Serial Galectin-3 Levels Strongly Predict HF, CVD Outcomes

Patrice Wendling

January 02, 2019

New research supports repeated measurement of galectin-3 (Gal-3), a biomarker of cardiac fibrosis and inflammation, to identify persons in the general community at risk of developing heart failure (HF) and cardiovascular disease (CVD).

Senior author Jennifer Ho, MD, Massachusetts General Hospital, Boston, and colleagues examined two Gal-3 measurements taken over the span of about a decade in more than 2000 participants in the Framingham Heart Study Offspring Cohort.

They found that a 1-standard deviation (SD) rise in log-Gal-3 levels, corresponding to a 3.3 ng/mL change, was associated with a 39% higher risk of new-onset HF after multivariable adjustment (hazard ratio [HR], 1.39; P = .0021).

This association extended to both HF with preserved and reduced ejection fraction (HR, 1.39 and 1.42; P value for both < .05).

Change in Gal-3 was also independently associated with a 29% increased risk of incident CVD (HR, 1.29; P = .001) and a 30% increased risk of all-cause mortality adjusted for prevalent HF (HR, 1.30; P < .0001).

Further, change in Gal-3 remained predictive of HF, CVD, and mortality even after further adjustment for baseline B-type natriuretic peptide levels.

"Previously, we've shown that a single measurement of galectin-3 predicts your future risk of heart failure," Ho said. "What's new is that we think serial measurements of galectin-3 may refine our understanding of future heart failure, cardiovascular risk above and beyond just a single measurement."

The study was published on December 17 in the Journal of the American College of Cardiology.

"The current study suggests that galectin-3 might be poised for clinical use to risk-stratify patients and intervene prior to the onset of symptomatic disease," G. Michael Felker, MD, MHS, Duke Clinical Research Institute, Durham, North Carolina, and Tariq Ahmad, MD, MPH, Yale University School of Medicine, New Haven, Connecticut, write in an accompanying editorial.

That said, they note that the first article to show Gal-3 levels had prognostic value in HF was published in 2006. Despite more than 700 publications now available on Gal-3 and soluble ST2, another biomarker cleared for use in HF, only incremental steps have been taken toward incorporating novel biomarkers into clinical practice.

"There is a serious need for greater objectivity at the bedside of cardiac patients, something that biomarkers such as galectin-3 can provide, allowing us to move past subjective measures of disease that continue to dictate clinical decision making," Felker and Ahmad said.

Clinical Correlates

To identify clinical determinants of change in Gal-3 among the 2477 study participants (mean age, 57 years; 55% women) with Gal-3 assessed at two examinations (1995 to 1998 and 2005 to 2008), the researchers used linear regression models adjusting for age, sex, and baseline Gal-3 levels at the earlier exam.

Between the two examinations, 39 participants developed HF, 108 developed CVD, and 198 developed chronic kidney disease (CKD). Over a mean follow-up of 7.8 years, 108 persons developed incident HF. Gal-3 levels changed in most participants over time, with more than 30% showing a greater than 20% change from baseline.

Older age, female sex, lower baseline Gal-3 levels, systolic blood pressure, current use of antihypertensive medications, diabetes, body mass index, smoking, baseline CVD, and baseline CKD were associated with greater increases in Gal-3 over a 10-year period.

The largest increases in Gal-3, however, occurred with intervening events including the development of HF and CKD, which were significantly associated with 17% and 19% increases in Gal-3, respectively (P for both < .0001). The development of CVD did not predict change in Gal-3.

The clinical correlates of change in Gal-3 are in keeping with prior studies but extend those findings by showing that diabetes and obesity are also associated with a rise in Gal-3 over nearly a decade, Ho noted.

Changelings

As one might expect, participants with consistently high levels of Gal-3 had a higher risk of developing HF compared with those with persistently low levels (HR, 2.28; P = .005).

Individuals who switched from low levels of Gal-3 at the first exam to high levels at the later exam, however, had an 82% increased risk of developing HF (HR, 1.82; P = .04).

"Conversely, and these are maybe the most interesting people, people who actually had high levels at baseline where we would have initially said you're at high risk of heart failure, if they are somehow able to lower their galectin-3 and have a low measure at the second time point, they were actually at low risk for heart failure," Ho said. Indeed, their hazard ratio for HF was 0.47 (P = .21).

Although not significant, progression of Gal-3 levels from low to high was associated with a 43% increase in CVD risk (HR, 1.43), while the opposite was seen when levels dropped from high to low at the later exam (HR, 0.86).

"What I think is exciting — and why I've kept studying galectin-3 even though it hasn't necessarily come into wide clinical practice — is if there's a way for us to potentially have a pathway to target in patients who are at high risk for future heart failure," Ho said. "That I think is really exciting and makes us think about disease prevention mechanistically in a very different way."

Biomarker Barriers

Felker and Ahmad point out that natriuretic peptides and high-sensitivity troponin are strong predictors of incident HF and that natriuretic peptide-guided prevention trials, such as STOP-HF and PONTIAC, have yielded significant reductions in incident HF.

There is also a compelling biological argument for including Gal-3 in the list of promising biomarkers for guiding primary prevention in heart disease, as the mechanisms that drive elevations in Gal-3 (fibrosis) are distinct from those that trigger rises in natriuretic peptides (myocardial stress) or troponin (myocardial injury).

Nevertheless, the editorialists said several steps must be taken to progress to a future of precision HF prevention where multiple biomarkers are measured in patients to assess their global risk and targeted interventions delivered to diminish that risk.

"First, we must generate new knowledge on the feasibility, efficacy, and cost-effectiveness of this approach," Felker and Ahmad said. "We still do not know if management of known risk factors guided by multiple biomarker levels can lead to prevention of heart failure; such a concept requires more clinical evidence and a better understanding of how levels of circulating markers reflect pathophysiologic processes."

"Second, we must address the barriers to bedside implementation of heart failure biomarkers that have led to a disconnect between a robust scientific enterprise and somewhat insipid clinical uptake," they said.

Ho said it is unclear how to overcome these barriers, but reiterated the value of thinking of Gal-3 not for risk prediction on a population-based level but as reflective of underlying mechanism.

"I think the term personalized medicine is probably a little overused, but if we can identify a specific mechanism at play in a given patient, we can then go after it," she said. "Galectin-3 is a pathway that can be inhibited."

In animal models, genetic disruption or pharmacological inhibition of Gal-3 prevents the development of HF. The researchers also recently completed enrollment of a small, randomized study of Gal-3 blockade with 5 grams thrice daily of modified citrus pectin or placebo in 59 patients with hypertension. Initial results may be available later this year, Ho said.

Gal-3 assays were provided by BG Medicine. The work was partially supported by the National Heart, Lung, and Blood Institute (NHLBI). Ho is supported by National Institutes of Health grants and by a Hassenfeld Research Scholar award from Massachusetts General Hospital, and has received research supplies from EcoNugenics. Felker has received grant support from the NHLBI, American Heart Association, Roche Diagnostics, Novartis, Merck, Amgen, and Cytokinetics; and has served as a consultant for Amgen, Medtronic, Bristol-Myers Squibb, Novartis, Cytokinetics, Roche Diagnostics, MyoKardia, Innolife, Cardionomic, EBR Systems, V-Wave, and SC Pharma. Ahmad has reported no relevant financial relationships.

J Am Coll Cardiol. 2018;72:3246-3254, 3255-3258. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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