Zhili Shao

Usefulness of Plasma Galectin-3 Levels in Systolic Heart Failure to Predict Renal Insufficiency and Survival

Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Increased galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indexes of systolic HF. We measured plasma galectin-3 in 133 subjects with chronic HF and 45 with advanced decompensated HF using echocardiographic and hemodynamic evaluations. In the chronic HF cohort, median plasma galectin-3 level was 13.9 ng/ml (interquartile range 12.1 to 16.9). Higher galectin-3 was associated with more advanced age (r = 0.22, p = 0.010), poor renal function (estimated glomerular filtration rate, r = -0.24, p = 0.007; cystatin C, r = 0.38, p <0.0001) and predicted all-cause mortality (hazard ratio 1.86, 95% confidence interval 1.36 to 2.54, p <0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, estimated glomerular filtration rate, left ventricular (LV) ejection fraction, and mitral early diastolic myocardial relaxation velocity at septal mitral annulus (hazard ratio 1.94, 95% confidence interval 1.30 to 2.91, p = 0.001). However, galectin-3 did not predict the combined end point of all-cause mortality, cardiac transplantation, or HF hospitalization (p >0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r = -0.05, p = 0.61), LV ejection fraction (r = 0.10, p = 0.25), or LV diastolic function (mitral early diastolic myocardial relaxation velocity at septal mitral annulus, r = 0.06, p = 0.52; left atrial volume index, r = 0.08, p = 0.41). In the advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indexes. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indexes.

Relation of systemic and urinary neutrophil gelatinase-associated lipocalin levels to different aspects of impaired renal function in patients with acute decompensated heart failure

Both urine and serum neutrophil gelatinase-associated lipocalin (NGAL) reflect active chronic kidney disease and predict acute kidney injury. However, a direct comparison of these markers in acute decompensated heart failure has not been performed. We prospectively evaluated 93 patients admitted with acute decompensated heart failure and treated with intravenous furosemide and measured both systemic (serum) and urine NGAL levels and their corresponding markers of estimated glomerular filtration rate, natriuresis (urine sodium), and diuretic response (net output, urine sodium/furosemide ratio). In our study cohort, the median urine and serum NGAL level was 34 ng/ml (interquartile range 24 to 86) and 252 ng/ml (interquartile range 175 to 350), respectively. The urine and serum NGAL levels correlated modestly (r = 0.37, p <0.001). Higher urine (but not systemic) NGAL correlated with the markers of impaired natriuresis and reduced diuresis (p <0.005 for all). In contrast, higher serum NGAL demonstrated a stronger relation with reduced glomerular filtration function (p <0.0001). Both markers predicted acute kidney injury (urine NGAL, odds ratio 1.7, p = 0.035; serum NGAL, odds ratio 1.9, p = 0.009). In conclusion, in patients with acute decompensated heart failure, urine NGAL levels reflect renal distal tubular injury with impaired natriuresis and diuresis, and systemic NGAL levels demonstrate a stronger association with glomerular filtration function. Both systemic and urine NGAL predict worsening renal function.

Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1.

OBJECTIVES This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure. BACKGROUND Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear. METHODS This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57). RESULTS Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] μmol/l vs. 0.87 [0.72 to 1.05] μmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (≥50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02). CONCLUSIONS Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA-producing enzyme, protein methyltransferase-1) in the human failing myocardium.

Usefulness of Elevated Urine Neopterin Levels in Assessing Cardiac Dysfunction and Exercise Ventilation Inefficiency in Patients With Chronic Systolic Heart Failure

Neopterin is synthesized by macrophages upon stimulation with gamma-interferon, and high neopterin production is associated with cellular immune activation and increased production of reactive oxygen species (oxidant stress), but the clinical utility of urine neopterin levels in patients with heart failure (HF) has not been explored. Fifty-three ambulatory patients with chronic systolic HF (left ventricular [LV] ejection fraction ≤40%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise testing. Urine neopterin levels were quantified by liquid chromatography with tandem mass spectrometric analyses and corrected to urine creatinine (Cr) levels. In our study cohort, median urine neopterin level was 60 μmol/mol Cr (interquartile range 40 to 86). There were modest correlations between urine neopterin levels and abnormalities in cardiac structure and function by echocardiography: LV ejection fraction (r = -0.33, p = 0.017), indexed LV end-diastolic volume (r = 0.31, p = 0.029), indexed LV end-systolic volume (r = 0.32, p = 0.024), and E/septal Ea (r = 0.28, p = 0.041). Although there was no significant correlation between urine neopterin and maximal oxygen uptake (peak VO2: r = -0.25, p = 0.07), there was a modest correlation between urine neopterin and maximal ventilation/carbon dioxide production ratio (VE/VCO2 max: r = 0.38, p = 0.005). In conclusion, increase in urine neopterin levels tracks with disease severity in patients with chronic systolic HF.

Pulmonary Hypertension Associated With Advanced Systolic Heart Failure

OBJECTIVES This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure. BACKGROUND Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear. METHODS This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57). RESULTS Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] μmol/l vs. 0.87 [0.72 to 1.05] μmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (≥50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02). CONCLUSIONS Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA-producing enzyme, protein methyltransferase-1) in the human failing myocardium.

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. HIGHLIGHTSHuman heart primarily expresses PON2 while lactonase activity was decreased.Mice with genetic deficiency of PON2 had dilated cardiac remodeling upon insults.PON2 deficiency lowered baseline SDH activity and increased ROS production in hypoxia.Strategies to upregulate PON2 function might lead to novel cardioprotective.

Dysregulated Arginine Metabolism and Importance of Compensatory Dimethylarginine Dimethylaminohydrolase-1 in Pulmonary Hypertension Associated with Advanced Systolic Heart Failure

OBJECTIVES This study sought to examine the hemodynamic determinants of dysregulated arginine metabolism in patients with acute decompensated heart failure and to explore possible mechanisms of arginine dysregulation in human heart failure. BACKGROUND Accumulating methylated arginine metabolites and impaired arginine bioavailability have been associated with heart failure, but the underlying pathophysiology remains unclear. METHODS This study prospectively determined plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and global arginine bioavailability ratio [GABR = arginine/(ornithine + citrulline)] by tandem mass spectrometry in subjects with advanced decompensated heart failure in the intensive care unit (n = 68) and with stable chronic heart failure (n = 57). RESULTS Compared with chronic heart failure subjects, plasma ADMA was significantly higher (median [interquartile range]: 1.29 [1.04 to 1.77] μmol/l vs. 0.87 [0.72 to 1.05] μmol/l, p < 0.0001), and global arginine bioavailability ratio significantly lower (median [interquartile range]: 0.90 [0.69 to 1.22] vs. 1.13 [0.92 to 1.37], p = 0.002) in advanced decompensated heart failure subjects. Elevated ADMA and diminished global arginine bioavailability ratio were associated with higher systolic pulmonary artery pressure (sPAP) and higher central venous pressure, but not with other clinical or hemodynamic indices. We further observed myocardial levels of dimethylarginine dimethylaminohydrolase-1 were increased in chronic heart failure without elevated sPAP (<50 mm Hg), but diminished with elevated sPAP (≥50 mm Hg, difference with sPAP <50 mm Hg, p = 0.02). CONCLUSIONS Dysregulated arginine metabolism was observed in advanced decompensated heart failure, particularly with pulmonary hypertension and elevated intracardiac filling pressures. Compared with hearts of control subjects, we observed higher amounts of ADMA-degradation enzyme dimethylarginine dimethylaminohydrolase-1 (but similar amounts of ADMA-producing enzyme, protein methyltransferase-1) in the human failing myocardium.