Mohamed Nabil Alama

Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the incidence of Familial Hypercholesterolemia; an in-silico approach

Background: Apolipoprotein E (APOE) gene is a ligand protein in humans which mediates the metabolism of cholesterol by binding to the low-density lipoprotein receptor (LDLR). P.Leu167del mutation in APOE gene was recently connected with Familial Hypercholesterolemia, a condition associated with premature cardiovascular disease. The consequences of this mutation on the protein structure and its receptor binding capacity remain largely unknown. Objective: The current study aims to further decipher the underlying mechanism of this mutation using advanced software-based algorithms. The consequences of disrupting the leucine zipper by this mutation was studied at the structural and functional level of the APOE protein. Methods: 3D protein modeling for both APOE and LDLR (wild types), along with APOE (p.Leu167del) mutant type were generated using homology modeling template-based alignment. Structural deviation analysis was performed to evaluate the spatial orientation and the stability of the mutant APOE structure. Molecular docking analysis simulating APOE-LDLR protein interaction was carried out, in order to evaluate the impact of the mutation on the binding affinity. Result: Structural deviation analysis for APOE mutated model showed low degree of deviance scoring root-mean-square deviation, (RMSD) = 0.322 Å. Whereas Docking simulation revealed an enhanced molecular interaction towards the LDLR with an estimation of +171.03 kJ/mol difference in binding free energy. Conclusion: This in-silico study suggests that p.Leu167del is causing the protein APOE to associate strongly with its receptor, LDLR. This gain-of-function is likely hindering the ability of LDLR to be effectively recycled back to the surface of the hepatocytes to clear cholesterol from the circulation therefore leading to FH.

Widowhood and severity of coronary artery disease: a multicenter study.

Objectives The aim of this study was to assess the association of widowhood with the severity and extent of coronary artery disease (CAD), and whether it is modified by sex or socioeconomic status. Patients and methods A total of 1068 patients undergoing coronary angiography at five centers in Saudi Arabia and the United Arab Emirates were included in the study. CAD was defined as more than 70% lumen stenosis in a major epicardial vessel or more than 50% in the left main coronary artery. Multivessel disease was defined as more than one diseased vessel. Results Of 1068 patients, 65 (6%) were widowed. Widowed patients were older (65±15 vs. 59±12), more likely to be female (75 vs. 25%), less likely to be smokers (18 vs. 47%), of lower economic and education status, and more likely to have undergone coronary angiography for urgent/emergent indications (75 vs. 61%) (P<0.05 for all). There was a significant association between widowhood and the number of coronary arteries with more than 70% lumen stenosis. Consequently, such a high degree of lumen stenosis in those who were widowed was more likely to require coronary artery bypass graft surgery (38 vs. 16%; P<0.01). After adjusting for baseline differences, widowhood was associated with a significantly higher odds of CAD [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI) 1.2–10.5] and multivessel disease (adjusted OR 4.6; 95% CI 2.2–9.6), but not left main disease (adjusted OR 1.3; 95% CI 0.5–3.1). All associations were consistent in men and women and not modified by age, community setting (urban vs. rural), employment, income, or educational levels (Pinteraction>0.1 for all). Conclusion Widowhood is associated with the severity and extent of CAD. The association is not modified by sex or socioeconomic status.

Polygamy and Risk of Coronary Artery Disease in Men Undergoing Angiography: An Observational Study

Epidemiologic evidence suggests a link between psychosocial risk factors such as marital status and coronary artery disease (CAD). Polygamy (multiple concurrent wives) is a distinct marital status practiced in many countries in Asia and the Middle East, but its association with CAD is not well defined. We conducted a multicenter, observational study of consecutive patients undergoing coronary angiography during the period from April 1, 2013, to March 30, 2014. Of 1,068 enrolled patients, 687 were married men. Polygamy was reported in 32% of married men (1 wife: 68%, 2 wives: 19%, 3 wives: 10%, and 4 wives: 3%). When stratified by number of wives, significant baseline differences were observed in age, type of community (rural versus urban), prior coronary artery bypass grafting (CABG), and household income. After adjusting for baseline differences, there was a significant association between polygamy and CAD (adjusted OR 4.6 [95% CI 2.5, 8.3]), multivessel disease (MVD) (adjusted OR 2.6 [95% CI 1.8, 3.7]), and left main disease (LMD) (adjusted OR 3.5 [95% CI 2.1, 5.9]). Findings were consistent when the number of wives was analyzed as a continuous variable. In conclusion, among married men undergoing coronary angiography for clinical indications, polygamy is associated with the presence of significant CAD, MVD, and LMD.

Socioeconomic Factors and Severity of Coronary Artery Disease in Patients Undergoing Coronary Angiography: A Multicentre Study of Arabian Gulf States

Introduction: Coronary artery disease (CAD) is a leading cause of death worldwide. The association of socioeconomic status with CAD is supported by numerous epidemiological studies. Whether such factors also impact the number of diseased coronary vessels and its severity is not well established. Materials and Methods: We conducted a prospective multicentre, multi-ethnic, cross sectional observational study of consecutive patients undergoing coronary angiography (CAG) at 5 hospitals in the Kingdom of Saudi Arabia and the United Arab Emirates. Baseline demographics, socioeconomic, and clinical variables were collected for all patients. Significant CAD was defined as ≥70% luminal stenosis in a major epicardial vessel. Left main disease (LMD) was defined as ≥50% stenosis in the left main coronary artery. Multi-vessel disease (MVD) was defined as having >1 significant CAD. Results: Of 1,068 patients (age 59 ± 13, female 28%, diabetes 56%, hypertension 60%, history of CAD 43%), 792 (74%) were from urban and remainder (26%) from rural communities. Patients from rural centres were older (61 ± 12 vs 58 ± 13), and more likely to have a history of diabetes (63 vs 54%), hypertension (74 vs 55%), dyslipidaemia (78 vs 59%), CAD (50 vs 41%) and percutaneous coronary intervention (PCI) (27 vs 21%). The two groups differed significantly in terms of income level, employment status and indication for angiography. After adjusting for baseline differences, patients living in a rural area were more likely to have significant CAD (adjusted OR 2.40 [1.47, 3.97]), MVD (adjusted OR 1.76 [1.18, 2.63]) and LMD (adjusted OR 1.71 [1.04, 2.82]). Higher income was also associated with a higher risk for significant CAD (adjusted OR 6.97 [2.30, 21.09]) and MVD (adjusted OR 2.49 [1.11, 5.56]), while unemployment was associated with a higher risk of significant CAD (adjusted OR 2.21, [1.27, 3.85]). Conclusion: Communal and socioeconomic factors are associated with higher odds of significant CAD and MVD in the group of patients referred for CAG. The underpinnings of these associations (e.g. pathophysiologic factors, access to care, and system-wide determinants of quality) require further study.

Impact of Implementing Cardiac CT in Evaluating Patients Suspected of Cardioembolic Stroke.

Background and Objectives In practice, clinical and logistic hurdles may hamper performing transesophageal echocardiography in stroke patients. Cardiac computed tomography (CT) is a recently introduced noninvasive modality able to detect various embolic causes. Thus, we retrospectively assessed possible added values of applying cardiac CT in the real-world work-up of suspected cardioembolic stroke cases. Methods Forty-seven patients were neurology service referrals for suspected cardioembolic stroke. The CT images and clinical reports of our cardiac CT radiologists were retrospectively evaluated. Cardiac CT was assessed in terms of detecting major embolic potential findings, potentially significant stroke-unrelated findings, and coronary arterial disease (CAD). Computed tomography results were correlated with echocardiographic reports. Results Cardiac CT showed findings of major embolic potential in 10 patients (21%, 5 thrombi cases, 2 vasculitis cases, 1 case of metastasis invading the left superior pulmonary artery, 1 myocardial infarction case, and 1 pulmonary arteriovenous malformations case), none of which were documented in echocardiography reports. Two cases (4%) with findings of major embolic potential where identified on echocardiography but not on CT (1 left atrial appendage thrombus and 1 mitral valve vegetation). Computed tomography of 13 patients (28%) showed 16 potentially significant stroke-unrelated findings. Twenty-one patients (47%) had unexpected CAD on CT, 11 (52%) of which were obstructive. Conclusions Implementing cardiac CT in assessing patients suspected of cardioembolic stroke added value to echocardiographic evaluation, by detecting major embolic potential findings. In addition, cardiac CT revealed additional potentially significant stroke-unrelated findings and CAD.

The Association Between Vitamin D Level and Restless Legs Syndrome: A Population-Based Case-Control Study

STUDY OBJECTIVES The pathophysiology of restless legs syndrome (RLS) may be related to abnormalities in central dopamine pathways. Vitamin D may play a role in the pathophysiology of RLS by modulating the dopaminergic system. The aim of our study is to examine the possible link between RLS and vitamin D deficiency. METHODS The total number of subjects enrolled was 201, including 78 patients with RLS based on the International RLS Study Group (IRLSSG) diagnostic criteria and 123 controls. Serum 25-hydroxy vitamin D levels were measured in both groups. RLS severity was assessed in all cases using the IRLSSG symptom severity rating scale. RESULTS Fifty-nine patients with RLS (75.6%) and 52 controls (42.3%) had a diagnosis of vitamin D deficiency, P < .001. The odds ratio (OR) of the development of RLS was 4.24 for those with a vitamin D level < 50 nmol/L compared to those with a vitamin D level ≥ 50 nmol/L (P < .001, 95% confidence interval [CI] 2.3-7.9). After adjusting for all other significant factors in the multivariate logistic model, vitamin D was significantly associated with RLS (OR 3.1, P < .002, 95% CI 1.51-6.38). Moreover, a dark or black skin color (OR 3.4, P < .001, 95% CI 1.5-6.3) and working as a teacher (OR 8.8, P < .001, 95% CI 3.4-23.5) were also independently significantly associated with RLS. CONCLUSIONS Our study identified an association between vitamin D deficiency and RLS. Consequently, vitamin D deficiency should be considered in the management of RLS. However, further studies are needed to evaluate the causality relationship between vitamin D level and RLS.

Inter-ethnic marriages and severity of coronary artery disease: A multicenter study of Arabian Gulf States

AIM To assess the association of inter-ethnic vs intra-ethnic marriage with severity of coronary artery disease (CAD) in men undergoing angiography. METHODS We conducted a prospective multicenter, multi-ethnic, cross sectional observational study at five hospitals in Saudi Arabia and the United Arab Emirates, in which we used logistic regression analysis with and without adjustment for baseline differences. RESULTS Data were collected for 1068 enrolled patients undergoing coronary angiography for clinical indications during the period of April 1st, 2013 to March 30th, 2014. Ethnicities of spouses were available only for male patients. Of those enrolled, 687 were married men and constituted the cohort for the present analysis. Intra-ethnic marriages were reported in 70% and inter-ethnic marriages in 30%. After adjusting for baseline differences, inter-ethnic marriage was associated with lower odds of having significant CAD [adjusted odds ratio 0.52 (95%CI: 0.33, 0.81)] or multi-vessel disease (MVD) [adjusted odds ratio 0.57 (95%CI: 0.37, 0.86)]. The adjusted association with left main disease showed a similar trend, but was not statistically significant [adjusted odds ratio 0.74 (95%CI: 0.41, 1.32)]. The association between inter-ethnic marriage and the presence of significant CAD and MVD was not modified by number of concurrent wives (P interaction > 0.05 for both). CONCLUSION Among married men undergoing coronary angiography, inter-ethnic, as compared to intra-ethnic, marriage is associated with lower odds of significant CAD and MVD.

An audit of in-hospital cardiopulmonary resuscitation in a teaching hospital in Saudi Arabia: A retrospective study

Objectives: Data reflecting cardiopulmonary resuscitation (CPR) efforts in Saudi Arabia are limited. In this study, we analyzed the characteristics, and estimated the outcome, of in-hospital CPR in a teaching hospital in Saudi Arabia over 4 years. Methods: A retrospective, observational study was conducted between January 2009 and December 2012 and included 4361 patients with sudden cardiopulmonary arrest. Resuscitation forms were reviewed. Demographic data, resuscitation characteristics, and survival outcomes were recorded. Results: The mean ± standard deviation age of arrested patient was 40 ± 31 years. The immediate survival rate was 64%, 43% at 24 h, and 30% at discharge. The death rate was 70%. Respiratory type of arrest, time and place of arrest, short duration of arrest, witnessed arrest, the use of epinephrine and atropine boluses, and shockable arrhythmias were associated with higher 24-h survival rates. A low survival rate was found among patients with cardiac types of arrest, and those with a longer duration of arrest, pulseless electrical activity, and asystole. Comorbidities were present in 3786 patients with cardiac arrest and contributed to a poor survival rate (P < 0.001). Conclusions: The study confirms the findings of previously published studies in highly developed countries and provides some reflection on the practice of resuscitation in Saudi Arabia.

Divorce and severity of coronary artery disease: A multicenter study

The association between marital status and coronary artery disease (CAD) is supported by numerous epidemiological studies. While divorce may have an adverse effect on cardiac outcomes, the relationship between divorce and severe CAD is unclear. We conducted a multicenter, observational study of consecutive patients undergoing coronary angiography during the period between April 1, 2013, and March 30, 2014. Of 1,068 patients, 124 (12%) were divorced. Divorce was more frequent among women (27%) compared to men (6%). Most divorced patients had been divorced only once (49%), but a subset had been divorced 2 (38%) or ≥3 (12%) times. After adjusting for baseline differences, there was no significant association between divorce and severe CAD in men. In women, there was a significant adjusted association between divorce and severe MVD (OR 2.31 [1.16, 4.59]) or LMD (OR 5.91 [2.19, 15.99]). The modification of the association between divorce and severe CAD by gender was statistically significant for severe LMD (Pinteraction 0.0008) and marginally significant for CAD (Pinteraction 0.05). Among women, there was a significant adjusted association between number of divorces and severe CAD (OR 2.4 [95% CI 1.2, 4.5]), MVD (OR 2.0 [95% CI 1.4, 3.0]), and LMD (OR 3.4 [95% CI 1.9, 5.9]). In conclusion, divorce, particularly multiple divorces, is associated with severe CAD, MVD, and LMD in women but not in men.