Clopidogrel attenuates coated-platelet production in patients undergoing elective coronary catheterization.

INTRODUCTION: Coated-platelets are a subclass of highly thrombotic activated platelets with an enhanced ability to generate thrombin. Excessive numbers of coated-platelets are believed to increase thrombotic risk. A previous report demonstrated that P2Y12 inhibition in vitro attenuates coated-platelet formation. The aim of this study was to determine the effect clopidogrel has on coated-platelet formation. METHODS AND RESULTS: We enrolled 27 patients undergoing elective coronary angiography. A total of 3 blood samples were taken from eligible patients: baseline, 24-hour postclopidogrel (preangiography), and 6-hour postangiography. Coated-platelet levels, expressed as percentage of total platelets, were determined with convulxin and thrombin with or without 1.5 or 6 microM adenosine diphosphate (ADP). Baseline levels of coated-platelets were 40.0% +/- 14.3% (mean +/- 1 SD). After clopidogrel exposure, the coated-platelet level was 32.8% +/- 13.6%, representing a significant 7.2% absolute reduction (AR) (17.8% relative reduction (RR); P < 0.0001). Clopidogrel significantly lowered the convulxin, thrombin plus ADP coated-platelet production (11.0% AR; 20.1% RR for 1.5 microM and 11.2% AR; 19.1% RR for 6 microM). CONCLUSIONS: This is the first report on the impact of in vivo administration of a P2Y12 antagonist on coated-platelet formation. The significance of a partial attenuation in coated-platelet potential has yet to be determined, but this could represent a new antithrombotic mechanism of clopidogrel beyond inhibition of ADP-induced aggregation.

Afterdepolarizations as a mechanism for the long QT syndrome: electrophysiologic studies of a case.

A young woman with palpitation and syncope was found to have ventricular tachyarrhythmia and a congenital long QT interval. The QT interval was shortened and the arrhythmia suppressed by propranolol. Electrograms recorded at various sites in both ventricles revealed a distinct diastolic slow wave that followed the T wave and measured 1.1 mV. Epinephrine infusion and emotion augumented this diastolic wave and induced ventricular ectopic complexes arising from this potential. Similar endocardial recordings in eight patients without a long QT interval showed diastolic slow waves that never exceeded 0.28 mV. In normal canine myocardium, afterdepolarizations can be induced by norepinephrine and blocked by propranolol. These findings suggest that the long QT syndrome is associated with abnormally large afterdepolarizations in ventricular myocardial cells, which are enhanced by beta-adrenergic stimulation to attain threshold and produce firing.

Noninvasive evaluation of aortic stenosis severity utilizing Doppler ultrasound and electrical bioimpedance.

Aortic valve area was calculated noninvasively in 30 patients with aortic stenosis undergoing cardiac catheterization. Continuous wave Doppler ultrasound was employed to estimate the mean transvalvular pressure gradient. The mean left ventricular outflow tract flow velocity and cross-sectional area were determined from pulsed Doppler and two-dimensional ultrasound recordings. Electrical transthoracic bioimpedance cardiography performed simultaneously with the ultrasonic study and repeated at the time of catheterization measured heart rate, systolic ejection period and cardiac output. These noninvasive data permitted calculation of aortic valve area using the Gorlin equation (range 0.21 to 1.75 cm2) and the continuity equation (range 0.25 to 1.9 cm2). Subsequent cardiac catheterization showed valve area to range from 0.21 to 1.75 cm2. The mean Doppler pressure gradient estimate was highly predictive of the gradient measured at catheterization (r = +0.92, SEE = 10). Bioimpedance cardiac output measurements agreed with the average of Fick and indicator dye estimates (r = +0.90, SEE = 0.52). Valve area estimates utilizing continuous wave Doppler ultrasound and electrical bioimpedance were superior (r = +0.91, SEE = 0.12) to estimates obtained utilizing the continuity equation (r = +0.76, SEE = 0.29) and were more reliable in the detection of patients with severe aortic stenosis (9 of 11 versus 6 of 11). These data show that 1) electrical bioimpedance methods accurately estimate cardiac output in the presence of aortic stenosis; 2) the hybridized bioimpedance-Doppler ultrasound method yields accurate estimates of aortic stenosis area; and 3) the speed, accuracy and cost-effectiveness of aortic stenosis evaluation may be improved by this hybridized approach.

Transmural myocardial infarction with the prolapsing mitral-leaflet syndrome and normal coronary arteries.

Clinical and electrocardiographic evidence of transmural myocardial infarction developed in two patients (a woman, age 38, and a boy, age 17) with prolapsing mitral-leaflet syndrome. Both had normal coronary angiograms and normal plasma lipid levels. Left ventricular angiography showed dyskinetic areas in both patients. Coronary artery embolism or prolonged coronary artery spasm may have been the underlying mechanism of production of myocardial infarction.

Iron measures in coronary angiography patients.

Excess iron has been postulated as a risk factor for coronary artery disease (CAD) because of its presence in atherosclerotic lesions, its ability to oxidize low density lipoprotein cholesterol (LDLc), and its promotion of oxygen reperfusion damage after an ischemic event. Whether iron, indirectly measured by its storage protein ferritin and its transport protein transferrin, is related to CAD was examined in a consecutive series of white male (n = 457) and female (n = 114) cardiac patients. Atherosclerosis measures were analyzed in patients grouped by tertiles of ferritin. A similar analysis was done with tertiles of transferrin. Contrary to expectations, men in the third tertile of ferritin had a smaller mean number of stenoses than men in the two lower tertiles (4.9 versus 5.6 and 5.9; P = 0.027); otherwise, there were no statistically significant differences in either number of lesions or extent of arterial narrowing based on tertiles of either measure. Separate multiple logistic regression models with age, fibrinogen, LDLc and triglycerides as covariates provided no evidence that ferritin (odds ratio = 0.88 with 95% C.I. = 0.72-1.07 for men and odds ratio = 0.79 with 95% C.I. = 0.54-1.16 for women) or transferrin (odds ratio = 0.60 with 95% C.I. = 0.31-1.16 for men and odds ratio = 1.33 with 95% C.I. 0.52-3.42 for women) were important correlates of the presence of atherosclerosis in this study.

Plasma apolipoprotein B and VLDL-, LDL-, and HDL-cholesterol as risk factors in the development of coronary artery disease in male patients examined by angiography.

To assess the potential use of plasma apolipoprotein B (ApoB) as a risk factor for coronary artery disease, this apolipoprotein was quantified by electroimmunoassay in 161 male patients with angiographically documented coronary atherosclerosis and 72 male patients with normal coronary arteries. In addition to ApoB, the analyzed lipoprotein profile included plasma total cholesterol, plasma triglyceride and VLDL-, LDL- and HDL-cholesterol levels. Age, plasma cholesterol, triglyceride, and VLDL- and LDL-cholesterol were significantly greater (P less than 0.05) for patients with coronary artery disease than for patients with normal arteries. In contrast, there was no difference in the mean levels of HDL-cholesterol between these 2 groups of patients. However, patients with HDL-cholesterol les than 40 mg/dl had a higher rate of coronary artery disease than those with HDL-cholesterol greater than 40 mg/dl (P less than 0.05). The results of multivariate analysis showed that age and plasma cholesterol were the 2 variables most significantly (P less than 0.01) related to the presence of coronary artery disease. However, in a subgroup of patients with plasma cholesterol less than 265 mg/dl, the most reliable variable was ApoB (P less than 0.01). For patients under 50 years of age ApoB and LDL-cholesterol were the most significant variables (P less than 0.05), whereas for patients at 50 years of age or older VLDL-cholesterol was the most significant variable (P less than 0.01). Results of this study indicate that measurement of ApoB may offer important predictive value for coronary artery disease, especially at lower levels of plasma cholesterol. Whether this and other conclusions also apply to general population, remains to be established in future studies.

Angiotensin-converting enzyme gene polymorphism in a cohort of coronary angiography patients.

An association between a polymorphism of the angiotensin-converting enzyme (ACE) gene and myocardial infarction (MI) in men has been previously reported. The present study examines the association between ACE genotype, atherosclerosis, MI, hypertension and other cardiovascular risk factors in Caucasian men (n=576) and women (n=124) who have undergone coronary angiography. Gene frequencies are also reported for African-American men (n=56). Genotype determination was based on the presence (allele I) or absence (allele D) of a 287 nucleotide Alu sequence in intron 16 of the ACE gene. Genotype frequencies for DD, ID and II were: 30.9, 47.7, 21.4% for Caucasian men; 28.2, 48.4, 23.4% for Caucasian women; and 30.4, 46.4, 23.2% for African-American men. There were no statistically significant associations between ACE genotype and number of plaques (> or =10% obstruction), lipid variables, or body mass index (BMI) for Caucasian men. Caucasian women with the DD genotype had on average fewer plaques, but this was accounted for by their younger ages. In Caucasian males, the DD genotype independently contributed to the presence of hypertension (odds ratio=1.8, 95% CI 1.1-2.9) after adjusting for age and BMI. In Caucasian males with total cholesterol levels less than 200 mg/dl (n=237), the DD (odds ratio=2.5, 95% CI 1.2-5.4) and ID genotypes (odds ratio=2.2, 95% CI 1.1-4.4) were associated with a history of MI.

Activated factor VII levels in patients with angiographically confirmed coronary artery disease.

We have examined factor VIIa levels in consecutive consenting patients undergoing coronary angiography (n = 702) to determine if levels are related to the presence of coronary arterial narrowing and to the degree and extent of that narrowing. Both men and women with clinically defined coronary artery disease (> or = 50% stenosis in at least 1 vessel) had factor VIIa levels that were similar to men and women with less stenosis or normal coronary arteries.

Fibrinogen levels in women having coronary angiography.

Fibrinogen has emerged as a risk factor for coronary artery disease in men that equals cholesterol in importance. It is known to play an important role in reparative processes, and evidence is accumulating that fibrinogen/fibrin accumulates at the site of minimal vascular injury. Fibrinogen contributes significantly to blood viscosity and its adherence to endothelium may mediate progression of atheromatous lesions. This study was designed to examine a number of markers of risk in a consecutive series of cardiology patients undergoing coronary catheterizations over a 15-month period. This article examines the level of fibrinogen in relation to the number of reported coronary stenoses and disease severity in a series of Caucasian female patients (n = 101). Women were classified as diseased if they had at least 1 lesion > or = 25% in the coronary anatomy and nondiseased if they had no lesions > or = 25%. The number of reported lesions correlates significantly with fibrinogen levels (r = 0.36, p = 0.0002). Women with fibrinogen levels > or = 283 mg/dl had a 3.2-fold increased risk (95% confidence interval 1.2 to 9.1) of having at least 1 stenosis > or = 25% after adjusting for age and diabetic status. Smoking and body mass index did not differ by disease status and thus did not confound the finding. Mean fibrinogen levels showed a progressive positive association with increasing clinically defined vessel involvement (stenosis > or = 50%).

Low- versus high-dose recombinant urokinase for the treatment of chronic saphenous vein graft occlusion.

Recanalization of a totally occluded saphenous vein graft (SVG) using commercially available urokinase from human kidney cells has been shown to be effective, but the duration of infusion and complications such as allergic reactions, bleeding events, and non-Q-wave myocardial infarction have limited its acceptance. Recently, genetic engineering has allowed the synthesis of recombinant urokinase (r-UK). Patients with an occluded SVG from 37 centers were randomized to receive a 6-hour infusion of either low-dose (125,000 IU/hour) or high-dose (350,000 IU/hour) r-UK followed by up to a maximum of 18 hours of r-UK (125,000 IU/hour) via a subselective catheter directly into the occluded vein graft. The primary study end point was final preintervention achievement of Thrombolysis In Myocardial Infarction (TIMI) flow > or = 2 using core angiographic analysis. One hundred seven patients were randomized and 98 received the study drug (low dose 52 patients, high dose 46 patients). TIMI flow > or = 2 after completion of the study drug was higher in the high-dose group (51% vs 24%, p = 0.019). This difference narrowed, but a trend was still evident on the final angiogram after adjunctive mechanical intervention (72% vs 58%, p = 0.254). Bleeding complications were frequent; severe or life-threatening bleeding occurred in 12% of patients on the low dose and 11% of patients on the high dose (p = NS), including 2 intracerebral bleeds, both of which were fatal with 1 in each group. Thus, in patients with an occluded SVG, a randomized trial of direct low-dose versus high-dose r-UK infusion demonstrated increased recanalization rates (TIMI flow > or = 2) in the high-dose arm. Percutaneous revascularization of SVG with r-UK can be accomplished with acceptable success rates, but complications are frequent.

Hemodynamic correlates of echocardiographic aortic root motion. Observations on normal subjects and patients with idiopathic hypertrophic subaortic stenosis.

In ten normal subjects, we observed an initial hump in the aortic root echocardiogram after the onset of the QRS complex, following which a sharp anterior motion was noted. The onset of the anterior motion of the aortic root coincided with the onset of the upstroke of the aortic root pressure pulse and the onset of the velocity signal in five of seven patients with coronary arterial disease; in the other two, the anterior aortic motion followed the onset of the pressure and velocity signal by 10 msec. The aortic root echocardiogram was abnormal in patients with idiopathic hypertrophic subaortic stenosis; the slope (normalized for the scales of time and depth) in early systole was steeper and in the latter part of systole was flatter than normal in these patients. The slope in early diastole was flatter and the slope due to atrial contraction was steeper in the patients with idiopathic hypertrophic subaortic stenosis than in the normal subjects. These features were consistent with rapid ejection in early systole and slow filling in the early phase of ventricular diastole in idiopathic hypertrophic subaortic stenosis. Fourier analysis of the wave form of the aortic root allowed separation between patients with idiopathic hypertrophic subaortic stenosis and normal subjects.

Plasma immunoglobulins in patients with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To assess immunoglobulin (Ig) concentrations in plasma and ascitic fluid of patients with severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Controlled clinical study. SETTING: Tertiary medical center. PATIENT(S): Ten patients with severe OHSS after ovulation induction for IVF and 10 controls who had undergone similar ovulation induction and did not develop OHSS. INTERVENTION(S): Three blood samples were obtained from each OHSS patient: one at the time of hospitalization for severe OHSS, one when significant clinical improvement was evident, and one at the first follow-up visit after discharge from the hospital. Blood samples were drawn from control patients 6-8 days after ET. Ascitic fluid was obtained from all patients with OHSS by therapeutic paracentesis. MAIN OUTCOME MEASURE(S): Immunoglobulin concentrations were assayed by radial immunodiffusion. RESULT(S): Significantly lower levels of gamma-globulins, specifically IgG and IgA, were detected in the plasma of patients with severe OHSS, whereas alpha- and beta-globulin levels as well as IgM levels were not significantly different from those in controls. Both IgG and IgA levels increased as patients clinically improved. Ascitic fluid contained high IgG, moderate IgA, and negligible IgM levels. CONCLUSION: Severe OHSS is characterized by hypogammaglobulinemia, attributed to leakage of medium-molecular-weight immunoglobulins such as IgG and IgA to the peritoneal cavity.

Role of factor V Leiden mutation in patients with angiographically demonstrated coronary artery disease.

The study sought to determine whether coagulation factor V Leiden (FV Leiden) plays a role in the pathogenesis of coronary artery disease and/or myocardial infarction. Association of FV Leiden with venous thromboembolism is well established in the literature, but the role of the mutation in arterial thrombotic events is controversial. Some studies have documented an association between the mutation and myocardial infarction and stroke in juveniles. Few studies have explored its possible contribution to coronary atherosclerosis. We screened FV genotype in 850 predominantly white coronary angiography patients. Coronary artery disease risk factors and history of myocardial infarction were then analyzed by genotype. The FV Leiden mutation occurred in 54 (6.4%) patients. There was one homozygote; a 37-year-old, white male smoker with a history of myocardial infarction. Gene frequencies for white males and females were similar: 0.965 for the normal allele and 0.035 for FV Leiden. Gene frequencies for both genders were in Hardy-Weinberg equilibrium. FV Leiden was not a useful predictor (p=0.23) of the presence of clinically defined atherosclerosis (> or = 50% stenosis) in a logistic regression model adjusting for age, lipoprotein (a), total cholesterol, triglycerides, high density lipoprotein cholesterol, and fibrinogen. In addition, there was no difference in frequency of FV Leiden among those with and without medical histories of myocardial infarction (p=0.51). Allelic frequencies of FV Leiden in this patient group do not differ significantly from those reported for white populations. The FV Leiden mutation in its heterozygous state is not independently associated with coronary artery disease or myocardial infarction.

Predictions of coronary artery stenosis by artificial neural network.

Data from angiography patient records comprised 14 input variables of a neural network. Outcomes (coronary artery stenosis or none) formed both supervisory and output variables. The network was trained by backpropagation on 332 records, optimized on 331 subsequent records, and tested on final 100 records. If 0.40 was chosen as the output distinguishing stenosis from no stenosis, 81 patients who had stenosis would have been identified, while 9 of 19 patients who did not have stenosis might have been spared angiography. The results demonstrated that artificial neural networks could identify some patients who do not need coronary angiography.

Commitment to work and the self-perception of disability.

Population surveys of the disabled frequently show large numbers of persons who report work activity despite a simultaneous response indicating that they are severely disabled. Using multinomial logit analysis, this article examines the characteristics of persons who express such a commitment to work. The characteristics examined are sex, race, age, family size, education, marital status, health status, and length of work experience prior to onset of disability. The logit analysis allows us to see which of these variables predict work behavior. Data from the 1972 Survey of Disabled and Nondisabled Adults and the 1974 Followup Survey are used. Data are shown in cross section (1972 and 1974) and longitudinally (patterns of change from 1972 to 1974). In 1972, the less severe the level of health problems, the higher the level of education, being male, and needing to help relatives financially were traits associated with the probability of working despite self-report of severe disability. Those who received funds from public income maintenance were not likely to have worked. Essentially, the same findings were obtained for 1974 cross sectionally and 1972-74 longitudinally. Comparison was also made between those severely disabled persons who worked full time and those who worked part time, for both 1972 and 1974. Basically, age and severity of health condition were associated with the probability of working full time as opposed to part time, suggesting that it is a work/no work decision that is more likely to discriminate among the work commitments of the severely disabled than is the type of work schedule.

Work while receiving disability insurance benefits: additional findings from the New Beneficiary Followup Survey.

From the foregoing analyses, the following picture emerges about persons who work after award of DI benefits: Almost one-quarter of the sample population attempted to reenter the labor force in the 10-year NBS-NBF period. The higher the level of education, the greater the proportion of persons who worked. Younger beneficiaries were more likely to work than older beneficiaries. About half of the beneficiaries who worked did so on a full-time (40-hour-or-more per week) basis. Most beneficiaries worked because of financial need. The profile of reasons for working did not vary across demographic groups and aspects of the first job held. Most beneficiaries began working without attributing this decision to an improvement in their health. Individuals pursued different methods of job search. No single approach emerged as the most successful. Job search modes did not vary for different groups and different jobs. Four activities were most likely to lead to job offers: persons checking where they had worked before, asking a friend, answering an ad, and following up a vocational rehabilitation lead. These findings were not conclusive because small numbers of persons engaged in these activities. Thirty percent of DI workers returned to their preentitlement employer. The beneficiaries' first postentitlement jobs had less exertion, fewer hours, and lower pay than did their job held prior to award. The likelihood of working was the same across a broad range of disabling health conditions. In terms of work return policy, formal work return programs aimed at young beneficiaries and those with higher levels of educational attainment would produce the greatest number of job placements. It appears that no targeting of programs is necessary along gender lines. The anomalous finding of an absence of the relationship between improvement in health and labor-force reentry requires further investigation. Any followup in this area of inquiry should plan to have the data collected close to the time of postentitlement job entry.

Industry, occupation, and disability insurance beneficiary work return.

This article uses the New Beneficiary Data System to describe the first job held after award of Disability Insurance benefits, in terms of occupation and industry. It examines work activity within sectors of employment, and looks at the issues of whether work return in certain industries and occupations varies according to the demographic characteristics of the beneficiaries. The article also presents data on sector-specific employer accommodations that can aid in sustained work return. Postentitlement work was fairly evenly distributed across occupational and industrial sectors. Persons with higher levels of educational attainment were found to be in white-collar employment sectors. There were noticeable differences in the availability of employer accommodations across postentitlement occupations and industries.

Employment and work adjustments of the disabled: 1972 survey of disabled and nondisabled adults.

Of the 15.6 million individuals in the United States who were currently disabled in 1972, 8 out of 10 were employed as the disability began. For these persons, several aspects of work adjustments after the onset of disability are examined here, with the measures of adjustment based on self-reports of the disabled. Women were less likely to be employed after onset than men. Those employed full time before they were disabled were more likely to work after onset than those who had been part-time workers. The relationship between duration of disability and employment varied with severity of disability. Among the severely disabled, those with a long-term disability were more likely not to work than were the recently disabled. Keeping the pre-onset work status varied with type of employment. For the severely and occupationally disabled, industries staffed by craftsmen and operatives had lower rates of retention than did other sectors. Most of those who returned to work after onset did so within 6 months. Men who returned to work did so more quickly than did women. Doctor's advice and family responsibility were the primary reasons for not returning to work.