Sacubitril/valsartan preserves regional cardiac function following myocardial infarction in rats.

Aims: Sacubitril/valsartan (Sac/Val) is used for treatment of heart failure. The effect of Sac/Val on regional dysfunction following myocardial infarction (MI) remains uncertain. This study aimed at understanding the effects of Sac/Val on regional function after MI.

Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis-Specific Transcriptional Signatures in Human Skin.

Objective: S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4 mice are protected from fibrosis.

Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis.

Objectives: We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc).

Methods: S100A4 protein concentration was measured by ELISA in serum of SSc (n=94) and healthy controls (n=15). Protein expression in skin fibroblast cultures from diffuse cutaneous SSc (SScF, n=6) and healthy controls (normal fibroblasts (NF), n=6) was assessed.

S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin.

Objectives: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis.

Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: The ARIADNE registry.

Aims: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group).

PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic heart failure in primary care (PREFER): a real-world study.

Objective: To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy.

Methods: PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist's referral and no later than 6 months after the baseline visit.

Utilization of sacubitril/valsartan in patients with heart failure with reduced ejection fraction: real-world data from the ARIADNE registry.

Aims: To compare baseline characteristics of patients with heart failure with reduced ejection fraction (HFrEF) initiated on sacubitril/valsartan compared with patients continued on conventional heart failure (HF)-treatment in a European out-patient setting.

Methods And Results: Between July 2016 and July 2019, ARIADNE enrolled 8787 outpatients aged ≥18 years with HFrEF from 17 European countries. Choice of therapy was solely at the investigators' discretion.

Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload.

Aims: Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin-angiotensin-aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF).

Methods And Results: Sprague-Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks.

OUTSTEP-HF: randomised controlled trial comparing short-term effects of sacubitril/valsartan versus enalapril on daily physical activity in patients with chronic heart failure with reduced ejection fraction.

Aims: OUTSTEP-HF compared the effect of sacubitril/valsartan vs. enalapril on 6-min walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF).

Methods And Results: Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311).

Rationale and study design of OUTSTEP-HF: a randomised controlled study to assess the effect of sacubitril/valsartan and enalapril on physical activity measured by accelerometry in patients with heart failure with reduced ejection fraction.

Aim: In PARADIGM-HF, sacubitril/valsartan demonstrated superiority to enalapril in reducing mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several patient-centred outcomes like improved physical activity and quality of life have been emphasised as important treatment goals in HF management. OUTSTEP-HF has been designed to evaluate the effect of sacubitril/valsartan compared with enalapril on non-sedentary daytime physical activity in patients with HFrEF.

CaMKII in addition to MLCK contributes to phosphorylation of regulatory light chain in cardiomyocytes.

The aim was to identify kinase activities involved in the phosphorylation of regulatory light chain (RLC) in situ in cardiomyocytes. In electrically stimulated rat cardiomyocytes, phosphatase inhibition by calyculin A unmasked kinase activities evoking an increase of phosphorylated RLC (P-RLC) from about 16% to about 80% after 80 min. The phosphorylation rate in cardiomyocytes was reduced by about 40% by the myosin light chain kinase (MLCK) inhibitor, ML-7.

Non-classical regulation of β1- and β 2-adrenoceptor-mediated inotropic responses in rat heart ventricle by the G protein Gi.

Studies suggest that increased activity of Gi contributes to the reduced β-adrenoceptor-mediated inotropic response (βAR-IR) in failing cardiomyocytes and that β2AR-IR but not β1AR-IR is blunted by dual coupling to Gs and Gi. We aimed to clarify the role of Gi upon the β1AR-IR and β2AR-IR in Sham and failing myocardium by directly measuring contractile force and cAMP accumulation. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation in cardiomyocytes from rats with post-infarction heart failure (HF) or sham operates (Sham).

PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.

Background And Purpose: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.

Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium.

Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments.

Expression of mRNA encoding G protein-coupled receptors involved in congestive heart failure--a quantitative RT-PCR study and the question of normalisation.

Congestive heart failure (CHF) induces changes in the neurohumoral system and gene expression in viable myocardium. Several of these genes encode G protein-coupled receptors (GPCRs) involved in mechanisms which compensate for impaired myocardial function. We used real-time quantitative RT-PCR (Q-RT-PCR) to investigate the expression of mRNA encoding 15 different GPCRs possibly involved in CHF, and the effect of normalisation to GAPDH mRNA (GAPDH) or 18S rRNA (18S).