JACC: HEART FAILURE
VOL. 3, NO. 1, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.10.003
EDITORIAL COMMENT
Biomarkers, Mineralocorticoid Receptor Antagonism, and Cardiorenal Remodeling* Mona Fiuzat, PHARMD,y John C. Burnett, JR., MDz
“We cannot solve our problems with the same
be associated with these effects provide new insights.
thinking we used when we created them.”
In the paper by Lax et al. (7), the investigators find
W
—Albert Einstein (1) ith the advances in our understanding of novel biomarkers in heart failure (HF), much research has focused on expanding
the role of biomarkers beyond that of prognosis. In particular, the question of whether these biomarkers may be informative in the selection of therapies as well as into pathobiology is an area of ongoing debate and intense investigation. Data have been inconclusive at best, while larger trials are ongoing to help answer this question (2,3). In recent years, trials have confirmed that mineralocorticoid receptor antagonists (MRAs) significantly improve long-term
that in a myocardial infarction (MI)–induced rat model, there was an elevation of a number of biomarkers of fibrosis and inflammation. Treatment with MRAs down-regulated the pro-fibrotic mediators galectin-3 (Gal-3), transforming growth factor b, and Smad-3 and enhanced fibroprotective interleukin (IL)-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. The authors also note that modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory biomarkers. Although the authors conclude that there were no differences observed between
outcomes in patients with systolic heart failure (4–6). Their mechanism of action includes modulating cardiac fibrosis as well as possible renal natriuretic actions in these patients (6). Thus, a deeper understanding of how MRAs affect biomarkers of fibrosis and inflammation and the process of fibrosis itself, rather than whether key biomarkers can predict the benefits of MRAs, is perhaps the pertinent link in the interaction between biomarkers, therapeutics, and disease mechanisms. In this issue of JACC: Heart Failure, 2 papers focus on the interaction between MRAs and their effects on biomarkers and fibrotic mechanisms in the left ventricle (LV), and the resultant outcomes that may
SEE PAGES 50 AND 59
eplerenone and spironolactone, the figures in the paper show some fine variations in the effects on various biomarkers, which could be an area for exploration in larger studies. Nonetheless, these studies underscore evidence that supports direct antifibrotic
properties
in
experimental
post-MI
remodeling, further supporting the importance of the original work by Zannad et al. (4) with eplerenone in the seminal EMPHASIS-HF (The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Subjects With NYHA Class II Chronic Systolic Heart Failure) trial. Importantly, one should take reassurance that the antifibrotic and antiremodeling
*Editorials published in JACC: Heart Failure reflect the views of the
actions of MRAs may be a class effect, but may
authors and do not necessarily represent the views of JACC: Heart Failure
also have slightly different interactions with these
or the American College of Cardiology.
markers, in view of the findings with 2 MRAs in
From the yDuke University Medical Center, Durham, North Carolina; and
the elegant study by Lax et al. (7). It would, how-
the zMayo Clinic, Rochester, Minnesota. Dr. Fiuzat has received research
ever, have been of interest to know more about
funding from BG Medicine, Critical Diagnostics, Roche Diagnostics; and has served as a consultant to Roche Diagnostics (minimal). Dr. Burnett
the kidney, especially if there was a natriuretic
has reported that he has no relationships relevant to the contents of this
and cardiac unloading action via such actions on
paper to disclose.
intravascular volume.
Fiuzat and Burnett
JACC: HEART FAILURE VOL. 3, NO. 1, 2015 JANUARY 2015:68–9
Biomarkers, MRAs, and Cardiorenal Remodeling
In the paper by Calvier et al. (8), hyperaldosteronism
MRAs protect against post-MI induced HF, with a
was induced in a rat model, with resultant renal and
focus on expression of myocardial genes which
cardiac hypertrophy and fibrosis, and the mechanistic
are linked to fibrosis and inflammation, as well as
role of Gal-3 in such cardiorenal injury was explored.
molecular mechanisms of myocardial remodeling.
Spironolactone or modified citrus pectin (a Gal-3 in-
These studies continue to support the importance
hibitor) treatment reversed the adverse cardiorenal
of aldosterone in the pathophysiology of myocar-
injury and fibrosis. In a murine model Gal-3 gene
dial and renal structural and functional dysfunction
knockout, the cardiorenal actions of aldosterone were
in HF.
abolished. Importantly, in the murine model of Gal-3
Several important points stand out that need
gene deletion, aldosterone failed to increase blood
further investigation: the potential mechanisms of
pressure, so once again, the role of blood pressure and
MRA benefit; the potential differences between the
sodium retention as indirect modulators of cardio-
MRAs that should be further studied; and impor-
renal injury remains to be fully elucidated. Nonethe-
tantly, the interaction between MRAs with novel
less, the authors conclude that an increase in Gal-3
biomarkers. When we think we know it all, we remain
expression with hyperaldosteronism was associated
intrigued by novel and important new insights, as
with cardiac and renal fibrosis and dysfunction, which
provided by the investigators of these 2 important
was prevented by pharmacological inhibition with an
studies.
MRA or with the use of a novel genetic mouse model of Gal-3. The authors appropriately conclude that Gal-3
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
may potentially be a biotarget for MRA intervention.
Mona Fiuzat, Duke University Medical Center, DUMC
These studies are timely and seek to provide insights into the potential mechanisms by which
Box 3356, Durham, North Carolina 27710. E-mail: mona.fi
[email protected].
REFERENCES 1. BrainyQuote.com. Albert Einstein. Available at: http://www.brainyquote.com/quotes/quotes/a/ alberteins121993.html. Accessed October 20,
4. Zannad F, McMurray JJ, Krum H, et al., EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symp-
7. Lax A, Sanchez-Mas J, Asensio-Lopez MC, et al. Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2
2014.
toms. N Engl J Med 2011;364:11–21.
2. Fiuzat M, Schulte PJ, Felker GM, et al. Relationship between Galectin-3 levels and mineralocorticoid receptor antagonist use in heart failure:
5. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized
signaling in left ventricular systolic dysfunction after acute myocardial infarction. J Am Coll Cardiol HF 2015;3:50–8.
analysis from the HF-ACTION study. J Card Fail 2014;20:38–44.
aldactone evaluation study investigators. N Engl J Med 1999;341:709–17.
3. Gullestad L, Ueland T, Kjekshus J, et al. Galectin-3 predicts response to statin therapy in the controlled
6. Brilla CG, Matsubara LS, Weber KT. Antifibrotic effects of spironolactone in preventing myocardial
rosuvastatin multinational trial in heart failure (corona). Eur Heart J 2012;33:2290–6.
fibrosis in systemic arterial hypertension. Am J Cardiol 1993;71:12A–6A.
8. Calvier L, Martinez-Martinez E, Miana M, et al. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries. J Am Coll Cardiol HF 2015;3:59–67.
KEY WORDS biomarkers, mineralicorticoid receptor antagonist, remodeling
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