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Using galectin-3 to reduce heart failure rehospitalization
Yang Xue1, Alan Maisel1 & W Frank Peacock*,2
ABSTRACT: Increasing attention is being paid towards reducing short-term heart failure readmissions in recent years. Biomarkers such as galectin-3 are likely to play pivotal roles in future heart failure management strategies as they can provide objective information on various pathophysiologic processes involved in heart failure. Galectin-3 is a biomarker of inflammation and fibrosis, which is strongly associated with adverse remodeling of the myocardium and subsequent left ventricular dysfunction. Clinically, elevated galectin-3 levels are associated with increased risk for short- and long-term risk for mortality and heart failure readmission. Galectin-3 can provide incremental predictive value for adverse events over natriuretic peptides. Although significant work is still required to further define the role of galectin-3, it has the potential to become an important part of future heart failure management algorithms by helping to provide an individualized risk profile, which can be used to optimize resource allocation and improve treatment outcomes. In recent years we have seen a significant shift in the management of heart failure (HF). Increasing emphasis is being placed on reducing HF-related hospitalizations, especially short-term readmission. This change largely stemmed from the increasing healthcare burden of HF management. In the last decade, both the prevalence and the incidence of HF have been steadily increasing. According to recent reports, there are almost 6 million patients with HF in the USA alone, with over 600,000 new cases of HF diagnosed each year. Among the elderly, HF is the number one reason for hospitalizations [1] . Furthermore, HF hospitalizations are associating with significant mortality and morbidity. Up to 25% of patients hospitalized for HF are readmitted within 30 days and 30% die within one year of the index HF admission [2,3] . On average, US$13,000 is spent per year on each HF patient with over half of the money spent on HF hospitalizations [4] . With increasingly limited resources available for the management of this growing healthcare challenge, there is a pressing need for better risk stratification and novel therapies to improve both short-term and long-term HF treatment outcomes, and reduce the per-patient cost of HF management. As HF is a complex disease process, improving treatment outcomes would require a multifaceted approach. Some HF management strategies attempted to improve compliance with the guidelines recommended therapies with a moderate degree of success [5] . Other strategies sought to improve patient education and provide intense outpatient monitoring with limited results [6] . It is becoming increasingly clear that due to the complexity of the pathophysiology of HF, an individualized approach is required to improve outcomes. This individualized approach for HF management hinges on accurate prognostic evaluation and tailored therapies based on an individual’s risk. While traditional risk stratification strategies using clinical predictors are useful from a population
KEYWORDS
• galectin-3 • heart failure • natriuretic peptides • prognosis • rehospitalization
Division of Cardiology, University of California San Diego, La Jolla, CA, USA Department of Emergency Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA *Author for correspondence: Tel.: +1 216 312 3292; [email protected] 1 2
10.2217/FCA.14.9 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 221–227
part of
ISSN 1479-6678
221
Special Report Xue, Maisel & Peacock standpoint, their effectiveness on an individual basis is quite limited [7] . Biomarkers representing different pathophysiological processes can be a very effective addition to traditional risk stratification models [8] . They can provide an individualized risk profile and help clinicians to focus resources on the patients with high risk for adverse outcomes. Galectin-3 & the pathophysiology of HF In recent years, many new HF biomarkers have emerged. Among them, galectin-3 is one of the most promising [9] . It is strongly associated with the risk of developing HF [10] . Galectin-3 is a 29–35-kDa chimaera-type galectin, which is present in many tissues [11] and has been linked to the development of HF, renal fibrosis and malignancies [9,12,13] . Galectin-3 is a product of many cell types including activated macrophages. Extracellularly, galectin-3 is an import mediator of macrophage cell migration and cell–cell interactions [14] . Intracellularly, galectin-3 is a regulator of cell cycle and apoptosis [15–17] . Galectin-3 has been associated with macrophage activation, extracellular collagen synthesis and tissue fibrosis [18] . In the heart, elevated galectin-3 levels are a strong indicator of cardiac fibrosis and adverse myocardial remodeling [19] . Galectin-3 is an important link between the inflammatory process in early-stage HF and fibrosis in latestage HF [20] . In HF patients, overexpression of galectin-3 leads to enhanced proliferation of fibroblasts, which promotes collagen deposition and tissue fibrosis. Overexpression of galectin-3 is also associated with elevated levels of type III N-terminal propeptide of procollagen, metallopeptidase inhibitor 1 and matrix metalloproteinase 2, supporting galectin-3’s role as a promoter of extracellular matrix turnover and tissue fibrosis [21] . Mice with decreased galectin-3 levels through gene knockout or pharmacologic inhibition had significantly less fibrosis and left ventricular dysfunction as a result of angiotensin II infusion when compared with wild-type mice [20] . On the other hand, recombinant galectin-3 infusion into the pericardium was associated with excess collagen deposition in the myocardium and cardiac dysfunction [10] . Clinically, serum levels of galectin-3 can be measured by a US FDA-approved ELISA [22] . Galectin-3 & the development of HF In clinical practice, since elevated galectin-3 level is associated with cardiac fibrosis and subsequent
222
Future Cardiol. (2014) 10(2)
development of HF, galectin-3 may be used identify individuals at high risk for HF long before the onset of overt HF symptoms. High galectin-3 levels were also associated with clinical risk factors for HF (age, NYHA class, VO2 max) and elevated HF biomarkers (b-type natriuretic peptide [BNP] N-terminal prohormone B-type natriuretic peptide [NT-proBNP] and C-reactive protein) [23] . In patients with acute coronary syndrome (ACS), elevated galectin-3 levels showed a graded association with subsequent development of HF. In a secondary analysis of the PROVE-IT TIMI 22 trial, patients who developed HF had significant higher galectin-3 levels compared with patients who did not develop HF (16.7 vs 14.6 µg/l; p = 0.004). Patients in the highest galectin-3 quartile had a 3.6-times higher risk for developing HF compared with patients in the lowest quartile (p = 0.003). Galectin-3 was an independent predictor of developing HF after adjustment for hypertension, diabetes and prior MI [24] . Elevated galectin-3 levels have also been associated with adverse remodeling in patients with NYHA class III/IV HF on serial echocardiograms performed 3 months apart. Patients who had adverse remodeling had significantly higher baseline galectin-3 levels (19.0 vs 14.7 µg/l; p = 0.004). Galectin-3 was not only an independent predictor of adverse remodeling after adjusting for gender, etiology of HF, NYHA-class and duration of HF, but also a better predictor of adverse remodeling than NT-proBNP (AUC = 0.66; p = 0.002 vs AUC = 0.572; p = 0.14) [25] . ●●Galectin-3 & HF prognosis
An elevated galectin-3 level is not only a risk factor of development HF, but also a potent prognostic biomarker in patients with HF. In the PRIDE study, patients who died within 60 days of a HF hospitalization had significantly higher galectin-3 levels compared with survivors (12.9 vs 7.3 ng/ml). In multivariate models that included NT-proBNP, age, glomerular filtration rate (GFR) and NYHA functional class, galectin-3 was the strongest predictor of 60-day mortality (hazard ratio [HR]: 10.3; p = 0.007) and the combined end point of 60-day mortality and recurrent HF (HR: 14.3; p
Using galectin-3 to reduce heart failure rehospitalization
Yang Xue1, Alan Maisel1 & W Frank Peacock*,2
ABSTRACT: Increasing attention is being paid towards reducing short-term heart failure readmissions in recent years. Biomarkers such as galectin-3 are likely to play pivotal roles in future heart failure management strategies as they can provide objective information on various pathophysiologic processes involved in heart failure. Galectin-3 is a biomarker of inflammation and fibrosis, which is strongly associated with adverse remodeling of the myocardium and subsequent left ventricular dysfunction. Clinically, elevated galectin-3 levels are associated with increased risk for short- and long-term risk for mortality and heart failure readmission. Galectin-3 can provide incremental predictive value for adverse events over natriuretic peptides. Although significant work is still required to further define the role of galectin-3, it has the potential to become an important part of future heart failure management algorithms by helping to provide an individualized risk profile, which can be used to optimize resource allocation and improve treatment outcomes. In recent years we have seen a significant shift in the management of heart failure (HF). Increasing emphasis is being placed on reducing HF-related hospitalizations, especially short-term readmission. This change largely stemmed from the increasing healthcare burden of HF management. In the last decade, both the prevalence and the incidence of HF have been steadily increasing. According to recent reports, there are almost 6 million patients with HF in the USA alone, with over 600,000 new cases of HF diagnosed each year. Among the elderly, HF is the number one reason for hospitalizations [1] . Furthermore, HF hospitalizations are associating with significant mortality and morbidity. Up to 25% of patients hospitalized for HF are readmitted within 30 days and 30% die within one year of the index HF admission [2,3] . On average, US$13,000 is spent per year on each HF patient with over half of the money spent on HF hospitalizations [4] . With increasingly limited resources available for the management of this growing healthcare challenge, there is a pressing need for better risk stratification and novel therapies to improve both short-term and long-term HF treatment outcomes, and reduce the per-patient cost of HF management. As HF is a complex disease process, improving treatment outcomes would require a multifaceted approach. Some HF management strategies attempted to improve compliance with the guidelines recommended therapies with a moderate degree of success [5] . Other strategies sought to improve patient education and provide intense outpatient monitoring with limited results [6] . It is becoming increasingly clear that due to the complexity of the pathophysiology of HF, an individualized approach is required to improve outcomes. This individualized approach for HF management hinges on accurate prognostic evaluation and tailored therapies based on an individual’s risk. While traditional risk stratification strategies using clinical predictors are useful from a population
KEYWORDS
• galectin-3 • heart failure • natriuretic peptides • prognosis • rehospitalization
Division of Cardiology, University of California San Diego, La Jolla, CA, USA Department of Emergency Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA *Author for correspondence: Tel.: +1 216 312 3292; [email protected] 1 2
10.2217/FCA.14.9 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 221–227
part of
ISSN 1479-6678
221
Special Report Xue, Maisel & Peacock standpoint, their effectiveness on an individual basis is quite limited [7] . Biomarkers representing different pathophysiological processes can be a very effective addition to traditional risk stratification models [8] . They can provide an individualized risk profile and help clinicians to focus resources on the patients with high risk for adverse outcomes. Galectin-3 & the pathophysiology of HF In recent years, many new HF biomarkers have emerged. Among them, galectin-3 is one of the most promising [9] . It is strongly associated with the risk of developing HF [10] . Galectin-3 is a 29–35-kDa chimaera-type galectin, which is present in many tissues [11] and has been linked to the development of HF, renal fibrosis and malignancies [9,12,13] . Galectin-3 is a product of many cell types including activated macrophages. Extracellularly, galectin-3 is an import mediator of macrophage cell migration and cell–cell interactions [14] . Intracellularly, galectin-3 is a regulator of cell cycle and apoptosis [15–17] . Galectin-3 has been associated with macrophage activation, extracellular collagen synthesis and tissue fibrosis [18] . In the heart, elevated galectin-3 levels are a strong indicator of cardiac fibrosis and adverse myocardial remodeling [19] . Galectin-3 is an important link between the inflammatory process in early-stage HF and fibrosis in latestage HF [20] . In HF patients, overexpression of galectin-3 leads to enhanced proliferation of fibroblasts, which promotes collagen deposition and tissue fibrosis. Overexpression of galectin-3 is also associated with elevated levels of type III N-terminal propeptide of procollagen, metallopeptidase inhibitor 1 and matrix metalloproteinase 2, supporting galectin-3’s role as a promoter of extracellular matrix turnover and tissue fibrosis [21] . Mice with decreased galectin-3 levels through gene knockout or pharmacologic inhibition had significantly less fibrosis and left ventricular dysfunction as a result of angiotensin II infusion when compared with wild-type mice [20] . On the other hand, recombinant galectin-3 infusion into the pericardium was associated with excess collagen deposition in the myocardium and cardiac dysfunction [10] . Clinically, serum levels of galectin-3 can be measured by a US FDA-approved ELISA [22] . Galectin-3 & the development of HF In clinical practice, since elevated galectin-3 level is associated with cardiac fibrosis and subsequent
222
Future Cardiol. (2014) 10(2)
development of HF, galectin-3 may be used identify individuals at high risk for HF long before the onset of overt HF symptoms. High galectin-3 levels were also associated with clinical risk factors for HF (age, NYHA class, VO2 max) and elevated HF biomarkers (b-type natriuretic peptide [BNP] N-terminal prohormone B-type natriuretic peptide [NT-proBNP] and C-reactive protein) [23] . In patients with acute coronary syndrome (ACS), elevated galectin-3 levels showed a graded association with subsequent development of HF. In a secondary analysis of the PROVE-IT TIMI 22 trial, patients who developed HF had significant higher galectin-3 levels compared with patients who did not develop HF (16.7 vs 14.6 µg/l; p = 0.004). Patients in the highest galectin-3 quartile had a 3.6-times higher risk for developing HF compared with patients in the lowest quartile (p = 0.003). Galectin-3 was an independent predictor of developing HF after adjustment for hypertension, diabetes and prior MI [24] . Elevated galectin-3 levels have also been associated with adverse remodeling in patients with NYHA class III/IV HF on serial echocardiograms performed 3 months apart. Patients who had adverse remodeling had significantly higher baseline galectin-3 levels (19.0 vs 14.7 µg/l; p = 0.004). Galectin-3 was not only an independent predictor of adverse remodeling after adjusting for gender, etiology of HF, NYHA-class and duration of HF, but also a better predictor of adverse remodeling than NT-proBNP (AUC = 0.66; p = 0.002 vs AUC = 0.572; p = 0.14) [25] . ●●Galectin-3 & HF prognosis
An elevated galectin-3 level is not only a risk factor of development HF, but also a potent prognostic biomarker in patients with HF. In the PRIDE study, patients who died within 60 days of a HF hospitalization had significantly higher galectin-3 levels compared with survivors (12.9 vs 7.3 ng/ml). In multivariate models that included NT-proBNP, age, glomerular filtration rate (GFR) and NYHA functional class, galectin-3 was the strongest predictor of 60-day mortality (hazard ratio [HR]: 10.3; p = 0.007) and the combined end point of 60-day mortality and recurrent HF (HR: 14.3; p
