B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure.

OBJECTIVES: We explored the stimulus for B-type natriuretic peptide (BNP) secretion in the clinical setting of heart failure (HF). BACKGROUND: Increasingly, plasma BNP levels are being incorporated into the clinical assessment and management of systolic heart failure (SHF) as well as diastolic heart failure (DHF). However, heterogeneity in BNP levels among individuals with HF can cause some confusion in interpreting results. METHODS: In 160 consecutive patients presenting with HF, we measured plasma BNP levels and performed echocardiography and cardiac catheterization. Systolic and diastolic meridional wall stress was calculated from echocardiographic and hemodynamic data. RESULTS: Although plasma BNP had a significant correlation (r2 = 0.296 [p < 0.001]) with left ventricular end-diastolic pressure (EDP) as previously reported, the correlation between plasma BNP and end-diastolic wall stress (EDWS) (r2 = 0.887 [p < 0.001]) was more robust. In a subanalysis of 62 patients with DHF, a similar result was obtained (r2 = 0.143 for EDP and r2 = 0.704 for EDWS). In a comparison between SHF and DHF, the BNP level was significantly higher in SHF (p < 0.001). Although EDP did not show any difference, EDWS was significantly higher in SHF than in DHF (p < 0.001). CONCLUSIONS: The present study shows that plasma BNP levels reflect left ventricular EDWS more than any other parameter previously reported, not only in patients with SHF, but also in patients with DHF. The relationship of left ventricular EDWS to plasma BNP may provide a better fundamental understanding of the interindividual heterogeneity in BNP levels and their clinical utility in the diagnosis and management of HF.     

Urinary B-type natriuretic peptide levels in the diagnosis and prognosis of heart failure

BackgroundPlasma B-type natriuretic peptide (BNP) is a useful biomarker for diagnosis and prognosis of heart failure (HF); however, urine BNP has never been calculated. We sought to compare urinary and plasma BNP levels and to investigate the potential diagnostic and prognostic value of this peptide in HF.Methods and ResultsUrine and plasma BNP levels were measured in 92 HF patients and 30 control subjects. Urinary BNP levels were higher in HF patients than in control subjects (P < .0001), correlating with plasma BNP levels (r = 0.64, P < .0001). Urine BNP was a good tool for the diagnosis of HF, the area under the curve (AUC) being 0.91 ± 0.06 (P < .0001). Urinary BNP levels had prognostic power for cardiac events (cardiac admissions + mortality) with an odds ratio of 6.6 (P < .05). To determine the prognostic power of urinary BNP in detecting 12-month cardiac mortality, we obtained an AUC of 0.76 ± 0.6 (P = .014).ConclusionsThe data suggest that urine BNP is a new candidate marker for diagnosis and prognosis of HF mortality and cardiac events. This raises the possibility of using this relatively simple noninvasive test in primary care settings or in specific conditions where the collection of blood samples could be difficult.     

Obesity,Brain Natriuretic Peptide Levels and Mortality in Patients Hospitalized With Heart Failure and Preserved Left Ventricular Systolic Function

BackgroundAn inverse relationship between brain natriuretic peptide (BNP) levels and body mass index (BMI) has been described for patients with left ventricular (LV) systolic dysfunction. In this study, the association of BMI, BNP levels and mortality in patients hospitalized for heart failure with preserved LV systolic function (HFpLVF) was investigated.MethodsOne hundred fifty consecutive patients (98% men) who were hospitalized with HFpLVF and had BNP levels measured on admission were analyzed. Patients were divided into categories of BMI: normal (BMI < 25 kg/m²), overweight (BMI 25–29.9 kg/m²) and obese (BMI ≥ 30 kg/m²). Relevant clinical and echocardiographic characteristics and all-cause mortality were obtained through chart review.ResultsBNP levels were significantly lower in obese (median = 227 pg/mL) and overweight (median = 396 pg/mL) patients compared with those with normal BMI (median = 608 pg/mL, P = 0.003). Higher BMI predicted BNP levels of <100 pg/mL. Compared with patients with normal BMI, overweight and obese patients had a significantly lower risk of total mortality, even after adjusting for other clinical characteristics, including log-transformed BNP levels, atrial fibrillation, the use of beta-blockers at discharge, age, hemoglobin levels and the presence of pulmonary congestion on admission. Higher BNP levels also independently predicted mortality.ConclusionsAn inverse relationship between BMI and BNP levels exists in patients hospitalized with HFpLVF. Higher BMI is associated with lower mortality, whereas higher BNP levels predict higher mortality in male patients with HFpLVF. These findings should be confirmed in a larger multicenter setting.     

Reduction in BNP Levels With Treatment of Decompensated Heart Failure and Future Clinical Events

BackgroundBrain natriuretic peptide (BNP) levels correlate with outcomes in patients with heart failure (HF). We sought to compare the relationship between absolute and relative changes in BNP with future clinical events, and whether serial BNP measurements add prognostic information in patients treated for decompensated HF.Methods and ResultsIn 203 patients treated for HF, increasing tertiles of BNP levels after treatment had a hazard ratio of 1.4 (1.1-1.7, P < .01) and increasing tertiles of percent reduction in BNP, had a hazard ratio of 0.7 (0.6-0.9, P = .005), respectively, for the combined end point of total mortality or readmission for HF. Higher baseline BNP levels did not decrease to lower BNP levels as often as lower BNP levels (P < .001). Follow-up BNP performed better in a model, incorporating age, ejection fraction, prior HF hospitalization, New York Heart Association Class, race, use of β-blockers and renin-angiotensin axis inhibitors and renal insufficiency, than did baseline BNP or percent reduction in BNP. More BNP measurements other than the follow-up BNP did not improve the fit of the model further.ConclusionsThese results suggest that both lower absolute BNP levels and greater percentage reduction in BNP with treatment of decompensated HF are associated with better event-free survival. Advocating a threshold BNP to which patients should be treated may not be possible given that high BNP levels tend not to decrease to levels associated with better outcomes during the short period of treatment. More BNP measurements do not add prognostic information beyond that provided by a single BNP level after treatment.     

Increased brain natriuretic peptide secretion is a marker of disease progression in nonobstructive hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) is associated with increased plasma brain natriuretic peptide (BNP), but sequential plasma and myocardial BNP assessment in stable and dilated HCM has never been performed.Methods and ResultsForty consecutive HCM patients (42 ± 8 years, 25 males) underwent cardiac catheterization, angiography, and left ventricular (LV) endomyocardial biopsy. During follow-up (70.5 ± 6.7 months), 30 patients (Group 1) remained stable whereas 10 patients (Group 2) progressed to dilated phase. Group 2 patients underwent a second invasive study with LV biopsy. BNP plasma levels were measured at baseline and at follow-up in all patients. All biopsies were processed for histology and immunohistochemistry with anti-BNP antibodies. BNP plasma levels remained unchanged in Group 1, whereas it significantly increased in all Group 2 patients who exhibited an elevation of LV and right ventricular end-diastolic pressure. Immunohistochemistry showed an increase of BNP-positive myocytes in follow-up biopsies when compared with baseline (75.0 ± 15.0 % versus 29.8 ± 10.0 %; P = .005) with a significant correlation with LV end-diastolic pressure (r = 0.78, P < .001) and plasma BNP (r = 0.83, P < .001).ConclusionsProgression to end-stage of HCM is characterized by further increase of myocardial and plasma BNP. Serial assessment of plasma BNP may provide noninvasive recognition of hemodynamic deterioration, allowing prompt institution of heart failure therapy.     

Impact of Obesity on Volume Status in Patients With Ambulatory Chronic Heart Failure

BackgroundFluid overload is common in heart failure (HF) and obesity; however, the relationship between the extent of intravascular volume expansion and indices such as body mass index (BMI) in obese and non-obese patients with HF has not been defined to address the issue of a HF obesity phenotype.MethodsTotal blood volume (TBV) was measured clinically using a radiolabeled albumin indicator-dilution technique in patients with predominately class III ambulatory chronic HF (N=66). Obesity was defined by BMI ≥30 kg/m².ResultsMarkedly increased intravascular volume expansion (defined by TBV expansion >+25% above normal) was highly prevalent in the obese (53%) compared to non-obese patients with HF (29%, P = .04) driven by plasma volume expansion. TBV was correlated with excess body weight and BMI (both P < .01). Also, cardiac index was higher, systemic vascular resistance lower, and left ventricular filling pressures comparable in obese compared with non-obese patients.ConclusionsQuantitative assessment of intravascular volume demonstrates for the first time that severe (not mild or moderate) volume expansion is highly common in obese patients with ambulatory chronic HF. This supports an evolving concept of an obesity-specific HF phenotype. Further study is needed to understand the mechanisms controlling volume regulation and the potential compensatory or detrimental impact on outcomes in obesity and HF.     

Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan

BackgroundB-type natriuretic peptide (BNP) immunoassays (BNP_ia) do not differentiate active and inactive forms. Inactive NT-proBNP is used to track heart failure (HF) during treatment with sacubitril/valsartan, which inhibits BNP degradation. Mass spectrometry (MS) may better assess effects of HF treatment on biologically active BNP1-32.Methods and ResultsWe developed a MS assay with immediate protease inhibition to quantify BNP1-32 over a linear range, using labeled recombinant BNP standard. In 4 healthy volunteers, BNP1-32 by MS (BNP_MS) increased from below the 5 pg/mL detection limit to 228 pg/mL after nesiritide. In patients with HF, BNP_MS was measured in parallel with BNP and NT-proBNP immunoassays before and during sacubitril/valsartan treatment. BNP_MS was 4.4-fold lower than BNP_ia in patients with HF. Among patients not taking sacubitril/valsartan and without end-stage renal disease, BNP_MS correlated with BNP_ia (r_s = 0.77, P < .001) and NT-proBNP (r_s = 0.74, P < .001). After a median of 8 weeks on sacubitril/valsartan, active BNP_MS levels decreased by 50% (interquartile range –98.3% to 41.7%, n = 22, P = .048) and correlated with NT-proBNP (r_s = 0.64, P < .001), but not with BNP_ia (r_s = 0.46, P = .057).ConclusionsActive BNP measured by MS accounts for only a small amount of BNP measured by immunoassays. Although decreased BNP production was anticipated to be masked by inhibition of degradation, levels of active BNP decreased during chronic sacubitril/valsartan treatment.     

Central Aortic Stiffness in Patients With Nonischemic Dilated Cardiomyopathy: Relationship With Neurohumoral Activation

BackgroundIncreased aortic stiffness has been found in heart failure (HF), but the underlying mechanisms remain to be elucidated. The aim of the present study was to examine the association between aortic stiffness and neurohumoral activation in patients with nonischemic dilated cardiomyopathy (NIDC).Methods and ResultsWe examined 101 patients with NIDC, New York Heart Association Class II-III, LVEF 33.3 ± 11.6%, and 33 controls. All subjects underwent blood sampling for plasma concentrations of renin, aldosterone, C-reactive protein (CRP), and brain natriuretic peptide (BNP). We evaluated the pulse wave velocity (PWV) of the proximal aorta in the region of the aortic arch with a new echo application. Patients showed increased PWV (P < .001), and increased plasma levels of log-renin (P < .001), log-aldosterone (P = .01), CRP (P = .01), and log-BNP (P = .01) compared with controls. PWV was correlated with log-BNP (r = 0.63, P < .001) and log-aldosterone (r = 0.34, P < .001) levels, with LV end-diastolic (r = 0.27, P = .01) and end-systolic (r = 0.33, P = 0.003) volumes, and the PW-tissue Doppler imaging systolic wave (r = –0.27, P = .006) and the E/e′ ratio (r = 0.45, P < .001). Linear regression analysis showed that log-BNP levels were independently associated with PWV.ConclusionsIn patients with HF from NIDC, there is evidence of increased aortic stiffness that is correlated with LV shape and function. Although aldosterone levels seem to influence the aortic PWV, BNP levels are the best independent predictor of increased PWV.     

Prognostic value of brain natriuretic peptide vs history of heart failure hospitalization in a large real-world population

BackgroundIn heart failure (HF) patients, both natriuretic peptides (NP) and previous HF hospitalization (pHFH) have been used to predict prognosis.HypothesisIn a large real‐world population, both NP levels and pHFH have independent and interdependent predictive value for clinical outcomes of HFH and all‐cause mortality.MethodsLinked electronic health records and insurance claims data from Decision Resource Group were used to identify HF patients that had a BNP or NT‐proBNP result between January 2012 and December 2016. NT‐proBNP was converted into BNP equivalents by dividing by 4. Index event was defined as most recent NP on or after 1 January 2012. Patients with incomplete records or age < 18 years were excluded. During one‐year follow up, HFH and mortality rates stratified by index BNP levels and pHFH are reported.ResultsOf 64 355 patients (74 ± 12 years old, 49% female) with available values, median BNP was 259 [IQR 101‐642] pg/ml. The risk of both HFH and mortality was higher with increasing BNP levels. At each level of BNP, mortality was only slightly higher in patients with pHFH vs those without pHFH (RR 1.2 [95%CI 1.2,1.3], P < .001); however, at each BNP, HFH was markedly increased in patients with pHFH vs those without pHFH (RR 2.0 [95%CI 1.9,2.1], P < .001).ConclusionIn this large real‐world heart failure population, higher BNP levels were associated with increased risk for both HFH and mortality. At any given level of BNP, pHFH added greater prognostic value for prediction of future HFH than for mortality.     

B-type natriuretic peptide levels in obese patients with advanced heart failure.

Although recent studies show that obesity, or elevated body mass index (BMI), is associated with lower levels of B-type natriuretic peptide (BNP), it is unknown whether BMI affects the prognostic value of BNP in heart failure (HF). This study confirms the relationship between high BMI and low BNP in patients with advanced systolic HF. Despite relatively lower levels of BNP in overweight and obesity, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality in HF at all levels of BMI.OBJECTIVES: This study aimed to examine the influence of obesity on the predictive value of the B-type natriuretic peptide (BNP) assay in heart failure (HF). BACKGROUND: Recent studies show that obesity, or elevated body mass index (BMI), is associated with lower circulating levels of BNP both in the general population and in patients with HF. METHODS: We analyzed data from 316 systolic HF (left ventricular ejection fraction [LVEF] < or =40%) patients [age, 53 +/- 13 years; mean LVEF, 24 +/- 7%; 48% ischemic] followed up at a university HF center. Patients were divided into categories of BMI: lean (BMI <25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI > or =30 kg/m2). RESULTS: The BNP levels were significantly lower in overweight and obese compared with lean patients (p = 0.0001); median BNP (interquartile range) for the lean (n = 131), overweight (n = 99), and obese (n = 86) groups was 747 (272 to 1,300), 380 (143 to 856), and 332 (118 to 617) pg/ml, respectively. In each BMI category, elevated BNP was significantly associated with worse symptoms and higher pulmonary capillary wedge pressure. Higher BNP was also a significant independent predictor of survival independent of BMI. Optimal BNP cutoff for prediction of death or urgent transplant in lean, overweight, and obese HF patients was 590, 471, and 342 pg/ml, respectively. CONCLUSIONS: Although BNP levels are relatively lower in overweight and obese HF patients, BNP predicts worse symptoms, impaired hemodynamics, and higher mortality at all levels of BMI.     

Greater Body Mass Index Is Associated With Poorer Cognitive Functioning in Male Heart Failure Patients

BackgroundHeart failure (HF) and obesity are associated with cognitive impairment. However, few studies have investigated the relationship between adiposity and cognitive functioning in HF for each sex, despite observed sex differences in HF prognosis. We tested the hypothesis that greater body mass index (BMI) would be associated with poorer cognitive functioning, especially in men, in sex-stratified analyses.Methods and ResultsParticipants were 231 HF patients (34% female, 24% nonwhite, average age 68.7 ± 7.3 years). Height and weight were used to compute BMI. A neuropsychology battery tested global cognitive function, memory, attention, and executive function. Composites were created using averages of age-adjusted scaled scores. Regressions adjusting for demographic and medical factors were conducted. The sample was predominantly overweight/obese (76.2%). For men, greater BMI predicted poorer attention (ΔR² = 0.03; β = −0.18; P = .01) and executive function (ΔR² = 0.02; β = −0.13; P = .04); these effects were largely driven by men with severe obesity (BMI ≥40 kg/m²). BMI did not predict memory (P = .69) or global cognitive functioning (P = .08). In women, greater BMI was not associated with any cognitive variable (all P ≥ .09).DiscussionHigher BMI was associated with poorer attention and executive function in male HF patients, especially those with severe obesity. These patients may therefore have more difficulties with the HF treatment regimen and may have poorer outcomes.     

Association between prehospital delay and subsequent clinical course in patients with/hospitalized for heart failure

BackgroundThe clinical consequences of prehospital delay in heart failure (HF) patients are unknown. This study explores the relationship between prehospital delay of HF patients and length of hospital stay, plasma values of brain natriuretic peptides (BNP) as well as the association of delay with all-cause mortality, readmission for HF, or all-cause readmissions during short- (60 days) and long-term (18 months) follow-up.MethodsData from 1023 hospitalized HF patients mean aged 71 years from the Coordinating study evaluating Outcomes of Advising and Counselling in HF study were analyzed.ResultsPatients who delayed less than 1 day had significantly shorter stay in hospital (10 days vs. 11 days, P = 0.033). They also had significantly (P = 0.004) lower median plasma values of BNP (377 pg/mL) at discharge compared to patients who delayed >24 hours (492 pg/mL). Delay was not related to all-cause mortality and/or readmissions for HF.ConclusionAlthough patients with a prehospital delay less than 1 day were more symptomatic on admission, they had a shorter hospital stay as well as lower plasma values of BNP at discharge. Delay was not associated hospital readmissions or mortality after discharge.     

Diminished Global Arginine Bioavailability as a Metabolic Defect in Chronic Systolic Heart Failure

BackgroundSystemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy.Methods and ResultsWe measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68–1.17] vs 0.61 [0.44–0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43–0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52–1.07] to 0.97 [0.81–1.20]; P = .019).ConclusionsIn patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.     

Usefulness of B-type natriuretic peptide levels to predict left ventricular filling pressures in patients with body mass index >35, 31 to 35, and < or =30 kg/m2

Noninvasive left ventricular (LV) pressure estimation in obese patients has not been well described. Simultaneous B-type natriuretic peptide (BNP) and echocardiographic Doppler examinations were performed in patients with dyspnea undergoing cardiac catheterization. Patients were divided into body mass index (BMI) >35 (markedly obese), 31 to 35 (obese), and < or =30 kg/m2 (nonobese). BNP levels and mitral early diastolic/tissue Doppler annular velocity (E/Ea) were compared with invasively measured LV end-diastolic and pre-atrial (pre-A) pressures. Seventy-two patients were studied. Except for BMI, LV mass index, and LV diastolic dimension, there were no significant differences in baseline, echocardiographic Doppler, or hemodynamic characteristics among the groups. However, BNP was significantly lower in markedly obese compared with obese and nonobese patients (116 +/- 187 vs 241 +/- 674 and 277 +/- 352 pg/ml, respectively; p = 0.03). BNP did not correlate with LV pre-A pressure in markedly obese patients (R = 0.13, p = 0.47), whereas BNP significantly correlated with this variable in the obese (R = 0.64) and nonobese (R = 0.58) groups. Mitral E/Ea significantly correlated with LV pre-A and LV end-diastolic pressures in all BMI groups. In markedly obese patients with dyspnea, BNP did not correlate with invasively measured LV filling pressure, whereas this correlated in obese and nonobese patients. However, mitral E/Ea significantly correlated with LV filling pressures in all BMI groups. In conclusion, BNP is not recommended for LV filling pressure estimation in ambulatory patients with dyspnea with BMI >35 kg/m2.     

Depressive Symptoms Affect the Relationship of N-Terminal Pro B-Type Natriuretic Peptide to Cardiac Event-Free Survival in Patients With Heart Failure

BackgroundBoth N-terminal pro B-type natriuretic peptide (NT-pro BNP) and depressive symptoms independently predict cardiac events in heart failure (HF) patients. However, the relationship among NT-pro BNP, depressive symptoms, and cardiac event is unknown.Methods and ResultsBlood was drawn to measure NT-pro BNP and depressive symptoms were measured by the Patient Health Questionnaire 9 (PHQ-9) among 210 patients with HF. Data about cardiac event-free survival were collected for the average follow-up period of 397 days. Cox proportional hazards regression with survival curves were used to determine the relationship of NT-pro BNP and depressive symptoms to cardiac event-free survival. Higher NT-pro-BNP confers greater risk of cardiac events among those with depressive symptoms than those without depressive symptoms (P for the interaction = .029). Patients with NT-pro BNP >581 pg/mL and total PHQ-9 score ≥10 had a 5.5 times higher risk for cardiac events compared with patients with NT-pro BNP ≤581 pg/mL and total PHQ-9 score < 10 (P = .001).ConclusionsThe prognostic association of NT-pro BNP with cardiac event-free survival in patients with HF differed by the presence of depressive symptoms. Monitoring and treatment of depressive symptoms may be important for improving cardiac event-free survival in patients with HF.     

Prognostic value of serum tenascin-C levels on long-term outcome after acute myocardial infarction

BackgroundTenascin-C (TN-C), an extracellular matrix glycoprotein, is not normally expressed in the adult heart but transiently reappears under various pathologic conditions to play important roles in tissue remodeling. It is unclear whether serum TN-C levels add prognostic information independent from traditional prognostic markers.Methods and ResultsWe assessed 239 patients with first ST-segment elevation myocardial infarction who underwent successful percutaneous coronary intervention. We measured serum TN-C and plasma B-type natriuretic peptide (BNP) levels on day 5 after admission and compared long-term clinical outcome. During the follow-up period (24.3 ± 13 months), 54 patients experienced primary composite cardiac events (cardiac death or hospitalization for worsening heart failure). Multivariable Cox proportional hazards analysis indicated that serum TN-C (hazard ratio 2.92, 95% confidence interval [CI] 1.55–5.67; P < .001) and plasma BNP levels (hazard ratio 1.84, 95% CI 1.17–2.97; P = .008) were significant independent predictors for cardiac events after adjustment for multiple confounders. The combination of TN-C and BNP resulted in an increase of the c-statistic from 0.821 to 0.877 (P < .001) and an integrated discrimination improvement gain of 14.0% (P < .001).ConclusionsSerum TN-C level on day 5 after admission is potentially useful for early risk stratification after AMI beyond established prognostic markers.     

The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure

BackgroundBody mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers’ association with prognosis in patients with acute heart failure (AHF).Methods and ResultsB-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5–24.9 kg/m²), overweight (25–29.9 kg/m²) or obese (≥ 30 kg/m²) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs.ConclusionsIn patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.     

Leptin and norepinephrine plasma concentrations during glucose loading in normotensive and hypertensive obese women

We performed this study to investigate whether changes in plasma glucose, insulin, and norepinephrine concentrations during an oral glucose tolerance test (OGTT) are associated with changes in plasma leptin levels in normotensive and hypertensive obese women. Plasma insulin, glucose, norepinephrine, and leptin concentrations were evaluated at the baseline and during OGTT in normotensive women (NT-Ob, N = 24, mean age 38.3 ± 1.8 years, body mass index [BMI] 37.9 ± 1.1 kg/m²) and hypertensive (HT-Ob, N = 25, mean age 37.7 ± 1.9 years, BMI 39.4 ± 1.3 kg/m²) obese women, and in a group of normal-weight women (controls, N = 20, mean age 38.3 ± 1.3 years, BMI 23.1 ± 0.4 kg/m²). The OGTT caused a significant increase in plasma leptin concentrations in both NT-Ob and HT-Ob groups, whereas no such change was detectable in control subjects. Area under curve (AUC) for plasma leptin showed a direct correlation with norepinephrine AUC in both NT-Ob (r = 0.73, P = .001) and HT-Ob (r = 0.74, P = .001) group, which was still detectable in multivariate analysis (P = .014 and P = .017, respectively). Our study confirms that glucose loading increases circulating leptin concentrations in obese women, and demonstrates the existance of an association between leptin and norepinephrine changes during OGTT in both normotensive and hypertensive obese women. We hypothesize that this association may reflect the lack of leptin suppression by catecholamines or a direct leptin-induced sympathoactivation. These findings suggest that leptin could be relevant in the regulation of blood pressure in obese women.     

Cardiopulmonary and Noninvasive Hemodynamic Responses to Exercise Predict Outcomes in Heart Failure

BackgroundAn impaired cardiac output response to exercise is a hallmark of chronic heart failure (HF). We determined the extent to which noninvasive estimates of cardiac hemodynamics during exercise in combination with cardiopulmonary exercise test (CPX) responses improved the estimation of risk for adverse events in patients with HF.Methods and ResultsCPX and impedance cardiography were performed in 639 consecutive patients (mean age 48 ± 14 years), evaluated for HF. Clinical, hemodynamic, and CPX variables were acquired at baseline and subjects were followed for a mean of 460 ± 332 days. Patients were followed for the composite outcome of cardiac-related death, hospitalization for worsening HF, cardiac transplantation, and left ventricular assist device implantation. Cox proportional hazards analyses including clinical, noninvasive hemodynamic, and CPX variables were performed to determine their association with the composite endpoint. There were 113 events. Among CPX variables, peak oxygen uptake (VO₂) and the minute ventilation (VE)/carbon dioxide production (VCO₂) slope were significant predictors of risk for adverse events (age-adjusted hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.05–1.11 for both; P < .001). Among hemodynamic variables, peak cardiac index was the strongest predictor of risk (HR 1.08, 95% CI 1.0–1.16; P = .01). In a multivariate analysis including CPX and noninvasively determined hemodynamic variables, the most powerful predictive model included the combination of peak VO₂, peak cardiac index, and the VE/VCO₂ slope, with each contributing significantly and independently to predicting risk; an abnormal response for all 3 yielded an HR of 5.1 (P < .001).ConclusionsThese findings suggest that noninvasive indices of cardiac hemodynamics complement established CPX measures in quantifying risk in patients with HF.     

Protein Carbamylation in Chronic Systolic Heart Failure: Relationship With Renal Impairment and Adverse Long-Term Outcomes

BackgroundProtein 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 ResultsIn 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).ConclusionsIn 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.