Heart failure is a syndrome of dyspnea and fatigue coupled with signs of impaired left ventricular filling or emptying. There are numerous etiologies of heart failure, including processes affecting the pericardium, myocardium, and valves. Heart failure imposes a heavy burden on individuals and society. The prevalence of heart failure in the United States is approximately 5.8 million,⁽¹⁾ with 56,565 attributable deaths in 2007.⁽²⁾ Estimates by the American Heart Association of annual direct healthcare costs associated with heart failure are $24.7 billion, with an additional $9.7 billion in annual indirect costs due to lost productivity.⁽³⁾

Serologic tests aiding in the diagnosis and management of heart failure have garnered considerable attention. Two serum biomarkers have gained widespread acceptance in the diagnosis of patients with heart failure: brain natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP). A link between levels of BNP and NT-proBNP and increased mortality has been established.^{(4, 5)} However, additional prognostic information with possible therapeutic implications beyond that provided by natriuretic peptides is being sought and may be found in the form of galectin-3 (gal-3).

Gal-3 is a β-galactoside-binding lectin 30 kD in size that is expressed and secreted by macrophages.⁽⁶⁾ It has been describe in both the cytoplasm and nuclei of cells, and interacts both extra- and intracellularly.⁽⁷⁾ Gal-3 appears to play an important role in the cardiac remodeling observed in heart failure. It first came to attention in animal studies searching for potential mediators of decompensated heart failure. A microarray analysis of gene expression in heart-failure prone rat myocardium progressing to early heart failure showed a greater than 5-fold increase in gal-3 expression compared to rats that remained compensated.⁽⁸⁾ Subsequently, Sharma et al. found increased expression of gal-3 in failure-prone rat myocardium as compared to compensated rats and controls.⁽⁹⁾ Further analyses by Sharma et al. demonstrated areas of myocardial fibrosis with colocalization of macrophages only in rats with heart failure; the compensated and control subjects remained fibrosis free.

Similar findings were also seen in a small cohort of human subjects undergoing aortic valve replacement. Gal-3 levels were compared in samples from patients with preserved and depressed LVEF. Relative expression of gal-3 was found to be 7.1+/-1.2 in depressed LVEF and 4.6+/-0.5 in preserved LVEF subjects (p<0.05). For comparison, samples from patients undergoing CABG without evidence of heart failure had the lowest relative expression of gal-3 mRNA: 3.4+/-0.21.⁽⁹⁾

The direct cardiac effects of gal-3 were also investigated by Sharma et al. by infusing gal-3 into the pericardial space of healthy rats.⁽⁹⁾ There was a significant decline in LVEF in the gal-3 infusion group compared to the control cohort (Table 1). Furthermore, there was an increase in total collagen and a skewing of the type I to type III collagen ratio toward type I in rats receiving intrapericardial gal-3. Type III collagen has elastic properties that facilitate elastic recoil, whereas type I collagen is a stiff protein with limited elasticity.^{(10, 11)} This phenomenon may help explain the impaired left ventricular relaxation often seen in heart failure.

Table 1: Comparison of Statistically Significant Echocardiographic Changes After Intrapericardial Infusion of Placebo or Galectin-3.(9) Echocardiographic measurements Placebo Galectin-3 LVEF (%) Baseline 67.3±2.5 66.1±1.6 Post-infusion (4 weeks) 66.0±0.4 51.8±3.1 Fractional Shortening (%) Baseline 0.31±0.02 0.29±0.03 Post-infusion (4 weeks) 0.27±0.01 0.33±0.05

Galectin 3 is readily measured from both serum and EDTA plasma samples with acceptable precision and accuracy.⁽¹²⁾ Several studies have examined the diagnostic and prognostic utility of gal-3 in heart failure and are summarized in Table 2. The first large study involved data from the PRIDE (Pro-BNP Investigation of Dyspnea in the Emergency Department) study.⁽¹³⁾ 599 subjects with acute shortness of breath were assigned a diagnosis of heart failure (n=209 (35%)) or noncardiac dyspnea and were followed for 60 days. Median concentrations of NT-proBNP and gal-3 were found to be significantly higher in patients with acute heart failure versus those without (NT-proBNP: 4,054 vs. 131 pg/ml, p<0.001; gal-3: 9.2 pg/ml vs. 6.9 pg/ml, p<0.001). Receiver-operator curves (ROC) constructed showed superiority of NT-proBNP relative to gal-3 in the diagnosis of acute heart failure (AUC: NT-proBNP 0.94, gal-3 0.72).

Table 2: Summary of Clinical Studies Examining Prognostic Utility of Gal-3 Study Subjects Outcome van Kimmenade et al.(13) 209 patients with acute HF followed for 60 days (subgroup of PRIDE study) Increased predictive power of 60-day mortality for gal-3 compared to NT-proBNP. (AUC: gal-3 0.74; NT-proBNP 0.67; p=0.05). For high gal-3: OR 10.3 (P<0.01) for death and OR 14.3 (P<0.001) for death/recurrent HF within 60 days Shah et al.(14) 105 patients with acute HF who underwent complete echocardiogram at presentation followed up to 4 years (subgroup of PRIDE study) High levels of gal-3 are a predictor of 4-year mortality independent of LV or RV function, with a HR (gal-3 > 14.97 ng/ml) of 5.5 (95% CI 2.0-15.0) Lok(15) 232 patients with NYHA class III-IV HF followed for 12 months (subgroup of DEAL-HF study) Elevated gal-3 in subjects who died compared to the 12-month survivors (20.1+/-8.1 ng/ml vs. 17.5+/-7.4 ng/ml, p=0.01). ROC analysis showed an AUC of 0.612 (p=0.004) for 12-month mortality, compared to 0.611 (p=0.004) for NT-proBNP. de Boer et al.(16) 592 patients hospitalized for HF with preserved or reduced LVEF followed for 18 months (subgroup of COACH study) Increasing hazard ratio in each quartile of gal-3 level (compared to lowest quartile) for death or HF hospitalization: 2nd HR 1.98 (CI 95% 1.29 - 3.02), 3RD HR 2.66 (95% CI 1.76 - 4.03), and 4th HR 3.34 (CI 2.23 - 5.01). Increased incremental risk for primary endpoint in patients with preserved LVEF compared to reduced LVEF. deFilippi and Felker(17) 310 HF patients presenting to ED followed for up to 4 years Increased all-cause mortality with high gal-3 over 350 days: 10.3% in the lowest quartile (gal-3 < 12.0 ng/ml); 32.5% in the highest quartile (gal-3 > 22.3 ng/ml). For 4-year mortality, HR for gal-3 was greater than NT-proBNP: HR per gal-3 log unit of 2.18 (95% CI 1.36-3.51) vs. HR per NT-proBNP log unit of 1.21 (95% CI 1.02-1.42) Ueland et al.(18) 168 patients with stable HF followed for mean of 2.9 years Higher gal-3 levels at baseline were associated with increased age, higher likelihood of NYHA class IV, lower exercise capacity, increased wall motion abnormality on echo, and higher creatinine, CRP, NT-proBNP, and WBC count. Felker et al.(19) 895 patients with LV systolic dysfunction and NYHA II-IV symptoms, with mean follow-up of 2.5 years (subgroup of HF-ACTION study) Incremental increase in hospitalizations with rising gal-3 (HR 1.10 per 5 ng/ml increase in gal-3, p<0.0001) Tang et al.(22) 133 patients with chronic stable systolic HF and 45 patients with advanced decompensated HF followed up to 5 years Increased mortality with climbing gal-3 (HR 1.87, 95% CI 1.36 - 2.55). Correcting for age, eGFR, NT-proBNP, cystatin C, and multiple echo parameters did not negate predictive power of gal-3 on mortality.

However, gal-3 demonstrated significant prognostic power for 60-day mortality, with higher initial gal-3 levels found in subjects who died during the 60-day follow-up period (median 12.9 ng/ml, interquartile range [IQR] = 9.3-16.5) compared to survivors (median 9.0 ng/ml, IQR = 7.3-11.6, p<0.001).⁽¹³⁾ Examination of the ROC for 60-day mortality demonstrated superiority of gal-3 compared to NT-proBNP in predicting survival (AUC: gal-3 0.74; NT-proBNP 0.67; p=0.05).

A separate subgroup analysis in 115 patients who had echocardiographic data available who were enrolled in the PRIDE study examined the relationship between gal-3 levels, echocardiographic findings, and mortality.⁽¹⁴⁾ During four-year follow-up, subjects with acute decompensated heart failure exhibited greater cardiac remodeling with corresponding left ventricular hypertrophy, reduced LVEF, and evidence of diastolic dysfunction. Evidence of right heart failure also correlated with increased gal-3. Gal-3 remained an independent predictor of 4-year mortality, with a median hazard ratio (gal-3 >14.97 ng/ml) of 5.5 (95% CI 2.0-15.0, p=0.001).⁽¹⁴⁾

A subgroup analysis of the DEAL-HF (Deventer-Alkmaar heart failure) study⁽¹⁵⁾ followed 240 patients for 12 months, with a primary endpoint of all-cause mortality and hospitalization for heart failure. Baseline gal-3 values were available for 232 of the 240 subjects. Gal-3 levels were significantly higher in subjects who died (n=98) compared to the 12-month survivors (20+/-8.1 ng/ml vs. 17.5+/-7.4 ng/ml, p=0.01). Adjustment for baseline characteristics and NT-proBNP had minimal effect on the predictive power of gal-3. The combination of high initial gal-3 and NT-proBNP had the highest predictive, yielding a 1.5 to 2 fold increase in mortality (p=0.036).

The COACH (Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) study⁽¹⁶⁾ underscores the prognostic utility of gal-3 in heart failure mortality. Approximately half of the patients enrolled in COACH underwent gal-3 testing during their index admission (592/1,023) and were followed for a mean duration of 18 months. Patients were also grouped based on LVEF: heart failure with preserved EF (HF-PEF) if they had a LVEF > 40% (n=107) or heart failure with reduced EF (HF-REF) if they had a LVEF of ≤ 40% (n=485). Hazard ratios for the primary outcome of death or heart failure hospitalization were calculated based on quartiles of the initial gal-3 measurements using the first quartile as the reference group. Progressively increasing hazard ratios were found with rising gal-3: 1.98 (95% CI 1.29-3.02) in the 2^nd quartile to 3.34 (95% CI 2.23-5.01) in the 4^th. The effects of age, gender, and BNP were negligible, though accounting for renal function and the presence of diabetes mellitus yielded modest reductions in the predictive power of gal-3. Comparison of the HF-PEF and HF-REF groups revealed significant differences in the predictive power of gal-3 based on LVEF. Comparable elevations in gal-3 were found to carry a higher incremental risk of reaching the primary endpoint in patients with HF-PEF than in subjects with HF-REF.⁽¹⁶⁾ No predictive benefit was identified with serial measurements of gal-3. In fact, levels remained stable over a 6-month period.⁽¹⁶⁾

Additional cohorts published by deFilippi and Felker,⁽¹⁷⁾ and Ueland et al.⁽¹⁸⁾ have also demonstrated a link between gal-3 and mortality in heart failure patients for follow-up periods as long as four years. At approximately one year, the mortality rate was 10.3% in the lowest quartile of gal-3 measurements (gal-3 < 12.0 ng/ml) compared to 32.5% in the highest quartile (gal-3 >22.3 ng/ml) in a group of heart failure patients presenting to the emergency department with acute dyspnea.⁽¹⁷⁾ The same study revealed a hazard ratio per gal-3 log unit of 2.18 (95% CI 1.36-3.51, p=0.001) compared to a hazard ratio per NT-proBNP log unit of 1.21 (95% CI 1.02-1.42, p=0.026) over the course of four years. Felker et al. have also shown gal-3 to be a useful predictor of hospital-free survival in the HF-ACTION cohort, with a hazard ratio of 1.10 per 5 ng/ml rise in gal-3 (p<0.0001).⁽¹⁹⁾

Gal-3’s effects on inflammation fibrosis are not limited to the heart. Elevated levels of gal-3 have been identified in renal failure, cirrhosis, and pulmonary fibrosis.^{(6, 20, 21)} Tang et al. have explored the potential role of gal-3 in the cardio-renal syndrome.⁽²²⁾ In cohorts of patients with either chronic systolic or acute decompensated heart failure, increasing gal-3 levels and mortality were again seen. As in the DEAL-HF and PRIDE studies,^{(13, 15)} increased gal-3 levels were also evident in the setting of impaired renal function.

Small studies of gal-3 as a therapeutic target have also been conducted. T-3999, a novel phenylpyridazinone derived from type IV phosphodiesterase III inhibitors, has decreased mortality and lower levels of inflammatory markers, including TGF-β and gal-3, in mice with dilated cardiomyopathy compared to placebo.⁽²³⁾ However, the widespread effects on inflammation suggest that this agent may have general anti-inflammatory effects not specific to gal-3. Direct inhibition of gal-3 has shown promise in the treatment of several forms of cancer,^(24-26) and may one day expand to the realm of heart failure.

Natriuretic peptides have gained widespread use in diagnosis and management of heart failure. However, novel biomarkers such as gal-3 may provide additional information and therapeutic targets in the future. Though its diagnostic power in acute decompensated heart failure is trumped by NT-proBNP, gal-3 may prove to be a therapeutic target. Ultimately, a combined approach, applying multiple tests simultaneously, may provide the most useful information.^{(13, 15-17, 19)} Further studies are needed to examine the role of gal-3 in the management of heart failure.

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Keywords: Cardiomyopathy, Dilated, Diabetes Mellitus, Dyspnea, Follow-Up Studies, Heart Failure, Inflammation, Pulmonary Fibrosis, Biomarkers, Hypertrophy, Natriuretic Peptide, Brain, Collagen Type I, Collagen Type III, Galectin 3, Cardio-Renal Syndrome, American Heart Association, Cost of Illness, Health Care Costs, Heart Failure

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