Skip Navigation


European Heart Journal Advance Access originally published online on October 6, 2006
European Heart Journal 2006 27(22):2623-2631; doi:10.1093/eurheartj/ehl305
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
27/22/2623    most recent
ehl305v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chung, I.
Right arrow Articles by Lip, G. Y.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chung, I.
Right arrow Articles by Lip, G. Y.H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Platelets and heart failure

Irene Chung and Gregory Y.H. Lip*

Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK

Received 28 March 2006; revised 14 September 2006; accepted 21 September 2006; online publish-ahead-of-print 6 October 2006.

* Corresponding author. Tel: +44 121 554 3801; fax: +44 121 554 4083. E-mail address: g.y.h.lip{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 
Heart failure is associated with increased risk of venous thromboembolism, stroke, and sudden death. Platelet abnormalities have been well described in heart failure but the significance of platelets in contributing to the thromboembolic complications of heart failure remains uncertain. Furthermore, the role of antiplatelet agents in heart failure remains unclear. This review will focus on platelet activation and the role of platelet dysfunction in heart failure, with particular regard to pathophysiology and outcome. The effects of heart failure therapeutics on platelet function and antiplatelet therapy in heart failure will also be discussed.

Key Words: Platelet activation • Heart failure • CD40L • P-selectin • Antiplatelet therapy


   Introduction
Top
 Abstract
 Introduction
Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 
Congestive heart failure (CHF) is a major global disease and is increasing in prevalence due to the increasing age of the general population and improved survival of patients with myocardial infarction. Despite significant advances in medical therapy, the mortality rate from severe CHF still remains over 60% within 5 years of diagnosis.1 CHF also has a significant impact on health-care costs, accounting for 2% of total UK National Health Service expenditure.2

It is well recognized that patients with CHF have increased risk of venous thromboembolism, stroke, and sudden death. For example, the incidence of stroke is ~4–5% in severe heart failure, when compared with 0.5% of the general population of the same age group.1 Sudden cardiac death may also have a similar thrombotic origin (i.e. intracardiac or intracoronary).2 These thrombosis-related complications in patients with CHF have been attributed to a pro-thrombotic state, the exact cause of which is not known.2

In 1856, Virchow described three components for the pathophysiology of thromboembolic disease—abnormal blood constituents, blood flow, and vessel wall. Although originally described for venous thrombosis, the concepts may nonetheless be applicable to occlusive arterial diseases. Various studies have generally concentrated on clotting factors, and markers of endothelial damage/dysfunction in heart failure, but not on platelets per se.3 Furthermore, a role for aspirin, which is the commonest prescribed antiplatelet agent, in patients with CHF has been debated, given recent clinical data.4–6

The aim of this review is to provide an overview of the pathophysiology of platelet activation and thrombogenesis in heart failure specifically, and to summarize present and future antiplatelet therapeutic options for heart failure.


   Search strategy
Top
 Abstract
 Introduction
 Search strategy
Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 
We searched MEDLINE using the following titles: ‘thromboembolism & heart failure’, ‘thrombogenesis & heart failure’, ‘platelet aggregation’, ‘platelet activation in heart failure’, ‘P-selectin & platelets’, ‘CD40L & platelets’, ‘CD63 & platelets’, ‘platelet microparticles’, ‘platelets & renin–angiotensin system’, ‘angiotensin & inflammation’, ‘platelets & sympathetic activation’, ‘platelets & TNF-{alpha}’, ‘platelets & nitric oxide’, ‘platelets & cytokines’, ‘antiplatelet agents in heart failure’. In total, 170 publications were reviewed and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies.


   Evidence that platelets are activated in heart failure
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 
Platelet abnormalities in CHF have been well described (Table 1). For example, heart failure patients have increased whole blood aggregation,7 platelet-derived adhesion molecules.8 CHF patients also have higher mean platelet volume9 and soluble (and platelet-bound) P-selectin, regardless of the aetiology.10,11 sCD40L was also shown to be increased in acute and chronic heart failure when compared with healthy controls and was shown to be correlated to NYHA and ejection fraction.12


View this table:
[in this window]
[in a new window]

  		Table 1 Markers of platelet activation and heart failure

 
Prognostic data on platelet markers in heart failure patients are limited. Indeed, platelet aggregation and flow cytometry abnormalities in stable heart failure patients do not appear to predict cardiovascular events.10,13 A study by Yin et al.,14 which included a high proportion of valvular disease in their patients with heart failure, found soluble P-selectin levels to be an independent significant predictor of cardiovascular events.

Although many studies have shown increased platelet activation in heart failure, none have specifically studied patients with isolated idiopathic cardiomyopathy, those without any vascular risk factors or subjects devoid of therapeutic agents. The study by Stumpf et al.15 did have a group of ischaemic heart disease patients for comparison, but they were mainly patients with known ischaemic heart disease admitted with non-cardiac chest pain. Clearly, the significance of platelet activation in heart failure, especially in relation to prognosis, requires further study.


   Mechanisms of platelet activation in heart failure
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 
Haemodynamic and vascular factors
Mehta and Mehta16 first reported in 1979 that patients with heart failure had significantly more circulating platelet aggregates than normal volunteers. During sodium nitroprusside infusion, the number of circulating platelet aggregates declined to normal levels and in vitro platelet aggregation responses to epinephrine and adenosine diphosphate were also significantly suppressed. The associated 30% decline in systemic vascular resistance and a 28% increase in cardiac output suggested that an increase in vascular resistance in heart failure may cause an increase in circulating platelet aggregates (Figure 1).


Figure 3051
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Possible mechanisms of platelet activation in heart failure.

 
Dilated cardiac chambers, poor contractility, regional wall abnormalities, and concomitant atrial fibrillation may all predispose to thromboembolism by facilitating stasis of intracardiac blood flow.17,18 Plasma levels of fibrinopeptide A and thrombin–antithrombin III complex are all increased in heart failure, and correlate positively with left ventricular end-diastolic volume and negatively with the fractional shortening of the left ventricle.19

Increased plasma levels of coagulation markers in those patients with lower ejection fractions suggests that a low cardiac output may promote a prothrombotic or hypercoagulable state.18 Indeed, patients with left ventricular dysfunction and aneurysm formation have significantly higher fibrin D-dimer (an index of thrombogenesis), fibrinogen (a coagulation factor), and von Willebrand factor (vWF, a marker of endothelial damage/dysfunction) levels, compared with those with normal cardiac function or healthy controls, in keeping with a prothrombotic state.20 Also, plasma viscosity, fibrinogen, vWF, and soluble P-selectin (a marker of platelet activation) are all elevated in patients with CHF compared with healthy controls, with plasma viscosity and fibrinogen levels being higher in patients with more severe symptoms, although soluble P-selectin was not correlated to ejection fraction.21

The sympathetic nervous system is activated in CHF and can be related to prognosis. Jafri et al.19 reported that patients with severe heart failure and high plasma norepinephrine concentration or low ejection fraction were more likely to have activation of platelets (higher plasma platelet factor 4, beta-thromboglobulin) and coagulation system (as indicated by higher plasma antithrombin III complexes, fibrinopeptide A, and D-dimers). The increased levels of circulating norepinephine in CHF may also lead to decrease in platelet alpha2 adrenoreceptors.22

Epinephrine increases platelet deposition on severely damaged vessel wall or immobilized collagen in experimental study.23 The catecholamine-potentiating effect on platelet activation appears to be mediated by the {alpha}2-adrenoceptor stimulation, as it is blunted by exposure to selective antagonists, such as yohimbine, and is cyclo-oxygenase independent as it is unaffected by aspirin treatment. Blocking fibrinogen binding (i.e. glycoprotein IIb/IIIa antagonist) prevents catecholamine-induced platelet aggregation.24

Infusion of angiotensin II into healthy subjects increases plasma ß-thromboglobulin, platelet surface expression of P-selectin, and platelet fibrinogen binding, whereas platelet aggregation is unaltered.25 Nonetheless, the actions of angiotensin on the heart are also complex. For example, angiotensins II and III increase cardiac contractility in some animals and in human myocardium in vitro, especially under hypoxic conditions.26 However, peripheral constriction and sodium retention stimulated by angiotensin II aggravates heart failure. Angiotensin II can also induce myocardial necrosis, fibrosis, and hypertrophy in animal studies.27 Furthermore, it increases nuclear factor-kappa B (NF-kB)-mediated myocardial expression of proinflammatory cytokines and chemokines.28

Pre-treatment of vascular muscle cells with angiotensin II enhances IL-18-induced NF-kB activation, thus increasing cytokine gene and mRNA expression and perpetuating a vicious circle involving the IL-18 signalling pathway.29 In contrast, ACE-inhibitor use attenuates angiotensin II-induced atherosclerosis and vascular inflammation.30 The progression of heart failure is also associated with cardiac angiotensin II formation, which is positively correlated to increasing end-systolic wall stress.31 In relation to platelets, angiotensin II causes thrombin-induced dose-dependent elevations of intraplatelet free calcium and increases platelet aggregation in essential hypertension.32 These lead to stimulation of the coagulation system, with increased plasma thrombin–antithrombin complex and prothrombin fragment F1+2 levels. Increased plasma concentrations of angiotensin II and endothelin, which correlate with plasma vWF, also suggests that haemostatic abnormalities may be in part due to neuroendocrine activation in heart failure.33 Furthermore, in vitro and ex vivo studies with angiotensin II receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.34

Nitric oxide and cytokines
The actions of nitric oxide on the cardiovascular system are complex, and a detailed treatise is beyond the scope of this article. Platelet-derived nitric oxide inhibits platelet aggregation via constitutive nitric oxide synthase (eNOS). Acute inhibition of endogenous nitric oxide production in humans causes rapid platelet activation in vivo, which is reversed by exogenous nitric oxide.35 Reduced vascular availability of nitric oxide is also associated with increased platelet activation, and is a risk factor for silent cerebral infarction in patients with atrial fibrillation.36 When platelet eNOS becomes uncoupled from its cofactor, tetrahydrobiopterin, it is associated with diminished platelet-derived nitric oxide production and increased superoxide O2– production.37

In in vivo studies, increased platelet O2– production correlates significantly with plasma TNF-{alpha} levels; however, in heart failure patients, TNF-{alpha} dose-dependently induces platelet O2– production and is inhibited by aspirin and NADPH (reduced nicotinamide adenosine dinucleotide phosphate) oxidase inhibitors suggesting that enhanced platelet O2– production is mediated by TNF-{alpha} via activation of arachidonic acid and NADPH oxidase pathways.38 There is also evidence to suggest that TNF-{alpha} may suppress eNOS and activate another isoform of NO synthase (iNOS) in patients with CHF in proportion to the severity of heart failure, and TNF-{alpha} may contribute to the enhanced systemic and local production of nitric oxide.39

Platelets can possibly induce pathology in heart failure via C-C chemokines secretion.40,41 For example, macrophage chemoattractant protein-1 (MCP-1), macrophage chemoattractant protinflammatory protein-1{alpha} (MIP-1{alpha}), and RANTES (regulated on activation normally T-cell expressed and secreted) are potent chemoattractants of monocytes and lymphocytes that can modulate other cell functions. C-C chemokines are increased in CHF and are inversely correlated to left ventricular ejection fraction and cardiac index, and positively correlated to NYHA classification.40 Activated platelets stimulate MCP-1 production in monocytes through enhanced RANTES secretion and direct platelet–monocyte contact, being mediated by platelet surface P-selectin. Raised MCP-1 levels from CHF patients may have enhancing effects on spontaneous reactive oxygen species generation in monocytes, which may be involved in apoptosis of cardiomyocytes. The increased reactive oxygen radials generation in monocytes may further enhance the synthesis of MCP-1 through an autocrine mechanism, possibly representing a vicious circle operating in CHF.


   Effect of heart failure therapeutics on platelets
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
Antiplatelet therapy in heart...
 Conclusion
 References
 
Diuretics
Most of the heart failure therapies have some anti-platelet properties. For example, diuretics such as hydrochlorothiazide, furosemide, spironolactone, and indapamide augment the synthesis of prostaglandins D2, E2, and I2, probably through facilitated reorientation of endoperoixe biotransformation. Apart from hydrochlorothiazde, they can also suppress thromboxane A2 production. Although spironolactone and indapamide42 can enhance lipoxygenase formation of hydroxyeicosatetraenoic acid, indapamide inhibits the second wave of platelet aggregation induced by adenosine diphosphate and collagen in platelet-rich plasma by 50%. In vitro, low doses of thrombin can inhibit platelet aggregation by 70%, via blocking calcium mobilization rather than by inhibiting the arachidonic acid pathway. In contrast, hydrochlorothiazide43 and frusemide44 have no significant effect on platelet aggregation (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Examples of studies of platelet abnormalities in congestive heart failure

 
Beta-blockers
The antiplatelet properties of ß-blocker are much less significant (Table 2). In vitro, propanolol and carvedilol reduce platelet aggregation induced by epinephrine and ADP,45 whereas atenolol increases fibrinogen binding in response to agonists46 but reduces ß-thromboglobulin in hypertensive subjects.47 In other work, ß-blockers (bisoprolol or carvedilol) failed to affect vWF and P-selectin levels in patients with heart failure.21

ACE-blocking agents
All ACE-blocking agents probably can inhibit platelet activation induced by angiotensin II, but there appears to be little consistency in the study findings in CHF48–59 (Table 3), possibly due to some underpowered studies with small sample sizes (e.g. n=10),55 or relatively short-term treatment durations (e.g. platelet indices were measured only 12 h after treatment).54 It may also be possible that ACE-inhibitors have a relative indirect action on platelets via altering the levels of angiotensin, whereas angiotensin receptor antagonists directly block the platelet angiotensin receptors.


View this table:
[in this window]
[in a new window]

  		Table 3 Effects of various cardiovascular drug treatments on platelet function

 
Treatment with ACE-inhibitors decreases levels of ß-thromboglobulin in hypertensive patients,48 while linsinopril reduces soluble P-selectin levels in patients with CHF.19 Captopril and fosinopril decrease thromboxane B2 concentrations, with no significant change in adenosine diphosphate, epinephrine, or thrombin-stimulated platelet aggregation when compared with baseline levels or between different ACE-inhibitors.49 In other studies, enalapril, fosinopril, and captopril reduce platelet aggregation in hypertensive patients.50–52 Treatment with captopril in patients with recent myocardial infarction also reduces the expression of glycoprotein IIb/IIIa receptors by 30%.53 Small studies on hypertensive humans report no change in ADP-induced aggregation or platelet factor 4 by captopril, quinalapril, or enalapril.54,55

Losartan suppresses thrombin-induced calcium transients and thromboxane release in a dose-dependent manner in platelets, thus counteracting exvivo platelet activation possibly via blockade of thromboxane A2 receptor-dependent signalling rather than acting at the AT1 receptor itself.57 Angiotensin-receptor blockade also reduces megakaryocyte size and ploidy bleeding time.58 However, these drugs do not have any significant effect on plasma soluble P-selectin, plasminogen activator-1, and vWF in hypertensive patients.59 Meanwhile, irbesartan has similar effects on platelet inhibition in both animals and human studies.60

Further evidence from animal studies suggests that combination of ACE- and aldosterone inhibition completely abolishes platelet activation61 suggesting that a more complete blockade of the renin–angiotensin–aldosterone system may offer even better platelet inhibition.


   Antiplatelet therapy in heart failure
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
Conclusion
 References
 
The benefit of antiplatelet agents in patients at risk of ischaemic events is well recognized in the ATTC (Antithrombotic Therapy Trialists' Collaboration) meta-analysis.62 In a recent analysis, Masoudi et al.6 showed that from a population of 24 012 patients with coronary artery disease and heart failure, aspirin remained associated with a lower risk of death or all-cause re-admission or re-admission for heart failure. However, there was no convincing evidence for routine use of anti-platelet agent in CHF patients from the two recent trials, the WASH (Warfarin/Aspirin Study in Heart failure)4 and WATCH (Warfarin and Antiplatelet therapy in Chronic Heart Failure)5 trials (Table 4).


View this table:
[in this window]
[in a new window]

  		Table 4 Effects of antiplatelet therapy in heart failure

 
In the small, pilot WASH4 study, there was no difference in mortality between placebo, aspirin, and warfarin. Similarly, in the WATCH5 study, there was no difference in mortality between aspirin, clopidogrel, and warfarin, although this may be underpowered as the trial ended early due to poor recruitment. Meta-analysis of the two studies suggests a weak trend in favour of a lower mortality with warfarin compared with aspirin (at least on an intention to treat analysis) (odds ratio 0.91 (0.67–1.22)]. Importantly, aspirin was shown to substantially increase hospitalizations for CHF in a meta-analysis of both studies [odds ratio 0.64 (0.48–0.85)].63 This again reiterates the potential mechanistic interaction between aspirin and ACE-inhibitors, and that clopidogrel may provide an alternative anti-platelet agent in CHF patients, especially in those who have recurrent decompensation and re-admissions for heart failure.

Guazzi et al.64 measured maximal exercise oxygen uptake (VO2max) in patients with CHF, and demonstrated an adverse effect when ACE-inhibitors were combined with aspirin, but not with ACE-inhibitors alone. Similarly, Kindsvater et al.65 also showed that VO2 max in patients with CHF who receive clopidogrel in conjunction with an ACE-inhibitor was greater than that with aspirin combined with an ACE-inhibitor.

In the PLUTO-CHF (Plavix Use for Treatment Of Congestive Heart Failure) trial,66 patients receiving both aspirin and clopidogrel had significantly greater inhibition of platelet activity than those who received aspirin alone. Although earlier studies of patients with non-ST-elevation myocardial infarction and unstable angina reported benefits from glycoprotein IIb/IIIa inhibitor use, a retrospective analysis of the PURSUIT (Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial67 showed no incremental benefit from the use of eptifibatide compared with standard treatment in patients with non-ST-segment elevation acute coronary syndrome and CHF.

The recent HELAS (Heart failure Long-term Antithrombotic Study) trial68 was probably too small and underpowered for any conclusions on antithrombotic therapy benefits in heart failure. Embolic events were relatively rare (2.2 events per 100 patient years) compared with death or hospitalization for heart failure, and only five strokes were recorded, with no peripheral or pulmonary thromboembolism and two myocardial infarction events. There were 9.6 deaths per 100 patient years for the entire population, predominantly due to worsening heart failure. Thus, the precise role for antiplatelet agents in heart failure management strategies is yet to be determined.

In the updated Cochrane systematic review of trials of antiplatelet agents vs. control or anticoagulation for heart failure in sinus rhythm69 found no evidence from long-term randomized trials to recommend routine use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm, and a possible interaction with ACE-inhibitors by aspirin may reduce its efficacy. When compared with aspirin, there was some evidence to indicate superior effects from oral anticoagulation in relation to hospitalizations, among patients with heart failure in sinus rhythm. The corresponding updated Cochrane systematic review on anticoagulation for heart failure in sinus rhythm70 found a reduction in mortality and cardiovascular events with anticoagulants compared with control, but concluded that this evidence needed to be interpreted with caution.


   Conclusion
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
References
 
Although platelets are well recognized to play a role in the thrombosis-related complications in CHF, it is not clear whether they are the main mechanism for the increased thromboembolism or they merely coexist as bystander, being related to the associated vascular disease. Perhaps studies of idiopathic cardiomyopathy without any concomitant vascular risk factor, perhaps with suitable ‘disease control’ groups may provide additional insights into the signifance of platelet activation in heart failure. The possible confounding effects on platelet function assessments by drugs commonly used in heart failure patients (e.g. ACE-inhibitors, beta-blockers, statins etc.) may make long-term prospective studies difficult to conduct in treatment naïve patients.

Indeed, the significance of current therapeutic heart failure treatments in reducing stroke and thromboembolic complications in CHF is under debate. For example, there is no randomized trial evidence to support the routine use of antiplatelet agents in all systolic heart failure patients. Some data even suggest that aspirin may potentially attenuate the beneficial effects of ACE-inhibitors and therefore, alternative antithrombotic agents in CHF may be warranted. A greater appreciation of the underlying platelet pathophysiology in CHF would inform our development of new therapeutic agents and aid our management startegies in this common and growing clinical problem.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Search strategy
 Evidence that platelets are...
 Mechanisms of platelet...
 Effect of heart failure...
 Antiplatelet therapy in heart...
 Conclusion
 References
 

  1. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. (2002) The current cost of heart failure to the national health service in the UK. Eur J Heart Fail 4:361–371.[CrossRef][ISI][Medline]
  2. Narang R, Cleland JGF, Erhardt JGF, Ball SG, Coats AJ, Cowley AJ, Dargie HJ, Hall AS, Hampton JR, Poole-Wilson PA. (1996) Mode of death in chronic heart failure: a request for more accurate classification. Eur Heart J 17:1390–1403.[Abstract/Free Full Text]
  3. Lip GYH and Gibbs CR. (1999) Does heart failure confer a hypercoagulable state? J Am Coll Cardiol 33:1424–1426.[Free Full Text]
  4. Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C, Ford I, Trainer A, Poole-Wilson PA. (2004) The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 148:157–164.[CrossRef][ISI][Medline]
  5. Massie B, Krol W, Ammon S, Armstrong P, Cleland J, Collins J. Warfarin and Antiplatelet therapy in Chronic Heart Failure (WATCH). http://www.acc04online.acc.org/ (9 March 2004)..
  6. Masoudi FA, Wolfe P, Havranek EP, Rathore SS, Foody JM, Krumholz HM. (2005) Aspirin use in older patients with heart failure and coronary artery disease. J Am Coll Cardiol 46:955–962.[Abstract/Free Full Text]
  7. Serebruany V, McKenzie M, Meister A, Fuzaylov S, Gurbel P, Atar D, Gattis W, O'Connor C. (2002) Whole blood impedence aggregometry for the assessment of platelet function in patients with congestive heart failure (EPCOT Trial). Eur J Heart Fail 4:461–467.[CrossRef][ISI][Medline]
  8. Serebruany VL, Murugesan SR, Pothula A, Atar D, Lowry DR, O'Connor CM, Gurbel PA. (1999) Increased soluble platelet/endothelial cellular adhesion molecule-1 and osteonectin levels in patients with severe congestive heart failure. Independence of disease etiology, and antecedent aspirin therapy. Eur J Heart Fail 1:243–249.[CrossRef][ISI][Medline]
  9. Erne P, Wradle J, Sanders K, Lewis SM, Maseri A. (1988) Mean platelet volume and size distribution and their sensitivity to agonists in patients with coronary artery disease and congestive heart failure. Thromb Haemost 59:259–263.[ISI][Medline]
  10. Gurbel PA, Gattis WA, Fuzaylov SF, Gaulden L, Hasselblad V, Serebruany VL, O'Connor CM. (2002) Evaluation of platelets in heart failure: is platelet severity related to etiology, functional class, or clinical outcomes? Am Heart J 143:1068–1075.[CrossRef][ISI][Medline]
  11. O'Connor CM, Gurbel PA, Serebruany VL. (1999) Usefulness of soluble and surface-bound P-selectin in detecting heightened platelet activity in patients with congestive heart failure. Am J Cardiol 83:1345–1349.[CrossRef][ISI][Medline]
  12. Ueland T, Aukrust P, Yndestad A, Otterdal K, Froland SS, Dickstein K, Kjekshus J, Gullestad J, Damas JK. (2005) Soluble CD40 ligand in acute and chronic heart failure. Eur Heart J 26:1101–1107.[Abstract/Free Full Text]
  13. Serebruany VL, Alford AB, Meister AF, Fuzaylov SY, Gattis WA, Gurbel PA, O'Connor CM. (2001) Clinical utility of the platelet function analyzer (PFA-100) for the assessment of the platelet status in patients with congestive heart failure (EPCOT trial). Thromb Res 101:427–433.[CrossRef][ISI][Medline]
  14. Yin WH, Chen JW, Jen HL, Chinag MC, Huang WP, Feng AN, Lin SJ, Young MS. (2003) The prognostic value of circulating soluble cell adhesion molecules in patients with chronic heart failure. Eur J Heart Fail 5:507–516.[CrossRef][ISI][Medline]
  15. Stumpf C, Lehner C, Eskafi S, Raaz D, Yilmaz A, Ropers S, Schmeisser A, Ludwig J, Daniel WG, Garlichs CD. (2003) Enhanced levels of CD154 (CD40 ligand) on platelets in patients with chronic heart failure. Eur J Heart Fail 5:629–637.[CrossRef][ISI][Medline]
  16. Mehta J and Mehta P. (1979) Platelet function studies in heart disease. VI. Enhanced platelet aggregate formation activity in congestive heart failure: inhibition by sodium nitroprusside. Circulation 60:497–503.[Abstract/Free Full Text]
  17. Sirajuddin RA, Miller AB, Geraci SA. (2002) Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm. J Card Fail 8:48–53.[CrossRef][ISI][Medline]
  18. Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. (1995) The coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol 25:1634–1640.[Abstract]
  19. Jafri SM, Ozawz T, Mammen E, Levine TB, Johnson C, Goldstein S. (1993) Platelet function, thrombin and fibrinolytic activity in patients with heart failure. Eur Heart J 14:205–212.[Abstract/Free Full Text]
  20. Lip GY, Lowe GD, Metcalfe MJ, Rumley A, Dunn FG. (1995) Effects of warfarin therapy on plasma fibrinogen, von Willebrand factor, and fibrin D-dimer in left ventricular dysfunction secondary to coronary artery disease with and without aneurysms. Am J Cardiol 76:453–458.[CrossRef][ISI][Medline]
  21. Gibbs CR, Blann AD, Watson RD, Lip GY. (2001) Abnormalities of hemorrheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm. Circulation 103:1746–1751.[Abstract/Free Full Text]
  22. Weiss RJ, Tobes M, Wertz CE, Smith CB. (1983) Platelet alpha2 adrenoreceptors in chronic congestive heart failure. Am J Cardiol 52:101–105.[CrossRef][ISI][Medline]
  23. Badimon L, Martinez-Gonzalez J, Royo T, Lassila R, Badiomn JJ. (1999) A sudden increase in plasma epinephrine levels transiently enhance platelet deposition on severely damaged arterial wall—studies in a porcine model. Thromb Haemost 82:1736–1742.[ISI][Medline]
  24. Anfossi G and Trovati M. (1996) Role of catecholamines in platelet function: pathophysiological and clinical significance. Eur J Clin Invest 26:353–370.[CrossRef][ISI][Medline]
  25. Larsson PT, Schwieler JH, Wallen NH. (2000) Platelet activation during angiotensin II infusion in healthy volunteers. Blood Coagul Fibrinolysis 11:61–69.[ISI][Medline]
  26. Moravec CS, Schluchter MD, Paranandi L. (1990) Inotropic effects of angiotensin II on human cardiac muscle in vitro. Circulation 82:1973–1984.[Abstract/Free Full Text]
  27. Weber KT, Sun Y, Cleutjens JPM. (1995) Structural remodeling of the myocardium postinfarction: potential mechanisms and influence of therapy. Cardiol Rev 3:53–65.
  28. Kawano S, Kubota T, Monden Y, Kawamura N, Tsutsui H, Takeshita A, Sunagawa K. (2005) Blockade of NF-kappa B ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II. Cardiovasc Res 67:689–698.[Abstract/Free Full Text]
  29. Sahar S, Dwarakanath RS, Reddy MA, Lanting L, Todorov I, Natarajan R. (2005) Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells: a novel cross-talk in the pathogenesis of atherosclerosis. Circ Res 96:1064–1071.[Abstract/Free Full Text]
  30. da Cunha V, Tham DM, Martin-McNulty B, Deng G, Ho JJ, Wilson DW, Rutledge JC, Vergona R, Sullivan ME, Wang YX. (2005) Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation. Atherosclerosis 178:9–17.[CrossRef][ISI][Medline]
  31. Serneri GG, Boddi M, Cecioni I, Vanni S, Coppo M, Papa ML, Bandinelli B, Bertolozzi I, Polidori G, Toscano T, Maccherini M, Modesti PA. (2001) Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Cir Res 88:961–968.[Abstract/Free Full Text]
  32. Touyz RM and Schiffrin EL. (1993) Effects of angiotensin II and endothelin-1 on platelet aggregation and cytosolic pH and free Ca2+ concentration in essential hypertension. Hypertension 22:853–862.[Abstract/Free Full Text]
  33. Sbarouni E, Bradshaw A, Andreotti F, Tuddenham E, Oakley CM, Cleland JG. (1994) Relationship between abnormalities and neuroendocrine activity in heart failure. Am Heart J 127:607–612.[CrossRef][ISI][Medline]
  34. Kalinowski L, Matys T, Chabielska E, Buczko W, Malinski T. (2002) Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release. Hypertension 40:521–527.[Abstract/Free Full Text]
  35. Schafer A, Wiesmann F, Neubauer S, Eigenthaler M, Bauersachs J, Channon K. (2004) Rapid regulation of platelet activation in vivo by nitric oxide. Circulation 109:1819–1822.[Abstract/Free Full Text]
  36. Minamino T, Kitakaze M, Sanada S, Asanuama H, Kurotobi T, Koretsune Y. (1998) Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation 98:1721–1727.[Abstract/Free Full Text]
  37. Dixon LJ, Morgan DR, Hughes SM, McGrath LT, El-Sherbeeny NA, Plumb RD, Devine A, Leahey W, Johnston GD, McVeigh GE. (2003) Functional conquences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation 107:1725–1728.[Abstract/Free Full Text]
  38. De Biase L, Pignatelli P, Lenti L, Tocci G, Piccioni F, Riondino S, Pulcinelli FM, Rubattu S, Volpe M, Violi F. (2003) Enhanced TNF-{alpha} and oxidative stress in patients with heart failure: effect of TNF-{alpha} on platelet O2– production. Thromb Haemost 90:317–325.[ISI][Medline]
  39. Sugamori T, Ishibashi Y, Shimada T, Takahashi N, Sakane T, Ohata S, Kunizawa Y, Inoue S, Nakamura K, Ohta Y, Shimizu H, Katoh H, Oyake N, Murakami Y, Hashimoto M. (2002) Increased nitric oxide in proportion to the severity of heart failure in patients with dilated cardiomyopathy: close correlation of tumour necrosis factor-alpha with systemic and local production of nitric oxide. Circ J 66:627–632.[CrossRef][ISI][Medline]
  40. Aukrust P, Ueland T, Muller F, Andreassen AK, Nordoy I, Aas H, Kjekshus J, Simonsen S, Froland SS, Gullestad L. (1998) Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation 97:1136–1143.[Abstract/Free Full Text]
  41. Damas JK, Gullestad L, Ueland T, Solum NO, Simonsen S, Froland SS, Aukrust P. (2000) CXC-chemokines, a new group of cytokines in congestive heart failure- possible role of platelets and monocytes. Cardiovasc Res 45:428–436.[CrossRef][ISI][Medline]
  42. Grose JH, Gbeassor FM, Lebel M. (1986) Differential effects of diuretics on eicosanoid biosynthesis. Postaglandins Leukat Med 24:103–109.[CrossRef]
  43. Rendu F, Bachelot C, Molle D, Caen J, Guez D. (1993) Indapamide inhibits human platelet aggregation in vitro: comparison with hydrochlorothiazide. J Cardiovas Pharmacol 22:Suppl. 6, S57–S63.
  44. Kribben A, Fritschka E, Sibold M, Fassbender M, Rothschild M, Distler A, Philipp T. (1988) Different effects of furosemide on alpha-adrenoceptors and on platelet aggregation in man. Klin Wochschr 66:624–627.[CrossRef]
  45. Gasser JA and Betterridge DJ. (1991) Comparison of the effects of carvediolol, propanolol, and verapamil on in vitro platelet function in healthy volunteers. J Cardiovasc Pharmacol 18:Suppl. 4, S29–S34.
  46. Knight CJ, Panesar M, Wilson DJ, Chronos NA, Patel D, Fox K, Goodall AH. (1997) Different effects of calcium antagonists, nitrates, and beta-blockers on platelet function. Possible importance for the treatment of unstable angina. Circulation 95:125–132.[Abstract/Free Full Text]
  47. Gleerup G, Mehlsen J, Winther K. (1995) Does calcium channel blockade and beta-adrenergic blockade affect platelet function and fibrinolysis to a varying degree? J Cardiovasc Pharmacol 25:87–89.[ISI][Medline]
  48. Gomi T, Ikeda T, Shibuya Y, Nagao R. (2000) Effects of antihypertensive treatment on platelet function in essential hypertension. Hypertens Res 23:567–572.[ISI][Medline]
  49. Moser L, Callahan KS, Cheung AK, Stoddard GJ, Munger MA. (1997) ACE inhibitors effects on platelet function in stages I-II hypertension. J Cardiovasc Pharmacol 30:461–467.[CrossRef][ISI][Medline]
  50. Someya N, Morotomi Y, Kodama K, Kida O, Higa T, Konda K, Tanaka K. (1984) Suppressive effect of captopril on platelet aggregation in essential hypertension. J Cardiovasc Pharmacol 6:840–843.[ISI][Medline]
  51. Persson K, Whiss PA, Nyhlen K, Jacobsson-Strier M, Glindell M, Andersson RG. (2000) Nitric oxide donors and angiotensin-converting enzyme inhibitors act in concert to inhibit human angiotensin-converting enzyme activity and platelet aggregation in vitro. Eur J Pharmacol 406:15–19.[CrossRef][ISI][Medline]
  52. Keidar S, Oiknine J, Leiba A. (1996) Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients. J Cardiovasc Pharmacol 27:183–186.[CrossRef][ISI][Medline]
  53. Zurbano MJ, Anguera I, Heras M, Roig E, Lozano M, Sanz G, Escolar G. (1999) Captopril administration reduces thrombus formation and surface expression of platelet glycoprotein IIb/IIIa in early postmyocardial infarction stage. Arterioscler Thromb Vasc Biol 19:1791–1795.[Abstract/Free Full Text]
  54. Birkebaek NH, Vejby-Christensen H, Jakobsen P, Winther K. (1988) The effect of nifedipine and captopril on platelet activation and prostanoid production in essential hypertension. J Hypertens 6:S378–S380.
  55. Gupta RK, Kjeldsen SE, Motley E, Weder AB, Zweifler AJ, Julius S. (1991) Platelet function during antihypertensive treatment with quinalapril, a novel angiotensin converting enzyme inhibitor. J Cardiovasc Pharmacol 17:13–19.[Medline]
  56. Nunez A, Gomez J, Zalba LR, Monton M, Jimenez A, Velasco S, Lopez-Blaya A, Uriarte AC, Casado S, Lopez-Farre A. (2000) Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan. J Renin Angiotensin Aldosterone Syst 1:175–179.[Medline]
  57. Schwemmer M, Sommer O, Bassenge E. (2001) Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling. Cardiovasc Drugs Ther 15:301–307.[CrossRef][ISI][Medline]
  58. Pathansali R, Smith NM, Bath PM. (2001) Prothrombotic megakaryocyte and platelet changes in hypertension are reversed following treatment: a pilot study. Platelets 12:144–149.[CrossRef][ISI][Medline]
  59. Li-Saw-Hee FL, Beevers DG, Lip GY. (2001) Effect of antihypertensive therapy using enalapril or losartan on haemostatic markers in essential hypertension: a pilot prospective randomized double-blind parallel group trial. Int J Cardiol 78:241–246.[CrossRef][ISI][Medline]
  60. Li P, Fukuhara P, Diz DI, Ferrario CM, Brosnihan KB. (2000) Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induecd vasoconstriction in canine coronary arteries and human platelet aggregation. J Pharmacol Exp Ther 292:238–246.[Abstract/Free Full Text]
  61. Schafer A, Fraccarollo D, Hildemann S, Christ M, Eigenthaler M, Kobsar A, Walter U, Bauersachs J. (2003) Inhibition of platelet activation in congestive heart failure by aldosterone. Thromb Haemost 89:1024–1030.[ISI][Medline]
  62. Antithrombotic Trialists' Collaboration. (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86.[Abstract/Free Full Text]
  63. Cleland JGF, Ghosh J, Freemantle N, Kaye GC, Nasir M, Clark AL, Coletta AP. (2004) Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-LIPIDS and cardiac resynchronisation therapy in heart failure. Eur J Heart Fail 6:501–508.[CrossRef][ISI][Medline]
  64. Guazzi M, Brambilla R, Reina G, Tumminello G, Guazzi MD. (2003) Aspirin-angiotensin-convering enzyme inhibitor coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin. Arch Intern Med 163:1574–1579.[Abstract/Free Full Text]
  65. Kindsvater S, Leclerc K, Ward J. (2003) Effects of coadministration of aspirin or clopidogrel on exercise testing in patients with heart failure receiving angiotensin-converting enzyme inhibitors. Am J Cardiol 91:1350–1352.[CrossRef][ISI][Medline]
  66. Serebruany VL, Malinin AI, Jerome SD, Lowry DR, Morgan AW, Sane DC, Tanguay JF, Steinhubl SR, O'connor CM. (2003) Effects of clopidgrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: the Plavix Use for Treatment Of Congestive Heart Failure (PLUTO-CHF) trial. Am Heart J 146:713–720.[CrossRef][ISI][Medline]
  67. Srichai MB, Jaber WA, Prior DL, Marso SP, Houghtaling PL, Menon V, Simoons ML, Harrington RA, Hochman JS, PURSUIT Investigators. (2004) Evaluating the benefits of glycoprotein IIb/IIIa inhibitors in heart failure at baseline in acute coronary syndromes. Am Heart J 147:84–90.[CrossRef][ISI][Medline]
  68. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. HELAS investigators. (2006) Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 8:428–432.[CrossRef][ISI][Medline]
  69. Lip GYH and Chung I. (2000) Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm. Cochrane Database Syst Rev doi:10.1002/14651858.CD003333.
  70. Lip GYH and Chung I. (2000) Anticoagulation for heart failure in sinus rhythm. Cochrane Database Syst Rev doi:10.1002/14651858.CD003336.
  71. Varo N, de Lemos JA, Libby P, Morrow DA, Murphy SA, Nuzzo R, Gibson CM, Cannon CP, Braunwald E, Schonbeck U. (2003) Soluble CD40L risk prediction after acute coronary syndrome. Circulation 108:1049–1052.[Abstract/Free Full Text]
  72. Chin BS, Blann AD, Gibbs CR, Chung NAY, Conway DS, Lip GY. (2003) Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure. Eur J Clin Invest 33:941–948.[CrossRef][ISI][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 ChestHome page
R. C. Becker, T. W. Meade, P. B. Berger, M. Ezekowitz, C. M. O'Connor, D. A. Vorchheimer, G. H. Guyatt, D. B. Mark, and R. A. Harrington
The Primary and Secondary Prevention of Coronary Artery Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest, June 1, 2008; 133(6_suppl): 776S - 814S.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. Y. Gasparyan, T. Watson, and G. Y.H. Lip
The Role of Aspirin in Cardiovascular Prevention: Implications of Aspirin Resistance
J. Am. Coll. Cardiol., May 13, 2008; 51(19): 1829 - 1843.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
C Stumpf, C Lehner, D Raaz, A Yilmaz, T Anger, W G Daniel, and C D Garlichs
Platelets contribute to enhanced MCP-1 levels in patients with chronic heart failure
Heart, January 1, 2008; 94(1): 65 - 69.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
27/22/2623    most recent
ehl305v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chung, I.
Right arrow Articles by Lip, G. Y.H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chung, I.
Right arrow Articles by Lip, G. Y.H.
Social Bookmarking