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Background: Inflammation has been associated with vascular access (VA) dysfunction. The adipocytokine leptin can directly induce pro-inflammatory T helper 1 immune responses and the pathogenesis of chronic inflammation. We explored the association between plasma leptin and VA dysfunction in patients on maintenance hemodialysis (HEMO)., Methods: A total of 344 consecutive patients who received anastomosis for VA at a single HEMO center between June 1, 2010 and December 31, 2021 were screened. Of these patients, 267 met the inclusion criteria and were included. ELISA was used to measure circulating levels of leptin., Results: The VA dysfunction group had a higher leptin level than the patent VA group. A higher concentration of leptin was independently and significantly associated with an elevated risk of VA dysfunction. Multiple logistic regression analysis showed that leptin, female sex, and hypertension were independently associated with VA dysfunction, even after adjusting for known biomarkers. We then evaluated the ability of leptin, female sex, and hypertension to predict the risk of VA dysfunction, and the area under the curve (AUC) for leptin was 0.626 (p = 0.0001). When leptin, female sex, and hypertension were added to this multivariate model, the AUC increased to 0.679 (p = 0.001) for leptin and hypertension, and 0.690 for leptin, hypertension, and female sex (p = 0.004). In addition, plasma leptin levels were associated with sex, body mass index, and hemoglobin., Conclusions: In addition to the association between leptin and VA dysfunction, hypertension and female sex independently predicted VA dysfunction in patients with HEMO., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Growth differentiation factor 1 (GDF1) is a member of the transforming growth factor-β (TGF-β) superfamily and a protective mediator against the development of post-infarction cardiac remodeling by negatively regulating MEK-ERK1/2 and Smad signaling pathways in the heart. The TGF-β/SMAD pathway has been shown to play a key role in the development of hepatic fibrosis. In addition, fatty liver disease has been associated with reduced MEK/ERK1/2 signaling. However, no previous study has investigated the association between GDF1 and liver fibrosis. Therefore, the aim of this study was to investigate the association between plasma GDF1 and liver fibrosis in patients with stable angina., Methods: We included 327 consecutive patients with stable angina. ELISA was used to measure circulating levels of GDF1, and the fibrosis-4 index was used to assess liver fibrosis., Results: The advanced liver fibrosis group had lower median plasma GDF1 levels than those with minimal liver fibrosis. There was a significant negative association between GDF1 plasma level and fibrosis-4 index (r = -0.135, p = 0.019). A lower concentration of GDF1 was significantly and independently associated with an increased risk of liver fibrosis when concentration was analyzed as a continuous variable and by tertile. In addition, fibrosis-4 index, aspartate aminotransferase (AST)-to-platelet ratio index, and AST/alanine aminotransferase ratio were significantly associated with GDF1 concentration., Conclusions: Our results indicated an association between low plasma GDF1 and liver fibrosis in the enrolled patients. Further investigations into the role of plasma GDF1 in the pathogenesis of liver fibrosis are warranted., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Objective: To compare the activity of high-density lipoprotein (HDL)-associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients., Methods: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C-reactive protein level, and lipid profiles) were recorded., Results: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 μmoles/minute/ml and 124.4 ± 33.4 μmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 μmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts., Conclusion: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population., (© 2018, American College of Rheumatology.)

Atherosclerotic cardiovascular disease is considered as the leading cause of mortality and morbidity worldwide. Accumulating evidence supports an important role for long noncoding RNA (lncRNA) in the pathogenesis of atherosclerosis. Nevertheless, the role of lncRNA in atherosclerosis-associated vascular dysfunction and the underlying mechanism remain elusive. Here, using microarray analysis, we identified a novel lncRNA RP11-714G18.1 with significant reduced expression in human advanced atherosclerotic plaque tissues. We demonstrated in both human vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that RP11-714G18.1 impaired cell migration, reduced the adhesion of ECs to monocytes, suppressed the neoangiogenesis, decreased apoptosis of VSMCs and promoted nitric oxide production. Mechanistically, RP11-714G18.1 could directly bind to its nearby gene LRP2BP and increased the expression of LRP2BP. Moreover, we showed that RP11-714G18.1 impaired cell migration through LRP2BP-mediated downregulation of matrix metalloproteinase (MMP)1 in both ECs and VSMCs. In atherosclerotic patients, the serum levels of LRP2BP were positively correlated with high-density lipoprotein cholesterol, but negatively correlated with cardiac troponin I. Our study suggests that RP11-714G18.1 may play an athero-protective role by inhibiting vascular cell migration via RP11-714G18.1/LRP2BP/MMP1 signaling pathway, and targeting the pathway may provide new therapeutic approaches for atherosclerosis., (© 2017 Australasian Society for Immunology Inc.)

Background: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF., Methods and Results: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR., Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Aims: Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF)., Methods and Results: We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01-1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82)., Conclusions: Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve outcomes., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure., Methods and Results: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18-1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52)., Conclusion: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area., (© 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: We aimed to characterize abnormal liver function tests in patients with heart failure (HF), as they are commonly encountered yet poorly defined., Methods and Results: We used data from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) to characterize associations with baseline liver function tests (LFTs). Each LFT was analysed as both a continuous and dichotomous variable [normal vs. abnormal; bilirubin >1.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >35 mmol/L]. Logistic regression assessed the association of LFTs and 30-day all-cause mortality and HF rehospitalization, and Cox proportional hazards assessed the association with 180-day all-cause mortality among patients alive at a 30-day landmark. In ASCEND-HF, 4228 (59%) had complete admission LFT data. Of these, 42% had abnormal bilirubin, 22% had abnormal ALT, and 30% had abnormal AST. Patients with abnormal LFTs were younger, had lower body mass index, and lower left ventricular ejection fraction. In multivariable models, increased total bilirubin was associated with increased 30-day mortality or HF rehospitalization [hazard ratio (HR) 1.17 per 1 mg/dL increase, 95% confidence interval (CI) 1.04, 1.32; P = 0.012], but not with an increase in 180-day mortality (HR 1.10, 95% CI 0.97, 1.25; P = 0.13) per 1 mg/dl increase. Compared with normal bilirubin levels, abnormal bilirubin was associated with increased 30-day mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54; P = 0.048) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62; P = 0.007). We found no association with AST or ALT and outcomes., Conclusion: Greater than 40% of patients hospitalized with acute HF had abnormal LFTs. After multivariable adjustment, only elevated bilirubin was independently associated with worse clinical outcomes and may represent an important prognostic variable., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: A longitudinal and comprehensive analysis of health-related quality of life (HRQOL) was performed during hospitalization for heart failure (HF) or soon after discharge., Methods and Results: A post-hoc analysis was performed of the ASCEND-HF trial. The EuroQOL five dimensions questionnaire (EQ-5D) was administered to study participants at baseline, 24 h, discharge/day 10, and day 30. EQ-5D includes functional dimensions mapped to corresponding utility scores (i.e. 0 = death and 1 = perfect health), and a visual analogue scale (VAS) ranging from 0 (i.e. 'worst imaginable health state') to 100 (i.e. 'best imaginable health state'). The association between baseline and discharge EQ-5D measurements and subsequent clinical outcomes including death and rehospitalization were assessed using multivariable logistic regression and Cox proportional hazards regression. A total of 6943 patients (97%) had complete EQ-5D data at baseline. Mapped utility and VAS scores (mean ± SD) increased over time, respectively, from 0.56 ± 0.23 and 45 ± 22 at baseline to 0.67 ± 0.26 and 58 ± 22 at 24 h and to 0.79 ± 0.20 and 68 ± 22 at discharge, and remained stable at day 30. Lower mapped utility scores at baseline [odds ratio (OR) per 0.1 decrease in utility score 1.03, 95% confidence interval (CI) 1.00-1.06] and discharge (OR 1.10, 95% CI 1.05-1.15) and VAS scores at baseline (OR per 10 point decrease 1.05, 95% CI 1.01-1.09) were significantly associated with increased risk of 30-day all-cause death or HF rehospitalization., Conclusions: Patients hospitalized for HF had severely impaired health status at baseline and, although this improved substantially during admission, health status remained abnormal at discharge., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes., Methods and Results: We measured plasma ET-1 at baseline, 48-72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9-10] pg/mL at baseline, 6.3 (IQR 4.9-8.1) pg/mL at 48-72 h, and 5.9 (IQR 4.7-7.9) pg/mL at 30 days (P < 0.001). Baseline and 48-72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.001 and HR 1.5, 95% CI 1.2-1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48-72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03-2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis., Conclusions: We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up-titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF)., Methods and Results: Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared with patients not converted (28 ± 7 vs. 25 ± 8 mmHg, respectively; P-value 0.024). Beneficial haemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m(2) without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value 0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up, primarily due to incident hypotension., Conclusion: The use of a standardized haemodynamically guided up-titration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Cardiac pump function is often quantified by left ventricular ejection fraction by various imaging modalities. As the heart is commonly conceptualized as a hydraulic pump, cardiac power describes the hydraulic function of the heart. We aim to describe the prognostic value of resting cardiac power index (CPI) in ambulatory patients with advanced heart failure., Methods and Results: We calculated CPI in 495 sequential ambulatory patients with advanced heart failure who underwent invasive haemodynamic assessment with longitudinal follow-up of adverse outcomes (all-cause mortality, cardiac transplantation, or ventricular assist device placement). The median CPI was 0.44 W/m(2) (interquartile range 0.37, 0.52). Over a median of 3.3 years, there were 117 deaths, 104 transplants, and 20 ventricular assist device placements in our cohort. Diminished CPI (<0.44 W/m(2) ) was associated with increased adverse outcomes [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.8-3.1, P < 0.0001). The prognostic value of CPI remained significant after adjustment for age, gender, pulmonary capillary wedge pressure, cardiac index, pulmonary vascular resistance, left ventricular ejection fraction, and creatinine [HR 1.5, 95% CI 1.03-2.3, P = 0.04). Furthermore, CPI can risk stratify independently of peak oxygen consumption (HR 2.2, 95% CI 1.4-3.4, P = 0.0003)., Conclusion: Resting cardiac power index provides independent and incremental prediction in adverse outcomes beyond traditional haemodynamic and cardio-renal risk factors., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: Loop diuretics are a cornerstone of heart failure (HF) treatment, but data regarding diuretic dose adjustments after a HF hospitalization and the association with subsequent outcomes are limited. This study was therefore conducted to determine these factors., Methods and Results: We analysed data from 6119 patients enrolled in ASCEND-HF, examining the association between loop diuretic use at the time of discharge, compared with admission, and the composite outcome of 30-day HF re-hospitalization or all-cause mortality. The majority of patients, 3921 (64%), were taking a loop diuretic on admission. At discharge, 3411 (56%) patients were prescribed higher doses compared with admission, including 1867 (31%) initiating daily outpatient diuretics; 1912 (31%) had no dose change and 795 (13%) were prescribed lower doses compared with admission. Initiation of an oral loop diuretic at discharge was independently associated with better 30-day outcomes compared with no dose change [adjusted odds ratio (OR) 0.51, 95% confidence interval (CI) 0.37-0.68]. However, for patients that were already established on a loop diuretic prior to admission, change in the dose at discharge was not associated with improved outcomes compared with no dose change (adjusted OR 0.92, 95% CI 0.79-1.07)., Conclusions: In a large multinational clinical trial, 56% of patients hospitalized with HF were either initiated on a daily loop diuretic at discharge or discharged on higher doses compared with admission. In patients established on diuretics prior to hospitalization, we found no association between changes to chronic doses at discharge and improved outcomes, whereas initiation of loop diuretic therapy was associated with better outcomes compared with no dose change., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: To study pulmonary vascular response patterns to exercise in heart failure with reduced ejection fraction (HFrEF) and pulmonary hypertension (PH)., Methods and Results: In this prospective single-centre cohort study, consecutive symptomatic HFrEF patients (n = 40) with mean pulmonary arterial pressure (MPAP) ≥25 mmHg, pulmonary artery wedge pressure (PAWP) >15 mmHg, and cardiac index <2.5 L/min.m(2) , received protocol-driven titrated sodium nitroprusside (SNP) and diuretics to reach mean arterial blood pressure 65-75 mmHg and PAWP ≤15 mmHg. Patients performed symptom-limited supine bicycle testing under continued SNP administration. Afterwards, SNP was gradually withdrawn, renin-angiotensin system blockers uptitrated, and hydralazine added to maintain haemodynamic targets. Subsequently, bicycle testing was repeated. Patients presented with pulmonary vascular resistance (PVR) = 3.8 ± 1.4 Wood Units at rest, decreasing to 2.9 ± 0.9 Wood Units after decongestion, with PH was completely reversed (MPAP <25 mmHg) in 22%. From rest to maximal exercise, the cardiac index did not change significantly (P = 0.334 under SNP; P-value = 0.552 under oral therapy). A dynamic exercise-induced PVR increase >3.5 Wood Units was noted in 19 patients (48%) under oral therapy vs. five (13%) under SNP. Such exercise-induced PVR increase was associated with a 33% relative decrease in right ventricular stroke work index (P = 0.037)., Conclusions: Even after thorough decongestion and under continuous afterload reduction, PH secondary to HFrEF is completely reversible in only a minority of patients. Others demonstrate an exercise-induced PVR increase, associated with impaired right ventricular stroke work, which might be ameliorated by nitric oxide donor support., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function., (© 2013 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.)

Obese patients have been noted to have better prognosis in many conditions including heart failure. We hypothesize that this favorable prognosis for obesity may not be seen in patients with morbid obesity and advanced heart failure. A total of 501 consecutive patients with advanced heart failure referred for heart transplant evaluation to the Cleveland Clinic were studied. Patients were categorized into 3 groups based on their body mass index score as nonobese (≤30 kg/m(2) ), obese (30.1-40 kg/m(2) ), and morbidly obese (≥40 kg/m(2) ). There were fewer cardiovascular risk factors in the morbidly obese group. Unadjusted event-free survival rates were 48.4%, 57.4%, and 28.6% in the nonobese, obese, and morbidly obese groups, respectively (P=.02). In univariate analysis, both the nonobese group (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.09-1.91; P=.01) and the morbidly obese group (HR, 2.46; 95% CI, 1.40-4.30; P=.002) had significantly higher risk of all-cause mortality/transplantation compared with the obese group. This difference persisted in multivariate analysis after adjustment for confounding factors. Our study re-emphasizes the presence of an obesity paradox even in patients with very advanced heart failure. This favorable prognosis, however, may not be relevant in patients with morbidly obesity. Cardiovascular risk factors may not contribute to this phenomenon., (© 2013 Wiley Periodicals, Inc.)

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., (© 2012 Wiley Periodicals, Inc.)

Worsening renal function (WRF) during treatment of acute decompensated heart failure (ADHF) is generally associated with adverse outcomes. An increase ≥0.3 mg/dL in creatinine level is widely used as the definition of WRF. The authors sought to determine the level of agreement between WRF based on changes in creatinine and changes in cystatin C (CysC) by analyzing data from 121 ADHF patients with available admission and day 3 creatinine and CysC levels. Admission creatinine and CysC levels were 1.39 (0.98-2.11) mg/dL and 1.95 (1.42-2.69) mg/L, respectively, and correlated well (r=0.81). On average, creatinine (-0.04±0.40 mg/dL) and CysC (0.001±0.34 mg/L) changed minimally from admission to day 3. Although the correlation between both markers on day 3 was still good (r=0.79), the correlation between changes therein was only modest (r=0.43). From the 14 and 15 patients who had WRF based on a ≥0.3 mg/dL increase in creatinine and ≥0.3 mg/L increase in CysC, respectively, only four (about 30%) met both definitions. These observations, together with recent insights in the inconsistencies of creatinine-defined concept of worsening renal function and outcomes, raises the need to research more reliable measures of renal function during treatment of ADHF., (© 2013 Wiley Periodicals, Inc.)

Aims: 'Worsening renal function' (WRF) and 'improvement in renal function' (IRF) monitored by changes in serum creatinine are frequently encountered during treatment of acute decompensated heart failure (ADHF). We sought to establish the important haemodynamic determinants of alterations in serum creatinine., Methods and Results: We reviewed data from 443 patients treated for ADHF with haemodynamic guidance in a single centre. WRF and IRF were defined as a 25% increase or decrease in estimated glomerular filtration rate (eGFR) from time of admission to pulmonary artery catheter removal, respectively. Of the 443 patients, 46 (10%) experienced WRF and 127 (29%) had IRF. Baseline eGFR was lower in patients with IRF when compared with stable patients or those with WRF (45 ± 25 vs. 63 ± 30 vs. 68 ± 27 mL/min/m(2), respectively, P < 0.0001). In contrast, the relative decrease in mean blood pressure (BP) was more pronounced in patients with WRF when compared with stable patients or those with IRF (15 ± 15 vs. 9 ± 17 vs. 4 ± 15%, respectively, P = 0.003). With larger decreases in mean BP, there was greater likelihood of experiencing WRF (P = 0.04) but less likelihood of experiencing IRF (P = 0.01). In contrast, the degree of changes in right atrial pressure or cardiac index did not affect the propensity for developing WRF or IRF. There was no difference in adverse clinical outcomes (death, heart transplantation, LV assist device implantation, or readmission) between the three groups (P = 0.56)., Conclusion: Blood pressure decrease, rather than alterations in cardiac output or central venous pressure, were associated with changes in serum creatinine during treatment of ADHF.

Current guidelines recommend tricuspid valve annuloplasty (TVP) together with mitral valve surgery in cases of tricuspid annulus dilation (≥40 mm) or functional tricuspid valve regurgitation >2/4. Baseline clinical and echocardiographic data of patients undergoing mitral valve surgery in a single tertiary care hospital between 2007 and 2010 were analyzed. Mortality and heart failure hospitalization data were collected and groups with or without TVP were compared. Patients with TVP (n=89) had similar baseline characteristics compared with patients without (n=86), except for lower right ventricular fractional area change and more concomitant aortic valve surgery. Mortality was higher in the TVP group at 30 days (14% vs 5%; P=.04), but the difference was no longer significant at the end of follow-up. More patients were hospitalized for heart failure in the TVP group (31% vs 17%; hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; P=.05). Right ventricular sphericity index was the only preoperative parameter predicting death or heart failure hospitalizations. In conclusion, patients undergoing TVP in addition to mitral valve surgery are at high risk for early death or subsequent heart failure hospitalizations, which might be partly explained by more complex heart disease. The extent of preoperative right ventricular remodeling may be predictive of adverse outcomes., (© 2012 Wiley Periodicals, Inc.)

Aims: Cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling, improved functional capacity, and better clinical outcome in patients with advanced chronic heart failure, reduced ejection fraction, and evidence of ventricular conduction delay, who are under optimal medical therapy. This study investigated whether these benefits can be extrapolated to older patients, typically not included in randomized clinical trials., Methods and Results: Consecutive patients who received a CRT device between October 2008 and June 2011, including optimization afterwards in a dedicated clinic, were stratified into 3 pre-specified groups, according to age: <70 years (n = 76); 70-79 years (n = 95); and ≥80 years (n = 49). Left ventricular remodelling, functional capacity, heart failure hospitalization, and mortality data were assessed during follow-up. Reverse left ventricular remodelling and improvement in New York Heart Association functional class were similar in all groups at 6 months after implantation. During mean follow-up of 20 months, 32 patients died and 66 were admitted for heart failure. Annualized mortality rates were significantly higher in elderly patients (6% vs. 8% vs. 15% in all groups, respectively; P < 0.001), but time to death or first heart failure admission was similar among age groups (P = 0.531). Progressive pump failure was the major cause of death (50%), with co-morbidity-related deaths also being frequent (41%)., Conclusion: Reverse left ventricular remodelling and functional capacity improvement after CRT are sustained at advanced age. Moreover, time to all-cause mortality or heart failure admission was similar, irrespective of age, in a context of maximized optimization including optimal medical therapy.

Simultaneous adherence with multiple self-care instructions among heart failure (HF) patients is not well described. Patient-reported adherence to 8 recommendations related to exercise, alcohol, medications, smoking, diet, weight, and symptoms was assessed among 308 HF patients using the Medical Outcomes Study Specific Adherence Scale questionnaire (0="never" to 5="always," maximum score=40). A baseline cumulative score of ≥32/40 (average ≥80%) defined good adherence. Clinical events (death/transplantation/ventricular assist device), resource utilization, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were compared among patients with and without good adherence. The mean follow-up was 2.0±1.0 years, and adherence ranged from 26.3% (exercise) to 89.9% (medications). A cumulative score indicating good adherence was reported by 35.7%, whereas good adherence with every behavior was reported by 9.1% of patients. Good adherence was associated with fewer hospitalizations (all-cause 87.8 vs 107.6; P=.018; HF 29.6 vs 43.8; P=.007) and hospitalized days (all-cause 422 vs 465; P=.015; HF 228 vs 282; P<.001) per 100-person-years and better health status (KCCQ overall score 70.1±24.6 vs 63.8±22.8; P=.011). Adherence was not associated with clinical events or functional capacity. Patient-reported adherence with HF self-care recommendations is alarmingly low and selective. Good adherence was associated with lower resource utilization and better health status., (© 2012 Wiley Periodicals, Inc.)

Aims: We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF., Methods and Results: Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes. Baseline cTnI was undetectable in 22% and elevated above the 99th percentile URL in 50% of subjects. cTnI levels did not differ based on HF aetiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as length of stay (P = 0.01) and worsening HF during the index hospitalization (P = 0.01), but was not associated with worsened post-discharge outcomes at 30 or 180 days. The relationship between cTnI and outcomes was generally linear and there was no evidence of a threshold effect at any particular level of cTnI., Conclusion: cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and predicts in-hospital outcome, but is not an independent predictor of long-term outcomes.

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., (© 2012 Wiley Periodicals, Inc.)

Aims: Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury., Methods and Results: Urinary NGAL (uNGAL) and urinary creatinine (uCreat) levels were measured in 141 consecutive patients hospitalized for ADHF and followed for 180 days for death or re-hospitalization. AKI was defined as a rise in serum creatinine ≥0.3 mg/dl in a 48 h period. Median uNGAL/uCreat levels on Day 1 (baseline) were similar between patients who did and did not develop AKI [22.8 (12.5-106.8) μg/g vs. 20.6 (12.4-52.0) μg/g, P = 0.55]. On Day 2 and beyond, the difference between the AKI and no AKI cohorts increased, but was only significant on Day 3 [36.2 (21.7-131.8) μg/g vs. 29.4 (11.4-54.6) μg/g, P = 0.02]. The area under the receiver operating characteristic curve for Day 2 uNGAL/uCreat (≥ or <32 µg/g) to predict AKI was 0.61. There was no difference in diuretic response between 'uNGAL/uCreat + ' (≥ 27 µg/g) and 'uNGAL/uCreat-' (<27 µg/g) patients. However 'uNGAL/uCreat + ' patients had more adverse events after 180 days (66% vs. 52%, P = 0.02)., Conclusions: In patients with ADHF who develop AKI following diuretic therapy, a minor rise in uNGAL precedes AKI. However, the degree of renal tubular insult was much lower than that observed in other forms of AKI.

A proliferation of mast cells around the small pulmonary blood vessels and the alveolar septae has been noted in models of pulmonary hypertension, and in plexiform lesions of pulmonary arterial hypertension (PAH) in patients. Here, we hypothesize that total mast cell numbers and activation are increased in PAH and that they contribute to vascular remodeling through cellular and soluble proangiogenic effectors. To test this, blood and urine were collected from patients with PAH (N=44), asthma (N=18) and healthy controls (N=29) to quantitate biomarkers of total body mast cell numbers and activation (total and mature tryptase, N-methyl histamine, leukotriene LTE(4) and prostaglandin PGD-M). Serum total tryptase was higher in PAH than that in controls suggesting greater numbers of mast cells, but indicators of mast cell activation (mature tryptase, LTE(4) and PGD-M) were similar among PAH, asthma, and controls. Immunohistochemistry of lung tissues identified mast cells as primarily perivascular and connective tissue chymase(+) type in PAH, rather than mucosal phenotype. Intervention with mast cell inhibitors cromolyn and fexofenadine was performed in 9 patients for 12 weeks to identify the influence of mast cell products on the pathologic proangiogenic environment. Treatment decreased total tryptase and LTE-4 levels over time of treatment. This occurred in parallel to a drop in vascular endothelial growth factor (VEGF) and circulating proangiogenic CD34+CD133+ progenitor cells, which suggests that mast cells may promote vascular remodeling and dysfunction. In support of this, levels of exhaled nitric oxide, a vasodilator that is generally low in PAH, increased at the end of the 12-week mast cell blockade and antihistamine. These results suggest that mast cells might contribute to the pulmonary vascular pathologic processes underlying PAH. More studies are needed to confirm their potential contribution to the disease.

Elevated red cell distribution width (RDW) has been associated with poor long-term outcomes in patients with systolic dysfunction. The relationship between baseline RDW and reverse ventricular remodeling in advanced heart failure patients undergoing cardiac resynchronization therapy (CRT) has not been established. The authors reviewed the pre-implant and follow-up echocardiograms of 233 patients undergoing the new implantation of a CRT device at the Cleveland Clinic between December 2001 and November 2006. Patients were included in the final cohort if they had an RDW level within 7 days of CRT implantation, a left ventricular ejection fraction (LVEF) ≤40%, and New York Heart Association class II to IV symptoms. Patients with a reduction in left ventricular end-systolic volume ≥15% following CRT were considered "responders." Multivariate models were created to assess the relationship between baseline RDW elevation with progressive remodeling and all-cause mortality. Of 233 patients, 217 patients met inclusion criteria. Patients in the highest RDW quartile (>16.1) derived significantly less improvement in LVEF (3.5%±9.3% vs 10.1%±10.9%, P=.001) than patients in the lowest quartile (<13.6). In multivariate analysis, elevated RDW was inversely associated with response (odds ratio, 0.83; 95% confidence interval, 0.69-0.99; P=.047). The presence of elevated RDW is associated with less reverse left ventricular remodeling in patients with advanced heart failure undergoing CRT., (© 2011 Wiley Periodicals, Inc.)

Compared with conventional diuretic (CD) therapy, ultrafiltration (UF) is associated with greater weight loss and fewer re-hospitalizations in patients admitted with decompensated heart failure (HF). Concerns have been raised regarding its safety and efficacy in patients with more advanced heart failure. The authors conducted a single-center, prospective, randomized controlled trial in patients with advanced HF admitted to an intensive care unit for hemodynamically guided therapy, comparing UF (n=17) with CD (n=19) at admission. The primary end point was the time required for pulmonary capillary wedge pressure (PCWP) to be maintained at a value of ≤18 mm Hg for at least 4 consecutive hours. Secondary end points included levels of cytokines and neurohormones, as well as several clinical outcomes. In our study cohort, the time to achieve the primary end point was lower in the UF group but did not reach statistical significance (P = .08). UF resulted in greater weight reduction, higher total volume removed, and shorter hospital length of stay. There were no differences in kidney function, biomarkers, or adverse events. In patients with advanced HF under hemodynamically tailored therapy, UF can be safely performed to achieve higher average volume removed than CD therapy without leading to adverse outcomes., (© 2011 Wiley Periodicals, Inc.)

Publications regarding the potential clinical utility of biomarker testing in the management of heart failure have been exponentially increasing over the last decade. The majority of non-cardiac biomarkers are commonly used to identify end-organ dysfunction or comorbidities. The diagnostic utility of natriuretic peptide testing has been well-established. Despite consistently demonstrating their prognostic values and some promising initial results, treatment guided by natriuretic peptide testing is still debated. Although cardiac troponins have been extensively used in diagnosis of myocardial injury, their primary use of biomarkers in advanced heart failure is prognostication and risk stratification. Congest Heart Fail. Congest Heart Fail. 2011;17:169-174. © 2011 Wiley Periodicals, Inc., (© 2011 Wiley Periodicals, Inc.)

Up to 30% of cardiac resynchronization therapy (CRT) patients are considered to be "nonresponders." While the absolute number might increase because of the increased use of CRT, this proportion remains stable. As a result, there is a pressing need for guidelines for practicing clinicians to maximize the effectiveness of CRT. This clinician update describes easy-to-comprehend cases that might provide a practical insight for cardiologists, as well as for all professionals who take care of patients with heart failure who have undergone CRT., (© 2011 Wiley Periodicals, Inc.)

Various inflammatory biomarkers predict long-term outcomes in patients with acute and chronic heart failure (HF). Their relative contributions when measured in combination have not been evaluated. The authors measured both plasma levels of high-sensitivity C-reactive protein (hsCRP) and myeloperoxidase (MPO) in 136 patients with chronic systolic HF (left ventricular ejection fraction ≤ 40%), and performed echocardiography with prospective follow-up of adverse clinical events (death, cardiac transplant, and HF hospitalizations) over 34 ± 17 months. A lack of significant correlation between log-transformed hsCRP and MPO (Spearman's r = 0.11, P = .185) was observed. Within the lower two hsCRP tertiles (<5.34 mg/L), patients with plasma MPO above median levels demonstrated a 2.9-fold increased risk in adverse clinical events (95% confidence interval [CI], 1.2-8.1; P < .05), whereas within lower plasma MPO levels (<303 pM), increase in hsCRP demonstrated a 1.9-fold increased risk (95% CI, 0.56-6.2; P = not significant). Combined analysis of hsCRP and MPO levels demonstrated a 6-fold increased risk (95% CI, 2.4-16.8; P < .01) when both markers were elevated. Stratifying patients according to hsCRP, MPO, and amino-terminal pro-B-type natriuretic peptide cutoff values provided a stepwise increment of risk prediction of adverse clinical events. Combining hsCRP and MPO measurements provided distinct and complementary prognostic value in a patient cohort of chronic systolic HF., (© 2011 Wiley Periodicals, Inc.)

Changes in intrathoracic impedance (Z) leading to crossing of a derived fluid index (FI) threshold has been associated with heart failure (HF) hospitalization. The authors developed a remote monitoring program as part of HF disease management and prospectively examined the feasibility and resource utilization of monitoring individuals with an implanted device capable of measuring Z. An HF nurse analyzed all transmitted data daily, as they were routinely uploaded as part of quarterly remote device monitoring, and called the patient if the FI crossed the threshold (arbitrarily defined at 60 Omega) to identify clinically relevant events (CREs) that occurred during this period (eg, worsening dyspnea or increase in edema or weight). A total of 400 uploads were completed during the 4-month study period. During this period, 34 patients (18%) had an FI threshold crossing, averaging 0.52 FI threshold crossings per patient-year. Thirty-two of 34 patients contacted by telephone (94%) with FI threshold crossing had evidence of CREs during this period. However, only 6 (18%) had HF hospitalizations, 19 (56%) had reported changes in HF therapy, and 13 (38%) reported drug and/or dietary plan nonadherence. The average data analysis time required was 30 min daily when focusing on those with FI threshold crossing, averaging 8 uploads for review per working day and 5 telephone follow-ups per week. Our pilot observations suggested that Internet-based remote monitoring of Z trends from existing device interrogation uploads is feasible as part of a daily routine of HF disease management., (2010 Wiley Periodicals, Inc.)

Natriuretic peptides have been used as tools for diagnosis and risk stratification in patients with heart failure, myocardial infarction, and unstable coronary syndromes, as well as in the general population. The biology of intra-assay and intraindividual variations of plasma natriuretic peptide levels is still not clearly understood despite their broad adoption in clinical practice. Interpretation of plasma natriuretic peptide levels therefore requires availability of the clinical context as well as considerations of various confounders. It is clear that high plasma natriuretic peptide levels can be highly suggestive of underlying myocardial disease, although a specific underlying cause cannot be identified based on the test results. The potential use of natriuretic peptide levels to monitor and guide patient management or detect subclinical disease states is currently under investigation.