Author + information
- David A. Morrow, MD, MPH⁎ ( and )
- Michelle L. O'Donoghue, MD, MPH
- ↵⁎Reprint requests and correspondence:
Dr. David A. Morrow, Brigham and Women's Hospital, Cardiovascular Division, 75 Francis Street, Boston, Massachusetts 02115
In the context of a declining rate of deaths due to coronary atherosclerosis, the prevention and management of heart failure (HF) have an emerging dominant role in cardiovascular care. Prognosis with HF is poor, with about 50% 4-year mortality (1), and definitive treatment is challenging, related in part to the heterogeneity of causes. Biomarkers linked to the onset and progression of HF are now of intense clinical and research interest, with several new biomarkers related to HF recently approved for clinical use. In this issue of the Journal, Ho et al. (2) report on one such biomarker, galectin-3 (Gal-3), and the incidence of new HF in apparently healthy Americans.
Gal-3 is a beta-galactoside-binding lectin expressed by activated macrophages and involved in numerous pathological processes, including inflammation, tumor growth, and fibrosis (3). In HF-prone animals, Gal-3 is markedly up-regulated in decompensated HF (4). Increased Gal-3 expression induces cardiac fibroblasts to proliferate and deposit type I collagen, contributing to myocardial fibrosis and adverse remodeling (3). These findings implicate Gal-3 as a possible causal participant in the development of HF.
Gal-3 has been examined as a potential diagnostic and prognostic marker for HF in humans. First studied in established HF, higher concentrations of Gal-3 were associated with an increased risk for death or recurrent HF independent of established risk factors in 4 studies ranging from 232 to 599 patients (5–8). In the largest published study (n = 895), Gal-3 was associated with HF severity and long-term outcomes, but did not add incrementally to natriuretic peptides (9). In the context of these data, Gal-3 was cleared for clinical use for prognostication in patients with established HF. However, Gal-3 does not appear useful for diagnosis of HF in patients with dyspnea (5).
Gal-3 has also been evaluated as a tool to forecast future HF. In a case-control study among patients stabilized after acute coronary syndromes, Gal-3 was associated with the risk for HF over 2 years (10). In a general population-based study of 7,968 subjects followed for 10 years, Gal-3 predicted all-cause death (11). Gal-3 was correlated with age, sex, and cardiovascular risk factors, but not the risk for cardiovascular death, leaving open whether Gal-3 is useful to identify primary prevention candidates at increased risk for developing HF.
To address this question, Ho et al. (2) measured Gal-3 in 3,353 subjects in the Framingham Offspring Cohort. In age-adjusted and sex-adjusted analyses, the risk for new HF over approximately 8 years increased by 28% for each standard deviation increase in log-transformed Gal-3 concentration. This relationship was independent of age, sex, blood pressure, diabetes, and body mass index. However, Gal-3 did not substantially improve on the clinical model for prognostication or discrimination, particularly when considering B-type natriuretic peptide. The investigators also examined the relationships between Gal-3 and left ventricular mass, systolic function, fractional shortening, and left atrial dimension assessed by echocardiography. Higher levels of Gal-3 were associated with increased left ventricular mass but not these other echocardiographic parameters.
The findings of Ho et al. (2) demonstrate for the first time a relationship between Gal-3 and future HF in the general population. Their observations are interesting and raise several questions.
Does this study establish the mechanism by which Gal-3 is associated with HF? Although experimental results implicate a direct contribution of Gal-3 to cardiac fibrosis and the unadjusted association with left ventricular mass in Ho et al's (2) study is supportive, these data leave open whether there is a definite link between Gal-3 and cardiac structural and functional changes in humans. Future studies with cardiac magnetic resonance imaging or positron emission tomography may help elucidate these relationships. Notably, Gal-3 was only weakly correlated with B-type natriuretic peptide (r = 0.05). The lack of an association with natriuretic peptides is consistent with Gal-3 acting as an “early warning” reflecting myocardial changes before the onset of hemodynamic strain. Supporting this concept, Gal-3 is up-regulated in animal models before the development of HF (4). Ho et al did not examine other emerging markers of hemodynamic stress or structural change, including midregional proadrenomedullin, ST2, collagen-related peptides, or high-sensitivity troponin. Also, the investigators hypothesize that renal dysfunction may mediate Gal-3's effects on cardiac remodeling; however, additional investigation should exclude renal function as a mere confounder.
Is Gal-3 sufficiently specific as a biomarker of cardiovascular risk? In this study, Gal-3 appeared to have a stronger association with death from noncardiovascular than cardiovascular causes. Because Gal-3 is common to inflammatory processes, it is up-regulated in varied fibrotic conditions, including of the liver, lung, and kidney (3). This lack of tissue specificity is likely to have implications for consideration of Gal-3 in screening strategies.
Is there sufficient evidence to use Gal-3 for screening of HF risk? The Ho et al. (2) findings are intriguing and add support for a link between Gal-3 and the development of HF in humans, but alone are insufficient to establish a role for Gal-3 in screening apparently healthy individuals. Gal-3 did not provide substantial incremental information for predicting HF when renal dysfunction and B-type natriuretic peptide were considered; nor were other emerging biomarkers of HF reported in their study. In addition, evidence would be needed to determine whether Gal-3 is helpful for guiding effective preventive interventions. In patients with systolic HF, lower levels of Gal-3 appear to identify patients who may benefit from statin therapy (12), and preliminary data suggest interactions with use of angiotensin-converting enzyme inhibitors and device therapy. However, as yet, no interactions between Gal-3 and interventions for HF prevention have been reported. Moreover, the Ho et al. (2) echocardiographic analyses reveal that Gal-3 did not identify patients with early systolic dysfunction, for whom the early initiation of an angiotensin-converting enzyme inhibitor may be useful. Although an association with HF with preserved ejection fraction is important, therapeutic options are even more limited for this syndrome.
Nevertheless, pre-clinical studies suggest that modification of Gal-3 levels may play a role in ameliorating the progression of HF. In a mouse genetic knockout model with significantly lowered Gal-3 expression, cardiac fibrosis is reduced and ventricular function improved. In addition, as described by Ho et al. (2), Gal-3 can be inhibited with modified citrus pectin, as well as other candidates.
The study by Ho et al. (2) is a step forward in the assessment of Gal-3 in cardiovascular disease. Because Gal-3 did not add convincingly to improve discrimination or reclassification of risk, appropriately, the investigators do not argue a role for routine screening. However, their findings lend support to the notion of Gal-3 as a causal factor in human cardiac disease. Further investigation of Gal-3 may lead to advances in our understanding of cardiac fibrosis and remodeling, as well as shine a light toward new therapies for a challenging and increasingly prevalent disease.
The TIMI Study Group of which Drs. Morrow and O'Donoghue are members has received significant research grant support from BG Medicine, Accumetrics, Amgen, AstraZeneca, Beckman-Coulter, Bristol-Myers Squibb, CV Therapeutics, Daiichi Sankyo Co. Ltd., Eli Lilly and Co., GlaxoSmithKline, Integrated Therapeutics, Merck and Co., Merck-Schering Plough Joint Venture, Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, Schering Plough, Siemens Medical Solutions, and Singulex. Dr. Morrow has received consulting fees from Beckman-Coulter, Critical Diagnostics, Genentech, Gilead, Instrumentation Laboratories, Johnson & Johnson, Menarini, Merck, Roche Diagnostics, and Servier. Dr. O'Donoghue has received research grant support from AstraZeneca, Genzyme, and GlaxoSmithKline.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Dickstein K.,
- Cohen-Solal A.,
- Filippatos G.,
- et al.
- Ho J.E.,
- Liu C.,
- Lyass A.,
- et al.
- Sharma U.C.,
- Pokharel S.,
- van Brakel T.J.,
- et al.
- van Kimmenade R.R.,
- Januzzi J.L. Jr.,
- Ellinor P.T.,
- et al.
- Lopez-Andres N.,
- Rossignol P.,
- Iraqi W.,
- et al.
- Felker G.M.,
- Fiuzat M.,
- Shaw L.K.,
- et al.
- Grandin E.W.,
- Jarolim P.,
- Murphy S.A.,
- et al.
- Gullestad L.,
- Ueland T.,
- Kjekshus J.,
- et al.