Myocardial Revascularization through Cardiac Venous System.

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MYOCARDIAL REVASCULARIZATION

THROUGH THE CARDIAC VENOUS SYSTEM

MARIA ERMELINDA ANTUNES SOARES RODRIGUES MUNZ

Tese de doutoramento em Ciências Veterinárias

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MARIA ERMELINDA ANTUNES SOARES RODRIGUES MUNZ

MYOCARDIAL REVASCULARIZATION THROUGH THE CARDIAC

VENOUS SYSTEM

Tese de Candidatura ao grau de Doutor em Ciências Veterinárias submetida ao Instituto de

Ciências Biomédicas Abel Salazar da

Universidade do Porto.

Orientador – Prof. Doutor Artur Manuel Perez Neves Águas

Categoria – Professor Catedrático

Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto

Co-orientador – Prof. Doutor Carlos Alberto da Silva Lopes

Categoria – Professor Catedrático Jubilado Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto

Co-orientador – Dr. Mário Jorge Gonçalves Santos Matos Amorim

Categoria – Docente Voluntário

Afiliação – Faculdade de Medicina da

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This work was supported by grants from FCT (Fundação para a Ciência e a Tecnologia) to UMIB (Unit for Multidisciplinary Biomedical Research), project reference PEst-OE/SAU/UI0215/2011-12.

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"A pessoa isolada é uma abstracção teórica que não tem sentido, porque cada um é uma consequência dos que se cruzam no trajecto de vida e compartilham o circunstancialismo existencial.”

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Acknowledgments

In this section (which I have heard is the most read!), I will mainly use my mother language, as most of the contributors are Portuguese. I apologize to my English-speaking friends…

Este trabalho e respetiva dissertação são um tributo, uma homenagem ao Prof. Doutor Nuno Grande (meu mestre de sempre e para sempre) e à Dra. Ana Maria Grande. Ao Prof. Nuno, gostaria de lha ter oferecido em vida, mas infelizmente já não foi possível… As palavras nesta altura de pouco valem e nunca serão suficientes. Neste momento, serve-me de consolo que tentei sempre transmitir-lhe todo o meu respeito, a minha admiração e o prazer de gozar da sua companhia, da sua amizade e dos seus ensinamentos. Um homem como nunca conheci, com qualidades ímpares nas mais diversas vertentes: como professor, como cientista, como amigo, e como pai e marido. Como professor, o Prof. Nuno possuía uma capacidade incrível de captar a atenção de todos nas suas aulas, nas suas apresentações, recorrendo às suas interessantes (e muitas vezes engraçadas) vivências e descobertas pessoais para manter a audiência cativada. Como cientista, com uma versatilidade e genialidade impressionantes, era capaz de debater e envolver-se nos mais variados temas. Este trabalho de investigação advém das suas experiências pioneiras nos anos sessenta… Como amigo, de uma bondade extrema para com todos e sempre disponível para uma palavra meiga. Como pai e marido,… um exemplo que tentarei sempre seguir, sem dúvida!

Em segundo lugar, devo agradecer ao meu ex-chefe e orientador, Prof. Doutor Artur Águas. Reconhecendo o trajeto já traçado nas minhas experiências prévias (estudo anatómico da circulação coronária no suíno) e a minha aptidão pela área cirúrgica, foi o Prof. Águas quem me propôs a ideia deste trabalho tão interessante e empolgante. Agradeço-lhe ter aceitado o ónus da orientação e me ter proporcionado sempre as condições necessárias para que esta investigação seguisse em frente.

Em seguida, devo agradecer a duas pessoas importantíssimas: o Dr. Mário Jorge Amorim e o Prof. Doutor Adelino Leite-Moreira. Sem o Jorge e as suas mãos mágicas, esta investigação nunca teria começado. Sem o Adelino e o seu apoio científico, esta tese nunca teria terminado. Obrigada, Jorge, espero manter sempre a tua amizade! Ao Adelino, devo dizer que, aparte o exemplo do Prof. Nuno, o admiro como um profissional

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e cientista exímio. Obrigada pela tua disponibilidade. Sei que não foi fácil. Não sei como vos agradecer aos dois… Talvez oferecendo um teto em futuras visitas a “down under”?

Ainda como membros indispensáveis nesta equipa, quero fazer um agradecimento especial por toda a dedicação do Doutor Miguel Faria, Dra. Joana Monteiro, Ana Pinto e Dra. Madalena Santos. Foi trabalho árduo, mas tivemos momentos muito divertidos, sem dúvida. Com a boa disposição contagiante da Ana, não seria possível doutra forma. Mesmo longe, guardarei sempre comigo a vossa amizade.

Um agradecimento também ao Prof. Doutor Carlos Lopes, pela sua co-orientação e pelas horas despendidas no planeamento, análise e explicação dos resultados histopatológicos.

Aos meus colegas de Departamento:

- apesar de fora do âmbito desta investigação, aproveito para agradecer à Prof. Doutora Paula Proença, colega de trabalho durante mais de dez anos, com quem tanto aprendi e partilhei. Obrigada, Paula.

- agradeço também ao Prof. Doutor Joaquim Reis o facto de me ter apresentado o Dr. Mário Jorge Amorim e o ter aliciado a envolver-se neste projeto.

- à Luzia e Raquel, pelo espetacular apoio gráfico. Obrigada, meninas! - ao Duarte, pelos bonitos desenhos incluídos nos artigos e na capa.

- à D. Manuela e Sr. Costa, pelo apoio técnico, quer no transporte dos suínos, quer nos trabalhos de injeção/corrosão em corações.

- à D. Alexandrina, pelos ensinamentos que nos transmitiu em vida…

Também devo agradecer ao Prof. Doutor Augusto Matos e toda a equipa do Departamento de Clínicas Veterinárias por disponibilizarem instalações, equipamento e materiais, para além de todo o apoio físico. Vocês foram impecáveis!

Por passarem além das suas obrigações, agradeço também:

- à empresa Ferjosama e à menina Susana, pelo fornecimento e transporte dos animais

- ao Dr. José Carlos Oliveira e D. Maria Júlia Reis, do Departamento de Química Clínica do Centro Hospitalar do Porto – HGSA, pelas inúmeras análises e ajuda na sua interpretação

- à Siemens e à Dra. Neusa Oliveira, pelas restantes análises efetuadas

- à Dra. Cláudia Moura, ao Dr. Renato Margato e ao João Oliveira, por todo o apoio técnico na execução, otimização e análise de resultados ecocardiográficos e electrocardiográficos.

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- à Joana e João Carvalheiro, pela vossa amizade e horas de filmagens e edição em frente a computadores não cooperantes.

- à Marta Santos e ao Ricardo Marcos, pela ajuda no planeamento e interpretação de lâminas histológicas

- aos alunos do 4º e 5º ano do MIMV, agora já formados, pela ajuda nas colheitas de sangue nos suínos.

- às senhoras da limpeza do ICBAS (especialmente a D. Lyubov), que com tanto carinho cuidaram dos animais.

Gostava ainda de agradecer a todos os meus amigos e amigas, que me souberam sempre ouvir e apoiar: às minhas “maridas” Cristina e Filipa e nossas “filhas adotadas” Cristina e Cláudia; ao Marco, Fátima, São e Sofia, meus melhores amigos; à Márcia, sempre à distância de um chat; à Elsa, à Lena e à D. Ana Paula Pereira, pela boa companhia e companheirismo; aos meus amigos na Austrália, Pilar, João Paulo, Armando e Susana… and to my new best friends Beth and Daniela.

I should also thank everyone at my new Faculty, especially Corinna and Glenn, for their full support during my first experience teaching in a foreign environment and for understanding “my phD handicap”. Thank you, guys!

E agora… Aqui em último plano mas certamente no topo da minha lista de prioridades e importância… A minha família. Agradeço aos meus pais, irmãos, cunhados, sobrinhos e família alemã por nunca me terem deixado baixar os braços e “obrigarem-me” a seguir em frente. Os lemas do meu pai sempre foram as minhas diretrizes na vida e, nesta fase, cito-o: “NADA ACABAR É NADA FAZER!” Espero que, com esta conquista, vos deixe a todos orgulhosos. Foi um dos meus objetivos.

Dir, lieber Michael, für deine Geduld und Unterstützung von Beginn an in guten wie in schwierigen Zeiten, e às minhas filhas, que foram privadas de atenção e tiveram de me suportar nos piores momentos, Ich kann dir nur sagen/só posso dizer: “Verzeih mir bitte, es wird nicht wieder vorkommen. Ich liebe euch wirklich sehr"/”Desculpem-me, não volta a acontecer. Prometo. Amo-vos muito.”

Em último lugar, quero também agradecer aos “participantes” nesta investigação, todos os porquinhos. Seria injusto não vos incluir nesta lista.

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List of publications which content is included in this thesis:

MR Munz, MA Faria, JR Monteiro, AP Águas and MJ Amorim (2011). “Surgical Porcine Myocardial Infarction Model Through Permanent Coronary Occlusion”. Comparative Medicine, 61 (5): 445-452.

Munz M, Amorim MJ, Faria M, Vicente C, Pinto A, Monteiro J, Leite-Moreira AF, Aguas AP “Cardiac venous arterialization in acute myocardial infarction: how great is the benefit?” Interactive CardioVascular and Thoracic Surgery (forthcoming, doi: 10.1093/icvts/ivs471)

Munz M, Silva AC, Pinto A, Santos M, Monteiro J, Faria M, Amorim MJ, Leite-Moreira AF “Cardiac venous anatomy in pigs and humans and its implications for myocardial retrograde perfusion” Journal of Cardiothoracic Surgery (submitted)

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ABSTRACT

Ischemic coronary disease is considered a major cause for mortality in developed countries and accounts for 7 million worldwide deaths per year. Most deaths are fast and current treatments tend to be more urgent and aggressive. At present, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty are the routine standard procedures to obtain myocardial revascularization in patients with severe ischemic coronary disease. Bypass grafting is a demanding surgical technique, whereas angioplasty does not involve anesthesia, is a much simpler method but of more limited long-term success. In fact, most angioplasty-treated vessels suffer restenosis, while bypass grafting has a lower incidence of reoperations. Each of these methods presents other important limitations, which are described in detail further on. As a major drawback, both bypass grafting and angioplasty overcome focal narrowings of proximal coronary arteries but are of little benefit for patients with diffuse multivessel coronary disease. These are the so-called “no-option” patients, which consist of 12 to 15% of the total population of candidates for myocardial revascularization.

Alternative surgical options for salvaging ischemic myocardium have been somewhat disregarded. Our research proposal aimed at revisiting, testing and optimizing cardiac venous arterialization as a surgical alternative to treat ischemic patients. This reperfusion technique consists on the use of cardiac veins to deliver arterial blood from a pulmonary vein or systemic artery to infarcted myocardial areas. Our goal was to evaluate the benefit of cardiac venous arterialization in reducing acute myocardial infarct size and its effects on cardiac performance. For this purpose, cardiac data from two groups of pigs were compared. In the control group, myocardial infarction was induced through simple surgical ligation of a branch from the left coronary artery. In the experimental group, besides coronary artery occlusion, cardiac veins were arterialized. Over 5 days, several diagnostic procedures were used in each group to characterize and measure the extent of myocardial infarct, namely ECG, echocardiography, cardiac biomarkers and histopathology.

Initially, to attain the most significant differences between the two groups and high survival rates in the control group, an ideal myocardial infarction model was investigated. This surgical model should present a reproducible and standardized myocardial lesion, associating the largest possible infarct extent to the lowest morbidity and mortality. The recognition of the most proper coronary occlusion site was achieved by separating pigs in groups subjected to permanent occlusions in different locations of either the left circumflex

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artery or the left anterior descending artery. The results demonstrated that proximal occlusions lead to high mortality rates, while distal occlusions induce rather small myocardial infarction areas. The optimal occlusion site was produced at the mid-point of the left anterior descending artery. This swine model was considered to be easily reproducible and consistent, with precise location of the site of occlusion, low mortality and surgical complication rates, and minimization of pain, suffering, and distress to the animals involved.

Our experiments on cardiac venous arterialization during acute myocardial infarction also suffered several changes for melioration of the model, both in the surgical technique and in the diagnostic protocols used. In the final stage, the left anterior descending vein was arterialized through anastomosis with the left internal mammary artery. Both the left anterior descending artery and vein were ligated, to produce ischemia and avoid backflow into the coronary sinus, respectively. Our results were remarkable. There was clear evidence of myocardial perfusion, with reduction of over 50% on infarct size (especially on the amount of necrotic tissue) and full protection of cardiac performance.

Nevertheless, cardiac venous arterialization on our pig model was not the full success we expected. Cardiac damage was still present: small endocardial infarcts were observed and concentration levels of cardiac biomarkers were as high as the ones from the control group. We speculated on several possible reasons for this event. Our major belief was that myocardial reperfusion through retrograde flow might be insufficient due the frequency and morphology of competent valves within the porcine cardiac venous system.

Being remarkably close to the human in vascular arrangement and heart topography, the pig is an excellent model for experimental cardiac surgery. In earlier studies, we have characterized the arterial cardiac system of the pig heart and compared it to the human coronary anatomy. For our study on the venous cardiac system of the pig, we have used the same vascular injection techniques and basic dissection, which are adequate for detailed anatomical characterizations. The analysis of the cardiac venous anatomy included the distribution pattern and course of cardiac veins, and a new insight on frequency, location, morphology and efficiency of venous valves. A comparison with the human pattern was performed, through examination of two human hearts and available human literature. Our results have shown that, although venous drainage was deemed quite similar between the two species, cardiac venous valves presented pertinent differences. In the analyzed porcine hearts, these anatomical barriers were found more frequently and showed less variability in shape than in humans. Additionally, they were

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also considered more competent in pigs, with complete luminal coverage in all examined valves.

These results indicate that efficacy of retrograde flow should be compromised by cardiac venous valves when pigs are used as experimental models. In humans, however, retrograde flow might be more successful, as cardiac venous valves are fewer and less competent. Ideally, techniques for overcoming these anatomical obstacles should be developed/planned for better efficacy of cardiac venous arterialization as an alternative to restore myocardial perfusion.

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RESUMO

A cardiopatia isquémica constitui uma elevada causa de morte em países desenvolvidos, com cerca de 7 milhões de mortes anuais a nível mundial. A maioria das mortes são rápidas e os tratamentos atuais tendem a ser mais urgentes e agressivos. Os procedimentos mais comuns para revascularização miocárdica de pacientes com sinais severos de doença coronária isquémica são atualmente a cirurgia de revascularização coronária (comummente designado por “bypass”) e a angioplastia coronária. O “bypass” é uma técnica cirúrgica exigente, ao invés da angioplastia, que não requer anestesia e é um método bastante mais simples, mas com taxas de sucesso inferiores a longo prazo. De facto, a maioria das artérias coronárias tratadas por angioplastia sofrem re-estenoses, enquanto o “bypass” tem uma baixa incidência de reoperações. Cada um destes métodos apresenta limitações importantes, que são descritas em pormenor adiante. Tanto o “bypass” como a angioplastia são tratamentos adequados em caso de estenoses focais e proximais das artérias coronárias, mas apresentam a mesma desvantagem importante: os pacientes com doença coronária multivascular difusa são considerados pacientes “sem opção”. Estes pacientes constituem 12 a 15% do total da população de candidatos à revascularização miocárdica.

As opções cirúrgicas alternativas para reperfusão do miocárdio têm sido um pouco negligenciadas. Propusemo-nos revisitar, testar e otimizar a arterialização de veias cardíacas como opção cirúrgica para o tratamento de pacientes com doença isquémica do coração. Esta técnica de reperfusão baseia-se na utilização de veias cardíacas como via de transporte de sangue arterial desde uma veia pulmonar ou artéria sistémica até áreas isquémicas do miocárdio. O nosso objetivo consistiu em avaliar a capacidade das veias cardíacas arterializadas em reduzir a dimensão de enfartes agudos do miocárdio e medir os seus benefícios na performance cardíaca. Para esse efeito, foram comparados dados cardíacos de dois grupos de suínos. No grupo controlo, foi induzido enfarte miocárdico por laqueação cirúrgica de um dos ramos principais da artéria coronária esquerda. No grupo experimental, para além desta oclusão coronária, as veias cardíacas foram arterializadas. Durante 5 dias, foram utilizados vários métodos de diagnóstico em ambos os grupos para caracterização e medição da extensão do enfarte, nomeadamente ECG, ecocardiografia, biomarcadores cardíacos e histopatologia.

No início do projeto, foi criado um modelo ideal de enfarte miocárdico que demonstrasse diferenças significativas em relação ao grupo experimental e com elevadas taxas de sobrevivência. Este modelo cirúrgico deveria apresentar uma lesão miocárdica

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reprodutível e padronizada, associando a maior extensão de enfarte à menor mortalidade e morbilidade possíveis. De forma a reconhecer o local mais apropriado para oclusão coronária, foram criados vários grupos de suínos sujeitos a laqueação permanente a diferentes níveis da artéria circunflexa esquerda ou da artéria descendente anterior. Os resultados demonstraram que as oclusões proximais resultam em elevadas taxas de mortalidade, enquanto as oclusões distais induzem lesões miocárdicas relativamente pequenas. O ponto de oclusão ideal foi conseguido no ponto médio da artéria descendente anterior. Este modelo suíno foi considerado facilmente reprodutível e consistente, com localização precisa do ponto de oclusão, baixas taxas de mortalidade e de complicações cirúrgicas, com minimização da dor, sofrimento e stress pelos animais envolvidos.

As nossas experiências em arterialização venosa cardíaca em caso de enfartes miocárdicos agudos sofreu alterações para melhoramento do modelo, tanto na técnica cirúrgica como nos protocolos de diagnóstico utilizados. Na fase final, a artéria descendente anterior foi arterializada através de uma anastomose com a artéria mamária interna. A artéria e veia descendente anterior foram laqueadas, de forma a produzir isquémia e evitar o refluxo de sangue para o seio coronário, respetivamente. Os resultados obtidos foram notáveis. A perfusão do miocárdio foi claramente evidente, com redução superior a 50% na dimensão do enfarte (especialmente na quantidade de tecido necrosado), e possibilitou a proteção total da performance cardíaca.

Apesar de tudo, a arterialização venosa cardíaca no nosso modelo suíno não alcançou o sucesso esperado. O dano cardíaco ainda era visível, com presença de pequenos enfartes endocárdicos e as concentrações dos biomarcadores cardíacos a atingirem valores tão elevados quanto os do grupo controlo. Especulámos sobre as possíveis razões para estas ocorrências. A nossa principal convicção residia numa insuficiente reperfusão do miocárdio por fluxo retrógrado em resultado da frequência e morfologia de válvulas competentes no sistema cardíaco venoso dos suínos.

O suíno é considerado um modelo excelente para experimentação cardíaca cirúrgica, devido às extraordinárias semelhanças aos humanos, em termos de arquitetura vascular e topografia cardíaca. Em estudos anteriores, fizemos a caracterização detalhada do sistema cardíaco arterial em corações de suíno e estabelecemos comparações com a anatomia vascular cardíaca do Homem. Para o estudo do sistema venoso cardíaco em suínos, utilizámos as mesmas técnicas de injeção vascular e disseção básica, métodos adequados em caracterizações anatómicas detalhadas. A análise da anatomia venosa cardíaca incluiu o estudo da distribuição e trajeto das veias cardíacas e uma nova perspetiva sobre a frequência, localização, morfologia e eficiência das válvulas venosas. Foram estabelecidas comparações ao sistema venoso cardíaco

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humano através da avaliação de dois corações humanos e literatura disponível. Os nossos resultados demonstraram que, apesar da drenagem venosa ser considerada semelhante entre as duas espécies, foram observadas diferenças pertinentes ao nível das válvulas venosas cardíacas. Nos corações de suíno analisados, estas barreiras anatómicas foram observadas com maior frequência e evidenciavam menor variabilidade na forma, comparativamente à espécie humana. Adicionalmente, foram consideradas mais competentes no caso dos suínos, com cobertura total do lúmen por todas as válvulas examinadas.

Estes resultados apontam para uma menor eficácia do fluxo retrógrado (devido a comprometimento por parte das válvulas venosas cardíacas) quando se utilizam suínos como modelos experimentais. Em humanos, no entanto, o fluxo retrógrado poderá ser mais bem-sucedido tendo em conta que as válvulas venosas cardíacas são menos numerosas e menos competentes. Idealmente, deveriam ser criadas/planeadas técnicas para ultrapassar estes obstáculos anatómicos de forma a melhorar a eficácia da arterialização de veias cardíacas como uma alternativa para restauração da perfusão miocárdica.

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INDEX

Chapter 1 - Introduction _________________________________________________ 1 1. Ischemic heart disease ________________________________________________ 2

1.1. Epidemiology and relevance ________________________________________ 3 1.2. Pathophysiology __________________________________________________ 5 1.2.1. Causes _______________________________________________________ 5 1.2.2. Consequences _________________________________________________ 6 1.2.2.1. At the cellular level __________________________________________ 6 1.2.2.2. At the tissue level __________________________________________ 10 1.2.2.3. At the organ level __________________________________________ 13 1.3. Therapeutic strategies ____________________________________________ 14 1.3.1. Revascularization techniques ____________________________________ 15 1.3.1.1. Disadvantages/risks/limitations ________________________________ 17 1.3.1.2. Alternatives _______________________________________________ 19 1.3.1.3. Myocardial Revascularization through the Cardiac Venous System ___ 21

Chapter 2 – Published manuscripts _______________________________________ 24

2.1. Surgical porcine myocardial infarction model through permanent coronary occlusion __________________________________________________________ 26

2.1.1. Abstract _____________________________________________________ 26 2.1.2. Introduction __________________________________________________ 26 2.1.3. Materials and Methods__________________________________________ 28 2.1.3.1. Anesthetic protocol _________________________________________ 28 2.1.3.2. Surgical procedures ________________________________________ 29 2.1.3.3. Diagnostic tests ____________________________________________ 31 2.1.3.4. Statistics _________________________________________________ 33 2.1.4. Results ______________________________________________________ 33 2.1.5. Discussion ___________________________________________________ 38 2.2. Cardiac venous arterialization in acute myocardial infarction: how great is the benefit? ____________________________________________________________ 44 2.2.1. Abstract _____________________________________________________ 44 2.2.2. Introduction __________________________________________________ 45 2.2.3. Materials and Methods__________________________________________ 46

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2.2.4. Results ______________________________________________________ 49 2.2.4.1. Electrocardiography ________________________________________ 49 2.2.4.2. Echocardiography __________________________________________ 49 2.2.4.3. Histological studies _________________________________________ 51 2.2.4.4. Cardiac biochemical markers _________________________________ 52 2.2.5. Discussion ___________________________________________________ 53 2.2.5.1. Our optimized model ________________________________________ 53 2.2.5.2. Analysis of results __________________________________________ 55 2.3. Cardiac venous anatomy in pigs and humans and its implications for

myocardial retrograde perfusion _______________________________________ 58 2.3.1. Abstract _____________________________________________________ 58 2.3.2. Introduction __________________________________________________ 59 2.3.3. Materials and Methods__________________________________________ 60 2.3.3.1. Vascular resin casting _______________________________________ 61 2.3.3.2. Dissection of cardiac veins ___________________________________ 61 2.3.4. Results ______________________________________________________ 62 2.3.4.1. Vascular resin casting _______________________________________ 62 2.3.4.2. Dissection of cardiac veins ___________________________________ 64 2.3.5. Discussion ___________________________________________________ 65

Chapter 3 - Discussion _________________________________________________ 71

3.1. The pig as animal model for IHD studies _____________________________ 73 3.2. Our learning curve for optimization on cardiac venous arterialization _____ 74 3.2.1. Validation of the ideal myocardial infarction model ____________________ 74 3.2.1.1. MI induction strategy adopted _________________________________ 74 3.2.2. Research progress_____________________________________________ 79 3.2.2.1. Phase I __________________________________________________ 79 3.2.2.2. Phase II __________________________________________________ 80 3.2.2.3. Phase III _________________________________________________ 80 3.2.2.4. Phase IV _________________________________________________ 81 3.2.2.5. Phase V _________________________________________________ 81 3.3. Diagnostic exams used ___________________________________________ 83 3.3.1. Cardiac biomarkers ____________________________________________ 84 3.3.2. Electrocardiographic evaluation ___________________________________ 84 3.3.3. Echocardiographic evaluation ____________________________________ 85 3.3.4. Histopathological studies ________________________________________ 86

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3.4. Understanding the incomplete success of cardiac venous arterialization __ 87 3.4.1. Variations in the distribution of epicardial veins, and frequency and morphology of competent valves may affect myocardial revascularization _________________ 87 3.4.2. Blocked drainage ______________________________________________ 89 3.4.3. Concomitant revascularization techniques __________________________ 90 3.4.4. Atherosclerotic disease in arterialized veins? ________________________ 91 3.4. Conclusion _____________________________________________________ 91

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ABBREVIATIONS

AUC – Area Under the Curve

CABG – Coronary Artery Bypass Graft CHF – Congestive Heart Failure ECG – ElectroCardioGraphy IHD – Ischemic Heart Disease IMA – Internal Mammary Artery LAD – Left Anterior Descending artery

LADd - Distal part of the Left Anterior Descending artery LADm - Midpoint of the Left Anterior Descending artery LADp - Proximal part of the Left Anterior Descending artery LADV – Left Anterior Descending Vein

LCX – Left Circumflex artery

LCXp - Proximal part of the Left Circumflex artery LIMA – Left Internal Mammary Artery

MI – Myocardial Infarction

MIDCABG - Minimally Invasive Direct Coronary Artery Bypass Grafting MMB - Mass assay of isoenzyme MB of creatine kinase

OPCAB – Off-Pump Coronary Artery Bypass PCI – Percutaneous Coronary Interventions

PICVA - Percutaneous In-situ Coronary Venous Arterialization PTA – Percutaneous Transluminal Coronary Angioplasty RCA – Right Coronary Artery

TECAB - Totally Endoscopic Coronary Artery Bypass WHO – World Health Organization

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Myocardial Revascularization through the Cardiac Venous System

Introduction

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1. Ischemic heart disease

Ischemia is a reduction (or loss) of blood supply in a tissue due to blocked arterial flow or reduced venous drainage (Myers RK, 2007; Mitchell RN, 2003). When the organ affected is the heart, the consequences are devastating, as vital organs such as kidney, liver and lungs are eventually stricken (Burns DK, 2003). Ischemic heart diseases (IHD) are usually caused by changes in atherosclerotic plaques at the coronary arteries (Burns DK, 2003; Van Vleet JF, 2007; Myers RK, 2007; Schoen FJ, 2010). Hence, IHD is also

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Introduction

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named coronary heart disease or coronary artery disease (Burns DK, 2003; Myers RK, 2007; Schoen FJ, 2010).

IHD include a group of related syndromes, such as angina pectoris (chest pain), myocardial infarction (MI), as well as sudden death and congestive heart failure of ischemic origin (Burns DK, 2003; Schoen FJ, 2010; Woolf, 1992). Although the ischemic cause underlies them all, these syndromes have different pathogenic mechanisms and clinical pictures (Mc Gee JO'D, 1992). Angina pectoris may be stable or unstable. It is caused by reversible, transient ischemia and only induces intermittent chest pain (Burns DK, 2003). MI, also called “heart attack”, is a more severe form, with local ischemia producing an area of myocardial necrosis. It is usually caused by complete thrombotic occlusion of a coronary artery (Burns DK, 2003; Schoen FJ, 2010). Sudden cardiac death results from a lethal rapid arrhythmia usually caused by marked coronary occlusion (more than 75%) (Burns DK, 2003; Schoen FJ, 2010; Mc Gee JO'D, 1992). Less frequently (in only 10 to 20% of cases), however, these fatal arrythmias may result from other non-atherosclerotic conditions (Van Vleet JF, 2007). Congestive heart failure of ischemic aetiology (CHF), also referred as ischemic cardiomyopathy, is usually a consequence of chronic and progressive myocardial dysfunction secondary to ischemia (Burns DK, 2003). CHF may also derive from non-atherosclerotic pathologies, such as chronic work overload, and may even occur in acute conditions, such as fluid overload, acute valvular dysfunction or a substantial MI (Myers RK, 2007).

1.1. Epidemiology and relevance

Cardiovascular disease is a global health problem. Eighty per cent of deaths from cardiovascular diseases occur in developed countries, mainly due to the outstanding aging of these modern societies (Schoen FJ, 2010; Galiñanes, 2005). In 2010, with the increased life span and the decrease in both mortality and birth rates, 11% of the world population was older than 60 years old. Within the high income group of countries*, however, this percentage had already reached 21% and it is predicted that, for Portugal itself, this number will rise close to 30% by 2050 (World Health Organization, 2012; Machado, 2007).

Life expectancy has increased due to biological changes, such as cleanliness of drinking water, improvements in hygiene and nutrition, and progress in quality of health care (including vaccination) and medication itself. Moreover, the quality of life has improved through enhanced psychosocial aspects, such as economic security, and family

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and social stability (Petrov, 2007). According to the WHO (World Health Organization), life expectancy at birth has globally increased from 64 (in 1990) to 68 years (in 2009). Considering only the high income group of countries, life expectancy rose from 68 to 78 years during this period (World Health Organization, 2012). Thus, as a consequence of the elderly living healthier and longer, it is understandable that most deaths occur from chronic diseases, such as cardiovascular disease, chronic obstructive lung disease, cancers, diabetes or dementia (World Health Organization, 2012). In fact, in a broad study from the WHO in 2008, it was estimated that, in high income countries, 71% of the total deaths would pertain to people older than 70 years old (World Health Organization, 2011).

Another important demographic issue is the amount of population living in urban areas. According to the WHO (2012), in the high income countries, the percentage of population living in urban areas was as high as 77%. These people are subject to higher stress, traffic pollution, smoking and obesity (due to a poorer nutrition and reduced physical activities), which are known for being common risk factors for chronic cardiovascular diseases (World Health Organization, 2012; Hoffmann B, et al., 2009; Brook, 2007; Petrov, 2007; Burns DK, 2003; Mitchell RN, 2010; Maxie MG, 2007; Schoen FJ, 2010).

Approximately one third of the world population dies from cardiovascular diseases, largely from IHD and stroke (Thygesen K, 2007; World Health Organization, 2011; Burns DK, 2003; Schoen FJ, 2010). They remain the leading causes of hospitalization and death in high and middle income groups (World Health Organization, 2011; Apple FS, 2006; Schoen FJ, 2010). In the study performed by WHO in 2008, the deaths caused by IHD were estimated to reach 15.6% in high income countries, while stroke and other cerebrovascular diseases were responsible for 8.7% of deaths. As for the middle income countries, numbers were also very high: 13.7% and 12.8%, respectively (World Health Organization, 2011). In the group of diseases included in IHD, MI is a major manifestation (Thygesen K, 2007). Approximately one third of patients who suffer an MI will eventually die (Mitchell RN, 2003; Burns DK, 2003). From these fatalities, 50% do not reach the hospitals alive (Burns DK, 2003; Mc Gee JO'D, 1992). The risk of MI increases throughout life. Within the range of 40 and 50 years old, men are 4 to 5 times more likely to develop MI than women (Burns DK, 2003; Machado, 2007). However, the risk is the same in both sexes after the 80s (Burns DK, 2003).

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1.2. Pathophysiology

1.2.1. Causes

As mentioned above, IHD is mainly (90%) caused by atherosclerotic plaques (Burns DK, 2003; Apple FS, 2006; Schoen FJ, 2010). These plaques (atheromas) are intimal lesions protruding into the arterial lumen, generating arterial stenosis, and have a tendency for disruption and thrombus formation (Mitchell RN, 2010; Apple FS, 2006). They are usually composed of a soft, necrotic, lipid core covered by a fibrous cap (Mitchell RN, 2010; Maxie MG, 2007) (Fig.1). The core contains cholesterol and cholesterol esters, dead cell debris, foam cells (lipid laden macrophages and smooth muscle cells), and eventually organized thrombus and plasma proteins (Mitchell RN, 2010; Ross, 1992). Macrophages, T cells and smooth muscle cells involve this central core, and, more superficially, a fibrous cap is visible, composed of smooth muscle cells and dense collagen (Mitchell RN, 2010; Ross, 1992).

Figure 1 – The major components of a well-developed intimal atheromatous plaque overlying an intact media. © 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 11-6, p. 496). Used with permission.

The most recent theory about the formation of atherosclerotic plaques states that, after an initial endothelial damage, the lesion progresses with accumulation of lipoproteins and monocyte and platelet adhesion, which is followed by migration of monocytes and smooth muscle cells into the intima (and activation of macrophages), and finally smooth muscle proliferation and accumulation of lipids and collagen (Mitchell RN, 2010; Apple FS, 2006; Maxie MG, 2007). These plaques are continuously growing due to on-going cell death, remodeling, and organization of thrombus, and may reach more than 1.5 cm in

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diameter (Mitchell RN, 2010). Thus, as they progress towards the arterial lumen, they may cause critical stenosis in these vessels and compromise distal blood flow. Moreover, the atherosclerotic plaques might also suffer abrupt alterations, such as erosion, ulceration, hemorrhage, fissuring or rupture (Burns DK, 2003; Mitchell RN, 2010; Schoen FJ, 2010; Ross, 1992). Besides expanding the total size of the plaque, these changes activate platelet aggregation with consequent induction of thrombosis, which may partially or completely occlude the arterial lumen (Schoen FJ, 2010; Burns DK, 2003; Mitchell RN, 2010). These sudden changes also activate inflammation, an important factor for atherosclerosis formation and remodeling (Schoen FJ, 2010). Additionally, as the plaque ruptures, the release of small atheromatous debris may cause embolization at distal branches of coronary arteries (Burns DK, 2003; Mitchell RN, 2010). Another complication of atherosclerotic plaques is aneurysmal dilation as the arterial wall gets progressively destroyed (Mitchell RN, 2010; Maxie MG, 2007). Other possible causes for IHD (or factors which may worsen the deleterious effects of atherosclerotic plaques) may include coronary artery vasospasms, lowered systemic blood pressure, emboli originating from vegetations in cardiac valves, systemic hypertension and pre-existing cardiac changes such as hypertrophy (Burns DK, 2003; Apple FS, 2006; Schoen FJ, 2010).

Atherosclerotic plaques are most frequently found at the abdominal aorta, but the coronary arteries are the second most affected vessels (Mitchell RN, 2010). The frequency of occlusion on the different coronary artery branches is variable. The most commonly hit is the left anterior descending artery, reaching 40 to 50% of MI cases. As for the right coronary artery, the occlusion occurs in 30 to 40% of the cases, while occlusion at the left circumflex artery only happens in 15 to 20% of the cases (Burns DK, 2003).

1.2.2. Consequences

1.2.2.1. At the cellular level

The ischemic injury to cells can be reversible or irreversible, depending on the severity and duration of the pathologic stimuli. In case of incomplete or brief blood flow occlusion, cells may undergo reversible changes. However, myocytes are very susceptible to ischemic injury because they depend almost exclusively on oxidative phosphorylation (Schoen FJ, 2010; Woolf, 1992). Therefore, with complete or prolonged occlusion (such as in MI), cells are irreversibly injured, cannot recover and will die (Mitchell RN, 2003; Myers RK, 2007) (Fig.2).

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Figure 2 – The relationship between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation is myocardial hypertrophy (lower left), caused by increased blood flow requiring greater mechanical effort by myocardial cells. This adaptation leads to thickening of the left ventricular wall to over 2 cm (normal, 1-1.5cm). In reversibly injured myocardium (illustrated schematically, right) there are generally only functional effects, without any readily apparent gross or even microscopic changes. In the specimen showing necrosis, a form of cell death (lower right), the light area in the postolateral left ventricle represents an acute myocardial infarction caused by reduced blood flow (ischemia). All three transverse sections of the heart have been stained with triphenyltetrazolium chloride, an enzyme substract that colors viable myocardium magenta. Failure to stain is due to enzyme loss following cell death. © 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 1-2, p. 6). Used with permission.

When irreversible injury is present, although gross or even microscopical changes are not evident, functional changes are already present (Mitchell RN, 2003). This occurs because cardiac cell activity relies on the integrity of all cellular systems. Thus, cells will stop contracting after 1 or 2 minutes of ischemic stimulus, although they will only die 20 to 30 minutes later (Mitchell RN, 2003; Kumar V, 2010; Maxie MG, 2007; Apple FS, 2006). Moreover, changes in the appearance of the cell will only be visible histologically after 4 to 12 hours (Burns DK, 2003; Mitchell RN, 2003; Myers RK, 2007; Kumar V, 2010; Maxie MG, 2007). Gross morphological changes will be evident even later (usually 18 to 24 hours after initial insult) (Mitchell RN, 2003; Burns DK, 2003; Myers RK, 2007; Maxie MG, 2007) (Fig.3).

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Figure 3 - Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly non-functional after the onset of injury, although they are still viable, with potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically this precedes ultrastructural, light microscopic, and grossly visible morphologic changes. © 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 1-7, p. 12). Used with permission.

A cell is considered irreversibly injured when mitochondrial and membrane structure and function cannot be restored (Mitchell RN, 2003; Myers RK, 2007; Maxie MG, 2007). At this point, necrosis takes place, a sequence of morphological cellular events following death (Mitchell RN, 2003). In fact, the age of a MI is possible to be determined as these sequential morphological changes are somehow predictable through time (Fig. 4):

- during the first 4 to 12 hours, coagulative necrosis develops and becomes microscopically evident (Kumar V, 2010). Coagulative necrosis results from enzymatic digestion of the cell and denaturation of proteins (Mitchell RN, 2003). After enzymatic degradation of organelles, the cytoplasm becomes vacuolated and calcification may ultimately occur (Kumar V, 2010). The nucleus may undergo condensation (pyknosis), fragmentation (karyorrhexis) or dissolution (karyolysis) (Burns DK, 2003; Mitchell RN, 2003). The cell membranes lose integrity, so leakage of cellular contents occurs and elicits inflammation of surrounding tissues (Kumar V, 2010). Cells appear swollen and hypereosinophilic, mainly due to the denaturation of intracytoplasmic proteins (Mitchell RN, 2003; Myers RK, 2007; Van Vleet JF, 2007; Kumar V, 2010). Interstitial edema is also evident at this initial stage and some degree of hemorrhage may be present (Apple FS, 2006; Burns DK, 2003).

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- by 24 hours, although the cells (and general tissue) maintain their basic outline, they lose cross-striations and usually present a glassy homogeneous appearance (Myers RK, 2007; Burns DK, 2003; Van Vleet JF, 2007; Apple FS, 2006). At the periphery of the MI, however, the fibres appear wavy as a result of some viable but mal-functioning stretching cells (Burns DK, 2003; Apple FS, 2006). Contraction bands may also be present, due to coagulative myocytolysis (Burns DK, 2003; Maxie MG, 2007). They result from hypercontraction and disruption of fibers, and appear as transversely oriented bars, intensely eosinophilic (Van Vleet JF, 2007; Schoen FJ, 2010). The leukocytes accumulate first at the periphery but then advance toward the center of the lesion (Apple FS, 2006). This leukocytic invasion reaches its peak on the 3rd day and then slowly decreases (Burns DK, 2003; Van Vleet JF, 2007). The interstitial tissue remains edematous (Apple FS, 2006). At this point, the nucleus may be absent (Mitchell RN, 2003; Myers RK, 2007; Kumar V, 2010; Apple FS, 2006).

- as a third step, after 4 days, the necrotic tissue starts to be reabsorbed by invading macrophages, again starting at the periphery of the lesion (Burns DK, 2003; Maxie MG, 2007; Apple FS, 2006). In areas where necrotic myocytes have been phagocytised, only sparse remnants of basal laminae are identified (Van Vleet JF, 2007). Granulation tissue (fibroblasts and capillaries) appear at the borders of the MI (Burns DK, 2003; Maxie MG, 2007).

- by day 10, the necrotic tissue has been dissolved and continues to be removed (Apple FS, 2006). Granulation tissue migrates toward the centre of the lesion, replacing all of the necrotic tissue (Burns DK, 2003; Maxie MG, 2007). Pigmented macrophages are abundant and collagenization begins at the margins of the MI (Burns DK, 2003; Apple FS, 2006).

- finally, after 4 to 8 weeks, most of the necrotic tissue has been reabsorbed and the capillaries disappear, and the lesion is converted into a collagen-rich scar with interspersed intact muscle fibers (Burns DK, 2003; Van Vleet JF, 2007; Apple FS, 2006).

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Figure 4 – Microscopic features of myocardial infarction and its repair. A, One-day-old infarct showing coagulative necrosis and wavy fibers (elongated and narrow, as compared with adjacent normal fibers at right). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. B, Dense polymorphonuclear leukocytic infiltrate in area of acute myocardial infarction of 3 to 4 days’ duration. C, Nearly complete removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days). D, Granulation tissue characterized by loose collagen and abundant capillaries. E, Well-healed myocardial infarct with replacement of the necrotic fibers by dense collagenous scar. A few residual cardiac muscle cells are present.© 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 12-15, p. 552). Used with permission.

1.2.2.2. At the tissue level

A MI consists of a localized necrotic part of the heart as a result of massive death of myocytes (Kumar V, 2010). Myocardial necrosis usually begins at a subendocardial level and spreads toward the epicardium (Burns DK, 2003; Apple FS, 2006). In fact, the subendocardium is more prone to ischemic injury for two reasons: it is the most distant part of the myocardium to be supplied with blood from the epicardial arteries, and the intramural pressures compromise the blood inflow (Burns DK, 2003; Maxie MG, 2007; Mc Gee JO'D, 1992). As necrosis progresses, it extends externally to reach more superficial layers of the myocardium (Fig. 5). The necrosis reaches its final size at 3-6 hours after onset and it may involve the full thickness of the ventricular wall (Burns DK, 2003). If the MI only involves the endocardium and/or the inner layer of myocardium, it is referred as a subendocardial infarct. If it extends all the way through the ventricular wall to the

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epicardium, then it is designated as a transmural infarct (Burns DK, 2003; Apple FS, 2006). In either case, the innermost part of the endocardium appears nearly normal (only slightly vacuolated) owing to the direct nutrition inflow from the ventricular cavity (Burns DK, 2003).

Figure 5 – Progression of myocardial necrosis after coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the center of the ischemic zone. The area that depends on the occluded vessel for perfusion is the “at risk” myocardium (shaded). Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle. © 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 12-12, p. 549). Used with permission.

In early stages of MI, the affected area may appear red at gross examination due to blood inflow into this area. This blood originates from the damaged vessel walls within the microcirculation and from backflow from venules (Mc Gee JO'D, 1992). With cell swelling, however, this blood is “squeezed” from the interstitial tissues and, 18 to 24 hours after MI onset, the infarcted area changes to a slightly pale or spotted appearance (Burns DK, 2003; Maxie MG, 2007; Mc Gee JO'D, 1992). Four days later, the margins tend to become more sharply defined. The central part turns gray and firm, while the edges are

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hyperaemic (because of trapped erythrocytes) or yellow (secondary to neutrophilic infiltration) (Burns DK, 2003; Maxie MG, 2007; Apple FS, 2006). Ten days after onset of MI, the appearance changes to a yellow, soft and sunken lesion (due to progression of leukocytic invasion) with purple borders (granulation tissue) (Burns DK, 2003; Apple FS, 2006). The removal of necrotic tissue gradually reduces the thickness of the ventricular wall in the area of the MI (Apple FS, 2006). Finally, after 8 weeks, the fibrous replacement is well established and the MI is considered healed, as a firm white grayish contracted scar (Burns DK, 2003; Van Vleet JF, 2007; Maxie MG, 2007; Apple FS, 2006).

The size of the MI is influenced by the location of the occlusion: the more proximal in the artery, the wider the area of MI (Burns DK, 2003; Mitchell, 2010). The degree of collateral circulation also affects the size of the MI (Burns DK, 2003; Apple FS, 2006). In fact, in slow developing occlusions, the growing collateral circulation may be sufficient to mitigate the effects of a high-grade or occlusive stenosis (Mitchell, 2010; Schoen FJ, 2010).

The location of the MI is dictated by the coronary artery occluded (Fig.6). If the artery affected is the left anterior descending (LAD), the MI will develop at the most apical and anterior parts of the left ventricle, involving also the anterior two thirds of the interventricular septum (Burns DK, 2003). When the left circumflex artery (LCX) is occluded, MI occurs at the lateral wall of the left ventricle. If the occlusion concerns the right coronary artery (RCA), then MI will take place at the basal and posterior parts of the left ventricle. Also the type of individual coronary artery dominance (left or right) will influence the areas of myocardium affected (Burns DK, 2003). Atherosclerotic plaques tend to be present in more than one of these 3 major epicardial vessels (LAD, LCX and RCA) (Schoen FJ, 2010). They tend to be located at the first centimetres of the LAD and/or LCX, or through the entire length of the RCA. They are not so common in secondary epicardial branches and are considered rare in intramural arteries (Schoen FJ, 2010).

The prognosis and risk of post-MI complications depend mostly on these two above- mentioned variables: infarct size and location (Schoen FJ, 2010). Anterior infarcts have a worse prognosis than posterior ones, and large transmural infarcts yield a higher probability of complications compared to endocardial MI (Schoen FJ, 2010). Post-MI complications may include: contractile dysfunction, arrhythmias, myocardial rupture, pericarditis, right ventricular infarction, infarct extension, infarct expansion and mural thrombus formation, ventricular aneurysm, papillary muscle dysfunction, and congestive heart disease (Schoen FJ, 2010).

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Figure 6 – Distribution of myocardial ischemic necrosis correlated with the location and nature of decreased perfusion. The positions of transmural acute infarcts resulting from occlusions of the major coronary arteries; top to bottom, left anterior descending, left circumflex, and right coronary arteries. © 2010 Kumar V et al, Robbins and Cotran Pathologic Basis of Disease, (Fig. 12-13, p. 551). Adapted and used with permission.

1.2.2.3. At the organ level

The heart circulation, as well as the splenic and renal, are considered end-arterial circulations. Thus, these organs have no alternative blood supply, and vascular occlusion will cause tissue death (Mitchell, 2010).

IHD are a common cause for left-sided CHF. It results from the inability of the heart to eject sufficient blood to meet the demands of the body, i.e., an inadequate cardiac output (Burns DK, 2003; Maxie MG, 2007; Apple FS, 2006). It is usually caused by loss and dysfunction of cardiac tissue, either from chronic heart diseases or from acute large MI (Apple FS, 2006; Schoen FJ, 2010).

At the onset of CHF, the non-infarcted segments of the heart go through adaptive processes to regain a normal cardiac output, which include cardiac dilatation (Frank-Starling mechanism) and/or hypertrophy, and activation of neurohumoral systems (Burns DK, 2003; Van Vleet JF, 2007; Maxie MG, 2007; Schoen FJ, 2010). All these compensatory mechanisms are able to increase up to 5 times the basal cardiac output (Maxie MG, 2007). The neurohumoral reactions include release of norepinephrine, activation of the renin-angiotensin-aldosterone system and release of natriuretic peptides

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(Burns DK, 2003; Maxie MG, 2007; Schoen FJ, 2010). Norepinephrine is released to increase heart rate, myocardial contractility and peripheral vascular resistance. The renin-angiotensin-aldosterone system promotes water and sodium retention, increase in blood volume and improvement in perfusion pressures (Schoen FJ, 2010; Maxie MG, 2007; Burns DK, 2003). In a first instance, if the increase in heart rate and the positive inotropic effect induced by cathecolamines are not enough to normalize the cardiac output, then the heart undergoes “remodeling”, through hypertrophy and dilatation (Burns DK, 2003; Van Vleet JF, 2007). Both hypertrophy and cardiac dilatation, however, result in a higher demand of oxygen due to an increase in cell mass, and ventricular wall tension (Burns DK, 2003; Schoen FJ, 2010). Additionally, the accompanying increase in heart rate and contractility also increase oxygen consumption and the lack of proportional increase in numbers of capillaries during ventricular remodeling result in a higher susceptibility of the myocardium to ischemic injury (Burns DK, 2003; Schoen FJ, 2010).

The cardiovascular system is a closed circuit, so failure on one side will eventually compromise the other side (Maxie MG, 2007; Schoen FJ, 2010). Hence, the pulmonary congestion and edema resulting from left-sided cardiac failure may in turn induce right-sided heart failure (Burns DK, 2003; Van Vleet JF, 2007). Signs of right-right-sided cardiac failure include congestion and enlargement of the liver, spleen, also congestion of the stomach and intestines (manifested as diarrhea), peripheral edema and ascites (Burns DK, 2003; Van Vleet JF, 2007; Maxie MG, 2007; Schoen FJ, 2010).

1.3. Therapeutic strategies

When MI is suspected, prompt and effective treatment is necessary to minimize the massive infarcted tissue and prevent death due to arrhythmia. An important goal is to save the infarcted area by maintaining a balance between supply and demand of oxygen to the myocardium. In the past, the appropriate therapy was considered to include relief of pain (morphine), rest, sedation (chlordiazepide or diazepam), and a quiet atmosphere, in order to lower the heart rate and thus reduce oxygen consumption. Oxygen was provided to raise arterial PO2. Additional medication was prescribed in case of arrhythmias

(procainamide, lidocaine, or quinidine), in the presence of heart failure (usually digoxin) and for thrombolysis of occlusive thrombus near an atherosclerotic plaque (streptokinase). Nowadays, however, it is known that the urgent reestablishment of blood perfusion reduces drastically the extent of myocardial damage and improves the prognosis (Apple FS, 2006). It is now apparent that both patients with partial and total coronary occlusion

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benefit from urgent invasive revascularization (Stanger O, 2006; Galiñanes, 2005; May SA, 2009; Apple FS, 2006). Patients with smaller myocardial damage often suffer repetitive episodes of MI, leading to increased morbidity and mortality over time (Apple FS, 2006). Thus, management of MI suggested by most guidelines is now aggressive and invasively oriented (Apple FS, 2006). Also prevention through control of risk factors is considered essential and is included in these guidelines (Apple FS, 2006; Schoen FJ, 2010). Prevention is used before the patients experience MI (primary prevention) or to avoid reinfarctions (secondary prevention) (Schoen FJ, 2010).

Given the pathophysiology of atherosclerotic plaques, the inhibition of platelet aggregation and inflammation are important steps in treating MI (Apple FS, 2006; Loop, 1998). Currently, the routine pharmacological and surgical therapies for patients with acute MI include: aspirin and heparin (to prevent further thrombosis); oxygen (to minimize ischemia); nitrates (for vasodilation and reversion of vasospasm); beta-blockers (to diminish cardiac oxygen demand and lower the risk for arrhythmias); ACE inhibitors (to lessen ventricular dilation) and revascularization maneuvers (to recover blood supply to injured area) (Schoen FJ, 2010; Apple FS, 2006).

1.3.1. Revascularization techniques

Reperfusion is considered the most effective mean to salvage ischemic myocardium, limit infarct size and improve function, through rapid restoration of blood flow (Schoen FJ, 2010). Ideally, reperfusion should be initiated within 20 min of initial ischemic insult, so that necrosis is completely prevented. After that, reperfusion will not be fully successful, but nonetheless important and beneficial in rescuing viable cells if within the first 6 hours post-ischemic insult (Schoen FJ, 2010). Reperfusion changes the appearance of a MI. The presence of a patchy nontransmural infarction is common after reperfusion as necrosis is stopped before it reaches the full thickness of the myocardium (Burns DK, 2003). Small infarcts also heal faster than larger ones (Burns DK, 2003).

Coronary interventions for reperfusion may include thrombolysis, percutaneous transluminal coronary angioplasty (PTCA) with or without stent placement, or coronary artery bypass graft (CABG) surgery (Schoen FJ, 2010). Thrombolysis (streptokinase or tPA) is used for dissolution of the lesion that caused the MI, while angioplasty and stenting aim to mechanically change it. Percutaneous coronary interventions (PCI) include PTCA and PTCA with stenting. PTCA consists on the dilation of focal stenosis through insertion and inflation of intravascular balloon-tipped catheters. In 90% of PTCAs, endovascular

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stents (expandable tubes of metallic mesh) are additionally implanted to reinforce arterial lumen dilation, by supporting the new stretched open position of the artery (Mitchell RN, 2010). CABG is a surgical technique which simply bypasses the lesion itself, providing blood distally to the occluded vessel, either by use of autologous or synthetic vascular grafts (Schoen FJ, 2010; Mitchell RN, 2010).

For proximal vascular narrowings in all presented scenarios, such as severe coronary disease, diabetic patients, or multi-vessel disease, CABG is the elective treatment and has become the “gold standard” since 1969 (Galiñanes, 2005; May SA, 2009). In these patients, it has been shown to improve survival compared to medical therapy (Stanger O, 2006; Galiñanes, 2005; May SA, 2009). This technique is performed through median sternotomy and allows direct visualization of all areas of the heart, hence the possibility of treating multi-vessel disease (Ochi M, 2003). Several studies report a better surgical outcome with off-pump CABG (OPCAB) than by use of cardiopulmonary bypass (on-pump CABG). It has been demonstrated that oxidative stress, inflammatory response, aortic dissection and postoperative bleeding were relatively higher when extra-corporeal circulation, cardioplegia and aortic manipulation were used. The consequences included pulmonary and renal insufficiency, and neurological complications due to reduced cerebral perfusion and development of cerebral micro-emboli (Galiñanes, 2005; Scarborough JE, 2003; Ochi M, 2003; Stanger O, 2006; May SA, 2009). With new technologic advances, these problems were overcome with surgeries being performed on the beating heart (OPCABG) and the perioperative mortality is as low as 1 to 2% (Galiñanes, 2005; Pennington, 2006; Scarborough JE, 2003; May SA, 2009). However, the option for on- or off-pump CABG is still debatable considering the type of patients, clinical conditions and surgeon’s experience (Galiñanes, 2005; Pennington, 2006; Ochi M, 2003; Stanger O, 2006; May SA, 2009).

An alternative to reduce invasive procedures is PTCA (Galiñanes, 2005). PTCA was introduced later than CABG and has the advantage that no anesthesia is required and hospital stay is short (Galiñanes, 2005). PCI was usually reserved for high-risk surgical patients or those with single-vessel disease (Stanger O, 2006; Galiñanes, 2005). With the development of newer stents coated with certain medicines (drug-eluting stents) for PTCA, restenosis was reduced (10-15%) and may nowadays also be applied to patients with left main and three-vessel coronary artery disease (Galiñanes, 2005; Loop, 1998; May SA, 2009; Mitchell RN, 2010; Jensen J, 2006).

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1.3.1.1. Disadvantages/risks/limitations

As a disadvantage of reperfusion techniques in general, hemorrhages are common as a result of leakage from injured microvascular ischemic vessels (Burns DK, 2003; Schoen FJ, 2010). Contraction bands, due to hypercontraction of myofibrils, are also prominent as a consequence of the rapid influx of calcium into the cells through the damaged plasma membranes (Burns DK, 2003; Schoen FJ, 2010).

Reperfusion also involves risks, namely reperfusion-injury, “no-reflow” phenomenon, “stunned myocardium” and reperfusion arrhythmias. When ischemic myocardium is reperfused, cell injury may be reversible and cells may recover completely. However, under certain circumstances, this blood reflow may induce new injury processes, causing death to cells that might otherwise recover (Mitchell RN, 2003; Myers RK, 2007; Kumar V, 2010). This phenomenon is referred as ischemia-reperfusion injury or simply reperfusion-injury (Myers RK, 2007; Schoen FJ, 2010). This mechanism is still unclear, but may occur due to overload in calcium influx, inflammatory cells and free radicals, and activation of the complement system (which cause loss of cell integrity) (Mitchell RN, 2003; Kumar V, 2010; Schoen FJ, 2010). These excessive free radicals and calcium also trigger undue arrhythmias during reperfusion. In the “no-reflow” phenomenon, the haemorrhages and endothelial swelling resulting from reperfusion in pre-injured ischemic microvascular walls lead to capillary occlusion and therefore limit blood supply to ischemic areas (Schoen FJ, 2010). After reperfusion, the affected area might also remain in a state of reversible cardiac failure with post-ischemic contractile dysfunction. This so-called “stunned myocardium” will only recover after several days (Schoen FJ, 2010).

The different reperfusion techniques also present limitations. Thrombolytic agents, for instance, will remove the thrombus, but not modify the original cause which is the underlying atherosclerotic plaque (Schoen FJ, 2010). These agents are also contraindicated when there is a risk of cranial hemorrhages. All three most common approaches for treatment of coronary diseases (PTCA, stenting and CABG) cause endothelial injury to arterial walls, which, as mentioned before, is considered the initial cause for atheroma formation (Mitchell RN, 2010; Jensen J, 2006).

Limitations of PCI

PTCA causes arterial wall stretching and rupture of plaques, in order to restore blood flow, and adjacent arterial walls suffer hemorrhages due to dissection (Mitchell RN, 2010). As short-term risks, abrupt occlusion may re-occur due to elastic recoil or negative