Galectin-3 in Heart Failure – Linking Fibrosis, Remodelling and Progression
Figure 3: Mortality at 350 Days in 310 Patients Presenting with Acute Decompensated Heart Failure
p=0.0011 for trend 35 30 25 20 15 10 5 0 Figure 4: Kaplan-Meier Curves for Survival
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 200 400 600 800
Gal-3 low/NT-proBNP low Gal-3 low/NT-proBNP high
Time (days)
Gal-3 high/NT-proBNP low Gal-3 high/NT-proBNP high
1 By galectin-3 quartile.
were measured in 599 of these subjects presenting to the emergency department (ADHF was present in 35%).11
2 3 Galectin-3 quartile
Table 2: Multivariate Cox Regression Analysis of Factors Influencing All-cause Mortality up to Four Years
Diagnostically, Gal-3 was
inferior to NT-proBNP (area under the curve 0.72 versus 0.94) for identifying ADHF from other aetiologies. For prognosis, by contrast, Gal-3 was a superior predictor of death or death/recurrent HF at 60 days in a multivariate adjusted analysis of the 209 subjects with HF. Synergism was also seen between Gal-3 and NT-proBNP, with the poorest outcomes for both end-points seen in subjects with elevated levels of both markers.
Recently, the patient cohort was expanded to include multiple centres with additional patients, many of whom are African-American, recruited from urban-based centres, including the University of Maryland and affiliates in Baltimore, as well as the University of California, Davis. Gal-3 and NT-proBNP were measured during the index dyspnoea presentation to the emergency department. In addition, the follow-up time for all-cause mortality was extended to four years. The results of this analysis were presented at the 2009 Heart Failure Society of America (HFSA) meeting.12
population are shown in Table 1 and include 310 patients. The mean age is 68.2±14.4 years, 39% are female, 69% are Caucasian and 79% have either New York Heart Association (NYHA) class III or IV HF. Compared with NT-proBNP, Gal-3 level appears to be less influenced by severity of symptoms (see Figure 2). However, despite only a modest relationship with presenting symptoms, Gal-3 shows a graded association with all-cause mortality. At approximately one year into follow-up, subjects with the Gal-3 levels in the lowest quartile (22.3ng/ml; see Figure 3). Importantly, Gal-3 levels continued to work synergistically with NT- proBNP levels for prediction of all-cause mortality in this heterogeneous cohort with extended follow-up. Kaplan-Meier curves based on receiver operator curve optimal cut-off levels for both markers show that the best prognosis was for those subjects with low
EUROPEAN CARDIOLOGY Variable
Log (Galectin-3) Age
Log (CRP) NYHA class
Log (NT-proBNP) Log (creatinine) Gender
Race, black Race, Hispanic
Hazard Ratio (95% CI) 2.18 (1.36, 3.51) 2.30 (1.45, 3.67) 1.18 (1.04, 1.35) 1.36 (1.05, 1.77) 1.21 (1.02, 1.42) 0.81 (0.46, 1.43) 1.05 (0.71, 1.54) 1.78 (0.90, 1.45) 0.76 (0.23, 2.44)
χ2
10.5 12.5 6.5 5.5 4.9 0.5 0.1 1.9 0.1
p-value 0.001
0.0004 0.011 0.019 0.026 0.4 0.8
0.079 0.6
Data for patients initially presenting with acute decompensated heart failure. For age, hazard ratio is relative to younger category (age ≤69 years). For race, hazard ratios are relative to Caucasian race category. For gender, hazard ratio is relative to female gender. For New York Heart Association (NYHA), hazard ratio is per increasing NYHA class. BMI = body mass index; CRP = C-reactive protein; NT-proBNP = N-terminal prohormone brain natriuretic peptide.
The baseline characteristics of the
levels of both markers and the poorest prognosis was in those subjects with elevated levels of both tests (see Figure 4). Importantly, an elevated Gal-3 identified subjects at increased risk despite a low NT- proBNP level. To confirm that Gal-3 levels remained independent of demographic factors, symptom status, generalised inflammation (as represented by C-reactive protein level) and NT-proBNP, a Cox multivariate analysis was performed on this expanded cohort over the duration of follow-up (see Table 2). Gal-3 was one of the most powerful predictors of mortality, with a hazard ratio of 2.18 per log unit for all- cause death with an associated χ2 of 10.5 (p=0.001) compared with NT- proBNP and a hazard ratio of only 1.21 per log unit with an associated χ2 of 4.9 (p=0.026).
Gal-3 has also been studied in chronic stable HF populations. The Deventer–Alkmaar heart failure study (DEAL-HF) included a total of 240 patients (232 with Gal-3 measured) with stable NYHA functional class III or IV HF who were randomised between 2000 and 2003 to a disease management programme or standard of care. The primary end-points were all-cause mortality and hospitalisation for HF over 12 months. Lok
35 4
By combined galectin-3 (Gal-3) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) categories. Receiver operating characteristic (ROC)-curve-derived cut-points for markers 12.4ng/ml for Gal-3 and 5,876pg/ml for NT-proBNP.
n=58
n=90 n=28
n=94 1,000 1,200 1,400 1,600
Mortality at 350 days (%)
Survival
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