Tiago Henriques-coelho | Universidade do Porto (original) (raw)

Papers by Tiago Henriques-coelho

The Journal of physiology, Jan 26, 2015

The present study tested whether submitting the healthy heart to intermittent and tolerable amoun... more The present study tested 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 submitted to treadmill running (Ex; n = 20), intermittent cardiac overload with dobutamine (ITO; 2 mg/kg,s.c.; n = 20) or placebo administration (Cont; n = 20) for 5 days/week during 8 weeks. Animals were then sacrificed for histological and biochemical analysis or submitted to left ventricular (LV) hemodynamic evaluation in baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 hours). Baseline cardiac function was enhanced only in Ex while the response to isovolumetric heartbeats was improved in both ITO and Ex. In contrast to Cont group, who developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress t...

Molecular therapy : the journal of the American Society of Gene Therapy, 2007

In utero gene transfer to the developing lung may have clinical or research applications. In this... more In utero gene transfer to the developing lung may have clinical or research applications. In this study, we developed a new method for specifically targeting the fetal rat lung with adeno and lentiviral vectors encoding the enhanced green fluorescence protein (EGFP) marker gene at E15.5 using ultrasound biomicroscopy (UBM). Survival rate, morphometric parameters, viral biodistribution, and lung transduction efficiency were analyzed and compared to the intra-amniotic route of administration. Expression of EGFP started as early as 24 and 72 h after the injection of adenoviral and lentiviral vectors, respectively. Both vectors transduced lung parenchyma with gene expression limited to interstitial cells of the injected region, in contrast to intra-amniotic injection, which targeted the pulmonary epithelium. Expression of EGFP was most intense at E18.5 and E21.5 for adenoviral and lentiviral vectors, respectively. In contrast to lentivirus, adenoviral expression significantly declined u...

Journal of pediatric surgery, 2005

Tetrasomy of the short arm of chromosome 9 constitutes a rare condition resulting in a well clini... more Tetrasomy of the short arm of chromosome 9 constitutes a rare condition resulting in a well clinically recognized syndrome. In our case, in addition to the characteristic phenotype at birth, the existence of a hernia-type Bochdalek diaphragmatic defect was found. Cytogenetic analysis revealed a nonmosaic case of an isochromosome of the entire short arm of chromosome 9 with no involvement of the heterochromatic region of the long arm: 47, XX, +i (9p). Because chromosome 9 contains several gene locus for enzymes and receptors of the retinoid pathway, this case potentially contributes to retinoid hypothesis in the etiology of congenital diaphragmatic hernia.

Acta Cardiologica, 2003

The rate of pressure rise (dP/dtmax) has mainly been studied in the left ventricle (LV), where it... more The rate of pressure rise (dP/dtmax) has mainly been studied in the left ventricle (LV), where it was demonstrated to be highly dependent of preload, but independent of afterload. Load dependence of right ventricular (RV) dP/dtmax is assumed to be similar to (LV)dP/dtmax, although this issue has not yet been investigated in detail. In the current study, we evaluated acute afterload dependence of dP/dtmax in both ventricles in rats. Adult Wistar rats (n = 8) were instrumented to record RV and LV pressures and septal-free wall diameters. RV and LV afterload elevations were performed by beat-to-beat graded constrictions of the pulmonary trunk or aortic root, respectively. Control cycles and low, moderate and high (isovolumetric) afterload levels were analysed. In both ventricles, afterload modulation of dP/dt was assessed by dP/dtmax normalized for end-diastolic dimensions (dP/dtmax/EDD) and by peak and mean accelerations of pressure rise. RV afterload elevation increased dP/dtmax, dP/dtmax/EDD, peak and mean acceleration of RV pressure rise, without changing the time from end-diastole to dP/dtmax. LV afterload elevations did not significantly change the corresponding left-sided parameters. In this study we demonstrated that, in contrast to the left ventricle, right ventricular dP/dtmax and dP/dtmax/EDD relation are significantly afterload sensitive. This should be taken into account for its application in the haemodynamic evaluation of cardiac function in experimental and clinical settings.

Revista Portuguesa de Cardiologia (English Edition), 2014

Pectus excavatum is the most common deformity of the thorax. A minimally invasive surgical correc... more Pectus excavatum is the most common deformity of the thorax. A minimally invasive surgical correction is commonly carried out to remodel the anterior chest wall by using an intrathoracic convex prosthesis in the substernal position. The process of prosthesis modeling and bending still remains an area of improvement. The authors developed a new system, i3DExcavatum, which can automatically model and bend the bar preoperatively based on a thoracic CT scan. This article presents a comparison between automatic and manual bending. The i3DExcavatum was used to personalize prostheses for 41 patients who underwent pectus excavatum surgical correction between 2007 and 2012. Regarding the anatomical variations, the soft-tissue thicknesses external to the ribs show that both symmetric and asymmetric patients always have asymmetric variations, by comparing the patients' sides. It highlighted that the prosthesis bar should be modeled according to each patient's rib positions and dimensions. The average differences between the skin and costal line curvature lengths were 84 ± 4 mm and 96 ± 11 mm, for male and female patients, respectively. On the other hand, the i3DExcavatum ensured a smooth curvature of the surgical prosthesis and was capable of predicting and simulating a virtual shape and size of the bar for asymmetric and symmetric patients. In conclusion, the i3DExcavatum allows preoperative personalization according to the thoracic morphology of each patient. It reduces surgery time and minimizes the margin error introduced by the manually bent bar, which only uses a template that copies the chest wall curvature.

Revista portuguesa de cardiologia : orgão oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology, 2006

Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by s... more Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by stimulating release of growth hormone. There is increasing evidence that ghrelin has a potent vasodilator effect. Recently, we demonstrated that exogenous administration of ghrelin modulates its endogenous levels and attenuates the majority of alterations induced by monocrotaline (MCT). In the present study, we evaluate the effects of chronic administration of ghrelin on hemodynamic and morphometric parameters of the right ventricle, as well as on myocardial levels of SERCA2a and endothelin-1. Adult Wistar rats were injected with MCT (60 mg/kg, sc) or just the vehicle (day 0). One week later, the animals treated with MCT were randomly divided into two groups and treated with ghrelin (100 microg/kg, bid, sc) or with a similar volume of vehicle. Between days 21-25 the animals were instrumented to record right ventricular (RV) pressures and samples were collected for morphological and molecu...

Revista Portuguesa de Cardiologia (English Edition), 2014

The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angio... more The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angiotensin type 1 receptor, AT1R. Although the quantities of the AT2R found in the adult are low, its expression rises in pathological situations. The AT2R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT2R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT1R inhibitor). After myocardial infarction, the AT2R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT2R promotes natriuresis. Until now, treatment directed at the renin-angiotensin-aldosterone system has been based on angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT2R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease.

Surgical Endoscopy, 2007

Background: Recently there has been an increasing enthusiasm for using natural orifices translume... more Background: Recently there has been an increasing enthusiasm for using natural orifices translumenal endoscopic surgery (NOTES) to perform scarless abdominal procedures. We have previously reported the feasibility and safety of the transvesical endoscopic peritoneoscopy in a long-term survival porcine model as useful for those purposes. Herein, we report our successful experience performing transvesical and transdiaphragmatic endoscopic approach to the thoracic cavity in a long-term survival study in a porcine model. Methods: Transvesical and transdiaphragmatic endoscopic thoracoscopy was performed in six anesthetized female pigs. A 5 mm transvesical port was created on the bladder wall and an ureteroscope was advanced into the peritoneal cavity. After diaphragm inspection, we introduced through the left diaphragmatic dome a ureteroscope into the left thoracic cavity. In all animals, we performed thoracoscopy as well as peripheral lung biopsy. Animals were sacrificed by day 15 postoperatively. Results: We easily introduced a 9.8 Fr ureteroscope into the thoracic cavity that allowed us to visualize the pleural cavity and to perform simple surgical procedures such as lung biopsies without complications. There were neither respiratory distress episodes nor surgical complications to report. Postmortem examination revealed complete healing of vesical and diaphragmatic holes, whereas no signs of infection or adhesions were observed in the peritoneal or thoracic cavities. Conclusion: This study demonstrates the feasibility of transvesical thoracoscopy in porcine model. However, although this study extends the potential applications of NOTES to the thoracic cavity, new instruments and further work are needed to provide evidence that this could be translated to humans and with advantages for patients.

Peptides, 2006

Ghrelin is a 28-amino-acid acylated peptide that was first isolated from the rat stomach endocrin... more Ghrelin is a 28-amino-acid acylated peptide that was first isolated from the rat stomach endocrine cells (X/A-like cells of oxyntic mucosa) . It is the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a), a G protein-coupled receptor, found mainly in the pituitary and hypothalamus, where ghrelin exerts a strong stimulatory effect on the GH release .

Life Sciences, 2006

Objective: We investigated the effects of acute volume and RV pressure overload on biventricular ... more Objective: We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, proinflammatory cytokines (IL-6 and TNF-a), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca 2+ -handling proteins (SERCA2a, phospholamban and calsequestrin). Methods: Male Wistar rats (n = 45) instrumented with pressure tip micromanometers in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. Results: BNP upregulation was restricted to the overloaded ventricles. TNF-a, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-a and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-a, IL-6, IGF-1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. Conclusions: Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts. D

Kidney International, 2007

2 Kidney International o r i g i n a l a r t i c l e M Moreira-Rodrigues et al.: Cardiac remodeli... more 2 Kidney International o r i g i n a l a r t i c l e M Moreira-Rodrigues et al.: Cardiac remodeling in PAN nephrosis

International Journal of Cardiology, 2012

Endocrinology, 2008

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zi... more The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various pro-inflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as, the pattern of pro-inflammatory cytokines gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during three weeks an injection of saline, vehicle (zinc+carboxymethyl cellulose) or thymulin (100 ng/kg, sc, qd). At days 23-25, the animals were anesthetized for hemodynamic recordings, whereas and heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin's vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.

Computer Methods in Biomechanics and Biomedical Engineering, 2014

Pectus carinatum (PC) is a chest deformity caused by a disproportionate growth of the costal cart... more Pectus carinatum (PC) is a chest deformity caused by a disproportionate growth of the costal cartilages compared to the bony thoracic skeleton, pulling the sternum towards, which leads to its protrusion. There has been a growing interest on using the 'reversed Nuss' technique as a minimally invasive procedure for PC surgical correction. A corrective bar is introduced between the skin and the thoracic cage and positioned on top of the sternum highest protrusion area for continuous pressure. Then, it is fixed to the ribs and kept implanted for about 2-3 years. The purpose of this work was to (a) assess the stresses distribution on the thoracic cage that arise from the procedure, and (b) investigate the impact of different positioning of the corrective bar along the sternum. The higher stresses were generated on the 4th, 5th and 6th ribs backend, supporting the hypothesis of pectus deformities correction-induced scoliosis. The different bar positioning originated different stresses on the ribs' backend. The bar position that led to lower stresses generated on the ribs backend was the one that also led to the smallest sternum displacement. However, this may be preferred, as the risk of induced scoliosis is lowered.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by va... more 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.

Basic Research in Cardiology, 2009

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocri... more Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged s and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

Basic Research in Cardiology, 2012

In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contrib... more In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP iso ) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP iso (r = -0.96), and directly related to changes in the time constant of relaxation s (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP iso (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterloadinduced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P \ 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.

AJP: Heart and Circulatory Physiology, 2006

Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocr... more Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats. .-In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in longstanding PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P Ͻ 0.001) and fibrosis (P ϭ 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P Ͻ 0.001), endothelin-1 (ET-1) (6-fold; P Ͻ 0.001), and type B natriuretic peptide (BNP) (15-fold; P Ͻ 0.001). Despite the similar upregulation of ET-1 (8-fold; P Ͻ 0.001) and overexpression of ACE (4-fold; P Ͻ 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P Ͻ 0.001) and relaxation (P ϭ 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P ϭ 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET A antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P ϭ 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis.

AJP: Heart and Circulatory Physiology, 2004

The Journal of physiology, Jan 26, 2015

The present study tested whether submitting the healthy heart to intermittent and tolerable amoun... more The present study tested 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 submitted to treadmill running (Ex; n = 20), intermittent cardiac overload with dobutamine (ITO; 2 mg/kg,s.c.; n = 20) or placebo administration (Cont; n = 20) for 5 days/week during 8 weeks. Animals were then sacrificed for histological and biochemical analysis or submitted to left ventricular (LV) hemodynamic evaluation in baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 hours). Baseline cardiac function was enhanced only in Ex while the response to isovolumetric heartbeats was improved in both ITO and Ex. In contrast to Cont group, who developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress t...

Molecular therapy : the journal of the American Society of Gene Therapy, 2007

In utero gene transfer to the developing lung may have clinical or research applications. In this... more In utero gene transfer to the developing lung may have clinical or research applications. In this study, we developed a new method for specifically targeting the fetal rat lung with adeno and lentiviral vectors encoding the enhanced green fluorescence protein (EGFP) marker gene at E15.5 using ultrasound biomicroscopy (UBM). Survival rate, morphometric parameters, viral biodistribution, and lung transduction efficiency were analyzed and compared to the intra-amniotic route of administration. Expression of EGFP started as early as 24 and 72 h after the injection of adenoviral and lentiviral vectors, respectively. Both vectors transduced lung parenchyma with gene expression limited to interstitial cells of the injected region, in contrast to intra-amniotic injection, which targeted the pulmonary epithelium. Expression of EGFP was most intense at E18.5 and E21.5 for adenoviral and lentiviral vectors, respectively. In contrast to lentivirus, adenoviral expression significantly declined u...

Journal of pediatric surgery, 2005

Tetrasomy of the short arm of chromosome 9 constitutes a rare condition resulting in a well clini... more Tetrasomy of the short arm of chromosome 9 constitutes a rare condition resulting in a well clinically recognized syndrome. In our case, in addition to the characteristic phenotype at birth, the existence of a hernia-type Bochdalek diaphragmatic defect was found. Cytogenetic analysis revealed a nonmosaic case of an isochromosome of the entire short arm of chromosome 9 with no involvement of the heterochromatic region of the long arm: 47, XX, +i (9p). Because chromosome 9 contains several gene locus for enzymes and receptors of the retinoid pathway, this case potentially contributes to retinoid hypothesis in the etiology of congenital diaphragmatic hernia.

Acta Cardiologica, 2003

The rate of pressure rise (dP/dtmax) has mainly been studied in the left ventricle (LV), where it... more The rate of pressure rise (dP/dtmax) has mainly been studied in the left ventricle (LV), where it was demonstrated to be highly dependent of preload, but independent of afterload. Load dependence of right ventricular (RV) dP/dtmax is assumed to be similar to (LV)dP/dtmax, although this issue has not yet been investigated in detail. In the current study, we evaluated acute afterload dependence of dP/dtmax in both ventricles in rats. Adult Wistar rats (n = 8) were instrumented to record RV and LV pressures and septal-free wall diameters. RV and LV afterload elevations were performed by beat-to-beat graded constrictions of the pulmonary trunk or aortic root, respectively. Control cycles and low, moderate and high (isovolumetric) afterload levels were analysed. In both ventricles, afterload modulation of dP/dt was assessed by dP/dtmax normalized for end-diastolic dimensions (dP/dtmax/EDD) and by peak and mean accelerations of pressure rise. RV afterload elevation increased dP/dtmax, dP/dtmax/EDD, peak and mean acceleration of RV pressure rise, without changing the time from end-diastole to dP/dtmax. LV afterload elevations did not significantly change the corresponding left-sided parameters. In this study we demonstrated that, in contrast to the left ventricle, right ventricular dP/dtmax and dP/dtmax/EDD relation are significantly afterload sensitive. This should be taken into account for its application in the haemodynamic evaluation of cardiac function in experimental and clinical settings.

Revista Portuguesa de Cardiologia (English Edition), 2014

Pectus excavatum is the most common deformity of the thorax. A minimally invasive surgical correc... more Pectus excavatum is the most common deformity of the thorax. A minimally invasive surgical correction is commonly carried out to remodel the anterior chest wall by using an intrathoracic convex prosthesis in the substernal position. The process of prosthesis modeling and bending still remains an area of improvement. The authors developed a new system, i3DExcavatum, which can automatically model and bend the bar preoperatively based on a thoracic CT scan. This article presents a comparison between automatic and manual bending. The i3DExcavatum was used to personalize prostheses for 41 patients who underwent pectus excavatum surgical correction between 2007 and 2012. Regarding the anatomical variations, the soft-tissue thicknesses external to the ribs show that both symmetric and asymmetric patients always have asymmetric variations, by comparing the patients' sides. It highlighted that the prosthesis bar should be modeled according to each patient's rib positions and dimensions. The average differences between the skin and costal line curvature lengths were 84 ± 4 mm and 96 ± 11 mm, for male and female patients, respectively. On the other hand, the i3DExcavatum ensured a smooth curvature of the surgical prosthesis and was capable of predicting and simulating a virtual shape and size of the bar for asymmetric and symmetric patients. In conclusion, the i3DExcavatum allows preoperative personalization according to the thoracic morphology of each patient. It reduces surgery time and minimizes the margin error introduced by the manually bent bar, which only uses a template that copies the chest wall curvature.

Revista portuguesa de cardiologia : orgão oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology, 2006

Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by s... more Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by stimulating release of growth hormone. There is increasing evidence that ghrelin has a potent vasodilator effect. Recently, we demonstrated that exogenous administration of ghrelin modulates its endogenous levels and attenuates the majority of alterations induced by monocrotaline (MCT). In the present study, we evaluate the effects of chronic administration of ghrelin on hemodynamic and morphometric parameters of the right ventricle, as well as on myocardial levels of SERCA2a and endothelin-1. Adult Wistar rats were injected with MCT (60 mg/kg, sc) or just the vehicle (day 0). One week later, the animals treated with MCT were randomly divided into two groups and treated with ghrelin (100 microg/kg, bid, sc) or with a similar volume of vehicle. Between days 21-25 the animals were instrumented to record right ventricular (RV) pressures and samples were collected for morphological and molecu...

Revista Portuguesa de Cardiologia (English Edition), 2014

The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angio... more The angiotensin type 2 receptor, AT2R, has been described as having opposite effects to the angiotensin type 1 receptor, AT1R. Although the quantities of the AT2R found in the adult are low, its expression rises in pathological situations. The AT2R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT2R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT1R inhibitor). After myocardial infarction, the AT2R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT2R promotes natriuresis. Until now, treatment directed at the renin-angiotensin-aldosterone system has been based on angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT2R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease.

Surgical Endoscopy, 2007

Background: Recently there has been an increasing enthusiasm for using natural orifices translume... more Background: Recently there has been an increasing enthusiasm for using natural orifices translumenal endoscopic surgery (NOTES) to perform scarless abdominal procedures. We have previously reported the feasibility and safety of the transvesical endoscopic peritoneoscopy in a long-term survival porcine model as useful for those purposes. Herein, we report our successful experience performing transvesical and transdiaphragmatic endoscopic approach to the thoracic cavity in a long-term survival study in a porcine model. Methods: Transvesical and transdiaphragmatic endoscopic thoracoscopy was performed in six anesthetized female pigs. A 5 mm transvesical port was created on the bladder wall and an ureteroscope was advanced into the peritoneal cavity. After diaphragm inspection, we introduced through the left diaphragmatic dome a ureteroscope into the left thoracic cavity. In all animals, we performed thoracoscopy as well as peripheral lung biopsy. Animals were sacrificed by day 15 postoperatively. Results: We easily introduced a 9.8 Fr ureteroscope into the thoracic cavity that allowed us to visualize the pleural cavity and to perform simple surgical procedures such as lung biopsies without complications. There were neither respiratory distress episodes nor surgical complications to report. Postmortem examination revealed complete healing of vesical and diaphragmatic holes, whereas no signs of infection or adhesions were observed in the peritoneal or thoracic cavities. Conclusion: This study demonstrates the feasibility of transvesical thoracoscopy in porcine model. However, although this study extends the potential applications of NOTES to the thoracic cavity, new instruments and further work are needed to provide evidence that this could be translated to humans and with advantages for patients.

Peptides, 2006

Ghrelin is a 28-amino-acid acylated peptide that was first isolated from the rat stomach endocrin... more Ghrelin is a 28-amino-acid acylated peptide that was first isolated from the rat stomach endocrine cells (X/A-like cells of oxyntic mucosa) . It is the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a), a G protein-coupled receptor, found mainly in the pituitary and hypothalamus, where ghrelin exerts a strong stimulatory effect on the GH release .

Life Sciences, 2006

Objective: We investigated the effects of acute volume and RV pressure overload on biventricular ... more Objective: We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, proinflammatory cytokines (IL-6 and TNF-a), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca 2+ -handling proteins (SERCA2a, phospholamban and calsequestrin). Methods: Male Wistar rats (n = 45) instrumented with pressure tip micromanometers in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. Results: BNP upregulation was restricted to the overloaded ventricles. TNF-a, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-a and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-a, IL-6, IGF-1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. Conclusions: Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts. D

Kidney International, 2007

2 Kidney International o r i g i n a l a r t i c l e M Moreira-Rodrigues et al.: Cardiac remodeli... more 2 Kidney International o r i g i n a l a r t i c l e M Moreira-Rodrigues et al.: Cardiac remodeling in PAN nephrosis

International Journal of Cardiology, 2012

Endocrinology, 2008

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zi... more The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various pro-inflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as, the pattern of pro-inflammatory cytokines gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during three weeks an injection of saline, vehicle (zinc+carboxymethyl cellulose) or thymulin (100 ng/kg, sc, qd). At days 23-25, the animals were anesthetized for hemodynamic recordings, whereas and heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin's vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.

Computer Methods in Biomechanics and Biomedical Engineering, 2014

Pectus carinatum (PC) is a chest deformity caused by a disproportionate growth of the costal cart... more Pectus carinatum (PC) is a chest deformity caused by a disproportionate growth of the costal cartilages compared to the bony thoracic skeleton, pulling the sternum towards, which leads to its protrusion. There has been a growing interest on using the 'reversed Nuss' technique as a minimally invasive procedure for PC surgical correction. A corrective bar is introduced between the skin and the thoracic cage and positioned on top of the sternum highest protrusion area for continuous pressure. Then, it is fixed to the ribs and kept implanted for about 2-3 years. The purpose of this work was to (a) assess the stresses distribution on the thoracic cage that arise from the procedure, and (b) investigate the impact of different positioning of the corrective bar along the sternum. The higher stresses were generated on the 4th, 5th and 6th ribs backend, supporting the hypothesis of pectus deformities correction-induced scoliosis. The different bar positioning originated different stresses on the ribs' backend. The bar position that led to lower stresses generated on the ribs backend was the one that also led to the smallest sternum displacement. However, this may be preferred, as the risk of induced scoliosis is lowered.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by va... more 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.

Basic Research in Cardiology, 2009

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocri... more Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged s and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

Basic Research in Cardiology, 2012

In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contrib... more In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP iso ) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP iso (r = -0.96), and directly related to changes in the time constant of relaxation s (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP iso (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterloadinduced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P \ 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.

AJP: Heart and Circulatory Physiology, 2006

Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocr... more Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats. .-In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in longstanding PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P Ͻ 0.001) and fibrosis (P ϭ 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P Ͻ 0.001), endothelin-1 (ET-1) (6-fold; P Ͻ 0.001), and type B natriuretic peptide (BNP) (15-fold; P Ͻ 0.001). Despite the similar upregulation of ET-1 (8-fold; P Ͻ 0.001) and overexpression of ACE (4-fold; P Ͻ 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P Ͻ 0.001) and relaxation (P ϭ 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P ϭ 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET A antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P ϭ 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis.

AJP: Heart and Circulatory Physiology, 2004