ABSTRACT
Background & objectives: Cytochrome P450, P2Y 12, cyclooxygenase-1 (COX1) and glycoprotein V1 (GPVI) gene polymorphisms are known to affect patient responsiveness towards aspirin and clopidogrel dual antiplatelet therapy (DAPT). The present study was undertaken to identify aspirin and clopidogrel non-responsiveness and its association with genetic polymorphism in patients with myocardial infarction (MI). Methods: A total of 207 MI patients who were on DAPT, were included. The DAPT non-responsiveness was determined by light transmittance aggregometry using arachidonic acid and adenosine diphosphate and high platelet reactivity by collagen. Platelet activation biomarkers, thromboxane B2 (TxB2)andsoluble CD40 ligand (sCD40L) were measured in plasma. Patient compliance was checked by estimating drug and its metabolite levels (aspirin and clopidogrel) in plasma using liquid chromatography-mass spectrometry/mass spectrometry. Genomic DNA was extracted, amplified by polymerase chain reaction and subsequently sequenced to identify CYP450, P2Y 12, COX1 and GPVI gene polymorphisms. Results: Of the 207 patients, 32 were non-responders. The DAPT non-responsiveness was found in 15.5 per cent patients. The non-responsiveness showed a significant and an independent association with gender [odds ratio (OR)=0.18, 95% confidence interval (CI)=0.01-0.78, P=0.023], TxB2(OR=1.00, 95% CI=1.00-1.01, P=0.013), CYP2C19*2 G>A (OR=3.33, 95% CI=1.04-10.69, P=0.044) and GPVI T>C (OR=0.23, 95% CI=0.08-0.67, P=0.007) after adjusting the demographic, clinical and genetic confounding factors when assessed between non-responder and responder compliant patients. Interpretation & conclusions: The study showed a significant association of genetic polymorphisms (CYP2C19*2 G>A and GPVI T>C) with DAPT non-responsiveness in MI patients. The findings of this study need further validation in a large cohort of patients with clinical follow up.
ABSTRACT
BACKGROUND: Biventricular pacing is beneficial in refractory systolic heart failure having QRS duration more than 130 msec by improving regional dysynchrony and decreasing diastolic mitral regurgitation. Current data show significant systolic dysynchrony in symptomatic systolic heart failure patients out of which nearly 40% have a QRS duration of less than 120 msec. Our study aims at assessing acute hemo-dynamic impact of Biventricular (BiV) and compare it with isolated left ventricular (LV) pacing in patients of systolic heart failure and QRS duration < or = 120 msec. METHODS: Seven patients with symptomatic systolic heart failure with LV Ejection fraction (LVEF) < or = 35% (mean 25.7 +/- 11.3%). NYHA functional class more than II and QRS duration < or = 120 msec (mean 92.8 +/- 17.0 msec) were studied at baseline and following BiV and LV pacing with AV delay 100 msec for 5 minutes in random order. Parameters analyzed were heart rate, systolic BP, pulse pressure, LV dimension, LVEF, cardiac output(CO), LV dP/dT, LV and RV isovolumic contraction time and aorto pulmonary flow delay. Duration of QRS complex at baseline and following pacing was noted. 'Responders' were defined as having increase in CO by at least 10% of mean basal cardiac output in study group. RESULTS: BiV pacing resulted in significant improvement in systolic BP (140.71 +/- 21.33 vs 149.29 +/- 19.67 mmHg, p = 0.02), pulse pressure (58.14 +/- 21.14 vs 67.29 +/- 19.57 mmHg, p = 0.01), LVEF (25.71 +/- 11.3 vs 32.86 +/- 4.60%, p = 0.01), CO (3.24 +/- 1.05 vs 3.89 +/- 1.1 l/min, p = 0.02) and LV dP/dT (0.69 +/- 0.22 vs 1.00 +/- 0.23 mmHg/msec, p = 0.001) with a trend towards reduction in LV isovolumic contraction time (115.28 +/- 21.61 vs 99.29 +/- 17.18 msec, p = 0.14) and aorto pulmonary flow delay (25.14 +/- 24.36 vs 12.14 +/- 36.15 msec, p = 0.32). LV pacing resulted in a trend towards improvement in parameters as compared to baseline, systolic BP (140.71 +/- 21.33 vs 146.71 +/- 23.03 mmHg, p = 0.16); pulse pressure (58.14 +/- 21.14 vs 63.29 +/- 26.59 mmHg, p = 0.2); LVEF (25.71 +/- 11.3 vs 33.27 +/- 10.0, p = 0.06); CO (3.24 +/- 1.05 vs 3.27 +/- 0.6 l/min, p = 0.88); LV dP/dT (0.69 +/- 0.22 vs 0.96 +/- 0.39 mmHg/msec, p = 0.16); LV isovolumic contraction time (115.28 +/- 21.61 vs 98.21 +/- 21.34 msec, p = 0.18); aortopulmonary flow delay (25.14 +/- 24.36 vs 5.21 +/- 30.1 msec, p = 0.2). Biventricular and LV pacing resulted in a non-significant increase in duration of paced QRS complexes (105.43 +/- 14.82 msec, p = 0.11 and 108.86 +/- 19.73, p = 0.15 respectively) as compared to 92.86 +/- 17.04 msec at baseline. Three out of 7 patients could be classified as 'responders' to biventricular pacing. CONCLUSION: BiV pacing, and not LV pacing, benefits patients of systolic heart failure (EF < or = 35%) and narrow QRS (< or = 120 msec) on surface ECG.