Luc W. Eurlings

Management of Chronic Heart Failure Guided by Individual N-Terminal Pro-B-Type Natriuretic Peptide Targets Results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) Study

OBJECTIVES The purpose of this study was to assess whether management of heart failure (HF) guided by an individualized N-terminal pro-B-type natriuretic peptide (NT-proBNP) target would lead to improved outcome compared with HF management guided by clinical assessment alone. BACKGROUND Natriuretic peptides may be attractive biomarkers to guide management of heart failure (HF) and help select patients in need of more aggressive therapy. The PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study is, to our knowledge, the first large, prospective randomized study to address whether management of HF guided by an individualized target NT-proBNP level improves outcome. METHODS A total of 345 patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission were included. After discharge, patients were randomized to either clinically-guided outpatient management (n = 171), or management guided by an individually set NT-proBNP (n = 174) defined by the lowest level at discharge or 2 weeks thereafter. The primary end point was defined as number of days alive outside the hospital after index admission. RESULTS HF management guided by this individualized NT-proBNP target increased the use of HF medication (p = 0.006), and 64% of HF-related events were preceded by an increase in NT-proBNP. Nevertheless, HF management guided by this individualized NT-proBNP target did not significantly improve the primary end point (685 vs. 664 days, p = 0.49), nor did it significantly improve any of the secondary end points. In the NT-proBNP-guided group mortality was lower, as 46 patients died (26.5%) versus 57 (33.3%) in the clinically-guided group, but this was not statistically significant (p = 0.206). CONCLUSIONS Serial NT-proBNP measurement and targeting to an individual NT-proBNP value did result in advanced detection of HF-related events and importantly influenced HF-therapy, but failed to provide significant clinical improvement in terms of mortality and morbidity. (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure [PRIMA]; NCT00149422).

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis

Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45–0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.

Atrial fibrillation and heart failure in cardiology practice: reciprocal impact and combined management from the perspective of atrial fibrillation: results of the Euro Heart Survey on atrial fibrillation.

OBJECTIVES Our aim was to identify shortcomings in the management of patients with both atrial fibrillation (AF) and heart failure (HF). BACKGROUND AF and HF often coincide in cardiology practice, and they are known to worsen each others prognosis, but little is known about the quality of care of this combination. METHODS In the observational Euro Heart Survey on AF, 5,333 AF patients were enrolled in 182 centers across 35 European Society of Cardiology member countries in 2003 and 2004. A follow-up survey was performed after 1 year. RESULTS At baseline, 1,816 patients (34%) had HF. Recommended therapy for HF with left ventricular systolic dysfunction (LVSD) with a beta-blocker and either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker was prescribed in 40% of HF patients, while 29% received the recommended drug therapy for both LVSD-HF and AF, consisting of the combination of a beta-blocker, either ACEI or angiotensin II receptor blocker, and oral anticoagulation. Rate control was insufficient with 40% of all HF patients with permanent AF having a heart rate < or =80 beats/min. In the total cohort, HF patients had a higher risk for mortality (9.5% vs. 3.3%; p < 0.001), (progression of) HF (24.8% vs. 5.0%; p < 0.001), and AF progression (35% vs. 19%; p < 0.001) during 1-year follow-up. Of all recommended drugs for AF and LVSD-HF, only ACEI prescription was associated with improved survival during 1-year follow-up (odds ratio: 0.51 [95% confidence interval: 0.31 to 0.85]; p = 0.011). CONCLUSIONS The prescription rate of guideline-recommended drug therapy for AF and LVSD-HF is low. Randomized controlled trials targeting this highly prevalent subgroup with AF and HF are warranted.

Intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsy-proven high PVB19 viral load.

BACKGROUND Parvovirus B19 (PVB19) persistence in the heart has been associated with progressive cardiac dysfunction and evolution to dilated cardiomyopathy. In the present study, we investigated whether immunomodulation with intravenous immunoglobulin (IVIg) in addition to conventional heart failure therapy is safe and achieves virus reduction. Such therapy might improve cardiac function in patients with chronic dilated cardiomyopathy (DCM) and a significant PVB19 viral load in the heart. METHODS PVB19 viral load was studied in 25 post-mortem cardiac samples of patients with a normal heart. Then, 17 consecutive patients (mean age 53 +/-3 years) with DCM and symptomatic heart failure for >1 year with a PVB19 viral load in endomyocardial biopsies of >250 copies/microg DNA were treated with a high dose of IVIg (2 g/kg). RESULTS The post-mortem cardiac samples revealed a PVB19 presence in 80% with a mean load of 131 +/-40 copies/microg DNA. In the treated patients, IVIg resulted in a significant decrease of PVB19 viral load from 1,420 +/-216 to 619 +/-200 copies/microg DNA (P=0.004) and significantly improved the ejection fraction from 33 +/-3% 6 months before treatment and 34 +/-3% at baseline to 41 +/-3% 6 months (P=0.001) after IVIg therapy. The New York Heart Association classification significantly improved from 2.5 +/-0.1 at baseline to 2.1 +/-0.1 at follow-up (P=0.004). No therapy-related complications were noted. CONCLUSIONS The present pilot study demonstrates that IVIg significantly reduces viral load and improves cardiac function in patients with DCM related to increased PVB19 viral load in the heart.

Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials.

Previous analyses suggest that heart failure (HF) therapy guided by (N‐terminal pro‐)brain natriuretic peptide (NT‐proBNP) might be dependent on left ventricular ejection fraction, age and co‐morbidities, but the reasons remain unclear.

A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ÉLAN-HF Score

Background Models to stratify risk for patients hospitalised for acute decompensated heart failure (ADHF) do not include the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels during hospitalisation. Objective The aim of our study was to develop a simple yet robust discharge prognostication score including NT-proBNP for this notorious high-risk population. Design Individual patient data meta-analyses of prospective cohort studies. Setting Seven prospective cohorts with in total 1301 patients. Patients Our study population was assembled from the seven studies by selecting those patients admitted because of clinically validated ADHF, discharged alive, and NT-proBNP measurements available at admission and at discharge. Main outcome measures The endpoints studied were all-cause mortality and a composite of all-cause mortality and/or first readmission for cardiovascular reason within 180 days after discharge. Results The model that incorporated NT-proBNP levels at discharge as well as the changes in NT-proBNP during hospitalisation in addition to age ≥75 years, peripheral oedema, systolic blood pressure ≤115 mm Hg, hyponatremia at admission, serum urea of ≥15 mmol/L and New York Heart Association (NYHA) class at discharge, yielded the best C-statistic (area under the curve, 0.78, 95% CI 0.74 to 0.82). The addition of NT-proBNP to a reference model significantly improved prediction of mortality as shown by the net reclassification improvement (62%, p<0.001). A simplified model was obtained from the final Cox regression model by assigning weights to individual risk markers proportional to their relative risks. The risk score we designed identified four clinically significant subgroups. The pattern of increasing event rates with increasing score was confirmed in the validation group (BOT-AcuteHF, n=325, p<0.001). Conclusions In patients hospitalised for ADHF, the addition of the discharge NT-proBNP values as well as the change in NT-proBNP to known risk markers, generates a relatively simple yet robust discharge risk score that importantly improves the prediction of adverse events.

Osteoglycin Prevents Cardiac Dilatation and Dysfunction After Myocardial Infarction Through Infarct Collagen Strengthening

Rationale: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy. Objective: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI). Methods and Results: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-&bgr; signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis. Conclusions: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure.

Multimarker Strategy for Short-Term Risk Assessment in Patients With Dyspnea in the Emergency Department The MARKED (Multi mARKer Emergency Dyspnea)-Risk Score

OBJECTIVES The study aim was to determine the prognostic value of a multimarker strategy for risk-assessment in patients presenting to the emergency department (ED) with dyspnea. BACKGROUND Combining biomarkers with different pathophysiological backgrounds may improve risk stratification in dyspneic patients in the ED. METHODS The study prospectively investigated the prognostic value of the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), Cystatin-C (Cys-C), high-sensitivity C-reactive protein (hs-CRP), and Galectin-3 (Gal-3) for 90-day mortality in 603 patients presenting to the ED with dyspnea as primary complaint. RESULTS hs-CRP, hs-cTnT, Cyst-C, and NT-proBNP were independent predictors of 90-day mortality. The number of elevated biomarkers was highly associated with outcome (odds ratio: 2.94 per biomarker, 95% confidence interval [CI]: 2.29 to 3.78, p < 0.001). A multimarker approach had incremental value beyond a single-marker approach. Our multimarker emergency dyspnea-risk score (MARKED-risk score) incorporating age ≥75 years, systolic blood pressure <110 mm Hg, history of heart failure, dyspnea New York Heart Association functional class IV, hs-cTnT ≥0.04 μg/l, hs-CRP ≥25 mg/l, and Cys-C ≥1.125 mg/l had excellent prognostic performance (area under the curve: 0.85, 95% CI: 0.81 to 0.89), was robust in internal validation analyses and could identify patients with very low (<3 points), intermediate (≥3, <5 points), and high risk (≥5 points) of 90-day mortality (2%, 14%, and 44% respectively; p < 0.001). CONCLUSIONS A multimarker strategy provided superior risk stratification beyond any single-marker approach. The MARKED-risk score that incorporates hs-cTnT, hs-CRP, and Cys-C along with clinical risk factors accurately identifies patients with very low, intermediate, and high risk.

Impact of worsening renal function related to medication in heart failure

Renal failure is a major challenge in treating heart failure (HF) patients. HF medication may deteriorate renal function, but the impact thereof on outcome is unknown. We investigated the effects of HF medication on worsening renal function (WRF) and the relationship to outcome.

Reversible isolated left ventricular non-compaction?

Isolated left ventricular non-compaction (LVNC), also known as left ventricular hypertrabeculation, is characterized by the presence of extensive myocardial trabeculation and deep intertrabecular recesses that communicate with the left ventricular cavity. It potentially leads to progressive cardiac failure, thromboembolism, and malignant cardiac arrhythmias. We describe a case of a heart failure patient with diagnostic criteria of LVNC that became less clear after standard heart failure treatment.