Sasidhar Guthikonda

Role of Reticulated Platelets and Platelet Size Heterogeneity on Platelet Activity After Dual Antiplatelet Therapy With Aspirin and Clopidogrel in Patients With Stable Coronary Artery Disease

OBJECTIVES The aim of this study was to evaluate the relationship between reticulated platelets (RPs), platelet size, and platelet function in patients with stable coronary artery disease (CAD) taking aspirin and clopidogrel. BACKGROUND Reticulated platelets are young platelets that are larger and possibly more active than non-RPs. METHODS Flow cytometry was used to measure RPs after staining with thiazole orange and to define the upper 20% and lower 20% of platelets by size. Platelet aggregation was measured with light transmission aggregometry (LTA); platelet activation was assessed by measuring activated platelet surface expression of P-selectin and glycoprotein (GP) IIb/IIIa. RESULTS Ninety patients were recruited and stratified into tertiles of %RPs. Patients in the upper tertile displayed greater platelet aggregation to 5-mumol/l adenosine diphosphate (ADP) (50.7 +/- 16.4% vs. 34.2 +/- 17.3%, p < 0.001), 1.5-mmol/l arachidonic acid (AA) (27.3 +/- 16.9% vs. 11.7 +/- 9.3%, p < 0.001), and 1-mug/ml collagen (18 +/- 11.6% vs. 12.1 +/- 8.7%, p < 0.05) and greater expression of GP IIb/IIIa (4.7 +/- 1.8% vs. 3.1 +/- 2.2%, p < 0.001). Frequency of low response to aspirin (AA LTA >20%) was higher in the upper tertile (53% vs. 17%, p < 0.001) compared with the lower tertile; low response to clopidogrel (ADP LTA >50%) was also elevated in the upper tertile (50% vs. 13%, p = 0.003). The larger platelet gate had a higher % of RPs compared with the smaller gate (15.4 +/- 16.7% vs. 1.7 +/- 2.3%, p < 0.001) and greater GP IIb/IIIa (5.7 +/- 3.1 vs. 2.1 +/- 1.2, p < 0.001) and P-selectin expression (7.8 +/- 4.9 vs. 4.6 +/- 2.7, p < 0.001). CONCLUSIONS The proportion of circulating RPs strongly correlates with response to antiplatelet therapy in patients with stable CAD. Large platelets exhibit increased reactivity despite dual antiplatelet therapy, compared with smaller platelets.

Homocysteine as a novel risk factor for atherosclerosis.

Homocysteine is a sulfhydryl amino acid formed during metabolism of methionine. Increasing evidence suggests that homocyst(e)ine may act as an independent risk factor for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. Recent prospective data have shown that homocyst(e)ine levels in the top 20% of the population increase the risk for ischemic heart disease by approximately twofold. Homocyst(e)ine seems to promote the progression of atherosclerosis by causing endothelial dysfunction, increasing oxidant stress, and promoting vascular smooth muscle growth. Recent human studies using methionine loading to experimentally induce moderate hyperhomocyst(e)inemia have demonstrated rapid and profound impairment of resistance and conduit artery endothelial function. No data are available from randomized, controlled trials of the effects of lowering plasma homocyst(e)ine on atherosclerotic vascular events; however, screening for hyperhomocyst(e)inemia should be actively considered in individuals with progressive and unexplained atherosclerosis. Both fasting and postmethionine load homocyst(e)ine levels should be measured. B vitamins, including folic acid and vitamins B6 and B12 are the mainstay of treatment of patients with hyperhomocyst(e)inemia. Primary prevention strategies await the completion of long-term, randomized, prospective studies.

What Is the Most Appropriate Methodology for Detection of Conduit Artery Endothelial Dysfunction

Background—Use of upper-arm arterial occlusion to induce reactive hyperemia, and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery, induces greater conduit vessel dilatation than lower-arm occlusion. However, brachial artery ischemia after upper arm arterial occlusion may make this approach unreliable. We studied whether upper or lower arm occlusions differ in their ability to detect endothelial dysfunction in cigarette smokers, and its improvement with an antioxidant strategy. Methods and Results—Ten cigarette smokers with a >20 pack year history and 10 age- and gender-matched healthy controls participated in a 2-phase randomized controlled study of xanthine oxidase inhibition, using a 600-mg oral dose of allopurinol administered beforehand. Endothelium-dependent dilatation was assessed using ultrasound-Doppler after lower and upper arm occlusion. After lower arm occlusion, FMD was significantly impaired in smokers compared with controls (3.8±1.1% versus 8.7±2.2%; P=0.001). However, after upper arm occlusion, brachial artery dilatation in smokers was higher (11.8±2.7%; P<0.0001 versus lower arm) and did not differ from controls (9.4±2.9%; P=0.3). There was no difference in endothelium-independent dilatation to sublingual nitroglycerin between smokers and controls. Inhibition of xanthine oxidase with allopurinol improved lower arm FMD (3.8±1.1 to 10.1±1.9%; P<0.0001), but did not improve upper arm FMD (11.8±2.7 to 14.1±3.7%; P=0.4). Conclusions—Although upper arm occlusion induces robust brachial vasodilatation, it cannot detect endothelial dysfunction induced by smoking or its improvement by inhibition of xanthine oxidase. The increase in brachial artery diameter with upper arm occlusion may be confounded by ischemia of the artery. Conduit artery FMD after release of lower arm occlusion appears to be a more valid method for assessment of endothelial function in humans.

Platelet reactivity among Asian Indians and Caucasians.

Asian Indians are reported to have higher mortality and morbidity from coronary artery disease (CAD) than other ethnic groups. This variation in events cannot be explained only by differences in conventional risk factors. Platelet activation is an important factor in the pathogenesis of CAD, however, there are limited data concerning platelet reactivity in Asian Indians. Therefore, we aimed to examine platelet reactivity in healthy Asian Indians vs. Caucasians. Thirty-five healthy, nonsmoking Asian Indians (mean age 30.1 ± 3.6 years, 31.4% women) were matched for age and sex with 35 healthy, nonsmoking Caucasians (mean age 30.8 ± 5 years, 31.4% women). Platelet reactivity was evaluated by measuring platelet aggregation, platelet leukocyte aggregates (PLA) formation in response to a 6-mer thrombin receptor agonist peptide (TRAP) at a final concentration of 40 µM and flow cytometry determined P-selectin expression induced by ADP, TRAP and arachidonic acid (AA). In addition, P-Selectin glycoprotein ligand-1 (PSGL-1) density on leukocytes was measured. There were no differences in platelet aggregation, basal PLA or PSGL-1 density on leukocytes between the two groups. AA-stimulated P-selectin expression was significantly higher in Asian Indians than in Caucasians (6.1 ± 0.51 vs. 4.2 ± 0.41 MFI, P < 0.02). After stimulation with TRAP, platelets from Asian Indians had increased PLA formation compared with Caucasians (41.6 ± 2.9% vs. 31.4 ± 2.7%, P < 0.02). AA induced P-selectin expression and TRAP stimulated PLA formation is increased in Asian Indians compared with Caucasians. These differences indicate an increase in measures of platelet reactivity among Asian Indians and may help elucidate the reported disparity in cardiovascular disease rates between the two ethnic groups.

Percutaneous Closure of Atrial Septal Defect

ATRIAL SEPTAL DEFECT (ASD) is a common congenital lesion in adults. Prolonged left-to-right shunting and excessive pulmonary blood flow may lead to pulmonary hypertension, Eisenmengers syndrome, and right heart failure. A significant ASD should be closed irrespective of age. Surgical closure of

Three-Dimensional Transesophageal Echocardiogram Provides Real-Time Guidance During Percutaneous Paravalvular Mitral Repair

A 65-year-old woman with severe paravalvular mitral regurgitation and chronic hemolytic anemia was referred for surgical consultation. Her medical history included rheumatic heart disease with mitral valve replacement in 1977, aortic valve replacement in 1988, and repeat mechanical mitral valve replacement in 2002. Predominant symptoms were New York Heart Association function class III dyspnea and fatigue. The patient was considered at high risk for surgical complication because of the 3 previous valve surgeries and significant pulmonary hypertension (systolic pulmonary pressure, 70 mm Hg). The Figure demonstrates repair of the significant paravalvular …

Erratum: Immature platelet fraction (IPF) determined with an automated method predicts clopidogrel hyporesponsiveness (Journal of Thrombosis and Thrombolysis DOI: 10.1007/s11239-011-0665-7)

Unfortunately, in the original publication, the sentence in abstract starting with ‘‘The frequency of clopidogrel hyporesponsiveness...’’ the P value is incorrectly given as P = 0.0001 and the sentence should read as follows: The frequency of clopidogrel hyporesponsiveness (aggregation [50% in response to 5 lM of ADP) was also higher in the upper tertile when compared to lower tertile, (60%) versus (10%) respectively (P = 0.02). The author regrets this error.

Is aspirin resistance valid

“The clinical impact of aspirin resistance with cardiovascular events is now becoming evident, with aspirin nonresponders having nearly a threefold increased risk of cardiovascular death” Aspirin resistance is an increasingly recognized phenomenon denoting a diminished platelet inhibitory effect of aspirin. It has been reported in approximately 10–30% of patients taking aspirin. The clinical impact of aspirin resistance with cardiovascular events is now becoming evident, with aspirin nonresponders having nearly a threefold increased risk of cardiovascular death. The mechanisms for this phenomenon and methods to treat it are still unclear. More research is necessary before recommendations for clinical practice can be made. Aspirin was the first antiplatelet drug used in