El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Soft skills / Revisón por pares

In the normal heart, the atrioventricular node (AVN) is part of the sole pathway between the atria and ventricles and is responsible for transmitting and coordinating atrial and ventricular contractions. The AVN electrically connects the atria and ventricles of the heart and is part of the electrical conduction system. Conduction within this system is highly regulated by the autonomic nervous system. The complex neurochemical anatomy of this region has been studied extensively in mice and other small animals but not in humans. The goal of this study was to provide detailed neurochemical characterization of parasympathetic (cholinergic) and sympathetic (noradrenergic) innervation of the human AVN, which is the lead component of the conducting system. Using immunohistochemistry, we have investigated the innervation of the AVN region in samples collected from human hearts that were rejected for transplantation. Tissues were fixed in 4% paraformaldehyde, cryoprotected, and sectioned frozen at 30um thickness. Sections through the AVN were cut in the horizontal plane and collected in representative sets on charged slides. Each set of slides was stained for a different phenotypic marker using the VECTOR Elite ABC kits and ImmmPACT VIP Chromogen. To aid in locating the AVN, we used anti-Connexin-43(Cx-43). Unlike surrounding myocardium, nodal tissue lacks significant Cx-43. Cholinergic nerves were stained with anti-vesicular acetylcholine transporter (VAChT).Noradrenergic nerves were stained with anti-tyrosine hydroxylase (TH). We evaluated tissue from two patients and obtained similar results. The AVN received prominent input from cholinergic and noradrenergic nerves, with cholinergic being dominant. The AVN displayed a greater density of parasympathetic and sympathetic innervation compared to surrounding regions. Sympathetic innervation is what causes an increase in conduction speed in the AVN, while parasympathetic innervation is what causes a decrease in conduction speed. Based on previous pharmacological evidence and observation of innervation in other species, the AVN is a highly controlled area for cardiac regulation. Our research implies that parasympathetic innervation is more highly regulated in the AVN and that parasympathetic innervation could play a larger role in cardiac conduction than sympathetic innervation.

ABSTRACT In pathological left ventricular hypertrophy (LVH) with a normal intrinsic myocardial function, eccentric chamber remodelling (cardiac dilatation) can produce a right shift in systolic pressure-volume (P-V) relations (systolic chamber dysfunction). Whether comparable degrees of cardiac dilatation in physiological (exercise-induced eccentric left ventricular remodelling) and pathological LVH produce similar effects on chamber function has not been determined. Hence, the aim of my thesis was to determine the impact of cardiac dilatation on systolic chamber function in chronically exercised rats with comparable increases in cardiac diastolic volumes as those produced by two rat models of pathological dilatation. Methods: Two models of cardiac dilatation were used, namely: (1) a model of pathological cardiac hypertrophy and dilatation (induced by chronic β-adrenoreceptor agonist administration to either Sprague-Dawley or spontaneously hypertensive rats), and (2) a model of physiological cardiac hypertrophy and dilatation (induced in Sprague-Dawley rats by 4-5 months of voluntary running activity on exercise wheels). 33 Sprague-Dawley rats were placed on spontaneous running wheels for 4-5 months (Exer group) and 24 Sprague-Dawley sedentary control rats (Con group) were placed individually in normal rat cages. To induced pathological dilatation, the β-agonist, isoproterenol (ISO) was administered daily to Sprague-Dawley rats for 7 months (SD-ISO, n=10) and to spontaneously hypertensive rats (SHR) for 4-5 months (SHR+ISO, n=22). Saline was administered daily to controls (SD, n=10; SHR, n=21) and to normotensive Wistar Kyoto rats (WKY, n=17). In isolated, perfused heart preparations, left ventricular (LV) dilatation was determined from the diastolic pressure-volume (P-V) relation and the volume intercept of the diastolic P-V relation (LV V0). Systolic chamber function was assessed by comparing LV developed pressures at specific filling volumes. Intrinsic systolic myocardial function was determined from the slope of the LV systolic developed stress-strain relation (myocardial systolic elastance). Results: ISO adminstered to SD and to SHR rats produced cardiac dilatation [LV V0 (ml): SD 0.20±0.01, SD-ISO 0.27±0.02, p<0.005; SHR 0.21±0.01, SHR-ISO 0.30±0.01, p<0.001], systolic chamber dysfunction (decrease in left ventricular developed pressures at incremental filling volumes) but normal intrinsic systolic myocardial function. Habitual exercise resulted in a right shifted LV diastolic P-V relation and an increased LV V0 (Exer 0.22±0.01, Con 0.18±0.01, p<0.005). In exercised rats (Exer-dilated, n=10) with equivalent dilatation as SD-ISO and SHR-ISO (LV V0 within 95% CI of SD-ISO and SHR-ISO), despite comparable LV diastolic P-V relations and LV V0 values (0.28±0.01); both systolic chamber function and intrinsic systolic myocardial function were normal. Conclusions: These data provide evidence to indicate that as compared to pathological dilatation, a similar extent of exercise-induced dilatation does not produce the same adverse effects on systolic chamber function.

Introduction: Takotsubo cardiomyopathy or stress cardiomyopathy is a syndrome of transient left ventricular (LV) dysfunction mimicking myocardial infarction, but lacking obstruction of coronary artery disease (CAD) or acute plaque rupture. A characteristic differentiation from CAD is that regional motional abnormality extends beyond a territory perfused with a single epicardial coronary artery. Clinically, it is characterized by apical ballooning of the LV due to due to depression of mid and apical segments, with hyperkinesis of cardiac basal walls. Women are affected more than men, predominantly in the postmenopausal age. Case Report: A 54-year-old Caucasian female with a history of COPD, hypertension, uncontrolled diabetes mellitus, hyperlipidemia, depression and ongoing tobacco use presented with complaints of worsening shortness of breath two days prior to admission. She denied chest pain, worsened cough, palpitations, nausea or vomiting. On examination, she was in distress and anxious, with labored breathing. Upon examining the chest, decreased air entry was present in both lung fields with bibasilar wheezing. Initial lab tests showed mild respiratory acidosis, with pH of 7.24, pCO2 of 47.4 and pO2 of 65. Troponins on the day of admission was Soon after admission, she started complaining of severe right neck pain. Repeat EKG revealed localized lateral J point, anteroseptal q waves and 4mm ST-segment elevation in leads V3 and V4 reciprocal changes and without chest pain. Repeat troponins were slightly elevated to 0.42 ng/ml and CK-MB was elevated to 20.2 ng/ml. A transthoracic echocardiogram showed regional abnormalities in left ventricle with the apex, mid to distal septum and the anterior part of septum was akinetic. Discussion: Takotsubo cardiomyopathy presents in 1 to 2 percent of troponin-positive acute coronary syndrome (ACS) with various clinical manifestations and various outcomes. Some patients have favorable outcomes based on their clinical performance and extent of cardiac muscle involvement. As in the case we presented, this syndrome can be entirely idiopathic, without a definitive underlying cause. Supportive management while hospitalized and early identification of complications improve the prognosis.

INTRODUCTION: Space exploration is ultra-hazardous and unpredictably dangerous. One area of significant concern is the exposure of astronauts to deep space radiation and the development of deleterious health effects. Earth's magnetic field and atmosphere both act to deflect the majority of deep space radiation, protecting humans on the surface of earth as well as astronauts in low Earth orbit missions. Because this type of radiation is not encountered terrestrially, very limited evidence exists in regards to the effects on the well-being. Deep space radiation, which consists of high charge and energy (HZE) particles, may be experimentally reproduced for studies using a particle accelerator. The long-term degenerative effects of cosmic irradiation on the cardiovascular system are vastly unknown. Detailing the molecular response within cardiomyocytes after exposure to HZE irradiation will provide needed knowledge for scientists to accurately assess the cardiovascular risks associated with deep space radiation exposure. OBJECTIVE: The primary objective of this study is to characterize the molecular alterations of gene expression within murine cardiomyocytes following exposure to two different types of HZE. METHODS: Wild type C57B1/6NT (Taconic) mice were exposed to either 90 cGy, 1 GeV proton (1H) or 15 cGy, 1 GeV/nucleon iron (56Fe) HZE particle-radiation. Radiation exposure was performed at the NASA Space Radiation Laboratory located at the Brookhaven National Laboratory (Upton, NY). Biological samples were taken and transcriptome profiling was performed at various time points following irradiation (1, 3, 7, 14, and 28 days). RESULTS: Samples exposed to 56Fe-IR displayed significant levels of gene modulation, while proton-irradiation failed to elicit significant alterations in cardiomyocyte gene transcription compared to sham-irradiated samples. Network pathway analysis of iron-irradiated samples identified multiple biological pathways being significantly modulated. These biological pathways included cell death and survival, free radical scavenging, and inflammatory processes. Multiple points of upstream transcription regulation were identified as key nodes for regulating downstream expression. Validation of the signal transduction network by protein analysis showed that particle-IR clearly regulates a long lived signaling mechanism for p38 MAPK signaling and NFATc4 activation. Electrophoresis mobility shift assays supported the role of transcription factors GATA-4, STAT-3 and NF-𝜅B as key regulators. CONCLUSIONS: The molecular response to 56Fe-IR is unique and induces long-term modulations of gene expression in cardiomyocytes that last up to at least 28 days following radiation exposure. However, exposure to 1H-IR failed to elicit significantly robust alterations in gene expression in cardiomyocytes. Additionally, proteins involved in signal transduction and transcriptional activation via DNA binding play a significant role in the molecular response following HZE particle radiation. This study may have multiple implications for NASA's efforts to develop cardio-degenerative risk estimates for astronauts participating in future deep space missions. By identifying molecular mechanisms and potential molecular markers, scientists can begin to assess excess relative risks and develop strategies to mitigate risks of developing physiological changes which may compromise future missions. This study may also have major safety implications for the increasing number of patients receiving conventional and particle radiotherapy.

Phenylethanolamine-N-methyltransferase (Pnmt), is the enzyme that catalyzes the conversion of noradrenaline to adrenaline. It has been found in the embryonic heart and in certain adult heart cells, including intrinsic cardiac adrenergic cells, intracardiac neurons, and cardiomyocytes, but their physiological role in the heart is not well understood. To determine the function of Pnmt-expressing cells in the developing heart, a novel genetically-targeted mouse model that causes selective cellular suicide of Pnmt-expressing cells was created by mating Pnmt-Cre Recombinase knock-in mice (PnmtCre/Cre) with ROSA26-eGFP-DTA (R26R+/DTA). The “cellular suicide” allele is the Diptheria Toxin A (DTA) gene fragment. Activation of the DTA suicide allele is dependent upon Cre expression, which is under the control of the endogenous Pnmt gene locus (i.e., expression is restricted to adrenaline-producing “adrenergic” cells). Ongoing studies in Dr. Ebert’s laboratory have shown that Pnmt-Cre/DTA mice have a loss of adrenergic cells in the adrenal gland and begin developing serious cardiac and neurological deficits within one month after birth. The purpose of my project is to examine the potential cardiac consequences of selective adrenergic cell ablation in this model. Aim 1 of this study is to analyze echocardiography data from mice with genetic ablation of adrenergic cells compared to age-matched (littermate) controls over the first 6-months after birth. Preliminary evidence indicates that there is substantial loss of function that progressively worsens with age in the ablation group compared to controls. Aim 2 of this study seeks to uncover evidence of adrenergic cell ablation in the heart using histological and immunofluorescence staining techniques. We predict that these experiments will provide physiological and anatomical evidence showing that Pnmt-expressing cells in the heart make significant contributions to cardiac development and function. This knowledge is expected to increase our basic understanding about the specific roles adrenergic cells play during heart, and could lead to the development of novel treatment strategies for certain types of cardiac defects in the future.

Yes / Poor medicines management places patients at risk, particularly during care transitions. For patients with heart failure (HF), optimal medicines management is crucial to control symptoms and prevent hospital readmission. This study explored the concept of resilience using HF as an example condition to understand how the system compensates for known and unknown weaknesses. We explored resilience using a mixed-methods approach in four healthcare economies in the north of England. Data from hospital site observations, healthcare staff and patient interviews, and documentary analysis were collected between June 2016 and March 2017. Data were synthesised and analysed using framework analysis. Interviews were conducted with 45 healthcare professionals, with 20 patients at three timepoints and 189 hours of observation were undertaken. We identified four primary inter-related themes concerning organisational resilience. These were named as gaps, traps, bridges and props. Gaps were discontinuities in processes that had the potential to result in poorly optimised medicines. Traps were features of the system that could produce errors or unintended adverse medication events. ‘Bridges’ were features of the medicines management system that promoted safety and continuity which ensured that, despite varying conditions, care could be delivered successfully. ‘Props’ were informal, temporary or impromptu actions taken by patients or healthcare staff to avoid potential adverse events. The numerous opportunities for HF patient safety to be compromised and sub-optimal medicines management during this common care transition are mitigated by system resilience. Cross-organisational bridges and temporary fixes or ‘props’ put in place by patients and carers, healthcare teams and organisations are critical for safe and optimal care to be delivered in the face of continued system pressures.

Heart disease is a major health problem affecting the octogenarian today. As age increases, so does the risk for heart disease. One accepted treatment for heart disease is open-heart surgery. The incidence of open-heart surgery performed on the octogenarian is increasing. Open-heart surgery has risks. It is costly and stressful for the patient and family. A major focus of the last decade has been on healthcare costs, outcomes, and quality of life. While information on functional status of the octogenarian following open-heart surgery is available, there is little information available related to the perceived quality of life in the octogenarian following open-heart surgery. Comprehensive tools specific to this population are also not available. The purpose of this study was to examine the perceived quality of life and functional status in the octogenarian following open-heart surgery. The theoretical framework used for this study was the Quality of Life (QOL) model adapted for cancer survivors (QOL-CS) (Ferrell et al., 1995). A descriptive research design was used. The sample frame included eligible octogenarians, who underwent open-heart surgery between January 1, 1998 and February 1, 1999, by a group of cardiac surgeons in the Central Florida area. The New York Heart Association (NYHA) functional status was used to assess the participant's functional level. To assess quality of life, the Quality of Life Scale/Cancer Survivor (Ferrell, Grant, & Hassey-Dow, 1995), in modified form, was used. Both instruments were assessed by a panel of experts to establish content validity. The QOL-CS tool had established validity, internal consistency, and reliability based on the literature review. Crohnbach's alpha measure of internal consistency was also performed on the revised tool. Pfeiffer's Short Portable Mental Status Questionnaire (SPMQ) was administered to assess the participant's mental status prior to their completing the QOLCS tool. The tools were administered over the phone or at the participants home based on their preference. Inclusion criteria were that the participant be between 80 and 90 years old at the time of having open-heart surgery. They also had to be mentally competent and able to understand the English language. The participants completed the SPMQ, a demographic questionnaire, and the QOL-CS modified for this population. The NYHA functional classification was made based on the participant's reported symptoms. Twenty-five people were operated on that fit the criteria and time frame, ten died prior to initiation of the study. Fifteen people were eligible for inclusion in the study, three were unable to be contacted and one refused to participate. Eleven subjects participated in the study. The QOL-CS tool analyzed the domains of physical, psychological, social, and spiritual well being on a Likert scale of one to ten. The mean results were as follows; physical 7.2, psychological 7.2, social 7.1, and spiritual 5.0. A majority of the subjects (73%) were in a NYHA functional class of I or II. The remaining subjects were in class III. This study revealed that for this group, quality of life was above average following open-heart surgery. Further research is needed on larger samples to confirm these results. As more and more open-heart surgeries are performed on the octogenarian, research should continue on the functional outcomes and quality of life associated with these interventions. A tool to examine quality of life, specific to this unique population should be developed.

Maternal cardiovascular adaptations appear to be essential in order to supply extra circulation to both the developing fetus and maternal system during a successful pregnancy. Since inadequate cardiovascular adjustments may produce abortions or maternal morbidity, the characterization of maternal cardiovascular changes during pregnancy and the elaboration of the underlying mechanism for these changes are essential to the understanding of how the heart enlarges during pregnancy and what significance this enlargement might have. To provide needed information regarding this time course and extent of maternal cardiac enlargement and the hormonal and hemodynamic changes which may be responsible for these changes, the guinea pig was used as an animal model to characterize the maternal cardiac, hemodynamic and hormonal changes during early, mid and late pregnancy.

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2017-06-09T17:39:16Z No. of bitstreams: 1 Bruno Leandro de Souza.pdf: 1656878 bytes, checksum: 18ca7a9e5002384728445b4498f2a549 (MD5) / Made available in DSpace on 2017-06-09T17:39:17Z (GMT). No. of bitstreams: 1 Bruno Leandro de Souza.pdf: 1656878 bytes, checksum: 18ca7a9e5002384728445b4498f2a549 (MD5) Previous issue date: 2017-03-21 / In Paraíba, until October 2011, there was no action directed at children with congenital heart disease. With the creation of the Pernambuco-Paraíba Pediatric Cardiology Network, the structuring of the pediatric cardiology service was started. Our objective in this study was to verify the impact of the implantation of the Pediatric Cardiology Network with the use of telemedicine in the care of children with congenital heart disease in the Arlinda Marques Pediatric Hospital from 2012. Method: This was a transversal in the Arlinda Marques Pediatric Hospital (CPAM), a reference hospital in the state of Paraíba for high complexity child care, located in the city of João Pessoa / PB. Clinical data (types of heart disease diagnosed and treated with surgical procedure, year of the procedure) and sociodemographic data (age group, sex, municipality of origin and characteristics of the municipality) were analyzed from records of children with congenital heart disease who performed CPAM surgery between 2010 and 2013. The data were analyzed by comparative tests between groups and tests of comparison of means that were defined after initial analysis of the data, considering that the value of "p" less than 0,05. Statistical analyzes were performed using software R. Results: Data from 260 patients were analyzed. There was an increase in the number of procedures after the implantation of the network from 99 to 163. 78% of the procedures were PCA, CIA, CIV and T4F, being statistically significant the increase after the implantation of the network for the procedures in patients with VSD (p = 0.03) and T4F (p = 0.04). The increase in procedures in the period 2012-2013 was statistically significant for children less than 1 years old (p = 0.01) and from the Sertão and Paraiba¿s Agreste (p <0.01). There was also a positive correlation between the period after the implementation of the program and assistance to children in municipalities with a lower percentage of urban area (p <0.001). Conclusion: The Network, which uses telemedicine as a fundamental tool to internalize and democratize health care, has had a positive impact on the care of children with congenital heart disease in the state of Paraíba, by increasing the number of services to children with congenital heart disease, especially In children under 1 year of age, and to expand the service coverage area, especially for the mesoregions of the hinterland and Agreste and municipalities with the highest percentage in the rural area. / Na Paraíba, não havia ações coordenadas para as crianças com cardiopatia congênita, até outubro de 2011. Com a criação da Rede de Cardiologia Pediátrica Pernambuco-Paraíba iniciou-se a estruturação do serviço de cardiologia pediátrica. O objetivo, neste estudo, foi analisar o impacto da implantação da Rede de Cardiologia Pediátrica com o uso da telemedicina no atendimento de crianças com cardiopatia congênita no Complexo de Pediatria Arlinda Marques a partir de 2012. Método: Tratou-se de um transversal no Complexo de Pediatria Arlinda Marques (CPAM), hospital referência no estado da Paraíba para atendimento infantil de alta complexidade, situado na cidade de João Pessoa/PB. Foram analisados dados clínicos (tipos de cardiopatia diagnosticada e tratada com procedimento cirúrgico, ano da realização do procedimento) e sociodemográficos (faixa etária, sexo, município de origem e características do município) a partir de registros de prontuários de crianças com cardiopatia congênita que realizaram cirurgia no CPAM entre os anos de 2010 e 2013. Os dados foram analisados por testes de comparação entre grupos antes da implantação (2010 e 2011) e depois (2012 e 2013). Para as análises estatísticas foi utilizado o programa software R. Resultados: Foram analisados os dados de 260 pacientes. Houve aumento do número de procedimentos após a implantação da rede de 99 para 163, sendo que 78% dos procedimentos foram de persistência do canal arterial, comunicação interatrial, comunicação interventricular e tetralogia de Fallot. Após a implantação da rede o aumento, dos procedimentos foi estatisticamente significante em pacientes com CIV (p = 0,03) e T4F (p = 0,04) e para crianças menores de 1 anos (p = 0,01), de pacientes procedentes do sertão e agreste paraibanos (p<0,01) e de assistência às crianças em municípios com menor percentual de zona urbana (p<0,001). Conclusão: A Rede de Cardiologia Pediátrica Pernambuco-Paraíba que o uso da telemedicina é uma ferramenta útil e importante para interiorizar e democratizar a assistência à saúde, pois trouxe impacto positivo para o atendimento às crianças com cardiopatias congênitas no estado da Paraíba ao ampliar o número de atendimentos a crianças com cardiopatia congênitas, sobretudo em menores de 01 ano, e ampliar a área de abrangência de atendimento, especialmente para as mesorregiões do sertão e do agreste e municípios da com maior percentual na zona rural.