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Funding Information: This work was funded by: i) national funds through FCT - Portuguese Foundation for Science and Technology, under the scope of the Cardiovascular R&D Center - UnIC (UIDB/00051/2020 and UIDP/00051/2020); ii) “la Caixa” Banking Foundation and FCT under the project code LCF/PR/HP17/52190002”; iii) the QREN project 2013/30196; and iv) the European Structural and Investment Funds (ESIF), under the Lisbon Portugal Regional Operational Program and National Funds through FCT [POCI-01-0145-FEDER-030985]. RNG and TLL were funded by the FCT individual fellowships [SFRH/BD/144490/2019] and [PD/BD/127997/2016], respectively. Funding sources had no interference in the design of the study, study governance, data collection and analysis, nor in manuscript writing or its scientific and intellectual content. Publisher Copyright: 2023 Raposo, Cerqueira, Leite, Moreira-Costa, Laundos, Miranda, Mendes-Ferreira, Coelho, Gomes, Pinto-do-Ó, Nascimento, Lourenço, Cardim and Leite-Moreira. Background: Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine. Methods: In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing. Results: As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = −2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC. Conclusion: Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect. publishersversion published

Introduction: Meta-analysis is the method to pool data from studies that report the same event in a comparable sample and, thus, summarize information from different populations. However, data extraction is limited to the information provided in the included studies. Frequently, individual patient information is not available, hence, real world data access is limited. Individual patient data (IPD) meta-analysis in a research area like health sciences constitutes the ideal method to analyse real world data, assuming a high level of evidence. (1) This method is based on a collaboration network in which variables can be merged among datasets once a single definition is determined reducing methodological heterogeneity. The use of IPD for meta-analysis has advantages, (allows adjustment for confounding factors), and limitations (obtaining individual patient data knowing that data collection and management are often unclear). (1, 2) To tackle high heterogeneity in a study-level meta-analysis, sensitivity analyses are recommended. Leave-one-out analysis is an option that evaluates the cumulative effect of each study by excluding one at a time, portraying its influence in the overall result (3). Considering the lack of long-term data on postoperative acute kidney injury (AKI) in coronary artery bypass grafting surgery (CABG) patients, paired with the expected study heterogeneity, we intend to summarize evidence regarding its effect on early and long-term survival, evaluate heterogeneity and perform sensitivity analysis. Methods: Systematic searches were performed in MEDLINE and ISI Web of Science, restricted by date of publication (January 1960–April 2021). Inclusion criteria comprised observational studies reporting incidence of postoperative AKI in adult patients, submitted to isolated CABG with at least 1-year of follow-up and survival estimates. Analyses were performed using Review Manager 5.4. and R environment. Random effects models were used to compute pooled HR and OR (95% CI), through generic inverse variance method and Mantel-Haenszel method or generalized linear mixed-effects model and logit-transformed proportions of AKI were used for analysis of prevalence data. Heterogeneity was defined using I2 statistics and was considered low (75%) (4). Between-study heterogeneity was studied using sensitivity analyses, namely, leave-one-out evaluations (metagen (meta R package)). Early and late survival were evaluated through this sensitivity analysis and were present according to each study impact on both effect size estimates and observed I2. (5) Results: Thirteen retrospective observational studies comprising 63209 patients were included, (N AKI=11366, N non-AKI=51843). AKI incidence ranged 0.6%-54% with a pooled incidence of 16%. Postoperative AKI was associated with higher early mortality (OR (95%CI): 7.59 (3.18-18.15), p 2 mg/dL according to preoperative renal function status, which differs from the most traditional criteria used by the other studies: increment of at least 0.3 mg/dL. Leave-one-out analysis showed that one must pay attention to real-world data, since different variable definitions, namely: different AKI definitions and the samples included in each study, influence overall measures. Acknowledgements: This study is funded by national funds through FCT - Portuguese Foundation for Science and Technology, under the scope of the Cardiovascular R&D Center – UnIC@RISE [grant numbers UIDB/00051/2020, UIDP/00051/2020]. R. Moreira is supported by FCT - Portuguese Foundation for Science and Technology, FSE – European Social Fund, NORTE 2020 - Programa Operacional Regional do Norte (POR-Norte), (UI/BD/150657/2020). References: Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. Bmj. 2010;340. Kanters S, Karim ME, Thorlund K, Anis A, Bansback N. When does the use of individual patient data in network meta-analysis make a difference? A simulation study. BMC medical research methodology. 2021;21(1):1-13. Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC medical research methodology. 2009;9(1):1-12. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Bmj. 2003;327(7414):557-60. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions: John Wiley & Sons; 2019. Ivert T, Holzmann MJ, Sartipy U. Survival in patients with acute kidney injury requiring dialysis after coronary artery bypass grafting. Eur J Cardiothorac Surg. 2014;45(2):312-7. Di Mauro M, Gagliardi M, Iacò AL, Contini M, Bivona A, Bosco P, et al. Does off-pump coronary surgery reduce postoperative acute renal failure? The importance of preoperative renal function. The Annals of thoracic surgery. 2007;84(5):1496-502. Lv M, Hu B, Ge W, Li Z, Wang Q, Han C, et al. Impact of Preoperative Occult Renal Dysfunction on Early and Late Outcomes After Off-Pump Coronary Artery Bypass. Heart, Lung and Circulation. 2021;30(2):288-95. Di Mauro M, Gagliardi M, Iacò AL, Contini M, Bivona A, Bosco P, et al. Does off-pump coronary surgery reduce postoperative acute renal failure? The importance of preoperative renal function. Ann Thorac Surg. 2007;84(5):1496-502., Journal of Statistics on Health Decision, vol. 4 n.º 1 (2022): Special Issue - Statistics on Health Decision Making: Real World Data

Portuguese Journal of Cardiac Thoracic and Vascular Surgery, Vol. 28 No. 4 (2021): October - December

Journal of Statistics on Health Decision, vol. 3 n.º 1 (2021): Special Issue - Statistics on Health Decision Making: Public Health

Background: In selected cases, aortic valve repair (RVAo) is an alternative to prostesic aortic valve replacement. Aim: To compare mid-term survival, need of reoperation and echocardiographic findings associated with RVAo. Methods: Retrospective single-center cohort study including consecutive patients younger than 70 years-old, with non-stenotic aortic valve disease, who underwent RVAo between 2012 and 2017. A comparison was made with a group of patients who underwent mechanical aortic valve replacement (SVAo) in the same period. The groups were characterized and compared using Chi-Square and t-tests for independent samples and survival and reoperation were analyzed using Kaplan-Meier curves and Cox regressions. Results: We included 72 patients submitted to RVAo. Mean follow-up time was 4 years, maximum 7. Although the mean age was relatively low (47��13 years), patients undergoing RVAo presented a lower prevalence of rheumatic etiology (3%). The cardiopulmonary bypass (148��74 minutes) and cross clamping aortic times (108��52 minutes) are the usual times for this type of surgery and similar to those of the comparing group (SVAo). In the echocardiographic follow-up (median of 3 months), we verified a left ventricular mass regression of 21% and a prevalence of aortic insufficiency of 4%. At 7 years, cumulative survival and freedom from reoperation of patients undergoing RVAo were 98.8% and 97.6%, respectively. Conclusion: RVAo can be a safe and effective alternative, with good mid-term results if patient selection is judicious., Portuguese Journal of Cardiac Thoracic and Vascular Surgery, Vol. 26 No. 2 (2019): April - June

Objectives: To compare 7-year survival and freedom from reoperation, as well as early clinical and hemodynamic outcomes, after surgical aortic valve replacement (SAVR) with mechanical or bioprosthetic valves in patients aged 50-70 years. Methods: single-center retrospective cohort study including adults aged 50-70 years who underwent SAVR in 2012 with a mechanical or bioprosthetic valve. Median follow-up was 7 years. Univariable analyses were performed using Kaplan- -Meier curves and Log-Rank tests for survival and freedom from reoperation analyses. Multivariable time-to-event analyses were conducted using Cox Regression. Results: Of a total of 193 patients, 76 (39.4%) received mechanical valves and 117 (60.6%) received bioprosthetic valves. A trend for better survival was found for mechanical prostheses when adjusting for EuroSCORE II (HR: 0.35; 95%CI: 0.12-1.02, p=0.054), but using a backward stepwise Cox regression prosthesis type was not retained by the model as an independent predictor of survival. Moreover, mechanical prostheses showed trends for higher freedom from reoperation (100% vs. 95.5%, Log-Rank, p=0.076), higher median EuroSCORE II (2.52% vs. 1.95%, p=0.06) and early mortality (7.9% vs. 2.6%, p=0.086). However, after adjusting for EuroSCORE II, there was no significant difference in early mortality (OR: 2.3, 95%CI: 0.5-10.5, p=0.272). Regarding hemodynamic performance at follow-up echocardiogram, there were no differences other than left ventricular mass regression, which was not as pronounced in the mechanical group (-12% vs. -21%, p=0.002). Conclusion: Mechanical and bioprosthetic aortic valves prostheses showed similar mid-term survival in the 50-70 age group. Further prospective and larger studies are needed to provide evidence-based recommendations on this topic., Portuguese Journal of Cardiac Thoracic and Vascular Surgery, Vol. 27 No. 3 (2020): July - September