Background Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI). Methods In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) <= 45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% +/- 5.4%, placebo: 4.0% +/- 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 +/- 13.3 ml/m(2), placebo: 5.1 +/- 18.9 ml/m(2), P = .54), and LVESVI (fulacimstat: 2.3 +/- 11.2 mL/m(2), placebo: 0.6 +/- 14.8 ml/m(2), P = .56) were observed in both treatment arms. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.

Abstract Introduction Adverse cardiac remodelling represents the most important risk factor for the development of heart failure (HF) after myocardial infarction (MI). Chymase is a protease that generates locally pro-fibrotic factors such as angiotensin II, TGFβ, and matrixmetallproteases that contribute to tissue remodelling. Purpose This phase IIa study examined the effects of the chymase inhibitor fulacimstat on functional parameters of adverse cardiac remodelling after acute MI. Methods A double-blind, multinational, randomized, placebo-controlled study was performed in patients after first STEMI who were treated with primary percutaneous coronary intervention within 24h of symptom onset. To enrich for patients at risk of adverse remodelling, main inclusion criteria were a left-ventricular ejection fraction (LVEF)≤45% and an infarct size>10% on day 5 to 9 post MI as measured by cardiac MRI. On day 6 to 12 post MI, patients were randomized to treatment with either 25 mg fulacimstat (n=54) or placebo (n=53) twice daily on top of standard of care. The changes in LVEF, LVEDVI, and LVESVI from baseline to 6 months of treatment were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated, 64.8% of patients treated with fulacimstat and 75.5% of patients treated with placebo reported treatment emergent adverse events. Fulacimstat achieved exposures that were approximately 10-fold higher than those predicted to be required for minimal therapeutic activity. After six months of treatment, there were no effects of fulacimstat compared to placebo on the changes in LVEF, LVEDVI, and LVESVI (see Table). Analysis of primary efficacy parameters Parameter Placebo Fulacimstat p-value LVEF (%) baseline 37.2±6.1 39.1±5.5 0.15 6 months 41.2±8.4 42.6±8.4 0.45 delta 4.0±5.0 3.5±5.4 0.69 LVEDVI (mL/m2) baseline 80.0±17.1 77.4±18.2 0.51 6 months 85.1±19.1 84.7±23.4 0.94 delta 5.1±18.9 7.3±13.3 0.54 LVESVI (mL/m2) baseline 50.5±13.0 47.3±12.3 0.26 6 months 51.1±16.9 49.6±18.1 0.71 delta 0.6±14.8 2.3±11.2 0.56 Data are given as mean ± standard deviation. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study. Acknowledgement/Funding The study was funded by its sponsor BAYER AG

Blood group systems based on red blood cell antigens are genetically determined and can identify patients at risk. Type non-O of the ABO blood group system has been associated with coronary artery disease, thrombosis, and a worse prognosis. The present study evaluated the distribution of blood group types in patients with heart failure (HF) and the impact on clinical outcome. We evaluated the ABO and Rhesus D antigen (RhD) blood types in a large cohort of chronic HF patients (n = 3,815). ABO blood type distribution in the HF population was not significantly different to that reported in the general national population (A 40%, B 20%, AB 8%, and O 33%). The percentage of Rh-negative per blood type was also similar (A 10%, B 9%, AB 10%, and O 7%). Patients with type 0 were more likely to be hypertensive compared with non-O type. Mean follow-up was 4.2 years. Overall survival during follow-up was 55%. Cox regression analysis after adjustment for significant predictors demonstrated that RhD-negative was associated with a worse prognosis in patients with ischemic cardiomyopathy (n = 2,881, 76 %): hazard ratio 1.26, 95% confidence interval 1.04 to 1.53, p = 0.02. Type non-O was also independently associated with a worse prognosis compared with type 0 in patients with non-ischemic cardiomyopathy: hazard ratio 1.32, 95% confidence interval 1.04 to 1.67, p = 0.02. In conclusion, blood group type distribution in HF patients are similar to the general population. RhD-negative is associated with a worse prognosis in patients with ischemic cardiomyopathy. (C) 2018 Elsevier Inc. All rights reserved.

Background: Acute myocarditis carries a variable prognosis. We evaluated the morbidity and mortality rates in patients with acute myocarditis and admission electrocardiographic predictors of outcome. Methods and Results: Patients admitted to a tertiary hospital with a clinical diagnosis of acute myocarditis were evaluated; 193 patients were included. Median follow-up was 5.7 years, 82% were male, and overal median age was 30 years (range 21-39). The most common clinical presentations were chest pain (77%) and fever (53%). The 30-day survival rate was 98.9%. Overall survival during follow-up was 94.3%. The most common abnormalities observed on electrocardiography were T-wave changes (36%) and ST segment changes (32%). Less frequent changes included abnormal T-wave axis (>105 degrees or < -15 degrees; 16%), abnormal QRS axis (12%), QTc >460 ms (11%), and QRS interval >= 120 ms (5%). Wide QRS-T angle 100) was demonstrated in 13% of the patients and was associated with an increased mortality rate compared with patients with a narrow QRS-T angle (20% vs 4%; P = .007). The rate of heart failure among patients with a wide QRS-T angle was significantly higher (36% vs 10%; P = .001). Cox regression analysis demonstrated that a wide QRS-T angle (100) was a significant independent predictor of heart failure (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.35-7.59; P < .01) and of the combined end point of death or heart failure (HR 2.56, 95% CI 1.14-5.75; P < .05). Conclusions: QRS-T angle is a predictor of increased morbidity and mortality in acute myocarditis.

BACKGROUND: Many patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure.METHODS: Patients with heart failure taking warfarin therapy (n = 145) were randomized to either standard care or a 1-time intervention assessing potential risk factors for lability of INR, in which they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal's linear model was assessed 3 months before and after the intervention.RESULTS: The patient-tailored intervention significantly increased anticoagulation control. The median TTR levels before intervention were suboptimal in the interventional and control groups (53% vs 45%, P = .14). After intervention the median TTR increased significantly in the interventional group compared with the control group (80% [interquartile range, 62%-93%] vs 44% [29%-61%], P <.0001). The intervention resulted in a significant improvement in the interventional group before versus after intervention (53% vs 80%, P <.0001) but not in the control group (45% vs 44%, P = .95). The percentage of patients with a TTR >= 60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group.CONCLUSIONS: Patient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure. (C) 2017 Elsevier Inc. All rights reserved.

Acute myocarditis is one of the most challenging diseases to diagnose and treat in cardiology. The true incidence of the disease is unknown. Viral infection is the most common etiology. Modern techniques have improved the ability to diagnose specific viral pathogens in the myocardium. Currently, parvovirus B19 and adenoviruses are most frequently identified in endomyocardial biopsies. Most patients will recover without sequelae, but a subset of patients will progress to chronic inflammatory and dilated cardiomyopathy. The pathogenesis includes direct viral myocardial damage as well as autoimmune reaction against cardiac epitopes. The clinical manifestations of acute myocarditis vary widely from asymptomatic changes on electrocardiogram to fulminant heart failure, arrhythmias and sudden cardiac death. Magnetic resonance imaging is emerging as an important tool for the diagnosis and follow-up of patients, and for guidance of endomyocardial biopsy. In the setting of acute myocarditis endomyocardial biopsy is required for the evaluation of patients with a clinical scenario suggestive of giant cell myocarditis and of those who deteriorate despite supportive treatment. Treatment of acute myocarditis is still mainly supportive, except for giant cell myocarditis where immunotherapy has been shown to improve survival. Immunotherapy and specific antiviral treatment have yet to demonstrate definitive clinical efficacy in ongoing clinical trials. This review will focus on the clinical manifestations, the diagnostic approach to the patient with clinically suspected acute myocarditis, and an evidence-based treatment strategy for the acute and chronic form of the disease.

The diagnosis of constrictive pericarditis should be considered in any patient with unexplained right heart failure. The differentiation between constrictive pericarditis and restrictive cardiomyopathy is based on a combination of clinical presentation, history and imaging, and on occasion, on the basis of invasive hemodynamic studies or biopsy. Pertinent anatomic and physiologic findings on cardiac imaging modalities including echocardiography, computed tomography and cardiac magnetic resonance imaging are reviewed, and in many cases the diagnosis can be determined on the basis of imaging. Hemodynamic studies may clarify the diagnosis, and biopsy may find treatable causes of disease.

Aims Vitamin D deficiency is a highly prevalent, global phenomenon. The prevalence in heart failure (HF) patients and its effect on outcome are less clear. We evaluated vitamin D levels and vitamin D supplementation in patients with HF and its effect on mortality. Methods and results 25‐Hydroxyvitamin D [25(OH)D] levels were evaluated in HF patients from a health maintenance organization (HMO), and compared them with those of the rest of the members of the HMO. Patients with HF ( n = 3009) had a lower median 25(OH)D level compared with the control group ( n = 46 825): 36.9 nmol/L (interquartile range 23.2–55.9) vs. 40.7 nmol/L (26.7–56.9), respectively, P < 0.00001. The percentage of patients with vitamin D deficiency [25(OH)D <25 nmol/L] was higher in patients with HF compared with the control group (28% vs. 22%, P < 0.00001). Only 8.8% of the HF patients had optimal 25(OH)D levels (≥75 nmol/L). Median clinical follow‐up was 518 days. Cox regression analysis demonstrated that vitamin D deficiency was an independent predictor of increased mortality in patients with HF [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.21–1.92, P < 0.001] and in the control group (HR 1.91, 95% CI 1.48–2.46, P < 0.00001). Vitamin D supplementation was independently associated with reduced mortality in HF patients (HR 0.68, 95% CI 0.54–0.85, P < 0.0001). Parameters associated with vitamin D deficiency in HF patients were decreased previous solar radiation exposure, body mass index, diabetes, female gender, pulse, and decreased calcium and haemoglobin levels. Conclusions Vitamin D deficiency is highly prevalent in HF patients and is a significant predictor of reduced survival. Vitamin D supplementation was associated with improved outcome.

Background: A seasonal variation in hospital admissions in patients with heart failure (HF) has been described and most admissions occur during the winter season. The effect of this seasonal variation on prognosis is less clear. Objectives: To evaluate the effect of the seasonal timing of hospital admission on clinical outcome in patients with HF. Methods: We prospectively enrolled 362 consecutive patients hospitalized with a definite clinical diagnosis of HF during a 2-year period. Patients were followed clinically for a period of 1 year. Results: There was a prominent seasonal variation in hospital admissions in patients with HF with peak admissions during the winter. The admission rate inversely correlated with the average monthly temperature. Admission during the summer season was a significant predictor of reduced survival (59 vs. 75%, p < 0.01). Cox regression analysis demonstrated that independent predictors of reduced survival after adjustment for other predictors were admission during the hottest 6 months or admission during the summer. In addition, increased mean environmental admission temperature was an independent predictor of reduced survival. Conclusions: Seasonal temperature has a significant effect on the rate of hospital admission in patients with HF. Admission during warmer weather is a sign of a poor prognosis. Copyright (C) 2011 S. Karger AG, Basel

AIMS A substantial proportion of patients with heart failure have preserved left ventricular ejection fraction (HF-PEF). Previous studies have reported mixed results whether survival is similar to those patients with heart failure and reduced EF (HF-REF). METHODS AND RESULTS We compared survival in patients with HF-PEF with that in patients with HF-REF in a meta-analysis using individual patient data. Preserved EF was defined as an EF ≥ 50%. The 31 studies included 41 972 patients: 10 347 with HF-PEF and 31 625 with HF-REF. Compared with patients with HF-REF, those with HF-PEF were older (mean age 71 vs. 66 years), were more often women (50 vs. 28%), and have a history of hypertension (51 vs. 41%). Ischaemic aetiology was less common (43 vs. 59%) in patients with HF-PEF. There were 121 [95% confidence interval (CI): 117, 126] deaths per 1000 patient-years in those with HF-PEF and 141 (95% CI: 138, 144) deaths per 1000 patient-years in those with HF-REF. Patients with HF-PEF had lower mortality than those with HF-REF (adjusted for age, gender, aetiology, and history of hypertension, diabetes, and atrial fibrillation); hazard ratio 0.68 (95% CI: 0.64, 0.71). The risk of death did not increase notably until EF fell below 40%. CONCLUSION Patients with HF-PEF have a lower risk of death than patients with HF-REF, and this difference is seen regardless of age, gender, and aetiology of HF. However, absolute mortality is still high in patients with HF-PEF highlighting the need for a treatment to improve prognosis.

BACKGROUND:Patients with heart failure (HF) have a poor prognosis. Heart failure centers with specialized nurse-supervised management programs have been proposed to improve prognosis.OBJECTIVES:To evaluate the clinical outcome of patients with HF treated at a multidisciplinary HF center of Clalit Health Services in Jerusalem in collaboration with Hadassah University Hospital.METHODS:We evaluated clinical outcome including hospitalizations and death in all HF patients followed at the HF center for 1 year.RESULTS:Altogether, 324 patients were included and followed at the HF center; 58% were males with a mean age of 76 +/- 11 years, and 58% were in New York Heart Association (NYHA) functional class Ill-IV. The overall 1 year survival rate was 91% and the 1 year hospitalization rate 29%. Comparing patients in the HF center to the whole cohort of patients with a diagnosis of HF (N = 6618) in Clalit Health Services in Jerusalem demonstrated a similar 1 year survival rate: 91% vs. 89% respectively but with a significantly reduced hospitalization rate: 29% vs. 42% respectively (P < 0.01). Cox regression analysis demonstrated that treatment in the HF center was a significant predictor of reduced hospitalization after adjustment for other predictors (hazard ratio 0.65, 95% confidence interval 0.53-0.80, P < 0.0001). A subset of patients that was evaluated (N = 78) showed significantly increased compliance. NYHA class improved in these patients from a mean of 3.1 +/- 0.1 to 2.6 +/- 0.1 after treatment (P < 0.0001).CONCLUSIONS:Supervision by dedicated specialized nurses in a HF center increased compliance, improved functional capacity in HF patients, and reduced hospitalization rate. HF centers should be considered part of the standard treatment of patients with symptomatic HF.

Renal function and urea are frequently abnormal in patients with heart failure (HF) and are predictive of increased mortality. The relative importance of each parameter is less clear. We prospectively compared the predictive value of renal function and serum urea on clinical outcome in patients with HF. Patients hospitalized with definite clinical diagnosis of HF (n = 355) were followed for short-term (1 yr) and long-term (mean, 6.5 yr) survival and HF rehospitalization.Increasing tertiles of discharge estimated glomerular filtration rate (eGFR) were an independent predictor of increased long-term survival (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.91; p = 0.01) but not short-term survival. Admission and discharge serum urea and blood urea nitrogen (BUN)/creatinine ratio were predictors of reduced short-and long-term survival on multivariate Cox regression analysis. Increasing tertiles of discharge urea were a predictor of reduced 1-year survival (HR, 2.13; 95% CI, 1.21-3.73; p = 0.009) and long-term survival (HR, 1.93; 95% CI, 1.37-2.71; p < 0.0001). Multivariate analysis including discharge eGFR and serum urea demonstrated that only serum urea remained a significant predictor of long-term survival; however, eGFR and BUN/creatinine ratio were both independently predictive of survival. Urea was more discriminative than eGFR in predicting long-term survival by area under the receiver operating characteristic curve (0.803 vs. 0.787; p = 0.01). Increasing tertiles of discharge serum urea and BUN/creatinine were independent predictors of HF rehospitalization and combined death and HF rehospitalization.This study suggests that serum urea is a more powerful predictor of survival than eGFR in patients with HF. This may be due to urea's relation to key biological parameters including renal, hemodynamic, and neurohormonal parameters pertaining to the overall clinical status of the patient with chronic HF.