Increased Risk of the APOB rs11279109 Polymorphism for CHD among the Kuwaiti Population.

BACKGROUND: Coronary heart disease (CHD) is among the leading causes of death in Kuwait. This case-control study investigated the genetic association of APOB rs11279109 with CHD in Kuwaitis. METHODS: The polymorphism was genotyped in 734 Kuwaiti samples by direct amplification. Statistical analysis with genetic modeling was used to assess its association with CHD. RESULTS: A statistically significant association (P < 0.001) between the rs11279109 DD genotype (OR: 2.43, CI: 1.34-4.41) with CHD was observed. A codominant genetic model revealed a 2.69 risk increase (CI: 1.57-4.61) for the DD genotype (P = 0.009) independent of age, sex, BMI, smoking, hypercholesterolemia, and ethnicity suggesting APOB rs11279109 as an indicator for the increased risk of CHD. CONCLUSION: The DD genotype may explain molecular mechanisms that underline increased LDL oxidation leading to arthrosclerosis. The findings emphasize the need to identify genetic markers specific to the CHD patient ethnic group in order to improve prognosis and help in early diagnosis and prevention.

Association of the insertion allele of the common ACE gene polymorphism with type 2 diabetes mellitus among Kuwaiti cardiovascular disease patients.

BACKGROUND AND OBJECTIVES: The D allele of the common angiotensin-converting enzyme (ACE) I/D gene polymorphism (rs4646994) predisposes to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, results on which allele predisposes to disease susceptibility remain controversial in Asian populations. This study was performed to evaluate the association of the common ACE I/D gene polymorphism with both T2DM and CVD susceptibility in an Arab population. METHODS: We genotyped the ACE I/D polymorphisms by direct allele-specific PCR in 183 healthy controls and 400 CVD patients with diabetes (n=204) and without (n=196). Statistical analysis comparing between the different groups were conducted using R statistic package "SNPassoc". RESULTS: Two genetic models were used: the additive and co-dominant models. The I allele was found to be associated with T2DM (OR=1.84, p=0.00009) after adjusting for age, sex and body mass index. However, there was no association with CVD susceptibility (p>0.05). CONCLUSION: The ACE I allele is found to be associated with T2DM; however, no association was observed with CVD. The inconsistency between studies is suggested to be attributed to genetic diversity due to the existence of sub-populations found in Asian populations.

RU28318, an aldosterone antagonist, in combination with an ACE inhibitor and angiotensin receptor blocker attenuates cardiac dysfunction in diabetes.

AIMS: We evaluated the effects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats. METHODS: Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated. RESULTS: Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. CONCLUSIONS: RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function) when administered to diabetic hearts after ischemia.

Chronic treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase, attenuates ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive diabetic animals.

Diabetes is associated with increased incidence of cardiovascular disease. Mechanisms that contribute to development of diabetic cardiopathy are not well understood. Phosphatidylinositol 3-kinase (PI3K) is a family of protein kinases that play an important role in regulation of cardiac function. It has been shown that inhibition of certain PI3K enzymes may produce cardiovascular protection. The aim of the present study was to determine whether chronic treatment with LY294002, an inhibitor of PI3K, can attenuate diabetes-induced cardiac dysfunction in isolated hearts obtained from normotensive and hypertensive rats. Recovery of cardiac function after 40 min of global ischemia and 30 min of reperfusion, measured as left ventricular developed pressure, left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance, was worse in hearts obtained from diabetic and/or hypertensive animals compared to their respective controls. Treatment with LY294002 (1.2 mg/kg/day) for 4 weeks significantly prevented diabetes-induced cardiac dysfunction in both normotensive and hypertensive rats. Treatment with LY294002 did not significantly alter blood pressure or blood glucose levels. These results suggest that inhibition of PI3K signaling pathways can prevent ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive rats without correcting hyperglycemia or high blood pressure.

Prevalence of overweight, obesity, and metabolic syndrome among adult Kuwaitis: results from community-based national survey.

BACKGROUND: Although, metabolic syndrome and obesity are cardiovascular risk factors, little systematically collected community-based data are available from the Arabian Gulf region. METHODS: We report a nationwide cross-sectional study from Kuwait. A random sample was selected. Demographic and clinical data were collected. Blood tests including fasting blood glucose, high-density lipoprotein cholesterol, and triglycerides were collected. Metabolic syndrome was defined according to International Diabetes Federation criteria. Overweight and obesity were defined as body mass index >or=25, and body mass index >or=30, respectively. RESULTS: Prevalence of overweight, obesity, and metabolic syndrome in adult Kuwaiti population were 80.4%, 47.5%, and 36.2%, respectively. Overweight and obesity rates were higher in women 81.9% and 53% compared to men 78% and 39.2%, respectively (P = .02, P > .001). MetS was equally distributed between men and women at 36.2% and 36.1%. CONCLUSIONS: Prevalence of overweight, obesity, and metabolic syndrome is alarmingly high in Kuwait. This requires urgent and active community-based public health intervention.

Percutaneous revascularization of unprotected left main: results of PCI using drug-eluting stent in ostial versus distal bifurcation disease.

BACKGROUND: Coronary artery bypass graft surgery is standard treatment for unprotected left main coronary artery disease. Recently, drug-eluting stents have been used to treat unprotected left main coronary artery disease. OBJECTIVE: To analyze data for consecutive patients treated at a single center with drug-eluting stents for unprotected left main coronary artery disease. RESULTS: Seventy-three patients underwent elective percutaneous coronary intervention of unprotected left main coronary artery disease. Twenty-one (30%) of the patients had disease involving the ostium or midshaft of the left main, while the remaining 52 (70%) patients had distal bifurcation disease. The group consisted of high-risk patients with an average European System for Cardiac Operative Risk Evaluation of 9% (range 0.9%-54%). After 1 year follow-up, 3 (4%) patients died; 8 patients (11%) had target vessel revascularization; 4 with repeat percutaneous coronary intervention; and 4 with coronary artery bypass graft surgery. All the events occurred in the distal bifurcation group. CONCLUSION: These results from a single-center registry suggest the safety of performing percutaneous coronary intervention with drug-eluting stents in unprotected left main coronary artery disease with low major adverse cardiac events (MACE) rates at 1 year.

Apolipoprotein E, CI and B gene polymorphisms in a sample of patients with coronary heart disease in the Kuwaiti population.

OBJECTIVES: The objective of this study was to investigate the possible association of clinical variables and apolipoprotein (APOE, APOCI and APOB) polymorphisms with the development of myocardial infraction (MI) and coronary heart disease (CHD) in Kuwaitis. SUBJECTS AND METHODS: APOE, APOCI and APOB genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism in 143 Kuwaiti CHD patients with (n = 88) and without (n = 55) MI and in 122 controls matched for gender and age. Statistical and genetic analyses of the genotype, allele and haplotype frequencies, as well as regression analyses of genetic and clinical variables were done. RESULTS: There was a statistically significant association between CHD and medical history of diabetes mellitus (p < 0.001), hypertension (p < 0.01), high cholesterol (p < 0.05) and family history of CHD (p < 0.001). A highly significant association (p < 0.001) was found, with an adjusted odds ratio of 9.32, for family history and the development of MI. No significant differences were found for allele or genotype frequencies between CHD patients and controls. CONCLUSION: The strong effect of family history suggests a major genetic component for the development of CHD in Kuwaitis, but this association does not appear to be related to the APO genes studied here. The results in this study encourages future research into these and other polymorphisms and their potential association with MI and CHD in the Kuwaiti population.

Accuracy of 64-multidetector-row computed tomography in the diagnosis of coronary artery disease.

OBJECTIVES: The aim of this prospective study was to assess the accuracy of 64-multidetector-row computed tomography coronary angiography (CTA) in the diagnosis of coronary artery disease (CAD). PATIENTS AND METHODS: Ninety-two patients suspected of having CAD underwent CTA using a 64-slice CT scanner before a scheduled, conventional coronary angiogram (CCA). Blinded assessment of CTA to detect CAD was performed. The accuracy of CTA in detecting significant stenoses (> or =50%) was compared to CCA. Data analysis was performed on 73 patients because the scans were nondiagnostic in 5 patients and 14 refused to undergo coronary angiography. RESULTS: The CTAs of 21 of these 73 patients were considered as normal; 19 were confirmed on CCA. For the remaining 52 diagnosed as abnormal, 51 were confirmed on CCA. For patient-based analysis, CTA had a sensitivity of 95%, a specificity of 96%, a positive predictive value of 98% and a negative predictive value of 90%. For the whole vessel, the sensitivity of CTA was 60-100%, for all vessels and the specificity was 82-100%. Pooled sensitivity was 92% and pooled specificity was 98%. For the segments, the sensitivity of CTA was 64% or above for all vessels except for the distal left anterior descending artery (40%), mid circumflex artery (50%) and posterior descending artery (60%); the pooled sensitivity was 79%. The specificity for the segments was 82-100% for all vessels and pooled specificity was 94%. CONCLUSION: The sensitivity and specificity for patient-based analysis and for the main coronary vessels were high whereas for the segments, the sensitivity was moderately good, but the specificity was high, confirming that a negative CTA is useful to rule out significant CAD. A coordinated classification system between radiologists and cardiologists is required to eliminate errors in segment classification.

Carina modification T stenting, a new bifurcation stenting technique: clinical and angiographic data from the first 156 consecutive patients.

OBJECTIVES: To describe a new technique, the Carina modification T stenting (CMT), which will provide an easily reproducible strategy for tackling bifurcation lesions in different patient and anatomic subsets. BACKGROUND: The optimal treatment of coronary bifurcation lesions remains problematic. The question of using one stent in the main vessel (MV) with PTCA of the side-branch (SB) versus stenting both arms (MV and SB) is debated. More importantly, the technique of choice once a two-stent approach is chosen is suboptimal because of technical difficulties encountered. This includes lack of osteal side branch coverage, difficulties with access to the side-branch for a mandatory final balloon kissing, and the presence of thrombogenic layers of crushed stents. METHODS: We describe here the CMT procedure for bifurcational coronary stenosis, and present the angiographic and clinical outcomes in 156 consecutive patients who underwent bifurcation PCI using CMT in our center. RESULTS: Short and medium term results show a 99% procedural success rate with low major adverse coronary events (MACE), including a low rate of clinical restenosis. MACE free survival rate at 48 months follow-up was 88%. CONCLUSIONS: The new CMT method of bifurcational PCI demonstrated advantages in terms of technical feasibility, ostial side branch coverage, and favorable patient outcome. Further evaluation with larger studies and long term follow-up is warranted.

One-year outcomes with the Taxus Liberté stent in the real world: the Taxus Olympia registry (phase I).

BACKGROUND: The Taxus Olympia registry is a prospective, postapproval registry collecting clinical outcomes data on patients receiving the Taxus Liberté paclitaxel-eluting stent during routine interventional cardiology practice. METHODS: Between February and July 2005, 529 patients receiving the Taxus Liberté stent at 16 centers in the Middle East, South/Central America, and Asia/Pacific regions were enrolled in Phase I of Olympia. The primary end-point was Taxus Liberté stent-related cardiac events (cardiac death, MI, and revascularization) at 30 days postimplant. Additional clinical assessment was conducted at 6 and 12 months. Olympia phases II and III are in clinical follow-up and will be reported separately. RESULTS: One-year clinical follow-up is available for 98% of patients. Complex patients and lesions were prevalent, including: 50% diabetes mellitus, 49% multivessel disease, 30% multiple stenting, 48% AHA/ACC type B2/C lesions, 19% long lesions (>26 mm), and 40% small vessels (30 days postprocedure. One-year cardiac event rates among complex subpopulations (diabetics 5.0%, multiple stents 3.8%, long lesions 3.1%, and small vessels 2.9%) were comparable to the overall study population. CONCLUSIONS: In conclusion, this first report of real-world experience with the Taxus Liberté stent demonstrates the safety and clinical utility of this stent in the broader spectrum of coronary disease treated in everyday practice.

Maternal-fetal transport kinetics of carboplatin in the perfused human placental lobule: in vitro study.

OBJECTIVE: Platinum-containing drugs are widely used in the treatment of various malignancies in humans. There is a paucity of data on maternal-fetal transport characteristics of one such widely used drug, carboplatin, and this prompted us to study its permeation characteristics in the human placenta in vitro. METHODS: Placentae from uncomplicated, normal pregnancies were collected postpartum. Carboplatin, along with antipyrine as internal reference marker were injected as a single bolus (100 ul) into the maternal arterial circulation of isolated perfused placental lobules and perfusate samples collected from both maternal and fetal circulations over a period of 5 minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution was used as the perfusate. Carboplatin concentration in various samples was determined by atomic absorption spectrophotometry, while antipyrine concentration was assayed by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using appropriate parameters. RESULTS: The differential transport rate of carboplatin for 10, 25, 50, 75, and 90% efflux fractions in fetal venous effluent averaged 0.60, 1.35, 2.52, 3.72, and 4.49 minutes in 12 perfusions, representing 1.16 +/- 0.10, 1.06 +/- 0.06, 1.00 +/- 0.02, 0.98 +/- 0.01, and 0.99 +/- 0.01, respectively, times the antipyrine reference value. Student's t-test did not show any significant difference (p > 0.05) between the control and study group data. The transport fraction (TF) of carboplatin, expressed as the fraction of the drug appearing in the fetal vein during a study period of 5 minutes, averaged 9.00 +/- 0.52% of bolus dose, while antipyrine TF averaged 68.60 +/- 2.01% of injected bolus dose, representing 13.1% of reference marker value. Student's t-test showed carboplatin and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, time for maximum response, and absorption and elimination rates of study and reference substances showed varying differences. CONCLUSIONS: We report for the first time that carboplatin transport from the maternal to the fetal circulation is relatively small in the human placenta at term. It is reasonable to assume that the risk for the neonate from carboplatin use in pregnancy is minimal when used in emergency clinical situations.

Maternal-fetal transport kinetics of methotrexate in perfused human placenta: in vitro study.

OBJECTIVE: Folate antagonists are widely used in the treatment of diverse cancerous states. A paucity of data on transport characteristics of one such widely used drug, methotrexate, in the human placenta, prompted us to study its permeation characteristics in vitro. METHODS: Placentas from normal pregnancies were collected post-partum. Methotrexate, along with antipyrine as reference marker were injected as a single bolus (100 microL) into the maternal arterial circulation of isolated perfused placental lobules; perfusate samples were collected from both maternal and fetal circulations over a study period of five minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution was used as the perfusate. The concentration of methotrexate in various samples was determined by high performance liquid chromatography, while antipyrine concentration was assayed by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using standard parameters. RESULTS: Differential transport rate of methotrexate for 10, 25, 50, 75 and 90% efflux fractions in fetal venous effluent averaged 0.52, 1.30, 2.37, 3.57 and 4.43 minutes in 12 perfusions, representing 1.01 + 0.08, 1.03 + 0.06, 0.95 + 0.03, 0.93 + 0.03, 0.93 + 0.03 respectively times antipyrine reference value. Student's t-test showed varying differences between the control and study group data. Transport Fraction (TF) of methotrexate, expressed as fraction of the drug appearing in fetal vein, during study period of 5 minutes averaged 24.00 + 2.50% of bolus dose while antipyrine TF averaged 68.73 + 2.01% of injected bolus dose, representing 24.00 percent of reference marker value. Student's t-test showed methotrexate and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, time for maximum response, absorption and elimination rates of study and reference substances showed varying differences. CONCLUSIONS: We report for the first time that the transport of methotrexate from maternal to fetal circulation is not negligible in human placenta at term. It is reasonable to assume that a direct risk for the fetus from methotrexate use in pregnancy cannot be excluded, and caution is warranted when it is used in emergency clinical situations.

Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heart.

The present study was designed to see if acute local inhibition of Ras-GTPase before or after ischemia (during perfusion) would produce protection against ischemia and reperfusion (I/R)-induced cardiac dysfunction. The effect of glibenclamide, an inhibitor of cardiac mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels, on Ras-GTPase-mediated cardioprotection was also studied. A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (P(max)) and left ventricular end-diastolic pressure (LVEDP). Perfusion with Ras-GTPase inhibitor FPT III before I/R [FPT(pre)], significantly enhanced cardiac recovery in terms of left ventricular contractility. P(max) was significantly higher at the end of 30 min reperfusion in FPT(pre)-treated hearts compared to pre-conditioned hearts. However, the degree of improvement in left ventricular contractility was significantly less when FPT III was given only after ischemia during reperfusion [FPT(post)]. Combination treatment with FPT III and glibenclamide before I/R resulted in significant reduction of FPT III-mediated cardioprotection. These data suggest that activation of Ras-GTPase signaling pathways during ischemia are critical in the development of left ventricular dysfunction and that opening of mitoK(ATP) channels, at least in part, contributes to cardioprotection produced by Ras-GTPase inhibition.

Impact of fasting in Ramadan in patients with cardiac disease.

OBJECTIVES: To investigate whether Ramadan fasting has any effect on patients with heart disease. METHODS: We prospectively studied 465 outpatients with heart disease who were fasting during the month of Ramadan from October 24 to November 24, 2003. These studied subjects were from various medical centers in the Gulf region; State of Qatar, Kuwait, United Arab Emirates, and Bahrain. We performed detailed clinical assessments one month before Ramadan, during Ramadan and one month after Ramadan and analyzed predictors of outcome. RESULTS: Overall, the mean age was 55.9+/-11.3 years (age range 32-72). Of the 465 patients treated, 363 (78.1%) were males and 102 (21.9%) females. Among them, 119 (25.6%) patients had congestive heart failure, 288 (62%) patients with angina, 22 (4.7%) patients with atrial fibrillation and 11 (2.4%) patients with prosthetic metallic valves. Three hundred and seventy (79%) had prior myocardial infarction (MI), 195 (17.2%) had prior coronary artery bypass surgery (CABG), and 177 (38%) had prior percutaneous coronary interventions (PCI). At the time of follow-up, we found that 91.2% could fast and only 6.7% felt worse while fasting in Ramadan. Of the studied subjects, 82.8% were compliant with cardiac medications and 68.8% were compliant with dietary instructions. We hospitalized 19 patients during Ramadan for cardiac reasons (unstable angina, worsening heart failure, MI, uncontrolled hypertension, subtherapeutic anticoagulation or arrhythmias) CONCLUSION: The effects of fasting during Ramadan on stable patients with cardiac disease are minimal. Most patients with stable cardiac disease can fast.