorphism as the independent predictor of angiographic restenosis and RTL. Relative risk of angiographic restenosis was 6.29 [95% confidence interval (CI), 1.80-22.05, P = 0.0004] for D/D genotype and 3.88 (95% CI 1.11-13.12, P = 0.029) for I/D genotype, whereas relative risk of RTL was 7.44 (95% CI 1.60-34.58, P = 0.01) for D/D genotype and 3.88 (95% CI 0.083-18.15, P = 0.085) for I/D genotype. CONCLUSIONS: The ACE I/D polymorphism is significantly associated with risk of angiographic and clinical restenosis after coronary stenting. Angiographic pattern of restenosis is also significantly associated with I/D polymorphism, diffuse type being more prevalent among subjects with D/D genotype.     

Association of angiotensin-I converting enzyme DD genotype with influenza pneumonia in the elderly

Background: Although angiotensin-I converting enzyme (ACE) is known to associate with cough reflex and inflammatory conditions, and both may participate in influenza pneumonia in the elderly, no study has been carried out on the association between influenza pneumonia and the insertion/deletion ( I/D ) polymorphism of the ACE gene ( ACE ).

Methods:

Methods: The subjects were 934 elderly inpatients (mean ± SD age of 82 ± 8 years) in a long-term care hospital. The association between ACE I/D and the incidence of influenza-pneumonia events was assessed over a winter season. Data were analyzed by multiple logistic regression analysis, with adjustment for age, gender, already known clinical risk factors, and ACE-inhibitor use.

Results:

Results: During the follow-up period, 330 patients developed influenza (Directigen FLU-A) and 89 developed influenza pneumonia (Center for Disease Control and Prevention (CDC) criteria with chest X-ray required), 16 fatal and 73 non-fatal. Compared to non-influenza subjects ( n = 604) and influenza patients without pneumonia ( n = 241), ACE DD genotype ( vs ID + II ) resulted in a significant risk for all pneumonia (relative risk 2.32 [95% CI: 1.30–4.14] and 2.76 [1.39–4.04]), non-fatal pneumonia (1.91 [1.01–3.63] and 2.57 [1.23–5.39]) and fatal pneumonia (6.27 [1.68–23.3] and 5.15 [1.29–20.5]).

Conclusion:

Conclusion: ACE I/D polymorphism is a strong and independent risk indicator of influenza pneumonia events in elderly inpatients.     

Prognostic impact of different regional referral practices for interventional investigation and coronary treatment after exercise testing: a population-based 5-year follow-up study

OBJECTIVE: To examine the association among different centres' referral practices for coronary angiography (CAG) after exercise testing, with 1- and 5-year outcomes. DESIGN: Observational population-based cohort study. SETTING: All 10 hospitals and six private practising consultants in Aarhus and Ringkjoebing counties (900 000 inhabitants), Denmark. SUBJECTS: All patients who in 1996 had an abnormal bicycle exercise test (n = 736). MEASUREMENTS: Referral for CAG, coronary intervention, cardiovascular and all-cause mortality, and myocardial infarction (MI). RESULTS: As an immediate consequence of the exercise test, 60.7% of subjects were referred for CAG. Based on the centres' fraction of patients referred for CAG, three categories of centres were defined: low (<33%), intermediate (33-66%) and high (>66%). A low compared with a high referral fraction was associated with a similar 5-year mortality and MI ratio [all-cause/cardiovascular mortality rate ratio (RR) = 1.33, 95% confidence interval (CI): 0.45-3.92/RR = 0.62, 95% CI: 0.25-1.57; and MI RR = 0.92, 95% CI: 0.45-1.86]. The same was found for an intermediate compared with a high fraction (all-cause/cardiovascular mortality RR = 0.92, 95% CI: 0.49-1.72/RR = 0.74, 95% CI: 0.42-1.33; and MI RR = 1.07, 95% CI: 0.68-1.70). Estimates were about the same after 1 year of follow-up with no major differences among centres in mortality or MI. CONCLUSIONS: Centres' different referral practices for interventional investigation and treatment were not associated significantly with short-term or long-term mortality or MI among patients with an abnormal exercise test.     

The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1

Plasminogen activator inhibitor type I (PAI-1) antigen concentrations follow a circadian oscillation peaking in the morning. Some individuals show no apparent circadian rhythm, while others show up to a 10-fold variation in PAI-1 over 24 hours. Results from experimental studies suggest that a polymorphism in the promoter of the gene for PAI-1 (4G5G) directly influences the circadian expression of the PAI-1 gene. We studied whether the diurnal variation of PAI-1 antigen differs for the genotypes of the 4G5G polymorphism. A population-based, cross-sectional study was performed among 263 subjects selected from the Rotterdam Study, a population-based cohort of 7983 men and women aged 55 years and older. The 4G allele was associated with a more pronounced circadian expression of PAI-1 antigen. Morning PAI-1 antigen concentrations were 79 ng/mL (95% confidence interval [CI], 68-92) in subjects homozygous for 4G, 62 ng/mL (95% CI, 54-72) in heterozygous subjects, and 59 ng/mL (95% CI, 49-71) in subjects homozygous for 5G. While respective PAI-1 antigen concentrations in the afternoon were 40 ng/mL (95% CI, 33-49), 41 ng/mL (95% CI, 37-47), and 40 ng/mL (95% CI, 49-71). These findings suggest that the morning increase in PAI-1 antigen concentration is more pronounced among subjects homozygous for the 4G allele compared with the morning increase among the other genotypes. Additionally, these findings show that homozygosity for the 4G allele is associated with increased PAI-1 levels during the morning only.     

Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HF-PEF) is a well-recognized complication of long-standing hypertension. However, beyond the control of the traditional cardiovascular risk factors, there are few other recommendations for its management. To examine the potential benefit of renin-angiotensin system (RAS) inhibition in HF-PEF, we performed a systematic review of the published medical literature. MEDLINE, EMBASE, and COCHRANE databases were searched from 1966 to 2011 for longitudinal studies examining HF-PEF patients receiving treatment with RAS inhibitors, either ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) in addition to their standard treatment compared to those receiving standard treatment alone. We examined the all-cause mortality, cardiovascular mortality, and hospitalizations for heart failure. A total of 12 studies with 11,259 participants were included in the analysis. Among the randomized clinical trials, with the use of RAS inhibitors over standard treatment, there was no improvement in all-cause mortality (RR: 0.99; 95 % CI: 0.88–1.12; p = 0.88), while there was a trend toward lowered rates of hospitalization (RR: 0.93; 95 % CI: 0.86–1.01; p = 0.08). There were no major differences in the outcomes between the ACE-I or ARB. However, among the observational studies with the use of RAS inhibitors, there was a significant benefit in all-cause mortality (RR: 0.76; 95 % CI: 0.62–0.93; p = 0.009), with no significant impact on the hospitalization rates. RAS inhibition in HF-PEF was not associated with significant reduction in all-cause or cardiovascular mortality, but randomized control trials appear to demonstrate a trend toward reduction in the risk for subsequent hospitalization. Further prospective randomized trials are warranted to confirm the effects of RAS inhibition on mortality and hospitalization.     

Significance of factor V, prothrombin, MTHFR, and PAI-1 genotypes in childhood cerebral thrombosis.

The aim of this study was to evaluate the significance of factor V (FV) G1691A, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G genotypes in development of childhood cerebral thrombosis (CT). A total of 113 Turkish children with CT were studied and compared with the control group. The carrier frequency of the factor V G1691A mutation was found to be significantly higher in the patient group (17.7%) than controls (7.4%). The presence of this genotype was associated with a 2.7-fold increased risk of developing CT (95% confidence interval [CI], 1.0-7.0). The prevalence of prothrombin G20210A mutation in 110 patients (4.5%) was insignificantly higher than controls (2.3%) (odds ratio, 2.0; 95% CI, 0.4-10.7). A statistically significant increase in the frequency of homozygous MTHFR C677T genotype was observed in 62 patients (11.3%) compared to controls (4.3%), and this genotype was associated with 2.8-fold increased CT risk (95% CI, 1.0-8.0). The incidence of PAI-1 4G/4G genotype in 65 patients (21.5%) was slightly lower than that of controls (26.0%), but the differences did not reach statistical significance (odds ratio, 0.8; 95% CI, 0.4-1.5). The results of this study suggested that factor V G1691A and MTHFR C677T genotypes may be associated with an increased risk of developing CT in Turkish children.     

High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age

BACKGROUND: A high total serum cholesterol level does not carry a risk of cardiovascular mortality among people 85 years and older and is related to decreased all-cause mortality. At this old age, there are few data on fractionated lipoprotein levels in the determination of cardiovascular disease risk. The aim of this study was to evaluate the relationships between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels and mortality from specific causes among people in the oldest age categories. METHODS: Between September 1, 1997, and September 1, 1999, a total of 705 inhabitants in the community of Leiden, the Netherlands, reached the age of 85 years. Among these old people, we initiated a prospective follow-up study to investigate determinants of successful aging. A total of 599 subjects participated (response rate, 87%) and all were followed up to September 2001. Serum levels of total, LDL, and HDL cholesterol were assessed at baseline along with detailed information on comorbid conditions. The main outcome measure was all-cause and specific mortality risk. RESULTS: During 4 years of follow-up, 152 subjects died. The leading cause of death was cardiovascular disease, with similar mortality risks in all tertiles of LDL cholesterol level. In contrast, low HDL cholesterol level was associated with a 2.0-fold higher risk of fatal cardiovascular disease (95% confidence interval [CI], 1.2-3.2). The mortality risk of coronary artery disease was 2.0 (95% CI, 1.0-3.9) and for stroke it was 2.6 (95% CI, 1.0-6.6). Both low LDL cholesterol and low HDL cholesterol concentrations were associated with an increased mortality risk of infection: 2.7 (95% CI, 1.2-6.2) and 2.4 (95% CI, 1.1-5.6), respectively. The risks were unaffected by comorbidity. CONCLUSION: In contrast to high LDL cholesterol level, low HDL cholesterol level is a risk factor for mortality from coronary artery disease and stroke in old age.