Author + information
- Brian L. Henry, MD, PhD∗ (, )
- David S. Schwartzman, MD and
- Guy Salama, PhD
- ↵∗University of Pittsburgh Medical Center, Heart and Vascular Institute, Scaife Hall 570.3, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213
We read with interest the article by Felker et al. (1) regarding the effect of serelaxin on the mode of death prevention in acute heart failure. This paper was a subgroup analysis of the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study intended to assess the effect of serelaxin on the specific mode of death in acute heart failure patients enrolled in the trial. The RELAX-AHF study demonstrated a reduction in the secondary endpoint of 180-day mortality in patients receiving a 48-h continuous infusion of 30 μg/kg/day serelaxin compared with placebo (2). Although designed for the treatment of acute heart failure, the mortality benefit observed with serelaxin treatment was driven by reductions in sudden cardiac death and other cardiovascular deaths, specifically stroke, whereas there was no difference in death due to heart failure. The study authors note that multiple mechanisms contribute to sudden cardiac death in heart failure, and serelaxin modulates a variety of biological pathways relevant to sudden cardiac death. The authors describe the reduction in the rate of fatal stroke as an “unexpected finding.” The accompanying editorial (3) notes that although these results “are encouraging, it is difficult to reconcile the main mortality findings of the RELAX-AHF trial with those of the current HF treatment paradigm because no short-term therapy for hospitalized or chronic HF has previously demonstrated long-term benefit.” Given the relatively small number of deaths in the RELAX-AHF trial (n = 107), it is possible that these differences are due to chance alone and will not be observed in the larger phase III serelaxin trial. However, there may be a plausible biological mechanism to explain these results.
We previously showed that in a spontaneously hypertensive rat model, which is highly susceptible to inducible atrial fibrillation, a 14-day treatment with continuous subcutaneous administration of 400 μg/kg/day of relaxin was able to suppress inducible atrial fibrillation (4). Examination of the effects of relaxin on the heart revealed that relaxin was able to improve the pathological structural and electrical remodeling present in spontaneously hypertensive rat hearts. The relaxin-treated rats had a significant reversal of cardiac fibrosis and cardiomyocyte hypertrophy. In addition to reversing pathological structural remodeling, relaxin increased cardiac conduction velocity. The increase in conduction velocity was not only secondary to the reversal of fibrosis but also an increase in the sodium current density (INa) caused by an up-regulation in the expression of voltage-gated Na+ channels (electrical remodeling). To extend human relevance to our rat model, we demonstrated that these electrical remodeling changes also occur in human cardiomyocytes derived from inducible pluripotent stem cells after only 24 to 48 h of relaxin exposure. It is important to note that our rat model received a higher dose of subcutaneously administered relaxin for 2 weeks, and regression of fibrosis was not seen within 48 h.
It is plausible that the observed reduction in sudden cardiac death and stroke in the RELAX-AHF trial could be explained by serelaxin-induced structural and electrical remodeling. Cardiac fibrosis and slowing of conduction velocity have been associated with increased risk of atrial and ventricular arrhythmias. It is possible that serelaxin decreased the risk of sudden cardiac death by improving cardiac conduction velocity in human heart failure patients through increasing INa and/or decreasing fibrosis. The unexpected reduction in fatal stroke could be explained by suppression of atrial fibrillation. It would be interesting to compare cardiac magnetic resonance images from patients before and after serelaxin treatment to better understand the antifibrotic effects of serelaxin, should a 2-day treatment be sufficient to reverse fibrosis. It would be valuable to interrogate implantable cardiac devices to quantify atrial and ventricular arrhythmia burden. It is not clear from the published literature whether these data exist, but we do know that approximately one-half of the RELAX-AHF patients had atrial fibrillation and >20% had a pacemaker or implantable cardioverter-defibrillator (2). We eagerly await results from future serelaxin studies and hope that the investigators consider the antifibrotic and antiarrhythmic effects of serelaxin in future analyses.
Please note: The authors have received grants from the National Institutes of Health (HL093074, UL1 RR024153, and UL1TR000005). Dr. Schwartzman has received grants from Boston Scientific and Medtronic and is a consultant for Atricure, Avery Dennison, Epicardial Frontiers, and Quant MD.
- American College of Cardiology Foundation
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