Recombinant Human Relaxin-2: (How) Can a Pregnancy Hormone Save Lives in Acute Heart Failure?

Acute heart failure (AHF) syndrome, characterized by pulmonary and/or venous congestion owing to increased cardiac filling pressures with or without diminished cardiac output, is still associated with high post-discharge mortality and hospitalization rates. Many novel and promising therapeutic approaches, among them endothelin-1, vasopressin and adenosine antagonists, calcium sensitization, and recombinant B-type natriuretic hormone, have failed in large studies. Likewise, the classic drugs, vasodilators, diuretics, and inotropes, have never been shown to lower mortality. The phase III trial RELAX-AHF tested recombinant human relaxin-2 (rhRlx) and found it to improve clinical symptoms moderately, to be neutral regarding the combination of death and hospitalization at day 60, to be safe, and to lower mortality at day 180. This review focuses on basic research and pre-clinical findings that may account for the benefit of rhRlx in AHF. The drug combines short-term hemodynamic advantages, such as moderate blood pressure decline and functional endothelin-1 antagonism, with a wealth of protective effects harboring long-term benefits, such as anti-inflammatory, anti-fibrotic, and anti-oxidative actions. These pleiotropic effects are exerted through a complex and intricate signaling cascade involving the relaxin-family peptide receptor-1, the glucocorticoid receptor, nitric oxide, and a cell type-dependent variety of kinases and transcription factors.