Inhibition of the extracellular enzyme A disintegrin and metalloprotease with thrombospondin motif 4 prevents cardiac fibrosis and dysfunction.

AIMS: Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis. METHODS AND RESULTS: The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e' and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-ß target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-ß levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-ß-binding proteins, i.e. latent-binding protein of TGF-ß and extra domain A-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity. CONCLUSION: Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-ß availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.

COVID-19: Symptoms, course of illness and use of clinical scoring systems for the first 42 patients admitted to a Norwegian local hospital. / Covid-19: Symptomer, forløp og bruk av kliniske skåringsverktøy hos de 42 første pasientene innlagt på et norsk lokalsykehus.

BACKGROUND: The COVID-19 outbreak is presenting the health system with new challenges, and there is a great need for knowledge about symptoms, clinical findings and course of illness in patients admitted to Norwegian hospitals with COVID-19. MATERIAL AND METHOD: In this observational qualitative study, all patients admitted to a Norwegian local hospital (Bærum Hospital) with proven COVID-19 infection were included consecutively from the start of the outbreak. We present here patient characteristics, symptoms, clinical findings, experience of using clinical scoring systems and course of illness based on data in medical records. RESULTS: In the period 9-31 March 2020, 42 patients, of whom 28 (67 %) were men, were admitted to hospital with COVID-19 infection. The median age was 72.5 years (range 30-95). Fever (79 %), reduced general condition (79 %), dyspnoea (69 %) and cough (67 %) were the most common symptoms. A total of nine patients (21 %) had a critical course of illness with treatment in the Intensive Care Department and/or death during their stay in hospital. Patients with a critical course had a higher average score on National Early Warning Score 2 (NEWS2) on admission (7.6 vs 3.3). Only one of the most severely ill patients scored ≥ 2 on the quick Sepsis-related Organ Failure Assessment (qSOFA) on admission. INTERPRETATION: Most patients admitted to our hospital with COVID-19 had a fever and respiratory tract symptoms. A high percentage of patients had a critical course of illness. A NEWS2 score of ≥ 5 on admission may be a useful aid in identifying patients at risk of a critical course of illness, while CRB-65 and qSOFA score ≥ 2 proved to be of little usefulness for this purpose in our material.