Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy.

BACKGROUND: The paraoxonase activity of the enzyme paraoxonase-1 (PON-1) associated with high-density lipoprotein (HDL) may significantly influence clopidogrel's antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON-1 activities and the Q192R genotype with clopidogrel's antiplatelet efficacy in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The platelet aggregation, P-selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON-1 Q192R genotype and to serum HDL-cholesterol levels, and PON-1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL-cholesterol levels and PON-1 activities at baseline (before clopidogrel loading) were not altered at 5- and 30-day post-clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non-responders (PRI: 64.2 ± 11.1%). HDL-cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non-responders. Similarly, the platelet activation markers were significantly higher in PON-1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. CONCLUSIONS: PON-1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.

Noninvasive indexes of left atrial diastolic function in hypertrophic cardiomyopathy.

OBJECTIVES: Our goal was to noninvasively assess left atrial diastolic function and its relation to the impaired left ventricular filling in patients with hypertrophic cardiomyopathy. METHODS AND RESULTS: We studied 34 patients with hypertrophic cardiomyopathy, 26 patients with secondary forms of left ventricular hypertrophy (aortic stenosis, fixed subaortic stenosis, hypertension), and 21 control subjects. Left atrial diastolic function was assessed by measuring acceleration time (SAT), deceleration time (SDT), and the EF (mean deceleration rate) slope of the pulmonary venous flow systolic wave (SW). Left ventricular diastolic function assessed by transmitral Doppler included peak early left ventricular and peak atrial filling velocities, the ratio of early-to-late peak velocities, isovolumic relaxation time, deceleration time, and EF slope. In patients with hypertrophic cardiomyopathy, acceleration time was significantly reduced (P<.05), deceleration time was significantly prolonged (P<.0001), and EF slope was significantly reduced (P<.01). These indexes were similar among the other two groups. No statistically significant difference existed between the subgroups of hypertrophic cardiomyopathy in the above indexes. Patients with hypertrophic cardiomyopathy and secondary forms of left ventricular hypertrophy had evidence of left ventricular diastolic dysfunction. In patients with hypertrophic cardiomyopathy, no correlation existed between left atrial and left ventricular diastolic function indexes (r = -0.26 to 0.33). CONCLUSIONS: Echocardiographic indexes of left atrial relaxation and filling are abnormal in patients with hypertrophic cardiomyopathy but not in secondary forms of left ventricular hypertrophy. These indexes are abnormal in all forms of hypertrophic cardiomyopathy irrespective of left ventricular outflow tract obstruction and distribution of hypertrophy; they are not solely attributable to left ventricular diastolic dysfunction. The above may imply that hypertrophic cardiomyopathy is a cardiac myopathic disease that involves the heart muscle as a whole, irrespective of distribution of hypertrophy and obstruction.