Noncompliance in antiplatelet trials: the AGATE trial perspective.
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Aspirin↗
Biomedical subjects
D Atar
Publications and source records attributed to D Atar.
Pharmacogenomics in cardiovascular clinical trials.
Genomics - having quickly emerged as the central discipline in basic science and biomedical research - is poised to take the center stage in clinical medicine as well over the next few decades. Although there is no specific regulatory guideline on the application of pharmacogenetics to drug development, some recommendations are already included in several published guidelines on drug development. The patients more likely to provide the most valuable information on the specific contribution of a given gene or its variant are those who fail to respond to a drug ('therapeutic failures') and those who develop toxicity to the drug. However, before drawing definite conclusions on subgroups following pharmacogenomic analyses, one must be aware of disease classification, data collection, and how much is known about the disease process. It seems reasonable to collect genomic DNA from all patients enrolled in clinical drug trials (along with appropriate consent to permit pharmacogenetic studies) for the purpose of post hoc analyses. One exception to post hoc genomic analysis is when patients with a specific genotype are excluded from randomization into a clinical trial. Physicians will need to understand the concept of genetic variability, its interactions with the environment (e.g. drug-drug or drug-disease interactions), and its implication for patient care.
Biomedical Research↗
Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin.
Clinical depression has been identified as an independent risk factor for increased mortality in patients with coronary artery disease. Enhanced platelet activity has been suggested as the mechanism responsible for this adverse association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelets in patients undergoing coronary stenting. We sought to determine whether concomitant therapy with SSRIs would yield additional anti-platelet benefit in patients with congestive heart failure (CHF) already treated with antecedent aspirin. A total of 88 patients with left ventricular ejection fraction (LVEF) <40% or CHF symptoms in the setting of preserved systolic function and NYHA Class II-IV were analyzed. Of these, 23 patients (26%) were chronic SSRI users (SSRI+), and 65 patients were free from SSRI therapy (SSRI-). All patients received aspirin (325 mg) for at least 1 month prior to platelet studies. Platelets were assessed by aggregometry, flow cytometry and a rapid analyzer. The SSRI+ group exhibited a substantial decrease in platelet activity when compared with SSRI- patients, as manifested by a significant reduction in ADP- (P=0.001), and collagen-induced (P=0.02) aggregation, and the expression of PECAM-1 (P=0.03), GPIb (P=0.03), GP IIb/IIIa antigen (P=0.02) and GP IIb/IIIa activity with PAC-1 antibody (P=0.04) and P-selectin (P=0.02). Therapy with SSRIs also resulted in the reduced formation of platelet-leukocyte microparticles (P=0.01). Epinephrine-induced aggregation in plasma, collagen-induced whole blood aggregation, closure time and expression of vitronectin receptor, CD63, CD107a, CD107b and CD151 did not differ between groups. In patients with CHF already on aspirin, SSRI therapy was associated with further inhibition of platelet function. This observation may help to explain some of the clinical benefits associated with SSRI therapy. Further clinical trials may help to elucidate the potential outcome benefits of SSRIs in other potential thrombotic circumstances.
Aged↗
Prevalence of impaired left ventricular systolic function and heart failure in a middle aged and elderly urban population segment of Copenhagen.
OBJECTIVE: To assess the prevalence of impaired left ventricular systolic function and manifest heart failure in a general population aged 50-89 years. DESIGN: In this cross sectional survey, participants filled in a heart failure questionnaire. ECG, blood tests, and echocardiography were performed. SETTING: The study population was recruited from general practitioners situated in the same urban area and examined in a university hospital in Copenhagen, Denmark. PARTICIPANTS: 764 participants (432 women and 332 men, median (SD) age 66 (11) years) participated. The study population was stratified to include a minimum of 150 persons in each age decade. MAIN OUTCOME MEASURES: Prevalence of impaired systolic function and manifest heart failure. RESULTS: The prevalence of systolic dysfunction (left ventricular ejection fraction < or = 40%) was more than twice as high among men (7.6%) as among women (2.6%). In the male population systolic heart failure (left ventricular ejection fraction < or = 40% and symptoms) was found in 1.8% of the 50-59 years age group and approximately doubled for each age decade to reach 13.9% in octogenarians. Among women systolic dysfunction increased from 0.8% to 4.3% in the same age groups. Asymptomatic cases accounted for 44.0% of all cases of systolic dysfunction in the male population and only 9.1% in the female population. CONCLUSIONS: In this age controlled population study impaired left ventricular systolic function and heart failure increased substantially with age and was more than twice as frequent among men as among women. Asymptomatic left ventricular dysfunction occurred more frequently in men than in women and was less prevalent with increasing age.
Age Factors↗
Whole blood impedance aggregometry for the assessment of platelet function in patients with congestive heart failure (EPCOT Trial).
OBJECTIVE: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of the whole blood aggregometry (WBA) in a random outpatient CHF population. METHODS: Blood samples were obtained for measurement of whole blood aggregation, shear-induced closure time, platelet contractile force, expression of GP IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. RESULTS: Substantial inter-individual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Surprisingly, aspirin use did not affect instrument readings as well. Whole blood aggregometry correlates well with the closure time (r(2)=0.587), and with GP IIb/IIIa expression (r(2)=0.435). Significant but less strong correlation has been observed for the WBA with platelet P-selectin expression (r(2)=0.295), and no correlation was present for the platelet contractile force measures (r(2)=0.030). CONCLUSIONS: Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes, in their platelet characteristics, whole blood impedance aggregometry is indeed capable to serve as a valuable diagnostic tool, and may be successfully used as an established screening device in this population. Ability of the whole blood aggregometry to predict clinical outcomes, or for the monitoring of anti-platelet agents in CHF patients, will be evaluated in the ongoing clinical trials.
Aged↗
Doppler indices of diastolic transmitral flow velocity are invalid indicators of myocardial ischaemia during high-dose dobutamine infusion in anaesthetized patients.
BACKGROUND AND OBJECTIVE: Doppler echocardiography of diastolic transmitral flow velocity is more sensitive for the detection of myocardial ischaemia in awake patients than echocardiographic analysis of systolic wall motion. However, its diagnostic value in anaesthetized patients is unknown. METHODS: Doppler indices of diastolic transmitral flow velocity previously found to be highly sensitive for detecting ischaemia in awake patients were studied in 72 anaesthetized patients with documented coronary artery disease undergoing dobutamine stress echocardiography. These Doppler indices were compared with standard echocardiographic and electrocardiographic criteria for ischaemia. RESULTS: Sixty-five patients showed evidence of ischaemia by standard echocardiographic and/or electrocardiographic criteria, and seven patients did not. Regardless of evidence of ischaemia by standard criteria, the Doppler indices changed similarly in both groups. Accordingly, only a minority of anaesthetized patients displayed the changes in Doppler indices of diastolic transmitral flow previously suggested to be sensitive for detecting ischaemia. CONCLUSIONS: The results do not confirm the diagnostic value of Doppler echocardiography of diastolic transmitral flow velocity for detecting ischaemia in anaesthetized patients undergoing dobutamine stress echocardiography during positive-pressure ventilation of the lungs.
Adult↗
Platelet activation as a universal trigger in the pathogenesis of acute coronary events after cocaine abuse.
Numerous reports document the widespread use of cocaine in most parts of the world, which confers an increased risk of vascular morbidity and mortality. The mechanisms responsible for this association are multifactorial, but platelet activation might play a substantial role linking these events. Contradictory data exist regarding the cellular mechanisms of cocaine's effects on thrombocytes. In terms of therapeutic interventions, a possible activation of platelets would conceptually require more aggressive anti-platelet therapy with aspirin, clopidogrel or other compounds, however, no data exist to date to support this approach. Further studies elucidating these issues are warranted. This review summarizes the latest and often confusing data on the interaction between cocaine and platelets in certain in vitro, animal and clinical scenarios.
Animals↗
Cardiac troponin I is modified in the myocardium of bypass patients.
BACKGROUND: Selective proteolysis of cardiac troponin I (cTnI) is a proposed mechanism of contractile dysfunction in stunned myocardium, and the presence of cTnI degradation products in serum may reflect the functional state of the remaining viable myocardium. However, recent swine and canine studies have not demonstrated stunning-dependent cTnI degradation. METHODS AND RESULTS: To address the universality of cTnI modification, myocardial biopsy samples were obtained from coronary artery bypass patients (n=37) before and 10 minutes after removal of cross-clamp. Analysis of biopsy samples for cTnI by Western blotting revealed a spectrum of modified cTnI products in myocardium both before and after cross-clamp, including degradation products (7 products resulting from differential N- and C-terminal processing) and covalent complexes (3 products). In particular, a 22-kDa cTnI degradation product with C-terminal proteolysis was identified, which may represent an initial ischemia-dependent cTnI modification, similar to cTnI(1-193) observed in stunned rat myocardium. Although no systematic change in amount of modified cTnI was observed, subgroups of patients displayed an increase (n=10, 85+/-5% of cTnI remaining intact before cross-clamp versus 75+/-5% after) or a decrease (n=12, 67+/-5% before versus 78+/-5% after). Electron microscopy demonstrated normal ultrastructure in biopsy samples, which suggests no necrosis was present. In addition, cTnI modification products were observed in serum through a modified SDS-PAGE methodology. CONCLUSIONS: cTnI modification, in particular proteolysis, occurs in myocardium of bypass patients and may play a key role in stunning in some bypass patients.
Biopsy↗
Extensive troponin I and T modification detected in serum from patients with acute myocardial infarction.
BACKGROUND: Cardiac troponin I and T (cTnI and cTnT) are specific biochemical serum markers for acute myocardial infarction (AMI). However, cTnI diagnostic assays are plagued by difficulties, resulting in >/=20-fold differences in measured values. These discrepancies may result from the release of the numerous cTnI modification products that are present in ischemic myocardium. The resolution of these discrepancies requires an investigation of the exact forms of cTnI present in the bloodstream of patients after myocardial injury. METHODS AND RESULTS: A western blot-direct serum analysis protocol was developed that allowed us to detect intact cTnI and a spectrum of up to 11 modified products in the serum from patients with AMI. For the first time, we document both a cTnI degradation pattern and the existence of phosphorylated cTnI in serum. The number and extent of these modifications reflect patterns similar to the time profiles of the routine clinical serum markers of total creatine kinase, creatine kinase-MB, and cTnI (determined by ELISA). Data from in vitro experiments, which were undertaken to study the degradation of human recombinant cTnI and cTnT when spiked in serum, indicate that some modification products present in patient serum existed in the myocardium and that recombinant cTnI alteration dramatically reduces the detectability of cTnI by the Immuno1 assay over time (our assay was unaffected). CONCLUSIONS: This pilot study defines, for the first time, what forms of cTnI and cTnT appear in the bloodstream of AMI patients, and it clarifies the lack of standardization between different cTnI diagnostic assays.
Biomarkers↗
Pathophysiology and therapeutic modification of thrombin generation in patients with coronary artery disease.
Thrombin plays a central role in thrombogenesis: it activates platelets, converts fibrinogen to fibrin, and activates factor XIII, which then crosslinks and stabilizes the fibrin clot. In addition, thrombin amplifies coagulation by activating factors VIII and V, key cofactors in the generation of activated factor X and thrombin, respectively. Even platelet function is influenced by thrombin. Hence, thrombin generation is most important both in the chronic progression of coronary atherosclerotic disease and in its conversion to acute events. To date, various therapeutic approaches capitalize on this knowledge by targeting specific thrombin-related pathways. Among the successful and carefully documented pharmacologic strategies in acute or chronic coronary heart disease are the use of unfractioned heparin, low-molecular-weight heparin, thrombolysis, hirudin, and/or inhibition of thrombin generation by glycoprotein IIb/IIIa antagonists, most often utilized on top of antiplatelet therapy (e.g., with acetylsalicylic acid) and/or vitamin K antagonism. The present review provides insights into the pathophysiology of thrombin generation in coronary atherosclerosis and gives an overview over the above mentioned therapeutic thrombin modifications.
Coronary Disease↗
Lack of nuclear apoptosis in cardiomyocytes and increased endothelin-1 levels in a rat heart model of myocardial stunning.
OBJECTIVE: Reperfusion injury may affect the cardiac NO and endothelin production. We investigated whether 20 min of total ischemia followed by 40 min of reperfusion can induce apoptosis in a Langendorff model of retrogradely perfused rat hearts (37 degrees C; paced at 300/'), and we attempted to correlate these findings with measured tissue NO and ET-1 levels. METHODS: An apoptosis detection system was utilized which catalytically incorporates fluorescein-12-dUTP at the 3'-OH DNA ends using the principle of the TUNEL assay, with direct visualization of the labeled DNA. ET-1 was measured by radioimmunoassay and NO3/NO2 by ion pairing HPLC on C18 reverse phase columns. RESULTS: None of the postischemic (n = 6) nor of the control perfused (90 min, n = 6) hearts showed signs of apoptosis, while those exposed to longer ischemia (40 min) and reperfusion (2 h) confirmed the presence of apoptotic cells. Myocardial ET-1 concentrations were 4.8 +/- 1.0 versus 8.3 +/- 2.5 pg/100 mg (control vs. ischemic hearts, respectively; mean +/- SD; p < 0.05). Myocardial NO contents showed no differences. CONCLUSION: These data suggest that the time window of apoptosis with detectable DNA fragmentation exceeds 20 min of global total ischemia and 40 min of reperfusion, a model frequently used for inducing myocardial stunning. While NO was not increased in postischemic hearts, increased ET-1 levels indirectly argue for a role of ET-1 as inducer of apoptosis, but only at a later stage of reperfusion.
Animals↗
The diagnostic value of Doppler echocardiographic indexes of diastolic filling for detecting demand ischemia in anesthetized patients.
UNLABELLED: In awake patients, Doppler indexes of transmitral flow velocities have been shown to be more sensitive for detection of myocardial ischemia than echocardiographic evaluation of systolic wall-motion. The diagnostic value of these indexes in anesthetized patients is unknown. It might differ from that in awake patients because anesthetics and sympathomimetic drugs, which are commonly used in surgical patients with coronary artery disease (CAD), independently affect transmitral flow velocities. METHODS: Several previously published transmitral Doppler echocardiographic indicators of ischemia (marked decreases in the ratio of peak early [E] to peak atrial [A] filling velocity [E/A], in the ratio of early to atrial time-velocity integral [E(I)/A(I)], in E, in E acceleration, and in total diastolic time-velocity integral) were compared with standard wall-motion analysis and ST-segment analysis during dobutamine stress echocardiography (DSE) in 17 anesthetized patients with CAD and 7 age-matched control patients at low risk of CAD. RESULTS: All patients with CAD but no control patients showed new systolic wall-motion abnormalities and/or ST-segment changes. Decreases of >10% in E/A and E(I)/A(I) were found in 88% and 71% of the patients with CAD and in 71% and 100% of the control patients, respectively. These decreases were found during dobutamine infusion at as low as 10 mcg/kg/min in several control patients. None of the other studied Doppler indexes were found useful to detect ischemia. CONCLUSIONS: Doppler echocardiography of diastolic transmitral flow velocities is of no appreciable diagnostic value for detecting ischemia in anesthetized patients who receive dobutamine at 10-40 mcg/kg/min.
Aged↗
Effect of coronary thrombolysis on the plasma concentration of osteonectin (SPARC, BM40) in patients with acute myocardial infarction.
Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet alpha-granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447. 7+/-20.6 ng/ml) and AMI patients (425.7+/-43.3 ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4+/-26.9 ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this alpha-granule constituent, challenge the postulate of uniform platelet activation in AMI patients.
Adult↗
Comparison of methods of fractional area change for detection of regional left ventricular dysfunction.
Three methods for assessment of fractional area change (FAC) and conventional versus cross-sectional segmentation were compared under conditions known to occur frequently during stress echocardiography. Quantitative analysis of 80 echocardiograms obtained from healthy subjects, patients with left ventricular (LV) dysfunction and after coronary artery bypass grafting included segmental and cross-sectional FACs by the centroid method with fixed and floating reference and a method with floating external reference. All segmental and cross-sectional FACs were equally sensitive to LV dysfunction, and segmental FACs failed to accurately predict the location of coronary lesions. The centroid method with floating reference and cross-sectional FACs were the least affected by surgery induced intrathoracic heart motion. In moderate to severe LV dysfunction FAC by the centroid method with floating reference and cross sections were rarely within normal limits. Cross-sectional FACs may prove to be useful in stress echocardiography. For viability studies segmental FAC by fixed reference appears to be the method of choice.
Adult↗
Atrioventricular plane motion during dobutamine-atropine stress echocardiography: the biphasic response in healthy subjects revisited.
This study was undertaken to establish normal values for the systolic atrioventricular plane motion (AVPM) from base to apex during dobutamine-atropine stress echocardiography (DASE) and to compare them with those of patients with coronary artery disease. The AVPM was measured at baseline, low dose and peak dobutamine-atropine infusion in 20 patients referred for coronary angiography and in 20 control subjects. Atrioventricular plane motion was measured at the posterior, anterior, septal, and lateral positions of the mitral annulus in the apical 2- and 4-chamber views by an observer blinded to clinical and angiographic data. In healthy subjects undergoing DASE, AVPM initially increased but subsequently decreased to below baseline values at peak stress. Atrioventricular plane motion at any stage and the changes therein during DASE were within the normal reference interval in the majority of patients. In conclusion, AVPM decreased during DASE in healthy subjects and was not a sensitive marker of coronary artery disease.
Adrenergic beta-Agonists↗
Troponin I measurement in the diagnosis of myocardial injury during pregnancy and delivery: two cases.
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Adult↗
Baseline platelet aggregation and major receptor expression predict subsequent activity following thrombolysis for acute myocardial infarction.
The early identification of patients with heightened platelet activity for aggressive antiplatelet regimens represents a critical clinical issue in acute myocardial infarction (AMI) therapy. We sought to determine whether the degree of pre-reperfusion platelet function is related to subsequent activity following thrombolysis. Platelets were investigated at baseline and at 24 h following thrombolytic therapy by aggregometry, and flow cytometry in 19 AMI patients enrolled in the GUSTO-III trial. Regression analysis revealed a significant correlation for 5 microM ADP (r2 = 0.529), 10 microM ADP (r2 = 0.445), thrombin (r2 = 0.226), collagen (r2 = 0.568), and ristocetin-induced aggregation (r2 = 0.964). Platelet expression linearly correlated for GPIIb/IIIa (r2 = 0.337), P-selectin (r = 0.817), PECAM-1 (r2 = 0.586), and the vitronectin receptor (r2 = 0.634). The data suggest that the baseline characteristics predict future platelet activity, and may prospectively identify patients who will benefit most from antiplatelet strategies after coronary thrombolysis.
Biomarkers↗
Is there a need for lumbar orthosis in mild compression fractures of the thoracolumbar spine?: A retrospective study comparing the radiographic results between early ambulation with and without lumbar orthosis.
Compression fractures of the thoracolumbar spine are common in spinal trauma. Most patients are treated with early ambulation. Bracing is an option not always recommended by the treating team. There are no definite recommendations so far regarding the need for lumbar orthosis in this type of injury. The authors retrospectively compared two methods for treating patients with compression as great as 30%: early ambulation with and without lumbar orthosis. The results show that although demographic variables, type of injury, and cause of injury were similar between the groups, neither treatment emerged as superior. Thoracolumbar fractures with compression as much as 30% can be treated with early ambulation and no external support. Close clinical and radiographic follow-up is essential.
Adult↗