Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure.

BACKGROUND: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). METHODS AND RESULTS: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6-12.1) µmol/L, 10.9 (8.4-14.0) µmol/L, and 43.8 (37.1-53.0) µmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9-13.2] vs 4.8 [3.4-9.8] µmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7-14.8] vs 4.7 [3.4-11.3] µmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22-2.20; P = .001), betaine (HR 1.51, 95% CI 1.10-2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10-1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03-2.14; P = .03). CONCLUSION: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.

Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes.

BACKGROUND: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF). METHODS AND RESULTS: In 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59-128) µmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = -0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3-2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2-3.1; P = .006). CONCLUSIONS: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.

Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system that has been recently identified in circulating form. We aimed to investigate the relationship among changes in soluble ACE2 (sACE2) activity, myocardial performance, and long-term clinical outcomes in patients with acute decompensated heart failure (ADHF). We hypothesized that increasing sACE2 activity levels during intensive medical treatment are associated with improved myocardial performance and long-term clinical outcomes. METHODS AND RESULTS: In 70 patients admitted to the intensive care unit with ADHF, serum sACE2 activity levels, echocardiographic data, and hemodynamic variables were collected within 12 hours of admission (n = 70) and 48-72 hours after intensive medical treatment (n = 57). The median [interquartile range] baseline and 48-72-hour serum sACE2 activity levels were 32 [23-43] ng/mL and 40 [28-60] ng/mL, respectively. Baseline serum sACE2 activity levels correlated with surrogate measures of right ventricular diastolic dysfunction, including right atrial volume index (RAVi; r = 0.31; P = .010), tricuspid E/A ratio (r = 0.39; P = .007), and B-type natriuretic peptide (r = 0.32; P = .008). However, there were no correlations between serum sACE2 and left ventricular systolic or diastolic dysfunction. After intensive medical therapy, a 50% increase in baseline serum sACE2 levels predicted a significant reduction in risk of death, cardiac transplantation, or ADHF rehospitalization, including after adjustment for baseline age, RAVi, and BNP levels (hazard ratio 0.35, 95% confidence interval 0.12-0.84; P = .018). CONCLUSIONS: In patients admitted with ADHF, increasing serum sACE2 activity levels during intensive medical therapy predict improved outcomes independently from underlying cardiac indices.

Increased exhaled nitric oxide levels after exercise in patients with chronic systolic heart failure with pulmonary venous hypertension.

BACKGROUND: Fractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated with systemic endothelial nitric oxide production, but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels with pulmonary arterial hypertension. Our objective was to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF. METHODS AND RESULTS: Thirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ± 13 years, 76% male, median LVEF 31%, interquartile range [IQR] 25%-40%), the mean eNO was 23 ± 9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1 ± 9 vs 19.5 ± 7 ppb; P = .013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r = 0.57; P = .0009) and indexed left atrium volume (r = 0.43; P = .014), but it did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score. CONCLUSIONS: In contrast to earlier reports, the increase in postexercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.

Subclinical echocardiographic abnormalities in phenotype-negative carriers of myosin-binding protein C3 gene mutation for hypertrophic cardiomyopathy.

BACKGROUND: Early diastolic myocardial tissue Doppler velocities have reported to be reduced in mutation-positive patients with hypertrophic cardiomyopathy (HCM) in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with HCM. Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM. METHODS: We evaluated 41 consecutive subjects with a known myosin-binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation positive without LVH (G+/LVH-, n = 35) were compared with healthy controls (n = 30) regarding tissue Doppler and segmental longitudinal strain measures. RESULTS: The G+/LVH- group was similar to the healthy controls with respect to chamber size, left ventricular mass index, and most diastolic filling parameters, including tissue Doppler-derived early diastolic annular velocities. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs 19.8 ± 1.8, P = .36), although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs 19.0 ± 4.0%, P = .02) and increase in the basal posterior (22.5 ± 5.2 vs 17.9 ± 5.2, P = .001) as well as mid posterior (21.8 ± 4.7 vs 18.2 ± 3.0, P = .001) walls. CONCLUSIONS: In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking-derived parameters of systolic and diastolic function compared with that of healthy subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.

Impact of left ventricular remodeling on diagnostic and prognostic value of tissue Doppler indices in chronic systolic heart failure.

BACKGROUND: The ratio of peak transmitral pulsed Doppler early velocity to early diastolic tissue Doppler velocity (TDI) of the lateral or septal mitral annulus (E/Ea) is considered a reliable estimation of LV filling pressure. We aim to examine the impact of left ventricular (LV) dimensions on the relationship between lateral and septal E/Ea in the determination of diastolic dysfunction patterns in the setting of chronic systolic heart failure (HF). METHODS AND RESULTS: In 207 patients with chronic systolic HF (LV ejection fraction ≤40%, New York Heart Association Classes I-IV), comprehensive transthoracic echocardiography was performed and long-term outcomes followed up to a median of 40 months. The median lateral and septal Ea (interquartile range) were 7.0 (4.7 to 9.5) cm/s and 4.5 (3.5 to 5.6) cm/s, respectively. The median E/lateral Ea, E/septal Ea, and E/average Ea (interquartile range) were 10.8 (7.1 to 15.1), 16.1 (11.1 to 23.0), and 12.7 (8.8 to 17.7), respectively. In the first 2 tertiles of indexed left ventricular end-diastolic volume (LVEDVi) (<92 mL/m(2) and 92 to 130 mL/m(2)), all 3 E/Ea indices rise with increasing diastolic stage (all P < .001). However, in the highest tertile of indexed LVEDVi (≥130 mL/m(2)), E/average Ea and E/septal Ea (but not E/lateral Ea) increased with increasing diastolic stage, and only E/septal Ea correlated with natriuretic peptide levels (r = 0.38, P = .018) and adverse cardiac events (Hazard ratio 1.91, 95% confidence interval 1.25 to 2.96, P = .003). CONCLUSIONS: In the setting of chronic systolic heart failure with extensive cardiac remodeling, septal TDI measurements may be more reliable and clinically relevant than lateral TDI measurements in the assessment of diastolic dysfunction.

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.

Antiinflammatory autoimmune cellular responses to cardiac troponin I in idiopathic dilated cardiomyopathy.

BACKGROUND: Autoimmune mechanisms, particularly through generation of autoantibodies, may contribute to the pathophysiology of idiopathic dilated cardiomyopathy (iDCM). The precise role of cellular autoimmune responses to cardiac-specific antigens has not been well described in humans. The purpose of this study was to characterize the cellular autoimmune response to cardiac troponin I (cTnI), specifically, the release of cytokines by peripheral blood mononuclear cells (PBMCs), in subjects with iDCM and healthy control subjects. METHODS AND RESULTS: We performed enzyme-linked immunospot assays on PBMCs isolated from subjects with iDCM and healthy control subjects to examine the ex vivo interferon-gamma (IFN-γ) and interleukin-10 (IL-10) production in response to cTnI exposure. Thirty-five consecutive subjects with iDCM (mean age 53 ± 11 years, 60% male, left ventricular ejection fraction 23 ± 7%) and 26 control subjects (mean age 46 ± 13 years, 46% male) were prospectively enrolled. IFN-γ production in response to cTnI did not differ between the groups (number of secreting cells 26 ± 49 vs 38 ± 53, respectively; P = .1). In contrast, subjects with iDCM showed significantly higher IL-10 responses to cTnI compared with control subjects (number of secreting cells 386 ± 428 vs 152 ± 162, respectively; P < .05). Among iDCM subjects, heightened IL-10 response to cTnI was associated with reduced systemic inflammation and lower prevalence of advanced diastolic dysfunction compared with those with normal IL-10 response to cTnI. CONCLUSIONS: Our preliminary findings suggest that a heightened cellular autoimmune IL-10 response to cTnI is detectable in a subset of patients with iDCM, which may be associated with reduced systemic levels of high-sensitivity C-reactive protein and lower prevalence of advanced diastolic dysfunction.

Predictors of mitral annulus early diastolic velocity: impact of long-axis function, ventricular filling pattern, and relaxation.

AIMS: Although left ventricular (LV) relaxation is well recognized as a predictor of mitral annulus (MA) early diastolic (E') velocity, its significance relative to other predictors of E' is less well understood. METHODS AND RESULTS: We assessed 40 healthy volunteers, 43 patients with acutely decompensated chronic systolic heart failure (HF), and 36 patients with hypertrophic obstructive cardiomyopathy (HOCM) using echocardiography and right or left heart catheterization. Data were obtained at baseline. In addition, in healthy volunteers haemodynamics were varied by graded saline infusion and low body negative pressure, while in HF patients it was varied by vasoactive drug treatment. E- and A-wave velocity (E/A) ratio of the mitral valve inflow, systolic MA velocity integral (s' integral) and E' and late velocity (A') of lateral and septal MA pulsed wave velocities were assessed by echocardiography. Time constant of isovolumic pressure decay τ(0)) was calculated from isovolumic relaxation time/[ln(aortic dicrotic notch pressure) - ln(LV filling pressure)]. In all three groups, s' integral was the strongest predictor of E' (partial r= 0.53-0.79; 0.81 for three groups combined), followed by E/A ratio (partial r= 0.10-0.78; 0.26 for all groups combined) and τ(0) (partial r= -0.1 to 0.023; -0.21 for all groups combined). CONCLUSION: In healthy adults, patients with systolic HF, or patients with HOCM, E' is related to LV long-axis function and E/A ratio, a global marker of LV filling. E' appears less sensitive to LV relaxation.

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 < or =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 < or =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. CONCLUSIONS: 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.

Plasma corin levels provide minimal prognostic utility incremental to natriuretic peptides in chronic systolic heart failure.

BACKGROUND: Corin is a serine protease that cleaves pro-atrial and pro-B-type natriuretic peptides into biologically active hormones. The relationship between soluble plasma corin levels, plasma natriuretic peptide levels, myocardial structure and performance, and long-term clinical outcomes in the setting of chronic systolic heart failure has not been described. METHODS AND RESULTS: In 126 patients with chronic systolic heart failure (left ventricular ejection fraction

Clinical significance of endogenous vasoactive neurohormones in chronic systolic heart failure.

BACKGROUND: Neurohormonal activation is a pathophysiological hallmark of acute and chronic heart failure (HF). The clinical significance of more recently discovered endogenous vasoactive hormones has not been well-characterized. METHODS AND RESULTS: In 154 subjects with stable, chronic systolic HF (New York Heart Association Class I-IV, left ventricular [LV] ejection fraction or=12.1 pM (HR: 2.02, 95% CI: 1.08-3.93, P = .029) and ET-1 >or=2.29 pM (HR: 2.52, 95% CI: 1.24-5.03, P = .011) remained significant independent risk factors for adverse clinical events. CONCLUSION: Higher levels of plasma levels of UCN-1 and ET-1 but not UT-II were associated with worse LV diastolic performance and poorer long-term clinical outcomes in patients with chronic systolic HF.

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.

Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction.

The aim of this study was to explore the relationship between serum soluble angiotensin converting enzyme 2 (sACE2), parameters of cardiopulmonary exercise testing and plasma asymmetric dimethylarginine (ADMA), a marker of oxidative stress-induced endothelial dysfunction. This has not been previously evaluated. We assessed 50 consecutive ambulatory patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) ≤45%. Their blood samples were collected for sACE2 and ADMA tests before they underwent symptom-limited cardiopulmonary exercise testing and transthoracic echocardiography. The majority of our study subjects had New York Heart Association functional class II (74%) and III (18%) presentation, and 42% of patients had ischemic etiology. Median sACE2 activity was 10.36 (7.00-14.47) ng/mL and mean ADMA was 0.90 ± 0.22. sACE2 activity was inversely correlated with pVO2 (r = -0.42, P = 0.00283), exercise time (r = -0.35, P = 0.0138) and LVEF (r = -0.548, P < 0.001), and positively correlated with VE/VCO2 slope (r = 0.294, P = 0.0405), ΔDBP (r = 0.315, P = 0.0278), mitral E/Ea ratio (r = 0.442, P = 0.00158) and ADMA levels (r = 0.351, P = 0.0134). Meanwhile, we observed a negative correlation between ADMA and pVO2 (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO2 slope (r = 0.515, P < 0.001), ΔDBP (r = 0.391, P = 0.00568), mitral E/Ea ratio (r = 0.426, P = 0.00219). In multivariate logistic regression analysis, sACE2 was independently associated with peak oxygen uptake (% predicted) after adjusting for body mass index (BMI) and mitral E/Ea ratio (odds ratio [OR] 0.81 (0.58-0.94), P = 0.041) and associated with oxygen pulse (VO2/HR) (%) after adjusting for age, gender, BMI and mitral E/Ea ratio (OR 0.83 [0.68-0.95], P = 0.025). Therefore in stable chronic systolic heart failure patients, higher sACE2 activity is independently associated with diminished exercise capacity and correlates with elevated systemic oxidative stress-mediated endothelial dysfunction.

Usefulness of C-reactive protein and left ventricular diastolic performance for prognosis in patients with left ventricular systolic heart failure.

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF]

Impact of myocardial function on cystatin C measurements in chronic systolic heart failure.

BACKGROUND: The influence of myocardial function on plasma levels of cystatin C (CysC), a sensitive marker of renal function, in chronic systolic heart failure (HF) has not been well established. METHODS: We prospectively identified 139 subjects with stable, chronic HF (left ventricular ejection fraction < or = 35%) and measured plasma levels of CysC. We prospectively tracked patients' long-term adverse clinical outcomes (death, cardiac transplantation, and HF hospitalizations). RESULTS: Plasma levels of CysC were elevated in 41% of patients with preserved renal function and directly correlated with N-terminal prohormone brain natriuretic peptide (r = 0.57, P < .0001). There was a significant association between CysC and mitral E/septal E' ratio (r = 0.34, P < .001), right ventricular systolic dysfunction severity (r = 0.30, P < .001), and mitral regurgitation severity (r = 0.31, P < .001), but not left ventricular ejection fraction. At the cutoff of 1.23 mg/dL, CysC remains a significant independent risk factor for adverse clinical outcomes (hazard ratio 1.88, 95% confidence interval 1.15-3.09, P = .012) after adjusting for estimated glomerular filtration rate, left ventricular ejection fraction, and E/septal E'. CONCLUSION: CysC is associated with more advanced left ventricular diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis in chronic systolic HF after adjusting for myocardial factors.

Relation of mechanical dyssynchrony with underlying cardiac structure and performance in chronic systolic heart failure: implications on clinical response to cardiac resynchronization.

AIMS: The aim of this study is to describe the relationship between ventricular mechanical dyssynchrony (VMD) and echocardiographic indices of cardiac remodelling. METHODS AND RESULTS: We evaluated 219 ambulatory patients with chronic systolic heart failure [left ventricular ejection fraction (LVEF) 40 ms and/or inter-VMD > 38 ms). In our study cohort, 59% of patients had evidence of dyssynchrony (including 44% with intra-VMD and 38% with inter-VMD, and 20% with both). Inter-VMD correlated with QRS width (r = 0.48, P < 0.0001) better than intra-VMD (r = 0.24, P < 0.001). Higher inter-VMD was associated with less restrictive filling patterns (rank sums P = 0.012) and larger left ventricular end-diastolic dimension (LVEDD, rank sums P = 0.020), but intra-VMD values were similar across diastolic stages and LVEDD tertiles. CONCLUSION: In chronic systolic heart failure, evidence of mechanical dyssynchrony is prevalent but the underlying cardiac structure and performance may influence the degree of inter-VMD more so than intra-VMD. Our data suggest that the extent of inter-VMD is directly related to the degree of dilatation of the heart but inversely to diastolic dysfunction.

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.

Effect of Gravitational Gradients on Cardiac Filling and Performance.

BACKGROUND: Gravity affects every aspect of cardiac performance. When gravitational gradients are at their greatest on Earth (i.e., during upright posture), orthostatic intolerance may ensue and is a common clinical problem that appears to be exacerbated by the adaptation to spaceflight. We sought to elucidate the alterations in cardiac performance during preload reduction with progressive upright tilt that are relevant both for space exploration and the upright posture, particularly the preload dependence of various parameters of cardiovascular performance. METHODS: This was a prospective observational study with tilt-induced hydrostatic stress. Echocardiographic images were recorded at four different tilt angles in 13 astronauts, to mimic varying degrees of gravitational stress: 0° (supine, simulating microgravity of space), 22° head-up tilt (0.38 G, simulating Martian gravity), 41° (0.66 G, simulating approximate G load of a planetary lander), and 80° (1 G, effectively full Earth gravity). These images were then analyzed offline to assess the effects of preload reduction on anatomical and functional parameters. RESULTS: Although three-dimensional end-diastolic, end-systolic, and stroke volumes were significantly reduced during tilting, ejection fractions showed no significant change. Mitral annular e' and a' velocities were reduced with increasing gravitational load (P < .001 and P = .001), although s' was not altered. Global longitudinal strain (GLS; from -19.8% ± 2.2% to -14.7% ± 1.5%) and global circumferential strain (GCS; from -29.2% ± 2.5% to -26.0% ± 1.8%) were reduced significantly with increasing gravitational stress (both P < .001), while the change in strain rates were less certain: GLSR (P = .049); GCSR (P = .55). End-systolic elastance was not consistently changed (P = .53), while markers of cardiac afterload rose significantly (effective arterial elastance, P < .001; systemic vascular resistance, P < .001). CONCLUSIONS: Preload modification with gravitational loading alters most hemodynamic and echocardiographic parameters including e' velocity, GLS, and GCS. However, end-systolic elastance and strain rate appear to be more load-independent measures to examine alterations in the cardiovascular function during postural and preload changes, including microgravity.