Physiologic Basis and Pathophysiologic Implications of the Diastolic Properties of the Cardiac Muscle

Although systole was for long considered the core of cardiac function, hemodynamic performance is evenly dependent on appropriate systolic and diastolic functions. The recognition that isolated diastolic dysfunction is the major culprit for approximately fifty percent of all heart failure cases imposes a deeper understanding of its underlying mechanisms so that better diagnostic and therapeutic strategies can be designed. Risk factors leading to diastolic dysfunction affect myocardial relaxation and/or its material properties by disrupting the homeostasis of cardiomyocytes as well as their relation with surrounding matrix and vascular structures. As a consequence, slower ventricular relaxation and higher myocardial stiffness may result in higher ventricular filling pressures and in the risk of hemodynamic decompensation. Thus, determining the mechanisms of diastolic function and their implications in the pathophysiology of heart failure with normal ejection fraction has become a prominent field in basic and clinical research

Operacionalização do heart team em Portugal

© 2013 Sociedade Portuguesa de Cardiologia Published by Elsevier España, S.L. All rights reserved.Whenever several therapeutic options exist, multidisciplinary decision-making is beneficial for the patient and for society at large. The main obstacles to the establishment of heart teams in Portugal are organizational and logistical. Implementing a heart team approach entails definition of the situations requiring multidisciplinary discussion, creation of clear lines of communication, written protocols and obtaining patient informed consent. The European Society of Cardiology guidelines define the clinical scenarios where intervention of the heart team is recommended.A decisão médica tomada em equipas multidisciplinares é uma mais-valia indiscutível para o doente e para a sociedade, particularmente quando existem várias opções terapêuticas. A falta de disponibilidade dos intervenientes, problemas logísticos e barreiras interdisciplinares são alguns dos obstáculos à operacionalização do Heart Team em Portugal. A operacionalização passa pela definição das situações que necessitam discussão multidisciplinar, a elaboração de protocolos escritos, a criação de vias de comunicação claras, a consignação das decisões tomadas e a informação fornecida ao doente. As situações, na doença coronária e na doença valvular, que requerem a intervenção do Heart Team estão definidas nas recomendações da Sociedade Europeia de Cardiologia.info:eu-repo/semantics/publishedVersio

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI.Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure–volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats.Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading.Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia

Cystic adenomatoid malformations are induced by localized FGF10 overexpression in fetal rat lung

Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.This project was in part funded by proceeds from the Ruth and Tristram C. Colket Jr. Chair in Pediatric Surgery (A.W.F.), and the Fundação para a Ciência e Tecnologia (POCI/SAUOBS/56428/2004). S.G. was supported by FCT grant ref. SFRH/BD/15260/2004

Targeted gene transfer to fetal rat lung interstitium by ultrasound-guided intrapulmonary injection

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 until final analysis at 1 week of age. This study demonstrates the feasibility of targeting the fetal rat lung interstitium with viral vectors under UBM guidance during the pseudoglandular stage. This model system may facilitate in vivo studies of dynamic lung morphogenesis and could provide insight into the efficacy of prenatal gene transfer strategies for treatment of specific lung disorders.FCT Grant (SFRH/BD/15260/2004) on behalf of the FCT Grant POCI/SAU-OBS/56428/200

N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants

Objective: In congenital diaphragmatic hernia (CDH) the severity of pulmonary hypertension (PH) is considered, by several authors, determinant of clinical outcome. Plasmatic N-terminal-pro-B type natriuretic peptide (NT-proBNP) might be useful in diagnosis and management of PH in newborns, although its interest in CDH infants remains to be defined. Early NT-proBNP levels were assessed in CDH infants and correlated with cardiovascular echocardiographic parameters. Patients and Methods: 28 newborns, CDH and age-matched controls were enrolled in a prospective study. Clinical condition, NT-proBNP plasmatic levels, echo parameters of PH and biventricular function were assessed at 24 h after delivery as well as survival outcome. Results: Estimated mean pulmonary pressure and NT-proBNP were significantly higher in CDH than control infants. NT-proBNP significantly correlated with estimated pulmonary artery pressure, right ventricular Tei index, and tricuspid E/A ratio. Additionally, we found that CDH infants with NT-proBNP >11,500 pg/ml experienced a worse prognosis. Conclusions: We demonstrated that PH is associated with NT-proBNP elevation and diastolic impairment in CDH infants. Early elevations in NT-proBNP levels seem to alert for a subset of CDH infants with worse prognosis. Copyrigh

Rationale, design and methodology for Intraventricular Pressure Gradients Study: a novel approach for ventricular filling assessment in normal and falling hearts

<p>Abstract</p> <p>Background</p> <p>Intraventricular pressure gradients have been described between the base and the apex of the left ventricle during early diastolic ventricular filling, as well as, their increase after systolic and diastolic function improvement. Although, systolic gradients have also been observed, data are lacking on their magnitude and modulation during cardiac dysfunction. Furthermore, we know that segmental dysfunction interferes with the normal sequence of regional contraction and might be expected to alter the physiological intraventricular pressure gradients. The study hypothesis is that systolic and diastolic gradients, a marker of normal left ventricular function, may be related to physiological asynchrony between basal and apical myocardial segments and they can be attenuated, lost entirely, or even reversed when ventricular filling/emptying is impaired by regional acute ischemia or severe aortic stenosis.</p> <p>Methods/Design</p> <p><it>Animal Studies: </it>Six rabbits will be completely instrumented to measuring apex to outflow-tract pressure gradient and apical and basal myocardial segments lengthening changes at basal, afterloaded and ischemic conditions. Afterload increase will be performed by abruptly narrowing or occluding the ascending aorta during the diastole and myocardial ischemia will be induced by left coronary artery ligation, after the first diagonal branch.</p> <p><it>Patient Studies: </it>Patients between 65-80 years old (n = 12), both genders, with severe aortic stenosis referred for aortic valve replacement will be selected as eligible subjects. A high-fidelity pressure-volume catheter will be positioned through the ascending aorta across the aortic valve to measure apical and outflow-tract pressure before and after aortic valve replacement with a bioprosthesis. Peak and average intraventricular pressure gradients will be recorded as apical minus outflow-tract pressure and calculated during all diastolic and systolic phases of cardiac cycle.</p> <p>Discussion</p> <p>We expect to validate the application of our method to obtain intraventricular pressure gradients in animals and patients and to promote a methodology to better understand the ventricular relaxation and filling and their correlation with systolic function.</p

Local modulation of the natriuretic peptide system in the rat remnant kidney

Background. The natriuretic peptide (NP) system plays a central role in the renal adaptations to acute volume expansion. However, the modulation of the NP system in chronic renal insufficiency (CRI) remains to be elucidated. In the present study, we evaluated cardiac haemodynamics, plasma type-B natriuretic peptide (BNP) levels and the expression of natriuretic peptide receptor A (NPR-A) and NPR-C in the renal cortex (RC) and medulla (RM) of Sham and 3/4 nephrectomized (3/4nx) rats, up to 26 weeks after surgery. Methods. Male Wistar-Han rats (190-220 g; n = 49) were randomly assigned to 3/4nx or Sham surgery. Two, 10 and 26 weeks after surgery, non-invasive blood pressure (BP) and left ventricular (LV) haemodynamics were performed, and urine and blood were collected for metabolic studies and plasma BNP determination. In addition, tissue samples from RC and RM were obtained for NPR-A and NPR-C quantification (RT-PCR and western blotting) as well as NPR-A immunodetection. Results. In 3/4nx rats, the progressive interstitial fibrosis and tubular atrophy were accompanied by a time-dependent increase of BP and impaired natriuretic response to volume expansion (VE). This was accompanied in 3/4nx rats by an early and time-dependent elevation of BNP circulating levels that was not associated with cardiac dysfunction or increased myocardial BNP gene expression. In 3/4nx rats, NPR-A expression in the remnant RM was consistently reduced at 2, 10 and 26 weeks, and this was accompanied by an increase in NPR-C expression in the remnant RC from 3/4nx rats. Conclusions. BP elevation and compromised natriuretic response to VE in 3/4nx rats is associated with increased circulating BNP levels in the absence of cardiac dysfunction. This is accompanied in 3/4nx rats by both impaired NPR-A expression in the RM and upregulation of NPR-C in the RC suggesting a novel mechanism for NP resistance in CRI