Risk Stratification In Heart Failure Research Articles

INTERMACS Profiling Identifies Risk of Death or VAD among Medically-Managed Advanced Heart Failure Patients

Purpose INTERMACS profiles provide important prognostic information for patients with advanced heart failure (HF) receiving mechanical support. The role for INTERMACS profiling of advanced HF patients undergoing an initial strategy of medical management is not yet known. Methods and Materials The MedaMACS Screening Pilot enrolled 167 pts with chronic NYHA Class III-IV HF, EF≤30%, and ≥1 HF hospitalization in the prior year. Pts were excluded if listed for transplant or on inotropes. Comprehensive data were collected from usual care, with INTERMACS profiles assigned at enrollment using standard definitions. Subjects were followed for 12mos, or until death, VAD or transplant. Event rates were calculated by the Kaplan-Meier method and risk of death or VAD was analyzed using Cox modeling. Results Mean age was 57yrs, EF 17%, 47% had an ischemic etiology, and 57% had HF >5yrs. At enrollment 23% of subjects were INTERMACS profile 4, 32% profile 5, and 45% profile 6/7. Cumulative follow-up was 117 patient-yrs. Patients in lower INTERMACS profiles had been hospitalized more often in the prior 6 mos, were less often on a beta-blocker, and had higher Seattle HF model scores. Lower INTERMACS profile was associated with increased risk of death or VAD by 12 months. [ figure 1 ] Successively lower INTERMACS profile remained strongly associated with failure of medical therapy (HR 1.61, 95%CI 1.12-2.39) after adjustment for renal function, right ventricular function, and Seattle HF score quartile. Conclusions INTERMACS profiles are a useful short-hand for risk stratification in advanced HF. Lower profiles identify patients who may benefit from current mechanical support devices under existing indications.

Combined Use of the Novel Biomarkers High-Sensitivity Troponin T and ST2 for Heart Failure Risk Stratification vs Conventional Assessment

ObjectiveTo assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. Patients and MethodsThe study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). ResultsDuring median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). ConclusionA multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.

Defining and Refining Heart Failure Risk Stratification to Optimize Patient Selection for Cardiac Transplantation

VO2, BNP, GFR, RAP, CI, LVEDP, EF, Na, BUN, MR, LVEDD, PCWP, PVCs, VT, QRS, LBBB, COPD, DM, TpnI, alb, CAD, OSA, Hct, RDW, CRT, ICD, HRV—the complex alphabet soup of heart failure risk assessment used to inform clinical decision making, select patient cohorts for trials, and ensure that expensive and supply-limited treatments are utilized in the most effective and equitable manner. Despite the seeming complexity of this task, heart failure clinicians have become facile at integrating multiple distinct variables into a cohesive understanding of risk using baseline patient characteristics, measures of cardiac structure and function, biomarkers, and assessment of functional capacity. The prognostic significance of many risk-associated parameters, such as ejection fraction, ventricular size, and the pathogenesis of heart failure are firmly established. However, recognition of the importance of common comorbidities and the rapidly evolving field of novel biomarkers that represent perturbation of normal biological pathways or markers of early organ damage have reshaped and refined contemporary risk assessment. More recently, larger datasets have facilitated the derivation and validation of multivariable risk-prediction models, such as the Heart Failure Survival Score, the Seattle Heart Failure Model, and the ESCAPE Risk Score.1–3 Article see p 6 In this issue of Circulation: Heart Failure , Kato et al4 re-examine the pivotal role of cardiopulmonary exercise testing in heart failure risk assessment and extend the sentinel work by Mancini that validated VO2 as a potent predictor of short- and intermediate-term mortality.5 Mancini’s original observation that a peak VO2 <14 mL/kg per min was associated with excessive morality led to its …

Reproducibility of planar 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy in patients with heart failure

PurposeDespite its high prognostic value, widespread clinical implementation of 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is hampered by a lack of validation and standardization. The purpose of this study was to assess the reliability of planar 123I-MIBG myocardial scintigraphy in patients with heart failure (HF).MethodsPlanar myocardial MIBG images of 70 HF patients were analysed by two experienced and one inexperienced observer. The reproducibility of early and delayed heart-to-mediastinum (H/M) ratios, as well as washout rate (WR) calculated by two different methods, was assessed using the intraclass correlation coefficient (ICC) and the Bland-Altman analysis. In addition, a subanalysis in patients with a very low H/M ratio (delayed H/M ratio <1.4) was performed. The delayed H/M ratio was also assessed using fixed-size oval and circular cardiac regions of interest (ROI).ResultsIntra- and interobserver analyses and experienced versus inexperienced observer analysis showed excellent agreement for the measured early and delayed H/M ratios and WR on planar 123I-MIBG images (the ICCs for the delayed H/M ratios were 0.98, 0.96 and 0.90, respectively). In addition, the WR without background correction resulted in higher reliability than the WR with background correction (the interobserver Bland-Altman 95 % limits of agreement were −2.50 to 2.16 and −10.10 to 10.14, respectively). Furthermore, the delayed H/M ratio measurements remained reliable in a subgroup of patients with a very low delayed H/M ratio (ICC 0.93 for the inter-observer analysis). Moreover, a fixed-size cardiac ROI could be used for the assessment of delayed H/M ratios, with good reliability of the measurement.ConclusionThe present study showed a high reliability of planar 123I-MIBG myocardial scintigraphy in HF patients, confirming that MIBG myocardial scintigraphy can be implemented easily for clinical risk stratification in HF.

New mechanism of elevated CA125 in heart failure: The mechanical stress and inflammatory stimuli initiate CA125 synthesis

Carbohydrate antigen 125 has been known as a membrane-associated mucin. It has found application as a tumor marker that may be elevated in the blood of some patients with ovarian cancer, or other benign conditions. Recently, increased serum carbohydrate antigen 125 levels have been documented in patients with heart failure. However, little is known about the pathophysiologic mechanism. It has been found that carbohydrate antigen 125 will be shed from surfaces of mesothelial cells in response to mechanical stress such as fluid overload, and inflammatory stimuli. High carbohydrate antigen 125 levels are closely related to the presence of serosal fluid and positively correlated with serum TNF-α, IL-6 and IL-10 levels in heart failure patients. This leads to proposed hypothesis that the mechanical stress and inflammatory stimuli both initiate carbohydrate antigen 125 synthesis. This finding suggests that carbohydrate antigen 125 might be a promising biomarker to evaluate the risk stratification of heart failure and monitor the process of therapy.

A New Scoring System for Evaluating the Risk of Heart Failure Events in Japanese Patients With Atrial Fibrillation

Risk stratification for heart failure (HF) in patients with atrial fibrillation (AF) has not been well established. The aim of this study was to identify the predictors of HF events in patients with AF, consequently developing a new risk-scoring system that stratifies the risk for HF events. In this prospective, single hospital-based cohort, all patients who presented from July 2004 to March 2010 were registered (Shinken Database 2004-2009). Follow-up was maintained by being linked to the medical records or by sending study documents of prognosis. Of the 13,228 patients in the Shinken Database 2004-2009, 1,942 patients with AF were identified. Of the patients with AF, HF events (hospitalization or death from HF) occurred in 147 patients (7.6%) during a mean follow-up period of 776 ± 623 days. After identifying the parameters that were independently associated with the incidence of HF events (coexistence of organic heart diseases, anemia [hemoglobin level <11 g/dl], renal dysfunction [estimated glomerular filtration rate <60 ml/min/m(2)], diabetes mellitus, and the use of diuretics), a new scoring system was developed, the H(2)ARDD score (heart diseases = 2 points, anemia = 1 point, renal dysfunction = 1 point, diabetes = 1 point, and diuretic use = 1 point; range 0 to 6 points). This scoring system discriminated the low- and high-risk populations well (incidence in patients scoring 0 and 6 points of 0.2% and 40.8% per patient-year, respectively) and showed high predictive ability (area under the curve 0.840, 95% confidence interval 0.803 to 0.876). In conclusion, the new H(2)ARDD score may help identify the population of patients with AF at high risk for HF events.

017 Microvolt T-wave Alternans (MTWA) testing in “real world” heart failure (HF): a study of prevalence and incremental prognostic value

BackgroundVentricular arrhythmias contribute to the high risk of death in heart failure (HF) and can be treated with an implantable cardioverter-defibrillator (ICD). Microvolt T-wave alternans (MTWA) testing examines beat-to-beat fluctuations...

The Etiology‐Filling Pattern‐Pulmonary Artery Pressure Score: A Simple Tool for Risk Stratification of Patients with Systolic Heart Failure

Heart failure (HF) is a leading cause of morbidity and mortality. The detection of patients at high risk for death is a major challenge in HF management. The authors compared the prognostic value of 23 clinical Doppler echocardiography and cardiopulmonary exercise indexes in a stable, moderately symptomatic, systolic HF outpatient population receiving optimal medical therapy. The end point was the incidence of overall mortality. Between January 2002 and December 2008, a total of 146 patients with left ventricular (LV) ejection fraction 0.31±0.8 and New York Heart Association functional class II or III were enrolled. The prognostic power of single variables was assessed using chi-square test for categoric variables and t test for continuous variables. Variables associated with the prespecified end point were included as predictors in a binary logistic regression multivariate model. At multivariate analysis, "restrictive" LV filling pattern (P=.004), ischemic etiology (P=.022), pulmonary artery systolic pressure (PASP) ≥50 mm Hg (P=.027), and peak oxygen uptake (VO(2) ) <15.9 mL/kg/min (P=.046) resulted independent predictors of the outcome. A simple risk score was then obtained using these significant independent variables, excluding peak VO(2) because of only borderline significance. Patients with ischemic etiology, restrictive LV filling pattern, and PASP ≥50 mm Hg have a very high risk of death (odds ratio, 33.77; 95% confidence interval, 5.74-198.8; P<.001, compared with patients with no risk factors). In this high-risk group, evaluation of peak VO(2) could be superfluous. A very simple clinical echocardiographic model based on etiology-LV filling and pulmonary pressure is a powerful tool for risk stratification of systolic HF in ambulatory patients.

Association of heart failure hospitalizations with combined electrocardiography and echocardiography criteria for left ventricular hypertrophy

The value of performing echocardiography in hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) is uncertain. Baseline echo- and electrocardiographic data and cardiovascular events over 4.8 years study treatment were assessed in 922 hypertensive patients in the Losartan Intervention For Endpoint reduction in hypertension echocardiography substudy. Patients were grouped according to presence of LVH on both electrocardiogram (ECG) and echocardiogram (n = 515), only on ECG (n = 172), only on echocardiogram (n = 135), or on none tests (n = 100). LVH was diagnosed by Sokolow Lyon and Cornell product criteria by electrocardiography and as LV mass index >116 g/m(2) in men and >104 g/m(2) in women by echocardiography. Patients with LVH on both tests were older, had higher systolic blood pressure and LV mass, lower LV systolic function, and included more patients with aortic regurgitation, albuminuria, and history of ischemic heart disease (all P < 0.05). Incidence of combined myocardial infarction, stroke, or cardiovascular death did not differ between groups. Incidence of hospitalization for heart failure was 5.3 and 2.6 times higher in patients with LVH on both tests compared to patients with LVH on ECG or echocardiogram only (P < 0.01). In Cox regression, LVH on both tests predicted hospitalization for heart failure (hazard ratio 4.29 (95% confidence interval 1.26-14.65), P = 0.020) independent of other covariates including study treatment allocation and history of ischemic heart disease. Our results suggest that combining LVH assessment on a single ECG and echocardiogram provides a simple tool for additional heart failure risk stratification in asymptomatic high-risk hypertensive patients.

The clinical value of the Tei index among Nigerians with hypertensive heart failure: correlation with other conventional indices.

Various conventional methods are used for functional evaluation and risk stratification in heart failure. A combined index of global myocardial performance called the Tei index has been described. The aim of this study was to evaluate the correlation of the Tei index with other conventional indices of systolic and diastolic function among Nigerians with hypertensive heart failure. Fifty-five subjects with hypertensive heart failure and 30 controls were examined, a clinical history was taken, and echocardiography was performed on them. The subjects were categorised into four groups based on their ejection fraction (normal ejection fraction, mild, moderate and severe heart failure). The Tei index was calculated as the sum of the isovolumic relaxation and contraction time, divided by the ejection time. Statistical analysis was done using SPSS 16.0. The Tei index was significantly higher among subjects with hypertensive heart failure compared with the controls (0.91 ± 0.33 vs 0.28 ± 0.16, p < 0.005). The Tei index also increased with the severity of the heart failure and was inversely correlated with ejection fraction (r = -0.697, p < 0.001) and fractional shortening (r = -0.580, p = 0.001). It was directly correlated with mitral E/A ratio (r = 0.246, p = 0.030), left ventricular internal diastolic dimension (r = 0.414, p = 0.002), left ventricular internal systolic dimension (r = 0.596, p < 0.001) and deceleration time (r = 0.219, p = 0.032). The Tei index correlated significantly with other conventional indices of systolic and diastolic function among Nigerians with hypertensive heart failure. It can be used as a risk-stratification index similar to other traditional indices of systolic and diastolic function.

Right ventricular function and dimensions in type 2 diabetes mellitus

Background Right ventricular (RV) function has proven to be of importance for patient risk stratification in heart failure and is associated with sudden death and exercise limitation. RV dysfunction might play an important role in diabetic cardiomyopathy. We therefore assessed RV function and volumes using MRI in patients with otherwise uncomplicated type 2 diabetes mellitus (T2DM), and compared RV parameters with those of the left ventricle (LV).

Echocardiography, Natriuretic Peptides, and Risk for Incident Heart Failure in Older Adults: The Cardiovascular Health Study

This study sought to examine the potential utility of echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for heart failure (HF) risk stratification in concert with a validated clinical HF risk score in older adults. Without clinical guidance, echocardiography and natriuretic peptides have suboptimal test characteristics for population-wide HF risk stratification. However, the value of these tests has not been examined in concert with a clinical HF risk score. We evaluated the improvement in 5-year HF risk prediction offered by adding an echocardiographic score and/or NT-proBNP levels to the clinical Health Aging and Body Composition (ABC) HF risk score (base model) in 3,752 participants of the CHS (Cardiovascular Health Study) (age 72.6 ± 5.4 years; 40.8% men; 86.5% white). The echocardiographic score was derived as the weighted sum of independent echocardiographic predictors of HF. We assessed changes in Bayesian information criterion (BIC), C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). We examined also the weighted NRI across baseline HF risk categories under multiple scenarios of event versus nonevent weighting. Reduced left ventricular ejection fraction, abnormal E/A ratio, enlarged left atrium, and increased left ventricular mass were independent echocardiographic predictors of HF. Adding the echocardiographic score and NT-proBNP levels to the clinical model improved BIC (echocardiography: -43, NT-proBNP: -64.1, combined: -68.9; all p < 0.001) and C index (baseline: 0.746; echocardiography: +0.031, NT-proBNP: +0.027, combined: +0.043; all p < 0.01), and yielded robust IDI (echocardiography: 43.3%, NT-proBNP: 42.2%, combined: 61.7%; all p < 0.001), and NRI (based on Health ABC HF risk groups; echocardiography: 11.3%; NT-proBNP: 10.6%, combined: 16.3%; all p < 0.01). Participants at intermediate risk by the clinical model (5% to 20% 5-yr HF risk; 35.7% of the cohort) derived the most reclassification benefit. Echocardiography yielded modest reclassification when used sequentially after NT-proBNP. In older adults, echocardiography and NT-proBNP offer significant HF risk reclassification over a clinical prediction model, especially for intermediate-risk individuals.

Left Atrial Function Predicts Heart Failure Hospitalization in Subjects With Preserved Ejection Fraction and Coronary Heart Disease: Longitudinal Data From the Heart and Soul Study

This study sought to determine whether left atrial (LA) dysfunction predicts heart failure (HF) hospitalization in subjects with preserved baseline ejection fraction (EF). Among patients with preserved EF, factors leading to HF are not fully understood. Cross-sectional studies have demonstrated LA dysfunction at the time of HF, but longitudinal data on antecedent atrial function are lacking. We performed resting transthoracic echocardiography in 855 subjects with coronary heart disease and EF ≥50%. Left atrial functional index (LAFI) was calculated as ([LA emptying fraction × left ventricular outflow tract-velocity time integral] / [indexed LA end-systolic volume]), where LA emptying fraction was defined as (LA end-systolic volume--LA end-diastolic volume) / LA end-systolic volume. We used Cox models to evaluate the association between LAFI and HF hospitalization. Over a median follow-up of 7.9 years, 106 participants (12.4%) were hospitalized for HF. Rates of HF hospitalization were inversely proportional to quartile (Q) of LAFI: Q1, 47 per 1,000 person-years; Q2, 18.3; Q3, 9.6; and Q4, 5.3 (p < 0.001). Each standard deviation decrease in LAFI was associated with a 2.6-fold increased hazard of adverse cardiovascular outcomes (unadjusted hazard ratio: 2.6, 95% confidence interval: 2.1 to 3.3, p < 0.001), and the association persisted even after adjustment for clinical risk factors, N-terminal pro-B-type natriuretic peptide, and a wide range of echocardiographic parameters (adjusted hazard ratio: 1.5, 95% confidence interval: 1.0 to 2.1, p = 0.05). Left atrial dysfunction independently predicts HF hospitalization in subjects with coronary heart disease and preserved baseline EF. The LAFI may be useful for HF risk stratification, and LA dysfunction may be a potential therapeutic target.

Risk Stratification in Heart Failure Using 123I-MIBG

Heart failure is a progressive, heterogeneous form of cardiovascular disease that requires treatment to be individualized depending on the presenting symptoms. A decision to use an implantable cardioverter-defibrillator (ICD) is based on chronic heart failure patients presenting with a New York Heart Association classification of II or III and a left ventricular ejection fraction (LVEF) less than or equal to 30%-35%. A large percentage of ICD devices, however, never deliver therapy during their lifetime, and as many as 33% of patients ineligible for an ICD (LVEF > 35%) die of sudden cardiac death. (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy identifies sympathetic nervous system dysfunction and has been shown to lead to better patient stratification. This article reviews the role of planar (123)I-MIBG global quantitation in improving differentiation of heart failure, regardless of the LVEF, to better identify those in whom an ICD is more likely to reap benefits. It goes on to explore the potential incremental benefit of SPECT-based regional quantitation to risk stratification and provides a case example in which (123)I-MIBG SPECT was used to inform a decision to not use an ICD in a patient eligible under the standard criteria.

Test the Heart Nerves: True Grit for Prognosis?

Introduction: Meta-iodobenzylguanidine (mIBG) is an analogue of guanethidine, a false neurotransmitter. Similarly to norepinephrine (NE), mIBG undergoes active uptake into the presynaptic sympathetic nerve endings through the NE transporter mechanism and is stored in citoplasmatic vesicles. In contrast to norepinephrine, mIBG is not catabolized by either monoamine oxidase or catechol-o-methyltransferase in the synaptic cleft, so that the molecule is kept intact in sympathetic vesicles. This favorable tracer kinetics provides the physiological basis for the scintigraphy imaging using the iodine-123–labeled compound (I-mIBG) that permits the quantitative assessment of the structural and functional integrity of the myocardial sympathetic nerve fibers [1]. Derangements of the cardiac sympathetic nervous system have been documented in the failing heart. Increased sympathetic activity is an early consequence of the reflex neuro-hormonal activation that occurs in heart failure (HF). As left ventricular (LV) dysfunction progresses, the chronic increase of sympathetic activity is associated with more marked changes in the cardiac adrenergic neurotransmission, leading to reduced reuptake of NE by the presynaptic fiber and reduced myocardial content of NE. The intensity of sympathetic activation correlates with the progression of LV dysfunction, symptom severity, and mortality [2]. This pathophysiological background constitutes the basis for the use of I-mIBG scintigraphy for risk stratification in HF [3]. Until recently, the evidence supporting the use of I-mIBG as a prognostic tool in HF consisted of only small singlecenter studies. More recently, the body of evidence showing the correlation of I-mIBG imaging with prognosis was reinforced by the positive results of a systematic review [4] and a retrospective multicenter European study [5]. The ADMIRE-HF trial, reported by Jacobson et al., is the first multicenter prospective trial to test the use of I-mIBG to risk-stratify patients with HF.

Cystatin C: a step forward in assessing kidney function and cardiovascular risk

The cardiorenal syndrome is a clinical manifestation of the bidirectional interaction between the heart and kidneys. Evaluating renal function is an essential part of the assessment of every cardiac patient. It has become clear that serum creatinine is not an accurate enough marker of glomerular filtration rate (GFR) and should not be used to evaluate kidney dysfunction. Creatinine-based estimates of GFR are preferred, but require renal function to be stable and are not suitable when changes in kidney function occur. Cystatin C (CysC) has been the target of much interest in the search for an alternative measure of GFR. As an endogenous biomarker, CysC possesses many of the properties required of a good marker of renal function. Compared with that of creatinine, plasma concentrations of CysC are less influenced by factors other than GFR. Consequently, CysC correlates with true GFR more accurately than creatinine. Equations for estimating GFR from CysC values have also been developed, which makes values easier to interpret and facilitates the clinical use of this new marker. The use of CysC in acute kidney injury has also shown promising results. CysC has been studied as a risk marker for prognosis in cardiovascular disease. This effect is attributed to the strong impact of renal dysfunction on progressive cardiovascular disease and impaired survival. Higher levels of CysC have consistently been predictive of incident or recurrent cardiovascular events and adverse outcomes. CysC is a predictor of the development of heart failure and increased levels of CysC have an independent association with higher mortality in both chronic and acute heart failure. In conclusion, CysC appears to be an interesting marker of renal function and is useful for risk stratification in heart failure.

Antigen carbohydrate 125 in heart failure: Not just a surrogate for serosal effusions?

Wehave readwith interest the letter CA-125andheart failure:Deja vu or “still to be seen” by Topatan B and Basaran A [1] where the authors concisely reviewed the current pathophysiological knowledgeof CA125 in heart failure (HF). As discussed by these authors, the pathogenesis of this biomarker's elevation inHF is complex andmultifactorial,with apparently different driven forces. For instances, a proinflammatory stimulus (IL-1, tumour necrosis factor-α, lipopolysaccharide) and mesothelial-induced stress appear thekeymechanisms related to the increaseof this biomarker in HF [1–5]. However, no clear evidence exists in regard to how these two mechanisms differentially participate in CA-125 elevation in individual patients with HF. Therefore, despite the fact that the presence of serosal effusion has shown to be importantly correlated to higher CA125 values [1], considering this biomarker just a simple surrogate for serosal effusion seems quite unfair. Along this line, we have new evidence pointing-out against the fact that CA125elevation represents justmerely a surrogate for mesothelial irritation. Since July 2008 to the end of July 2010we included in an ambulatory continuous peritoneal dialysis program17 patientswith advanced congestive HF that meet the following criteria: a) NYHA III/IV despite standard pharmacological treatment; b) estimated glomerular filtration rate b60 ml/min/1.73 m; c) clinical evidence of systemic congestion and; d) at least two admissions for acute HF. Clinical characteristics of the sample are shown in the supplementary file. The peritoneal dialysis program consisted of 2 to 3-day time exchange with dialysate solution (1.36%–2.27% of glucose) with the aim to decrease the grade of systemic congestion. In these patients, and despite the peritoneal irritation induced by the presence of an osmotic solution into the peritoneum, we observed a sustained and sizable CA125 reduction at 45 [70.86 (46.14–206.7)U/ml vs 28.77 (22.09–38.6)U/ml, p=0.002] and 120 days after dialysis onset [70.86 UI/ml (46.14–206.7) vs 27.47 (16.7– 30.05)UI/ml, pb0.001] as shown in Fig. 1a. In fact, whereas only 11.8% (n=2) of patients showed CA125 serum values within normal ranges (CA125b35 U/ml) at the moment of peritoneal dialysis onset, 70.6% (n=12) and 82.3% (n=14) of the patients displayed CA125b35 U/ml at 45 and 120 days, respectively (pb0.05 for both comparisons). Paralleling to this decrease in CA125 values, an improvement in the NYHA functional class and an increase of the relative lymphocyte count (as a marker of improvement of the inflammatory state) were observed (Fig. 1b and c). With this data, we aim to stress the concept that CA125 is more than a simple surrogate for the presence of serosal effusions and mesothelial irritation, under the assumption that peritoneal dialysate is a well known irritator of the peritoneum [6,7]. Nevertheless, why most of the studies assessing the role of CA125 in HF have shown a close relationship with the presence of serosal effusions? Obviously, this question is still unsolved, although we hypothesize that CA125 is synthesized by mesothelial cells in response to certain mechanisms activated in the congestive states, and supported by recent evidence showing a pathogenic role of venous congestion in triggering a proinflammatory state [8,9], which at the end, would activate themesothelial cells to synthesize CA125. In this framework, CA125 increase and serosal effusion are parallel processes caused by the similar pathophysiological mechanisms although not necessarily a cause–effect phenomenon. No matter which pathophysiological mechanism is behind the kinetic of this biomarker, there are certain properties that make CA125 serum determination a promising tool for HF risk stratification: a) wide availability, b) additional prognostic utility beyond clinical and biochemical markers (including natriuretic peptides) [5] and; c) in contrast of cytokines and other inflammatory markers that exhibit high variability [10], CA125 changes over time are sustained (half-life higher than 1 week) and correlated with clinical status and prognosis [11,12]. Finally, we believe there is still much to be seen regarding this biomarker, and encourage researchers in HF field to focus into the pathophysiology, biological role and the clinical utility of this glycoprotein for monitoring and guiding therapy in HF setting. The following is the supplementary material related to this article. Table 1. Baseline characteristics of the study sample. Supplementary materials related to this article can be found online at doi:10.1016/j.ijcard.2010.12.027. This study was supported by unrestricted grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, RED HERACLES RD06/0009/1001 (Madrid, Spain), Ayuda para proyectos de grupos emergentes ano 2010 de la Conselleria de Sanitat de Valencia (DOCV 6.175, 30/12/2009-Annex III), Sociedad Espanola de Cardiologia (Beca Esteve 2009) and Fresenius Medical Care. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [13].

Prognostic value of endothelial microparticles in patients with heart failure

Heart failure (HF) is associated with endothelial dysfunction. Endothelium-derived microparticles (EMPs) are a novel quantitative plasma marker of endothelial dysfunction. We investigated whether plasma levels of EMPs can predict future cardiovascular events in patients with HF. We enrolled 169 consecutive HF patients (70 ischaemic, 99 non-ischaemic HF) with New York Heart Association (NYHA) class I or more. Plasma CD144-positive EMP levels were measured by flow cytometry in the HF patients and in 31 healthy subjects. We followed the HF patients for mean 30 months. Endpoints were: a composite of cardiovascular events (myocardial infarction, stroke, re-hospitalization for HF, and cardiovascular death) and all-cause mortality. Endothelium-derived microparticle levels increased significantly with NYHA functional class [EMP median (range): healthy, 0.325 (0.164-0.354) ×10⁶/mL; NYHA I, 0.484 (0.426-0.575); II, 0.646 (0.439-0.795); and III/IV, 0.786 (0.569-1.026), P < 0.001]. A total of 33 cardiovascular events and 22 all-cause deaths were registered. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the high-EMP group, but there was only a borderline difference for all-cause mortality (above median; log rank test P = 0.01, P = 0.053, respectively). Multivariate Cox regression analysis adjusted for clinical factors, identified high-EMP levels as an independent predictor of future cardiovascular events, but not for all-cause mortality in HF patients [hazard ratio (95% confidence interval): 2.423 (1.034-5.681), P = 0.04 for cardiovascular events; and 2.095 (0.825-5.323), P = 0.12 for all-cause mortality]. Endothelial dysfunction assessed by plasma levels of EMPs can independently predict future cardiovascular events in patients with HF. Endothelium-derived microparticles are a potentially useful biomarker of endothelial dysfunction in HF risk stratification.

Development of a Cardiopulmonary Exercise Prognostic Score for Optimizing Risk Stratification in Heart Failure: The (P)e(R)i(O)dic (B)reathing During (E)xercise (PROBE) Study

Background Cardiopulmonary exercise testing (CPET) provides powerful information on risk of death in heart failure (HF). We sought to define the relative and additive contribution of the 3 landmark (CPET) prognostic markers—peak oxygen consumption (VO 2), minute ventilation/carbon dioxide production (VE/VCO 2) slope, and exercise periodic breathing (EPB)—to the overall risk of cardiac death and to develop a prognostic score for optimizing risk stratification in HF patients. Methods and Results A total of 695 stable HF patients (average LVEF: 25 ± 8%) underwent a symptom-limited CPET maximum test after familiarization and were prospectively tracked for cardiac mortality. At multivariable Cox analysis EPB emerged as the strongest prognosticator. Using a statistical bootstrap technique (5000 data resamplings), point estimates, and 95% confidence intervals were obtained. Thirty-two configurations were adopted to classify patients into a given cell, according to EPB presence or absence and values of the 2 other covariates. Configurations without EPB and with VE/VCO 2 slope ≤30 were not significantly different from 0 (reference value). Statistical power of configurations increased with higher VE/VCO 2 slope and lower peak VO 2. This prompted us to formulate a score including EPB as a discriminating variable, the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE), which ranges between -1 and 1, with zero as reference configuration, that would help to optimize the prognostic accuracy of CPET-derived variables. The greatest PROBE score impact was provided by EPB, followed by VE/VCO 2 slope, whereas peak VO 2 added minimal prognostic power. Conclusions EPB with an elevated VE/VCO 2 slope leads to the highest and most precise PROBE score, whereas no additional risk information emerges when EPB is present with a peak VO 2 ≤10 mL O 2·kg −1·min −1. PROBE score appears to provide a step forward for optimizing CPET use in HF prognostic definition.

Inflammatory Markers and Incident Heart Failure Risk in Older Adults: The Health ABC (Health, Aging, and Body Composition) Study

The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults.Inflammation is associated with HF risk factors and also directly affects myocardial function.The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white).During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001).Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.