New Laboratory Tests

Galectin-3: the first novel cardiovascular in-vitro diagnostic in 5 years.

By Pieter Muntendam MD, President & CEO, BG Medicine, Inc.

Heart failure (HF) is one of the most important medical conditions in the Western World, responsible for more loss of life and hospitalizations than all common cancers combined1-3. Over the past 15 years a growing body of literature points to the importance of fibrosis in the development and progression of HF4-7. In 2004 two important discoveries implicated galectin-3 in HF development: firstly, gene transcripts in the myocardium were studied in the Ren-2 rat HF model. Up-regulation of the galectin-3 gene (Lgals3) best predicted HF development4,8. The follow-up observation that administeration of purified galectin-3 in an experimental model induced fibrosis in the myocardium, thereby reducing cardiac output, led to the hypothesis that galectin-3 was a mediator of the fibrotic form of HF4. If it could be measured in plasma a simple blood test could identify patients with HF on the basis of active fibrosis.

In November 2010 the FDA cleared the assay to measure galectin-3 in plasma or serum. This was the first novel cardiovascular in-vitro diagnostic to be cleared by the FDA in >5 years and marks the first clinical application derived from the galectin-3 research. Galectin-3 has since been the subject of over 1,500 scientific articles9. It is a member of a family of proteins that bind to certain specific carbohydrates via a carbohydrate recognition domain (CRD), which generally inactivates the protein10. This built-in on-off switch is an important reason for the enthusiasm in the scientific community because of the potential for novel therapeutics.

Galectin-3 levels measured in over 1000 volunteers age 55+ years followed a close to normal distribution. Heart failure patients with levels >17.8 ng/mL had increased risk for hospitalization and death, after adjusting for established factors such as age, gender, NYHA class and ejection fraction. Approximately 30-50% of patients with HF have elevated levels of galectin-311-19.

Natriuretic peptides (e.g. BNP, NT-proBNP) reflect cardiac overload and stretch12,13,18. Galectin-3 is related to an underlying disease process and is unaffected by the degree of decompensation19. Combining the two tests enhances clinical utility; patients with low levels of both biomarkers have the best prognosis, while patients with elevated levels of both the worst. If one but not the other is elevated patients have an intermediate risk. For use as prognostic markers they are independent and complementary14,15.



Prognostic information alone maybe clinically useful e.g for decisions regarding referrals, discharge planning and selection for tele-monitoring or disease management. However, based on the biology it is possible that patients with low levels of galectin-3 may respond differently to certain drugs. If confirmed, this would strengthen the concept of categorizing patients with HF based on biomarkers; for galectin-3, the identification of a sub-group of patients with an inherently progressive form of HF characterized by high levels of fibrogenesis17,20.

Heart failure is generally considered an end stage disease that has an insidious onset. In most patients this is preceded by conditions such as ischemic heart disease or chronic hypertension. However, only a minority of patients with these pre-existing conditions develop HF. Based on the biology of the disease process it is likely that galectin-3 elevation precedes the onset of HF symptoms. If so, measurement of galectin-3 could identify those with highest near-term risk. A recent case-control study in patients with acute coronary syndrome confirmed that elevated levels are associated with an increased likelihood of subsequently developing HF21. If confirmed, galectin-3 could be used to identify those at risk for HF development and for the first time provide a model of secondary HF prevention.

Probably the most intriguing discovery is that galectin-3 can be inhibited by natural carbohydrates derived from dietary pectins, present in the vegetables and fruits we eat22,23. In animal experiments, these natural carbohydrates bind to the galectin-3 CRD and inhibit galectin-3 dependent fibrogenesis, perhaps explaining why a diet rich in fruits and vegetables reduces HF incidence24. This is important for all, but in particular those patients with chronic conditions such as high blood pressure, lipid disorders, and diabetes who are found to have elevated levels of galectin-3.

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