Biomarkers Of Remodeling Research Articles

Anti-IL-17A treatment reduces serum inflammatory, angiogenic and tissue remodeling biomarkers accompanied by less synovial high endothelial venules in peripheral spondyloarthritis

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation. The exact pathophysiology underlying these processes remains elusive. We propose that the extensive neoangiogenesis in SpA could play a role both in sustaining/enhancing inflammation and in new bone formation. While ample data is available on effects of anti-TNF on angiogenesis, effects of IL-17A blockade on serum markers are largely unknown. We aimed to assess the impact of secukinumab (anti-IL-17A) on synovial neoangiogenesis in peripheral SpA, and how this related to changes in inflammatory and tissue remodeling biomarkers. Serum samples from 20 active peripheral SpA patients included in a 12 week open-label trial with secukinumab were analyzed for several markers of angiogenesis and tissue remodeling. Synovial biopsies taken before and after treatment were stained for vascular markers. Serum levels of MMP-3, osteopontin, IL-6 (all P < 0.001), IL-31, S100A8, S100A9, Vascular Endothelial Growth Factor A (VEGF-A), IL-33, TNF-α (all P < 0.05) decreased significantly upon anti-IL17A treatment. Secukinumab treatment resulted in a decrease in the number of synovial high endothelial venules and lymphoid aggregate score. These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts angiogenesis and tissue remodeling/new bone formation. This may have important implications for disease progression and/or structural damage.

Virtual reality adds value to analysis of aneurysms post-flow diversion, coiling, and clipping

Purpose: The purpose of this study was to measure sensitivity of virtual reality (VR) in detecting biomarkers of neurovascular remodeling suboptimally evaluated in digital subtraction angiography (DSA) of treated unruptured, intracranial aneurysms. Methods: The sensitivity of virtual reality and digital subtraction angiography in detection of neurovascular biomarkers in aneurysms treated with flow diversion, coiling, and clipping were evaluated. Validated grading scales were integrated into a standardized rating platform. The respective novel and conceptual measures of minimal imaging important difference (MIID) and number needed to image (NNI) were calculated for each biomarker. Results: In flow diversion, coiling, and clipping, minimal imaging important difference and number needed to image were associated with virtual reality in detection of abnormal biomarkers, with the exception of stasis phase associated with digital subtraction angiography. Number needed to image was associated with flow diversion stent stenosis (RR: 7.00, 95% CI 0.37 to 131.97; OR: 7.46, 95% CI 0.38 to 148.49). Minimal imaging important difference was greatest in residual aneurysm filling (25%±66, 95% CI) in flow diversion and Meyer score in coiling (42.5%±17.69, 95% CI) and clipping (22.2%±13.58, 95% CI). Regression models demonstrated minimal imaging important difference and number needed to image shared a significant correlation (R20.99, 95% CI, p&lt;0.001). Conclusion: Virtual reality adds value to digital subtraction angiography in evaluation of aneurysms treated with flow diversion, coiling, and clipping. Larger, prospective studies are warranted to increase statistical power and validate clinical significance.

Reduced Remodeling Biomarkers Tissue Expression in Nanotextured Compared With Polyurethane Implants Capsules: A Study in Rats.

In the biological response to biomaterials, the implant shell plays a key role in immune and inflammatory reactions. We hypothesized that the capsules formed around nanotextured implants exhibit an immunohistochemical behavior different to those formed around polyurethane implants. The aim of this study was to evaluate through immunohistochemistry markers the capsules formed around nanotextured and polyurethane implants. Sixty albino female Wistar rats were divided into 2 groups (nanotextured and polyurethane), with 30 animals in each group. A mini silicone implant was inserted on the back of the animals. After a predetermined period, the animals were killed, and the capsules formed around the implants were studied. The capsules in the 30-, 60-, and 90-day subgroups were analyzed via immunohistochemistry to detect markers for fibroblast α smooth muscle actin (α-SMA), transforming growth factor β (TGF-β), cluster of differentiation 34 (CD34), and CD68, via picrosirius staining to determine the density of type I and III collagen fibers and via hematoxylin and eosin staining to assess capsule thickness. A Wilcoxon-Mann-Whitney test was used to compare the groups, and a Kruskal-Wallis test was used to compare the subgroups. Lower α-SMA, TGF-β, CD34 and CD68 immunoexpression was observed in the nanotextured 30- and 60-day subgroups than in the corresponding polyurethane subgroups. In the 90-day subgroup, more pronounced α-SMA and CD34 immunoexpression was observed in the nanotextured group; however, TGF-β and CD68 immunoexpression remained lower. The nanotextured implants showed reduced capsular thickness and greater formation of type I collagen in all the analyzed subgroups. Nanotextured implants led to reduced immune and inflammatory reactions compared with polyurethane implants according to all analyzed variables.

Impact of Dehydroepiandrosterone (DHEA) on Bone Mineral Density and Bone Mineral Content in a Rat Model of Male Hypogonadism.

Objectives: The present study examined the effect DHEA (dehydroepiandrosterone) on bone mineral content (BMC) and bone mineral density (BMD) and biomarkers of bone remodeling in orchidectomized male rats. Material and Methods: A total of 32 male rats were divided equally into four groups (n = 8): (i) control group (C), (ii) control treated with DHEA (Control + DHEA), (iii) orchidectomized (ORCH) group that underwent bilateral orchidectomy and (iv) orchidectomized (ORCH) rats treated with DHEA (ORCH+DHEA). DHEA treatment started 4 weeks after orchidectomy and continued for 12 weeks. After 12 weeks the bone mineral density (BMD) and bone mineral content (BMC) were assayed in the tibia and femur of the right hind limb of each rat. We also measured the serum levels of the bone turnover markers deoxypyridinoline (Dpd), N-telopeptide of type I collagen (NTx), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase 5b (TRAP-5b) and osteocalcin (OC) as well as receptor activator of nuclear factor kappa B (RANK) and osteoprotegerin (OPG). Results: Orchidectomy in rats caused significant reduction in BMD, BMC, serum levels of testosterone, PTH (parathyroid hormone), OPG, OC and ALP with significant rise in serum levels of TRAP-5B, RANK, Dpd and NTx1 (p < 0.05). On the other hand, DHEA therapy for 12 weeks caused significant improvement in all studied parameters except NTx1 (p < 0.05). Conclusions: DHEA corrected hypogonadism-induced osteoporosis in male rats probably via inhibiting osteoclastogenesis, stimulating the activity of osteoblasts and stimulating the secretion of PTH and testosterone.

Post-Myocardial Infarction Ventricular Remodeling Biomarkers-The Key Link between Pathophysiology and Clinic.

Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective in early detection of remodeling phenomena. There are six main processes that promote the remodeling and each of them has specific biomarkers that can be used in predicting the evolution (myocardial necrosis, neurohormonal activation, inflammatory reaction, hypertrophy and fibrosis, apoptosis, mixed processes). Some of the biomarkers such as creatine kinase–myocardial band (CK-MB), troponin, and N-terminal-pro type B natriuretic peptide (NT-proBNP) were so convincing that they immediately found their place in the post infarction patient evaluation protocol. Others that are related to more complex processes such as inflammatory biomarkers, atheroma plaque destabilization biomarkers, and microRNA are still being studied, but the results so far are promising. This article aims to review the markers used so far, but also the existing data on new markers that could be considered, taking into consideration the most important studies that have been conducted so far.

Abstract 13897: Native T1-mapping by Cardiac MRI as a Biomarker of Remodeling in Boys With Duchenne Muscular Dystrophy

Cardiac magnetic resonance (CMR) is an important tool to assess cardiac disease progression in boys with Duchenne muscular dystrophy (DMD), with native (pre-contrast) myocardial T1-mapping considered a possible biomarker of fibrosis. Due to its thin wall and highly trabeculated structure, the right ventricle (RV) remains understudied in DMD despite pre-clinical evidence of RV involvement. After determining the most robust method of obtaining RV-T1, we assessed the hypothesis that RV-T1 distinguishes healthy controls from boys with DMD. Boys with DMD (N=27) and age-matched healthy control boys (N=17) were prospectively enrolled for a 3T CMR exam (Skyra, Siemens). The CMR exam included standard functional imaging, LGE imaging, and native T1 maps acquired at diastasis. Native RV-T1 was evaluated in four regions of interest (ROIs): 1 pixel (px) along the RV centerline, 3px dilated RV centerline, a segment within the RV lateral wall, and the RV inferior wall (Figure 1). Robustness was assessed in controls only and was defined as an acceptable number of pixels, coefficient of variation (COV) per ROI, percentage of readable images, and lowest inter-observer variability across three observers. Subsequently, a t-test assessed the difference between boys with DMD and controls using the most robust RV ROI. Comparing the four ROIs, we found an average size of the ROI of 65, 196, 23, 25 px; a COV of 13.4%, 16.6%, 6.0%, 9.9%; and 75%, 75%, 93%, 81% of readable images. Intra-class correlation (0.75) was highest and both mean bias (20ms) and limits of agreement (100ms) were lowest for the RV 1px ROI. Using the 1px ROI, the RV-T1 was higher and more variable in boys with DMD compared to controls (1526 [1457,1650] ms vs. 1432 [1390,1486] ms; p&lt;0.0001). Native RV-T1 is elevated in boys with DMD, if measured along a 1px centerline ROI. The methods described herein may enable using native RV-T1 as a biomarker of fibrosis in DMD and other pathologies. Correlation with functional indices is pending.

Abstract 15018: Incremental Prognostic Utility of Adverse Right Ventricular Remodeling in Patients With Covid-19 Infection: A Multicenter Cohort Study

Introduction: COVID-19 is a growing pandemic that confers augmented risk for RV dysfunction and dilation; prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. Hypothesis: To test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. Methods: Consecutive adult COVID-19 patients undergoing clinical transthoracic echo at three NYC hospitals were studied; images were analyzed by a central core lab blinded to clinical and biomarker data. Results: Of 510 patients (64±14 years, 66% male) studied, RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p=0.015). During inpatient follow-up (median 20 days), there were 165 deaths (32%) and 229 discharges (45%). RV dysfunction (HR 2.25 [CI 1.26-3.98]; p=0.006) and dilation (HR 1.82 [CI 1.11-2.97]; p=0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR 1.39 [CI 1.01-1.90]; p=0.04). Figure 1A demonstrates prognostic utility for each echo-quantified RV parameter (p&lt;0.05) in relation to all-cause mortality. Figure 1B shows RV indices to provide risk stratification beyond biomarker strata, as evidenced by greatest risk for death among patients with both adverse RV remodeling and positive biomarkers, and lesser risk among patients with isolated biomarker elevations. RV remodeling conferred over a 2-fold increase in mortality risk (HR 2.68 [CI 1.70-4.23]; p&lt;0.001), which remained significant when controlling for biomarker elevations, irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. (p&lt;0.01). Conclusions: Adverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.

Correlation between sestrin2 expression and airway remodeling in COPD

BackgroundAirway remodeling is a major pathological characteristic of chronic obstructive pulmonary disease (COPD), and has been shown to be associated with oxidative stress. Sestrin2 has recently drawn attention as an important antioxidant protein. However, the underlying correlation between sestrin2 and airway remodeling in COPD has yet to be clarified.MethodsA total of 124 subjects were enrolled in this study, including 62 control subjects and 62 COPD patients. The pathological changes in airway tissues were assessed by different staining methods. The expression of sestrin2 and matrix metalloproteinase 9 (MMP9) in airway tissues was monitored by immunohistochemistry. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the serum concentrations of sestrin2 and MMP9. The airway parameters on computed tomography (CT) from all participants were measured for evaluating airway remodeling. The relationship between serum sestrin2 and MMP9 concentration and airway parameters in chest CT was also analyzed.ResultsIn patients with COPD, staining of airway structures showed distinct pathological changes of remodeling, including cilia cluttered, subepithelial fibrosis, and reticular basement membrane (Rbm) fragmentation. Compared with control subjects, the expression of sestrin2 and MMP9 was significantly increased in both human airway tissues and serum. Typical imaging characteristics of airway remodeling and increased airway parameters were also found by chest CT. Additionally, serum sestrin2 concentration was positively correlated with serum MMP9 concentration and airway parameters in chest CT.ConclusionIncreased expression of sestrin2 is related to airway remodeling in COPD. We demonstrated for the first time that sestrin2 may be a novel biomarker for airway remodeling in patients with COPD.

Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen-related genes.

IntroductionVariants in collagen‐related genes COL1A1, COL3A1, COL5A1 and COL5A2 are associated with Ehlers‐Danlos syndrome (EDS), a heterogeneous group of connective tissue disorders strongly associated with increased bleeding. Of patients with incompletely explained bleeding diathesis, a relatively high proportion were shown to harbour at least one heterozygous variant of unknown significance (VUS) in one of these genes, the vast majority without meeting the clinical criteria for EDS.AimTo investigate the functional consequences of the identified variants by assessing the formation and degradation of types I, III and V collagen, in addition to plasma levels of ascorbic acid (AA).MethodsA total of 31 patients harbouring at least one heterozygous VUS in COL1A1, COL3A1, COL5A1 or COL5A2 and 20 healthy controls were assessed using monoclonal antibodies targeting neo‐epitopes specific for collagen formation and degradation. Plasma AA levels were measured in patients using high‐performance liquid chromatography.ResultsSerum levels of C5 M (degradation of type V collagen) were decreased in patients compared with healthy controls (p = .033). No significant differences were found in biomarkers for remodelling of types I and III collagen. A significant negative correlation between bleeding (ISTH‐BAT score) and plasma AA levels was shown (r = −.42; r2 = .17; p = .020). Suboptimal or marginally deficient AA status was found in 8/31 patients (26%).ConclusionFunctional investigations of collagen remodelling were not able to identify any clear associations between the identified variants and increased bleeding. The negative correlation between plasma AA levels and ISTH‐BAT score motivates further investigations.

A Novel Vitamin D Receptor Agonist, VS-105, Improves Bone Mineral Density without Affecting Serum Calcium in a Postmenopausal Osteoporosis Rat Model.

Background and objectives:VS-105, a novel vitamin D receptor agonist with significantly less hypercalcemic side effects than calcitriol, is a useful tool to investigate whether or not a vitamin D receptor agonist at non-hypercalcemic doses could improve bone mineral density (BMD).Methods:VS-105 and calcitriol were evaluated in an ovariectomized (OVX) osteoporosis rat model and in calvariae bone organ culture.Results:Treatment of OVX rats by VS-105 (0.1, 0.2 or 0.5 μg/kg, intraperitoneal, 3×/week, for 90 days) significantly improved BMD in the L3 lumbar vertebra in a dose-dependent manner (sham vs. OVX/vehicle: 324 ± 14 vs. 279 ± 10 mg/cm2; VS-105 at 0.1, 0.2 and 0.5 μg/kg: 306 ± 9, 329 ± 12, and 327 ± 10 mg/cm2, respectively) without affecting serum calcium (Ca). Calcitriol at 0.1 μg/kg significantly increased BMD but it also increased serum Ca. VS-105 and calcitriol at the test doses significantly suppressed serum parathyroid hormone and promoted tibia bone growth. With respect to biomarkers of bone remodeling, calcitriol and VS-105 both significantly elevated serum osteocalcin. In the calvariae bone organ culture, net Ca release was significantly less in VS-105-treated groups (vs. calcitriol).Conclusions:VS-105 is efficacious in improving BMD in a dose range that does not affect serum Ca in OVX rats; the improvement in BMD by VS-105 is attributable to increased osteoblastic activity and reduced osteoclastic bone resorption.

MIR1183 as a new tissue biomarker with triggered acute response and upregulation in chronic atrial and ventricular remodeling

Abstract Background and purpose Cardiac remodeling can be caused by a variety of insults linked to either stretch or tachycardia as a triggering mechanism. We aimed to investigate similarities and differences of the transcriptomic profiles in response to either acute stretch or tachycardia in isolated human atrial myocardium. In addition, we tested the highest acutely regulated target for its chronic regulation in human tissue with atrial or ventricular cardiac remodeling. Methods For acute trigger testing we applied either stretch (high pre- and afterload) or sustained tachycardia (2.5 Hz) for 6 hours in isolated atrial human trabeculae from cardiac surgery patients (all in sinus rhythm, SR). We performed gene expression profiling by RNA microarrays (n=5 per group) as a remodeling readout. For chronic regulation we performed qPCR of selected genes of interest in right atrial appendage tissue obtained from cardiac surgery patients with persistent atrial fibrillation compared to control patients with SR (n=6 per group), and also in ventricular tissue samples from failing hearts (from transplanted dilative cardiomyopathy patients) or non-failing control hearts (from multi-organ donors denied for transplantation), n=6 per group. Results The expression patterns of stretch and tachycardia were largely independent with 1305 transcripts regulated solely by stretch and 1837 transcripts by tachycardia with p&amp;lt;0.05. In contrast, the fraction of commonly regulated genes was small (65 transcripts with p&amp;lt;0.05). However, this fraction contained the strongest upregulated transcript, the microRNA precursor gene MIR1183, which was similarly upregulated by both triggers (4.1fold in stretch and 2.7fold in tachycardia, both p&amp;lt;0.05). MIR1183 also showed upregulation in two important chronic remodeling settings: In atrial samples with persistent atrial fibrillation in comparison to sinus rhythm, it was 2.8fold upregulated, and in ventricular samples from dilative cardiomyopathy hearts it was 1.6fold upregulated (p&amp;lt;0.05 for both). A functional role of MIR1183 in remodeling was also suggested by significant downregulation of its predicted downstream target genes ADAM20 and PLA2G7. Our ongoing research aims to confirm upregulation also in the circulating expression levels of the mature form of MIR1183 in human plasma samples in a cohort of atrial fibrillation patients with diseased atria, these findings will also be presented at scientific sessions. Conclusion Stretch and tachycardia show distinct transcriptomic signatures in human atrial trabeculae but share the strongest upregulated gene MIR1183 and consistent regulation of its downstream targets. This is present in an acute as well as chronic remodeling setting. Expression levels of MIR1183 might serve as a biomarker for atrial remodeling and to some extend ventricular remodeling and have potential functional significance in cardiac disease. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical University of Graz

Dynamics of Galectin-3 serum levels after percutaneous occlusion of the left atrial appendage: a new surrogate parameter for successful LAA closure?

Abstract Introduction Left atrial cardiac tissue remodeling following left atrial appendage closure (LAAC) is a scientifically neglected phenomenon until now but might have impact on functional outcome of patients suffering from atrial fibrillation (AF). Thus, our study is focused on quantification of key biomarkers reflecting fibrosis development as a major component within cardiovascular tissue remodeling. Methods Patients (CHA2DS2VASC score ≥1, HASBLED score ≥3) with bleeding complications under anticoagulation therapy and therefore eligible for LAAC were included in the present study. Serum levels of biomarkers of cardiac fibrosis and remodeling (Galectin-3, ST2/IL-2, ST2/IL-1, B domain containing Tenascin-C (B+ Tn-C), C domain containing Tenascin- C (C+ Tn-C)) were determined before device implantation (baseline), 45 days (45d) and 6 months (6M) after LAAC using commercially available ELISAs. To quantify functional outcome, all patients performed a 6-minutes walk test (6- MWT). Transesophageal echocardiography (TEE) was carried out to assess success of the LAAC procedure regarding peri-device leakage (PDL). Results We included 33 patients (age: 73.5±6.7 years; 21 men (64%) and 12 women (36%); BMI: 29.1±5.1 kg/m2; CHA2DS2VASC score: 4.2±1.2; left ventricular ejection fraction: 61.1±9.3%; mean occluder size: 25.9±3.9 mm; type of AF: 46% paroxysmal (15 patients), 55% permanent (18 patients)). Complete LAAC (without any residual low) was achieved in 60% (19 patients) after 45 days and in 87% (29 patients) after 6 months. At baseline, Galectin-3 levels did not show a relevant difference regarding the type of AF (paroxysmal AF: 14.7±5.4 ng/ml vs. permanent AF: 13.1±6.3 ng/ml; p=0.45). We observed a significant increase of serum levels of Galectin-3 [ng/ml] after 45 days vs. baseline (baseline: 13.3±5.8 vs. 45d: 18.3±10.6; p=0.005) with a return to baseline levels after 6 months (baseline: 13.3±5.8 vs. 6M: 12.5±5.4; p=0.28). Compared to patients with successful LAAC, patients with PDL had a trend towards higher levels of Galectin-3 after 6 months (11.3±5.5 ng/ml vs. 16.1±4.1 ng/ml, p=0.09). Measurements of other fibrosis markers were statistically not significantly different. The walking distance measured by the 6-MWT increased significantly from 298.5±89.5 meters at baseline to 335.5±95.1 meters (p=0.04) after 45d and remained significantly elevated after 6M (346.7±122.7 meters; p=0.02). Conclusion The implantation of an LAA occluder device is accompanied by significantly increased circulating levels of the fibrosis biomarker Galectin-3 after 45 days in patients with AF. The regression in serum levels after 6 months probably reflects a successful fibrotic remodeling in the left atrial appendage over time and might be used as surrogate parameter for LAAC success. Increased and stable exercise tolerance after 45 days can be observed. Funding Acknowledgement Type of funding source: None

Relevant correlation of Galectin-3 with a novel morphological classification system for LAA closure – the end of echocardiographic follow up after occluder implantation?

Abstract Introduction Echocardiographic detection of residual peri-device leakage (PDL) after percutaneous left atrial appendage closure (LAAC) remains crucial. Significance of PDL and cardiac tissue remodeling after LAAC are still poorly understood but might have diagnostic implications. This study aims to characterize and verify if a novel echocardiographic classification system to asses the success of LAAC in combination with quantifiable biomarkers of cardiovascular tissue remodeling can help in the prediction of PDL. Methods Patients eligible for LAAC were included. Serum levels of the cardiac remodeling marker Galectin-3 were determined before device implantation (baseline), 45 days (45d) and 6 months (6M) after LAAC using ELISAs. Transesophageal echocardiography (TEE) was carried out to assess success of the LAAC procedure. All echo images were retrospectively evaluated by two independent investigators. Based on the amount of echodensity and luceny inside the devices after LAAC, three types can be distinguished that grade the degree of closure of the LAA. Type A has complete homogenous echodensity in 0, 45, 90 and 135°, indicating completely thrombosed device. Type B shows inhomogeneous echo-lucencies (&amp;lt;50% of device). Type C describes a partially thrombosed device with echo-lucencies &amp;gt;50%. Novel classification according to Hamadanchi, Jena, Germany (Fig. 1). Results We included 44 patients (characteristics listed in Table 1). Complete LAAC (without any residual flow) was achieved in 64% (28 patients) after 45 days and in 80% (35 patients) after 6 months. Mean PDL diameter was 3.5±1.5mm. Type A showed the lowest rate of PDL after 45d (Type A: 22% vs. Type B: 33% vs. Type C: 88%; p=0.007) and after 6M (Type A: 12% vs. Type B: 28% vs. Type C: 100%; p=0.002). Galectin-3 levels did not show a relevant difference regarding the type of AF at baseline (paroxysmal AF: 11.7±5.4 ng/ml vs. permanent AF: 12.1±6.3 ng/ml; p=0.45). We observed a significant increase and distribution of serum levels of Galectin-3 [ng/ml] after 45 days among the three types (Baseline: 13.1±5.8; 45d: 16.3±7.2 (Type A) vs. 19.2±8.6 (Type B) vs. 25.8±9.4 (Type C); p=0.031) followed after 6 months by a drop of Galectin-3 for type A and B toward and below baseline levels (6M: 8.9±3.1 (Type A) vs. 12.4±5.5 (Type B)) whereas type C persisted in showing elevated Galectin-3 levels compared to all other types (6M: 17.5±4.5 (Type C); p&amp;lt;0.001), Fig. 2. Correlation analysis shows a significant negative correlation trend between Galectin-3 and mean PDL diameter (−0.51; p=0.016) after 45 days and a relevant positive correlation after 6 months (0.58; p=0.017). Conclusion After LAAC, Galectin-3 levels are elevated, as a marker of myocardial fibrosis in the LAA. Depending on the degree of closure of the LAA, Galectin-3 decreases to the baseline level or stays elevated in case of relevant PDL and could therefore be considered as a new biomarker for closure success. Funding Acknowledgement Type of funding source: None

Attenuation of Cardiomyocyte Hypertrophy via Depletion Myh7 using CASAAV.

Myh7 is a classic biomarker for cardiac remodeling and a potential target to attenuate cardiomyocyte (CM) hypertrophy. This study aimed to identify the dominant function of Myh7 after birth and determine whether its removal would affect CM maturation or contribute to reversal of pathological hypertrophy phenotypes. The CASAAV (CRISPR/Cas9-AAV9-based somatic mutagenesis) technique was used to deplete Myh6 and Myh7, and an AAV dosage of 5 × 109 vg/g was used to generate a mosaic CM depletion model to explore the function of Myh7 in adulthood. CM hypertrophy was induced by transverse aortic constriction (TAC) in Rosa26Cas9-P2A-GFP mice at postnatal day 28 (PND28). Heart function was measured by echocardiography. Isolated CMs and in situ imaging were used to analyze the structure and morphology of CM. We discovered that CASAAV successfully silenced Myh6 and Myh7 in CMs, and early depletion of Myh7 led to mild adulthood lethality. However, the Myh7 PND28-knockout mice had normal heart phenotype and function, with normal cellular size and normal organization of sarcomeres and T-tubules. The TAC mice also received AAV-Myh7-Cre to produce Myh7-knockout CMs, which were also of normal size, and echocardiography demonstrated a reversal of cardiac hypertrophy. In conclusion, Myh7 has a role during the maturation period but rarely functions in adulthood. Thus, the therapeutic time should exceed the period of maturation. These results confirm Myh7 as a potential therapeutic target and indicate that its inhibition could help reverse CM hypertrophy.

Influence of sex on the age-related adaptations of neuromuscular function and motor unit properties in elite masters athletes.

Masters athletes maintain high levels of activity into older age and allow an examination of the effects of aging dissociated from the effects of increased sedentary behaviour. Evidence suggests masters athletes are more successful at motor unit remodelling, the reinnervation of denervated fibres acting to preserve muscle fibre number, but little data are available in females. Here we used intramuscular electromyography to demonstrate that motor units sampled from the tibialis anterior show indications of remodelling from middle into older age and which does not differ between males and females. The age-related trajectory of motor unit discharge characteristic differs according to sex, with female athletes progressing to a slower firing pattern that was not observed in males. Our findings indicate motor unit remodelling from middle to older age occurs to a similar extent in male and female athletes, with discharge rates progressively slowing in females only. Motor unit (MU) remodelling acts to minimise loss of muscle fibres following denervation in older age, which may be more successful in masters athletes. Evidence suggests performance and neuromuscular function decline with age in this population, although the majority of studies have focused on males, with little available data on female athletes. Functional assessments of strength, balance and motor control were performed in 30 masters athletes (16 male) aged 44-83years. Intramuscular needle electrodes were used to sample individual motor unit potentials (MUPs) and near-fibre MUPs in the tibialis anterior (TA) during isometric contractions at 25% maximum voluntary contraction, and used to determine discharge characteristics (firing rate, variability) and biomarkers of peripheral MU remodelling (MUP size, complexity, stability). Multilevel mixed-effects linear regression models examined effects of age and sex. All aspects of neuromuscular function deteriorated with age (P<0.05) with no age×sex interactions, although males were stronger (P<0.001). Indicators of MU remodelling also progressively increased with age to a similar extent in both sexes (P<0.05), whilst MU firing rate progressively decreased with age in females (p=0.029), with a non-significant increase in males (p=0.092). Masters athletes exhibit age-related declines in neuromuscular function that are largely equal across males and females. Notably, they also display features of MU remodelling with advancing age, probably acting to reduce muscle fibre loss. The age trajectory of MU firing rate assessed at a single contraction level differed between sexes, which may reflect a greater tendency for females to develop a slower muscle phenotype.

Native T1 Mapping Magnetic Resonance Imaging as a Quantitative Biomarker for Characterization of the Extracellular Matrix in a Rabbit Hepatic Cancer Model.

To characterize the tumor extracellular matrix (ECM) using native T1 mapping magnetic resonance imaging (MRI) in an experimental hepatic cancer model, a total of 27 female New Zealand white rabbits with hepatic VX2 tumors were examined by MRI at different time points following tumor implantation (day 14, 21, 28). A steady-state precession readout single-shot MOLLI sequence was acquired in a 3 T MRI scanner in prone position using a head-neck coil. The tumors were segmented into a central, marginal, and peritumoral region in anatomical images and color-coded T1 maps. In histopathological sections, stained with H&E and Picrosirius red, the regions corresponded to central tumor necrosis and accumulation of viable cells with fibrosis in the tumor periphery. Another region of interest (ROI) was placed in healthy liver tissue. T1 times were correlated with quantitative data of collagen area staining. A two-way repeated-measures ANOVA was used to compare cohorts and tumor regions. Hepatic tumors were successfully induced in all rabbits. T1 mapping demonstrated significant differences between the different tumor regions (F(1.43,34.26) = 106.93, p < 0.001) without interaction effects between time points and regions (F(2.86,34.26) = 0.74, p = 0.53). In vivo T1 times significantly correlated with ex vivo collagen stains (area %), (center: r = 0.78, p < 0.001; margin: r = 0.84, p < 0.001; peritumoral: r = 0.73, p < 0.001). Post hoc tests using Sidak’s correction revealed significant differences in T1 times between all three regions (p < 0.001). Native T1 mapping is feasible and allows the differentiation of tumor regions based on ECM composition in a longitudinal tumor study in an experimental small animal model, making it a potential quantitative biomarker of ECM remodeling and a promising technique for future treatment studies.

Status and prospects: personalized treatment and biomarker for airway remodeling in asthma.

Airway remodeling, as a major characteristic of bronchial asthma, is critical to the progression of this disease, whereas it is of less importance in clinical management. Complying with the current stepwise treatment standard for asthma, the choice of intervention on the clinical status is primarily determined by the patient’s treatment response to airway inflammation. However, a considerable number of asthmatic patients, especially severe asthmatic subjects, remain uncontrolled though they have undergone fortified anti-inflammation treatment. In the past few years, a growing number of biologics specific to asthma phenotypes have emerged, bringing new hope for patients with refractory asthma and severe asthma. While at the same time, the effect of airway remodeling on asthma treatment has become progressively prominent. In the era of personalized treatment, it has become one of the development directions for asthma treatment to find reliable airway remodeling biomarkers to assist in asthma phenotypes classification, and to further combine multiple phenotypes to accurately treat patients. In the present study, the research status of airway remodeling in asthma is reviewed to show the basis for classifying and treating such disease. Besides, several selected airway remodeling biomarkers and possibility to use them in individual treatment are discussed as well. This study considers that continuously optimized mechanisms and emerging biomarkers for airway remodeling in the future may further support individual therapy for asthma patients.

Prognostic Utility of Right Ventricular Remodeling Over Conventional Risk Stratification in Patients With COVID-19

BackgroundCoronavirus disease 2019 (COVID-19) is a growing pandemic that confers augmented risk for right ventricular (RV) dysfunction and dilation; the prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. ObjectivesThe purpose of this study was to test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. MethodsConsecutive COVID-19 inpatients undergoing clinical transthoracic echocardiography at 3 New York City hospitals were studied; images were analyzed by a central core laboratory blinded to clinical and biomarker data. ResultsIn total, 510 patients (age 64 ± 14 years, 66% men) were studied; RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p = 0.007). During inpatient follow-up (median 20 days), 77% of patients had a study-related endpoint (death 32%, discharge 45%). RV dysfunction (hazard ratio [HR]: 2.57; 95% confidence interval [CI]: 1.49 to 4.43; p = 0.001) and dilation (HR: 1.43; 95% CI: 1.05 to 1.96; p = 0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR: 1.39; 95% CI: 1.01 to 1.90; p = 0.041). RV indices provided additional risk stratification beyond biomarker strata; risk for death was greatest among patients with adverse RV remodeling and positive biomarkers and was lesser among patients with isolated biomarker elevations (p ≤ 0.001). In multivariate analysis, adverse RV remodeling conferred a >2-fold increase in mortality risk, which remained significant (p < 0.01) when controlling for age and biomarker elevations; the predictive value of adverse RV remodeling was similar irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. ConclusionsAdverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.

Effects of Hepatitis C Virus (HCV) Eradication on Bone Mineral Density in Human Immunodeficiency Virus/HCV-Coinfected Patients.

Little is known about the effects of eradication of hepatitis C virus (HCV) on bone mineral density (BMD) and biomarkers of bone remodeling in human immunodeficiency virus (HIV)/HCV-coinfected patients. We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization BMD categories at both sites, and plasma concentrations of soluble receptor activator of NF-κβ ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks. A total of 238 patients were included. The median age was 49.5 years, 76.5% were males, 48.3% had cirrhosis, 98.3% were on antiretroviral therapy, median CD4+ cell count was 527 cells/μL, and 86.6% had HIV-1 RNA <50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon (peg-IFN) and ribavirin (RBV) plus 1 direct-acting antiviral in 53.4%, peg-IFN/RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained virologic response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P = .801) or the FN (P = .911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P = .205), OPG (P = .249), or sRANKL/OPG ratio (P = .123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline and week 96. SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons.

Cell Free and Exosomal Micro RNAs: Novel Biomarkers for Adverse Cardiac Remodelling and Heart Failure

The prevalence of heart failure (HF) due to cardiac remodelling after acute myocardial infarction (AMI) does not decrease regardless of implementation of new technologies supporting opening culprit coronary artery and solving of ischemia-relating stenosis with primary percutaneous coronary intervention (PCI). Numerous studies have examined the diagnostic and prognostic potencies of circulating cardiac biomarkers in acute coronary syndrome / AMI and HF after AMI, and even fewer have been depicted the utility of biomarkers in AMI patients undergoing primary PCI. The aim of the review is focused an attention on non-coding cell-free and exosomal micro RNA as biomarkers of HF. Although there is a large number of evidence regarding predicative value of signature of miRNA in adverse cardiac remodelling and HF with different phenotypes, large clinical trials are required to be performed in the future to clearly elucidate whether miRNAs could be suitably for personalizing HF therapy.