[In patients with coronary artery disease and left ventricular contractile insufficiency the pathogenicity of smoking associates with imbalance in metabolism of homocysteine]. / U chorych z miazdzyca tetnic wiencowych i niewydolnoscia skurczowa lewej komory, szkodliwosc palenia wiaze sie z zaburzeniami metabolizmu homocysteiny.

Development of the systolic left ventricular insufficiency in patients with coronary artery disease (CAD) markedly decreases the survival rates, so the factors affecting the clinical status of these patients should be reevaluated. The left ventricular contractile function has been assessed by measurements of the left ventricular ejection fraction (LVEF) values. The studied group of 160 males comprised 102 CAD patients diagnosed by coronarography, and 58 persons without CAD and left ventricular systolic insufficiency. The CAD patients were divided into 2 subgroups according to the LVEF values: 53 patients qualified to have normal left ventricular contractile function (with LVEF > 40%), and 49-patients, with LVEF < or = 40%, were considered as subgroup with the left ventricular contractile insufficiency. In the case-control set up the effects of smoking, concentrations of homocysteine (Hcy) and folic acid (FA) and of the known risk factors of the vascular diseases in the development of the left ventricular contractile insufficiency were assessed. Moreover, analysis was performed of the association between LV insufficiency and the statin therapy and the number of infarcts. LV insufficiency in CAD patients associated with increased diastolic pressure (p = 0.006) and with increased uric acid concentrations in plasma (p = 0.02). The smoking, decrease in HDL-C and increased index TC/HDLC were the risk factors of CAD, independent of the LV insufficiency. In comparison to the CAD patients with the preserved systolic function, in the group of CAD patients with LV systolic insufficiency, more persons had recurrent infarcts (34.7% vs. 5.7%), and less persons had no infarct (8.2% vs. 20.8%, p < 0.05). In CAD patients with LV systolic insufficiency smoking associated with the higher values of HC/FA index (p = 0.01), younger age of the patients (p = 0.01), the number of persons not treated with statins (0.01) and the number of persons not having had heart infarct before (p < 0.05). These findings confirm both the effects of infarcts on the development of LV insufficiency, and the presumed association between the pathogenicity of smoking in LV insufficiency and the unbalanced metabolism of Hcy. The straight of the effect of smoking on the development of LV insufficiency in susceptible persons is shown also by the findings of the younger age of the smoking CAD patients as compared to the nonsmoking patients with LV insufficiency.

[The different genotypes of MTHFR 1298A>C and PON1 -108C>T polymorphisms confer the increased risk of the abdominal aortic aneurysm in the smoking and nonsmoking persons]. / Rózne genotypy polimorfizmów MTHFR 1298a>C i PON1 -108c>T sa czynnikami ryzyka wystapienia tetniaka aorty brzusznej u osób palacych i niepalacych.

In abdominal aortic aneurysm (AAA) both the etiology and the pathogenesis are of the multifactorial character. The genetic component in the determination of this disease is proven by its familial occurrence. Smoking represents the best recognized risk factor of the AAA development. Increased concentrations of homocysteine (Hcy) in plasma are the common finding in these patients. It is assumed that the Hcy thiolactone, the most reactive metabolite of Hcy, may participate in the aortic wall destruction in AAA. The polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C) influence tissue concentrations of the Hcy. Paraoxonase (PON1), the enzyme associated in plasma with the HDL fraction, as lactonase detoxicates the Hcy thiolactone. The promotor polymorphism of PON1 - 108C>T gene may determine the lower activity of this enzyme. In the case-control study of 106 patients with AAA and 97 healthy persons, the effects of selected genetic and nongenetic risk factors on development of AAA were assessed, considering the possibilities of interaction between them. It was found, that the arterial hypertension, cigarette smoking and the lower HDL fraction are independent risk factors of AAA. The arterial hypertension was a risk factor both in the smoking and the nonsmoking males, whereas the lower HDL fraction has been the risk factor only for the smoking men. By the multivariate analysis in the nonsmoking males the MTHFR 1298 AC and CC genotypes increased the risk of AAA development 4,8-fold in relation to the MTHFR 1298 AA nonsmoking males. In reference to the genotypes of the expected high impact on the metabolism of Hcy and of Hcy thiolactone, the genotypes of MTHFR 677TT and PON1 -108CT and TT were more frequent in smoking ones, but the difference was not significant. This observation fits with the assumption that the influence of smoking on the occurrence of AAA prevails over that of genetic variability. When the patients age was considered in the analysis, the PON1 -108CT and TT genotypes were identified as the significant risk factors for the development of AAA in the older smokers.

[The normotensive carriers of the MTHFR 677T allele, displaying the increased risk of development of the abdominal aortic aneurysm (AAA), occur at the highest frequency among the smoking patients]. / Nosiciele allela MTHFR 677T, zwiekszajacego ryzyko wystapienia tetniaka aorty brzusznej (AAA) u osób z prawidlowym cisnieniem tetniczym, wystepuja najczesciej w grupie chorych palacych.

Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Smoking, hypertension and several genetic factors are recognized as relevant for the pathogenesis of AAA. We studied association between the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (677C>T) and the occurrence of hypertension and smoking status in the group of 74 male patients with AAA. In the patients group, the smoking hypertensive persons represented the largest subgroup (43%). We determined the the MTHFR 677C>T polymorphism in AAA patients and compared it to that in 71 healthy normotensive males. The frequencies of the 677T allele and MTHFR 677C>T genotypes were similar in both groups, but the subgroup of normotensive AAA patients (n=29) displayed significantly increased frequencies of 677T allele (0.4) and of 677CT and TT genotypes (69%), as compared to those in the control group (0.28 and 46%, respectively). This corresponds to the 3.3-fold greater risk of AAA in normotensive subjects with the 677T allele of MTHFR, as compared to the homo-zygotes 677CC (p<0.03; 95% CI=1.2-9.2). The highest frequencies of MTHFR 677T allele (0.43) and 677CT and TT genotypes (73%) were found in the subgroup of normotensive smoking patients (n=22).

Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele.

Abdominal aortic aneurysm (AAA) presents itself as a progressive dilation of the abdominal aorta, leading--if untreated--to rupture. It is a common disease of the elderly, with a complex etiology. Several genetic, biochemical and environmental factors are recognized as relevant for the pathogenesis of AAA. We determined the polymorphism of the MTHFR (methylenetetrahydrofolate reductase) gene within the fourth exon (C677T) in 63 patients with AAA and compared it to that in 75 subjects of the population sample. The frequencies of the C/C, C/T and T/T genotypes were 65%, 27%, and 8% in the population sample and 33%, 60%, and 6% in the patients. This corresponds to a 4.4-fold greater risk of AAA in subjects who have the 677C/T variant of MTHFR, as compared with those who are 677C/C (p < 0.0001; 95% CI=2.11-9.34). The frequency of allele MTHFR 677T in patients (0.37) was higher than in the population sample (0.21; p < 0.007). This association between the common allele of the MTHFR gene--MTHFR 677T--and the development of AAA suggests that elevated homocysteine (Hcy) may disturb the function of the aortic wall. The disturbance may involve enhancement of elastin degradation, the process enhanced by mild hyperhomocysteinemia in minipigs. The magnitude of this effect, which refers to the AAA patients unselected for familial occurrence, indicates that the disturbance of aortic wall physiology caused by the presence of the MTHFR 677T allele is greater than the effect of the earlier described allele disequilibrium at the polymorphic alleles of the PAI1 (plasminogen activator inhibitor 1) gene seen only in familial cases of AAA.