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.

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.

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.

Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure.

BACKGROUND: Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes. METHODS AND RESULTS: We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383-812) pM. Higher MBG was associated with higher myeloperoxidase (r=0.42, P<0.0001), B-type natriuretic peptide (r=0.25, P=0.001), and asymmetrical dimethylarginine (r=0.32, P<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s', r=-0.39, P<0.0001) and predicted increased risk of adverse clinical outcomes (MBG≥574 pmol/L: hazard ratio 1.58 [1.10-2.31], P=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis. CONCLUSIONS: In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis.

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.

Precision of echocardiographic estimates of right atrial pressure in patients with acute decompensated heart failure.

BACKGROUND: Several methods that estimate right atrial pressure (RAP) from echocardiographic parameters have been proposed. However, their precision (i.e., how much they decrease RAP estimation uncertainty) is unknown. The aim of this prospective study was to evaluate and compare the precision of previously proposed RAP estimates in patients with acute decompensated heart failure. METHODS: Echocardiographic and invasive hemodynamic data were acquired in 75 patients with acute decompensated heart failure. Measurements were made at the start and 48 to 72 hours after the beginning of treatment. RAP was estimated by method 1, using the cutoffs defined by inferior vena cava diameter (IVCd) and IVCd percentage change (IVCd%change) during inspiration, and by method 2, using IVCd%change and systolic to diastolic hepatic flow ratio (S/Dhep). Method 3 was used in patients with sinus rhythm, using the ratio of early tricuspid inflow and early diastolic tissue Doppler tricuspid annular velocities (E/E'ta). RAP was also estimated by resting IVCd, IVCd during inspiration, IVCd%change, right ventricular regional isovolumetric relaxation time, E/E'ta, right atrial volume index, S/Dhep, right ventricular Tei index, right ventricular E/A, and right atrial emptying fraction. Precision gain was measured as the difference between the standard deviation of RAP and the standard error of the estimate of RAP. RESULTS: Method 1 (r = 0.48, P < .05), IVCd during inspiration (r = 0.49, P < .0001), IVCd%change (r = 0.41, P < .0001) and IVCd (r = 0.40, P < .0001) had the highest correlation with RAP. The highest gain in precision was also observed with the above methods (9%, 13%, 9%, and 8%, respectively). All other parameters had poor correlation with RAP. CONCLUSION: In patients with advanced heart failure, echocardiographic RAP prediction methods showed only modest precision. Furthermore, none of the tested methods resulted in clinically relevant improvements of RAP estimates. Estimating RAP from a single IVCd measurement is at least as precise as using complex prediction methods.

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.

Right ventricular global longitudinal strain provides prognostic value incremental to left ventricular ejection fraction in patients with heart failure.

BACKGROUND: Right ventricular (RV) global longitudinal strain (RV strain) is a sensitive measure of RV mechanics. Its relationship with standard clinical markers and long-term events in chronic systolic heart failure is not well established. The aim of this study was to examine the ability of RV strain to provide incremental prognostic value to left ventricular (LV) ejection fraction (LVEF) in patients with chronic systolic heart failure. METHODS: In 171 patients with chronic systolic heart failure (LVEF ≤ 35%), a retrospective substudy of RV strain was performed using Velocity Vector Imaging to analyze previously recorded, comprehensive echocardiographic images. Death, cardiac transplantation, and heart failure hospitalization were tracked for 5 years. RESULTS: In this study cohort (mean age, 57 ± 14 years; mean LVEF, 25 ± 6%), mean RV strain was -11.6 ± 5.4%. More impaired RV strain was associated with increasing New York Heart Association class (rank-sums P < .0001) and greater LV volume (LV end-systolic volume index: r = 0.35, P < .0001). Worse RV strain was associated with reduced LVEF (r = -0.45, P < .0001), worse LV diastolic dysfunction (E/e' septal: r = 0.19, P = .017; left atrial volume index: r = 0.18, P = .031), and standard indices of RV systolic and diastolic dysfunction (RV s': r = -0.43, P < .0001; RV e'/a': r = 0.16, P = .0040; right atrial volume index: r = 0.20, P = .015). RV strain predicted long-term adverse events (hazard ratio, 1.30; 95% confidence interval, 1.02-1.70; P = .037). Furthermore, RV strain ≥ -14.8% predicted adverse events after adjustment for age, LVEF, RV s', E/e' septal, and right atrial volume index. CONCLUSION: In patients with chronic systolic heart failure, worse RV strain provides prognostic value incremental to LV function.

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.

Impact of left ventricular diastolic function on left atrial mechanics in systolic heart failure.

The relation between left atrial (LA) mechanics and left ventricular (LV) diastolic function and adverse cardiovascular events are not well established in chronic systolic heart failure (HF). In 108 patients, we performed comprehensive echocardiography with an assessment of LA global longitudinal strain (LAε) by Velocity Vector Imaging. We also performed complete diastolic examinations including mitral inflow, pulmonary vein flow, and tissue Doppler. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort (age 57 ± 15 years, LV ejection fraction 25 ± 6%), mean global LA negative (εnegative), positive (εpositive), and total ε (εtotal) were -6.8 ± 4.4%, 7.7 ± 5.7%, and 14.5 ± 8.2%, respectively. All LAε indexes correlated with individual indexes of LV diastolic dysfunction, including mitral flow early (E) to late diastolic velocity ratio (p <0.05 for all), mitral deceleration time (p <0.01 for all), E to early diastolic velocity of the septal mitral annulus (e') ratio (p <0.05 for all), pulmonary vein flow systolic to diastolic velocity ratio (p <0.001 for all), and maximal LA volume index (p <0.01 for all). All LAε indexes increased across diastolic stage (p <0.001 for all). In multivariate logistic regression analysis, LAεnegative and LAεtotal were associated with the presence of LV diastolic dysfunction grade III even after adjustment for E/e' septal and LA volume index. In Cox proportional hazards analysis, lower magnitude LAεnegative predicted long-term adverse clinical events. In conclusion, more impaired LA mechanics are associated with more severe diastolic dysfunction and predict long-term adverse events in patients with chronic systolic HF.

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.

Nitric oxide bioavailability and adiponectin production in chronic systolic heart failure: relation to severity of cardiac dysfunction.

Adiponectin is an anti-inflammatory, antiatherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailability. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA), and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman's r = 0.41, P < 0.001) and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) levels (r = 0.55, P < 0.001), inversely correlated with GABR (r = -0.39, P < 0.001), and were not associated with high-sensitivity C-reactive protein (P = 0.81) or myeloperoxidase (P = 0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r = 0.33, P = 0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums P = 0.002), right ventricular (RV) systolic dysfunction (rank sums P = 0.002), and RV diastolic dysfunction (rank sums P = 0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (hazard ratio, 95% confidence interval 1.45 [1.02-2.07], P = 0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels.

Prognostic implications of relative hypochromia in ambulatory patients with chronic systolic heart failure.

Iron insufficiency has been associated with heart failure, but the impact of a reduction of hemoglobin content in the erythrocytes as estimated by mean corpuscular hemoglobin concentration (MCHC) to myocardial structure, performance, and long-term clinical outcomes has not been well-established. The authors examined hematologic data and long-term outcomes of 197 ambulatory patients with chronic systolic and symptomatic heart failure who underwent comprehensive echocardiographic evaluation. The authors observed that relative hypochromia (defined as low MCHC) was associated with higher natriuretic peptide levels (NT-proBNP, r =-0.40, P<.0001) and lower estimated glomerular filtration rate (eGFR; r = 0.45, P <. 0001) and correlated modestly with indices of left and right ventricular diastolic dysfunction (all P<.05), but were not related to left ventricular ejection fraction (LVEF, r=0.17, P=.079). After 5 years of follow-up, lower MCHC levels were associated with higher risk of death, transplant, or heart failure hospitalization after adjusting for age, LVEF, eGFR, and New York Heart Association class (hazard ratio, 1.34; 95% confidence interval, 1.04-1.72; P=.025), particularly in those with above-median hemoglobin (>13.8 g/dL; hazard ratio, 2.02; 95% confidence interval, 1.44-2.81, P<.0001). Taken together, the observations imply that physicians should take notice of the presence of relative hypochromia particularly in the absence of anemia in the setting of chronic systolic heart failure.

Effects of percutaneous stimulation of both sympathetic and parasympathetic cardiac autonomic nerves on cardiac function in dogs.

OBJECTIVE: Augmentation of left ventricular (LV) contractility and heart rate (HR) by sympathetic nerve stimulation and amelioration of heart failure by vagal nerve stimulation has been reported. However, the effects of concomitant electrical stimulation of both sympathetic and parasympathetic cardiac nerves in tissues such as those of the cardiac plexus remain unclear. This study sought to assess acute changes in cardiac function and hemodynamics in response to endovascular cardiac plexus stimulation (CPS). METHODS: Twelve dogs received endovascular CPS via a bipolar catheter within the right pulmonary artery. Stimulation frequency (20 Hz) and pulse width (4 milliseconds) were fixed; voltage varied (range, 15-60 V). RESULTS: Results fell into three categories: 1, no response (n = 4); 2, an increase in systemic arterial pressure that was dependent on electrode placement (n = 4); and 3, a very reproducible and stable increase in aortic pressure (n = 4). In the third group, mean systolic aortic pressures, maximum value of the first derivative of LV pressure, and LV stroke work increased with stimulation (P < 0.02 for all parameters) as did cardiac output, end-systolic elastance, and preload recruitable stroke work (P = 0.03). Systemic and pulmonary vascular resistance, central venous pressure, pulmonary arterial pressure, and HR remained unchanged (P > 0.05). CONCLUSIONS: In contrast to conventional inotropic agents, endovascular CPS induced significant and selective increases in LV contractility without increasing HR. Efforts to optimize electrode placement and fixation will improve the reproducibility of endovascular CPS treatment.

Incremental prognostic value of assessing left ventricular myocardial mechanics in patients with chronic systolic heart failure.

OBJECTIVES: This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF). BACKGROUND: Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. METHODS: In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. RESULTS: In our study cohort (age 57 ± 14 years, left ventricular ejection fraction [LVEF] 26 ± 6%, median N-terminal pro-B-type natriuretic peptide [NT-proBNP] 1,158 pg/ml), the mean GLS was -7.1 ± 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = -0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s': r = -0.30, p < 0.0001), and RV diastolic function (RV e'/a': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS ≥-6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011). CONCLUSIONS: In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF.

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.

Effect of epivascular cardiac autonomic nerve stimulation on cardiac function.

BACKGROUND: The cardiac plexus contains sympathetic and parasympathetic cardiac nerves. Our goal was to assess the hemodynamic and functional effects of stimulating the cardiac autonomic nervous system (CANS) at the epivascular surfaces of the cardiac plexus. Although CANS therapy to modulate cardiovascular function has drawn widespread interest, research has focused only on stimulating parasympathetic or sympathetic nerves, not both at once. METHODS: Using general anesthesia and an open-chest surgical procedure, 12 dogs received epivascular stimulation of the cardiac plexus. A bipolar electrode was placed between the right pulmonary artery (PA) and the ascending aorta, with the stimulation frequency/pulse width held constant (20 Hz/4 ms) and the voltage varied (10-50 V). Left ventricular (LV) pressure-volume loops and hemodynamic data were recorded with and without stimulation. RESULTS: In all dogs, aortic and LV systolic pressures, maximum rate of change of LV pressure, and LV stroke work increased (p<0.0001), as did cardiac output (2.9±1.0-0.4±1.0 L/min; p=0.001), end-systolic elastance (1.2±0.4-1.5±0.5 mm Hg/mL; p=0.0001), preload recruitable stroke work (30.1±11.0-39.3±7.8 mm Hg; p=0.003), and LV ejection fraction (p=0.012). Systemic vascular resistance increased slightly (p=0.04), and pulmonary vascular resistance decreased (p=0.01). Mean heart rate and pulmonary arterial, central venous, and left atrial pressures remained unchanged (p>0.1). CONCLUSIONS: In contrast to inotropic drugs, epivascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in heart rate.

Association between systemic neutrophil gelatinase-associated lipocalin and anemia, relative hypochromia, and inflammation in chronic systolic heart failure.

Neutrophil gelatinase-associated lipocalin (NGAL) is upregulated systemically and by renal tubular cells in response to inflammation and ischemia. Recent interests in NGAL have focused on its ability to predict worsening renal function. However, as an iron-regulatory glycoprotein, the relationship between systemic NGAL levels and indices of anemia has not been examined. In 130 patients with chronic systolic heart failure, the authors examined the relationship between plasma NGAL levels and indices of anemia independent of underlying renal function and systemic markers of inflammation and oxidant stress. Plasma NGAL levels were significantly elevated in patients with anemia vs without anemia (121 [interquartile range, 98-197] vs 72 [interquartile range, 57-98] ng/mL, P<.001). Plasma NGAL levels were inversely correlated with indices of anemia including red blood cell count (r=-0.38, P<.0001), hemoglobin (r=-0.41, P<.0001), and red cell distribution width (r=0.25, P=.007), even in patients with relatively preserved renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) ; n=83, P<.05 for all). Higher plasma NGAL levels were associated with presence of anemia independent of estimated glomerular filtration rate, plasma high-sensitivity C-reactive protein, and myeloperoxidase levels (odds ratio, 2.38; 95% confidence interval, 1.02-6.20; P=.045). Hence, systemic NGAL levels are independently associated with indices of anemia.

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.

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.