A Discussion of Relaxin as a Possible Treatment for Heart Failure

The hormone relaxin did well in an early clinical trial as a treatment for heart failure, but failed in a larger trial. Researchers here determine that the benefits observed in animal models and patients are probably due to interactions between relaxin and Wnt signaling, a pathway important in regeneration. The actions of this pathway are very complicated and situational, as is true of most regulators of development and regeneration. Given the presently successful trajectory of Samumed, a regenerative medicine company focused on developing therapeutics based on manipulation of Wnt signaling, it is understandable that numerous other groups have attempted much the same in recent years. Manipulation of pathways central to processes such as regeneration is a road littered with failures, unfortunately, thanks to the complexity of the biochemistry.

Based on intriguing clinical and pre-clinical data, relaxin (RLX) engendered significant enthusiasm as a potential therapy for cardiopulmonary diseases. In the acute heart failure trial RELAX-AHF, RLX treatment improved patient survival by a remarkable 37% in 6 months. These exciting results led the FDA to declare RLX as a "break-through" therapy made all the more significant because the trial included patients with systolic and diastolic HF. Unfortunately, the reduced mortality benefits were not duplicated in a subsequent larger clinical trial sponsored by Novartis.

Detailed analysis of the larger trial has not been reported and the failure of RLX to significantly reduce mortality is not fully understood. A possible explanation is that the control group of patients receiving standard of care for heart failure fared considerably better than in earlier trials but another problem has been the design methodology of a 2-days treatment which has justifiably received substantial criticism. Our previous studies on the effects of RLX in experimental animals provide compelling evidence of significant beneficial effects of the hormone in cardiac physiology. We reported that RLX suppressed atrial fibrillation in aged rats by increasing conduction velocity (CV) of atrial action potentials. These effects were linked to increased expression of the voltage-gated sodium channel (Nav1.5), and a marked decrease in fibrosis, both effects confirmed here in ventricles. At the cellular level, the reversal of fibrosis required more than a week due to the slow turn-over of collagen in the extracellular matrix. Besides electrical and extracellular matrix remodeling, we reported that RLX acted as a potent anti-immune and anti-inflammatory agent in the ventricles of aged animals.

Our results show that RLX's effects in heart tissue are largely mediated by the modulation of canonical Wnt signaling which can act as a master controller of gene expression in heart and other organs. While RLX and Wnt signaling have been investigated in models of cancer, there is no work on the interactions of the RLX and Wnt pathways in adult heart and 'healthy' aging as a precursor of cardiac diseases. Wnt signaling in the heart is complex, and different Wnt ligands have distinct effects. Many details of the mechanism by which RLX modulates canonical Wnt signaling remain to be explored. Nonetheless, these findings demonstrate a close interplay between RLX and Wnt-signaling resulting in myocardial remodeling and reveal a fundamental mechanism of great therapeutic potential.

Link: https://doi.org/10.1038/s41598-019-53867-y

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