Allen G. Borowski

Tissue Doppler Imaging in the Estimation of Intracardiac Filling Pressure in Decompensated Patients With Advanced Systolic Heart Failure

Background— The ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity (E/Ea) has been correlated with pulmonary capillary wedge pressure (PCWP) in a wide variety of cardiac conditions. The objective of this study was to determine the reliability of mitral E/Ea for predicting PCWP in patients admitted for advanced decompensated heart failure. Methods and Results— Prospective consecutive patients with advanced decompensated heart failure (ejection fraction ≤30%, New York Heart Association class III to IV symptoms) underwent simultaneous echocardiographic and hemodynamic evaluation on admission and after 48 hours of intensive medical therapy. A total of 106 patients were included (mean age, 57±12 years; ejection fraction, 24±8%; PCWP, 21±7 mm Hg; mitral E/Ea ratio, 20±12). No correlation was found between mitral E/Ea ratio and PCWP, particularly in those with larger left ventricular volumes, more impaired cardiac indexes, and the presence of cardiac resynchronization therapy. Overall, the mitral E/Ea ratio was similar among patients with PCWP >18 and ≤18 mm Hg, and sensitivity and specificity for mitral E/Ea ratio >15 to identify a PCWP >18 mm Hg were 66% and 50%, respectively. Contrary to prior reports, we did not observe any direct association between changes in PCWP and changes in mitral E/Ea ratio. Conclusion— In decompensated patients with advanced systolic heart failure, tissue Doppler–derived mitral E/Ea ratio may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy.

Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Predicting Worsening Renal Function in Acute Decompensated Heart Failure

BACKGROUND The development of worsening renal function (WRF, defined as creatinine rise >or=0.3mg/dL) occurs frequently in the setting of acute decompensated heart failure (ADHF) and strongly predicts adverse clinical outcomes. Neutrophil gelatinase-associated lipocalin (NGAL) is produced by the nephron in response to tubular epithelial damage and serves as an early marker for acute renal tubular injury. We sought to determine the relationship between admission serum NGAL levels and WRF in the setting of ADHF. METHODS AND RESULTS We measured serum NGAL levels in 91 patients admitted to the hospital with ADHF. Patients were adjudicated by independent physician into those that did or did not develop WRF over the ensuing 5 days of in-hospital treatment. In our study cohort (68% male, mean age 61+/-15 years, mean left ventricular ejection fraction 31+/-14%), median admission serum NGAL level was 165 ng/mL (interquartile range [IQR] 108-235 ng/mL). Thirty-five patients (38%) developed WRF within the 5-day follow-up. Patients who developed WRF versus those without WRF had significantly higher median admission serum NGAL levels (194 [IQR 150-292] ng/mL vs. 128 [IQR 97-214] ng/mL, P=.001). High serum NGAL levels at admission were associated with greater likelihood of developing WRF (odds ratio: 1.92, 95% confidence interval 1.23-3.12, P=.004). In particular, admission NGAL >or=140 ng/mL had a 7.4-fold increase in risk of developing WRF, with a sensitivity and specificity of 86% and 54%, respectively. CONCLUSIONS The presence of elevated admission serum NGAL levels is associated with heightened risk of subsequent development of WRF in patients admitted with ADHF.

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.

Right atrial volume index in chronic systolic heart failure and prognosis.

OBJECTIVES The aim of this study was to determine the relationship between right atrial volume index (RAVI) and right ventricular (RV) systolic and diastolic function, as well as long-term prognosis in patients with chronic systolic heart failure (HF). BACKGROUND RV dysfunction is associated with poor prognosis in patients with HF, although echocardiographic assessment of RV systolic and diastolic dysfunction is challenging. The ability to visualize the RA allows a quantitative, highly reproducible assessment of the RA volume that can be indexed to body surface area. METHODS The ADEPT (Assessment of Doppler Echocardiography for Prognosis and Therapy) trial enrolled 192 subjects with chronic systolic HF (left ventricular ejection fraction [LVEF] <or=35%). The RA volume was calculated by Simpsons method using single-plane RA area and indexed to body surface area (RAVI). RV systolic function was graded as normal, mild, mild-moderate, moderate, moderately severe, or severe dysfunction. RESULTS In our study cohort, the mean RAVI was 28 +/- 15 ml/m(2), and increased with worsening RV systolic dysfunction, LVEF, and LV diastolic dysfunction (Spearmans r = 0.61, r = 0.26, and r = 0.51, respectively; p < 0.001 for all). RAVI correlated modestly with echocardiographic estimates of RV diastolic dysfunction, including tricuspid early/late velocities ratio (Spearmans r = 0.34, p < 0.0001), hepatic vein systolic/diastolic ratio (Spearmans r = -0.26, p < 0.001) but not tricuspid early/tricuspid annular early velocities ratio (E/Ea) (Spearmans r = 0.12, p = 0.11). Increasing tertiles of RAVI were predictive of death, transplant, and/or HF hospitalization (log-rank p = 0.0002) and remained an independent predictor of adverse clinical events after adjusting for age, B-type natriuretic peptide, LV ejection fraction, RV systolic dysfunction, and tricuspid E/Ea ratio (hazard ratio: 2.00, 95% confidence interval: 1.15 to 3.58, p = 0.013). CONCLUSIONS In patients with chronic systolic HF, RAVI is a determinant of right-sided systolic dysfunction. This quantitative and reproducible echocardiographic marker provides independent risk prediction of long-term adverse clinical events.

Right Ventricular Response to Intensive Medical Therapy in Advanced Decompensated Heart Failure

Background—Right ventricular (RV) systolic dysfunction is a strong predictor of adverse outcomes in heart failure, yet quantitatively assessing the impact of therapy on this condition is difficult. Our objective was to compare the clinical significance of changes in RV echocardiographic indices in response to intensive medical treatment in patients admitted to the hospital with acute decompensated heart failure (ADHF). Methods and Results—Serial comprehensive echocardiography was performed in 62 consecutive patients with ADHF, and adverse events (death, cardiac transplantation, assist device, heart failure rehospitalization) were prospectively documented. RV peak systolic strain was assessed using speckle-tracking longitudinal strain analysis as the average of the basal, mid-, and apical segment of the RV free wall. Other conventional parameters of RV function (RV fractional area change, RV myocardial performance index, tricuspid annular peak systolic excursion, and tissue Doppler peak tricuspid annular systolic velocity) were measured for comparison. In our study cohort [left ventricular ejection fraction, 26±10%; cardiac index, 2.0±0.6 L/(min · m2)], overall mean RV peak systolic strain was −14±4% at baseline and −15±4% at 48 to 72 hours (P=0.27). Among all the RV functional indices measured, only RV peak systolic strain at 48 to 72 hours was associated with adverse events (P=0.02). In particular, improvement in RV peak systolic strain after intensive medical treatment was associated with lower adverse events in this patient population (26% versus 78%; hazard ratio, 0.13; 95% CI, 0.02 to 0.84; P=0.02). Conclusion—Dynamic improvement in RV mechanics in response to intensive medical therapy was associated with lower long-term adverse events in patients with ADHF than in patients not showing improvement.

Renal Dysfunction is a Stronger Determinant of Systemic Neutrophil Gelatinase-Associated Lipocalin Levels Than Myocardial Dysfunction in Systolic Heart Failure

BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) is released by renal tubular cells in response to inflammation and injury. Recent studies have demonstrated that NGAL is up-regulated in cardiomyocytes within the failing myocardium. However, the overall relationship between systemic NGAL levels and myocardial structure and performance has not been established. METHODS AND RESULTS We measured systemic NGAL levels in 130 subjects with chronic systolic heart failure (HF) and comprehensive echocardiographic evaluation, as well as 69 subjects with acute decompensated systolic HF and hemodynamic evaluation. In the chronic HF cohort, higher plasma NGAL levels were modestly associated with increasing age (r = 0.18; P = .035), higher New York Heart Association functional class (rank sums: P = .022) and impaired renal function (eGFR: r = -0.53; P < .0001; cystatin C: r = 0.60; P < .0001). Plasma NGAL levels were modestly associated with indices of diastolic dysfunction (mitral E/Ea: r = 0.27; P = .002; LAVi: r = 0.25; P = .011; tricuspid E/Ea: r = 0.20; P = .029), but not after adjustment for renal function (P > .10 for all). In Cox proportional hazards analysis, plasma NGAL predicted cardiac death or transplantation after adjustment for age, gender, left ventricular ejection fraction, and mitral E/Ea (hazard ratio 1.68, 95% confidence interval 1.08-2.57; P = .022), but not after adjustment for renal function (P = .83). In the acute HF cohort, we did not observe any relationship between NGAL and hemodynamic indices, but NGAL strongly correlated with renal function. CONCLUSIONS Systemic NGAL levels are largely determined by underlying impairment of renal rather than myocardial function. Our findings did not support any prognostic significance or relationship between systemic NGAL levels and indices of cardiac structure and function after adjustment for underlying renal function.

Diminished Antioxidant Activity of High-Density Lipoprotein–Associated Proteins in Systolic Heart Failure

Background—Diminished serum arylesterase activity, catalyzed by the high-density lipoprotein–associated paraoxonase-1, is associated with heightened systemic oxidative stress and atherosclerosis risk. In the present study, we sought to determine the prognostic role of serum arylesterase activity in subjects with systolic heart failure, particularly in relation to established cardiac biomarkers. Methods and Results—We measured serum arylesterase activity in 760 subjects with impaired left ventricular systolic function (left ventricular ejection fraction <50%), and prospectively followed major adverse cardiac events (including death, nonfatal myocardial infarction, and stroke) for 3 years. In our study cohort (mean age, 64±11 years; 74% men; median left ventricular ejection fraction, 35%; median creatinine clearance, 96 mg/dL), mean serum arylesterase activity (98±25 &mgr;mol/L/min/mL) was lower compared with that in healthy control subjects (mean, 115±26 &mgr;mol/L/min/mL, P<0.01) but higher compared with advanced decompensated heart failure subjects (mean, 69±22 &mgr;mol/L/min/mL, P<0.01). Within our cohort, there was modest correlation between serum arylesterase activity and high-density lipoprotein cholesterol (r=0.33, P<0.01) as well as B-type natriuretic peptide (r=−0.23, P<0.01). Lower serum arylesterase activity was a strong predictor of poorer outcomes (hazard ratio, 2.94; 95% confidence interval, 1.54, 5.62; P<0.001). After adjusting for traditional risk factors, medication use, B-type natriuretic peptide, and creatinine clearance, lower serum arylesterase still conferred an increased risk of major adverse cardiac events at 3 years (hazard ratio, 2.69; 95% confidence interval, 1.37 to 5.28; P=0.004). Conclusions—In patients with systolic heart failure, decreased serum arylesterase activity, a measure of diminished antioxidant properties of high-density lipoprotein, predicts higher risk of incident long-term adverse cardiac event independent of established clinical and biochemical risk factors.

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.

Impact of left ventricular volume/mass ratio on diastolic function

AIMS To assess the impact of left ventricular (LV) volume/mass ratio on diastolic function parameters in subjects with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and healthy controls. METHODS AND RESULTS We performed echocardiography in 44 healthy controls, 35 HCM subjects, 29 DCM subjects with narrow QRS complex (DCM-n), and 27 DCM subjects with wide QRS complex (DCM-w). Mitral annulus velocity (E(a)) and transmitral E-wave velocity were used to estimate time constant of isovolumic pressure decay (tau). LV flow propagation velocity (V(p)) and early intraventricular pressure gradient (IVPG) were derived from colour M-mode of LV inflow. We calculated LV twist and peak untwisting rate (UntwR) by speckle tracking. Mean LV volume/mass ratio was 0.34 +/- 0.09 mL/g in healthy controls, 0.15 +/- 0.06 mL/g in HCM, 0.6 +/- 0.2 mL/g in DCM-n, and 0.8 +/- 0.3 mL/g in DCM-w patients (P < 0.001 for all groups). Resting LV ejection fractions were 63 +/- 7, 64 +/- 8, 31 +/- 8, and 26 +/- 8%, respectively (P < 0.01 vs. controls for DCM groups). In a multivariate analysis, LV volume/mass ratio remained a strong independent predictor of V(p) (P < 0.001), IVPG (P = 0.009), and UntwR (P < 0.001) but not for E(a) (P = 0.25). CONCLUSION LV volume/mass ratio had influences on diastolic function parameters independent of intrinsic diastolic function and filling pressures. It should be considered when assessing patients suspected of LV diastolic dysfunction.

Comprehensive Left Atrial Appendage Optimization of Thrombus Using Surface Echocardiography: The CLOTS Multicenter Pilot Trial

BACKGROUND The aim of this study was to determine the ability to identify thrombus within the left atrial appendage (LAA) in the setting of atrial fibrillation (AF) using transthoracic echocardiography (TTE). In AF, the structure and function of the LAA has historically been evaluated using transesophageal echocardiography (TEE). The role of TTE remains undefined. METHODS The Comprehensive Left Atrial Appendage Optimization of Thrombus (CLOTS) multicenter study enrolled 118 patients (85 men; mean age, 67 +/- 13 years) with AF of >2 days in duration undergoing clinically indicated TEE. On TEE, the LAA was evaluated for mild spontaneous echo contrast (SEC), severe SEC, sludge, or thrombus. Doppler Tissue imaging (DTI) peak S-wave and E-wave velocities of the LAA walls (anterior, posterior, and apical) were acquired on TTE. Transthoracic echocardiographic harmonic imaging (with and without intravenous contrast) was examined to determine its ability to identify LAA SEC, sludge, or thrombus. RESULTS Among the 118 patients, TEE identified 6 (5%) with LAA sludge and 2 (2%) with LAA thrombi. Both LAA thrombi were identified on TTE using harmonic imaging with contrast. Anterior, posterior, and apical LAA wall DTI velocities on TTE varied significantly among the 3 groups examined (no SEC, mild SEC, severe SEC, sludge or thrombus). An apical E velocity < or = 9.7 cm/s on TTE best identified the group of patients with severe SEC, sludge, or thrombus. An anterior S velocity < or = 5.2 cm/s on TTE best identified the group of patients with sludge or thrombus. CONCLUSIONS The CLOTS multicenter pilot trial determined that TTE is useful in the detection of thrombus using harmonic imaging combined with intravenous contrast (Optison; GE Healthcare, Milwaukee, WI). Additionally, LAA wall DTI velocities on TTE are useful in determining the severity of LAA SEC and detecting sludge or thrombus.