Coronary Artery Disease: Atar D

Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Anonymous00206, Anonymous00207. · European Society of Cardiology · G Ital Cardiol (Rome). · Pubmed #18383763 No free full text.

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Aarønaes M, Atar D, Bonarjee V, Gundersen T, Løchen ML, Mo R, Myhre ES, Omland T, Rønnevik PK, Vegsundvåg J, Westheim A. · Hjertemedisinsk avdeling, Rikshospitalet, 0027 Oslo. · Tidsskr Nor Laegeforen. · Pubmed #17237863 links to  free full text

Abstract: Congestive heart failure is a major health problem in the western world and the prevalence of patients with this diagnosis increases. About 2% of the adult population are affected; the majority are elderly, which represents a challenge when it comes to assessment and treatment. This article concerns the aetiology and diagnosis of congestive heart failure and provides a suggestion for guidelines. The proposed guidelines are aimed at primary, secondary and third line health care providers in Norway, and are based on previously published Norwegian guidelines and international guidelines. Hypertension and coronary artery disease account for 75-80% of known cases of congestive heart failure. The patient's history and risk factors must be investigated. Laboratory tests emphasising organ functions are important, and these should include measurement of B-type natriuretic peptide (BNP). Electrocardiograms and chest X-rays should be taken as well. All patients with suspected impaired left ventricular ejection fraction should undergo an echocardiographic examination. Invasive tests, and non-invasive imaging should be used for selected groups of patients only.

Pothula A, Serebruany VL, Gurbel PA, McKenzie ME, Atar D. · Sinai Hospital, Center for Thrombosis Research, Baltimore, MD, USA. · Eur J Pharmacol. · Pubmed #10940351 No free full text.

Abstract: 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.

Malinin AI, Atar D, Callahan KP, McKenzie ME, Serebruany VL. · Center for Thrombosis Research, Sinai Hospital of Baltimore, Johns Hopkins University, 2401 West Belvedere Avenue, Schapiro Research Building R 202, Baltimore, MD 21215, USA. · Eur J Pharmacol. · Pubmed #12591106 No free full text.

Abstract: We sought to assess how one tablet of non-enteric coated aspirin (325 mg) affects human platelets in subjects with risk factors for coronary artery disease. Data from 63 individuals with multiple cardiac risk factors were analyzed. Platelets were assessed twice at baseline (pre-aspirin), and after 3-4 h (post-aspirin). We employed 5 microM epinephrine-induced conventional aggregometry, closure time with epinephrine/collagen cartridge by PFA-100(R) (Dade-Behring), and aspirin response units (ARU) stimulated by propyl gallat with Ultegra (Accumetrics, San Diego, CA, USA) for measuring platelet function. In addition, the expression of platelet receptors was determined by using the following monoclonal antibodies: anti-CD31, CD41, CD42b, CD51/CD61, CD62p, CD63, CD107a, and CD151. Platelet-leukocyte formation was detected utilizing dual antibodies for a pan-platelet marker CD151, and CD14, a monocyte/macrophage marker. PAC-1 was used to measure fibrinogen-platelet binding. One pill of aspirin significantly decreased platelet-rich plasma (PRP) aggregation (74.18+/-16.75% vs. 24.92+/-8.64%; p<0.0001) and resulted in reduction of the aspirin response units (ARU) (662.24+/-65.65 vs. 451.05+/-69.31; p<0.0001). There was also prolongation of the closure time (194.4+/-25.3 vs. 258.63+/-55.61 s; p<0.0001). High correlation (r(2)=0.73-0.86) between platelet analyzer readings and aggregation was observed. One tablet of aspirin moderately inhibited expression of most surface platelet receptors measured, and such inhibition reached significance (p<0.05) for PAC-1, CD31, CD41, CD42, CD62p, and CD151. We conclude that a single dose of aspirin affects major platelet receptors, presumably directly or indirectly through the inhibition of prostanoids via platelet cyclooxygenase-1 blockade. The Ultegra Analyzer with a novel cartridge seems to be reliable in reflecting aspirins' effects on platelets and could be used in the future in clinical practice for monitoring aspirin therapy.

Seeberger MD, Filipovic M, Rohlfs R, Dergeloo O, Studer W, Atar D, Buser P, Skarvan K. · Department of Anesthesia, University of Basel, Kantonsspital, Switzerland. · Int J Card Imaging. · Pubmed #11482709 No free full text.

Abstract: 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.

Carstensen S, Hoest U, Kjoeller-Hansen L, Saunamäki K, Atar D, Kelbaek H. · Department of Medicine B, The Heart Centre at Rigshospitalet, University of Copenhagen, Denmark. · Int J Card Imaging. · Pubmed #11219597 No free full text.

Abstract: 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.

McDonough JL, Labugger R, Pickett W, Tse MY, MacKenzie S, Pang SC, Atar D, Ropchan G, Van Eyk JE. · Department of Physiology, Queen's University, Kingston, Ontario, Canada, K7L 3N6. · Circulation. · Pubmed #11136686 links to  free full text

Abstract: 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.

van Zyl LT, Lespérance F, Frasure-Smith N, Malinin AI, Atar D, Laliberté MA, Serebruany VL. · Department of Psychiatry, Queen's University, Kingston, ON, Canada. · J Thromb Thrombolysis. · Pubmed #18188512 No free full text.

Abstract: BACKGROUND AND PURPOSE: Major depression is an independent risk factor for increased morbidity and mortality in patients with coronary artery disease (CAD). Increased platelet activity and vascular endothelial dysfunction are possible pathways through which depression may increase cardiovascular risk. Citalopram exhibits strong selective inhibition of human platelet activation, but little is known about its effects on vascular endothelium. We assessed whether treatment of depressed CAD patients with citalopram alters platelet/endothelial biomarkers. The study was performed within the framework of the CREATE trial. METHODS: We assessed the effect of citalopram on P-selectin, beta-thromboglobulin (betaTG), soluble intercellular cell adhesion molecule-1 (sICAM-1), and total nitric oxide (tNO). Plasma samples were obtained at baseline and week 12 from subjects randomized to citalopram 20-40 mg daily (n = 36), or placebo (n = 21). Anticoagulants, aspirin, and clopidogrel were permitted. RESULTS: Treatment with citalopram was associated with greater increase in tNO over 12 weeks compared to placebo (P = 0.005). There were no differences for the other biomarkers such as P-selectin (P = 0.70), betaTG (P = 0.46) and ICAM (P = 0.59). CONCLUSION: Treatment with citalopram for 12 weeks in depressed CAD patients is associated with enhanced production of nitric oxide despite the co-administration of commonly prescribed anti-platelet regimens including aspirin and clopidogrel. Clinical implications of these findings are unclear, but improved endothelial function is implied by the increased NO production, suggesting that citalopram may be of particular benefit for patients with comorbid depression and vascular disease including CAD, stroke, peripheral artery disease, and diabetes.

Serebruany VL, Malinin AI, Atar D. · HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD 21204, USA. · Cardiology. · Pubmed #17264511 No free full text.

Abstract: BACKGROUND: Numerous randomized studies have shown that the combination of clopidogrel with aspirin yields better clinical outcomes than monotherapy in patients with acute vascular events. However, the impact of the aspirin dose on the antiplatelet potency of clopidogrel is unclear. We sought to compare the antiplatelet profile of aspirin 81 mg (n = 252) versus aspirin 325 mg (n = 459) before and during conventional clopidogrel loading (300 mg), and/or clopidogrel maintenance (75 mg/daily) therapy. METHODS: Secondary post hoc analysis of an existing dataset consisting of 711 patients after coronary stenting (n = 601) and ischemic stroke (n = 110) treated previously with aspirin for at least 1 month, and then with aspirin + clopidogrel for at least 7 days was performed. Platelet assessments include conventional and whole blood aggregometry, rapid cartridge-based analyzers, and expression of platelet/endothelial cell adhesion molecule-1, P-selectin, and GPIIb/IIIa activity by flow cytometry measured before and after addition of clopidogrel. RESULTS: There was a small but consistent yet non-significant trend towards more potent platelet inhibition with aspirin 325 mg compared to aspirin 81 mg for every platelet activation parameter before addition of clopidogrel. However, after loading and/or 1 week of chronic treatment with clopidogrel + aspirin, measured platelet parameters became very similar between the groups, and identical for collagen-induced aggregation and PFA-100 analyzer readings. CONCLUSIONS: Before addition of clopidogrel, aspirin 325 mg has a tendency to provide stronger platelet inhibition than aspirin 81 mg. However, when clopidogrel and aspirin are used in combination, the higher aspirin dose does not translate into superior antiplatelet action. Given that the existing body of evidence supports the comparable efficacy and, particularly, superior safety of lower versus higher doses of aspirin, aspirin 81 mg should be the dose used in combination with clopidogrel.

Serebruany V, Malinin A, Ziai W, Atar D, Pokov A, Jilma B, Hanley D. · Heart Drug Research Laboratories, Johns Hopkins University, Baltimore, Md 21204, USA. · Cerebrovasc Dis. · Pubmed #16340184 No free full text.

Abstract: BACKGROUND: Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the post stroke population. The reason for and the underlying mechanism of AR is unknown. We hypothesized that excessive formation of thrombin on the platelet surface may contribute to this phenomenon and assessed how dipyridamole affects multiple platelet and thrombin generation biomarkers in AR patients after ischemic stroke. METHODS: Whole blood samples from 20 post stroke AR patients were pretreated with dipyridamole, simulating the therapeutic range, and then incubated for 45 min at 37 degrees C. Platelet characteristics were assessed by aggregometry, cartridge-based analyzer, and receptor expression by flow cytometry. Markers of thrombin generation were measured in the autologous plasma by ELISA. RESULTS: Pretreatment of blood with dipyridamole resulted in 22-26% diminished expression of intact PAR-1 receptor (p=0.021 and p=0.024) and 28-31% decrease of annexin V binding (p=0.031 and p=0.02) after incubation with 2 microg/ml and 4 microg/ml of dipyridamole, respectively. Platelet aggregation and thrombin generation markers were not affected in vitro by dipyridamole. CONCLUSIONS: Dipyridamole may be capable of overcoming increased prothrombinase complex formation and be in part able to compensate for AR in patients with moderate carotid stenosis. This phenomenon may explain the clinical advantages of Aggrenox, known to reduce ischemic events in post stroke patients as proven in clinical trials, though an additional antithrombotic benefit beyond the platelet inhibition by aspirin alone.

Serebruany VL, Glassman AH, Malinin AI, Atar D, Sane DC, Oshrine BR, Ferguson JJ, O'Connor CM. · Sinai Center for Thrombosis Research, Johns Hopkins University, 2401 West Belvedere Avenue, Schapiro Research Building-R 202, Baltimore, MD 21215, USA. · Eur J Heart Fail. · Pubmed #12921813 No free full text.

Abstract: 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.

Filipovic M, Seeberger MD, Rohlfs R, Dergeloo O, Studer W, Atar D, Buser P, Skarvan K. · University of Basel, Department of Anaesthesia, Switzerland. · Eur J Anaesthesiol. · Pubmed #12442927 No free full text.

Abstract: 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.

Carstensen S, Bundgaard H, Kjøller-Hansen L, Atar D, Ali SM, Saunamäki K, Kelbaek H. · Department of Medicine, The Heart Centre at Rigshospitalet, University of Copenhagen, Denmark. · Int J Cardiovasc Imaging. · Pubmed #12123308 No free full text.

Abstract: AIMS: The conventional analysis of dobutamine-atropine stress echocardiography (DASE) is poorly defined and subject to considerable variation. The aim of this study was to investigate the reproducibility of strictly standardised qualitative analysis in DASE. METHODS AND RESULTS: Strict criteria for standardised DASE interpretation were defined through logistic regression analysis on categorical parameters obtained from 20 patients with coronary artery disease (CAD) and 20 healthy controls subjected to DASE. Three expert echocardiographers analysed DASE recordings from 100 consecutive patients referred for coronary angiography. Specificity for CAD and for predicting significant stenosis of a major coronary artery was 94% (95% CI: 83-100%) and 79% (95% CI: 63-96%), whereas sensitivity was 49% in both cases (95% CI: 38-60% and 37-61%). Within and between observer reproducibility was moderate to fair (kappa = 0.56 and 0.38; 95% CI: 0.40-0.72 and 0.24-0.52). In patients without prior myocardial infarction and in echogenic patients within observer reproducibility was good (kappa = 0.72 and 0.74; 95% CI: 0.52-0.92 and 0.56-0.92). CONCLUSIONS: Observer variation was not eliminated in standardised qualitative DASE interpretation based on criteria that predicted the presence of CAD with a high specificity and reproducibility was good only in certain subgroups of patients.

Carstensen S, Høst U, Atar D, Saunamäki K, Kelbaek H. · Department of Medicine B, Heart Center, Rigshospitalet, University of Copenhagen, Denmark. · J Am Soc Echocardiogr. · Pubmed #11029711 No free full text.

Abstract: 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.

Serebruany VL, Murugesan SR, Pothula A, Atar D, Lowry DR, O'Connor CM, Gurbel PA. · Center for Thrombosis Research, Sinai Hosital of Baltimore, MD 21215, USA. · Eur J Heart Fail. · Pubmed #10935670 No free full text.

Abstract: BACKGROUND: Platelet-endothelial interactions modulated by adhesion molecules, may play an important role in the pathogenesis of congestive heart failure (CHF). Soluble levels of these molecules and platelet-derived substances are reportedly elevated in patients with CHF. However, no data are available on the plasma levels of Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1), and platelet-derived osteonectin in this growing population. METHODS AND RESULTS: Soluble levels by ELISA were prospectively determined in patients with severe CHF (n = 37) and correlated to etiology and antecedent aspirin use, and compared with 14 healthy control subjects. Left ventricular dysfunction was attributed to idiopathic dilated cardiomyopathy in 18 and coronary artery disease in 19 patients. Twenty-one patients were aspirin-free and 16 patients were using aspirin (81-500 mg daily). Elevated soluble PECAM-1 (51.31+/-2.44 ng/ml, P = 0.0001), and osteonectin (826.27+/-22.37 ng/ml, P = 0.0001) were observed in patients with CHF, as compared to healthy controls (32.56+/-1.21 ng/ml, and 478.02+/-31.32 ng/ml, respectively). Neither etiology of CHF, nor antecedent aspirin therapy significantly affects the levels of PECAM-1 or osteonectin. CONCLUSIONS: Despite long-term aspirin therapy and independently of the etiology of the disease, soluble PECAM-1 and osteonectin were elevated in the majority of patients with severe CHF, suggesting platelet-endothelial activation. The present data provide additional evidence that more potent anti-platelet and endothelial preservation regimens deserve further study in the heart failure population.