Subjects with microvascular angina have longer GT repeats polymorphism in the haem oxygenase-1 gene promoter.

Objective: Few studies have investigated haem oxygenase-1 gene (HMOX1) promoter polymorphism in microvascular angina (MVA).Materials and methods: HMOX1 promoter (GT)n repeats were examined in healthy controls (N = 220) and MVA subjects (N = 181).Results: The distribution of genotype of SS, SL and LL were significantly different in MVA (17%, 51%, 33%) vs. normal controls (35%, 46%, 20%) (p < 0.001, S allele: ≤30 repeats, L allele: >30 repeats). In multivariate analysis, carrier of L allele (odds ratio 2.772, p < 0.001) was a significant predictor for the diagnosis of MVA.Conclusions: Subjects with MVA had longer HMOX1 promoter (GT)n repeats than the healthy controls. Trial registration number: NCT01198730 at https://clinicaltrials.gov.

Serum paraoxonase 1 activity and oxidative markers of LDL in patients with cardiac syndrome X.

OBJECTIVE: Myocardial ischaemia in cardiac syndrome X (CSX) is believed to be due to microvascular dysfunction. Increased oxidative stress is one of the suspected mechanisms of microvascular dysfunction. The aim of this study was to evaluate the oxidative status in patients with CSX, by determining serum paraoxonase-1 (PON 1) activity in addition to LDL-oxidation markers. METHODS AND RESULTS: This cross-sectional study consisted of patients with CSX (group I, n = 30), patients with coronary artery disease (group II, n = 31), and healthy controls (group III, n = 32). Lipid parameters, PON-1 activity, and LDL oxidation markers (conjugated-diene and thiobarbituric acid-reactive substance-TBARS) were measured. Endothelium-dependent vasodilatation was determined by brachial artery ultrasonography. There were no significant differences in serum LDL, apolipoprotein-B, baseline LDL-diene, and LDL-TBARS levels between groups. There were no differences in both apolipoprotein-A1 and HDL levels between group I and group III. Apolipoprotein-A1 and HDL levels were significantly lower in group II than group I patients (P < 0.001). PON-1 activity was lowest in group II patients. Average PON-1 activity in group I was in between of group II and group Ill. The percent change of LDL-diene levels after stimulation was significantly higher in group II than in groups I and III (P = 0.005 and P = 0.02, respectively). The percent change of LDL-TBARS levels was lowest in group I (P = 0.03). There was a moderate correlation between endothelium-dependent vasodilatation and PON-1 activity in group I (r = 0.43, P = 0.04). CONCLUSIONS: Enhanced oxidative stress might be one of the causes of impaired endothelial functions resulting in myocardial ischaemia and chest pain in patients with CSX. The relatively preserved HDL and apolipoprotein-A1 levels in patients with CSX might be a protective mechanism against progression of coronary microvascular dysfunction to atherosclerotic coronary artery disease.

Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese.

BACKGROUND: Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. METHODS AND RESULTS: The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. CONCLUSIONS: There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.

Plasma matrix metalloproteinase-3 level is an independent prognostic factor in stable coronary artery disease.

BACKGROUND: Recent evidence suggests the important role of matrix metalloproteinases (MMPs) in the progression of atherosclerosis and development of clinical events. We assessed the prognostic value of different plasma MMPs in patients with stable coronary artery disease (CAD). MATERIALS AND METHODS: A total of 165 consecutive nondiabetic patients with angiographically significant CAD (n = 150) or normal coronary angiograms despite exercise-induced myocardial ischemia (cardiac syndrome X, n = 15) and 17 normal subjects were evaluated. In each subject, plasma inflammatory markers including high sensitivity C-reactive protein (hsCRP) and MMP-2, 3 and 9 were measured. In CAD patients, major cardiovascular events including cardiac death, nonfatal myocardial infarction, unscheduled coronary revascularization and hospitalization as a result of unstable angina were prospectively followed up for more than 6 months. RESULTS: Plasma levels of MMPs were significantly higher in CAD patients than in those with cardiac syndrome X and in normal subjects (MMP-2: 914.76 +/- 13.20 vs. 830.79 +/- 31.95 vs. 783.08 +/- 28.40 ng mL(-1), P = 0.002; MMP-3: 129.59 +/- 4.21 vs. 116.86 +/- 8.09 vs. 91.71 +/- 9.55 ng mL(-1), P = 0.011; MMP-9: 31.42 +/- 2.84 vs. 11.40 +/- 5.49 vs. 6.71 +/- 2.89 ng mL(-1), P = 0.006). In CAD patients, there were 48 major cardiovascular events during a mean follow-up period of 17.74 +/- 0.85 months. The numbers of diseased vessels (HR = 2.19, 95% CI 1.20-1.02, P = 0.011), plasma hsCRP (HR = 2.21, 95% CI 1.18-4.11, P = 0.013) and MMP-3 level (HR = 2.46, 95% CI = 1.15-5.28, P = 0.021) were associated with the development of cardiovascular events. However, only the plasma MMP-3 level was an independent predictor of the adverse events in CAD patients (HR = 2.47, 95% CI 1.10-5.54, P = 0.028). CONCLUSIONS: Plasma MMP levels were increased in CAD patients. Plasma MMP-3 level, rather than hsCRP, was an independent prognostic marker for future cardiovascular events, suggesting its potential role in risk stratification and clinical management of stable CAD.

Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac Syndrome X: role of superoxide dismutase activity.

BACKGROUND: Morbidity of patients with Syndrome X (SX; chest pain and normal coronary angiograms) is high and is associated with continuing episodes of chest pain and hospitalization. Impairment of microvascular endothelial function caused by increased oxidative stress has been suggested to be a mechanism of the disease. Superoxide dismutase (SOD) is the major antioxidant enzyme system of the vascular wall. This study sought to establish whether combination treatment with ACE inhibitors and statins reduces oxidative stress and improves quality of life of patients with cardiac SX. METHODS AND RESULTS: Forty-five patients with SX were randomly assigned to receive either a combination of ramipril (10 mg/d) and atorvastatin (40 mg/d) or placebo for 6 months. We determined the activity of extracellular SOD and its relation to flow-dependent endothelium-mediated dilation (FMD) and quality of life (exercise capacity and score with Seattle Angina Questionnaire [SAQ]) before and after treatment. After 6 months, patients with SX who received atorvastatin and ramipril had significantly reduced (P=0.001) SOD levels (188.1+/-29.6 U/mL). No significant changes were seen on placebo (262.9+/-48.8 U/mL). Reduction of SOD after therapy was negatively correlated with FMD (r=0.38; P=0.01) and positively with total cholesterol (r=-0.56; P<0.001). At follow-up, patients taking atorvastatin and ramipril improved their quality of life both in terms of exercise duration (by 23.46%) and SAQ (by 64.1%). CONCLUSIONS: Six months of therapy with atorvastatin and ramipril improves endothelial function and quality of life of patients with SX. Reduced SOD activity may reflect low superoxide anion production. Benefits of these drugs may be related to reduction of oxidative stress.

Nitric oxide synthase gene G298 allele. Is it a marker for microvascular angina in hypertensive patients?

BACKGROUND: Nitric oxide (NO) has an important effect on blood pressure, arterial wall, and the basal release of endothelial NO in hypertension (HPN) may be reduced. Until now, there is no solid data revealing the potential role of the polymorphism of the nitric oxide synthase gene (NOS) in patients with HPN and microvascular angina. AIM: The aim of the present study is to investigate the gene of endothelial nitric oxide synthase (eNOS), as the polymorphism of this gene may be a putative candidate for HPN and initiate the process of atherosclerosis. METHODS: Sixty participants were recruited for this study; 50 were hypertensive patients complaining of chest pain [30 of them have electrocardiogram (EKG) changes of ischemia], 20 had isolated HPN, and 10 healthy volunteers served as control. All patients underwent stress myocardial perfusion imaging (MPI) and coronary angiography. Genotyping of eNOS for all patients and controls was performed. The linkages between HPN, microvascular angina and eNOS gene polymorphism were investigated. RESULTS: MPI and coronary angiography revealed that 15 patients had chest pain with true ischemia and reversible myocardial perfusion defects (multiple and mild) but normal epicardial coronary arteries (microvascular angina), while 15 patients had significant coronary artery disease (CAD), and 20 hypertensive patients showed normal perfusion scan and coronary angiography. The prevalence of the NOS G(298) allele was higher in the hypertensive group with microvascular angina (documented by MPI) than it was among the control participants (P<.005). The eNOS allele was significantly higher in the hypertensive group than in the control participants, but there was no significant difference in homozygote mutants among hypertensive participants, x-syndrome and patients with CAD. CONCLUSION: eNOS gene polymorphism is proved to be an important etiology in microvascular angina (x-syndrome) among hypertensive patients. In addition, the eNOS mutant gene showed a significant increase in isolated HPN and in patients with CAD.

Membrane Na+ K+ ATPase inhibition related dyslipidemia and insulin resistance in neuropsychiatric disorders.

There are several reports in literature implicating cholesterol metabolism in the pathogenesis of neuronal degenerations, oncogenesis, functional neuropsychiatric disorders and multiple sclerosis. Biosynthesis of cholesterol takes place by the isoprenoid pathway, which also produces digoxin, an inhibitor of membrane Na(+)-K+ ATPase. Inhibition of this enzyme results in intracellular Mg++ deficiency which can influence cholesterol metabolism. Digoxin also influences transport of tryptophan and tyrosine which are precursors of various neurotransmitters. Alterations in digoxin, membrane Na(+)-K+ ATPase and also in neurotransmitters have been reported in the disorders mentioned above. In view of this, serum lipid profile, activity of plasma HMG CoA reductase (the major rate limiting step in the isoprenoid pathway), RBC membrane Na(+)-K+ ATPase activity, serum Mg++ concentration, concentration of digoxin and concentration of serum neurotransmitters were studied in some neuropsychiatric disorders. The serum serotonin level was increased while that of serum dopamine and noradrenaline was reduced. Serum digoxin levels were high and RBC membrane sodium-potasium ATPase activity and serum magnesium were reduced. There was a reduction in HDL cholesterol and increase in plasma triglycerides (pattern similar to insulin resistance and syndrome X) in most of the disorders studied. The HMG CoA reductase activity was high, the serum total cholesterol was increased while RBC membrane cholesterol was reduced in most of the cases. The significance of increased digoxin with consequent inhibition of membrane Na(+)-K+ ATPase in relation to changes in cholesterol metabolism and insulin resistance type of dyslipidemia is discussed in this paper.

Angiotensin-converting enzyme insertion/deletion polymorphism in angina pectoris with normal coronary arteriograms.

We investigated the relation between angiotensin-converting enzyme gene insertion/deletion polymorphism and syndrome X (angina with normal coronary arteriogram). The results of our study suggest that this polymorphism does not play a major role in the pathogenesis of microvascular angina.