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European Journal of Heart Failure 2007 9(2):124-128; doi:10.1016/j.ejheart.2006.05.009
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© 2007 European Society of Cardiology

Viewpoint: The prothrombotic state in heart failure: A maladaptive inflammatory response?

Aun-Yeong Chong and Gregory Y.H. Lip*

Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital Dudley Road, Birmingham B18 7QH, England, United Kingdom

* Corresponding author. Tel.: +44 121 507 5080; fax: +44 121 554 4083. E-mail address: g.y.h.lip{at}bham.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Endothelial dysfunction,...
 3. Treatment options in...
 4. Unresolved questions
 5. Conclusion
 References
 
Patients with heart failure (HF) are at an increased risk of stroke, sudden death and venous thromboembolism, which are all linked to thrombus formation (thrombogenesis). The present ‘viewpoint’ article will discuss how the prothrombotic state in HF may be perpetuated by a chronic inflammatory state that is maladaptive. Indeed, there is considerable evidence that thrombogenesis and endothelial (dys)function can be intimately linked to inflammation in HF.

Key Words: Prothrombotic state • Inflammation • Heart failure

Received September 28, 2005; Revised April 7, 2006; Accepted May 17, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Endothelial dysfunction,...
 3. Treatment options in...
 4. Unresolved questions
 5. Conclusion
 References
 
Patients with heart failure (HF) are at an increased risk of stroke and venous thromboembolism. Data from SOLVD (Studies Of Left Ventricular Dysfunction) and V-HeFT (Veteran Affairs Vasodilator Heart Failure Trials) showed that mild to moderate heart failure was associated with an annual stroke risk of 1.5%, escalating to 4% in severe heart failure. This is further supported by data from the SAVE (Survival and Ventricular Enlargement) trial that showed a graded inverse relationship between ejection fraction and risk of stroke, with every 5% decrease in ejection fraction resulting in an 18% increase in the risk of stroke [1].

Sudden death accounts for significant mortality in HF. While death is often presumed to be a consequence of ventricular arrhythmias, it could also be caused by (frequently unrecognised) thromboembolism. One retrospective study of deep vein thrombosis (DVT) in the outpatient heart failure population showed that an EF<20% was associated with an odds ratio of 38.3 (95% CI 9.6, 152.5) for developing DVT [2]. In addition, post-mortem studies show a significantly higher incidence of pulmonary embolism and coronary thrombosis in patients with HF. Data from the ATLAS (Assessment of Treatment with Lisinopril and Survival) and DIG (Digitalis Investigation Group) trials linked low ejection fraction with increased incidence of sudden death [3,4] and analysis of autopsy data from ATLAS showed that a significant number of these patients died from coronary thrombosis [5].

Simplistically, the root of the prothrombotic state in HF is impaired blood flow due to poor myocardial contraction, compounded by the abundance of adhesion molecules and an imbalance between natural procoagulants and anticoagulants. Furthermore, HF is associated with a dysfunctional endothelium that normally serves as an anticoagulant barrier, as well as to segregate the procoagulants from the underlying thrombogenic subendothelial layer.

The present ‘viewpoint’ article will discuss the possibility that the prothrombotic state in HF is not necessarily initiated, but is perpetuated by a chronic inflammatory state that is maladaptive. Indeed, there is considerable evidence that thrombogenesis and endothelial (dys)function can be intimately linked to inflammation. We should emphasise that we are not intending to provide a systematic review of thrombogenesis, endothelial perturbation and inflammation, but a perspective on how these processes are intimately linked in established HF.


   2. Endothelial dysfunction, inflammation and thrombogenesis
Top
 Abstract
 1. Introduction
 2. Endothelial dysfunction,...
3. Treatment options in...
 4. Unresolved questions
 5. Conclusion
 References
 
HF is associated with increased plasma von Willebrand factor (vWf) [6,7]. vWf has binding sites for glycoprotein Ib, glycoprotein IIb/IIIa, collagen and vitronectin, mediating platelet adhesion to other platelets and to the subendothelium. HF is also associated with increased soluble P-selectin, an adhesion molecule, as well as a marker of platelet activation [7,8]. vWf and P-selectin, from the {alpha} granules of platelets and Weibel-Palade bodies in endothelial cells, are released and migrate to the membrane surface when the endothelium is injured. In addition, vWf is released into the extracellular matrix. In combination, vWf and P-selectin facilitate platelet adhesion at sites of endothelial injury [9].

Tissue factor (TF) is a procoagulant molecule found on monocytes and transported to platelets via a T-cell dependent process. It is not normally expressed by resting endothelial cells but can be induced by vascular endothelial growth factor (VEGF), tumour necrosis factor-{alpha} (TNF-{alpha}), and interleukin-1 (IL-1), all of which are raised in HF [10,11]. On the other hand, TF expression by endothelial cells in vitro is abrogated by angiopoietin (Ang)-1, an endothelial-specific angiogenic factor, via activation of the intracellular phosphatidylinositol 3' kinase/Akt pathway [12]. Pizurki et al. showed that Ang-1 also inhibited VEGF-induced endothelial permeability, polymorphonuclear cell adherence to the endothelium as well as IL-8 production by the endothelial cell [13]. A more recent study by while a more recent study by Fiedler et al. showed that mice deficient in Ang-2 cannot elicit an inflammatory response and that Ang-2 promotes leucocyte adhesion by sensitizing endothelial cells to TNF-{alpha} and modulating TNF-{alpha} induced expression of endothelial cell adhesion molecules [14]. Our data show that Ang-1 levels in acute and chronic HF are no different from normal controls, while those of VEGF, TNF-{alpha} and Ang-2 are raised [15]. As Ang-1 and -2 are natural antagonists binding a common receptor tie-2, an imbalance of these factors could perpetuate the inflammatory and prothrombotic state [16,17].

Elevated CRP (usually recognised as a marker of inflammation) is associated with a worse outcome in cardiovascular disease states, including myocardial infarction, acute coronary syndrome and HF [18]. Higher CRP levels are found in the offspring of patients with premature myocardial infarction [19]. In human CRP-transgenic mice, arterial injury resulted in more rapid and higher incidence of occlusive thrombosis, although the exact mechanism(s) remains ill-defined [20]. CRP can directly increase TF levels in monocytes and endothelial cells as well as induce expression of ICAM-1, VCAM-1, E-selectin, IL-1β and TNF-{alpha} and via the latter two, stimulate expression of TF [20-22]. Therefore, CRP is both proinflammatory and prothrombotic.

Nitric oxide (NO), secreted by the endothelium, inhibits platelet activation, adhesion and aggregation by activating guanylyl cyclase, with consequent suppression of P-selectin expression and thromboxane A2 synthesis [23,24]. There is also anecdotal evidence that in humans, a deficiency in vascular bioactive NO promotes arterial thrombosis and exogenous NO results in prolonged bleeding time and haemorrhage [24]. NO production by endothelial nitric oxide synthase (eNOS) is impaired in the presence of endothelial dysfunction as confirmed by impaired flow-mediated dilatation in HF. On the other hand, iNOS is induced by inflammatory cytokines (TNF-{alpha}, IL-1β and IL-6), hypoxia and ischaemia. In animal studies, high levels of NO produced by iNOS exert a negative inotropic effect on the myocardium and also contribute to myocyte apoptosis, probably as a result of accumulation of superoxide radicals [25-30]. Hence, it is likely that inflammatory cytokines in HF worsen the condition, but results from human trials utilising anti-TNF therapy have proved disappointing despite promising haemodynamic results in vitro [31,32].

Thrombomodulin (TM) also plays a crucial role in maintaining homeostasis of the coagulation system. It has an intracellular tail that anchors it to the endothelial cell, as well as a lectin-like domain and 6 extracellular growth factor domains [33]. TM binds and activates protein C (a process mediated by thrombin binding regions 5 and 6 of the growth factor domains), which then complexes with protein S to inactivate factors Va and VIIIa, acting as a natural anticoagulant. The lectin-like domain, on the other hand, inhibits neutrophil interaction with the endothelial cell, and may therefore play an anti-inflammatory role [34]. In contrast, soluble fragments of TM, of which the lectin-like domain is a part, are the result of proteolytic cleavage of the membrane-bound molecule. Indeed, soluble thrombomodulin (sTM) is increased where there is endothelial cell membrane injury due to neutrophil-derived proteolytic enzymes and inflammatory cytokines such as TNF-{alpha}. However, IL-1 and TNF-{alpha}, both inflammatory cytokines, have been shown to downregulate TM expression by the endothelial cell [35,36]. As IL-1 and TNF-{alpha} levels are raised in HF, a more prothrombotic endothelial surface would therefore result. Furthermore, the loss of the lectin-like domain of membrane-bound TM equates to its inability to inhibit the interaction between neutrophils and the endothelial surface, hence perpetuating the inflammatory response and endothelial damage.

Increased circulating endothelial cells (CECs) have been shown in myocardial infarction, acute coronary syndromes and critical limb ischaemia [37,38], consistent with the pathophysiology of these conditions whereby endothelial integrity is compromised. More recently, we have shown that CECs are also increased in HF [39]. The shedding of endothelial cells would expose the underlying prothrombotic subendothelium. While CECs may not be apoptotic, separation from the underlying basement membrane results in deprivation of survival factors and eventual cell death [40]. In vitro studies involving human umbilical vein endothelial cells (HUVECs) suggest that apoptotic endothelial cells have the potential for binding and activating platelets by the increased expression of phosphatidylserine and loss of anticoagulant membrane components, thereby promoting a prothrombotic milieu [41,42]. While a causal relationship has not been established between CECs and inflammation, it is likely as raised number of CECs are seen in other inflammatory disease states such as vasculitis and acute thermal injury [43,44].

Other data suggest that Ang-1 inhibits the upregulation of TF by TNF-{alpha} [12] and plays an anti-inflammatory role [45]. Recently published data on the angiopoietin-tie-2 system in the rat model indicates that Ang-2 also mediates the proinflammatory role of TNF-{alpha} by promoting leucocyte adhesion to activated endothelial cells [14]. Data from the mouse model also shows that Ang-2 promotes extravasation of cell poor fluid in the presence of ongoing inflammation. Ang-1 on the other hand, decreases permeability across the endothelial layer in various vascular beds in the mouse model and reduces lung water content in lipopolysaccharide-induced endotoxic shock [46]. Our data in HF show that while the level of Ang-2 is increased, Ang-1 levels are no different from controls. This imbalance may, in part, be responsible for pulmonary and/or peripheral oedema, as seen in HF.


   3. Treatment options in HF—impact on the inflammatory and prothrombotic states
Top
 Abstract
 1. Introduction
 2. Endothelial dysfunction,...
 3. Treatment options in...
4. Unresolved questions
 5. Conclusion
 References
 
ACE inhibitors, aldosterone antagonists and beta blockers have been shown to have a beneficial effect on mortality in HF. It is noteworthy that universally, an improvement in the endothelial profile is accompanied by an improvement in the inflammatory profile.

ACE inhibitors have been shown to improve FMD, presumably by increasing eNOS. ACE inhibitors also reduce vWf, reflecting improved endothelial function and amelioration of the prothrombotic state. Both ACE inhibitors and angiotensin receptor blockers (ARBs) reverse remodelling with a resultant decrease in left ventricular end diastolic volume and improved ejection fraction [47]. Furthermore, the ACE inhibitor, trandolapril and the aldosterone receptor antagonist, eplerenone have also been shown to decrease platelet activation as measured by soluble P-selectin [48]. Therefore, current evidence suggests that inhibition of the renin-angiotensin-aldosterone axis improves the prothrombotic state in HF.

Exercise training, and more recently cardiac resynchronisation therapy (CRT) have also been shown to have beneficial effects on HF, with the latter reducing heart failure mortality [49,50]. However, the underlying mechanism remains unclear. It is possible that the improvement in haemodynamics (i.e. flow), especially following CRT may impact on the levels of adhesion molecules and inflammatory cytokines which then affect the coagulation cascade. It would certainly be interesting to see if thromboembolic events are reduced by CRT.

HMG-CoA reductase inhibitors (statins) may improve the inflammatory and thrombotic state in HF. Statins have been shown to improve endothelial function, reduce CRP and depress the inflammatory response in HF with observational and retrospective analyses favouring the use of statins in HF. However, low cholesterol per se has been shown to be associated with a higher mortality in HF. The overall effect of the balance between the pleiotrophic effects and cholesterol-lowering effect of statins is still debated [51-57]. The endotoxin-lipoprotein hypothesis suggests that there is a lower critical threshold of lipoprotein concentration below which the body's defence against endotoxin is impaired [56]. The ongoing randomised CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial is currently investigating the effect of rosuvastatin on HF and may perhaps cast some light on this topic.

The role of anticoagulation in HF remains unclear. A systematic review of randomised clinical trials and observational studies by our department showed that the available evidence does not support routine anticoagulation in patients with HF [58]. One epidemiological study showed that antithrombotic therapy in severe heart failure was associated with improved survival, while retrospective analyses of V-HeFT I and II showed no benefit in patients with NYHA class II and III symptoms with an annual risk of thromboembolism of 1.6-3.5% [59-61]. The WASH (Warfarin/Aspirin Study in Heart failure) and the more recently concluded WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) studies showed no mortality benefit of anticoagulation over antiplatelet therapy in heart failure [62,63]. However, the lack of a placebo group limits the interpretation of the results.

Anti-TNF therapy, on the other hand, has been shown to decrease CRP and IL-6 [31]. However, clinical trials with these agents did not improve mortality. Various hypotheses have been put forward, with some suggesting that TNF-{alpha} may be beneficial after all in HF by increasing NO via iNOS as well as preventing apoptosis in myocytes under stress [64]. Furthermore, TNF-{alpha} mediates the expression of VEGF, Ang-1 and Ang-2 which may impact on the survival of endothelial cells. While there are data to suggest that antagonising TNF-{alpha} improves forearm blood flow probably by disinhibiting eNOS expression, these manifestations may in fact be limited to the periphery and not occur within the myocardium itself. Systemic infusion of anti-TNF-{alpha} monoclonal antibody or TNF-{alpha} receptors may inhibit TNF-{alpha} in the circulation and impair both angiogenesis and endothelial repair, but at the same time, leave myocardial TNF-{alpha} unaffected, resulting in continued myocyte apoptosis. Our understanding of the interplay of cytokines in inflammation remains very limited. What is clear from the trials so far is that the inhibition of just one cytokine or its receptor, within a complex array, is too simplistic and may actually be detrimental.


   4. Unresolved questions
Top
 Abstract
 1. Introduction
 2. Endothelial dysfunction,...
 3. Treatment options in...
 4. Unresolved questions
5. Conclusion
 References
 
Several questions remain unresolved. Is there a genetic predisposition to endothelial dysfunction? While we have been selected throughout evolution to survive by mounting a profound inflammatory response designed to ensure survival from trauma, i.e. an efficient coagulation system and healing by scar formation, this response appears to be deleterious in modern day diseases. It also begs the question whether the stronger the inflammatory response, the worse the prognosis. If we recognise that there is a lack of relationship between the degree of endothelial dysfunction and ejection fraction in HF, and studies show that markers of inflammation and endothelial dysfunction are better prognostic markers than ejection fraction itself, then this is certainly plausible.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Endothelial dysfunction,...
 3. Treatment options in...
 4. Unresolved questions
 5. Conclusion
References
 
In HF, the prothrombotic state is multifactorial and intimately linked to inflammation (Fig. 1). The reduction in thrombogenesis in HF therefore requires a multi-pronged attack to dampen inflammation, improve endothelial function and restore the natural balance of pro- and anticoagulants. Indeed, inflammation is the body's generic response to any insult-physical, chemical or biological-and while intended to protect and heal, may ultimately be detrimental in ‘modern’ day diseases.


Figure 01
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  		Fig. 1 Relationship between the prothrombotic state and inflammation.

 

   References
Top
 Abstract
 1. Introduction
 2. Endothelial dysfunction,...
 3. Treatment options in...
 4. Unresolved questions
 5. Conclusion
 References
 
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