The role of the endothelin system in myocardial infarction—new therapeutic targets?

R Berger* and R Pacher

University Hospital of Vienna, Vienna, Austria

Received August 26, 2002; accepted August 28, 2002 * Corresponding author. Department of Cardiology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. Tel.: +431-40400-4614; fax: +431-4081148
rberger{at}gmx.at

See doi:10.1016/S1095-668X(02)00420-7for the article to which this editorial refers.

Endothelin (ET)-1, a 21-amino acid peptide, represents the major isoform of the endothelin peptide family, which further includes ET-2, ET-3, and ET-4.1 It is the most potent vasoconstrictor known and stimulates cell proliferation in various tissues. The biologically inactive precursor big ET is converted to the mature peptide by the endothelin-converting-enzyme. ETAreceptors, which lead to increased intracellular calcium concentrations, induce vasoconstriction and cell proliferation. ETBreceptors which mediate the release of NO and prostacyclin cause vasodilatation and are involved in the clearance of ET-1 and in the inhibition of the endothelin-converting-enzyme.

1. Endothelin and (coronary) atherosclerosis

In atherosclerosis, the production of ET-1 is stimulated and both tissue and plasma ET-1 levels are positively correlated with the extent of atherosclerosis.1 Moreover, in patients with coronaryartery disease, tissue ET-1 levels are related to the extent of angina. Various risk factors for atherosclerosis such as diabetes mellitus, smoking and hypercholesterolaemia enhance endothelial ET-1 secretion.2,3 Oxidized LDL stimulates the production of ET-1 in human macrophages and endothelial cells.4 It is suggested that arterial hypertension is associated with elevated tissue ET-1 levels and/or with altered sensitivity to endogenous ET-1. ET-1 acts as the natural counterpart of nitric oxide (NO), which exerts vasodilating, antithrombotic and antiproliferative effects. The increased release of ET-1 mediates vasoconstriction and smooth muscle cell proliferation via ETAreceptors, acts as chemoattractant for circulating monocytes and induces neutrophil adhesion, platelet aggregation andadhesion molecule expression.1,5 Thereby, ET-1 is involved in atherogenesis and promotes lesion growth and coronary thrombosis.

In fact, chronic ETAreceptor blockade reduces the extent of atherosclerosis in apolipoprotein E-deficient mice.6 Moreover, long-term ETAreceptor antagonism has been demonstrated to decrease macrophage infiltration in fatty steaks in cholesterol-fed hamsters.7 In animal models of myocardial injury after ischemia and reperfusion, mixed ETA/Bas well as selective ETAreceptor blocker reduced myocardial infarct size.1 One mechanism maybe, that mainly ET-1 contributes to the resting tone in human atherosclerotic plaques (including stenoses) and ETAreceptor antagonism seems to have the potential to reduce the haemodynamic significance of coronary stenoses.1 Inconclusion, inhibiting the progression of atherosclerosis, preventing restenosis after PTCA andimproving outcome in patients with myocardialinfarction represent attractive indications for endothelin-antagonism, but results from largeclinical trials are currently not available.

2. Endothelin and myocardial infarction/remodelling

Loss of myocytes during myocardial infarction is associated with increased wall stress and, in an adaptational process, this increased wall stress leads to molecular cardiac remodelling. Thereby, both re-expression of the foetal program (changes in genetic expression and activation of proteinsynthesis) directly due to increased mechanical stretch, and various phenotypic modifications including neurohormonal activation are involved in cardiac remodeling.8 Hypertrophy is an important step towards adaptation, as it increases the available contractile units and decreases wall stress (Laplace law). Moreover, changes in genetic expression result in the production of a slow contracting myosin heavy chain thereby improving myocardial economy. In addition, the myocardial economy is improved by reduction of the sympathetic drive through down-regulation of ß1-adrenoceptors. Nevertheless, as differentiated adult cardiac myocytes have little or no capacity to divide, overload-induced hypertrophy due to the activation of the foetal programme may represent an unnatural growth response and may contribute to the increased rates of programmed cell death (apoptosis).9 Fibrosis in the noninfarcted myocardium is multifactorial and is caused by neurohormonal activation, hypoxia, inflammatoryprocesses and other mechanisms. The progression of disease with a shift from asymptomatic left ventricular dysfunction to symptomatic heart failure may develop due to the limitations of the positive effects of the adaptational process and due to the increase of the negative effects of remodelling: the beneficial effects caused by the isomyosin shift that improve myocardial economy reach their maximum when the fast isoform has been completely replaced by the slow-contracting myosin chain. The growing amount of fibrosis aggravates systolic dysfunction, increases myocardial stiffness and facilitates re-entry arrhythmias. In addition, apoptosis decreases the number of myocytes. The final result of myocardial remodelling varies and depends on the prevalence of the contributing factors (e.g. re-expression of the foetal programme due to mechanical stretch, neurohormonal factors). Beneficial treatment supports the positive developments during the adaptational process (reduction of the sympathetic drive by beta-blocker, thereby improving myocardial economy) and attenuates the negative effects of remodelling (antifibrotic effects of ACE-inhibitors and aldosterone antagonists, reduction of myocardial hypertrophy by long-term treatment with ACE-inhibitors and beta-blockers).

ET-1 plasma levels are elevated in patients with acute myocardial infarction and predict 1-yearsurvival. The question arises whether plasma levels are elevated due to stimulated myocardial orextracardiac production. Indeed, an increased myocardial expression of preproET-1 (ET-1 precursor) mRNA was observed in animal models of myocardial hypertrophy and congestive heart failure, suggesting stimulated cardiac production during myocardial infarction. Nevertheless, Tsutamoto and co-workers demonstrated in their recent work measuring ET-1 plasma levels in the aortic root and in the sinus coronarius, that the myocardiumextracts ET-1 during infarction.10 Thus, despite possible increased myocardial production, themain source of elevated ET-1 plasma levels seems to be extracardial. In chronic heart failure, the pulmonary bed is mainly responsible for elevated ET-1 plasma levels via reduced pulmonary clearance and increased ET-1 production modulatedby baroreflexes.11 A positive correlation between pulmonary vascular distension (cardiac fillingpressures and pulmonary arterial pressure) and ET-1 levels is well known. Nevertheless, despite the mainly extracardial source of ET-1 plasma levels in myocardial infarction, the findings of Tsutamoto et al. underscore that this hormonal system is of relevance not only in regard tovasoactive effects but also in regard to myocardial interferences.

ET-1 has positive inotropic effects via calcium-sensitisation and increase of intracellular calcium in vitro. Nevertheless, ET-1 infusions in animals result in a decline of cardiac output due to the vasoconstrictive actions of ET-1, resulting in reduced myocardial perfusion and increased afterload. Thus, the effects of ET-1 on myocardial contractility12 seem to be a question of dose, as endothelin antagonism worsens contractility in healthy humans (with normal ET-1 plasma levels) but improves contractility in advanced left ventricular dysfunction.13 Moreover, ET-1 acts as a growth-promoter on cardiomyocytes and this effect is potentiated by the RAAS system and hypoxia. In addition, ET-1 enhances myocardial fibrosis via increase of cardiac fibroblast proliferation, extracellular matrix deposition, and the expression of adhesion molecules.1,11 Tsutamoto and colleagues showed that, independent of infarct size, theextent of plasma ET-1 extracted across theheart in acute myocardial infarction is correlated to the absolute change of LVEDVI after 1 month. These findings suggest that elevated transcardiac ET-1 extraction through the heart contributes to post-infarct remodelling in patients with acute myocardial infarction.10 Thus, the blockade of the endothelin system seems tobe a valuable therapeutic target to prevent orat least attenuate the process of myocardialremodelling.

Indeed, chronic blockade of the endothelial system reduces ventricular dilatation and prolongs survival in experimental models of heart failure.14 In humans, endothelin-receptor antagonism hasalready been demonstrated to improve the haemodynamic derangement and clinical status ofpatients.1 Nevertheless, the proof of a beneficial effect of endothelin antagonists on the survival of heart failure patients is still missing. Up to now, the ENABLE trial was the only clinical trial addressing this issue in about 1600 CHF patients, but failed to demonstrate a survival benefit in the bosentan (mixed ETA/Breceptor blocker) treated group.Remarkably, only in the bosentan group, a significant fluid retention could be observed during the first 2 weeks of treatment, which developed possibly due to changes in renal function and not dueto worsening heart failure. Bosentan reduces natriuretic peptide levels in CHF patients, a favourable prognostic sign indicating decreased wall stress, but also a possible mechanism contributing to fluid retention by decreasing diuresis.15 Whether this fluid retention contributed to the failure of the drug and whether increased diuretic therapy during the initialization of the therapy could improve the outcome, has to be evaluated. Maybe other compounds, like endothelin-converting-enzyme inhibitors which influence the natriuretic peptide system in the contrary direction compared to bosentan,can meet the expectations concerning this newsubstance class.

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Related articles in EHJ:

Relationship between transcardiac gradient of endothelin-1 and left ventricular remodelling in patients with first anterior myocardial infarction
T. Tsutamoto, A. Wada, M. Hayashi, T. Tsutsui, K. Maeda, M. Ohnishi, M. Fujii, T. Matsumoto, T. Yamamoto, T. Takayama, C. Ishii, and M. Kinoshita
EHJ 2003 24: 346-355. [Abstract] [Full Text]