European Journal of Heart Failure

European Journal of Heart Failure 1999 1(4):309-312; doi:10.1016/S1388-9842(99)00049-5

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© 1999 European Society of Cardiology

How are cytokines activated in heart failure?

Walter J. Paulus

Cardiovascular Center O.L.V. Ziekenhuis, Moorselbaan 164, B 9300 Aalst, Belgium

Received June 28, 1999; Revised July 15, 1999; Accepted August 9, 1999

	1. Introduction

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
Proinflammatory cytokines such as interleukin 1, interleukin 6 and tumor necrosis factor (TNF) were recently identified as contributors to the syndrome of chronic heart failure [1] and to the underlying cardiomyopathic process of adverse left ventricular remodeling and of progressive left ventricular dysfunction [2,3]. Due to this role of proinflammatory cytokines, ‘the cardioinflammatory response to heart failure’ was recently proposed as a new heart failure paradigm with implications for both prognosis and treatment [4]. The origin of these proinflammatory cytokines in heart failure patients remains unclear so far and has been the subject of controversy. Two divergent explanations have been proposed, namely endotoxin-induced immune activation because of bowel oedema and myocardial cytokine production because of hemodynamic overload. Due to the therapeutic implications, such as sterilisation of the gut with antibiotics or inhibition of endotoxin-induced cytokine expression with amiodarone [5] or digitalis [6], a critical evaluation of both explanations is needed.

	2. Endotoxin-induced cytokine production

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
This explanation was first proposed by Anker et al. [7] because of concurrent elevation of soluble CD 14 and cytokines in heart failure patients. CD 14 receptors of immune-competent cells interact with bacterial endotoxin. This interaction causes signal transduction for cytokine production and shedding of the extracellular domain of the CD 14 receptor which shows up in serum as soluble CD 14. The same investigators recently demonstrated high endotoxin levels in heart failure patients with peripheral oedema [8]. In the same group of patients, these high endotoxin levels were paralleled by elevated TNF levels. In heart failure patients without peripheral oedema, no elevation of endotoxin or of TNF was observed. Following a diuretic treatment period of 23 days, there was a fall in endotoxin level but no change in TNF. Only after 41 days did a non-significant trend for lower TNF concentrations occur.

From these findings, the authors concluded that elevated plasma levels of cytokines in heart failure resulted from a cascade of events consisting of mesenteric venous congestion, bowel-wall oedema, intestinal bacterial translocation, endotoxin release into the circulation and subsequent immune activation because of endotoxin binding to the CD 14 receptor (Fig. 1). This explanation, however, fails to accommodate certain clinical and experimental observations. Elevations in plasma cytokines have been observed in patients with NYHA class II failure [9] most of whom do not have peripheral oedema. Patients with prominent right heart failure because of pulmonary hypertension or constrictive pericarditis have not been shown to have higher elevations of plasma cytokines. Intensive diuretic treatment of class IV heart failure patients has previously been demonstrated not to result in lower plasma levels of interleukin 6 or TNF [10]. In a pacing heart failure dog model, 3 weeks of rapid pacing resulted in a 100-fold increase in plasma TNF level and immunohistochemical staining of left ventricular myocardium for TNF [11]. In the same model, immunohistochemical examination for TNF of the spleen, which is part of the splanchnic circulation and hence directly exposed to bacterial translocation from the gut, showed equal staining intensity in failing and control dogs. These experiments therefore rebut endotoxin-induced immune activation as the cause of elevated circulating cytokines. Moreover, concentrations of circulating endotoxin observed in oedematous heart failure patients [8] are 5000-fold less than the concentration needed to stimulate cytokine expression in cardiac myocytes [12].

View larger version (14K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Endotoxin-induced cytokine expression. Elevated plasma levels of cytokines in heart failure result from a cascade of events consisting of mesenteric venous congestion, bowel-wall oedema, intestinal bacterial translocation, endotoxin release into the circulation and immune activation as evident from elevated TNF levels and soluble CD14 levels.

 

	3. Myocardial cytokine production

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
The myocardial cytokine production hypothesis is based on clinical reports from two laboratories demonstrating myocardial expression of TNF in the failing human heart [2,3]. Experimental proof of myocardial production of TNF was subsequently derived from isolated cat hearts, which were subjected to variable levels of left ventricular distending pressure [13] (Fig. 2). At low left ventricular distending pressure, there was minimal elevation of myocardial TNF production. At high left ventricular distending pressure, there was a robust myocardial expression of TNF production, which was reversed after insertion of a left ventricular venting tube or after addition to the perfusate of substances, which interfered with the myocardial signal transduction cascade. A similar induction of myocardial expression of growth factors by left ventricular distension was recently observed in an isolated rat heart model [14]. In this model, 30 min of elevated left ventricular end-diastolic pressure (=35 mmHg) resulted in a substantial myocardial production of transforming growth factor β and of vascular endothelial growth factor. In human non-ischemic dilated cardiomyopathy with elevated left ventricular end-diastolic pressure (>16 mmHg), myocardial expression of inducible nitric oxide synthase gene was recently shown to correlate with left ventricular stroke work [15]. In the same patient group, myocardial colocalisation of inducible nitric oxide synthase and of TNF had previously been demonstrated [2,3]. These experimental and clinical data provide solid support for a diastolic wall stress induced myocardial production of cytokines, growth factors and stress proteins.

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Myocardial cytokine production. Elevated LV diastolic wall stress induces myocardial expression of TNF, which causes LV contractile dysfunction and LV dilatation, thereby further augmenting LV diastolic wall stress.

 
In a group of patients with mild to moderate heart failure, Munger et al. [16] found no significant difference between plasma levels of arterial and of coronary sinus blood of interleukin 1, interleukin 6, soluble interleukin 2 receptor and TNF. This absence of a transmyocardial gradient for cytokines and cytokine receptors was frequently cited as an argument against significant myocardial production of these substances. The magnitude of a transmyocardial gradient depends on the rate of production by the myocardium, on the rate of removal from the systemic circulation and also on the rate of diffusion from the interstitial space into the coronary sinus effluent. The presence of a diffusion barrier between the interstitial space and the coronary venous system was recently demonstrated in an isolated dog heart preparation using selective micropipette insertion into the interstitial space. Following infusion of angiotensin I through the micropipette, there was a 100-fold elevation of angiotensin II in the interstitial space without a detectable change in coronary sinus or arterial angiotensin II level [17]. A similar diffusion barrier between interstitial space and coronary sinus venous system not only exists for proteins but also for highly diffusable molecules such as NO. In a group of human transplant recipients, systemic and coronary sinus plasma nitrite/nitrate levels were uniformly comparable, despite variable gene expression of inducible NO synthase in endomyocardial right ventricular biopsies [18]. Because of this diffusion barrier between the interstitial space and the coronary venous effluent, absence of a transmyocardial gradient of cytokines does not rule out myocardial production of cytokines but suggests limited contribution of myocardial production to elevated systemic levels of cytokines.

	4. Extramyocardial cytokine production

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
Because of multiple organ involvement in the heart failure syndrome, a single source of cytokine production such as the gut or the heart seems unlikely. In heart failure, impaired vasodilator reserve and decreased aerobic enzyme activity could result in tissue hypoxia especially of skeletal muscles. Tissue hypoxia and free radical production are potent stimuli for NF-B mediated cytokine production, which could trigger a cascade of events consisting of expression of iNOS, skeletal muscle apoptosis and skeletal muscle wasting [19]. Measures of oxidative stress such as plasma lipid peroxides and malondialdehyde have indeed been shown to correlate with soluble TNF receptors in patients with heart failure [20]. Elevated plasma levels of cytokines could further reduce the endothelium-dependent vasodilator response [10,21], thereby creating a vicious circle of more severe tissue hypoperfusion, more profound tissue hypoxia and more intense cytokine production (Fig. 3).

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Extramyocardial cytokine production. Impaired vasodilator reserve of peripheral tissue, especially skeletal muscle, causes tissue hypoxia, free radical production and NF-B mediated cytokine production. Elevated plasma levels of cytokines cause further reduction of vasodilator reserve, thereby creating a vicious circle.

 

	5. Summary

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
In the dilated and failing heart, elevated LV end-diastolic wall stress causes myocardial expression of cytokines, which directly or indirectly influence LV contractile performance and remodeling [22]. Due to poor diffusion of cytokines into the coronary effluent, the contribution of this myocardial production to the raised plasma levels is probably limited. Raised plasma levels of cytokines in heart failure are therefore more likely the result of extramyocardial production because of altered tissue perfusion and tissue hypoxia possibly modulated by bacterial endotoxin release from the gut.

	Notes

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 
^* E-mail address: walter.paulus{at}ping.be (W. J. Paulus)

	References

Top Notes 1. Introduction 2. Endotoxin-induced cytokine... 3. Myocardial cytokine... 4. Extramyocardial cytokine... 5. Summary References

 

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