[Delayed graft function : an ongoing clinical challenge]. / Reprise retardée de fonction du greffon après transplantation rénale : un challenge clinique toujours d'actualité.

Delayed Graft Function (DGF) is defined as the need for dialysis during the first week after transplantation. DGF is frequent and mostly derived from the ischemia/reperfusion cascade to which the graft is subjected throughout the transplantation process. A graft biopsy is recommended after 7 days of DGF to exclude an episode of acute rejection. Note that DGF per se is associated with an increased risk of acute graft rejection, as well as with a shorter long-term graft survival. Several strategies are being studied to mitigate the ischaemic damage, thereby improving graft quality. Among these, cellular therapy using mesenchymal stromal cells (MSC) is promising, in particular via the administration of MSC in the machine perfusion during the preservation of the graft. We will discuss here the different definitions of DGF and the main predictive factors of DGF, as well as the impact on the graft outcomes. The current strategies to prevent DGF will be briefly reviewed.

La reprise retardée de fonction du greffon rénal (DGF en anglais pour Delayed Graft Function), définie notamment par la nécessité de dialyse durant la 1ère semaine après transplantation, reste un événement fréquent. La DGF résulte principalement des phénomènes d'ischémie/reperfusion auxquels le greffon est soumis tout au long du processus de transplantation. Néanmoins, une biopsie du greffon est préconisée après 7 jours de DGF afin d'exclure une cause non ischémique telle qu'un rejet aigu. La DGF est per se associée à un risque accru de rejet du greffon, ainsi qu'à une moins bonne survie du greffon rénal au long cours. Plusieurs stratégies sont étudiées afin d'atténuer les dommages ischémiques et améliorer la qualité du greffon. Parmi celles-ci, la thérapie cellulaire par cellules stromales mésenchymateuses est prometteuse, notamment via l'administration de celles-ci dans la machine de perfusion lors de la préservation du greffon. Nous aborderons les différentes définitions de la DGF ainsi que ses principaux facteurs prédictifs, l'impact sur le devenir du greffon et, brièvement, les stratégies actuelles dans le cadre de la prévention de la DGF.

Effects of chronic moderate alcohol consumption on right ventricle and pulmonary remodelling.

NEW FINDINGS: What is the central question of this study? Does the consumption of a moderate amount of alcohol differentially impact the heart ventricles and pulmonary vasculature. What is the main finding and its importance? Moderate alcohol consumption for a short period of time impaired pulmonary vascular cellular renewal through an apoptosis resistance pattern that ultimately affected the right ventricular function and structure. These findings support the need for a deeper understanding of effects of moderate alcohol consumption on the overall cardiovascular and pulmonary systems. ABSTRACT: Over the past decades, observational studies have supported an association between moderate alcohol consumption and a lower risk of cardiovascular disease and mortality. However, recent and more robust meta-analyses have raised concerns around the robustness of the evidence for the cardioprotective effects of alcohol. Also, studies of the functional, structural and molecular changes promoted by alcohol have focused primarily on the left ventricle, ignoring the fact that the right ventricle could adapt differently. The aim of this study was to evaluate the bi-ventricular impact of daily moderate alcohol intake, during a 4-week period, in a rodent model. Male Wistar rats were allowed to drink water (Control) or a 5.2% ethanol mixture (ETOH) for 4 weeks. At the end of the protocol bi-ventricular haemodynamic recordings were performed and samples collected for further histological and molecular analysis. ETOH ingestion did not impact cardiac function. However, it caused right ventricle hypertrophy, paralleled by an activation of molecular pathways responsible for cell growth (ERK1/2, AKT), proteolysis (MURF-1) and oxidative stress (NOX4, SOD2). Furthermore, ETOH animals also presented remodelling of the pulmonary vasculature with an increase in pulmonary arteries' medial thickness, which was characterized by increased expression of apoptosis-related proteins expression (BCL-XL, BAX and caspases). Moderate alcohol consumption for a short period of time impaired the lungs and the right ventricle early, before any change could be detected on the left ventricle. Right ventricular changes might be secondary to alcohol-induced pulmonary vasculature remodelling.

Post-Match Recovery in Soccer with Far-Infrared Emitting Ceramic Material or Cold-Water Immersion.

We investigated the effects of two common recovery methods; far-infrared emitting ceramic materials (Bioceramic) or cold-water immersion on muscular function and damage after a soccer match. Twenty-five university-level soccer players were randomized into Bioceramic (BIO; n = 8), Cold-water immersion (CWI; n = 9), or Control (CON; n = 8) groups. Heart rate [HR], rating of perceived exertion [RPE], and activity profile through Global Positioning Satellite Systems were measured during the match. Biochemical (thiobarbituric acid reactive species [TBARS], superoxide dismutase [SOD], creatine kinase [CK], lactate dehydrogenase [LDH]), neuromuscular (countermovement [CMJ] and squat jump [SJ], sprints [20-m]), and perceptual markers (delayed-onset muscle soreness [DOMS], and the perceived recovery scale [PRS]) were assessed at pre, post, 24 h, and 48 h post-match. One-way ANOVA was used to compare anthropometric and match performance data. A two-way ANOVA with post-hoc tests compared the timeline of recovery measures. No significant differences existed between groups for anthropometric or match load measures (P > 0.05). Significant post-match increases were observed in SOD, and decreases in TBARS in all groups (p < 0.05), without differences between conditions (p > 0.05). Significant increases in CK, LDH, quadriceps and hamstring DOMS (p < 0.05), as well as decreases in 20-m, SJ, CMJ, and PRS were observed post-match in all groups (p < 0.05), without significant differences between conditions (p > 0.05). Despite the expected post-match muscle damage and impaired performance, neither Bioceramic nor CWI interventions improved post-match recovery.

Challenges of BDNF-based therapies: From common to rare diseases.

Neurotrophins are a well-known family of neurotrophic factors that play an important role both in the central and peripheral nervous systems, where they modulate neuronal survival, development, function and plasticity. Brain-derived neurotrophic factor (BDNF) possesses diverse biological functions which are mediated by the activation of two main classes of receptors, the tropomyosin-related kinase (Trk) B and the p75 neurotrophin receptor (p75NTR). The therapeutic potential of BDNF has drawn attention since dysregulation of its signalling cascades has been suggested to underlie the pathogenesis of both common and rare diseases. Multiple strategies targeting this neurotrophin have been tested; most have found obstacles that ultimately hampered their effectiveness. This review focuses on the involvement of BDNF and its receptors in the pathophysiology of Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Rett Syndrome (RTT). We describe the known mechanisms leading to the impairment of BDNF/TrkB signalling in these disorders. Such mechanistic insight highlights how BDNF signalling compromise can take various shapes, nearly disease-specific. Therefore, BDNF-based therapeutic strategies must be specifically tailored and are more likely to succeed if a combination of resources is employed.

(Un)Equitable distribution of health resources and the judicialization of healthcare: 10 years of experience in Brazil.

BACKGROUND: Equity has been acknowledged as a required principle for the fulfilment of the universal right to health once it seeks to tackle avoidable and unfair inequalities among individuals. In Brazil, a country marked by iniquities, this principle was adopted in the Brazilian National Health System (SUS) organization. But the phenomenon known as judicialization of healthcare, anchored in the argument of universality of the right, has been consolidated as a health policy parallel to the SUS. The analysis of these lawsuits distribution according to their beneficiaries' socio-economic profile can contribute to the verification of the judicialization's potential for reducing inequalities, thus becoming an auxiliary activity in the fulfilment of the universal and egalitarian right to health. This study aimed to assess what socioeconomic factors are associated to municipalities that had larger numbers of beneficiaries from lawsuits in health in the state of Minas Gerais, Brazil, from 1999 to 2009. METHODS: It is a descriptive quantitative study of the residence municipalities of beneficiaries registered in database regarding all deferred lawsuits against the state of Minas Gerais from 1999 to 2009. The verification of cities' socio-economic profile was performed based on information of the Brazilian Institute of Geography and Statistics' 2010 Demographic Census and on indexes derived from it. The variables studied for each municipality were: number of beneficiaries; resident population; Social Vulnerability Index (IVS); and Municipal Human Development Index (IDHm). Descriptive and statistical analysis were used to verify factors associated with a larger number of beneficiaries in a municipality. RESULTS: Out of 853 municipalities in Minas Gerais, 399 were registered as residence of at least one of the 6.906 beneficiaries of studied lawsuits. The residence non-information index was 11,5%. The minimum number of identified beneficiaries living in a municipality was 1 (one) while the maximum was 1920. The binary logistic regression revealed that high and very high IDHm (OR = 3045; IC = 1773-5228), IVS below 0.323 (OR = 2044; IC = 1099- 3800) and population size above 14.661 inhabitants (OR = 6162; IC = 3733-10,171) are statistically associated to a greater number of beneficiaries of lawsuits in health within a municipality. CONCLUSIONS: The judicialization of health care in Minas Gerais, from 1999 to 2009, didn't reach the most vulnerable municipalities. On the contrary, it favored a concentration of health resources in municipalities with better socioeconomic profiles. The register of all beneficiaries' municipalities of residence as well as individual socioeconomic data can contribute to a more conclusive analysis. Nevertheless, in general, the results of this study suggest that the judicial health policy conducted from 1999 to 2009 was not an auxiliary tool for the fulfilment of an equitable right to health in Minas Gerais.

High Density of Periaortic Adipose Tissue in Abdominal Aortic Aneurysm.

OBJECTIVES: Perivascular adipose tissue (PVAT) is currently seen as a paracrine organ that produces vasoactive substances, including inflammatory agents, which may have an impact on the vasculature. In this study PVAT density was quantified in patients with an aortic aneurysm and compared with those with a non-dilated aorta. Since chronic inflammation, as the pathway to medial thinning, is a hallmark of abdominal aortic aneurysms (AAAs), it was hypothesised that PVAT density is higher in AAA patients. METHODS: In this multicentre retrospective case control study, three groups of patients were included: non-treated asymptomatic AAA (n = 140), aortoiliac occlusive disease (AIOD) (n = 104), and individuals without aortic pathology (n = 97). A Hounsfield units based analysis was performed by computed tomography (CT). As a proxy for PVAT, the density of adipose tissue 10 mm circumferential to the infrarenal aorta was analysed in each consecutive CT slice. Intra-individual PVAT differences were reported as the difference in PVAT density between the region of the maximum AAA diameter (or the mid-aortic region in patients with AIOD or controls) and the two uppermost slices of infrarenal non-dilated aorta just below the renal arteries. Furthermore, subcutaneous (SAT) and visceral (VAT) adipose tissue measurements were performed. Linear models were fitted to assess the association between the study groups, different adipose tissue compartments, and between adipose tissue compartments and aortic dimensions. RESULTS: AAA patients presented higher intra-individual PVAT differences, with higher PVAT density around the aneurysm sac than the healthy neck. This association persisted after adjustment for cardiovascular risk factors and diseases and other fat compartments (ß = 13.175, SE 4.732, p = .006). Furthermore, intra-individual PVAT differences presented the highest correlation with aortic volume that persisted after adjustment for other fat compartments, body mass index, sex, and age (ß = 0.566, 0.200, p = .005). CONCLUSION: The results suggest a relation between the deposition of PVAT and AAA pathophysiology. Further research should explore the exact underlying processes.

Trans-umbilical laparoscopic-assisted appendectomy in the pediatric population: comparing single-incision and 2-trocar techniques.

INTRODUCTION: Trans-umbilical laparoscopic-assisted appendectomy (TULAA) combines advantages of open surgery with benefits of laparoscopy and can be performed either by single-incision or with two trocars; the present study aims to compare outcomes and cost of these techniques in a pediatric serie. MATERIAL AND METHODS: Patients undergoing TULAA between July 2013 and June 2014 were retrospectively reviewed. There were two groups: A (single-incision) - one umbilical trocar for a telescope with inbuilt working channel; and B (2-trocar) - one umbilical trocar for a 'standard' telescope plus a supra-pubic trocar for instruments. RESULTS: One-hundred and eighty-nine patients (112 males, age: 12[2-17] years) underwent TULAA; 32(17%) presented with perforated appendicitis. Group A encompassed 157 and group B 32 patients; age, gender, proportion of perforated appendicitis, and follow-up were similar. Operative time was 46 [21-145] min in group A, and 54.5[30-111] in group B (A vs B, p = 0.087). Length of hospital stay was 2 [1;22] days in group B, and 2 [0;24] in group A (A vs B, p = 0.136). The prevalence of post-operative complications was similar: 11 (7%) cases in group A and 2 (6.3%) intra-abdominal abscesses in group B. Using disposable trocars, the more expensive starting point of single-incision technique may be reversed after 27 procedures. CONCLUSION: Single-incision and 2-trocar TULAA are effective techniques with low complication rates and similar outcomes. Despite being technically more demanding, single incision may be advantageous because there are no visible scars, and potentially cheaper in hospitals where disposable trocars are used.

[Perspectives and research challenges in abdominal aortic aneurysm calcification]. / Perspetivas e desafios do estudo da calcificação no aneurisma da aorta abdominal.

Abdominal aortic aneurysm (AAA) remains a relevant cause of mortality in Western countries. There is a need for continuous identification of risk factors for aneurysmal progression and predictors of treatment response to optimize the therapeutic strategy to be offered to these patients. Vascular calcification has been studied in several capillary beds as a cardiovascular risk factor. However, the importance of abdominal aortic calcification (AC) in AAA remains incompletely clarified, and the available evidence is scattered and heterogeneous. The objective of this review is to describe the possible impact of AC on aneurysmal progression and rupture, as well as on the response to endovascular correction. It should be noted that the establishment of a validated, quick and easy to use method for assessing AC would be of great clinical and/or research utility.

O aneurisma da aorta abdominal (AAA) permanece uma causa relevante de mortalidade nos países ocidentais. É premente a contínua identificação de fatores de risco de progressão aneurismática bem como de preditores de resposta ao tratamento na otimização da estratégia terapêutica a oferecer a estes doentes. A calcificação vascular tem sido estudada em diversos leitos capilares como um fator de prognóstico cardiovascular. Contudo, a importância da calcificação da aorta abdominal (CA) no AAA permanece incompletamente esclarecida, sendo a prova científica disponível dispersa e heterogénea. O objetivo desta revisão é descrever o eventual impacto da CA na progressão e rutura aneurismática, bem como na resposta à correção endovascular do AAA. Salienta-se que o estabelecimento de um método validado, rápido e fácil de usar para avaliar a CA seria de grande utilidade clínica e/ou investigacional.

HMGB1 down-regulation mediates terameprocol vascular anti-proliferative effect in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.

Mini-Review on Cachexia-Related miRNA.

Cachexia, or muscle wasting, is a complex metabolic syndrome associated with an underlying illness and characterized by loss of muscle mass. It is a rather prevalent condition, with impacts on patient survival, response to treatment, and quality of life. Treatment options are sparse because of cachexia's multifactorial pathogenesis. Recently, attention has focused on microRNAs (miRNAs) as potential therapeutic targets of several diseases. miRNAs are small, 18- to 25-base-long constructs that regulate gene expression on a post-transcriptional level, selectively activating or repressing elements of specific signaling pathways. In this review, we investigated whether miRNAs play any role in cachexia's biochemical pathways and if miRNA targeting has any significant impact on preclinical models of cachexia.

Fetal programming as a predictor of adult health or disease: the need to reevaluate fetal heart function.

Epidemiologic and experimental evidence suggests that adverse stimuli during critical periods in utero permanently alters organ structure and function and may have persistent consequences for the long-term health of the offspring. Fetal hypoxia, maternal malnutrition, or ventricular overloading are among the major adverse conditions that can compromise cardiovascular development in early life. With the heart as a central organ in fetal adaptive mechanisms, a deeper understanding of the fetal cardiovascular physiology and of the echocardiographic tools to assess both normal and stressed pregnancies would give precious information on fetal well-being and hopefully may help in early identification of special risk groups for cardiovascular diseases later in life. Assessment of cardiac function in the fetus represents an additional challenge when comparing to children and adults, requiring advanced training and a critical approach to properly acquire and interpret functional parameters. This review summarizes the basic fetal cardiovascular physiology and the main differences from the mature postnatal circulation, provides an overview of the particularities of echocardiographic evaluation in the fetus, and finally proposes an integrated view of in utero programming of cardiovascular diseases later in life, highlighting priorities for future clinical research.

Multidimensional Frailty and Pain in Community Dwelling Elderly.

Objective: To examine the relationship between frailty and pain, particularly to analyze whether pain predicts physical, psychological and social frailty, after controlling for the effects of life-course determinants and comorbidity. Design: Cross-sectional. Methods: A nonprobabilistic sample of 252 community dwelling elderly was recruited. Frailty and determinants of frailty were assessed with the Tilburg Frailty Indicator and pain was measured with the Pain Impact Questionnaire. Hierarchical and logistic regression analyses were conducted. Results: In this study, 52.4% of the participants were aged 80 years and over, and 75.8% were women. Pain and frailty were higher in women, and physical frailty was higher in those aged ≥80 years. After controlling for the effects of the determinants and comorbidity, pain predicted 5.8% of the variance of frailty, 5.9% of the variance of physical frailty, and 4.0% of the variance of psychological frailty, while the prediction of social frailty was nonsignificant. Overall, a greater pain impact score was associated with the presence of frailty (odds ratio 1.06; 95% CI 1.03­1.10; P < 0.001). Conclusion: Frailty was independently predicted by pain, emphasizing the importance of its treatment, potentially contributing to the prevention of vulnerability, dependency, and mortality. Nonetheless, longitudinal studies are required to better understand the possible association between pain and frailty.

2D:4D digit ratio is associated with cognitive decline but not frailty in community-dwelling older adults.

OBJECTIVES: To understand the relation between 2D:4D ratio, frailty, and cognitive decline in community-dwelling elderly people. METHODS: A total of 175 community-dwelling elderly people were included. To determine frailty, participants completed the Tilburg Frailty Indicator (TFI) and the Survey of Health, Ageing and Retirement in Europe (SHARE-FI). Cognitive functioning was determined using the Mini-Mental State Examination (MMSE). 2D and 4D finger lengths of each hand were measured using a scanner. Barthel Index, Lawton, and Brody scale were also completed for each participant to determine the level of daily living functioning. RESULTS: We did not find any correlations between 2D:4D ratio and frailty measures. We found a significant correlation between 2D:4D ratio and MMSE scores in the women sampled. CONCLUSIONS: We cannot ascertain any contribution of prenatal exposure to androgens to the frailty status of community-dwelling elderly people. We found that reduced prenatal exposure to testosterone in women may contribute to the prevention of cognitive decline in elderly women.

Exercise Training in Pulmonary Hypertension and Right Heart Failure: Insights from Pre-clinical Studies.

Exercise training (ExT) is widely used for the prevention and treatment of several chronic cardiovascular diseases. However, only recently it started to be recognized as safe and beneficial in pulmonary arterial hypertension. Despite the consistency of its favorable effects on exercise tolerance and quality of life, the mechanisms underlying these meaningful clinical improvements remain unclear. Current studies emphasize the exercise-induced changes on skeletal muscle but the impact of ExT at the level of the pulmonary circulation and right ventricle should not be overlooked. In this chapter, we summarize the main findings from pre-clinical studies analyzing the impact of exercise in pulmonary hypertension and right heart failure.

Vascular access in neonates.

The aim of this review was to provide updated and recent literature on vascular access in neonates in order to help neonatologists in their clinical practice, using as data sources textbooks, recent published articles from Pubmed, Cochrane reviews and web guidelines.

Cardiac injury biomarkers in paediatric age: Are we there yet?

The aim of this article is to evaluate the clinical utility of cardiac injury biomarkers in paediatric age. In December 2015, a literature search was performed (PubMed access to MEDLINE citations; http://www.ncbi.nlm.nih.gov/PubMed/ ). The search strategy included the following medical subject headings and text terms for the key words: "cardiac injury biomarkers", "creatine kinase-MB", "myoglobin", "troponin", "children", "neonate/s", "newborn/s", "infant/s" and echocardiography. In the paediatric population, troponins show a good correlation with the extent of myocardial damage following cardiac surgery and cardiotoxic medication and can be used as predictors of subsequent cardiac recovery and mortality. Elevation of cardiac injury biomarkers may also have diagnostic value in cases when cardiac contusion or pericarditis is suspected. Cardiac injury biomarkers are very sensitive markers for the detection of myocardial injury and have been studied in healthy newborns, after tocolysis, intrauterine growth restriction, respiratory distress and asphyxia. The proportion of newborns with elevated troponin was higher than that in ill infants, children, and adolescents and in healthy adults, suggesting that myocardial injury, although clinically occult, is common in this young age group. Results suggest that significant elevation of cord troponin is an excellent early predictor of severity of hypoxic-ischaemic encephalopathy and mortality in term infants. Cardiac biomarkers may also benefit centres without on-site echocardiography with evidence showing good correlation with echo-derived markers of myocardial function. Further studies are needed to better clarify the role of cardiac biomarkers in paediatric age and their correlation with echocardiographic parameters.

The Utility of Brain Natriuretic Peptide in Pediatric Cardiology: A Review.

OBJECTIVE: The aim of this article is to evaluate the clinical utility of brain natriuretic peptide in pediatric patients, examining the diagnostic value, management, and prognostic relevance, by critical assessment of the literature. DATA SOURCES: In December 2015, a literature search was performed (PubMed access to MEDLINE citations; http://www.ncbi.nlm.nih.gov/PubMed/) and included these Medical Subject Headings and text terms for the key words: "brain natriuretic peptide," "amino-terminal pro-brain natriuretic peptide," "children," "neonate/s," "newborn/s," "infant/s," and "echocardiography." STUDY SELECTION: Each article title and abstract was screened to identify relevant studies. The search strategy was limited to published studies in English language concerning brain natriuretic peptide/amino-terminal pro-brain natriuretic peptide in pediatric patients. DATA EXTRACTION: Data on age, gender, type of clinical condition, brain natriuretic peptide assay method, cardiac function variables evaluated by echocardiography, and prognosis were extracted. DATA SYNTHESIS: Brain natriuretic peptide reference values in healthy newborns, infants, and children are presented. Brain natriuretic peptide diagnostic accuracy in newborns, infants, and children suspected to have congenital heart defects is discussed, and brain natriuretic peptide prognostic value reviewed. The data suggest that the determination of brain natriuretic peptide levels improves the diagnostic accuracy in the assessment of heart disease in the pediatric population. Brain natriuretic peptide assay may increase the accuracy of neonatal screening programs for diagnosing congenital heart defects. Echocardiographic variables correlated to brain natriuretic peptide levels. Additionally, brain natriuretic peptide levels predicted adverse outcomes in the postoperative period. CONCLUSIONS: Brain natriuretic peptide assessment is a reliable test to diagnose significant structural or functional cardiovascular disease in children. In the integrated follow-up of these cases, several physiologic and clinical variables must be considered; brain natriuretic peptide may be an additional helpful marker. Nevertheless, larger prospective studies are warranted to elucidate the true prognostic value of brain natriuretic peptide in pediatric patients.

Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or ß-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and magnitude of the stimuli, may play a role in the development of an adaptive or maladaptive phenotype.

Cellular interplay in pulmonary arterial hypertension: implications for new therapies.

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future.

Cardioprotective effects of early and late aerobic exercise training in experimental pulmonary arterial hypertension.

Clinical studies suggest that aerobic exercise can exert beneficial effects in pulmonary arterial hypertension (PAH), but the underlying mechanisms are largely unknown. We compared the impact of early or late aerobic exercise training on right ventricular function, remodeling and survival in experimental PAH. Male Wistar rats were submitted to normal cage activity (SED), exercise training in early (EarlyEX) and in late stage (LateEX) of PAH induced by monocrotaline (MCT, 60 mg/kg). Both exercise interventions resulted in improved cardiac function despite persistent right pressure-overload, increased exercise tolerance and survival, with greater benefits in EarlyEX+MCT. This was accompanied by improvements in the markers of cardiac remodeling (SERCA2a), neurohumoral activation (lower endothelin-1, brain natriuretic peptide and preserved vascular endothelial growth factor mRNA), metabolism and mitochondrial oxidative stress in both exercise interventions. EarlyEX+MCT provided additional improvements in fibrosis, tumor necrosis factor-alpha/interleukin-10 and brain natriuretic peptide mRNA, and beta/alpha myosin heavy chain protein expression. The present study demonstrates important cardioprotective effects of aerobic exercise in experimental PAH, with greater benefits obtained when exercise training is initiated at an early stage of the disease.