Elie Chammas

Large scale association analysis identifies three susceptibility loci for coronary artery disease.

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR = 0.68, p = 0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR = 1.33, p = 0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.

Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR1 as a Major Determinant of Coronary Artery Stenosis

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10−5). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10−6), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10−10). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.

Value of aortic arch analysis during routine transthoracic echocardiography in adults.

AIMS Despite the recommendations of the American Society of Echocardiography, the majority of clinicians and sonographers do not perform aortic arch analysis routinely during transthoracic echocardiography (TTE). The European guidelines remain unclear. The aim of our study is to evaluate the usefulness of aortic arch analysis during routine TTE in adults. METHODS AND RESULTS We performed aortic arch analysis on all 2000 adult patients (mean age 52, range 18-89) referred to our echocardiography lab for transthoracic echocardiograms between January and December 2007. Adequate study was obtained in 1826 patients (91% of cases). Suprasternal notch views and aortic arch analysis were normal in 1787 patients (98%) and abnormal in 39 patients (2%). Among patients with abnormal findings, 32 patients (82%) had aortic arch plaques, 24 of them (75%) had plaques <4 mm, and 8 patients (25%) had plaques > or =4 mm. Four patients (10%) had aortic arch aneurysms (diameter > or =4.5 cm). Other abnormal findings included one case of coarctation of the aorta, one case of a floating thrombus in a right pulmonary artery branch, one case of severe stenosis of the inominate artery, and one case of type A aortic dissection. Subsequently, 7 patients (18%) underwent surgery, 4 patients (10%) were started on oral anticoagulation therapy, and 28 patients (72%) treated with an antiplatelet and risk factors modification. CONCLUSION Aortic arch analysis showed significant pathology in 2% of the adult population undergoing routine TTE. This led to therapeutic interventions in all patients with abnormal findings, and to curative therapy in more than quarter of them. Aortic arch analysis should be mandatory during a routine exam and part of any standard digital acquisition protocol for TTE in adults.

Impact of inflammation, gene variants, and cigarette smoking on coronary artery disease risk

BackgroundThe role of inflammation in coronary artery disease (CAD) pathogenesis is well recognized. Moreover, smoking inhalation increases the activity of inflammatory mediators through an increase in leukotriene synthesis essential in atherosclerosis pathogenesis.AimThe aim of this study is to investigate the effect of “selected” genetic variants within the leukotriene (LT) pathway and other variants on the development of CAD.MethodsCAD was detected by cardiac catheterization. Logistic regression was performed to investigate the association of smoking and selected susceptibility variants in the LT pathway including ALOX5AP, LTA4H, LTC4S, PON1, and LTA as well as CYP1A1 on CAD risk while controlling for age, gender, BMI, family history, diabetes, hyperlipidemia, and hypertension.Resultsrs4769874 (ALOX5AP), rs854560 (PON1), and rs4646903 (CYP1A1 MspI polymorphism) are significantly associated with an increased risk of CAD with respective odds ratios of 1.53703, 1.67710, and 1.35520; the genetic variant rs9579646 (ALOX5AP) is significantly associated with a decreased risk of CAD (OR 0.76163). Moreover, a significant smoking-gene interaction is determined with CYP1A1 MspI polymorphism rs4646903 and is associated with a decreased risk of CAD in current smokers (OR 0.52137).ConclusionThis study provides further evidence that genetic variation of the LT pathway, PON1, and CYP1A1 can modulate the atherogenic processes and eventually increase the risk of CAD in our study population. Moreover, it also shows the effect of smoking-gene interaction on CAD risk, where the CYP1A1 MspI polymorphism revealed a decreased risk in current smokers.

Association of hypertension with coronary artery disease onset in the Lebanese population

The onset of coronary artery disease (CAD) is influenced by cardiovascular risk factors that often occur in clusters and may build on one another. The objective of this study is to examine the relationship between hypertension and CAD age of onset in the Lebanese population.This retrospective analysis was performed on data extracted from Lebanese patients (n = 3,753). Logistic regression examined the association of hypertension with the age at CAD diagnosis after controlling for other traditional risk factors. The effect of antihypertensive drugs and lifestyle changes on the onset of CAD was also investigated.Results showed that hypertension is associated with late onset CAD (OR=0.656, 95% CI=0.504-0.853, p=0.001). Use of antihypertensive drugs showed a similar association with delayed CAD onset. When comparing age of onset in CAD patients with traditional risk factors such as hypertension, diabetes, hyperlipidemia, obesity, smoking and family history of CAD, the age of onset was significantly higher for patients with hypertension compared to those with any of the other risk factors studied (p < 0.001).In conclusion, hypertension and its treatment are associated with late coronary atherosclerotic manifestations in Lebanese population. This observation is currently under investigation to clarify its genetic and/or environmental mechanisms.

Association of waterpipe smoking with myocardial infarction and determinants of metabolic syndrome among catheterized patients

Abstract Background: Waterpipe smoking is a rising global public health epidemic perceived by many users to be less harmful, though its toxicity overlaps or even exceeds that of cigarette smoking. Short-term cardiovascular changes due to waterpipe smoking are well established, but longer-term health impacts are still not fully elucidated. Objective: We aim to investigate the association of waterpipe smoking with myocardial infarction among patients undergoing cardiac catheterization. Methods: The study was performed on Lebanese patients referred for cardiac catheterization. Patient’s blood was collected for metabolic measures and questionnaires were filled out to include socio-demographic, behavioral and pertinent medical characteristics of the study subjects. Results: Myocardial infarction is significantly and independently associated with waterpipe smoking, with odds ratio (OR) of 1.329 (95% CI: [1.04–1.68]; p = .021), which is lower than that for cigarette smoking (OR = 1.87, 95% CI: [1.63–2.15]; p < .001). Only diabetes showed significant association with waterpipe smoking among MI enrollees (OR = 1.66, 95%CI: [1.04–2.63]; p = .032). Conclusion: The study provides yet another evidence for the adverse cardiovascular effects of waterpipe smoking on a clinical level. The harmful effects of waterpipe smoking should be underscored by health care professionals.

Association Between Sedentary Lifestyle and Diastolic Dysfunction Among Outpatients With Normal Left Ventricular Systolic Function Presenting to a Tertiary Referral Center in the Middle East

Sedentary lifestyle has become prevalent in our community. Recent data showed controversy on the effect of regular exercise on left ventricular compliance and myocardial relaxation.