Influence of MTHFR C677T gene polymorphism in the development of cardiovascular disease in Egyptian patients with rheumatoid arthritis.

OBJECTIVE: To investigate the association between increased carotid intima-media thickness (CIMT), homocysteine level, and MTHFR C677T (rs1801133) gene polymorphism in Egyptian people with rheumatoid arthritis (RA). SUBJECTS AND METHODS: 280 Egyptian women (160 RA patients and 120 controls) were included in the study. CIMT was measured using high resolution B-mode ultrasonography and homocysteine levels were measured using enzyme-linked immunosorbent assay. While, MTHFR C677T polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found that subjects who carried the TT genotype and T allele were significantly more likely to develop RA with 2.9 and 1.5 fold, respectively. RA patients carrying the T allele presented a statistically significant increased risk of developing atherosclerosis compared with those carrying the C allele. Moreover, MTHFR TT genotype was independent risk factor of thick CIMT. CONCLUSIONS: C677T MTHFR gene polymorphism is associated with RA in Egyptians. MTHFR 677TT carriers had higher concentrations of serum Hcy than did subjects harboring the CC and CT genotypes. The presence of 677T allele increases the risk of atherosclerosis in patients with RA. This increased risk of atherosclerosis could be due to hyperhomocysteinemia.

LDLR, ApoB and ApoE genes polymorphisms and classical risk factors in premature coronary artery disease.

Lipoproteins play a central role in the development of atherosclerotic disease. So, with their ability to affect lipid levels, the LDLR, ApoB and ApoE polymorphisms could be one of the factors influencing development of atherosclerosis. This hypothesis has been tested in different populations with conflicting results. The purpose of the present study was to investigate the association between the LDLR, ApoB and ApoE genes polymorphisms with premature CAD (PCAD) in Egyptians. One hundred thirty-five patients of PCAD and one hundred thirty-two ages and sex matched control subjects were included in the study. LDLR and ApoB genes polymorphisms were analyzed by polymerase chain reaction (PCR). The ApoE genotypes were identified by multiplex amplification refractory mutation system (multi-AMRS). We found that LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele increased the risk of PCAD by 1.8, 2.1 and 12.1 respectively. The present study proved that smoking, metabolic syndrome, ApoB X(+)X(+) genotype and ApoE E4 allele were independent risk factors for the development of PCAD. This is the first study investigate the association between low density lipoprotein receptor, apolipoprotein B and apolipoprotein E genes polymorphisms with PCAD and lipid levels in Egyptians and we concluded that the LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may be associated with an increased risk for development of PCAD by elevated levels of total cholesterol (TC) and low density lipoprotein (LDLc). The coexistence of CAD risk factors with LDLR A(+)A(+) genotype, ApoB X(+) allele and ApoE E4 allele may increase the risk of the development of PCAD in Egyptian patients.

Matrix Metalloproteinase 3 Gene Polymorphism and Its Level Predict Morbidity After Acute Myocardial Infarction.

OBJECTIVES: Matrix metalloproteinase is responsible for ventricular remodeling after acute myocardial infarction (MI). The purpose of the present study was to determine whether the matrix metalloproteinase 3 (MMP-3) polymorphism and its level predict morbidity after acute MI (AMI). METHODS: We studied 112 patients with AMI and 140 controls. All patients were followed for AMI complications during their hospitalization and 6 months after. Serum MMP-3 was measured. MMP-3-1612 5A/6A polymorphism was genotyped by polymerase chain reaction. RESULTS: We observed that the serum MMP-3 levels were significantly increased in patients with AMI with morbidity compared with patients without complications. Also, MMP-3 levels in patients with AMI carrying 5A/5A were elevated compared with those carrying 6A/6A. The frequencies of 5A/5A genotypes were significantly increased in patients with AMI compared with controls, and patients with AMI carrying 5A/5A had a fivefold increased risk of developing morbidity. The impairment of left ventricular function (ΔFS [fractional shortening] and ΔEF [ejection fraction]) was observed more in the 5A/5A genotype compared with the 6A/6A genotype. A significant inverse correlation between predischarge MMP-3 levels and FS and EF was found at 6 months follow-up. CONCLUSIONS: MMP-3 polymorphism has a significant association with the risk of developing morbidity after AMI. Higher predischarge MMP-3 levels are associated with left ventricular dysfunction after AMI.

A new metabolic mechanism for absence of pain in patients with silent myocardial ischemia.

BACKGROUND AND AIMS: We undertook this study to detect if there is a relationship between lactate production in the myocardium and the presence or absence of chest pain in patients with coronary artery disease (CAD). METHODS: Forty six patients with significant CAD including left anterior descending artery underwent echocardiography study, coronary angiography and pacing-induced ischemia. Serum lactate levels were determined in four blood samples, from mid-LV cavity and from coronary sinus before and after pacing-induced ischemia. Twenty eight patients comprised angina group and 18 patients comprised silent myocardial ischemia (SMI) group during pacing-induced ischemia. RESULTS: Eighteen patients (64.3%) of angina group had lactate production during ischemia. Eighteen patients of SMI group (100%) had diminished lactate extraction, and none had lactate production. CONCLUSION: The novel finding of this study is that the major difference in metabolism during SMI and angina pectoris is in the state of lactate production, which is absent during SMI and present during angina. We assume that lactate is the stimulus of cardiac ischemic pain and when its level increases, it stimulates pain receptors leading to chest pain.

Relation of PAI-1 and TPA genes polymorphisms to acute myocardial infarction and its outcomes in Egyptian patients.

Endogenous fibrinolysis is a protective mechanism against arterial thrombotic occlusion, which would otherwise lead to permanent tissue damage as acute myocardial infarction (AMI). We aimed to investigate the association of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (TPA) genes polymorphisms with myocardial infarction and its outcomes in Egyptian patients. 184 patients with AMI and 184 controls were included in the study. PAI-1 and TPA genes polymorphisms were analyzed by polymerase chain reaction. All patients were followed for AMI complications during their hospitalization. We found a significant association among TPA ID, II genotypes, and I allele and increased risk of AMI by 2.1, 3.2, and 1.9 fold, respectively. Also, the frequencies of PAI-1 4G/4G genotype and 4G allele were significantly increased in patients with AMI as compared to the control group. Furthermore, AMI patients with PAI-1 4G/4G genotype were significantly more likely to have morbidity and mortality complications as compared to AMI patients without complications (P = 0.00 and 0.048, respectively). We concluded that 4G/4G genotype and 4G allele of the PAI-1 gene are associated with risk of AMI and its morbidity. The PAI-1 4G/4G genotype is associated with mortality of AMI. There is also an association between TPA ID, II genotypes, and I allele with increased risk of AMI.

Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism.

BACKGROUND: Epidemiological studies have shown a strong inverse relationship between high-density lipoprotein (HDL) cholesterol (HDLc) levels and coronary artery disease (CAD), and a low concentration of plasma HDLc is considered an independent risk factor for premature atherosclerosis. Mutations in ATP-binding cassette A1 transporter (ABCA1), cholesteryl ester transfer protein (CETP), and lecithin: cholesterol acyltransferase (LCAT) reduce HDLc in humans. OBJECTIVE: To date, no study had tested the association between these polymorphisms and premature CAD (PCAD) in the Egyptian population. Here we searched for ABCA1 (rs2230806), CETP (rs708272), and LCAT (rs5923) mutations in the Egyptian population and investigated the possible association between these gene polymorphisms and PCAD. We aimed to investigate the association between ABCA1, CETP, and LCAT gene polymorphisms and PCAD in Egyptians. METHODS: A total of 235 Egyptians-116 with documented PCAD (PCAD group) and 119 controls-were enrolled in the study. RESULTS: Mutation carriers with low HDLc had an elevated risk of PCAD (odds ratio [OR] = 11.38 for ABCA1 mutation carriers, P = .000; OR = 5.41 for CETP mutation carriers, P = .000; OR = 5.92 for LCAT mutation carriers, P = .000). Moreover, mutations in ABCA1, CETP, and LCAT were significantly associated with hyperlipidemia in this study. CONCLUSION: These observations show that the R allele of ABCA1, the B1 allele of CETP, and the T allele LCAT genes are associated with PCAD in Egyptians. They have more considerable effect on patients with low HDLc.

Association of angiotensin II type I and type II receptor genes polymorphisms with the presence of premature coronary disease and metabolic syndrome.

Premature coronary artery disease (PCAD) is known to have a particularly strong genetic component. We aimed to investigate the association between angiotensin II receptor type 1 (ATR1) or type II (ATR2) genes polymorphisms and PCAD with or without metabolic syndrome in males. 132 male patients with PCAD and 132 controls were included in the study. ATR1 and ATR2 genes polymorphisms were analyzed by polymerase chain reaction. The present study revealed that ATR1 CC genotype and ATR2 G allele increased the risk of PCAD by 2.9 and 1.3 respectively as well as they increased susceptibility to metabolic syndrome by 4.5 and 2.3 respectively. The present study proved that diabetes, smoking, obesity, total cholesterol, triglycerides, LDLc and HDLc were independent risk factors for the development of PCAD. We concluded that ATR1 CC genotype and ATR2 G allele increased the susceptibility of Egyptian males to have PCAD. The increased susceptibility to have metabolic syndrome could be one of the mechanisms leading to the development of PCAD in subjects carrying one or both of these polymorphisms.

Human C-reactive protein gene polymorphism and metabolic syndrome are associated with premature coronary artery disease.

The aim of this study was to investigate the association between C-reactive protein (CRP) gene polymorphism and metabolic syndrome (MetS) with premature coronary artery disease (PCAD). 116 patients with PCAD (58 with MetS and 58 without MetS) and 119 controls were included in the study. CRP gene +1059 G>C polymorphism was analyzed by polymerase chain reaction. Serum hs-CRP was measured using high-sensitivity enzyme-linked immunosorbent assay. Carriers of C allele of the CRP +1059 G>C polymorphism had 3.37 fold increased risk to develop MetS in patients with PCAD. In addition CRP gene and hs-CRP levels were independent risk factors for PCAD and MetS. The present study provides new evidence that the presence of CRP +1059 G>C polymorphism and hs-CRP levels are independent determinants of PCAD and MetS in Egyptians. The results of our study suggest a synergistic effect of CRP C allele with classical risk factors such as hypertension, obesity, dyslipidemia and MetS.

Synergistic effect between lipoprotein lipase and apolipoprotein C3 genes in determining the severity of coronary artery disease.

A number of genetic variants have been identified in the lipoprotein lipase (LPL) gene. We aimed to investigate the possible associations between LPL gene and apolipoprotein C3 (APOC3) gene polymorphisms with coronary artery disease (CAD) and its severity, as well as the interaction between these polymorphisms and classical risk factors. The HindIII variant of LPL and APOC3 were genotyped in 156 CAD patients and 154 subjects as a control group. We found that the odds ratio (OR) estimating the effect of joint exposure to H2H2 genotype of LPL and S2S2 genotype of APOC3 was significantly higher than the OR estimating the effect of each factor in the absence of the other. The present study points to a synergistic interaction between H2H2 genotype of LPL gene and S2S2 genotype of APOC3 gene that leads to increased severity of CAD. Smoking, low HDL, and diabetes increased the severity of CAD in patients carrying these risky genotypes.

Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.

Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients.

Leptin, leptin gene and leptin receptor gene polymorphism in heart failure with preserved ejection fraction.

Heart failure with a normal ejection fraction (HFNEF) is common in obesity and coronary artery disease (CAD). Both ischemia and reperfusion induce leptin (LEP) and leptin receptor (LEPR) gene expression. We aimed to investigate the possible associations of serum leptin, leptin gene and leptin receptor gene polymorphism with HFNEF in patients with CAD. 100 Egyptian CAD patients with HFNEF and 100 healthy subjects (the control group) were genotyped for LEP and LEPR polymorphism. Leptin levels were measured. Serum leptin levels were significantly increased in patients compared to the control group. There was a significant increase in the leptin gene (AA genotype) and the leptin receptor gene (RR genotype) in HFNEF patients compared to the control group. Leptin levels, leptin gene (AA genotype) and LEPR (RR genotype) were more associated with NYHA III than with NYHA I and II. We thus concluded that HFNEF is associated with increased serum leptin levels, and the LEP AA genotype or LEPR RR genotype carries at least a threefold increased risk of developing HFNEF.

Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats.

Catechin has anti-inflammatory and antioxidative effects. Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the adriamycin use in the treatment of malignant tumors. Thus, the present study aimed to assess the antioxidant and anti-inflammatory effects of catechin on adriamycin-induced cardiotoxicity in rats. Forty-five rats were allocated to three groups: control group, adriamycin group and adriamycin + catechin group. We performed the following measurements: lipid peroxidation (MDA), catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities as well as, the expression of inflammatory cytokines genes namely nuclear factor kappa-B, tumor necrosis factor and inducible nitric oxide synthase. Catechin administration significantly decreased MDA level and significantly increased CAT, GSH-Px and SOD activities. Also, catechin significantly decreased the expression levels of inflammatory cytokines. Catechin provided cardioprotection on adriamycin-induced cardiotoxicity through their antioxidant and anti-inflammatory properties.

Noninvasive prediction of left ventricular end-diastolic pressure in patients with coronary artery disease and preserved ejection fraction.

BACKGROUND: The aim of this study was to compare 3 different available methods for estimating left ventricular end-diastolic pressure (LVEDP) noninvasively in patients with coronary artery disease and preserved left ventricular ejection fraction (EF). METHODS: We used 3 equations for noninvasive estimation of LVEDP: The equation of Mulvagh et al., LVEDP(1) = 46 - 0.22 (IVRT) - 0.10 (AFF) - 0.03 (DT) - (2 ÷ E/A) + 0.05 MAR; the equation of Stork et al., LVEDP(2) = 1.06 + 15.15 × Ai/Ei; and the equation of Abd-El-Aziz, LVEDP(3) = [0.54 (MABP) × (1 - EF)] - 2.23. ( ABBREVIATIONS: A, A-wave velocity; AFF, atrial filling fraction; Ai, time velocity integral of A wave; DT, deceleration time; E, E-wave velocity; Ei, time velocity integral of E wave; IVRT, isovolumic relaxation time; MABP, mean arterial blood pressure; MAR, time from termination of mitral flow to the electrocardiographic R wave; Ti, time velocity integral of total wave.) RESULTS: LVEDP measured by catheterization was correlated with LVEDP(1) (r = 0.52, P < 0.001), LVEDP(2) (r = 0.31, P < 0.05), and LVEDP(3) (r = 0.81, P < 0.001). CONCLUSIONS: The equation described by Abd-El-Aziz, LVEDP = [0.54 MABP × (1 - EF)] - 2.23, appears to be the most accurate, reliable, and easily applied method for estimating LVEDP noninvasively in patients with preserved left ventricular ejection fraction and an LVEDP < 20 mm Hg.

Association of lipoprotein lipase and apolipoprotein C-III genes polymorphism with acute myocardial infarction in diabetic patients.

Lipoprotein lipase (LPL) and Apolipoprotein C-III (APOC-III) play an important role in lipid metabolism. The aim of this study was to explore the possible associations of the gene polymorphisms (LPL HindIII, LPL Ser(447)-Ter and APOC3 SstI), diabetes mellitus, and plasma lipids with myocardial infarction. The polymorphisms were assessed by restriction assay in 200 Egyptian MI patients (100 diabetic and 100 non-diabetic) and 100 healthy controls. This study demonstrated that individuals with the H2H2 genotype or S2 allele have more than three times higher relative risk of suffering from MI than those carrying the H1H1 or S1S1. Type 2 DM mainly lowers HDL-C levels in MI patients who carry H2H2 or S2S2 genotype and increases TC, TG, and LDL levels in MI patients carrying H2H2 or S2S2 genotype compared with non-diabetic MI patients carrying the same genotypes. In S447X polymorphism, it was observed that DM led to loss of the protective lipid profile in MI patients carrying 447XX genotype. These findings suggest that H2H2 or S2S2 genotypes are associated with dyslipidemia and increased risk of myocardial infarction. The S447X polymorphism is associated with a favorable lipid profile. However, the association of diabetes mellitus with these polymorphisms leads to unfavorable lipid profile.

Evaluation of cardiac function in patients with liver cirrhosis.

AIM OF THE STUDY: To study the cardiac function in patients with liver cirrhosis. METHODS: Thirty patients with liver cirrhosis, referred to as group I (G 1), were selected. They were subdivided according to Child-Pugh classification into 3 groups: A, B, and C. Thirty healthy subjects, referred to as group II (G II), were selected as a control group. All persons were examined by resting ECG, abdominal ultrasound, laboratory tests, and echo-Doppler evaluation of systolic and diastolic functions of both ventricles using 2-D, M-mode, conventional Doppler, and tissue Doppler parameters. RESULTS: Systolic and diastolic blood pressures were significantly reduced with increased resting HR and CO in G I (p<0.05). The QTc interval was prolonged in G I (0.45±0.03 ms; p<0.001) but EDV, ESV, EF%, and S´ velocity were not significantly different in both study groups for both ventricles. LAD, MPI, LVPWT, and, IVST were significantly increased in G I (p<0.05). E/A and E´/A´ ratios were reversed in G I with increased DT/E for both ventricles (p<0.001). No significant difference was found among Child A, B, C subgroups except for the LAD which was significantly increased in Child C (p<0.05). There was a significant inverse correlation between serum albumin and left ventricular MPI (r=-0.4, p<0.05). CONCLUSION: Many cardiovascular abnormalities occur in patients with liver cirrhosis that mandate echocardiographic evaluation especially in cases who undergo any procedure which may affect the hemodynamics.

The relationship between paraoxonase1-192 polymorphism and activity with coronary artery disease.

OBJECTIVE: We tested the association between PON1 polymorphism, PON1 activity, oxidative susceptibility of LDL and coronary artery disease in Egyptians. METHODS: PON1 polymorphism, serum PON1 activity, lipoprotein oxidation susceptibility and lipid profile were measured. RESULTS: Levels of HDL and paraoxonase activity were significantly decreased in CAD patients compared to control group, and in patients with three vessels compared to those of single or two vessels disease. High-activity allele (R) has a more atherogenic lipid profile than for the low activity allele (Q). PON1 RR genotype has nine fold risks to develop CAD in Egyptians while those with PON1 QR genotype have four fold risks. CONCLUSION: The PON1 activity is lower in subject with CAD and there is a significant relationship between activity of PON1 and the severity of coronary atherosclerosis. Also, we provide evidence of a significant association between R allele of the PON1 polymorphism and the development of coronary artery disease.

A-wave acceleration: a new Doppler echocardiographic index for evaluation of left ventricular diastolic dysfunction in elderly patients.

Age alters Doppler indexes of left ventricular diastolic performance. Thus, the Doppler detection of left ventricular diastolic dysfunction in the elderly is difficult. The reliability of Doppler indexes in detecting left ventricular diastolic dysfunction in the elderly patients with cardiac diseases known to affect diastolic function were evaluated. Diastolic function using pulsed Doppler in 6 groups of 10 subjects each: elderly normal, young normal, and elderly with hypertrophic cardiomyopathy, aortic stenosis, coronary artery disease, and dilated cardiomyopathy was tested. The comparison of elderly normal with young normal showed that A-wave acceleration did not change significantly. Comparing elderly normal to elderly with diseases showed that all tested indexes except A-wave acceleration failed to separate normal elderly from diseased elderly. A-wave acceleration appears to be a useful index that can help in diagnosis of left ventricular diastolic dysfunction in elderly patients independent of age effects.