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Background: This study focuses on biomarkers in infants after open heart surgery, and examines the association of high‐sensitive troponin T (hs‐cTnT), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) with postoperative acute kidney injury (AKI), ventilatory support time and need of vasoactive drugs. Methods: Secondary exploratory study from a double‐blinded clinical randomized trial (Mile‐1) on 70 infants undergoing open heart surgery with cardiopulmonary bypass (CPB). In this sub‐study, the entire study population was examined without considering the study drugs. The biomarkers' peak concentration (highest concentration at 2 or 6 h post‐CPB) were used for statistical analyses. Results: Peak IL‐8, hs‐cTnT, and IL‐6 occurred at 2 h post‐CPB for 96%, 79%, and 63% of the patients, respectively. The odds ratio of developing AKI2‐3 for IL‐6 > 293 pg/mL was 23.4 (95% CI 5.3;104.0), for IL‐8 > 100 pg/mL it was 11.5 (3.0;44.2), and for hs‐cTnT >5597 pg/mL it was 6.1 (1.5; 24.5). In more than two third of the patients with the highest peak concentrations of IL‐8, IL‐6, and hs‐cTnT, there was a need for ventilatory support for >24 h and use of vasoactive drugs at 24 h post‐CPB, while in less than one third of the patients with the lowest peak concentrations of IL‐8 and hs‐cTnT such requirements were observed. Conclusions: The peak biomarker concentrations and CPB‐time strongly predicted AKI2‐3, with IL‐6 and IL‐8 emerging as strongest predictors. Furthermore, our findings suggest that measuring hs‐cTnT and IL‐8 just 2 h post‐CPB‐weaning may assist in identifying infants suitable for early extubation and highlight those at risk of prolonged ventilation. [ABSTRACT FROM AUTHOR]

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)-β 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-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β 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-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Objectives: The effect of long-term adaptive servo-ventilation (ASV) on cardiovascular mortality and admission rates in patients with chronic heart failure (CHF) and Cheyne-Stokes respiration (CSR) has not been much studied. The aim of this study was primarily to investigate whether ASV therapy significantly reduced these parameters.Design: We included 75 CHF patients on optimal medication and CSR ≥25% of sleeping time, in New York Heart Association (NYHA) classes II-IV and left ventricular ejection fraction (LVEF) ≤ 45%. Thirty-one patients were treated with ASV for >3-18 months and 44 patients served as a control group.Results: Seven deaths (16%) in the control group and one death (3%) in the ASV treatment group had cardiovascular etiology. There was no significant difference between the two groups regarding cardiovascular death (log rank p = 0.07; HR 0.18 (95% CI 0.02-1.44), p = 0.11) and combined cardiovascular death or readmissions, but there was a trend toward better outcome regarding cardiovascular event-free survival (log rank p = 0.06; HR 0.53 (95% CI 0.27-1.05).Conclusions: In CHF patients with CSR, 18 months ASV treatment did not significantly affect cardiovascular death or combined cardiovascular death or hospital admissions. But there was a trend toward better combined outcome. [ABSTRACT FROM AUTHOR]

Background: We hypothesized that cleavage of the extracellular matrix (ECM) proteoglycans versican and aggrecan by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases, which contributes to stress-induced ECM-reorganization in atherogenesis and osteoarthritis, also play a role in heart failure development. Objectives: The primary objective was to identify alterations in expression of ADAMTS versicanases and aggrecanases during development of heart failure, while evaluation of the effects of in vivo modulation of relevant changes in ADAMTS activity constituted the secondary objective. Methods: Myocardial levels of versican, aggrecan, and their ADAMTS cleaving proteases were examined in Wistar rats six weeks after aortic banding (AB), and versican and selected ADAMTS versicanases were further analyzed in neonatal cardiomyocytes (NCM) and cardiac fibroblasts (NFB) after stimulation by inflammatory mediators. Based on the initial findings, ADAMTS4 was selected the most promising therapeutic target. Thus, rats with AB were treated with pentosan polysulfate (PPS), a polysaccharide with known ADAMTS4-inhibitory properties, and effects on versican fragmentation, left ventricular function and geometry were evaluated. Results: We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01) after AB. Following PPS-treatment, we observed an ∼80% reduction in myocardial ADAMTS4 mRNA (p = 0.03), and ∼50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05), suggesting reduced versicanase activity. Conclusions: Our findings suggest that AB induces an increase in myocardial ADAMTS4 versicanase activity, and that PPS-treatment improved systolic function in the pressure-overloaded heart, holding promise as a novel therapeutic agent in heart failure. [ABSTRACT FROM AUTHOR]