Mitral ring calcification in idiopathic hypertrophic subaortic stenosis

Platelet survival time was measured in eight men who had an acute transmural myocardial infarction and were subsequently found to have a normal coronary arteriogram. Platelet survival (chromium-51 labeling) was shortened in all men (2.4 ± 0.11 days; average half-time ± standard error of the mean) and different from that in eight age-matched normal men (3.7 ± 0.08 days) (P <0.001). Three patients had recurrent venous thromboembolism and one had had iliofemoral arterial thromboembolism. Platelet survival was shortened (2.9 ± 0.12 days) in 11 of 16 age-matched men with transmural infarction who had arteriographic evidence of coronary obstructive disease. These results suggest that platelet survival time is shortened in patients with infarction who subsequently are shown to have a normal coronary arteriogram and that arterial thrombosis may be responsible for the infarction.     

Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes

Reduced antiplatelet effect of aspirin has been reported in patients with type 2 diabetes, and recent studies suggest that once-daily aspirin provides insufficient platelet inhibition. We investigated if the effect of aspirin declined during the 24-hour dosing interval in patients with coronary artery disease and type 2 diabetes, and whether this correlated with increased platelet turnover. Furthermore, the intra-individual variation in platelet aggregation was determined during a 28-day period. We included 47 patients with coronary artery disease and type 2 diabetes treated with aspirin 75?mg daily. Blood samples were obtained 1 and 24 hours after aspirin intake, and this was repeated three times with a 2-week interval between each visit. Platelet aggregation was evaluated by impedance aggregometry (Multiplate® Analyzer) using arachidonic acid (1.0?mM) and collagen (3.2?µg/ml) as agonists. Markers of platelet turnover were measured by flow cytometry. Compliance was confirmed by serum thromboxane B₂. Platelet aggregation levels measured 1 and 24 hours after aspirin intake were compared using the mean of 1- and 24-hour measurements at the three study visits. The difference in platelet aggregation was 70?±?97?AU?×?min (p?<?0.0001) when using arachidonic acid as agonist and 33?±?76?AU?×?min (p?=?0.01) when using collagen. Markers of platelet turnover correlated positively, though not significantly, with residual platelet aggregation 24 hours after aspirin intake (p values 0.06 and 0.07). Median intra-individual variation of platelet aggregation was 9–16%. Patients with coronary artery disease and type 2 diabetes had increased platelet aggregation at the end of the 24-hour aspirin dosing interval. Platelet turnover did not correlate significantly with residual platelet aggregation, although a trend was observed. The intra-individual variation of platelet aggregation after aspirin intake was low.     

Workshop: Developing an Agenda for Anticoagulation Management Research

Background. Platelet activation after myocardial infarction and thrombolytic treatment has been documented; but its relationship with the onset of symptoms and with thrombolysis, and the influence of aspirin in this setting is not well defined. In this study we measured platelet activity in the early phase of myocardial infarction treated with either streptokinase or rt-PA and evaluated influence of aspirin in this framework. Methods. 41 patients (age 57 ± 6 years) were treated with thrombolytic therapy during myocardial infarction; 21 patients with 1,5 million units of streptokinase (Group 1) and 20 patients with 100 mg of rt-PA (Group 2); 10 randomly selected patients in each group were given 500 mg aspirin i.v. prior to infusion of thrombolytic drug and, subsequently, 325 mg aspirin a day orally. Consecutive samples of beta-thromboglobulin (BTG), a marker of platelet activity, were collected at admission and after thrombolysis for the following 48 hours. Results. At admission, BTG plasma levels averaged 125 ± 31 IU/ml in Group 1 and 134 ± 35 IU/ml in Group 2 (p = 0.81). Thrombolysis was followed by a similar increase of platelet activity with maximal values reached at the 3rd hour in both groups (196 ± 43 IU/ml in Group 1 and 192 ± 39 in Group 2: p < 001 versus baseline and p NS between the groups). Higher levels of BTG were observed in streptokinase-treated group starting from the 24th hour (p < 0.05). Patients treated with aspirin showed lower levels of BTG only from the 48th hour after thrombolysis in both groups. An inverse correlation was found between time elapsed from onset of symptoms to admission and BTG value on admission (r = −0.86 p < 0.001); in patients admitted within two hours from the beginning of symptoms, with higher levels of BTG, thrombolysis not induced a significant increase of platelet activity; who was observed in patients admitted later. Conclusions. A marked platelet activation is more evident in the first hours of myocardial infarction and is differently influenced by thrombolytic treatment in relation with the delay of patient presentation. Both streptokinase and rt-PA induce a similar increase of platelet activity which is more persistent after streptokinase; cyclooxygenase inhibition seems to influence the platelet activity only from the second day. Condensed abstract. Influence of aspirin on platelet activity during myocardial infarction treated with thrombolytic therapy is not well defined. Twenty-one patients treated with streptokinase (Group 1) and 20 patients treated with rt-PA (Group 2) were randomly selected to give 500 mg of aspirin i.v. prior thrombolysis and subsequently 325 mg a day orally. Platelet activity was evaluated through determination of beta-thromboglobulin plasma levels. Thrombolysis was followed by a similar increase of platelet activity in both groups with maximal values reached at the 3rd hour; higher levels of beta-thromboglobulin were observed in streptokinase-treated group starting from 24th hour. Treatment with aspirin reduced beta-thromboglobulin plasma levels only at 48th hour in both groups. This revised version was published online in August 2006 with corrections to the Cover Date.     

Hemodynamic effects of nifedipine in congestive heart failure

Nifedipine, a potent coronary vasodilator, was administered in a single sublingual dose of 20 mg to eight patients with mild to moderate congestive heart failure. Nifedipine produced a slight increase in heart rate (mean ± standard error of the mean 73.3 ± 3.2 versus 80.9 ± 2.1 beats/min, p <0.025) and an increase in cardiac index (from a control value of 3.51 ± 0.22 to 4.06 ± 0.31 liters/min per m², p <0.01). Arterial blood pressure decreased from $\text{112.9 ±}\text{6.2}\text{67.7 ± 4.2}\text{(}\text{mean}\text{84.9 ± 4.0)}\text{to}\text{100.8 ±}\text{4.4}\text{56.4 ± 11.0}\text{(}\text{mean}\text{76.1 ± 4.3)}$ mm Hg (p <0.01) and total systemic vascular resistance also decreased from a control value of 15.6 ± 1.0 to 12.4 ± 0.8 units (p <0.01) after administration of nifedipine. These data suggest that nifedipine may be useful for vasodilation in congestive heart failure.     

A Sex-dependent Effect of Aspirin on Platelet Membrane Fluidity

Aspirin, 250 mg/day, was administered to 14 normolipidemic healthy subjects for 7 days. Platelet lipid composition was determined in washed platelets by quantitating cholesterol to phospholipid molar ratio. Platelet membrane fluidity was measured by steady state fluorescence polarization using the probe diphenyl hexatriene. Upon 7 days aspirin ingestion platelet lipid composition was not altered. There was a sex-dependent effect of aspirin administration on platelet membrane fluidity. Whereas overall platelet membrane fluidity did not change at 37°C, there was a significant decrease in female subjects; the anisotropy parameter which is inversely related to membrane fluidity increased from 0.937±0.043–1.048 ±0.027 (p<0.01). In male subjects there was an increase in platelet membrane fluidity, which was significant at 25° C; the anisotropy parameter decreased from 1.350 ± 0.039–1.283±0.023 (p < 0.05). These results indicate that aspirin alters the membrane dynamics of platelets. This effect results from mechanisms other than alterations in platelet cholesterol or phospholipid content and operates in an opposite direction in men and women.     

HDL-cholesterol and other plasma lipid and lipoprotein concentrations in middle-aged male and female tennis players

Fasting plasma lipid and lipoprotein concentrations were determined in 25 men and 25 women (mean ages 42 and 39 yr respectively) whose exclusive mode of regular exercise was tennis play. When compared to a sedentary group matched for age, sex, and education, the tennis players exhibited similar plasma total cholesterol and LDL-cholesterol concentrations and significantly lower triglyceride and VLDL-cholesterol concentrations. Plasma HDL-cholesterol was significantly higher in the tennis players($\text{57.8 ± 13.9}\text{versus}\text{46.2 ± 12.0}\text{mg}\text{100}\text{ml}$ in the men and $\text{73.9 ± 12.3}\text{versus}\text{61.7 ± 13.3}\text{mg}\text{100}\text{ml}$ in the women). When we simultaneously controlled for age, relative weight, cigarette smoking, alcohol intake, and oral contraceptive use (in females), the significance of the difference in plasma HDL-cholesterol as well as triglyceride and VLDL-cholesterol concentrations was unaffected in the males but substantially reduced in the females. It is concluded that frequent tennis playing is associated with increased plasma HDL-cholesterol concentrations and that this relationship is independent of other factors known to alter plasma HDL-cholesterol concentration.     

Can resistance to aspirin be reversed after an additional dose?

Aspirin resistance or aspirin non-responsiveness is a recently described phenomenon which has been consistently associated with an increased risk of cardiovascular events. This study was designed to determine the effects of an additional dose of 100 mg of aspirin on platelet function and proportion of aspirin non-responders using the platelet function analyzer-100 (PFA-100), in a well characterized population of stable coronary heart disease patients already on long-term aspirin treatment. Platelet function was assessed using PFA-100 in 141 patients (64.8 ± 10.1 years, 87.9% men) on long-term aspirin treatment (100 mg/day) before and 1 h after “in site” oral aspirin administration (100 mg). Prevalence of aspirin non-responders using PFA-100 was 50.7% (95% confidence interval 42.4–59). One hour after 100 mg of oral aspirin, reassessment of aspirin effects showed a prevalence of non-responders using PFA of 35.0% (95% CI 27.3–43.2) (P < 0.001 vs. pre-dose proportion). Using the PFA-100 system, reassessment of platelet function following oral administration of daily aspirin dosage significantly reduces the number of stable coronary disease patients considered to be non-responders to such treatment.     

Exercise training improves lipoprotein lipid profiles in patients with coronary artery disease

The effects of endurance exercise training on plasma lipoprotein lipids were determined in 10 men, ages 46 to 62 years, with coronary artery disease (CAD). Patients maintained body weight, health-related behaviors, and stable diets throughout the program. Training was at 50% to 85% of maximal oxygen consumption (V?O₂ max) for 40 to 60 minutes, 3 to 5 days/week for 29 ± 7 weeks. Training increased V?O₂ max (31 ± 19%, p < 0.001), reduced plasma cholesterol (C) (?8 ± 4%, p < 0.01), low-density lipoprotein-C (LDL-C) (?9 ± 9%, p < 0.01), and triglyceride (TG) (?13 ± 32%, p < 0.05) concentrations, and increased high-density lipoprotein-C (HDL-C) levels (11 ± 13%, p < 0.05) and $\text{HDL-C}\text{LDL-C}$ ratios (25 ± 20%, p < 0.01). Changes in LDL-C and V?O₂ max were correlated (r = ?0.73, p ± 0.01), while the changes in LDL-C and HDL-C each correlated inversely with pretraining lipoprotein levels (^rLDL-C = ?0.77, p < 0.01; ^rHDL-C = ?0.68, p < 0.05). Thus potentially “antiatherogenic” benefits of exercise seem to be due to a training effect, since they correlate best with changes in V?O₂ max and are maximal in patients with initially low V?O₂ max, high LDL-C, and low HDL-C levels.     

Sulfinpyrazone and aspirin increase epicardial coronary collateral flow in dogs

Clinical studies suggest that sulfinpyrazone and aspirin may be useful in the treatment of coronary artery disease. It was previously shown that pretreatment with a completely platelet-inhibitory dose of aspirin is associated with increased epicardlal collateral flow 4 hours after coronary occlusion in dogs. In this study evaluation was made of platelet inhibitory doses of sulfinpyrazone (30 mg/kg) and aspirin (3 mg/kg) and an aspirin dose (30 mg/kg) 10-fold greater than the minimal dose necessary for complete platelet inhibition. Collateral flow (ml/min per g) was measured 5 minutes after temporary (pretreatment) occlusion of the left anterior descending coronary artery. After release of the occlusion and recovery, a drug dose or saline solution was given, permanent (post-treatment) occlusion instituted, and flow measurement repeated 5 minutes and 4 hours later. Administration of sulfinpyrazone (11 dogs) caused an increase in flow to the ischemic epicardium from 5 minutes after the pretreatment occlusion to 5 minutes after the post-treatment occlusion (mean ± standard error of the mean): Δ = 0.09 ± 0.02, p < 0.01. However, a significant increase was not found in the control group (11 dogs) or in either aspirin-treated group (8 dogs each). All the drug doses caused a significant increase in epicardial collateral flow from 5 minutes after the post-treatment occlusion to 4 hours after the same occlusion: sulfinpyrazone, Δ = 0.08 ± 0.03, p < 0.025; aspirin, 3 mg/kg, Δ = 0.16 ± 0.06, p < 0.05; and aspirin, 30 mg/kg, Δ = 0.14 ± 0.05, p < 0.05. No significant increase was observed during the same interval in control dogs. Endocardial collateral flow 4 hours after post-treatment occlusion was slightly increased in relation to pretreatment values in the sulfinpyrazone group but not in any of the remaining groups. Enhanced collateral flow after coronary occlusion may contribute to some of the beneficial effects ascribed to sulfinpyrazone and aspirin in coronary artery disease.     

Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation. III. Clinical trial

Thallium-201 myocardial imaging was performed at rest, after maximal treadmill exercise and during coronary vasodilatation induced by the intravenous administration of dipyridamole in 62 patients undergoing coronary angiography. Myocardial images after dipyridamole infusion were compared with rest and exercise thallium-201 images to determine the utility of pharmacologic stress for detecting coronary artery disease. Dipyridamole, 0.142 mg/min, was infused for 4 minutes with electrocardiographic and blood pressure monitoring, and thallium-201 was injected intravenously 4 minutes after infusion.Myocardial/background count ratios of 2.3 ± 0.5 (mean ± 1 standard deviation) after the administration of dipyridamole were higher than similar ratios for exercise images (2.1 ± 0.5; P < 0.001). The sensitivity of thallium-201 imaging for detecting significant coronary artery disease was equal for dipyridamole and exercise stress. In 51 patients with a 50 percent or greater stenosis of one or more coronary arteries, image defects were identified in 34 of 51 (67 percent) exercise and dipyridamole images. Twenty of 51 patients (39 percent) had abnormal rest images; in 17 of 20 patients, new or increased image defects were present after exercise and the infusion of dipyridamole. One of 11 patients (9 percent) with no stenosis of 50 percent or greater had a defect on exercise and dipyridamole images. Six of seven patients with new or enlarged image defects after the intravenous administration of dipyridamole also had new or enlarged defects after the oral administration of dipyridamole.After the infusion of dipyridamole, the heart rate increased from 64 ±10 beats/min supine to 88 ± 13 beats/min standing (P < 0.001), and blood pressure decreased from $\text{129 ±}\text{16}\text{80}\text{± 9}\text{to}\text{120 ±}\text{17}\text{75}\text{± 9}\text{mm Hg}\text{(P < 0.001)}$. Angina and S-T depression occurred more frequently with exercise than with dipyridamole. S-T depression occurred in only two patients (3 percent) with dipyridamole, suggesting that diagnostic images were often obtained without significant ischemia. This study demonstrates that pharmacologic coronary vasodilatation is as effective as maximal treadmill exercise in creating myocardial perfusion abnormalities detectable with thallium-201 imaging in man.     

Antiplatelet Versus Warfarin Therapy: Platelet, Neutrophil, and Thrombus Deposition for Intracoronary Stents in a Porcine Model

Antiplatelet therapy may offer an advantage over warfarin in reducing adverse clinical events after intracoronary stem implantation. The mechanism of this effect has not been elucidated but platelet adhesion may play a predominant role in the process of subacute stent thrombosis. This study compared the effect on platelet, neutrophil, and thrombus deposition of three different anticoagulation regimens (aspirin/warfarin vs aspirin/ticlopidine vs aspirin alone) after intracoronary stenting in juvenile swine. Thirty stents were deployed in 15 juvenile farm swine randomized to one of 3 anticoagulation protocols: aspirin 325 mg/day; aspirin 325 mg/day and ticlopidine 500 mg/day; aspirin 325 mg/day and warfarin 0.1 mg/kg/day. Autologous platelets were labeled using ¹¹¹Indium-oxime and a slotted tube metal stent was deployed using a high pressure balloon. Platelet deposition in the stented segment was determined at 24 hours. Each segment was analyzed by light microscopy to document an injury score; mean and maximum thrombus deposition per strut were measured; and neutrophils were counted on each metal strut and in the vessel wall. Platelet deposition at 24 hours was significantly higher in the aspirin/warfarin group (3.69 ± 1.16 ± 10⁸ plts/cm²) than in the aspirin/ticlopidine (1.74 ± 0.45 ± 10⁸ plts/cm², P = 0.0009) or aspirin (2.42 ± 2.13 ± 10⁸ plts/cm², P = 0.03) groups. There was no significant difference between the aspirin and aspirin/ticlopidine groups (P = 0.9). Mean thrombus area per strut was significantly greater in the aspirin/warfarin group (0.027 ± 0.006 mm²) compared to the aspirin/ticlopidine group (0.017 ± 0.002 mm², P = 0.002). The majority of the thrombus (79%) but minority of neutrophils (24%) were found on the stent struts. In this coronary stent model, warfarin given with aspirin was associated with greater thrombogenicity and more platelet deposition than either aspirin/ticlopidine or aspirin alone.     

Effect of buformin on splanchnic carbohydrate and substrate metabolism in healthy man

The effect of buformin (100 mg b.i.d. for 5 days) on carbohydrate metabolism, both splanchnic glucose output (SGO) and net substrate exchange were studied in 6 healthy male volunteers in the basal state and following glucose ingestion (100 g). Control studies without buformin were also performed in 5 men. Splanchnic glucose and substrate exchange was determined by means of the hepatic venous catheter technique. SGO was 154 ± 18 (SEM) mg/min in the postabsorptive state and increased 33.3 ± 2.8 g above the basal level during the 150 min period following glucose ingestion. Buformin administration did not alter basal SGO (157 ± 26 mg/min), nor the splanchnic exchange of pyruvate, alanine, glycerol, OH-butyrate and acetoacetate. Splanchnic lactate balance was altered by buformin and net lactate output occurred. Following glucose ingestion the rise in splanchnic lactate output was increased, whereas no change in SGO ($\text{32.9 ± 3.5 g}\text{150 min}$) and splanchnic exchange of the other substrates was observed. The increase in arterial blood glucose concentration following oral glucose loading was reduced by buformin pretreatment (p < 0.0005). The insulin production rate (basal, 16 ± 2 mU/min; following oral glucose, $\text{13 ± 2 U}\text{150 min}$) as calculated from C-peptide release from the splanchnic area was unchanged by buformin. Except for a marked rise in splanchnic lactate production, buformin did not alter splanchnic carbohydrate metabolism after orally ingested glucose in healthy man. The diminished increase in arterial blood glucose concentration associated with unaltered insulin production suggests that buformin facilitates glucose utilization by peripheral tissues.     

Effects of clofibrate and sulfinpyrazone on platelet survival time in coronary artery disease.

Platelet survival time was measured (autologous labelling with 51chromium) in 68 men with coronary artery disease (CAD). Survival was shortened slightly (3.2 +/- 0.04 days; mean +/- SEM) as compared to normal (3.7 +/- 0.04 days; N = 18; P less than 0.001), and 60% had shortened survival (less than 3.3 days). Thirty-seven had hyperlipoproteinemia (36 with Type IV and one with Type III) and platelet survival was shortened (3.1 +/- 0.10 days) and significantly different from survival of men with normal lipoproteins (3.3 +/- 0,12 days; P less than 0.05). Twenty-two with shortened platelet survival and CAD received either clofibrate or sulfinpyrazone. Clofibrate prolonged platelet survival (2.6 +/- 0.09 to 3.4 +/- 0,14 days; P less than 0.001) and ten of 12 had prolongation of survival. Sulfinpyrazone increased survival (2.8 +/- 0.12 to 3.6 +/- 0.21; P less than 0.001) and nine of ten had prolognation of platelet survival. Clofibrate lowered serum cholesterol and tryglyceride but alteration in lipids did not correlate with alteration of survival. Sulfinpyrazone did not alter lipids. Data suggest that survival is shortened in CAD and that clofibrate and sulfinpyrazone alter survival. Platelet suppressant agents may prove beneficial in reducing the extent and complications of atherosclerotic arterial injury.     

Plasma heparin neutralizing activity in coronary artery disease

Platelets contain heparin neutralizing activity that is released into plasma after platelet aggregation. Increased amounts of plasma heparin neutralizing activity were found in patients with acute myocardial infarction, unstable angina pectoris and stable arteriographically confirmed coronary artery disease. Plasma heparin neutralizing activity levels provide additional evidence for a role of platelet aggregation in coronary artery disease.     

Reversal of diuretic-induced increases in serum low-density-lipoprotein cholesterol by the betablocker pindolol

Seventeen patients with mild to moderate essential hypertension received during three consecutive 4 wk periods a matched placebo, the thiazide-like diuretic, clopamide in a low dosage of 5 mg/day, or this diuretic combined with the betablocker, pindolol in a low dosage of 10 mg/day. Compared to placebo conditions, clopamide monotherapy significantly increased serum low-density lipoprotein cholesterol (LDL-C) by 13% (p < 0.025). Following addition of pindolol, serum LDL-C was restored to control values. These variations in serum LDL-C were unrelated to concomitant changes in blood pressure, plasma potassium, renin activity or aldosterone levels. Blood pressure in the supine position was reduced from $\text{152}\text{99}\text{±}\text{13}\text{9}\text{mm Hg (+SD)}$ to $\text{141}\text{93}\text{±}\text{15}\text{7}\text{mm Hg}$ following diuretic-monotherapy and to $\text{139}\text{90}\text{±}\text{12}\text{9}\text{mm Hg}$ following diuretic-betablocker combination treatment. These findings suggest that antihypertensive combination treatment with low doses of clopamide and pindolol is not only effective and well tolerated, but may also avoid the increase in serum LDL-C levels occurring when the thiazide-like diuretic is given alone.     

Acute effects of ethanol on myocardial blood flow in the nonischemic and ischemic heart

To determine the effects of ethanol on myocardial blood flow in the non-ischemic and ischemic heart, coronary blood flow was measured with radionuclide-tagged microspheres in the anesthetized dog before and after intravenous administration of 1.7 g/kg body weight of ethanol. In non-ischemic dogs, at an average peak blood ethanol level of 225 ± 8 mg/dl (mean ± standard error of the mean), left atrial pressure increased from 5.7 ± 0.6 to 7.7 ± 0.8 mm Hg (p <0.01) and heart rate slowed from 179 ± 8 to 171 ± 8 min^?1 (p <0.001) but mean aortic pressure and cardiac output were unchanged. Average myocardial blood flow increased from 122 ± 5 to 143 ± 8 ml/min per 100 g (p <0.001). In dogs given ethanol after coronary occlusion, at an average peak blood ethanol level of 201 ± 13 mg/dl, left atrlal pressure increased from 6.3 ± 0.6 to 7.4 ± 1.4 mm Hg (p <0.05) but there was no significant change in heart rate, mean aortic pressure or peak positive first derivative of left ventricular pressure ($\text{dP}\text{dt}$). In these dogs, there was a significant change (F = 6.47, p <0.001) in the distribution of myocardial blood flow. In the nonischemic zone, blood flow increased from 118 ± 7 to 148 ± 14 ml/min per 100 g (p <0.005), whereas in the ischemie zone it declined from 30 ± 6 to 20 ± 5 ml/min per 100 g (p <0.02). Myocardial tissue demonstrating myocardial perfusion equal to or greater than 80 percent of preligation levels showed a significant increment of blood flow after ethanol; by contrast, myocardial tissue having blood flow levels equal to or less than 60 percent of preligation levels showed a significant decline in blood flow.Thus, ethanol increases coronary blood flow in the nonischemic myocardium. However, in the acutely ischemic heart, ethanol produces an unfavorable redistribution of myocardial blood flow with flow in the non-ischemic myocardium increasing, at least in part, at the expense of blood flow to ischemic myocardium, producing in effect a “coronary steal.”     

Antiplatelet effect of 50-mg maintenance dose of clopidogrel compared to 200 mg ticlopidine: a preliminary study

In the United States and Europe, patients with coronary stents are maintained on 75 mg clopidogrel. Because the maintenance dose of ticlopidine in patients with coronary stents is 100 mg twice daily in Japan and 250 mg twice daily in the United States and Europe, in Japanese patients a lower dose of clopidogrel may achieve an antiplatelet effect comparable to 200 mg ticlopidine. Platelet aggregation was evaluated in 104 consecutive patients on 50 mg clopidogrel plus aspirin (n = 54) and 200 mg ticlopidine plus aspirin (n = 50). Platelets were stimulated with adenosine diphosphate (5 and 20 μmol/l) and aggregation was assessed by optical aggregometry. There was no significant difference in platelet aggregation induced with 5 (37% ± 11% vs 38% ± 15%, not significant) and 20 μmol/l adenosine diphosphate (48% ± 13% vs 51% ± 12%, not significant) between 50 mg clopidogrel and 200 mg ticlopidine. In Japanese patients, there is the possibility that a maintenance dose of 50 mg clopidogrel on platelet inhibition is comparable to 200 mg ticlopidine.     

Comparison between a new platelet count drop method PL-11, light transmission aggregometry,VerifyNow aspirin system and thromboelastography for monitoring short-term aspirin effects in healthy individuals

Platelet function has been described by many laboratory assays, and PL-11 is a new point-of-care platelet function analyzer based on platelet count drop method, which counts platelet before and after the addition of agonists in the citrated whole blood samples. The present study sought to compare PL-11 with other three major more established assays, light transmission aggregometry (LTA), VerifyNow? aspirin system and thromboelastography (TEG), for monitoring the short-term aspirin responses in healthy individuals. Ten healthy young men took 100?mg/d aspirin for 3-day treatment. Platelet function was measured via PL-11, LTA, VerifyNow and TEG, respectively. The blood samples were collected at baseline, 2 hour, 1 day during the aspirin treatment and 1 day, 5?±?1 days, 8?±?1 days after the aspirin withdrawal. Moreover, 90 additional healthy subjects were recruited to establish a reference range for PL-11. Platelet function of healthy subjects decreased significantly 2 hours after 100?mg/d aspirin intake and began to recover during 4–6 days after the aspirin withdrawal. Correlations between methods were PL-11 vs. LTA (r?=?0.614, p?<?0.01); PL-11 vs. VerifyNow (r?=?0.829, p?<?0.01); PL-11 vs. TEG (r?=?0.697, p?<?0.001). There was no significant bias between PL-11 and LTA at baseline (bias?=?1.94%, p?=?0.804) using Bland-Altman analysis, while the data of PL-11 were significantly higher than LTA (bias?=?24.02%, p?<?0.001) during the aspirin therapy. The reference range for PL-11 in healthy young individuals was from 66.8 to 90.5% (95%CI). When aspirin low-responsiveness was defined as LTA?>?20%, the cut-off values for each method were, respectively: PL-11?>?50%, VerifyNow?>?533 ARU, TEG?>?60.2%. The results of different platelet function assays were uninterchangeable for monitoring aspirin response and correlations among them were also varied. Correlations among PL-11 and other three major assays suggested the ability of PL-11 to assess the treatment effects of aspirin. But a large cohort study is needed to confirm the cut-off value of aspirin response detected by PL-11.     

Platelet factor XIIIa release during platelet aggregation and plasma clot strength measured by thrombelastography in patients with coronary artery disease treated with clopidogrel

Abstract

It has been estimated that up to half of circulating factor XIIIa (FXIIIa) is stored in platelets. The release of FXIIIa from platelets upon stimulation with adenosine diphosphate (ADP) in patients with coronary artery disease treated with dual antiplatelet therapy has not been previously examined. Samples from 96 patients with established coronary artery disease treated with aspirin and clopidogrel were examined. Platelet aggregation was performed by light transmittance aggregometry in platelet-rich plasma (PRP), with platelet-poor plasma (PPP) as reference, and ADP 5?µM as agonist. Kaolin-activated thrombelastography (TEG) was performed in citrate PPP. PRP after aggregation was centrifuged and plasma supernatant (PSN) collected. FXIIIa was measured in PPP and PSN. Platelet aggregation after stimulation with ADP 5?µM resulted in 24% additional FXIIIa release in PSN as compared to PPP (99.3?±?27 vs. 80.3?±?24%, p?<?0.0001). FXIIIa concentration in PSN correlated with maximal plasma clot strength (TEG-G) (r?=?0.48, p?<?0.0001), but not in PPP (r?=?0.15, p?=?0.14). Increasing quartiles of platelet-derived FXIIIa were associated with incrementally higher TEG-G (p?=?0.012). FXIIIa release was similar between clopidogrel responders and non-responders (p?=?0.18). In summary, platelets treated with aspirin and clopidogrel release a significant amount of FXIIIa upon aggregation by ADP. Platelet-derived FXIIIa may contribute to differences in plasma TEG-G, and thus, in part, provide a mechanistic explanation for high clot strength observed as a consequence of platelet activation. Variability in clopidogrel response does not significantly influence FXIIIa release from platelets.     

Effects of diastolic synchronized retroperfusion on regional coronary blood flow in experimental myocardial ischemia

Coronary venous retroperfusion has previously been suggested as a potential mode of treatment of myocardial ischemia. This study was designed to examine the actual changes in regional myocardial blood flow that occur with diastolic synchronized retroperfusion of the coronary sinus. Coronary sinus retroperfusion consisted of (1) diastolic augmentation of delivery of arterial blood into the acutely ischemic myocardium, and (2) systolic facilitation of coronary venous drainage. This was achieved using a gas-actuated electrocardiogram-synchronized retroperfusion pump that propels arterial blood during diastole through an autoinflatable bladder catheter. Hemodynamic data and measurements of ischemic tissue injury (S-T segment mapping) and regional myocardial blood flow (radioactive microsphere technique) were obtained before and after 1 and 2 hours of coronary arterial occlusion. Experiments were performed in 19 open chest dogs: Retroperfusion was instituted after the 1st hour of coronary occlusion and maintained for the subsequent hour in 8 dogs and the results were compared with those obtained in 6 randomly selected untreated dogs. In five additional dogs, the fraction of microspheres escaping myocardial entrapment in either an anterograde or a retrograde direction was determined. In both treated and untreated dogs, changes in hemodynamics, S-T segment mapping and regional myocardial blood flow showed the same trend up to 1 hour of coronary occlusion. Synchronized retroperfusion resulted in a minor but significant decrease in heart rate and an increase in stroke volume. As early as 15 minutes after the start of synchronized retroperfusion, there was a significant decrease in S-T segment elevation (from 5.95 ± 1.01 to 3.09 ± 0.58 mV [mean ± standard error of the mean], p <0.01) that was maintained for the subsequent hour; in the control series, S-T segment elevation was unaffected. After 1 hour of retroperfusion, regional transmural flow increased in the nonischemic zone from 0.84 ± 0.07 to 1.05 ± 0.10 ml/min per g (p <0.05) with an unchanged $\text{endocardial}\text{epicardial}$ flow ratio (1.10 ± 0.04 and 1.11 ± 0.04 before and 1 hour after treatment, respectively). In the ischemic zone, 1 hour of retroperfusion increased transmural flow by 59.3 percent (from 0.32 ± 0.05 to 0.51 ± 0.04 ml/min per g, p <0.05) with a greater increase in endocardial flow (from 0.19 ± 0.02 to 0.35 ± 0.03 ml/min per g, p <0.05) than in epicardial flow (from 0.43 ± 0.05 to 0.59 ± 0.06 ml/min per g, p <0.01) leading to a significant increase in $\text{endocardial}\text{epicardial}$ flow ratio (from 0.46 ± 0.05 to 0.64 ± 0.07, p <0.01).These experimental data show that retroperfused arterial blood reaches the ischemic as well as the nonischemic zones and is favorably redistributed toward the endocardium. Thus, diastolic synchronized retroperfusion is capable of restoring nutritional blood flow to approximately 50 percent of normal control flow. This improvement in myocardial perfusion might be of value in delaying irreversible myocardial ischemia.