F. Martins

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.

Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats.

Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm.

Exercise Training Potentiates The Cardioprotective Effects of Stem Cells Post-infarction

BACKGROUND Preconditioning of cell recipients may exert a significant role in attenuating the hostility of the infarction milieu, thereby enhancing the efficacy of cell therapy. This study was conducted to examine whether exercise training potentiates the cardioprotective effects of adipose-derived stem cell (ADSC) transplantation following myocardial infarction (MI) in rats. METHODS Four groups of female Fisher-344 rats were studied: Sham; non-trained rats with MI (sMI); non-trained rats with MI submitted to ADSCs transplantation (sADSC); trained rats with MI submitted to ADSCs (tADSC). Rats were trained 9 weeks prior to MI and ADSCs transplantation. Echocardiography was applied to assess cardiac function. Myocardial performance was evaluated in vitro. Protein expression analyses were carried out by immunoblotting. Periodic acid-Schiff staining was used to analyse capillary density and apoptosis was evaluated with terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. RESULTS Echocardiography performed 4 weeks after the infarction revealed attenuated scar size in the both sADSC and tADSC groups compared to the sMI group. However, fractional shortening was improved only in the tADSC group. In vitro myocardial performance was similar between the tADSC and Sham groups. The expression of phosphoSer473Akt1 and VEGF were found to be higher in the hearts of the tADSC group compared to both the sADSC and sMI groups. Histologic analysis demonstrated that tADSC rats had higher capillary density in the remote and border zones of the infarcted sites compared to the sMI rats. CONCLUSIONS Preconditioning with exercise induces a pro-angiogenic milieu that may potentiate the therapeutic effects of ADSCs on cardiac remodelling following MI.

AB0581 Two years existence of reuma.pt/vasculitis – the portuguese registry of vasculitis

Background The vasculitides are a group of relatively rare diseases with different manifestations and outcomes. New therapeutic options have led to the need for long-term registries. The Rheumatic Diseases Portuguese Register, Reuma.pt, is an electronic clinical record, created in 2008, which currently includes specific protocols for 11 diseases and >16000 patients registered from 79 national and international rheumatology centres. Since October 2014, a dedicated protocol to vasculitis has been created as part of the European Vasculitis Society initiative of having compatible European registries. Objectives To describe the structure of Reuma.pt/Vasculitis and characterize the patients registered over the last two years. Methods We developed a dedicated web-based software to enable prospective collection and central storage of anonymised data from patients with vasculitis. All Portuguese rheumatology centres were invited to participate. Data regarding demographics, diagnosis, classification criteria, imaging and laboratory tests, outcome measures of prognosis, damage, disease activity and quality of life, and treatment were collected. We performed a cross-sectional descriptive analysis of all patients registered up to January 2017. Results A total of 492 patients, with 1114 visits, from 11 centres were registered in Reuma.pt/Vasculitis. The mean age was 53±20 years at last visit; 68% were females. The diagnoses followed the 2012 Chapel Hill Consensus nomenclature (Table 1). The most common diagnoses were Behçets disease (BD) (39%) and giant cell arteritis (GCA) (20%). Patients with BD met the International Study Group 1990 criteria, the International Criteria for BD 2006 and 2013 in 84%, 95% and 95% of cases, respectively. Patients with GCA met the 1990 American College of Rheumatology criteria in 95% of cases. Data on vascular ultrasound was available in 74% of patients; 73% compatible with the diagnosis. Assessment of the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI) was available for all vasculitides and the Five Factor Score calculation of survival rate for ANCA associated vasculitis (AAV) and polyarteritis nodosa (PAN). The mean BVAS at first visit was 18±7 for AAV and 15±9 for PAN; the mean VDI at last visit was 3±2 for AAV and 2±2 for PAN. Health related quality of life assessments (SF-36, EQD5, FACIT and HADS) were also collected. Treatment registry with the disease assessment variables shown in graphics was available for all patients; only 6% were under biologic treatment. Conclusions Reuma.pt/Vasculitis is a registry adapted for routine care, allowing an efficient data repository at a national level with the potential to link with other international databases. It facilitates research, trials recruitment, service planning and benchmarking. Disclosure of Interest None declared

AB0965 Single Nucleotide Polymorphisms in TNFA1P3 and PTPN2 Are Associated with a Poor Outcome in Juvenile Idiopathic Arthritis. Data From Reuma.PT

Background Genetic variants have been identified associated with the susceptibility to Juvenile idiopathic arthritis (JIA). Little is known about the genetic determinants of disease severity and long-term outcomes. Objectives This study aimed to assess the genetic determinants of poor outcome in Portuguese patients with JIA. Methods Our study relied on Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA receiving biological therapies and synthetic DMARDs. Subject and disease characteristics of patients with the diagnosis of JIA were collected prospectively and a blood sample for DNA analysis stored. Poor prognosis was defined as CHAQ/HAQ >0.75 at the last visit and/or the need for biological therapy. A previously selected panel of 31 single nucleotide polymorphisms (SNPs) was studied to verify if there was any association with poor prognosis. Results 291 patients out of the 812 JIA patients registered in Reuma.pt, had a blood sample to perform the genetic analysis. From those, 267 had CHAQ/HAQ registered. The mean age was 19.9±11.3 years, 65% females. The mean age at JIA onset was 6.9±4.7 years. Of the 267 patients analyzed, 85 match our criteria of poor prognosis. In univariate analysis, including all disease categories of JIA, we found significant associations with poor prognosis for allele A of TNFA1P3/20 rs6920220, allele G of TRAF1/C5 rs3761847 and allele G of PTPN2 rs7234029. In multivariate models, the associations for TNFA1P3/20 rs6920220 (odds ratio =1.88 [95% CI 1.13-3.14]) and PTPN2 rs7234029 (OR 1.75 [1.03-3.00]) remained significant at the 5% level, while TRAF1/C5 rs3761847 (OR 1.53 [0.95-2.47]) was no longer significant. Conclusions TNFA1P3/A20 and PTPN2 were associated with poor prognosis in Portuguese patients with JIA. These genes were also associated with susceptibility to JIA. Further studies in independent populations are needed to strengthen the knowledge in this field. Disclosure of Interest None declared

PReS-FINAL-2163: Disease activity in a juvenile idiopathic arthritis population after 5 years follow-up

The main goal of juvenile idiopathic arthritis (JIA) treatment is to achieve a long-term remission or, at least, low levels of disease activity.

PReS-FINAL-2095: Older age predicts poor response to 6-months methotrexate therapy in a juvenile idiopathic arthritis cohort of patients

The identification of predictive factors of poor response to methotrexate (MTX) in juvenile idiopathic arthritis (JIA) patients could contribute to optimize the treatment strategy, namely by the earlier introduction of biological treatments.

PReS-FINAL-2021: JADAS-CRP instead of JADAS-ESR...results from REUMA.PT

Recently, Juvenile Arthritis Disease Activity Score (JADAS) was found to be a valid instrument for assessment of disease activity. JADAS was developed with erythrocyte sedimentation rate (ESR) because C-reactive protein (CRP) values were not available in all databases used to validate the tool. Nordal et al compared recently in a Nordic population the JADAS based on CRP with JADAS based on ESR and concluded that these instruments correlated closely, indicating that both scores can be recommended for assessing disease activity in JIA.

AB0282 DAS28, CDAI and SDAI cutoffs do not translate same information - results from the rheumatic diseases portuguese register, reuma.pt

Background DAS28, CDAI and SDAI are frequently used indexes to assess disease activity in RA patients. Cutoffs were defined to differentiate the states of disease activity that a patient can experience: remission or, low, moderate and high disease activity. DAS28 intervals for these states are, respectively, [0, 2.6[, [2.6, 3.2], ]3.2, 5.1] and ]5.1, +∞[. CDAI intervals are [0, 2.8], ]2.8, 10], ]10, 22] and ]22, +∞[, and SDAI intervals are [0, 3.3], ]3.3, 11], ]11, 26] and ]26, +∞[. Taking into account the CDAI and SDAI cutoffs, new cutoffs for DAS28 have been proposed: [0, 2.4], ]2.4, 3.6], ]3.6, 5.5] and ]5.5, +∞[. Objectives To assess disease activity states classified by DAS28, CDAI and SDAI, and to analyze their concordance in a Portuguese population Methods Patients with RA under biological therapy and followed up in the Reuma.pt were included in this analysis. A total of 1635 patients were included and 7316 visits were analyzed, 2285 of which were previous to the onset of biological agents, 2998 visits were within 2 years of biological treatment and 2033 visits occurred 2 or more years after starting biological treatment. Overall Pearson’s correlation coefficients (PCCs) were calculated for the 3 indexes. Chi-square tests were performed to analyze visits distributions for all disease activity states and indexes. PCCs were also calculated to test the concordance of DAS28 with both CDAI and SDAI indexes, varying each one of these indexes along their scales with an interval of 0.1. Results A strong concordance was found between the 3 indexes throughout the 7316 visits: r=0.881 for DAS28/CDAI, r=0.876 for DAS28/SDAI and r=0.973 for the CDAI/SDAI correlation (all PCCs with p<0.001). However, when the different disease activity states were analyzed, both chi-square tests and PCCs revealed that these cutoffs were non-concordant. The hypothesis that the distributions were the same was rejected for all the compared cutoffs. For example, the correspondence between the new proposed cutoffs for DAS28 with CDAI (p=5.08966E-55) and SDAI (p=6.3064E-34) cutoffs was strongly rejected. For these DAS28 cutoffs (2.4, 3.6 and 5.5), the best correlation with CDAI was obtained at the cutoffs of 4, 10.1 and 26, and with SDAI at the cutoffs of 4.7, 11.1 and 28.1. The hypothesis that these 3 distributions are the same was not rejected (p=0.991). We also found that when considering all visits with DAS28 <2.6, average patient global (PG) assessment score was 1.92 (on a scale of 0 to 10) and the average weight of PG was 11.16% for DAS28, 52.93% for CDAI and 45.61% for SDAI. According to the 2011 ACR/EULAR definitions of remission in RA, PG should not be higher than 1. Conclusions DAS28, CDAI and SDAI cutoffs do not translate the same clinical information in Reuma.pt. Since disease perception is influenced by several factors (e.g., culture), and PG weight in CDAI and SDAI indexes is considerably higher than in DAS28, established CDAI and SDAI cutoffs probably should not be universally applied. Disclosure of Interest None Declared