Galectins are a family of soluble β-galactoside-binding lectins that play many important regulatory roles in inflammation, immunity, and cancer. Recently, a role for galectin-3 in the pathophysiology ...of heart failure (HF) has been suggested. Numerous studies have demonstrated the up-regulation of galectin-3 in hypertrophied hearts, its stimulatory effect on macrophage migration, fibroblast proliferation, and the development of fibrosis. The latter observation is particularly relevant as cardiac remodelling is an important determinant of the clinical outcome of HF and is linked to disease progression and poor prognosis. Because galectin-3 expression is maximal at peak fibrosis and virtually absent after recovery, routine measurement in patients with HF may prove valuable to identify those patients at highest risk for readmission or death, thus enabling physicians to tailor the level of care to individual patient needs. This review summarizes the most recent advances in galectin-3 research, with an emphasis on the role galectin-3 plays in the development and progression of HF.
Background Galectin-3 is a new biomarker involved in inflammation and fibrogenesis and could therefore contribute to myocardial remodeling. We examined the prognostic value of baseline galectin-3 in ...a substudy involving approximately 30% of participants in the CORONA study. Methods Patients (n = 1462) aged >60 years with systolic, ischemic heart failure (HF) were randomized to 10 mg/d rosuvastatin or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, or stroke (n = 408). Results In the unadjusted analysis, galectin-3 was associated with all end points considered, except hospitalization for worsening of HF. In multivariable analyses, adjusting for other clinical and biochemical predictor variables, galectin-3 was significantly associated with the primary end point (hazard ratio HR 1.53 1.10-2.12, P = .011) as well as all-cause (HR 1.61 1.20-2.29, P = .002) and cardiovascular mortality (HR 1.70 1.19-2.42, P = .003), sudden death (HR 1.83 1.14-2.94, P = .012), and the coronary end point (HR 1.48 1.03-2.12, P = .035). However, when N-terminal pro–brain natriuretic peptide was added to the model, galectin-3 association with the end points was markedly attenuated and no longer significant. Conclusions Galectin-3 is not associated with outcome in older patients with advanced chronic systolic HF of ischemic etiology when adjusting for N-terminal pro–brain natriuretic peptide and may therefore have limited use in the prognostication of elderly patients with systolic HF in clinical practice.
The identification of asymptomatic individuals at risk for near-term atherothrombotic events to ensure optimal preventive treatment remains a challenging goal. In the BioImage Study, novel approaches ...are tested in a typical health-plan population. Based on certain demographic and risk characteristics on file with Humana Inc, a total of 7,687 men 55 to 80 years of age and women 60 to 80 years of age without evidence of atherothrombotic disease but presumed to be at risk for near-term atherothrombotic events were enrolled between January 2008 and June 2009. Those who met the prespecified eligibility criteria were randomized to a telephonic health survey only (survey only: n = 865), standard risk assessment (Framingham only: n = 718), or comprehensive risk assessment in a dedicated mobile facility equipped with advanced imaging tools (n = 6,104). Baseline examination included assessment of cardiovascular risk factors and screening for subclinical (asymptomatic) atherosclerosis with quantification of coronary artery calcification by computed tomography (CT), measurement of intima-media thickness, presence of carotid atherosclerotic plaques and abdominal aortic aneurysm by ultrasound, and ankle brachial index. Participants with one or more abnormal screening test results underwent advanced imaging with contrast-enhanced magnetic resonance imaging for carotid and aortic plaques, contrast-enhanced coronary CT angiography for luminal stenosis and noncalcified plaques, and 18F-fluorodeoxyglucose–positron emission tomography/CT for carotid and aortic plaque inflammation. Plasma, PAXgene RNA, and DNA samples were obtained, frozen, and stored for future biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging. The BioImage Study will help identify those patients with subclinical atherosclerosis who are at risk for near-term atherothrombotic events and enable a more personalized management of care.
CXCL12 encodes stromal cell-derived factor 1α (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease and endothelial ...progenitor cell numbers, whereas variation at the CXCR4 locus is associated with leukocyte telomere length, which has been shown to be associated with coronary artery disease. Therefore, we examined the relationships of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors, leukocyte telomere length, and endothelial progenitor cells.
SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relationships of SDF-1 to new-onset CVD, myocardial infarction, heart failure, and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, leukocyte telomere length, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of high-density lipoprotein-cholesterol and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency (P=0.02) but not with leukocyte telomere length. During follow-up (median, 9.3 years), there were 263 new-onset CVD events, 160 myocardial infarctions, 200 heart failure events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with heart failure (P=0.04) and all-cause mortality (P=0.003) but not with CVD (P=0.39) or myocardial infarction (P=0.10). The association of SDF-1 levels with myocardial infarction was attenuated after adjustment for high-density lipoprotein-cholesterol.
After adjusting for traditional CVD risk factors, SDF-1 is associated with heart failure and all-cause mortality risk. Additional studies are needed to determine whether measurement of SDF-1 levels has clinical use.
Abstract Background The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend primary prevention with statins for individuals with ≥7.5% 10-year risk for ...atherosclerotic cardiovascular disease (ASCVD). Everyone living long enough will become eligible for risk-based statin therapy due to age alone. Objectives This study sought to personalize ACC/AHA risk-based statin eligibility using noninvasive assessment of subclinical atherosclerosis. Methods In 5,805 BioImage participants without known ASCVD at baseline, those with ≥7.5% 10-year ASCVD risk were down-classified from statin eligible to ineligible if imaging revealed no coronary artery calcium (CAC) or carotid plaque burden (cPB). Intermediate-risk individuals were up-classified from optional to clear statin eligibility if CAC was ≥100 (or equivalent cPB). Results At a median follow-up of 2.7 years, 91 patients had coronary heart disease and 138 had experienced a cardiovascular disease event. Mean age of the participants was 69 years, and 86% qualified for ACC/AHA risk-based statin therapy, with high sensitivity (96%) but low specificity (15%). CAC or cPB scores of 0 were common (32% and 23%, respectively) and were associated with low event rates. With CAC-guided reclassification, specificity for coronary heart disease events improved 22% (p < 0.0001) without any significant loss in sensitivity, yielding a binary net reclassification index (NRI) of 0.20 (p < 0.0001). With cPB-guided reclassification, specificity improved 16% (p < 0.0001) with a minor loss in sensitivity (7%), yielding an NRI of 0.09 (p = 0.001). For cardiovascular disease events, the NRI was 0.14 (CAC-guided) and 0.06 (cPB-guided). The positive NRIs were driven primarily by down-classifying the large subpopulation with CAC = 0 or cPB = 0. Conclusions Withholding statins in individuals without CAC or carotid plaque could spare a significant proportion of elderly people from taking a pill that would benefit only a few. This individualized disease-guided approach is simple and easy to implement in routine clinical practice.
Background: Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream ...target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). Methods: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. Results: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. Conclusions: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection.
Background Aortic stenosis (AS) is characterized by inflammation, fibrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms differently. Galectin-3 (Gal-3) is a pro-inflammatory ...and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-differential role of Gal-3 in AS. Methods 226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with inflammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments. Results Proteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men's VICs as compared to women's. In human AVs, Gal-3 protein levels were significantly higher in men, with stronger immunostaining in VICs with myofibroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with inflammatory markers in both sexes. Gal-3 expression was also positively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of inflammatory, osteogenic and angiogenic markers in male's VICs, while it only upregulated inflammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharmacological inhibitors (modified citrus pectin and G3P-01) prevented the upregulation of inflammatory, osteogenic and angiogenic molecules. Conclusions Gal-3 plays a sex-differential role in the setting of AS, and it could be a new sex-specific therapeutic target controlling pathological features of AS in VICs. Graphical Keywords: Galectin-3, Aortic stenosis, Sex differences, Valve interstitial cell, Inflammation, Calcification, Angiogenesis
Abstract Background Although recent studies suggest that measuring coronary artery calcification (CAC) may be superior to indirect atherosclerotic markers in predicting cardiac risk, there are ...limited data evaluating imaging-based biomarkers that directly quantify atherosclerosis in different vascular beds performed in a single cohort. Objectives The BioImage Study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population) sought to identify imaging biomarkers that predict near-term (3-year) atherothrombotic events. Methods The BioImage Study enrolled 5,808 asymptomatic U.S. adults (mean age: 69 years, 56.5% female) in a prospective cohort evaluating the role of vascular imaging on cardiovascular risk prediction. All patients were evaluated by CAC and novel 3-dimensional carotid ultrasound. Plaque areas from both carotid arteries were summed as the carotid plaque burden (cPB). The primary endpoint was the composite of major adverse cardiac events (MACE) (cardiovascular death, myocardial infarction, and ischemic stroke). A broader secondary MACE endpoint also included all-cause death, unstable angina, and coronary revascularization. Results Over a median follow-up of 2.7 years, MACE occurred in 216 patients (4.2%), of which 82 (1.5%) were primary events. After adjustment for risk factors, and compared with individuals without any cPB, hazard ratios for MACE were 0.78 (95% confidence interval CI: 0.31 to 1.91), 1.45 (95% CI: 0.67 to 3.14), and 2.36 (95% CI: 1.13 to 4.92) with increasing cPB tertile, with similar results for CAC. Net reclassification significantly improved with either cPB (0.23) or CAC (0.25). MACE rates increased simultaneously with higher levels of both cPB and CAC. Conclusions Detection of subclinical carotid or coronary atherosclerosis improves risk predictions and reclassification compared with conventional risk factors, with comparable results for either modality. Cost-effective analyses are warranted to define the optimal roles of these complementary techniques. (BioImage Study: A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population; NCT00738725 )
Abstract Objectives This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a ...systematized approach according to suggested requirements for validation of new biomarkers. Background Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. Methods From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro–B-type natriuretic peptide. Interactions with statin treatment were also assessed. Results The two models—model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine C-C motif ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)—significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell’s C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. Conclusions In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.
Coronary arterial calcification, Agatston unitsdagger 46.0 (0.0 to 245.0) 29.0 (0.0 to 227.5) -27.9 -51.1 to -4.7 0.019 Carotid plaque, mm2dagger 183.8 (0.0 to 555.9) 112.8 (0.0 to 367.2) -8.7 -73.5 ...to 56.0 0.79 Carotid intima media thickness, mmlow * 0.76 ± 0.16 0.74 ± 0.13 -1.7% -6.3 to 3.0 0.47 Table 1 Association of APOC3 Loss-of-Function Mutation Carrier Status With Blood Lipid Levels and Subclinical Atherosclerosis Values are represented as effect estimates (95% confidence intervals) between APOC3 loss-of-function mutation carriers and noncarriers after adjustment for covariates.
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