Introduction: Cardiovascular surgery is a relatively young but progressively evolving field in medicine. More specifically, in the past decades, cardiac surgery achieved significant advances in understanding the causes, progression and treatments of ischemic heart disease (IHD). The IHD is the most common coronary disease, and it ranks first in morbidity and mortality in the developed world. It justifies the need for significant fundamental research as well as its study in clinical practice. It now includes specialized cardiovascular centres with the complex specialized treatments. A group of interventional cardiologists capable of performing routine examinations of the coronary veins using selective angiography has been established. They can eventually also perform percutaneous coronary interventions with direct stent implants. Thus the advances have been made in comprehensive indication of the patients towards their optimal treatments under the regime of a cardio-team. Such team comprises of a cardio-surgeon, interventional cardiologist, echocardiography specialist and the attending physician who is usually the cardiologist. The IHD treatments involve preventive cardiology with the regime measures and checks, pharmacotherapy, interventional cardiology and cardiac surgery to spa treatment and...

La dégénérescence vasculaire et l’incapacité l’organisme à produire des vaisseaux sanguins de façon adéquate lors d’une condition ischémique est un fait saillant des rétinopathies ischémiques telles que la rétinopathie du prématuré (ROP). La ROP demeure la principale cause de défaillance visuelle et dans les cas extrêmes, de cécité chez les nourrissons prématurés. Elle présente deux phases distinctes soit une phase initiale clef de vasooblitération (VO) rétinienne et choroïdale qui entraînent la deuxième phase de néovascularisation (NV) rétinienne désorganisée et excessive. Au cours du développement normal, la NV oculaire a recours au phénomène d’angiogenèse qui consiste en la formation de nouveaux capillaires à partir de vaisseaux préexistants et de vasculogenèse qui consiste en la formation de nouveaux capillaires à partir de cellules endothéliales progénitrices dérivées de la moelle osseuse (BM-EPCs). Cette vasculogenèse implique la mobilisation des EPCs de la moelle osseuse vers la circulation afin d’être recrutées au site de NV pour contribuer de façon directe, soit en intégrant directement les structures vasculaires pour former des néovaisseaux, ou bien de façon indirecte par leur activité paracrine en libérant différents facteurs de croissance vasculaires. Toutefois, les mécanismes moléculaires impliqués dans la dysfonction des EPCs lors de la ROP sont encore mal compris. Au cours de mon mémoire, mes travaux ont ciblé la première phase de VO rétinienne afin de promouvoir la revascularisation par une thérapie basée sur une supplémentation d’EPCs natives ou reprogrammées. Compte tenu du rôle capital des EPCs dans la NV, mon mémoire s’est d’abord intéressé au rôle de Nogo-A (une protéine de la famille de réticulon), connue pour son action anti-angiogénique, sur l'activité fonctionnelle des EPCs en condition de ROP. Pour ce faire, nous avons utilisé un modèle de rétinopathie induite par l’oxygène (OIR) simulant la ROP. L’objectif global de ce projet consiste à évaluer l’interrelation entre l’effet de l’hyperoxie (une condition clef de la ROP) sur la voie de signalisation Nogo-A et de son récepteur NgR1 sur la fonction des EPCs. Premièrement, les résultats obtenus montrent une augmentation de l’expression de Nogo-A et NgR1 chez les BM-EPCs soumis ex vivo à l’hyperoxie, mais aussi dans les EPCs extraites des rats OIR. En addition, l’augmentation de l’expression de Nogo-A/NgR1 par l’hyperoxie corrèle avec la dysfonction angiogénique des EPCs caractérisées par une diminution de leurs capacités de migration et de tubulogenèse. De façon intéressante, l’inhibition de Nogo-A (par un peptide neutralisant) améliore la capacité migratoire et tubulogénique des EPCs, et protège leur fonction contre l’hyperoxie. Également, l’inhibition de Nogo-A induit l’expression du facteur angiogénique et mobilisateur d’EPCs, SDF-1, suggérant que NgR1 régule négativement l’expression de SDF-1. Par ailleurs, nous avions également pour objectif final d’évaluer l’efficacité protectrice d’une supplémentation d’EPCs natives ou reprogrammées (Nogo-/-) pour améliorer la revascularisation rétinienne dans un modèle de rat OIR. Les résultats montrent qu’une supplémentation intrapéritonéale d’EPCs natives diminue significativement la VO rétinienne, mais que cet effet pro-angiogénique devient plus prononcé par le traitement d’EPCs préconditionnées (reprogrammées par l’inhibition de Nogo-A) chez les rats OIR. Collectivement, nos résultats démontrent que : 1) l’hyperoxie cause une dysfonction angiogénique des BM-EPCs en induisant Nogo-A ce qui contribue à la VO rétinienne chez les rats OIR, et que 2) une supplémentation d’EPCs conditionnées (reprogrammées par l’inhibition de Nogo-A) est plus efficace qu’une supplémentation d’EPCs natives pour améliorer la réparation vasculaire rétinienne. Pour conclure, nous mettons donc en évidence une cible potentielle qui est la protéine Nogo-A afin de préserver l’activité biologique des EPCs et ultimement, l’intégrité vasculaire chez les rats OIR. / Vascular degeneration and the inability of the body to produce adequate blood vessels during an ischemic condition is a salient feature of ischemic retinopathies such as retinopathy of prematurity (ROP). ROP remains the leading cause of visual impairment and in extreme cases, blindness in premature infants. It presents two distinct phases: a key initial phase of retinal and choroidal vasoobliteration (VO) which leads to the second phase of disorganized and excessive retinal neovascularization (NV). During normal development, ocular NV uses the phenomenon of angiogenesis which consists of the formation of new capillaries from pre-existing vessels and vasculogenesis which consists of the formation of new capillaries from progenitor endothelial cells derived from the marrow bone (BM-EPCs). This vasculogenesis involves the mobilization of EPCs from the bone marrow to the circulation in order to be recruited at the NV site to contribute directly, either by directly integrating the vascular structures to form new vessels, or indirectly by their paracrine activity by releasing different vascular growth factors. However, the molecular mechanisms involved in the dysfunction of EPCs during ROP are still poorly understood. During my thesis, my work targeted the first phase of retinal VO in order to promote revascularization by therapy based on supplementation of native or reprogrammed EPCs. Given the capital role of EPCs in NV, my thesis was first interested in the role of Nogo-A (a protein of the reticulon family), known for its anti-angiogenic action, on the functional activity of EPCs in ROP condition. To do this, we used an oxygen-induced retinopathy (OIR) model simulating ROP. The overall objective of this project is to assess the interrelationship between the effect of hyperoxia (a key condition of ROP) on the Nogo-A signaling pathway and its NgR1 receptor on the function of EPCs. First, the results obtained show an increase in the expression of Nogo-A and NgR1 in BM-EPCs subjected to hyperoxia ex vivo, but also in EPCs extracted from OIR rats. In addition, the increase in the expression of Nogo-A / NgR1 by hyperoxia correlates with the angiogenic dysfunction of EPCs characterized by a decrease in their capacity for migration and tubulogenesis. Interestingly, inhibition of Nogo-A (by a neutralizing peptide) improves the migratory and tubulogenic capacity of EPCs, and protects their function against hyperoxia. Also, inhibition of Nogo-A induces expression of the angiogenic and mobilizing factor of EPCs, SDF-1, suggesting that NgR1 negatively regulates the expression of SDF-1. In addition, our final objective was also to evaluate the protective efficacy of supplementation of native or reprogrammed EPCs (Nogo - / -) to improve retinal revascularization in an OIR rat model. The results show that intraperitoneal supplementation of native EPCs significantly decreases retinal VO, but that this pro-angiogenic effect becomes more pronounced by treatment of preconditioned EPCs (reprogrammed by inhibition of Nogo-A) in OIR rats. Collectively, our results demonstrate that: 1) hyperoxia causes angiogenic dysfunction of BM-EPCs by inducing Nogo-A which contributes to retinal VO in OIR rats, and that 2) supplementation of conditioned (reprogrammed by inhibition of Nogo-A) is more effective than supplementation of native EPCs in improving retinal vascular repairs. To conclude, we therefore highlight a potential target which is the Nogo-A protein in order to preserve the biological activity of EPCs and ultimately, vascular integrity in OIR rats.

La cardiomyopathie ischémique et l’insuffisance cardiaque (IC) sont deux des principales causes de morbidité et de mortalité dans les pays industrialisés. L’IC représente la condition finale résultant de plusieurs pathologies affectant le myocarde. Au Canada, plus de 400 000 personnes souffrent d’IC. Malgré la grande variété de traitements disponibles pour prendre en charge ces patients à haut risque de mortalité, l’évolution et le pronostic clinique de cette population demeurent sombres. Les thérapies de régénération par transplantation cellulaire représentent de nouvelles approches pour traiter les patients souffrant d’IC. L’impact de cette approche cellulaire et les mécanismes qui sous-tendent l’application de ce nouveau mode de traitement demeurent obscurs. Les hypothèses proposées dans cette thèse sont les suivantes : 1) l’évolution à long terme des patients qui se présentent en IC grave est nettement défavorable malgré les techniques actuelles de revascularisation chirurgicale à cœur battant; 2) la thérapie cellulaire et, plus spécifiquement, l’injection intracoronaire précoce de milieu de culture cellulaire, permet d’améliorer la récupération fonctionnelle du ventricule gauche suite à un infarctus aigu du myocarde; et 3) la mobilisation de l’axe cœur-moelle osseuse constitue un mécanisme de réponse important lors de la survenue d’un événement ischémique chronique affectant le myocarde. / Congestive heart failure (CHF) remains a leading cause of mortality in the developed world. There are more than 400,000 diagnosed cases of this pathology in Canada. Despite the numerous treatment options available for patients presenting with left ventricular dysfunction, the evolution of this population is still dismal. Stem cell transplantation is a potential approach to repopulate the injured myocardium, to treat heart failure, and to restore cardiac function. However, the exact mechanisms underlying the beneficial effects of this approach remain to be elucidated. The hypotheses of this thesis are the following: 1) the long-term evolution of patients undergoing coronary artery bypass graft surgery is still poor, even when considering the use of new innovative surgical strategies such as off-pump coronary revascularization; 2) the intracoronary injection of concentrated biologically active factors secreted by stem cells can achieve early protection of the ischemic myocardium and preserve heart function; and 3) the bone marrow/heart interaction in a critical axis is involved in chronic myocardial repair following persistent ischemic injury.

L'objectif principal de ce travail est d’étudier en profondeur certaines techniques biostatistiques avancées en recherche évaluative en chirurgie cardiaque adulte. Les études ont été conçues pour intégrer les concepts d'analyse de survie, analyse de régression avec “propensity score”, et analyse de coûts. Le premier manuscrit évalue la survie après la réparation chirurgicale de la dissection aigüe de l’aorte ascendante. Les analyses statistiques utilisées comprennent : analyses de survie avec régression paramétrique des phases de risque et d'autres méthodes paramétriques (exponentielle, Weibull), semi-paramétriques (Cox) ou non-paramétriques (Kaplan-Meier) ; survie comparée à une cohorte appariée pour l’âge, le sexe et la race utilisant des tables de statistiques de survie gouvernementales ; modèles de régression avec “bootstrapping” et “multinomial logit model”. L'étude a démontrée que la survie s'est améliorée sur 25 ans en lien avec des changements dans les techniques chirurgicales et d’imagerie diagnostique. Le second manuscrit est axé sur les résultats des pontages coronariens isolés chez des patients ayant des antécédents d'intervention coronarienne percutanée. Les analyses statistiques utilisées comprennent : modèles de régression avec “propensity score” ; algorithme complexe d'appariement (1:3) ; analyses statistiques appropriées pour les groupes appariés (différences standardisées, “generalized estimating equations”, modèle de Cox stratifié). L'étude a démontrée que l’intervention coronarienne percutanée subie 14 jours ou plus avant la chirurgie de pontages coronariens n'est pas associée à des résultats négatifs à court ou long terme. Le troisième manuscrit évalue les conséquences financières et les changements démographiques survenant pour un centre hospitalier universitaire suite à la mise en place d'un programme de chirurgie cardiaque satellite. Les analyses statistiques utilisées comprennent : modèles de régression multivariée “two-way” ANOVA (logistique, linéaire ou ordinale) ; “propensity score” ; analyses de coûts avec modèles paramétriques Log-Normal. Des modèles d’analyse de « survie » ont également été explorés, utilisant les «coûts» au lieu du « temps » comme variable dépendante, et ont menés à des conclusions similaires. L'étude a démontrée que, après la mise en place du programme satellite, moins de patients de faible complexité étaient référés de la région du programme satellite au centre hospitalier universitaire, avec une augmentation de la charge de travail infirmier et des coûts. / The main objective of this work is to study in depth advanced biostatistical techniques in adult cardiac surgery outcome research. The studies were designed to incorporate the concepts of survival analysis, regression analysis with propensity score, and cost analysis. The first manuscript assessed survival, and cardiovascular specific mortality, following surgical repair of acute ascending aortic dissection. The statistical analyses included survival analyses with multiphase parametric hazard regression and other parametric (exponential, Weibull), semi-parametric (Cox) or non-parametric models (Kaplan Meier), comparison with the survival of a matched cohort for age, gender and race using State lifetables, and modelization with bootstrapping and multinomial logit models. The study showed that the early and late survival following surgical repair has improved progressively over 25 years in association with noticeable changes in surgical techniques and preoperative diagnostic testing. The second manuscript focused on outcomes following isolated coronary artery bypass grafting in patients with a history of percutaneous coronary intervention. The statistical analyses included multivariable regression models with propensity score, complex matching algorithm (1:3) and appropriate statistical analyses for matched groups (standardized differences, generalized estimating equations, and survival analyses with stratified proportional hazards models). The study showed that remote prior percutaneous coronary intervention more than 14 days before coronary artery bypass grafting surgery was not associated with adverse outcomes at short or long-term follow-up. The third manuscript evaluated the financial consequences and the changes in case mix that occurred at an academic medical center subsequent to the implementation of a satellite cardiac surgery program. The statistical analyses included two-way ANOVA multivariable regression models (logistic, linear or ordinal), propensity score, and cost analyses using Log-Normal parametric models. “Survival” analyses models were also explored, using “cost” instead of “time” as the outcome of interest, and led to similar conclusions. The study showed that, after implementation of the satellite cardiac surgery program, fewer patients of lower complexity came to the academic medical center from the satellite program area, with a significant increase in nursing workload and costs.

Les rétinopathies ischémiques (RI) sont la cause majeure de cécité chez les personnes âgées de moins de 65 ans. Il existe deux types de RIs soit la rétinopathie du prématuré (ROP) ainsi que la rétinopathie diabétique (RD). Les RIs sont décrites en deux phases soit la phase de vasooblitération, marquée par une perte importante de vaisseaux sanguins, et une phase de néovascularisation secondaire à lʼischémie menant à une croissance pathologique de vaisseaux. Cette seconde phase peut générer des complications cliniques telles quʼun oedème dans lʼhumeur vitré ainsi que le détachement de la rétine chez les patients déjà atteints dʼune RI. Les traitements approuvés pour les RIs visent à réduire la formation des vaisseaux pathologiques ou lʼoedème; mais ceux-ci malheureusement ne règlent pas les problèmes sous-jacents tels que la perte vasculaire et lʼischémie. La rétine est un tissu hautement vascularisé qui contribue à lʼirrigation et à lʼhoméostasie des neurones. Lʼinteraction neurovasculaire, comprenant de neurones, vaisseaux et cellules gliales, contribue au maintien de cette homéostasie. Durant le développement, les neurones et les cellules gliales jouent un rôle important dans la vascularisation de la rétine en sécrétant des facteurs qui stimulent l'angiogenèse. Cependant, nos connaissances sur lʼinteraction neurovasculaire dans les RIs sont limitées. En identifiant les interactions importantes entre les cellules composant cette unité neurovasculaire dans la rétine, nous pourrons viser des cibles qui engendreront une revascularisation seine afin de diminuer les signes pathologiques chez les patients atteints dʼune RI. Les travaux présentés dans cette thèse visent à mieux expliquer cette interaction neurovasculaire en soulignant des concepts importants propres aux RIs. En utilisant un modèle de rétinopathie induite par lʼoxygène chez la souris, qui reproduit les caractéristiques importantes de la ROP (et en certaines instances, la RD), nous identifions quelques molécules clés jouant un rôle significatif dans les RIs soit la sémaphorine 3A (sema3A), lʼIL-1β, ainsi que le récepteur PAR2. Nos résultats démontrent que Sema3A, sécrétée par les cellules ganglionnaires rétiniennes (CGRs) durant une ischémie, empêche la revascularisation normale et que cette expression est induite par lʼIL-1β provenant des microglies activées. En bloquant Sema3A directement ou via lʼinhibition de lʼIL- 1β, nous remarquons une revascularisation seine ainsi quʼune diminution importante des vaisseaux pathologiques. Cela nous indique que Sema3A est impliquée dans la guidance vasculaire et quʼelle contribue à la pathogenèse des RIs. Lʼactivation de façon exogène de PAR2, identifié aussi comme régulateur du récepteur de lʼIL-1β (IL- 1RI) sur les CGRs, se traduit par une diminution séquentielle de lʼIL-1RI et de Sema3A ce qui mène également à une revascularisation seine. En conclusion, ces travaux soulignent lʼimportance de lʼinteraction neurovasculaire ainsi que la guidance vasculaire dans les RIs. Ils renforcent lʼimportance de la communication entre neurone, vaisseau et microglie dans la pathogenèse des RIs. Finalement, nous identifions quelques molécules clés qui pourront servir comme cibles afin de lutter contre lʼischémie qui cause des problèmes vasculaires chez les patients atteints dʼune RI. / Ischemic retinopathies (IRs), namely, retinopathy of prematurity (ROP) and diabetic retinopathy (DR), are the major cause of blindness in persons under the age of 65. IRs are biphasic disorders described by an initial vasoobliterative phase marked by a persistent microvascular degeneration, which leads to ischemia. Retinal ischemia, secondary to vessel loss, incites a second neovascularization phase represented by an aberrant, misdirected neovessel formation into the vitreous, which can cause adverse clinical complications including vitreous hemorrhaging and tractional retinal detachment. While current treatments aim at reducing vitreous/retinal hemorrhaging and/or pathological pre-retinal neovascularization, these regimens fail to address the underlying problem; that is, microvascular decay and retinal ischemia. The retina is a highly metabolic tissue that requires a significant amount of nutrients and oxygen. This is supplied by an intricate and highly regulated vascular network required to maintain homeostasis and proper function. The intricate cellular interactions in the neurovascular unit – the consortium of vessel, neurons and support glia – are required for regulating and maintaining homeostasis under normal conditions. However, the understanding of how this unit functions under ischemic stress, that which is seen in patients suffering from IRs, is not well defined. The present work underlines several important concepts of neurovascular coupling in IRs in efforts to identify potential therapeutic agents that may help curb retinal ischemia by stimulating normal revascularization. Using a mouse model of oxygen-induced retinopathy (OIR), which reproduces the salient features of ROP (and in some instances DR), we identified key players involved in generating the pathophysiological signatures associated with IRs; namely, semaphorin3A (Sema3A), interleukin-1β (IL-1β) and protease-activated receptor 2 (PAR2). Our results show that neuronal-derived Sema3A, secreted by ischemic retinal ganglion cells (RGCs), acts as a potent vaso-repulsive molecules that impedes normal revascularization. Activated microglia contribute to this process by secreting IL-1β, which induces paracrine release of Sema3A expression contributing to microvascular decay as well as pathological pre-retinal neovascularization. Inhibition of Sema3A or IL-1β translates to rapid revascularization and, as a result, a significant reduction in pathological neovessel formation. These results demonstrate that Sema3A is directly involved in vascular guidance and precipitates the pathophysiological features associated with IRs. PAR2, found on RGCs, was also identified as a key regulatory mechanism involved in dampening IL-1β induced Sema3A mediated vascular decay by reducing IL-1 receptor (IL-1RI). Exogenous activation of neuronal PAR2 translates to a sequential reduction of both IL-1RI and Sema3A resulting in accelerated revascularization and consequentially pre-retinal neovascularization. In conclusion, these studies highlight the importance of neurovascular coupling associated with IRs. Herein, we demonstrate the consorted interaction between neuron, vessel and glia and its impact on shaping the retinal vasculature during disease. Moreover, we underscore the significant impact of neuronal guidance cues in manifesting the salient vascular features of IRs. Finally, we identify key players that may serve as potential therapeutic avenues in curbing retinal ischemia in efforts to reduce vascular complications associated with IRs.

INTRODUÇÃO: A inflamação atua diretamente na gênese, progressão e manutenção da aterosclerose. A proteína C reativa ultrassensível (PCRus) é um biomarcador inflamatório preditor de eventos cardiovasculares (ECVs). OBJETIVOS: Analisar o comportamento da PCRus na revascularização do miocárdio (RM) com e sem circulação extracorpórea (CEC) nos períodos pré e pós-operatório e correlacioná-los com as variáveis biológicas e laboratoriais. MÉTODOS: Estudo clínico prospectivo não-randomizado, com 136 pacientes pertencentes ao The Medicine, Angioplasty or Surgery Study V (MASS-V Trial) sendo 93 do sexo masculino e 43 do sexo feminino. Foram elencados 69 pacientes para Grupo 1 (G1= RM com CEC) com média de idade de 61,7 anos e 67 pacientes foram elencados para o Grupo 2 (G2= RM sem CEC) com média de idade de 62,6 anos. Todos os participantes do estudo tiveram amostras de sangue coletadas para análise de glicose, triglicérides (TG), creatinina, colesterol total (CT), high density lipoprotein (HDL), low density lipoprotein (LDL) e creatinofosfoquinase (CPK) no pré-operatório. A coleta das amostras de creatinofosfoquinase MB (CKMB), troponina I (TnI) e proteína C reativa ultrassensível (PCRus), foi realizada no pré-operatório e após 6h, 12h, 24h, 36h, 48h e 72h do ato cirúrgico. Também foram obtidas no pré-operatório as variáveis biológicas de cada paciente (idade, tabagismo, diabetes mellitus (DM), lesão de tronco em coronária esquerda (TCE), índice de massa corpórea (IMC), infarto do miocárdio prévio (IAM prévio), fibrose do miocárdio). A presença de fibrose miocárdica foi analisada através de ressonância magnética cardíaca (RMC) 2 dias antes da cirurgia (F1= fibrose pré-operatória) e com 6 dias após a cirurgia (F2= fibrose pós-operatória). A PCRus foi analisada de maneira uni e bivariada com as variáveis laboratoriais e biológicas elencadas para este estudo. Foram incluídos todos os pacientes angiograficamente documentados com estenose multiarterial proximal > 70% e isquemia documentada por teste de esforço (TE) ou classificação de angina estável (Classe II ou III) pela Canadian Cardiovascular Society (CCS). Não foram incluídos neste estudo reoperações, cirurgias combinadas, infarto agudo do miocárdio (IAM) recente ( <= 6 meses), doença inflamatória recente, trombose venosa profunda (TVP) ou tromboembolismo pulmonar recente (TEP), insuficiência renal aguda (IRA) ou insuficiência renal crônica (IRC). RESULTADOS: Os grupos foram considerados comparáveis em função das variáveis biológicas e laboratoriais analisadas, exceto pela maior ocorrência de hipertensão arterial no G1 e de IAM no G2. Observou-se que houve aumento dos valores da PCRus obtidos no pós em relão ao pré-operatório (p < 0,001). Essa alteração foi significativa em relação às técnicas de RM empregadas. Uma análise bivariada correlacionou a área sob a curva da PCRus e as demais variáveis analisadas e não foi observada significância estatística (p > 0,05) com exceção da área sob a curva encontrada da creatinofosfoquinase (CPK) que resultou em uma correlação positiva no G1 (p=0,015). CONCLUSÕES: Houve aumento da PCRus no pós em relação ao pré-operatório. Este aumento ocorreu em todos os momentos avaliados do pós-operatório. Não houve diferença de comportamento da PCRus entre as técnicas de revascularização do miocárdio empregadas / INTRODUCTION: The inflammation acts directly on atherosclerosis genesis, progression and maintenance. Ultrassensitive C- reactive protein (usCRP) is an inflammatory biomarker that predicts cardiovascular events (CVEs). OBJECTIVES: To analyze the behavior of the usPCR in the MR (myocardial revascularization) with and without extracorporeal circulation (ECC) in the pre and postoperative periods and correlate them with the biological and laboratory variables. METHODS: A prospective non-randomized clinical study with 136 patients belonging to The Medicine, Angioplasty or Surgery Study V (MASS-V Trial), 93 males and 43 females. Sixty-nine patients were enrolled for Group 1 (G1 = MR with ECC) with a mean age of 61.7 years and 67 patients were assigned to Group 2 (G2 = MR without ECC) with a mean age of 62.6 years. All participants in the study had blood samples collected to analyse of glucose, triglycerides (TG), creatinine, total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and creatinephosphokinase (CPK) in the preoperative. The samples of creatinephosphokinase MB (CKMB), Troponin I (ITn) and usCRP were collected in the preoperative and after 6, 12, 24, 36, 48, and 72 hours from the surgery. The laboratory analysis provided the usCRP that was analyzed in a univariate and bivariate way. We also analyzed in the preoperative biological variables of each patient (age, smoking, diabetes mellitus (DM), left coronary trunk lesion (LCT), body mass index (BMI), previous myocardial infarction (previous AMI), myocardial fibrosis). The presence of myocardial fibrosis was analyzed by cardiac magnetic resonance imaging (CMR) 2 days before surgery (F1 = preoperative fibrosis) and 6 days after surgery (F2 = postoperative fibrosis). The usCRP was analyzed in a univariate and bivariate way using with the laboratory and biological variables listed for this study. All angiographically documented patients with > 70% proximal multiarterial stenosis and ischemia, documented by stress test (ST) or classification of stable angina (Class II or III), according to the Canadian Cardiovascular Society (CCS), were included. Reoperations, combined surgeries, recent acute myocardial infarction (AMI) ( <=6 months), recent inflammatory disease, deep venous thrombosis (DVT) or recent pulmonary thromboembolism (PTE), acute renal failure (ARF), or chronic renal failure (CRF), were not included. RESULTS: The groups were considered comparable according to the biological and laboratory variables analyzed, except for the greater occurrence of SAH in G1 and AMI in G2. It was observed that there was an increase in the usCRP values obtained in the postoperative period in relation to the preoperative period (p < 0.001). This change was significant in relation to the MR techniques employed. A bivariate analysis correlated the area under the usCRP curve and the other variables analyzed and no statistical significance was observed (p > 0.05) except for the area under the creatine phosphokinase (CPK) curve that resulted in a positive correlation in G1 (p=0.015). CONCLUSIONS: There was an increase in usCRP in the postoperative period compared to the preoperative period. This increase occurred in all moments assessed postoperatively. There was no difference in the usCRP behavior between the two myocardial revascularization techniques employed

INTRODUÇÃO: A utilização de enxertos arteriais na revascularização cirúrgica do miocárdio já está bem estabelecida atualmente pelos cirurgiões cardiovasculares, e sua esqueletização tem apresentado algumas vantagens, a princípio com a artéria torácica interna esquerda. OBJETIVO: Com o objetivo de analisar esse método de dissecção na artéria radial, foram avaliados os desempenhos funcional e hemodinâmico bem como as características morfoanatômicas e histológicas dos enxertos aortocoronários de artéria radial, esqueletizados ou com tecidos adjacentes, na revascularização cirúrgica do miocárdio. MÉTODOS: Foram comparados 40 pacientes, distribuídos randomicamente em dois grupos. No grupo I foi utilizada artéria radial esqueletizada (20 pacientes) e no grupo II, artéria radial com tecidos adjacentes (20 pacientes), para os ramos marginais da artéria coronária esquerda. No total, 39 pacientes foram submetidos a cinecoronariografia e fluxometria com cateter-guia Doppler de 12 MHz (0,014 polegada, Flowire, Jometrics Inc.), no pós-operatório imediato. RESULTADOS: Os dois grupos apresentaram características demográficas semelhantes. As variáveis intra-operatórias principais da artéria radial também foram semelhantes, com comprimento de 17,1 cm no grupo I e de 16,3 cm no grupo II, e débito livre de 80,3 ml/min no grupo I e de 95,5 ml/min no grupo II. Não foram observadas diferenças morfoanatômicas e histológicas nos grupos comparados. Os diâmetros dos enxertos de artéria radial, calculados por meio de angiografia quantitativa no pós-operatório, foram semelhantes (2,66 mm no grupo I e 2,53 mm no grupo II), assim como as variáveis fluxométricas (fluxo sanguíneo de 54,9 ml/min no grupo I e de 44,28 ml/min no grupo II, e reserva de fluxo de 2,12 no grupo I e de 2 no grupo II). Por outro lado, a cinecoronariografia revelou presença de oclusão em um enxerto e estenose em cinco enxertos no grupo II, enquanto o grupo I apresentou estenose em apenas um enxerto de artéria radial (p = 0,091). CONCLUSÕES: Os enxertos aortocoronários de artéria radial tiveram bom desempenho funcional e hemodinâmico precoce. Não houve diferença entre os grupos quanto ao desempenho funcional e hemodinâmico precoce, e quanto às características morfoanatômicas e histológicas. / BACKGROUND: The use of artery grafts in the surgical revascularization of the myocardium is currently a well-established procedure by cardiovascular surgeons, and its skeletonization has posed some advantages, in principle, with the left internal thoracic artery. OBJECTIVE: With the purpose of analyzing this radial artery harvest method, the study evaluated the functional and hemodynamic early performance, as well as the morphological anatomic and histological features of the aortic coronary grafts of the radial artery, skeletonized or with surrounding tissues, in the surgical revascularization of the myocardium. METHODS: The study compared 40 patients, randomly distributed in two groups. In Group I, we employed a skeletonized radial artery (20 patients), and in Group II, the radial artery with surrounding tissues (20 patients), for the marginal branches of the left coronary artery. In total, 39 patients underwent cinecoronariography and fluxometry with a 12-MHz Doppler guide catheter (0.014 in., Flowire, Jometrics Inc.), in the immediate postoperative period. RESULTS: Both groups presented similar demographic features. The main intra-surgical variables of the radial artery were also similar, with an extension of 17.1 cm in Group I, and 16.3 cm in Group II, and the free flow was of 80.3 ml/min in Group I, and of 95.5 ml/min in Group II. No morphological anatomic and histological differences were observed in the compared groups. The diameters of the radial artery grafts, which were calculated by quantitative angiography in the postoperative period, were similar (2.66 mm in Group I, and 2.53 mm in Group II), as well as the flow variables (blood flow of 54.9 ml/min in Group I, and of 44.28 ml/min in Group II, and a flow reserve of 2.12 in Group I, and of 2 in Group II). On the other hand, the cinecoronariography revealed the presence of an occlusion in one graft, and of stenosis in five grafts of Group II, while Group I presented stenosis in only one radial artery graft (p = 0.091). CONCLUSIONS: The aortic coronary grafts of the radial artery displayed good functional and hemodynamic early performance. There was no difference between the groups regarding functional and hemodynamic early performance, and the morphological anatomical and histological features.

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT

INTRODUÇÃO: A inflamação atua diretamente na gênese, progressão e manutenção da aterosclerose. A proteína C reativa ultrassensível (PCRus) é um biomarcador inflamatório preditor de eventos cardiovasculares (ECVs). OBJETIVOS: Analisar o comportamento da PCRus na revascularização do miocárdio (RM) com e sem circulação extracorpórea (CEC) nos períodos pré e pós-operatório e correlacioná-los com as variáveis biológicas e laboratoriais. MÉTODOS: Estudo clínico prospectivo não-randomizado, com 136 pacientes pertencentes ao The Medicine, Angioplasty or Surgery Study V (MASS-V Trial) sendo 93 do sexo masculino e 43 do sexo feminino. Foram elencados 69 pacientes para Grupo 1 (G1= RM com CEC) com média de idade de 61,7 anos e 67 pacientes foram elencados para o Grupo 2 (G2= RM sem CEC) com média de idade de 62,6 anos. Todos os participantes do estudo tiveram amostras de sangue coletadas para análise de glicose, triglicérides (TG), creatinina, colesterol total (CT), high density lipoprotein (HDL), low density lipoprotein (LDL) e creatinofosfoquinase (CPK) no pré-operatório. A coleta das amostras de creatinofosfoquinase MB (CKMB), troponina I (TnI) e proteína C reativa ultrassensível (PCRus), foi realizada no pré-operatório e após 6h, 12h, 24h, 36h, 48h e 72h do ato cirúrgico. Também foram obtidas no pré-operatório as variáveis biológicas de cada paciente (idade, tabagismo, diabetes mellitus (DM), lesão de tronco em coronária esquerda (TCE), índice de massa corpórea (IMC), infarto do miocárdio prévio (IAM prévio), fibrose do miocárdio). A presença de fibrose miocárdica foi analisada através de ressonância magnética cardíaca (RMC) 2 dias antes da cirurgia (F1= fibrose pré-operatória) e com 6 dias após a cirurgia (F2= fibrose pós-operatória). A PCRus foi analisada de maneira uni e bivariada com as variáveis laboratoriais e biológicas elencadas para este estudo. Foram incluídos todos os pacientes angiograficamente documentados com estenose multiarterial proximal > 70% e isquemia documentada por teste de esforço (TE) ou classificação de angina estável (Classe II ou III) pela Canadian Cardiovascular Society (CCS). Não foram incluídos neste estudo reoperações, cirurgias combinadas, infarto agudo do miocárdio (IAM) recente ( <= 6 meses), doença inflamatória recente, trombose venosa profunda (TVP) ou tromboembolismo pulmonar recente (TEP), insuficiência renal aguda (IRA) ou insuficiência renal crônica (IRC). RESULTADOS: Os grupos foram considerados comparáveis em função das variáveis biológicas e laboratoriais analisadas, exceto pela maior ocorrência de hipertensão arterial no G1 e de IAM no G2. Observou-se que houve aumento dos valores da PCRus obtidos no pós em relão ao pré-operatório (p < 0,001). Essa alteração foi significativa em relação às técnicas de RM empregadas. Uma análise bivariada correlacionou a área sob a curva da PCRus e as demais variáveis analisadas e não foi observada significância estatística (p > 0,05) com exceção da área sob a curva encontrada da creatinofosfoquinase (CPK) que resultou em uma correlação positiva no G1 (p=0,015). CONCLUSÕES: Houve aumento da PCRus no pós em relação ao pré-operatório. Este aumento ocorreu em todos os momentos avaliados do pós-operatório. Não houve diferença de comportamento da PCRus entre as técnicas de revascularização do miocárdio empregadas / INTRODUCTION: The inflammation acts directly on atherosclerosis genesis, progression and maintenance. Ultrassensitive C- reactive protein (usCRP) is an inflammatory biomarker that predicts cardiovascular events (CVEs). OBJECTIVES: To analyze the behavior of the usPCR in the MR (myocardial revascularization) with and without extracorporeal circulation (ECC) in the pre and postoperative periods and correlate them with the biological and laboratory variables. METHODS: A prospective non-randomized clinical study with 136 patients belonging to The Medicine, Angioplasty or Surgery Study V (MASS-V Trial), 93 males and 43 females. Sixty-nine patients were enrolled for Group 1 (G1 = MR with ECC) with a mean age of 61.7 years and 67 patients were assigned to Group 2 (G2 = MR without ECC) with a mean age of 62.6 years. All participants in the study had blood samples collected to analyse of glucose, triglycerides (TG), creatinine, total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and creatinephosphokinase (CPK) in the preoperative. The samples of creatinephosphokinase MB (CKMB), Troponin I (ITn) and usCRP were collected in the preoperative and after 6, 12, 24, 36, 48, and 72 hours from the surgery. The laboratory analysis provided the usCRP that was analyzed in a univariate and bivariate way. We also analyzed in the preoperative biological variables of each patient (age, smoking, diabetes mellitus (DM), left coronary trunk lesion (LCT), body mass index (BMI), previous myocardial infarction (previous AMI), myocardial fibrosis). The presence of myocardial fibrosis was analyzed by cardiac magnetic resonance imaging (CMR) 2 days before surgery (F1 = preoperative fibrosis) and 6 days after surgery (F2 = postoperative fibrosis). The usCRP was analyzed in a univariate and bivariate way using with the laboratory and biological variables listed for this study. All angiographically documented patients with > 70% proximal multiarterial stenosis and ischemia, documented by stress test (ST) or classification of stable angina (Class II or III), according to the Canadian Cardiovascular Society (CCS), were included. Reoperations, combined surgeries, recent acute myocardial infarction (AMI) ( <=6 months), recent inflammatory disease, deep venous thrombosis (DVT) or recent pulmonary thromboembolism (PTE), acute renal failure (ARF), or chronic renal failure (CRF), were not included. RESULTS: The groups were considered comparable according to the biological and laboratory variables analyzed, except for the greater occurrence of SAH in G1 and AMI in G2. It was observed that there was an increase in the usCRP values obtained in the postoperative period in relation to the preoperative period (p < 0.001). This change was significant in relation to the MR techniques employed. A bivariate analysis correlated the area under the usCRP curve and the other variables analyzed and no statistical significance was observed (p > 0.05) except for the area under the creatine phosphokinase (CPK) curve that resulted in a positive correlation in G1 (p=0.015). CONCLUSIONS: There was an increase in usCRP in the postoperative period compared to the preoperative period. This increase occurred in all moments assessed postoperatively. There was no difference in the usCRP behavior between the two myocardial revascularization techniques employed

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT