The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease.

BACKGROUND: Disturbances in fibrinolytic activity, such as increase in plasminogen activator inhibitor (PAI) activity, have been linked with an increased risk for coronary artery disease (CAD) and myocardial infarction (MI). Since 4G4G homozygotes of an insertion/deletion (4G/5G) gene variation in the promoter of PAI-I have been shown to have increased levels of PAI-I, we analysed the relation of this gene polymorphism to CAD and MI in a population of 2565 participants who underwent coronary angiography for diagnostic purposes. RESULTS: In the total sample, the PAI-I 4G/4G genotype was associated with the presence, but not with the extent of CAD. However, in a subgroup of former and present smokers (n = 1782) or of individuals with a BMI above the mean value of 26.9 kg x m(-2) (n = 1269), the PAI-I 4G4G genotype was not only associated with the presence, but also with the extent of CAD, defined either by the number of diseased vessels or by the CHD score according to Gensini. This observation also applied to other high-risk groups of individuals with high BMI and hypertension (n = 869), of subjects with high fibrinogen plasma levels (>3.53 g x l(-1), mean value) and hypertension (n = 599) and of former and present smokers with high fibrinogen and hypertension (n = 452). An association of the gene variation with MI was not detected. CONCLUSIONS: The present data indicate that the 4G/4G genotype of the PAI-I gene polymorphism is an independent risk factor for coronary artery disease and that the additional presence of major cardiovascular risk factors accelerates the risk for this disease.     

The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS

Intoduction

Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with worse outcome in ALI/ARDS. A single guanosine insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene, may play an important role in the regulation of PAI-1 expression. The objective of the study was to evaluate the effect of this polymorphism on the outcome of critically ill patients with ALI/ARDS.

Materials and Methods

52 consecutive ventilated patients with ALI/ARDS were studied. Bronchoalveolar lavage was performed within 48 hours from diagnosis. Measurement of plasma and BALF PAI-1 activity and D-dimers levels, and 4G/5G genotyping of PAI-1 were carried out. The primary outcome was 28-day mortality, and secondary outcomes included organ dysfunction and ventilator-free days.

Results

17 patients were homozygotes for the 4G allele. Severity scores were not different between subgroups upon study enrollment. 28-day mortality was 70.6% and 42.9% for the 4G-4G and the non-4G-4G patients, respectively (p = 0.06). PAI-1 activity levels and D-dimer in plasma and BALF were not significantly different between the 4G-4G and the non-4G-4G subgroups. In the multivariate analysis, genotype 4G/4G was the only variable independently associated with 28-day mortality (Odds Ratio = 9.95, 95% CI: 1.79-55.28, p = 0.009). Furthermore, genotype 4G/4G and plasma PAI-1 activity levels were independently negatively associated with ventilator free days (p = 0.033 and p = 0.008, respectively).

Conclusions

ALI/ARDS patients, homozygous for the 4G allele of the PAI-1 gene, experienced higher 28-day mortality. This genotype was associated with a reduction in the number of days of unassisted ventilation and was inversely associated with the number of days without organ failure.     

Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease

Increased circulating levels of type 1 plasminogen activator inhibitor (PAI-1) have been associated with coronary artery disease (CAD). However, genetic and environmental determinants of PAI-1 expression are only partially understood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and antigen, no association has been found between PAI-1 antigen levels and the PAI-1 promoter 4G/5G genotype. The aim of the present study was to analyze the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in post-menopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variations in PAI-1 levels after hormone replacement therapy (HRT). No differences between 4G/5G allele distribution in the groups studied were observed. The group of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G allele dosage and PAI-1 antigen levels, which were also influenced by the triglyceride levels but not by estrogen or glucose levels. After hormone replacement therapy the decrease in PAI-1 levels was correlated with the 4G allele dosage. We conclude that in the group of postmenopausal women with CAD the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more evident than in the control groups, and that the decrease in PAI-1 levels after HRT in CAD women correlates with the 4G allele dosage.     

Vagal neurostimulation in patients with coronary artery disease

We tested the hypotheses that (1) progression of coronary artery disease (CAD) increases sympathetic inflow to the heart, thus impairing cardiac blood supply, and (2) reduced sympathetic tone improves cardiac microcirculation and ameliorates severity of anginal symptoms. Electrical irritation of the nerve auricularis--a sensitive ramus of the vagus nerve--provides a central sympatholytic action. Using this technique, we studied the effects of vagal neurostimulation (VNS) on hemodynamics, the content of atrial noradrenergic nerves and the microcirculatory bed of CAD patients. VNS was performed in the preoperative period of CAD patients with severe angina pectoris. The comparison groups consisted of untreated patients with CAD or Wolff-Parkinson-White syndrome. Atrial tissue of patients with this syndrome (n = 6); with effort angina (n = 14); with angina at rest (n = 10); and with severe angina treated with VNS (n = 8) contained the following volume percentages of noradrenergic nerves: 1.7+/-0.1%, 1.3+/-0.3%, 0.5+/-0.1% (p < 0.05 vs. the other groups) and 1.3+/-0.2%, respectively. In these groups, cardiac microcirculatory vessels (diameter, 10-20 microm) had the following densities: 2.7+/-0.2%, 3.4+/-0.2%, 2.0+/-0.4% (p < 0.05 vs. the other groups) and 3.3+/-0.3%, respectively. VNS treatment abolished angina at rest, decreased heart rate and blood pressure. It improved left ventricular ejection fraction from 50+/-1.5% to 58+/-1.0% (p < 0.05), also changing left ventricular diastolic filling. The ratio of time velocity integrals of the early (Ei) to late (Ai) waves increased from 1.07+/-0.12 to 1.65+/-0.17 after VNS (p < 0.05). In electrocardiograms of VNS-treated patients, QRS- and QT-duration were shortened. the PQ-interval did not change, but T-wave configuration improved. In the postoperative period, heart failure occurred in 90% of the control group. vs. 12% in patients treated with VNS (p < 0.05). We conclude that CAD is characterized by overactivity of sympathetic cardiac tone. Vagal stimulation reduced sympathetic inflow to the heart, seemingly via an inhibition of norepinephrine release from sympathetic nerves. VNS' sympatholytic/vagotonic action dilated cardiac microcirculatory vessels and improved left ventricular contractility in patients with severe CAD.     

The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction.

Several studies have found an association between high plasminogen activator inhibitor-1 (PAI-1) levels and myocardial infarction. Whether this is causal or a consequence of atherosclerosis or tissue damage, remains unclear. Homozygous carriers of the 4G allele of the 4G/5G polymorphism in the PAI-1 gene have higher PAI-1 levels compared to carriers of the 5G allele in healthy persons in some studies, but not all. If PAI-1 levels are causally related to myocardial infarction, one would expect more homozygous carriers of the 4G allele among patients, provided that these carriers have high PAI-1 levels among healthy persons in that population. We investigated the distribution of this polymorphism in the "Study of Myocardial Infarctions Leiden" (SMILE), including 331 men with a myocardial infarction and 302 control subjects and measured PAI-1 antigen levels among the latter. Secondly, we looked into the association of cardiovascular risk factors with PAI-1 levels. We did not find an increase in risk of myocardial infarction in carriers of the 4G allele. Neither did we find an association, nor a trend, between the 4G/5G polymorphism and PAI-1 antigen levels in control subjects. Controls with obesity, hypertension, or who smoked had significant higher PAI-1 antigen levels compared with persons without these factors. High cholesterol and triglyceride levels were also associated with high PAI-1 antigen levels, and HDL-cholesterol levels showed an inverse association. We conclude that the 4G/5G polymorphism in the PAI-1 gene is not associated with the risk of myocardial infarction. As we did not find any association between this polymorphism and PAI-1 antigen levels in healthy persons, we cannot draw any conclusions about the causality of PAI-1 itself for myocardial infarction.     

Antithrombotic effects of aspirin based on PLA1/A2 glycoprotein IIIa polymorphism in patients with coronary artery disease

OBJECTIVE: The diallelic glycoprotein IIIa polymorphism P1A1/A2 was attributed to be an inherited risk factor for coronary events. Whether this polymorphism affects response to aspirin in patients with coronary artery disease is not known. METHODS: We assessed thrombin generation (prothrombin fragment F1+2) in consecutive blood samples collected from bleeding-time wounds in 28 men with coronary artery disease; P1A2 carriers, n=9; P1A1/A1, n=19. Thrombin generation and bleeding time were measured before and after 2 weeks of aspirin 300 mg/day. RESULTS: Aspirin-depressed thrombin generation in A1 homozygotes (p=0.04), but not in A2 carriers. Bleeding time after aspirin was also prolonged in A1 subjects only (p=0.02). CONCLUSION: Genotyping for glycoprotein IIIa polymorphism might be helpful in predicting antithrombotic action of aspirin in secondary prevention of coronary artery disease.     

Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV1691 G-A

A decreased fibrinolytic activity due to increased levels of plasminogen activator inhibitor-1 has been shown in deep vein thrombosis patients. Elevated plasma plasminogen activator inhibitor-1 levels are associated with the 4G allele of a 4G/5G polymorphism located in the promoter region of the plasminogen activator inhibitor-1 gene. Because there is no existing data in the Turkish population, we aimed to study these mutations in patients with deep vein thrombosis (n = 136) and normal controls (n = 113), consecutively selected among unrelated healthy subjects without personal and familial history of atherothrombosis from Ankara, Turkey. DNA was extracted by conventional methods, and polymerase chain reaction of the plasminogen activator inhibitor-1 4G/5G polymorphism was performed according to a previously described method. Genotype distributions of FV 1691G-A and plasminogen activator inhibitor-1 4G/5G are as follows: plasminogen activator inhibitor-1 4G (patients) 0.562, plasminogen activator inhibitor-1 4G (controls) 0.50 (p = 0.6); FV1691A (patients) 0.147, FV1691A (controls) 0.035 (p = 0.005). Our data indicated that plasminogen activator inhibitor-1 4G/5G does not have an effect on the thrombotic risk. Carrying the 4G allele either in heterozygous or homozygous state increases the risk in the presence of FV1691A (odds ratio: 9.8 and 6.9, confidence interval 95% 2.9-32.7 and 1.3-35.8). FV1691A is an independent risk factor for thrombosis (odds ratio: 5.5, confidence interval: 95% 2.5-12.1). We concluded that coexistence of FV1691A and plasminogen activator inhibitor-1 4G allele leads to an increased risk for thrombosis leading a further evidence to another prothrombotic factor that may be necessary for the development of a manifest thrombotic event.     

The GPIIIa PlA polymorphism and the platelet hyperactivity in Tunisian patients with stable coronary artery disease treated with aspirin

Background

Various genetic polymorphisms have been proposed to explain the persistent platelet hyperactivity (HPR) under aspirin treatment. PlA polymorphism of platelet GPIIIa receptor has been largely studied. However, its influence on platelet sensitivity to aspirin remains controversial.

Objectives

The aim of this prospective study is to investigate whether this PlA polymorphism is associated with a greater prevalence of HPR in stable coronary artery disease patients Material and Methods: 188 stable coronary artery disease patients were included. Platelet aspirin inhibitory effect was determined with PFA-100 using Collagen/Epinephrine closure time (CEPI-CT). A CEPI-CT<160 sec was defining the HPR status. GPIIIa PlA polymorphism was established using polymerase chain reaction and classical restriction fragments length polymorphism.

Results

The observed frequencies of different genotypes were not different from those predicted by the Hardy-Weinberg equilibrium: PlA1/lA1 (55.3%), PlA1/PlA2 (39.4%) and PlA2/PlA2 (5.3%). HPR patients with inadequate aspirin inhibition were significantly more often homozygous PlA1/A1 (65.4% vs. 47.7%, p = 0.015). After multivariate analysis, PlA1/A1 genotype was the only independent risk factor for persistent HPR (OR: 2.07; 95% CI [1.14 to 3.76; p = 0.016).

Conclusion

In CAD patients receiving daily low dose of aspirin, there is a significant and independent association between the expression of GPIIIa PlA1 allele and the occurrence of persistent HPR detected with PFA-100.     

Plasminogen activator inhibitor-1 4G/5G polymorphism in breast cancer patients and its association with tissue PAI-1 levels and tumor severity

BACKGROUND: The plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism may have significance for PAI-1 expression. High levels of PAI-1 in breast cancer patients are associated with a poor prognosis. In this study, we analyzed the influence of the PAI-1 4G/5G polymorphism on tissue PAI-1 levels and its association with tumor severity in women with breast cancer. MATERIAL AND METHODS: We studied 104 women with breast carcinoma (patient group) and 104 healthy age-matched women (control group). In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. In patients, PAI-1 levels were quantified in breast cancer tissue by using an ELISA. RESULTS: The frequency of the PAI-1 4G allele tended to be higher in patients than in controls (p=0.062). The presence of the 4G allele (4G/5G plus 4G/4G genotypes) was significantly higher among patients with histological grade 3 tumors than among those with grade 1 tumors (p=0.026). Furthermore, patients with the 4G/4G genotype had significantly higher tissue PAI-1 levels than those with the 5G/5G genotype. Moreover, tissue PAI-1 antigen levels were significantly and positively correlated with tumor severity (p=0.003) and tumor size (p=0.009). However, no significant differences in PAI-1 level were observed in relation to menopause, hormone receptor or nodal status. CONCLUSION: Tissue PAI-1 antigen levels and tumor severity seem to be associated with the PAI-1 4G/5G polymorphism. Further studies with a larger number of patients are needed to clarify the influence of this polymorphism in breast cancer.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.     

Progression of carotid atherosclerosis in Japanese patients with coronary artery disease.

BACKGROUND AND PURPOSE: Along with the recent changes in lifestyle in Japan, the incidence of coronary artery disease has increased while the incidence of stroke appears to be decreasing. We investigated the relation between the progression of carotid atherosclerosis and the severity of coronary artery disease in the Japanese population. METHODS: The 2-year change in extracranial carotid atherosclerosis in 50 Japanese patients who underwent coronary angiography was evaluated using carotid echotomography. To quantify the extent of carotid atherosclerosis, the maximal thickness measurements of all plaques were summed for an individual plaque score, except for new plaques found on reexamination. Carotid disease progression was evaluated by the sum of plaque score change and the thickness of the new plaque found on reexamination. RESULTS: The plaque score changed by -3.2 to 10.1 mm (mean +/- SD, 1.06 +/- 2.42 mm). The extent of coronary atherosclerosis (p less than 0.02) and serum total cholesterol level (p less than 0.01) were different between the progressing (n = 17) and the nonprogressing (n = 30) groups of carotid atherosclerosis when the progressing group included the patients with a delta plaque score of greater than or equal to 1.0 mm. Neither age, serum triglyceride level, serum high-density lipoprotein cholesterol level, pack-years of smoking, percentage of smokers, percentage of hypertensive patients, nor percentage of diabetic patients was different between the two groups. Carotid disease progression was significantly higher in patients with three-vessel coronary disease than in patients without significant coronary artery disease (p less than 0.005). There was a significant positive linear correlation between carotid disease progression and Gensini's coronary artery disease score (R = 0.411, p less than 0.005). CONCLUSIONS: Our data showed that severe coronary artery disease and a high serum total cholesterol level were strong predictors for carotid disease progression in Japanese patients with high rates of coronary artery disease.     

Exercise-based cardiac rehabilitation and parasympathetic function in patients with coronary artery disease: a systematic review and meta-analysis

Clinical Autonomic Research - The effects of exercise-based cardiac rehabilitation (CR) on parasympathetic modulation are controversial. This systematic review and meta-analysis aims to (a)...     

Platelet production in myocardial infarction and sudden cardiac death

Megakaryocyte cytoplasmic volumes were studied in 13 subjects 18 +/- 2 days after admittance to the coronary care unit. Seven had suffered a myocardial infarction (MI group) while six had chest pain but no recent infarction. Megakaryocytes were also studied in 10 subjects suffering coronary sudden unexpected death (CSD group) and 11 subjects suffering sudden unexpected un-natural death. There was no significant difference between the megakaryocyte cytoplasmic volume distributions of the MI and CSD groups, although they had a significantly greater mean (p less than 0.01) and range (p less than 0.001) than their respective control groups. There was no significant difference in platelet volumes observed within 24 hr of the infarct and 18 +/- 2 days later. Mean platelet volume was significantly correlated (r = 0.89, p less than 0.006) to mean megakaryocyte cytoplasmic volume in the MI group. A computer simulation of platelet production showed no significant difference between platelet volumes observed in the MI group and those estimated to be circulating before death in the CSD group.     

Psychophysiological factors in ventricular arrhythmias and sudden cardiac death

Plasma catecholamine levels were measured preceding programmed electrophysiological studies of patients who had survived a ventricular tachyarrhythmia episode. Psychological assessments of desire for control, locus of control and behavior pattern were obtained. Psychophysiological variables were analysed with respect to the severity of arrhythmias induced by the electrophysiological procedure. Analysis of data from 17 subjects showed desire for control was significantly higher in those with induced sustained arrhythmias than in those in which nonsustained arrhythmias were induced. No relationship was found between behavior pattern and arrhythmia severity or plasma catecholamine levels. There was a significant interaction between desire for control and behavior pattern with respect to epinephrine level. The findings indicate that psychological factors such as desire for control may be associated with potentially lethal arrhythmias and implicated in sudden cardiac death.