Features of endothelial cells in blood samples may eventually permit prediction of atherosclerotic plaque rupture events.

Coronary artery disease (CAD) remains the number one cause of death in industrialized countries despite our collective efforts to minimize attributable risk from known contributors to CAD such as hypertension, dyslipidemia, and smoking. In addition, clinical trials have consistently demonstrated a family history of coronary disease to be predictive for future cardiovascular events beyond that which would be explained by traditional risk factors. These findings support and have prompted widespread investigation into the genomic basis of CAD and myocardial infarction (MI). Recent advances in genotyping technology have allowed for easier identification and confirmation of susceptibility genes for complex traits across different cohorts via increased power of studies stemming from faster accrual of cases and control subjects and more precise genetic mapping. These technological advances have resulted in defining the genes contributing to a substantial or even majority of population-attributable risk for type 2 diabetes and age-related macular degeneration (AMD) cases. Similar progress in replicating novel susceptibility genes for CAD and specifically MI is now rapidly occurring, with a recent gene marker on chromosome 9p21 representing a highly significant and common variant susceptibility factor. With improved resequencing technology and better phenotypic characterization of our CAD cases and control subjects, we should achieve successes in gene identification and confirmation similar to diabetes and AMD, thereby allowing us to better quantify CAD risk earlier in life and institute more effective therapy reducing the individual propensity to develop CAD.

Over 1 million coronary stent procedures are performed annually in the U.S., with dual-antiplatelet therapy, which includes the use of both aspirin and clopidogrel, being a cornerstone in the management of these patients after coronary intervention. Now, recent data have surfaced demonstrating altered active metabolite levels of clopidogrel in patients harboring hepatic cytochrome gene variants. These variants, which have been validated through genome-wide association as the dominant explanation for the marked heterogeneity of clopidogrel response, are linked to a significant increase in the risk for bleeding, stent thrombosis, myocardial infarction, and death. With viable alternatives to clopidogrel now available, including higher clopidogrel maintenance and loading doses, prasugrel, and ticagrelor, clinicians can now effectively guide therapy in those with at-risk gene variants by simple genotyping. Such an individualized approach can potentially prevent tens of thousands of adverse cardiovascular events in the over 30% of those with European ancestry and over 40% of those with Asian or African ancestry who harbor these important clopidogrel gain-of-function and loss-of-function alleles.

Elevated levels of circulating endothelial cells (CECs) occur in response to various pathological conditions including myocardial infarction (MI). Here, we adapted a fluid phase biopsy technology platform that successfully detects circulating tumor cells in blood of cancer patients (HD-CTC assay), to create a High-Definition Circulating Endothelial Cell (HD-CEC) assay for the detection and characterization of CECs. Peripheral blood samples were collected from 79 MI patients, 25 healthy controls and 6 patients undergoing vascular surgery (VS). CECs were defined by positive staining for DAPI, CD146 and von Willebrand Factor and negative staining for CD45. In addition, CECs exhibited distinct morphological features that enable differentiation from surrounding white blood cells. CECs were found both as individual cells and as aggregates. CEC numbers were higher in MI patients compared with healthy controls. VS patients had lower CEC counts when compared with MI patients but were not different from healthy controls. Both HD-CEC and CellSearch® assays could discriminate MI patients from healthy controls with comparable accuracy but the HD-CEC assay exhibited higher specificity while maintaining high sensitivity. Our HD-CEC assay may be used as a robust diagnostic biomarker in MI patients.