Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.

Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion.

Coronary bifurcation lesions.

Coronary bifurcations are prone to develop atherosclerotic plaque due to turbulent blood flow and high shear stress. These lesions amount to 15-20% of the total number of interventions. The true bifurcation lesion consist of >50% diameter obstruction of the main vessel (MV) and of the side branch (SB) in an inverted "Y" fashion. Treatment of coronary bifurcation lesions represents a challenging area in interventional cardiology but recent advances in percutaneous coronary interventions (PCI) have led to the dramatic increase in the number of patients successfully treated percutaneously. When compared with non-bifurcation interventions, bifurcation interventions have a lower rate of procedural success, higher procedural costs, longer hospitalization and a higher clinical and angiographic restenosis. Introduction of drug-eluting stents (DES) has resulted in a lower event rate and reduction of main vessel (MV) restenosis in comparison with historical controls. However, side branch (SB) ostial residual stenosis and long-term restenosis remains a problem. Although stenting the MV with provisional SB stenting seems to be the prevailing approach, in the era of DES various two-stent techniques have emerged to allow stenting of the large side branch.

Angina pectoris in severe aortic stenosis.

We studied the value of angina pectoris as a predictor of significant coronary artery disease (CAD) in very elderly patients with severe aortic stenosis (AS). The study population consisted of patients with age at least 70 years who were referred for balloon aortic valvuloplasty (n = 90 patients). Routine coronary angiography was performed before the valvular intervention. Patients were grouped according to the presence or absence of angina pectoris. Of the patients with angina pectoris, 78% had obstructive (>50% diameter stenosis) CAD on coronary angiogram, while only 17% of patients without angina pectoris had obstructive CAD (p < 0.01). Angina pectoris had a sensitivity of 78% and a specificity of 82% for prediction of obstructive CAD. This suggests that in elderly patients with severe AS, the presence of angina pectoris is a strong determinant of CAD, and the absence of angina strongly suggests absence of obstructive CAD. In a very elderly population, appropriate decision-making with respect to AS management should not await diagnostic coronary angiography.