Author + information
- ↵∗Reprint requests and correspondence:
Dr. Mona Fiuzat, Duke University Medical Center, DUMC Box 3356, Durham, North Carolina 27710.
“We cannot solve our problems with the same thinking we used when we created them.”
—Albert Einstein (1)
With 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 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 be associated with these effects provide new insights. In the paper by Lax et al. (7), the investigators find 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 β, 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 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 actions of MRAs may be a class effect, but may also have slightly different interactions with these markers, in view of the findings with 2 MRAs in the elegant study by Lax et al. (7). It would, however, have been of interest to know more about the kidney, especially if there was a natriuretic and cardiac unloading action via such actions on intravascular volume.
In the paper by Calvier et al. (8), hyperaldosteronism was induced in a rat model, with resultant renal and cardiac hypertrophy and fibrosis, and the mechanistic role of Gal-3 in such cardiorenal injury was explored. Spironolactone or modified citrus pectin (a Gal-3 inhibitor) treatment reversed the adverse cardiorenal injury and fibrosis. In a murine model Gal-3 gene knockout, the cardiorenal actions of aldosterone were abolished. Importantly, in the murine model of Gal-3 gene deletion, aldosterone failed to increase blood pressure, so once again, the role of blood pressure and sodium retention as indirect modulators of cardiorenal injury remains to be fully elucidated. Nonetheless, the authors conclude that an increase in Gal-3 expression with hyperaldosteronism was associated with cardiac and renal fibrosis and dysfunction, which was prevented by pharmacological inhibition with an MRA or with the use of a novel genetic mouse model of Gal-3. The authors appropriately conclude that Gal-3 may potentially be a biotarget for MRA intervention.
These studies are timely and seek to provide insights into the potential mechanisms by which MRAs protect against post-MI induced HF, with a focus on expression of myocardial genes which are linked to fibrosis and inflammation, as well as molecular mechanisms of myocardial remodeling. These studies continue to support the importance of aldosterone in the pathophysiology of myocardial and renal structural and functional dysfunction in HF.
Several important points stand out that need further investigation: the potential mechanisms of MRA benefit; the potential differences between the MRAs that should be further studied; and importantly, the interaction between MRAs with novel biomarkers. When we think we know it all, we remain intrigued by novel and important new insights, as provided by the investigators of these 2 important studies.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Fiuzat has received research funding from BG Medicine, Critical Diagnostics, Roche Diagnostics; and has served as a consultant to Roche Diagnostics (minimal). Dr. Burnett has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵BrainyQuote.com. Albert Einstein. Available at: http://www.brainyquote.com/quotes/quotes/a/alberteins121993.html. Accessed October 20, 2014.
- Gullestad L.,
- Ueland T.,
- Kjekshus J.,
- et al.
- Lax A.,
- Sanchez-Mas J.,
- Asensio-Lopez M.C.,
- et al.
- Calvier L.,
- Martinez-Martinez E.,
- Miana M.,
- et al.