98
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
conduction velocity was not only secondary to the
Mode of Death Prevention by Serelaxin
reversal of fibrosis but also an increase in the sodium current density (I Na ) caused by an up-regulation in the expression of voltage-gated Naþ channels (electrical remodeling). To extend human relevance to our rat
We read with interest the article by Felker et al. (1)
model, we demonstrated that these electrical remod-
regarding the effect of serelaxin on the mode of death
eling changes also occur in human cardiomyocytes
prevention in acute heart failure. This paper was a
derived from inducible pluripotent stem cells after
subgroup analysis of the RELAX-AHF (Efficacy and
only 24 to 48 h of relaxin exposure. It is important to
Safety of Relaxin for the Treatment of Acute Heart
note that our rat model received a higher dose of
Failure) study intended to assess the effect of ser-
subcutaneously administered relaxin for 2 weeks, and
elaxin on the specific mode of death in acute heart
regression of fibrosis was not seen within 48 h.
failure patients enrolled in the trial. The RELAX-AHF
It is plausible that the observed reduction in sud-
study demonstrated a reduction in the secondary
den cardiac death and stroke in the RELAX-AHF trial
endpoint of 180-day mortality in patients receiving a
could be explained by serelaxin-induced structural
48-h continuous infusion of 30 mg/kg/day serelaxin
and electrical remodeling. Cardiac fibrosis and slow-
compared with placebo (2). Although designed for the
ing of conduction velocity have been associated with
treatment of acute heart failure, the mortality benefit
increased risk of atrial and ventricular arrhythmias.
observed with serelaxin treatment was driven by re-
It is possible that serelaxin decreased the risk of
ductions in sudden cardiac death and other cardio-
sudden cardiac death by improving cardiac conduc-
vascular deaths, specifically stroke, whereas there
tion velocity in human heart failure patients through
was no difference in death due to heart failure.
increasing I Na and/or decreasing fibrosis. The unex-
The study authors note that multiple mechanisms
pected reduction in fatal stroke could be explained
contribute to sudden cardiac death in heart failure,
by suppression of atrial fibrillation. It would be
and serelaxin modulates a variety of biological path-
interesting to compare cardiac magnetic resonance
ways relevant to sudden cardiac death. The authors
images from patients before and after serelaxin
describe the reduction in the rate of fatal stroke as an
treatment to better understand the antifibrotic ef-
“unexpected finding.” The accompanying editorial (3)
fects of serelaxin, should a 2-day treatment be
notes that although these results “are encouraging, it
sufficient to reverse fibrosis. It would be valuable
is difficult to reconcile the main mortality findings of
to
the RELAX-AHF trial with those of the current HF
quantify atrial and ventricular arrhythmia burden.
treatment paradigm because no short-term therapy
It is not clear from the published literature whether
for hospitalized or chronic HF has previously de-
these data exist, but we do know that approxi-
monstrated long-term benefit.” Given the relatively
mately one-half of the RELAX-AHF patients had
small number of deaths in the RELAX-AHF trial
atrial fibrillation and >20% had a pacemaker or
(n ¼ 107), it is possible that these differences are due
implantable cardioverter-defibrillator (2). We eagerly
to chance alone and will not be observed in the larger
await results from future serelaxin studies and
phase III serelaxin trial. However, there may be a
hope that the investigators consider the antifibrotic
plausible biological mechanism to explain these
and antiarrhythmic effects of serelaxin in future
results.
analyses.
interrogate
implantable
cardiac
devices
to
We previously showed that in a spontaneously
with continuous subcutaneous administration of
*Brian L. Henry, MD, PhD David S. Schwartzman, MD Guy Salama, PhD
hypertensive rat model, which is highly susceptible to inducible atrial fibrillation, a 14-day treatment 400 mg/kg/day of relaxin was able to suppress in-
*University of Pittsburgh Medical Center
ducible atrial fibrillation (4). Examination of the ef-
Heart and Vascular Institute
fects of relaxin on the heart revealed that relaxin was
Scaife Hall 570.3
able to improve the pathological structural and elec-
200 Lothrop Street
trical remodeling present in spontaneously hyper-
Pittsburgh, Pennsylvania 15213
tensive rat hearts. The relaxin-treated rats had
E-mail: [email protected]
a significant reversal of cardiac fibrosis and car-
http://dx.doi.org/10.1016/j.jacc.2014.12.079
diomyocyte hypertrophy. In addition to reversing
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.
pathological
structural
remodeling,
relaxin
in-
creased cardiac conduction velocity. The increase in
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
REFERENCES 1. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol 2014;64:1591–8. 2. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29–39. 3. Greene SJ, Gheorghiade M. Matching mechanism of death with mechanism of action: considerations for drug development for hospitalized heart failure. J Am Coll Cardiol 2014;64:1599–601. 4. Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 2013;113:313–21.
clinical outcomes (4) and end-organ function (5) seen in the RELAX-AHF study. As noted, the ongoing RELAX-AHF2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) study (NCT01870778) will provide more definitive data on the efficacy of serelaxin in acute heart failure. The interesting data provided by Dr. Henry and colleagues suggest additional avenues of research for the potential role of serelaxin in the treatment of cardiovascular disease. *G. Michael Felker, MD, MHS Marco Metra, MD John R. Teerlink, MD
REPLY: Mode of Death Prevention
*Duke Clinical Research Institute
by Serelaxin
2400 Pratt Street Durham, North Carolina 27705
We thank Dr. Henry and colleagues for their interest in our study on the mode of death in the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study of serelaxin in acute heart
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.12.078 Please note: Drs. Felker, Teerlink, and Metra have received consulting fees from Novartis.
failure (1). The authors provide very interesting data from their own laboratory on the possible role of serelaxin in modulating cardiac fibrosis, myocyte hypertrophy, and cardiac conduction (2) and speculate that these mechanisms may be potential explanations for the reduction in sudden death and fatal stroke observed with serelaxin treatment in the RELAX-AHF study. As the authors point out, there are substantial differences in dose, duration of exposure, and disease state between their experimental model and our clinical trial results, making it difficult to draw any definitive conclusions about the possible role of these
REFERENCES 1. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol 2014;64:1591–8. 2. Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 2013;113:313–21. 3. Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 2009;14: 321–9. 4. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised,
mechanisms in our findings. Importantly, however,
placebo-controlled trial. Lancet 2013;381:29–39.
their data do underscore the pleiotropic nature of the
5. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 2013;61: 196–206.
biological effects of relaxin (3), which may in part explain the favorable impact of serelaxin therapy on
99
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
conduction velocity was not only secondary to the
Mode of Death Prevention by Serelaxin
reversal of fibrosis but also an increase in the sodium current density (I Na ) caused by an up-regulation in the expression of voltage-gated Naþ channels (electrical remodeling). To extend human relevance to our rat
We read with interest the article by Felker et al. (1)
model, we demonstrated that these electrical remod-
regarding the effect of serelaxin on the mode of death
eling changes also occur in human cardiomyocytes
prevention in acute heart failure. This paper was a
derived from inducible pluripotent stem cells after
subgroup analysis of the RELAX-AHF (Efficacy and
only 24 to 48 h of relaxin exposure. It is important to
Safety of Relaxin for the Treatment of Acute Heart
note that our rat model received a higher dose of
Failure) study intended to assess the effect of ser-
subcutaneously administered relaxin for 2 weeks, and
elaxin on the specific mode of death in acute heart
regression of fibrosis was not seen within 48 h.
failure patients enrolled in the trial. The RELAX-AHF
It is plausible that the observed reduction in sud-
study demonstrated a reduction in the secondary
den cardiac death and stroke in the RELAX-AHF trial
endpoint of 180-day mortality in patients receiving a
could be explained by serelaxin-induced structural
48-h continuous infusion of 30 mg/kg/day serelaxin
and electrical remodeling. Cardiac fibrosis and slow-
compared with placebo (2). Although designed for the
ing of conduction velocity have been associated with
treatment of acute heart failure, the mortality benefit
increased risk of atrial and ventricular arrhythmias.
observed with serelaxin treatment was driven by re-
It is possible that serelaxin decreased the risk of
ductions in sudden cardiac death and other cardio-
sudden cardiac death by improving cardiac conduc-
vascular deaths, specifically stroke, whereas there
tion velocity in human heart failure patients through
was no difference in death due to heart failure.
increasing I Na and/or decreasing fibrosis. The unex-
The study authors note that multiple mechanisms
pected reduction in fatal stroke could be explained
contribute to sudden cardiac death in heart failure,
by suppression of atrial fibrillation. It would be
and serelaxin modulates a variety of biological path-
interesting to compare cardiac magnetic resonance
ways relevant to sudden cardiac death. The authors
images from patients before and after serelaxin
describe the reduction in the rate of fatal stroke as an
treatment to better understand the antifibrotic ef-
“unexpected finding.” The accompanying editorial (3)
fects of serelaxin, should a 2-day treatment be
notes that although these results “are encouraging, it
sufficient to reverse fibrosis. It would be valuable
is difficult to reconcile the main mortality findings of
to
the RELAX-AHF trial with those of the current HF
quantify atrial and ventricular arrhythmia burden.
treatment paradigm because no short-term therapy
It is not clear from the published literature whether
for hospitalized or chronic HF has previously de-
these data exist, but we do know that approxi-
monstrated long-term benefit.” Given the relatively
mately one-half of the RELAX-AHF patients had
small number of deaths in the RELAX-AHF trial
atrial fibrillation and >20% had a pacemaker or
(n ¼ 107), it is possible that these differences are due
implantable cardioverter-defibrillator (2). We eagerly
to chance alone and will not be observed in the larger
await results from future serelaxin studies and
phase III serelaxin trial. However, there may be a
hope that the investigators consider the antifibrotic
plausible biological mechanism to explain these
and antiarrhythmic effects of serelaxin in future
results.
analyses.
interrogate
implantable
cardiac
devices
to
We previously showed that in a spontaneously
with continuous subcutaneous administration of
*Brian L. Henry, MD, PhD David S. Schwartzman, MD Guy Salama, PhD
hypertensive rat model, which is highly susceptible to inducible atrial fibrillation, a 14-day treatment 400 mg/kg/day of relaxin was able to suppress in-
*University of Pittsburgh Medical Center
ducible atrial fibrillation (4). Examination of the ef-
Heart and Vascular Institute
fects of relaxin on the heart revealed that relaxin was
Scaife Hall 570.3
able to improve the pathological structural and elec-
200 Lothrop Street
trical remodeling present in spontaneously hyper-
Pittsburgh, Pennsylvania 15213
tensive rat hearts. The relaxin-treated rats had
E-mail: [email protected]
a significant reversal of cardiac fibrosis and car-
http://dx.doi.org/10.1016/j.jacc.2014.12.079
diomyocyte hypertrophy. In addition to reversing
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.
pathological
structural
remodeling,
relaxin
in-
creased cardiac conduction velocity. The increase in
JACC VOL. 66, NO. 1, 2015
Letters
JULY 7, 2015:91–9
REFERENCES 1. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol 2014;64:1591–8. 2. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29–39. 3. Greene SJ, Gheorghiade M. Matching mechanism of death with mechanism of action: considerations for drug development for hospitalized heart failure. J Am Coll Cardiol 2014;64:1599–601. 4. Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 2013;113:313–21.
clinical outcomes (4) and end-organ function (5) seen in the RELAX-AHF study. As noted, the ongoing RELAX-AHF2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) study (NCT01870778) will provide more definitive data on the efficacy of serelaxin in acute heart failure. The interesting data provided by Dr. Henry and colleagues suggest additional avenues of research for the potential role of serelaxin in the treatment of cardiovascular disease. *G. Michael Felker, MD, MHS Marco Metra, MD John R. Teerlink, MD
REPLY: Mode of Death Prevention
*Duke Clinical Research Institute
by Serelaxin
2400 Pratt Street Durham, North Carolina 27705
We thank Dr. Henry and colleagues for their interest in our study on the mode of death in the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study of serelaxin in acute heart
E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2014.12.078 Please note: Drs. Felker, Teerlink, and Metra have received consulting fees from Novartis.
failure (1). The authors provide very interesting data from their own laboratory on the possible role of serelaxin in modulating cardiac fibrosis, myocyte hypertrophy, and cardiac conduction (2) and speculate that these mechanisms may be potential explanations for the reduction in sudden death and fatal stroke observed with serelaxin treatment in the RELAX-AHF study. As the authors point out, there are substantial differences in dose, duration of exposure, and disease state between their experimental model and our clinical trial results, making it difficult to draw any definitive conclusions about the possible role of these
REFERENCES 1. Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol 2014;64:1591–8. 2. Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 2013;113:313–21. 3. Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 2009;14: 321–9. 4. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised,
mechanisms in our findings. Importantly, however,
placebo-controlled trial. Lancet 2013;381:29–39.
their data do underscore the pleiotropic nature of the
5. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 2013;61: 196–206.
biological effects of relaxin (3), which may in part explain the favorable impact of serelaxin therapy on
99
