Sandra Sanders-van Wijk

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.

Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF.

NT‐proBNP‐guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT‐proBNP‐guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT‐proBNP‐guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME‐CHF) was assessed.

Long-Term Results of Intensified, N-Terminal-Pro-B-Type Natriuretic Peptide–Guided Versus Symptom-Guided Treatment in Elderly Patients With Heart FailureClinical Perspective

Background— Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy. Methods and Results— Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ⩽45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06; P=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13; P=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90; P=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not (P<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP–guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival. Conclusions— Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN43596477.

Long-term results of intensified, N-terminal-pro-B-type natriuretic peptide-guided versus symptom-guided treatment in elderly patients with heart failure: five-year follow-up from TIME-CHF.

Background— Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy. Methods and Results— Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ⩽45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06; P=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13; P=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90; P=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not (P<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP–guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival. Conclusions— Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN43596477.

Prediction of survival and magnitude of reverse remodeling using the ST2-R2 score in heart failure: A multicenter study

BACKGROUND Cardiac remodeling and its reversibility are key in HF outcomes. The ST2-R2 score was recently developed to predict relevant left ventricular (LV) reverse remodeling (R2) in patients with heart failure (HF). In the present study we sought to validate the ST2-R2 score for grading improvement in LV ejection fraction (EF) and LV size at one year, and to evaluate its prognostic implication up to 4 years. METHODS A total of 569 patients with baseline LVEF <40% from three international cohorts (Barcelona, TIME-CHF, and PROTECT) were included in the study. Patients were classified into four strata based on their ST2-R2 score, which took into account concentrations of the biomarker ST2, non-ischemic etiology, absence of left bundle branch block, HF duration, baseline LVEF, and β-blocker treatment. RESULTS A significant relationship was observed between ST2-R2 scores and changes in LVEF and indexed LV sizes. LVEF recovery (from +5.6% to +17.3%; p<0.001), percentage reduction in LV end-systolic volume index (from -6.1% to -32.1%; p<0.001) and in LV end-systolic diameter index (from -1.1% to -18.6%; p<0.001) increased over the ST2-R2 strata. A similar trend was observed with diastolic parameters. Improvement in LV function and size was inversely predictive of mortality. Hazard ratios for risk of death, using the lower ST2-R2 score strata (<9) as a reference, were 0.49 (p<0.001; score 9-11), 0.27 (p<0.001; score 12-14), and 0.17 (p<0.001; score 15-17). CONCLUSIONS The ST2-R2 score predicts reverse LV remodeling in HF patients and is useful for predicting mortality up to 4years.

Long-Term Results of Intensified, N-Terminal-Pro-B-Type Natriuretic Peptide–Guided Versus Symptom-Guided Treatment in Elderly Patients With Heart Failure

Background— Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy. Methods and Results— Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ⩽45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06; P=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13; P=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90; P=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not (P<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP–guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival. Conclusions— Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN43596477.

Improving kNowledge Transfer to Efficaciously RAise the level of Contemporary Treatment in Heart Failure (INTERACT-in-HF): Study protocol of a mixed methods study

Heart failure is a complex disease with poor outcome. This complexity may prevent care providers from covering all aspects of care. This could not only be relevant for individual patient care, but also for care organisation. Disease management programmes applying a multidisciplinary approach are recommended to improve heart failure care. However, there is a scarcity of research considering how disease management programme perform, in what form they should be offered, and what care and support patients and care providers would benefit most. Therefore, the Improving kNowledge Transfer to Efficaciously Raise the level of Contemporary Treatment in Heart Failure (INTERACT-in-HF) study aims to explore the current processes of heart failure care and to identify factors that may facilitate and factors that may hamper heart failure care and guideline adherence. Within a cross-sectional mixed method design in three regions of the North-West part of Europe, patients (n = 88) and their care providers (n = 59) were interviewed. Prior to the in-depth interviews, patients were asked to complete three questionnaires: The Dutch Heart Failure Knowledge scale, The European Heart Failure Self-care Behaviour Scale and The global health status and social economic status. In parallel, retrospective data based on records from these (n = 88) and additional patients (n = 82) are reviewed. All interviews were audiotaped and transcribed verbatim for analysis.

Cost-Effectiveness Benefits of a Disease Management Program:The REMADHE Trial Results

BACKGROUND Published studies have generated mixed, controversial results regarding the cost-effectiveness of heart failure disease management programs (HF-DMPs). This study assessed the cost-effectiveness of an HF-DMP in ambulatory patients compared with usual care (UC). METHODS In the prospective randomized REMADHE trial, we evaluated incremental costs per quality-adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 ± 1.75 years. RESULTS The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US

N-Terminal Pro-B-Type Natriuretic Peptide-Guided Therapy in Chronic Heart Failure Reduces Repeated Hospitalizations-Results From TIME-CHF

7345 (2.5%-97.5% bootstrapped confidence interval -16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US