Wouter C. Meijers

Elevated plasma galectin-3 is associated with near-term rehospitalization in heart failure: A pooled analysis of 3 clinical trials

BACKGROUND Rehospitalization is a major cause for heart failure (HF)-related morbidity and is associated with considerable loss of quality of life and costs. The rate of unplanned rehospitalization in patients with HF is unacceptably high; current risk stratification to identify patients at risk for rehospitalization is inadequate. We evaluated whether measurement of galectin-3 would be helpful in identifying patients at such risk. METHODS We analyzed pooled data from patients (n = 902) enrolled in 3 cohorts (COACH, n = 592; PRIDE, n = 181; and UMD H-23258, n = 129) originally admitted because of HF. Mean patient age was between 61.6 and 72.9 years across the cohorts, with a wide range of left ventricular ejection fraction. Galectin-3 levels were measured during index admission. We used fixed and random-effects models, as well as continuous and categorical reclassification statistics to assess the association of baseline galectin-3 levels with risk of postdischarge rehospitalization at different time points and the composite end point all-cause mortality and rehospitalization. RESULTS Compared with patients with galectin-3 concentrations less than 17.8 ng/mL, those with results exceeding this value were significantly more likely to be rehospitalized for HF at 30, 60, 90, and 120 days after discharge, with odds ratios (ORs) of 2.80 (95% CI 1.41-5.57), 2.61 (95% CI 1.46-4.65), 3.01 (95% CI 1.79-5.05), and 2.79 (95% CI 1.75-4.45), respectively. After adjustment for age, gender, New York Heart Association class, renal function (estimated glomerular filtration rate), left ventricular ejection fraction, and B-type natriuretic peptide, galectin-3 remained an independent predictor of HF rehospitalization. The addition of galectin-3 to risk models significantly reclassified patient risk of postdischarge rehospitalization and fatal event at each time point (continuous net reclassification improvement at 30 days of +42.6% [95% CI +19.9%-65.4%], P < .001). CONCLUSIONS Among patients hospitalized for HF, plasma galectin-3 concentration is useful for the prediction of near-term rehospitalization.

Biomarkers and low risk in heart failure. Data from COACH and TRIUMPH

Traditionally, risk stratification in heart failure (HF) emphasizes assessment of high risk. We aimed to determine if biomarkers could identify patients with HF at low risk for death or HF rehospitalization.

Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process.

Galectin-3 and heart failure : Prognosis, prediction & clinical utility

Heart failure (HF) is a leading cause of mortality in the western world. Despite advances in the treatment of HF, like the use of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and implantable cardiac defibrillators, prognosis of HF patients remains poor. For clinicians dealing with HF patients, risk prediction in both acute, chronic, and new onset HF remains a challenge. Biomarkers might help in risk stratification and may guide the proper use of limited resources and therapy. Galectin-3 is an emerging biomarker which has been linked to tissue fibrosis, a hallmark in cardiac remodeling and HF. Galectin-3 can reliably be measured in the circulation, and several recent studies have shown the prognostic value of galectin-3 in acute and chronic HF, and its potential utility in the general population. The purpose of this review was to summarize the literature and explore the potential role of galectin-3 as a biomarker in HF.

Renal handling of galectin-3 in the general population, chronic heart failure, and hemodialysis.

Background Galectin‐3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin‐3 levels. We aimed to describe galectin‐3 renal handling in HF. Methods and Results In Sprague–Dawley rats, we infused galectin‐3 and studied distribution and renal clearance. Furthermore, galectin‐3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin‐3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin‐3. Plasma galectin‐3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P<0.001), while urinary galectin‐3 in HF patients was comparable (28.1 ng/mL versus 35.1 ng/mL, P=0.830). The calculated galectin‐3 excretion rate was lower in HF patient (2.3 mL/min [1.5 to 3.4] versus 3.9 mL/min [2.3 to 6.4] in control subjects; P=0.005). This corresponded with a significantly lower fractional excretion of galectin‐3 in HF patients (2.4% [1.7 to 3.7] versus 3.0% [1.9 to 5.5]; P=0.018). These differences, however, were no longer significant after correction for age, gender, diabetes, and smoking. HF patients who received diuretics (49%) showed significantly higher aldosterone and galectin‐3 levels. Hemodialysis patients (n=105; mean age 63 years; 65% male), without urinary galectin‐3 excretion, had strongly increased median plasma galectin‐3 levels (70.6 ng/mL). Conclusions In this small cross‐sectional study, we report that urine levels of galectin‐3 are not increased in HF patients, despite substantially increased plasma galectin‐3 levels. The impaired renal handling of galectin‐3 in patients with HF may explain the described relation between renal function and galectin‐3 and may account for the elevated plasma galectin‐3 in HF.

Variability of biomarkers in patients with chronic heart failure and healthy controls

Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF.

Galectin-3 and post-myocardial infarction cardiac remodeling

This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling. Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in order to preserve cardiac function. A hallmark herein is fibrosis formation, both in the early and late phase following acute myocardial infarction. Galectin-3, a β-galactoside-binding lectin, which is a shared factor in fibrosis formation in multiple organs, has an established role in cardiac fibrosis in the setting of pressure overload, neuro-endocrine activation and hypertension, but its role in post- myocardial infarction remodeling has received less attention. However, accumulative experimental studies have shown that myocardial galectin-3 expression is upregulated after myocardial infarction, both on mRNA and protein level. This already occurs shortly after myocardial infarction in the infarcted and border zone area, and also at a later stage in the spared myocardium, contributing to tissue repair and fibrosis. This is associated with typical aspects of fibrosis formation, such as apposition of matricellular proteins and increased factors of collagen turnover. Interestingly, myocardial fibrosis in experimental post-myocardial infarction cardiac remodeling could be attenuated by galectin-3 inhibition. In clinical studies, circulating galectin-3 levels have been shown to identify patients at risk for new-onset heart failure and atrial fibrillation. Circulating galectin-3 levels also predict progressive left ventricular dilatation after myocardial infarction. From literature we conclude that galectin-3 is an active player in cardiac remodeling after myocardial infarction. Future studies should focus on the dynamics of galectin-3 activation after myocardial infarction, and study the possibilities to target galectin-3.

From Inflammation to Fibrosis—Molecular and Cellular Mechanisms of Myocardial Tissue Remodelling and Perspectives on Differential Treatment Opportunities

Purpose of ReviewIn this review, we highlight the most important cellular and molecular mechanisms that contribute to cardiac inflammation and fibrosis. We also discuss the interplay between inflammation and fibrosis in various precursors of heart failure (HF) and how such mechanisms can contribute to myocardial tissue remodelling and development of HF.Recent FindingsRecently, many research articles attempt to elucidate different aspects of the interplay between inflammation and fibrosis. Cardiac inflammation and fibrosis are major pathophysiological mechanisms operating in the failing heart, regardless of HF aetiology. Currently, novel therapeutic options are available or are being developed to treat HF and these are discussed in this review.SummaryA progressive disease needs an aggressive management; however, existing therapies against HF are insufficient. There is a dynamic interplay between inflammation and fibrosis in various precursors of HF such as myocardial infarction (MI), myocarditis and hypertension, and also in HF itself. There is an urgent need to identify novel therapeutic targets and develop advanced therapeutic strategies to combat the syndrome of HF. Understanding and describing the elements of the inflammatory and fibrotic pathways are essential, and specific drugs that target these pathways need to be evaluated.

The ARCHITECT galectin-3 assay: comparison with other automated and manual assays for the measurement of circulating galectin-3 levels in heart failure

Heart failure (HF) is a common disease and affects millions of patients worldwide. Diagnosis, risk assessment and treatment of HF are difficult and therefore there is a need for additional tools to improve clinical performance. Biomarkers may be helpful in this respect. Galectin-3 is a relatively new biomarker that has been shown to have strong associations with the development of HF. Galectin-3 plays a role in inflammation and fibrosis, which are key elements in the pathophysiology of HF. Circulating plasma or serum galectin-3 levels have strong associations with the severity of HF and may be used to prognosticate or risk-stratify HF patients. Currently, there are several commercially available assays that can measure circulating galectin-3. This article describes the role galectin-3 plays in HF and its prognostic consequences. We will summarize the technical specifications of various manual and automated galectin-3 assays, which may help in HF management.

Serial galectin-3 and future cardiovascular disease in the general population

Background Lifetime risk for cardiovascular (CV) disease is high but predicting incident events on an individual level remains difficult. Single measurements of galectin-3, a marker of tissue fibrosis, predict mortality and new-onset heart failure (HF). Persistently elevated levels may indicate a clinically silent disease process. Objectives Our aim was to establish the value of serial galectin-3 measurements to predict CV outcomes in the general population. Methods Plasma galectin-3 was measured in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study at baseline and after ∼4 years. Changes in serial galectin-3 were expressed as categorical changes or absolute change from baseline and were related to subsequent outcome. Results Serial galectin-3 was measured in 5958 subjects (mean age 49±12 years; 49% female). The median duration of follow-up was 8.3 years. Persistently elevated galectin-3 (defined as highest quartile at baseline and highest quartile during visit 2, n=757 subjects) was associated with a higher risk for new-onset HF, CV mortality, all-cause mortality, new-onset atrial fibrillation and CV events, compared with subjects with non-persistently elevated galectin-3. After multivariable adjustments for baseline characteristics, serial galectin-3 remained an independent predictor of new-onset HF (HR 1.85 (1.10–3.13); p=0.02) but not for other outcomes. Serial measurements provided more accurate prognostic value to predict new-onset HF, compared with a single baseline measurement (Harrells C: 0.72 (0.68–0.75) vs 0.68 (0.65–0.72); p=0.002, respectively) with significant net reclassification. Conclusions Persistently elevated galectin-3 predicts new-onset HF after adjustment for covariates, and serial measurements provide more accurate prognostic information compared with single determination of galectin-3. This may help to identify individuals who are at risk for incident HF and might provide a measure to monitor interventions.