Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast.
There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis.
Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure.
The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.
These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.
Experimental studies and clinical trials have demonstrated that ET-1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure.
A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients.
The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure.
Elevated ET-1 was associated with worse HF, lower right ventricular function, higher pulmonary pressure, and higher left atrial volume index despite similar left ventricular function.
Our meta-analysis provided evidence that increased plasma levels of ET-1, big ET-1, and CT-proET-1 were associated with poor prognosis or mortality for HF populations.
Finally, elevated natriuretic peptides, ST2, endothelin-1, mid-regional-pro-adrenomedullin, copeptin, and galectin-3 have all been well validated to predict death and heart failure following a MI and provide risk stratification information for heart failure.
Our study shows that fenofibrate may protect against ET-1-induced cardiomyocyte hypertrophy and enhanced adiponectin expression through modulation of PPARα expression in vitro and limitation of daunorubicin cardiotoxicity in vivo, suggesting a novel mechanistic insight into the role of PPARα and adiponectin in cardiac hypertrophy and heart failure.