Endothelial Glycocalyx as Biomarker for Cardiovascular Diseases: Mechanistic and Clinical Implications.

INTRODUCTION: The endothelial surface layer is covered with abundant proteoglycans, of which syndecans and glycosaminoglycans are major constituents. RECENT FINDINGS: Among the endothelial glycocalyx (eGC) constituents, syndecan-1 (sdc1) is a main component, and an elevated serum level of sdc1 may indicate the degradation of eGC. In patients with ischemic heart disease or heart failure, elevation of serum sdc1 has been associated with worsening cardiac and renal function; however, the causal relationship between degradation of eGC and clinical outcomes is unclear. Herein, we review the previous literature on eGC in cardiovascular and noncardiovascular diseases and their clinical implications.

Usefulness of Serum Biomarkers of Endothelial Glycocalyx Damage in Prognosis of Decompensated Patients with Heart Failure with Reduced Ejection Fraction.

The surface layer of endothelium contains the endothelial glycocalyx (eGC), consisting of proteoglycan polymers. Syndecan-1, heparan sulfate, and hyaluronic acid are major constituents of eGC, and their increasing detection in serum represents active degradation of eGC. Serum was obtained from patients with no heart failure (non-HF) and with HF with reduced ejection fraction (HFrEF) of <40%, either stable chronic HF (CHF) or acute decompensated HF (ADHF). Syndecan-1, heparan sulfate, and hyaluronic acid were measured for comparisons in the groups, adjusting for clinical and laboratory values. In our study cohort, 51 non-HF, 66 ADHF, and 72 patients with CHF were enrolled. Between ADHF and CHF, left ventricular (LV) mass index, LV ejection fraction, and pulmonary capillary wedge pressure did not differ. Patients with ADHF had significantly higher levels of eGC constituents compared with CHF and non-HF. During follow-up, 21 patients with HF died, and the mortality rate was higher in patients with higher serum syndecan-1 or heparan sulfate (log-rank p = 0.007 and 0.016, respectively). In multivariate analysis, a doubling of serum heparan sulfate concentration amounted to a 31.5% increase in all-cause mortality (hazard ratio = 1.315, confidence interval = 1.012-1.709, p = 0.040). In conclusion, serum biomarkers of eGC were elevated in ADHF (but not in CHF) in patients with HFrEF, suggesting the potential roles of eGC degradation and endothelial dysfunction in HF decompensation. Only elevated heparin sulfate was associated with higher all-cause mortality after adjusting for traditional risk variables in patients with HFrEF.

Paraoxonase 2 prevents the development of heart failure.

BACKGROUND: Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression. METHODS AND RESULTS: Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function. CONCLUSION: Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.

Circulating intestinal fatty acid-binding protein (I-FABP) levels in acute decompensated heart failure.

BACKGROUND: Venous congestion has become increasingly recognized as a potential contributor to end-organ dysfunction in heart failure. Elevated I-FABP, which is excreted specifically from damaged intestinal epithelial cells, has been found in patients with abdominal hypertension and intestinal ischemia. We hypothesize that elevated intestinal fatty acid-binding protein (I-FABP) levels would identify patients with more advanced heart failure who have venous and intestinal congestion. METHODS: Baseline serum I-FABP levels were measured in 69 acute decompensated heart failure (ADHF) patients admitted to the intensive care unit for invasive hemodynamic monitoring and tailored medical therapy. Comprehensive echocardiography examinations were performed in all study patients, and clinical outcomes (death, cardiac transplant or left ventricular assist device placement) were assessed. RESULTS: The median circulating I-FABP level was 853pg/ml (interquartile range: 533 to 1448pg/ml). Age, gender, race, and baseline comorbidities were comparable between patients with low and high I-FABP levels. Although there were no significant correlations between I-FABP levels and invasively-measured hemodynamic parameters nor echocardiographic parameters, patients with higher I-FABP levels (≥853g/ml) had significantly worse clinical outcomes compared to those with lower I-FABP levels (<853pg/ml, P=0.025). CONCLUSION: Circulating I-FABP levels had no association with invasively-measured hemodynamic parameters, but were associated with adverse clinical outcomes in patients with ADHF with systolic dysfunction.