Pentosan Polysulfate Decreases Myocardial Expression of the Extracellular Matrix Enzyme ADAMTS4 and Improves Cardiac Function In Vivo in Rats Subjected to Pressure Overload by Aortic Banding

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

Hitting the Target! Challenges and Opportunities for TGF-β Inhibition for the Treatment of Cardiac fibrosis

Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β’s physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development

Obstructive sleep apnea versus central sleep apnea: prognosis in systolic heart failure

Background: In chronic heart failure (CHF), obstructive sleep apnea (OSA) and Cheyne-Stokes respiration (CSR) are associated with increased mortality. The present study aimed to evaluate the prognostic effect of CSR compared to OSA, in otherwise similar groups of CHF patients. Methods: Screening for sleep-disordered breathing (SDB) was conducted among patients with CHF of New York Heart Association (NYHA) class II–IV, and left ventricular ejection fraction (LVEF) of ≤45%. The study included 43 patients (4 women) with >25% CSR during sleeping time, and 19 patients (2 women) with OSA and an apnea-hypopnea index (AHI) of ≥6. Patients were followed for a median of 1,371 days. The primary endpoint was mortality, and the secondary endpoint was combined mortality and hospital admissions. Results: Baseline parameters did not significantly differ between groups, but CSR patients were older and had higher AHI values than OSA patients. Five OSA patients (26%) died, and 14 (74%) met the combined end-point of death or hospitalization. CSR patients had significantly higher risk for both end-points, with 23 (53%) deaths [log-rank P=0.040; HR, 2.70 (1.01–7.22); P=0.047] and 40 (93%) deaths or readmissions [log-rank P=0.029; HR, 1.96 (1.06–3.63); P=0.032]. After adjustment for confounding risk factors, the association between CSR and death remained significant [HR, 4.73 (1.10–20.28); P=0.037], hospital admission rates were not significantly different. Conclusions: Among patients with CHF, CSR was associated with higher mortality than OSA independently of age and cardiac systolic function. CSR was also an age-independent predictor of unfavorable outcome, but hospital admission rates were not significantly different between the two groups after adjustment

Annual decline in forced expiratory volume and airway inflammatory cells and mediators in a general population-based sample

Background Few studies have examined the relationships between sputum inflammatory markers and subsequent annual decline in forced expiratory volume in 1 s (dFEV1). This study investigated whether indices of airway inflammation are predictors of dFEV1 in a general population-based sample. Methods The study, conducted from 2003 to 2005, included 120 healthy Norwegian subjects aged 40 to 70 years old. At baseline, the participants completed a self-administered respiratory questionnaire and underwent a clinical examination that included spirometry, venous blood sampling, and induced sputum examination. From 2015 to 2016, 62 (52%) participants agreed to a follow-up examination that did not include induced sputum examination. Those with a FEV1/forced vital capacity (FVC) ratio <  0.70 underwent a bronchial reversibility test. The levels of cytokines, pro-inflammatory M1 macrophage phenotypes were measured in induced sputum using bead-based multiplex analysis. The associations between cytokine levels and dFEV1 were then analysed. Results The mean dFEV1 was 32.9 ml/year (standard deviation 26.3). We found no associations between dFEV1 and the baseline indices of sputum inflammation. Seven participants had irreversible airflow limitation at follow-up. They had lower FEV1 and gas diffusion at baseline compared with the remaining subjects. Moreover, two of these individuals had a positive reversibility test and sputum eosinophilia at baseline. Conclusions In this cohort of presumably healthy subjects, we found no associations between sputum inflammatory cells or mediators and dFEV1 during 10 years of follow-up

Cytokine levels in patients with juvenile dermatomyositis assessed median 16.8 years after disease onset, and in controls.

<p>Values for cytokine levels are mean (SD) pg/ml; n: all JDM = 54, controls = 54, JDM active = 28, JDM inactive = 26. p value when comparing cytokine levels in all JDM and controls; for the comparison active <i>vs</i> inactive JDM, no differences were detected. The cytokines shown were selected based on associations seen in the present and/or previous studies on dermatomyositis or other rheumatic diseases. JDM: juvenile dermatomyositis; MCP: monocyte chemoattractant protein; IP: interferon-inducible protein; IL: interleukine; TNF: tumor necrosis factor; Ra: receptor antagonist; TGF: transforming growth factor; Th1/Th2, IFN-γ/IL-4.</p

Characteristics and disease parameters in 54 patients with juvenile dermatomyositis and in 54 controls.

<p>Values are number (%), median (range) or mean (SD). JDM: juvenile dermatomyositis; NA: not applicable; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; SF-36 PCS: Short Form 36 physical component Summary; CHAQ: Childhood Health Assessment Questionnaire; DMARDs: disease modifying anti-rheumatic drugs; MDI: Myositis Damage Index; DAS: Disease Activity Score.</p><p>*p<0.05.</p>‡<p>n<i> = </i>46 pairs, only assessed in those >13 years;</p>†<p>n = 50 pairs.</p

Correlations between MCP-1, eotaxin and disease variables in patients with juvenile dermatomyositis 1 year post -diagnosis.

<p>MCP: monocyte chemoattractant protein; r: Spearman correlation coefficient; MDI: Myositis Damage Index; DAS: Disease Activity Score.</p