Endothelins: a Possible Mechanism of Cytostatics-induced Cardiomyopathy

Abstract

Endothelium responds to physical and chemical stimuli by synthesis and release of a variety of vasoactive and signal molecules. Cardiac performance is regulated by cardiac endothelial cells in a paracrine manner, analogous to vascular endothelial control of vascular tone. Endothelin-1 (ET-1), one of the most potent vasoconstrictor peptides, which is synthetized and released by endothelial cells. The role of ET-1 in some special pathological state is still unclear. Authors have investigated the effect of anthracyclines (maximal dose: 450 mg/bodysurface m2) on left ventricular systolic and diastolic function and on the level of plasma ET-1, in 31 (13 male, aged 19-70 years, mean: 38.9) patients suffered from Hodgkin (24) and Non-Hodgkin (7) lymphomas. They have also studied the association between plasma ET-1 concentration and echocardiographic parameters. Serum ET-1 was measured by ELISA method. Left ventricular function analyzed by echocardiography: ejection fraction (EF), time velocity integral (VTI), E and A waves, E/A ratio, deceleration time (DT), Doppler index were assessed. Statistical analysis was made by the Wilcoxon rank test. ET-1 plasma level decreased significantly after therapy (5.6 +/- 3.5 vs. 3.1 +/- 0.9 pg/ml, P < 0.0006). EF (56.4 +/- 5.0% vs. 48.7 +/- 5.1%, P < 0.0001) decreased, and DT (168.1 +/- 36.8 ms vs. 206.5 +/- 58.8 ms, P < 0.0073) increased significantly after administration of anthracycline, showing that both systolic and diastolic left ventricular performance was deteriorated. There was no difference in other echocardiographic parameters before and after therapy. In conclusion, decrease of serum ET-1 concentration might be a result of anthracyclin's direct cytotoxic effect and the decreasing level of ET-1 may play a role in the reduction of the EF. More studies are needed to evaluate the presence and severity of endothelial damage, and long-term follow-up may reveal the importance of low ET-1 level and may show the time is needed for the restoration of the ET-1 concentration to the basic level after cessation of cytostatic therapy.

Anthracycline Cardiotoxicity: From Bench to Bedside

“…Cardiac endothelial cells and fibroblasts may be more sensitive to the toxic effects of doxorubicin than are cardiomyocytes, suggesting that cardiomyocyte deterioration may be preceded by alterations in matrix composition, in paracrine signals, and in doxorubicin distribution across extracellular fluids and cardiomyocytes 64. Studies of endothelial cells support this concept,65,66 but more studies are needed to obtain a comprehensive picture.…”

Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

“…Table 2 shows schematically the different cardiovascular cellular and extracellular targets of CT [30-33]. It is worthy of note that some of these detrimental effects are actually used even beneficially in medicalized intracoronary stents to prevent restenosis after percutaneous coronary angioplasty.…”

Subacute Anthracycline Cardiotoxicity

“…4 Other mechanisms have been proposed, including pathogenic roles for vasoactive peptides, direct cellular toxicity from anthracycline metabolites and, more recently, anthracycline deregulation of the nitric oxide network 6 and anthracycline induced increased endothelin (ET-1) levels. 7 We suspect our case represents a florid example of the same pathogenic mechanism which produces chronic myocardial injury. Increased vascular permeability and subsequent myocardial oedema may be the consequence of TLR 2 mediated inflammatory response with increased pro-inflammatory cytokine production.…”