Avaliação do efeito da suplementação com colesterol na hipertensão arterial pulmonar experimental

Cardiac cachexia (CC) is a serious complication of heart failure (HF), characterized by involuntary weight loss, independent of food intake and associated with poor prognosis. Given the lack of therapeutic strategies for CC, further research is needed to explore its complex pathophysiology and to test new preventive and therapeutic approaches. The cholesterol paradox is based on reports that low total cholesterol and low-density lipoprotein serum levels worsen prognosis in HF. Considering the endotoxin-lipoprotein hypothesis, which states that higher circulating levels of cholesterol and lipoproteins can attenuate the CC-related immune activation, we hypothesized that enhancing cholesterol intake would ameliorate HF and CC in experimental pulmonary arterial hypertension (PAH). This study aimed to test the endotoxin-lipoprotein hypothesis in vivo by evaluating functional and molecular effects of a cholesterol supplemented diet in monocrotaline (MCT)-induced rat PAH. Wistar Han rats were injected with MCT (60 mg/kg) or an equal volume of vehicle and, five days after, MCT-injected rats were randomly allocated to consume either normal diet or a cholesterol supplemented diet (cholesterol 2 % and cholic acid 0.25 %). Between the 25th and 30th day, animals underwent echocardiographic and haemodynamic evaluation. We assessed body weight (BW) evolution, peak of oxygen consumption, cardiomyocyte cross-sectional area and pulmonary arterioles wall-thickness. Plasma concentration of total cholesterol, high density lipoprotein-cholesterol (HDL-C), non-HDL cholesterol, triglycerides, tumour necrosis factor alpha (TNF-α) and endotoxin LPS was also determined. The results showed that MCT effectively induced the development of PAH and right ventricle hypertrophy and failure, accompanied by a significant reduction of BW, which is related with CC. Cholesterol supplemented diet induced a significant increase of plasma total cholesterol, HDL-C and non-HDL cholesterol concentration, liver weight and left ventricle cardiomyocyte cross-sectional area. We found also a trend towards lower plasma levels of TNF-α and endotoxin LPS, suggesting that the higher lipoprotein content might reduce the inflammatory activation induced by endotoxin LPS. Further research is needed regarding cholesterol supplementation in CC, in order to clarify these effectsA caquexia cardíaca (CC) é uma complicação da insuficiência cardíaca (IC), caracterizada pela perda de peso involuntária, independente do consumo alimentar e associada a um mau prognóstico. Devido à falta de estratégias terapêuticas, é necessária mais investigação sobre a complexa fisiopatologia da CC, de forma a testar novas abordagens preventivas e terapêuticas. O paradoxo do colesterol baseia-se em estudos que associam baixos níveis séricos de colesterol total e de lipoproteína de baixa densidade a um pior prognóstico na IC. Considerando a hipótese da endotoxina-lipoproteína, que sugere que elevados níveis de colesterol e lipoproteínas possam atenuar a ativação imunológica associada à CC, admitimos a hipótese de que o aumento do consumo de colesterol na dieta poderia melhorar a IC e a CC na hipertensão arterial pulmonar (HAP) experimental. Este estudo teve como objetivo testar a hipótese da endotoxina-lipoproteína in vivo, pela avaliação dos efeitos funcionais e moleculares de uma dieta suplementada com colesterol no modelo animal de HAP induzido pela administração de monocrotalina (MCT). Ratos Wistar Han foram injetados com MCT (60 mg/kg) ou com um volume igual de veículo e, após cinco dias, os ratos injetados com MCT foram aleatoriamente repartidos para consumirem uma dieta normal ou uma dieta suplementada com colesterol (2 % de colesterol e 0.25 % de ácido cólico). Entre o 25º e 30º dia, os animais foram submetidos a uma avaliação ecocardiográfica e hemodinâmica. Foram determinadas a evolução do peso corporal, o pico de consumo de oxigénio, a área de secção transversal dos cardiomiócitos e o espessamento da parede de arteríolas pulmonares. A concentração plasmática de colesterol total, lipoproteína de alta densidade (HDL-C), colesterol não-HDL, triglicerídeos, fator de necrose tumoral alfa (TNF-α) e endotoxina LPS foram também determinadas. Os resultados demonstraram que a MCT induziu efetivamente o desenvolvimento de HAP, hipertrofia e insuficiência do ventrículo direito, acompanhado pela redução significativa do peso corporal, associado com a CC. A suplementação da dieta com colesterol induziu um aumento significativo da concentração plasmática de colesterol, HDL-C e colesterol não-HDL, um aumento da massa do fígado e da área de secção transversal dos cardiomiócitos do ventrículo esquerdo. Verificámos uma tendência para a redução dos níveis de TNF-α e endotoxina LPS, o que sugere que um aumento dos níveis circulantes de lipoproteínas pode reduzir a ativação inflamatória induzida pela endotoxina LPS. Assim, é necessária mais investigação acerca da suplementação com colesterol na CC, de forma a clarificar estes efeitosMestrado em Bioquímic

Exploring the factor structure of neurocognitive measures in older individuals

Here we focus on factor analysis from a best practices point of view, by investigating the factor structure of neuropsychological tests and using the results obtained to illustrate on choosing a reasonable solution. The sample (n=1051 individuals) was randomly divided into two groups: one for exploratory factor analysis (EFA) and principal component analysis (PCA), to investigate the number of factors underlying the neurocognitive variables; the second to test the "best fit" model via confirmatory factor analysis (CFA). For the exploratory step, three extraction (maximum likelihood, principal axis factoring and principal components) and two rotation (orthogonal and oblique) methods were used. The analysis methodology allowed exploring how different cognitive/psychological tests correlated/discriminated between dimensions, indicating that to capture latent structures in similar sample sizes and measures, with approximately normal data distribution, reflective models with oblimin rotation might prove the most adequate.The study is integrated in the ‘‘Maintaining health in old age through homeostasis (SWITCHBOX)’’ (http://www.switchbox-online.eu/) collaborative project funded by the European Commission FP7 initiative (grant HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). NCS is supported by a SwitchBox post-doctoral fellowship, LA and PSM are supported by "MyHealth” project (Contract DoIT-13853)" doctoral fellowships

Poor sleep quality associates with decreased functional and structural brain connectivity in normative aging: A MRI multimodal approach

Sleep is a ubiquitous phenomenon, essential to the organism homeostasis. Notwithstanding, there has been an increasing concern with its disruption, not only within the context of pathological conditions, such as neurologic and psychiatric diseases, but also in health. In fact, sleep complaints are becoming particularly common, especially in middle-aged and older adults, which may suggest an underlying susceptibility to sleep quality loss and/or its consequences. Thus, a whole-brain modeling approach to study the shifts in the system can cast broader light on sleep quality mechanisms and its associated morbidities. Following this line, we sought to determine the association between the standard self-reported measure of sleep quality, the Pittsburgh Sleep Quality Index (PSQI) and brain correlates in a normative aging cohort. To this purpose, 86 participants (age range 52-87 years) provided information regarding sociodemographic parameters, subjective sleep quality and associated psychological variables. A multimodal magnetic resonance imaging (MRI) approach was used, with whole-brain functional and structural connectomes being derived from resting-state functional connectivity (FC) and probabilistic white matter tractography (structural connectivity, SC). Brain regional volumes and white matter properties associations were also explored. Results show that poor sleep quality was associated with a decrease in FC and SC of distinct networks, overlapping in right superior temporal pole, left middle temporal and left inferior occipital regions. Age displayed important associations with volumetric changes in the cerebellum cortex and white matter, thalamus, hippocampus, right putamen, left supramarginal and left lingual regions. Overall, results suggest that not only the PSQI global score may act as a proxy of changes in FC/SC in middle-aged and older individuals, but also that the age-related regional volumetric changes may be associated to an adjustment of brain connectivity. These findings may also represent a step further in the comprehension of the role of sleep disturbance in disease, since the networks found share regions that have been shown to be affected in pathologies, such as depression and Alzheimer's disease.Financial support was provided by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and National Funds through FCT-Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038, by the project NORTE-01-0145-FEDER-000013 [supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 (P2020) Partnership Agreement, through the European Regional Development Fund (FEDER)], by POCI-01-0145-FEDER-016428 [supported by the Operational Programme Competitiveness and Internationalization (COMPETE 2020) and the Regional Operational Program of Lisbon and National Funding through Portuguese Foundation for Science and Technology (FCT, Portugal)], and by the Portuguese North Regional Operational Programme [ON.2 – O Novo Norte, under the National Strategic Reference Framework (QREN), through FEDER]. The work was also developed under the scope of the projects SwitchBox (European Commission, FP7; contract HEALTH-F2-2010-259772) and TEMPO-Better mental health during aging based on temporal prediction of individual brain aging trajectories (Fundação Calouste Gulbenkian; Contract grant number P-139977). LA, TC, RM, PSM, and CP-N were supported by FCT PhD scholarships [SFRH/BD/101398/2014 to LA; SFRH/BD/90078/2012 to TC; PDE/BDE/113604/2015 from the PhD-iHES Programme to RM; PDE/BDE/113601/2015 to PSM; PD/BD/106050/2015 from the Inter-University Doctoral Programme in Aging and Chronic Disease (PhDOC) to CP-N] and AC by a scholarship from the project NORTE-08-5639-FSE-000041 (NORTE 2020; UMINHO/BD/51/2017). NCS was a recipient of a Research Assistantship by the through the FCT Investigator Programme 200∞ Ciência.info:eu-repo/semantics/publishedVersio

Longitudinal measurement invariance of memory performance and executive functioning in healthy aging

In this work, we examined the longitudinal measurement invariance of a battery composed of distinct cognitive parameters. A sample of 86 individuals (53.5% females; mean age = 65.73), representative of the Portuguese older population, with respect to sex, age and level of education was assessed twice over an average of two years. By means of a confirmatory factor analysis approach, we tested whether a two-factor solution [corresponding to measures of memory performance (MEM) and executive functioning (EXEC)] was reliable over time. Nested models of longitudinal invariance demonstrated the existence of partial strong invariance over time. In other words, this indicates that there is an equivalence of the factorial structure and factor loadings for all items; this was also observed for the item intercepts for all the items, except for one of the items from the EXEC dimension. Stability coefficients revealed high associations between the dimensions over time and that, whereas there was a significant decline of the MEM across time, this was not observed for the EXEC dimension. These findings reveal that changes in MEM and EXEC scores can be attributed to true changes on these constructs, enabling the use of this battery as a reliable method to study cognitive aging.PSM (ref: PDE/BDE/113601/2015 - PhD-iHES program), TCC (ref: SFRH/BD/90078/2012), LA (SFRH/BD/101398/2014) and CPN (ref: PD/BD/106050/2015 - PhDOC program) were supported by FCT fellowship grants. The work has been developed under the scope of the projects NORTE-01-0145-FEDER-000013 supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 (P2020) Partnership Agreement, through the European Regional Development Fund (FEDER) and POCI-01-0145-FEDER-016428 supported by the Operational Programme Competitiveness and Internationalization (COMPETE 2020) and the Regional Operational Program of Lisbon and National Funding through Portuguese Foundation for Science and Technology (FCT, Portugal); and, by the Portuguese North Regional Operational Programme (ON.2 - O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, the Fundação Calouste Gulbenkian (Portugal) (contract grant number: P-139977; project "TEMPO - Better mental health during ageing based on temporal prediction of individual brain ageing trajectories") and SwitchBox-FP7-HEALTH-2010-grant 259772-2info:eu-repo/semantics/publishedVersio

Assessing cognitive function in older adults using a videoconference approach

Background: The use of communication technologies is an emerging trend in healthcare and research. Despite efficient, reliable and accurate neuropsychological batteries to evaluate cognitive performance in-person, more diverse and less expensive and time consuming solutions are needed. Here we conducted a pilot study to determine the applicability of a videoconference (VC, Skype (R)) approach to assess cognitive function in older adults, using The Telephone Interview for Cognitive Status-Modified - Portuguese version (TICSM-PT). Methods: After inclusion and exclusion criteria, 69 individuals (mean age = 74.90 +/- 9.46 years), selected from registries of local health centers and assisted-living facilities, were assessed on cognitive performance using videoconference, telephone and in-person approaches. Findings: The videoconference administration method yielded comparable results to the traditional application. Correlation analyses showed high associations between the testing modalities: TICSM-PT VC and TICSM-PT telephone (r=0.885), TICSM-PT VC and MMSE face-to-face (r=0.801). Using the previously validated threshold for cognitive impairment on the TICSM-PT telephone, TICSM-PT VC administration presented a sensitivity of 87.8% and a specificity of 84.6%. Interpretation: Findings indicate for the range of settings where videoconference approaches can be used, and for their applicability and acceptability, providing an alternative to current cognitive assessment methods. Continued validation studies and adaptation of neuropsychological instruments is warranted.This work was funded by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772), and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte), under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), and by the Fundacao Calouste Gulbenkian (Portugal) (Contract grant number: P-139977; project "Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)"). TCC and LA are recipients of a doctoral fellowship from the Portuguese Foundation for Science and Technology (FCT, Portugal; SFRH/BD/90078/2012 and SFRH/BD/101398/2014, respectively, the latter from the POCH program and co-financed by the Fundo Social Europeu and MCTES); PSM is supported by the FCT fellowship grant (PDE/BDE/113601/2015 from the PhD-iHES program); and, NCS of a Research Assistantship by FCT through the "FCT Investigator Programme (2008 Ciencia)".info:eu-repo/semantics/publishedVersio

Iron status is associated with mood, cognition, and functional ability in older adults: a cross-sectional study

Several conditions are risk factors for iron deficiency (ID), some of which are highly prevalent in older individuals. Despite the amount of evidence pointing for a role of ID in cognition, mood and physical functional ability, the research addressing these associations in older individuals is still scarce. In the present study, 162 older community-dwelling individuals (29.53% classified as ID) were enrolled in a cross-sectional analysis and characterized regarding cognition, mood, functional ability, general nutritional intake and iron status. Assessment of iron status was performed using several blood biomarkers. Storage and erythropoiesis dimensions were positively associated with memory, along with an interaction (moderator effect) between iron storage and nutritional status. A more depressed mood was negatively associated with (iron) transport, transport saturation and erythropoiesis dimensions, and functional tiredness was positively associated with the erythropoiesis dimension. These observations indicate that lower iron status is associated with depressive mood, functional tiredness and poorer memory ability, with the latter moderated by nutritional status. These findings suggest that using iron as a continuous variable may be useful in finding associations with iron homeostasis, eventually missed when iron levels are considered within the usual classification groups.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), by the Fundacao Calouste Gulbenkian (Portugal) (contract grant number: P-139977; project "Better Mental Health during Ageing based on Temporal Prediction of Individual Brain Ageing Trajectories (TEMPO)") and by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772). C.P.-N was supported by the Portuguese Science Foundation (FCT) doctoral scholarship PD/BD/106050/2015 via the Inter-University PhD Programme in Ageing and Chronic Diseases, T.C.C. was a recipient of a doctoral fellowship from the Portuguese Foundation for Science and Technology (FCT; SFRH/BD/90078/2012), L.A. was a recipient of a doctoral fellowship from the Portuguese Foundation for Science and Technology (FCT; SFRH/BD/101398/2014), P.S.M. was supported by the FCT fellowship grant with the reference PDE/BDE/113601/2015 from the PhDiHES program, N.C.S. was a recipient of a research assistantship by the through the FCT Investigator Programme 200 infinity Ciencia

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion

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.publishersversionpublishe

Asymmetrical subcortical plasticity entails cognitive progression in older individuals

Structural brain asymmetries have been associated with cognition. However, it is not known to what extent neuropsychological parameters and structural laterality covary with aging. Seventy-five subjects drawn from a larger normal aging cohort were evaluated in terms of MRI and neuropsychological parameters at two moments (M1 and M2), 18 months apart. In this time frame, asymmetry as measured by structural laterality index (ΔLI) was stable regarding both direction and magnitude in all areas. However, a significantly higher dispersion for this variation was observed in subcortical over cortical areas. Subjects with extreme increase in rightward lateralization of the caudate revealed increased M1 to M2 Stroop interference scores, but also a worsening of general cognition (MMSE). In contrast, subjects showing extreme increase in leftward lateralization of the thalamus presented higher increase in Stroop interference scores. In conclusion, while a decline in cognitive function was observed in the entire sample, regional brain asymmetries were relatively stable. Neuropsychological trajectories were associated with laterality changes in subcortical regions.This work was supported by the project NORTE‐01‐0145‐FEDER‐000013 through the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and funded by the European Commission (FP7) “SwitchBox ‐ Maintaining health in old age through homeostasis” (Contract HEALTH‐F2‐2010‐259772), and co‐financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, and by the Fundação Calouste Gulbenkian (Portugal) (Contract grant number: P‐139977; project “TEMPO ‐ Better mental health during ageing based on temporal prediction of individual brain ageing trajectories”) and by “PANINI ‐ Physical Activity and Nutrition INfluences In ageing” (European Commission (Horizon 2020), Contract GA 675003). Individual authors were supported under: "SwitchBox" to PM and NCS; Fundação para a Ciência e a Tecnologia (FCT) grants SFRH/BD/52291/2013 to ME and PD/BD/106050/2015 to CPN via Inter‐University Doctoral Programme in Ageing and Chronic Disease (PhDOC), PDE/BDE/113601/2015 to PSM and PDE/BDE/113604/2015 to RM via PhD Program in Health Sciences (Applied) (Phd‐iHES), SFRH/BD/90078/2012 to TCC, SFRH/BD/101398/2014 to LA and SFRH/BPD/80118/2011 do HLAinfo:eu-repo/semantics/publishedVersio

Arbustus unedo essence: morphological and genetic characterization of the strawberry tree of Castelo de Paiva

O medronheiro é um arbusto da região mediterrânica que pode ser encontrada por todo o país. Ao contrário do que verifica na região sul do país, no concelho de Castelo de Paiva é atribuída uma reduzida importância económica a esta espécie. Com o intuito de preservar e potenciar a produção desta espécie e contribuir para a dinamização da economia do concelho, procedeu-se à caracterização morfológica e genética de uma amostra da população de medronheiros de Castelo de Paiva. A caracterização morfológica e genética foi realizada para um total de 10 genótipos. Para tal recolheram-se 70 folhas aleatoriamente em cada árvore. Em 40 folhas mediu-se o comprimento, largura, comprimento do pedúnculo, peso fresco, peso seco e determinou-se a área foliar. Dos caracteres morfológicos analisados, aqueles que se revelaram mais úteis na distinção dos vários genótipos foram: comprimento do pedúnculo, peso fresco e peso seco. As restantes 30 folhas foram utilizadas para a caracterização genética. Esta caracterização foi realizada recorrendo a um marcador de DNA, ISSR. Os 5 primeiros exemplaresutilizados na técnica de ISSR demonstraram-se polimórficos. Os resultados da caracterização genética sugerem que a variabilidade genética na população é média a alta.The strawberry tree is a shrub native in the Mediterranean region and it can be found throughout Portugal. Unlike the case in the southern region of the country, in Castelo de Paiva a minor economic importance is given to this species. In order to preserve, to enhance the production of this species and to contribute to the boosting of the economy of the region, we proceeded to the characterization of a small sample population of this fruit tree of Castelo de Paiva in what concerns to its morphology and genetics. The morphological and genetic characterization was performed for a total of 10 genotypes. For this, 70 leaves were randomly collected from each tree. For 40 leaves, it was measured the length, the width, the peduncle length, the wet weight, the dry weight and determined the leaf area. Of the morphological characteristics analyzed, the ones that proved most useful in distinguishing the various genotypes were: the length peduncle, the wet weight and the dry weight. The remaining 30 leaves were used in the genetic characterization. This characterization was performed using a DNA marker, the ISSR. The 5 primers used in the ISSR technique proved to be polymorphic. The results from the genetic characterization suggest that variability in population genetics is medium to high

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion

BackgroundHuman 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.MethodsIn 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.ResultsAs 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.ConclusionIntracoronary 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