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Artigo de Reviso

Fisiopatologia da Insuficincia Cardaca Crnica [39]


Mariana Seixas-Cambo, Adelino F. Leite-Moreira
Servio de Fisiologia da Faculdade de Medicina da Universidade do Porto, Porto, Portugal Centro de Cirurgia Torcica, Hospital de So Joo, Porto, Portugal Rev Port Cardiol 2009; 28 (4):439:471

RESUMO A insuficincia cardaca (IC) uma sndrome caracterizada pela reduo do dbito cardaco e aumento da presso venosa, acompanhada de alteraes moleculares que, por sua vez, conduzem a uma deteriorao progressiva do corao e morte prematura dos cardiomicitos. O organismo dispe de mecanismos compensatrios para atenuar o deficiente bombeamento de sangue, que no seu conjunto definem uma resposta neurohumoral. Esta compreende trs elementos fundamentais: 1) reaco hemodinmica de defesa (visa manter a presso de perfuso de rgos nobres e o dbito cardaco, atravs da reteno hidrossalina, vasoconstrio arteriolar e aumento da estimulao cardaca), mediada por cascatas de sinalizao, controladas por mensageiros extracelulares que no actuam apenas no corao; 2) resposta inflamatria (o corao e outros rgos parecem actuar como se estivessem a reagir a agentes estranhos; destaca-se o papel das citocinas pr-inflamatrias, quer na circulao sistmica, quer localmente no miocrdio; do stress oxidativo e dos radicais livres de oxignio); e 3) resposta hipertrfica com remodelagem ventricular, a qual inclui alteraes da biologia e estrutura dos cardiomicitos e na geometria da cmara ventricular. Os mecanismos neurohumorais classificam-se em reguladores (com propriedades vasoconstritoras, antinatriurticas, inotrpicas e proliferativas) e contrarreguladores (efeitos diametralmente opostos). Afiguram-se como deletrios a longo-prazo, contribuindo para a

ABSTRACT Pathophysiology Failure of Chronic Heart

Heart failure is a medical condition characterized by reduced cardiac output (CO) and increased venous pressure, associated with underlying molecular changes and subsequent damage to and death of cardiac muscle cells. The body has its own ways of increasing lowered CO, which together make up the neurohumoral response. This is composed of three basic elements: 1) a hemodynamic defense reaction which maintains perfusion pressure in the major organs by increasing circulating blood volume, inducing vasoconstriction and stimulating the heart; 2) an inflammatory response (in which the body organs act as if they were facing an exogenous agent), in which inflammatory cytokines and reactive oxygen species play an important role; 3) a hypertrophic response and ventricular remodeling, with structural changes in cardiac muscle cells and in the shape of the ventricular chamber. Neurohumoral mechanisms are classified according to their effects: regulatory (increasing vasoconstriction, sodium retention, inotropism and proliferation); and counter-regulatory (with the opposite effects). Ultimately, they are responsible for the failing heart. Our aim is to bring together data on the mechanisms of progression to heart failure, elucidating the relationships between the

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Recebido para publicao: Setembro de 2008 Aceite para publicao: Dezembro de 2008 Received for publication: September 2008 Accepted for publication: December 2008

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instalao e cronicidade da IC. O objectivo deste trabalho foi compilar informao existente sobre a fisiopatologia da IC crnica (ICC), realando a interaco entre todos estes mecanismos para o desenvolvimento e auto-agravamento da IC, com particular incidncia nos potenciais alvos teraputicos que da advm.

biological agents involved, particularly those susceptible to pharmacological modification.

Palavras-Chave Insuficincia cardaca; Neuro-hormonas; Citocinas; Angiotensina; Sistema endotelina; Peptdeos natriurticos; Sistema dopaminrgico; Sistema nervoso autnomo; xido ntrico; Remodelagem ventricular.

Key words Heart failure; Neurohormones; Cytokines; Angiotensin; Endothelin system; Natriuretic peptides; Autonomic nervous system; Dopaminergic system; Nitric oxide; Ventricular remodeling.

INTRODUO

INTRODUCTION eart failure (HF) is a clinical syndrome that has an enormous impact on modern societies due to its high mortality and morbidity. It is characterized by reduced cardiac output and increased venous pressure, accompanied by molecular changes that lead to progressive heart failure and premature death of cardiomyocytes(1). The hearts pump function can be compromised through two mechanisms: reduction in volume of blood ejected under pressure to the aorta and pulmonary trunk as a result of depressed myocardial contractility (diminished inotropism), known as forward failure, and inadequate venous return to the heart arising from impaired ventricular filling and relaxation (diminished lusitropy), termed backward failure. HF can thus be classified as systolic or diastolic respectively(1). In the case of chronic HF (CHF), systolic and diastolic dysfunction are more appropriately defined in terms of changes in ventricular architecture (size, shape and wall thickness). Left ventricular systolic CHF is thus characterized by dilatation and wall thinning (eccentric hypertrophy), while diastolic CHF is typically shown by a noncompliant ventricular chamber with thickened walls and of reduced or normal size (concentric hypertrophy)(1). Various mechanisms can damage the heart, and so different pathogenic processes may underlie similar symptoms. Adding to the

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insuficincia cardaca (IC) uma sndrome clnica com incontestvel impacto nas sociedades actuais pelas elevadas taxas de mortalidade e morbilidade a que est associada. Caracteriza-se por uma reduo do dbito cardaco e aumento da presso venosa, acompanhadas de alteraes moleculares que, por sua vez, conduzem a uma deteriorao progressiva do corao e morte prematura dos cardiomicitos(1). A funo de bomba do corao pode ser comprometida por dois mecanismos: reduo da ejeco do sangue sob presso para a aorta e tronco pulmonar, por depresso da contractili dade miocrdica (diminuio do inotropismo) -forward failure-, e esvaziamento inadequado do reservatrio venoso que transporta sangue para o corao, por comprometimento do enchimento e relaxamento ventriculares (diminuio da lusitropia) -backward failure. A IC pode, assim, ser classificada, respectivamente, em sistlica e diastlica(1). Relativamente IC Crnica (ICC), as disfunes sistlica e diastlica so mais apropriadamente definidas em termos da alterao da arquitectura ventricular (tamanho, forma da cavidade e espessura da parede). A ICC sistlica do ventrculo esquerdo caracteriza-se, em termos arquitecturais, por um corao dilatado de paredes finas (hipertrofia excntrica), enquanto que a ICC diastlica, tipicamente, se expressa por um ventrculo de paredes espessadas, no complacente, com dimenses reduzidas ou

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normais (hipertrofia concntrica)(1). Diversos mecanismos podem lesar o corao, pelo que sintomatologia semelhante pode ter subjacente vrios processos patognicos. Paralelamente a esta complexidade, o organismo dispe de mecanismos compensatrios (resposta neurohumoral) para atenuar o deficiente bom beamento de sangue. A resposta neurohumoral compreende trs elementos fundamentais: reaco hemodinmica de defesa (visa manter a presso de perfuso de rgos nobres e o dbito cardaco); resposta inflamatria (o corao e outros rgos parecem actuar como se estivessem a reagir a agentes estranhos); e resposta hipertrfica com remodelagem ventricular(1). Tais mecanismos, inicialmente benficos, afiguram-se como noci vos posteriormente contribuindo para a deteriorao progressiva dos cardiomicitos em sobrecarga. Esta dualidade verifica-se tambm na teraputica farmacolgica da IC: muitos dos frmacos que melhoram os sintomas a curto-prazo podem agravar o prognstico a longo-prazo e vice-versa. Da decorre a extrema importncia da compreenso da fisiopatologia desta sndrome, para melhor a tratar. RESPOSTA NEUROHUMORAL 1) Reaco hemodinmica de defesa Em 1983, Peter Harris estabeleceu uma analogia entre as alteraes hemodinmicas que ocorrem na IC e as que se verificam durante o exerccio e a hemorragia: estas trs situaes despertam uma reaco de defesa hemodinmica, com o objectivo de manter a presso sangunea. Esta resposta apesar de comum, difere no que respeita durao, sendo marca da IC o seu carcter progressivo(1). A reteno hidrossalina, a vasoconstrio arteriolar e o aumento da estimulao cardaca so os trs componentes principais dessa reaco de defesa mediada por cascatas de sinalizao, controladas por mensageiros extracelulares que actuam no s no corao mas tambm nos rins, vasos sanguneos e msculo esqueltico. Os diferentes mediadores qumicos intervenientes nessas respostas supostamente reguladoras (visam a homeostasia a curto-prazo, ainda que deletrias a longo-prazo) podem condicionar respostas semelhantes, muitas

complex nature of HF, the body has its own ways of increasing lowered cardiac output, which together make up the neurohumoral response. This is composed of three basic elements: a hemodynamic defense reaction which main tains perfusion pressure in the major organs and cardiac output; an inflammatory response, in which the heart and other organs act as if they were facing an exogenous agent; and a hypertrophic response with ventricular remodeling(1). These mechanisms, which are initially beneficial, are ultimately harmful as they contribute to progressive degeneration of overloaded cardiomyocytes. This duality is also found in pharmacological HF therapy, in that many drugs that improve symptoms in the short term can worsen long-term prognosis, and vice versa. This is why it is extremely important to understand the pathophysiology of the syndrome in order to improve treatment. NEUROHUMORAL RESPONSE 1) Hemodynamic defense reaction In 1983, Peter Harris pointed out the similarity between the hemodynamic changes that occur in HF and those found in exercise and hemorrhage: all three situations provoke a hemodynamic defense reaction aimed at maintaining blood pressure, but the duration of the response differs, the characteristic of HF being its progressive nature(1). Water and sodium retention, arteriolar vaso constriction and increased cardiac stimulation are the three main components of this defense reaction, which is mediated by signaling cascades controlled by extracellular messengers that act not only in the heart but also in the kidneys, blood vessels and skeletal muscle. The different chemical mediators involved in these regulatory effects (which are designed to maintain homeostasis in the short term but are harmful in the long term) can produce similar, even identical, responses, despite being produced by different classes of receptors. These mediators can also simultaneously produce counter-regulatory responses (so termed despite their generally beneficial effect), whose effects are diametrically opposed to the first type in that they increase diuresis and vasodilation, reduce cardiac stimulation and inhibit cell proliferation.

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vezes sobreponveis, apesar de condicionadas por classes de receptores distintas. Esses mediadores podem tambm, simultaneamente, evocar respostas contrarreguladoras (assim designadas apesar do seu carcter geralmente benfico), com efeitos diametralmente opostos aos j descritos: promoo da diurese, relaxamento vascular, reduo da estimulao cardaca e inibio do crescimento celular. Essas respostas contrarreguladoras espelham um princpio fundamental da biologia: sempre que sinais reguladores activam um processo so necessrios sinais contra-reguladores para o desactivar(1,2). 1.1) Reteno hidrossalina O edema, a anasarca e a dispneia, as principais manifestaes clnicas da IC, so causadas por acumulao tecidular de fluidos. A origem do edema reside na reteno renal de sdio e gua, e no na incapacidade do corao bombear sangue do sistema venoso. A expanso do volume extracelular na IC , primariamente, condicionada pela reteno de sdio. A incapacidade de regulao da osmolaridade plasmtica causa excessiva reteno de gua. O resultado uma hiponatremia de diluio. Na IC, a reteno inapropriada de sdio ocorre, fundamentalmente, por aumento da reabsoro do sdio pelo epitlio tubular. A alterao hemodinmica mais importante a nvel renal a constrio das arterolas eferentes do glomrulo, que aumenta a presso intraglomerular e, consequentemente, a taxa de filtrao glomerular. As alteraes resultantes nas presses onctica e hidrosttica intra-renais promovem a reabsoro de sdio(1). Seguidamente explana-se o papel de alguns dos mediadores intervenientes na reteno hidrossalina no contexto da IC. A activao do sistema renina-angiotensina e do sistema nervoso simptico, bem como as aces da endotelina, ainda que tenham repercusses renais, sero abordados na seco seguinte, pelos seus marcados efeitos vasoconstritores. Aldosterona O aumento da secreo desta hormona esteride, pela zona glomerulosa da glndula suprarrenal, representa o principal estmulo para a reteno de sdio pelo rim, ao nvel dos tbulos distais. Na IC, o mecanismo

These counter-regulatory responses reflect a fundamental principle of biology: whenever regulatory signals activate a process, counterregulatory signals are necessary to deactivate it(1,2). 1.1) Water and sodium retention Edema, anasarca and dyspnea, the main clinical manifestations of HF, are caused by accumulation of fluid in tissues. Edema results from retention of water and sodium in the kidneys rather than from the hearts inability to pump blood from the venous system. The extracellular volume expansion seen in HF is primarily due to sodium retention, while the inability to regulate plasma osmolarity causes excessive water retention. The result is dilutional hyponatremia. In HF, salt retention mainly occurs due to increased sodium reabsorption by the renal tubular epithelium. The most important hemodynamic alteration in the kidneys is constriction of glomerular efferent arterioles, which increases intraglomerular pressure and hence glomerular filtration rate. The resulting changes in intrarenal oncotic and hydrostatic pressures promote sodium reabsorption(1). The role of some mediators of water and salt retention in HF are explained below. Activation of the renin-angiotensin system and the sympathetic nervous system, as well as the action of endothelin, will be discussed in the following section since, while they do have renal repercussions, their vasoconstrictor effects are more important. Aldosterone Increased secretion of the steroid hormone aldosterone by the adrenal glomerular zone is the main stimulus for sodium retention in renal distal tubules. The mechanism underlying aldosterone secretion in HF differs significantly from its activation in physiological conditions, in which hyperkalemia, stress and circadian variations, regulated by adrenocorticotropic hormone (ACTH), are the main factors. Curiously, aldosterone secretion in HF is regulated by different neurohumoral mediators at different stages: at the onset of HF, there is an increase in catecholamines, vasopressin and endothelin, while the main stimulus following diuretic therapy is angiotensin II (Ang II), levels of which rise as a result of activation of the renin-

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que conduz secreo de aldosterona difere substancialmente do que activado em situaes fisiolgicas, nas quais a hipercalmia, o stress e as variaes diurnas, reguladas pela hormona adrenocorticotrpica (ACTH), constituem os principais potenciadores. Paradoxalmente, na IC, a secreo de aldosterona regulada pelos mediadores neurohumorais, os quais diferem ao longo do tempo: no incio do desenvolvimento da IC, h aumento das catecolaminas, vasopressina e endotelina; aps teraputica com diurticos, o principal estmulo a Angiotensina II (Ang II), cujos nveis aumentam em consequncia da activao do sistema renina-angiotensina(3). Na IC, a estimulao -adrenrgica e a Ang II aumentam o transporte de sdio no tbulo proxi mal, com consequente diminuio do sdio que chega ao ducto colector, o que explica a persis tente reteno de sdio mediada pela aldosterona e a ausncia do fenmeno de escape nestes doentes(4). A par do aumento da reabsoro de sdio, a aldosterona promove a excreo renal de potssio, condicionando hipocalmia e alcalose metablica, frequentes na IC grave. Tambm apresenta efeitos mitognicos, contribuindo assim para a hipertrofia e fibrose miocrdicas. Esta aco promotora do crescimento, que condiciona remodelagem vascular, dependente do sdio, e sugere que a aldosterona promove a entrada de sdio nos fibroblastos, em parte pela activao ou recrutamento de bombas de sdio, de uma reserva pr-existente, inserindo-as na membrana celular, possivelmente por exocitose(5). Os antagonistas da aldosterona (p.ex. espiro nolactona) previnem a fibrose e remodelagem miocrdicas na IC, para alm de condicionarem um efeito inotrpico negativo. H evidncia cientfica que demonstra aumento da sobrevida na IC com a utilizao de espironolactona(5,6). Arginina-Vasopressina (Hormona anti diu rtica) Esta hormona, sintetizada nos ncleos supraptico e paraventricular do hipotlamo e armazenada na pituitria posterior, tem uma potente aco vasoconstritora. Tambm aumenta a permeabilidade dos ductos colectores renais gua, inibindo a diurese. A importncia dos subtipos de receptores na determinao da resposta s molculas de sinalizao extracelular ilustrada pela

angiotensin system (RAS)(3). In HF, alpha-adrenergic stimulation and Ang II increase sodium transport in the proximal tubule, leading to a decrease in the quantity of sodium reaching the collecting duct, which explains the persistent aldosterone-mediated sodium retention and the absence of the escape phenomenon in these patients(4). As well as increased sodium reabsorption, aldosterone promotes renal excretion of potassium, resulting in hypokalemia and metabolic alkalosis, which are common in severe HF. It also has mitogenic effects, thus contributing to myocardial hyper trophy and fibrosis. This growth-promoting action, which leads to vascular remodeling, is sodium-dependent and suggests that aldosterone promotes sodium uptake by fibroblasts, in part by activating or recruiting sodium pumps from a pre-existing pool and inserting them in the cell membrane, possibly through exocytosis(5). Aldosterone antagonists such as spirono lactone prevent myocardial fibrosis and remodeling in HF, as well as having a negative inotropic effect, and there is evidence that spironolactone improves survival in HF(5,6). Arginine vasopressin (antidiuretic hormone) This hormone, produced in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary, has a potent vasoconstrictor action and also increases the permeability to water of renal collecting ducts, inhibiting diuresis. Vasopressin is a good example of the importance of receptor subtypes in determining response to extracellular signaling molecules, as it can have vasoconstrictor and vasodilator effects depending on the receptor type: activation of V1 receptors causes vasoconstriction, while V2 receptors lead to vasodilation. The strongest effect on blood pressure is mediated by V1 receptors; V2 receptors are thought to play a role in local regulation of renal function. As with aldosterone, vasopressin release in severe HF is not under normal physiological control. Rather than responding to plasma osmolarity, vasopressin levels are affected by arterial underfilling and the central effect of increased Ang II levels. With worsening HF, particularly after administration of diuretics, both mechanisms increase vasopressin release, leading to increased thirst, reabsorption of water

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vasopressina, que apresenta, simultaneamente, efeitos vasoconstritores e vasodilatadores, mediante os receptores onde actua: a activao dos receptores V1 causa vasoconstrio, enquanto que os receptores V2 condicionam vasodilatao. O efeito mais importante na presso arterial o mediado pelos receptores V1. Os receptores V2, provavelmente, desempenham um papel na regulao local da funo renal. Tal como no caso da aldosterona, a libertao da vasopressina na IC grave no se encontra sob o habitual controlo fisiolgico. Em vez de responder osmolaridade plasmtica, os nveis de vasopressina so determinados pela reduo do enchimento arterial e um efeito central de aumento dos nveis de Ang II. Com o agravamento progressivo da IC, particularmente aps administrao de diurticos, ambos os mecanismos aumentam a libertao de vasopressina, com consequente aumento da sede e da reabsoro de gua, promovendo hiponatremia de diluio(3). No intuito de avaliar os possveis efeitos favorveis dos inibidores dos receptores da vasopressina na IC, tm sido desenvolvidos estudos com os mesmos. O estudo ECLIPSE (Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure) demonstrou que o antagonismo dos receptores V2 da vasopressina resulta em efeitos agudos, hemodinmicos e renais, favorveis em doentes com IC reduo da presso de encravamento pulmonar e aumento do dbito urinrio. Contudo, levantou novas questes sobre o significado a longo-prazo desses benefcios identificados a curto-prazo(7). Peptdeos natriurticos O corao no tem apenas uma funo de bomba; funciona igualmente como rgo endcrino. Esta descoberta por De Bold, em 1979,(8) atravs da constatao da existncia de grnulos nos cardiomicitos auriculares de Rato, com propriedades diurticas e natriurticas, impulsionou investigaes posteriores que per mitiram identificar quatro peptdeos natriurticos tipo A (ANP), tipo B (BNP), tipo C (CNP) e tipo D (DNP) - sintetizados e segregados pelo corao. Ainda que estruturalmente semelhantes, distinguem-se em termos genticos. O ANP e o BNP so os mais amplamente estudados. O CNP encontrado no crebro, pituitria, rins e endotlio vascular; existe em pequena

and dilutional hyponatremia(3). Various studies have assessed the possible benefits of vasopressin receptor antagonists in HF. The Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure (ECLIPSE) trial demonstrated that inhibition of vasopressin V2 receptors produces acute hemodynamic and renal benefits in HF patients, including reduced pulmonary wedge pressure and increased urinary output. However, it raised new questions as to the long-term effect of these short-term benefits(7). Natriuretic peptides The heart is not only a pump but also an endocrine organ. This discovery by De Bold in 1979(8), based on his observation of granules in rat atrial myocytes with diuretic and natriuretic properties, stimulated research which subsequently identified four natriuretic peptides type A (ANP), type B (BNP), type C (CNP) and type D (DNP) synthesized and secreted by the heart. Although structurally similar, they are genetically different. ANP and BNP have been most thoroughly studied. CNP is found in the brain, pituitary, kidneys and vascular endothelium; low levels are present in the circulation and the heart, acting primarily as a clearance receptor in a paracrine manner. DNP was identified only recently and although its role in the pathophysiology of HF is still unclear, levels are elevated in this pathology(9). The cardiac natriuretic peptide system is activated early in HF. Plasma levels of these peptides are characteristically high in HF, due partly to hemodynamic overload arising from increased transmural pressure and consequent atrial distension, which stimulates expression of the genes that code for them(10). In physiological conditions, ANP is produced mainly in the atria, while BNP is also found in the brain and possibly in the ventricles. Both subtypes are stored in atrial granules, the proportion of ANP being higher. Under pathological conditions, the proportions of ANP and BNP are reversed, and ventricular granules appear. Curiously, the gene for ANP, which is normally present in fetal but not in adult ventricles, is again expressed in adult HF patients, reflecting a reversion to the fetal phenotype(11). In HF, particularly if severe, genetic expression of BNP in the heart is also mainly ventricular(9).

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quantidade na circulao e no corao, actuando primariamente como um receptor de depurao, de forma parcrina. O DNP foi identificado mais recentemente; apesar do seu papel na fisiopatologia da IC estar ainda pouco clarificado, sabe-se que os seus nveis esto elevados nessa patologia(9). O sistema dos peptdeos natriurticos cardacos precocemente activado na IC. Os nveis plasmticos desses peptdeos encontram-se caracteristicamente elevados na IC, devido em parte, sobrecarga hemodinmica (com o aumento da presso transmural e consequente distenso auricular) estimular a expresso dos genes que os codificam(10). Em situaes fisiolgicas, o ANP produzido principalmente nas aurculas, enquanto o BNP, para alm da produo auricular, tambm encontrado no crebro e, possivelmente, nos ventrculos. Ambos os peptdeos so armazenados em grnulos auriculares sendo mais elevada a proporo de ANP. Em situaes patolgicas, ocorre uma inverso da relao da quantidade de ANP e BNP, acompanhada pelo aparecimento de grnulos ventriculares. Curiosamente, o gene que codifica o ANP, que normalmente est presente nos ventrculos fetais mas no nos adultos, volta a expressar-se nos ventrculos de coraes de adultos com IC, o que revela uma reverso para o fentipo fetal(11). Na IC, sobretudo se grave, tambm o BNP passa a ter expresso gnica cardaca maioritariamente ventricular(9). Os peptdeos natriurticos actuam atravs da activao de trs tipos de receptores: tipo A (liga-se ao ANP e BNP), tipo B (liga-se preferencialmente ao CNP) e tipo C(9). Desempenham um papel primordial como agentes contrarreguladores da IC em virtude dos seus efeitos diurtico (dilatao das arterolas aferentes, relaxamento das clulas mesangiais e aumento da resistncia da arterola eferente), natriurtico e vasodilatador. Manifestam tambm um efeito inibitrio sobre o sistema nervoso simptico, contribuindo para a diminuio dos nveis de adrenalina, no Homem, quer em situaes fisiolgicas quer na IC. A nvel do sistema cardiovascular, o ANP e o BNP revelam ainda uma actividade antimitognica, intervindo assim na modulao do crescimento vascular(9). Porm, na IC grave, verifica-se uma atenuao do efeito natriurtico do ANP e do BNP, o que poder ser explicado por uma multiplicidade

Natriuretic peptides activate three types of receptors: type A (which binds to ANP and BNP), type B (which binds preferentially to CNP) and type C(9). They play a fundamental role as counterregulatory agents in HF because of their effects on diuresis (efferent arteriolar dilation, mesangial cell relaxation and increased efferent arteriolar resistance), natriuresis and vasodilation. They also have an inhibitory effect on the sympathetic nervous system, reducing adrenaline levels in humans, both in physiological conditions and in HF. ANP and BNP also have an antimitogenic effect in the cardiovascular system, modulating vascular growth(9). However, the natriuretic effect of ANP and BNP is weakened in severe HF, which may be explained by various factors including reduced renal perfusion, increased renal sympathetic and RAS activity, and diminished receptor expression and activity. The resulting water and salt retention contributes to progression of the syndrome(9). The early activation of natriuretic peptides in HF and their link to its severity prompted studies to assess their value as diagnostic and prognostic markers; the significance of BNP levels for the diagnosis of HF is now well established, and BNP can also distinguish between patients with acute dyspnea of cardiac and non-cardiac cause(9). Various studies have assessed the prognostic value of the inactive amino-terminal fragment of BNP (NT-proBNP) in decompensated HF, which is released into the circulation in quantities equimolar to the active carboxy-terminal portion (BNP)(12). In one recently published study, NTproBNP levels in patients hospitalized for decompensated HF correlated with the risk for rehospitalization or death within six months of discharge, which highlights the value of this peptide as a prognostic marker in decompensated HF and its possible use in clinical practice(13). A study by von Haehling et al.(14) documented the prognostic value in CHF of midregional pro-atrial natriuretic peptide (MR-proANP) as determined by immunoassay, and showed that it correlated strongly with HF severity. The properties of BNP have been put to therapeutic use through the creation of a synthetic form by recombinant technology. Clinical trials of the resulting drug nesiritide have proved promising, with improvement in hemodynamic profile(9).

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de factores: diminuio da perfuso renal, aumento da actividade simptica renal e do sistema renina-angiotensina e diminuio da expresso e actividade dos receptores. A reteno hidrossalina resultante contribui para a progresso da sndrome(9). As caractersticas dos peptdeos natriurticos (activao precoce na IC e relao com a sua gravidade) fomentaram estudos no sentido de avaliar o seu valor como marcadores de diagnstico e prognstico da IC. Actualmente, est bem estabelecido o significado dos nveis de BNP para o diagnstico de IC. O BNP permite distinguir entre doentes com dispneia aguda de causa cardaca e no-cardaca(9). Diversos estudos avaliaram o valor pro gnstico da poro aminada, inactiva, do BNP (NT-proBNP), na IC descompensada, a qual libertada para a circulao de forma equimolar parte activa carboxilada (BNP)(12). Num estudo recentemente publicado, os valores de NT-proBNP em doentes internados por IC descompensada correlacionam-se com o risco de reinternamento ou morte nos seis meses aps a alta. Estes resultados realam o interesse deste peptdeo como factor de prognstico da IC descompensada e destacam a sua eventual aplicao na prtica clnica(13). Um estudo de von Haehling e col(14) documentou o papel do MR-proANP, determinado por imunoensaio, no prognstico da ICC. Os nveis dessa sequncia do precursor do ANP (pr-ANP) correlacionamse fortemente com a gravidade da IC. As propriedades do BNP foram aplicadas na teraputica atravs da criao, por tecnologia recombinante, da forma sinttica do BNP. Os estudos clnicos realizados com este frmaco nesiritide mostraram-se promissores dada a melhoria do perfil hemodinmico verificada(9). 1.2) Vasoconstrio O aumento da resistncia vascular perifrica aumenta a ps-carga, pelo que reduz o dbito cardaco e aumenta o consumo de energia pelo corao. A par disso, esta resposta vasoconstritora tambm reduz a perfuso renal e heptica, o que pode exacerbar a falncia destes rgos verificada nos estdios finais da IC. Na IC, o estmulo mais importante para a vasoconstrio a activao simptica, atravs da libertao de noradrenalina que actuar nos receptores -1 adrenrgicos do msculo liso arte

1.2) Vasoconstriction Greater peripheral vascular resistance increases afterload, reducing cardiac output and increasing the hearts energy consumption. At the same time, vasoconstriction reduces renal and hepatic perfusion, which exacerbates failure of these organs as seen in end-stage HF. In HF, the most important stimulus for vasoconstriction is sympathetic activation through release of norepinephrine, which acts on alpha-1 adrenergic receptors in arteriolar smooth muscle. The mediators and counter-regulators of this maladaptive response are discussed below. Renin-angiotensin system Renin, which is released by renal juxtaglomerular cells, is a protease that in the liver catalyzes hydrolysis of angiotensinogen (an inactive protein) into angiotensin I, an inactive precursor that is converted in the lungs by angiotensin-converting enzyme (ACE) into Ang II, a potent vasoconstrictor that is the most important biologically active element of the RAS. Traditionally, Ang II has been considered a systemic hormone that regulates blood pressure, aldosterone release and sodium reabsorption (a circulating RAS hormone, as described above). However, it is also produced locally in tissue, in the brain, the kidneys and the heart, where it acts at a paracrine and autocrine level. In this case, it appears to be involved in regulating cell proliferation and apoptosis, cell migration, inflammation, and synthesis and release of other mediators, such as platelet-derived growth factor PDGF and endothelin-1, and extracellular matrix formation(15). This local cardiac system of Ang II production is activated in HF. Curiously, systemic RAS activation occurs relatively late in the natural history of HF, mainly following diuretic therapy. Ang II has various regulatory effects through activation of multiple intracellular pathways following binding to different receptor subtypes, the most important being AT-1 and AT-2, which activate completely separate pathways within the cardiovascular system. AT-1 receptors, which predominate in the adult heart, mediate vasoconstriction, increased cardiac contractility, proliferation of myocardial and vascular fibrous tissue, cardiomyocyte hypertrophy, antinatriuresis, production of oxygen free

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riolar. A seguir sero explorados os mediadores vasoconstritores e os contrarreguladores dessa resposta desadaptativa. Sistema renina-angiotensina (SRA) A renina, libertada pelas clulas justa glomerulares renais, uma protease que catalisa, a nvel heptico, a hidrlise do angiotensinognio (uma protena inactiva) em angiotensina I, um percursor inactivo que, nos pulmes, convertido, pela enzima conversora da angiotensina (ECA) em Ang II, um potente vasoconstritor e o elemento com actividade biolgica mais relevante do SRA. Classicamente, a Ang II era considerada uma hormona sistmica reguladora da presso arterial, da libertao de aldosterona e da reabsoro de sdio (SRA clssico, circulante; descrito acima). Porm, este mediador tambm formado localmente, a nvel tecidular, no crebro, rim ou corao, onde actua de forma parcrina ou autcrina. A este nvel parece estar envolvida no controlo da proliferao celular e apoptose, da migrao celular, da inflamao, da sntese e libertao de outros mediadores (como o factor de crescimento derivado das plaquetas [PDGF] ou a endotelina-1) e da formao da matriz extracelular(15). Este sistema cardaco local de formao de Ang II activado na IC. Curiosamente, a activao do SRA sistmico ocorre relativamente tarde na histria natural da IC, sobretudo aps o incio da teraputica com diurticos. A Ang II exerce variados efeitos reguladores mediante a activao de mltiplas vias intracelulares, na sequncia da ligao a diferentes subtipos de receptores, sendo os mais importantes os AT-1 e AT-2 que, a nvel cardiovascular, sinalizam vias completamente distintas. Os receptores AT-1, predominantes no corao adulto, medeiam as seguintes aces da Ang II: vasoconstrio, aumento da contractilidade cardaca, proliferao do tecido fibroso miocrdico e vascular, hipertrofia dos cardiomicitos, efeito antinatriurtico, produo de radicais livres de oxignio e induo da infla mao e trombose. A activao dos receptores AT-2 tem efeitos opostos aos descritos para os AT-1, nomeadamente vasodilatao, inibio da sntese de colagnio, fibronectina e cnases proteicas activadas por mitognios(16). Os receptores AT-2 desempenham um papel primordial du

radicals, and induction of inflammation and thrombosis. Activation of AT-2 receptors has the opposite effects to those described for AT-1, notably vasodilation and inhibition of collagen, fibronectin and mitogen-activated protein kinase (MAPK)(16). AT-2 receptors play a central role in embryonic development, with elevated expression in fetal tissues, particularly mesenchyma, which then diminishes after birth. In adults with HF, there is a reduction in the density of AT-1 receptors in the heart, while expression of AT-2 receptors increases in parallel with progression of interstitial fibrosis, cardiac remodeling and rising intracardiac filling pressures(16,17). This is a further example of the reversion to fetal phenotype that accompanies the hypertrophic response in the adult heart. Although in general the effects of stimulation of AT-2 receptors are cardioprotective, some may be harmful, since they appear to be implicated in contractile dysfunction following cardiac ischemiare perfusion and in ventricular hypertrophy and remodeling(17). Ang II also appears to play a part in regulating other mediators in the hemodynamic defense reaction by stimulating the secretion of aldosterone, vasopressin, catecholamines and endothelin. This explains how it amplifies various pathways that are activated in HF, thus perpetuating and exacerbating the many vicious cycles of the syndrome. This interaction has a significant impact in clinical and therapeutic terms(1). Other enzymes besides ACE produce Ang II, notably chymase, cathepsin G and carboxypeptidase. In the human heart, around 90% of local Ang II formation is chymasedependent. Levels of this enzyme are higher in the ventricles, whereas the action of ACE is mainly in the atria, which suggests an uneven distribution of the two enzymes between the cardiac chambers. Although in physiological conditions chymase plays an important role in Ang II formation in tissue, the ACE pathway appears to be more important in HF. The vasodilator action of heptapeptide angiotensin-(1-7), Ang-(1-7), formed from Ang I or Ang II by various endopeptidases, appears to be direct or mediated by NO release or by increasing the vasodilator response of bradykinin(18). Research suggests that Ang-(1-7) has a cardioprotective role; when administered

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rante o desenvolvimento embrionrio, pois a sua expresso elevada nos tecidos fetais, especialmente nos mesenquimatosos, diminuindo aps o nascimento. No adulto com IC, ocorre uma reduo da densidade dos receptores AT-1 no corao, enquanto a expresso dos receptores AT-2 aumenta em paralelo com a progresso da fibrose intersticial, da remodelagem cardaca e da elevao das presses de enchimento intracardacas(16,17). Esta alterao, mais uma vez, exemplifica a reverso para o fentipo fetal que acompanha a resposta hipertrfica do corao adulto. Apesar dos efeitos da estimulao dos receptores AT-2 serem, geralmente, associados a aces cardioprotectoras, algumas das aces podem ser prejudiciais, pois parecem estar implicadas na disfuno contrctil aps a isquemia-reperfuso cardaca e na hipertrofia e remodelagem ventriculares(17). A Ang II tambm exerce um papel regulador sobre outros mediadores da reaco hemodinmica de defesa: estimula a secreo de aldosterona, vasopressina, catecolaminas e endotelina. Da decorre o seu efeito amplificador de diferentes vias activadas na IC, perpetuando e agravando muitos ciclos viciosos nessa sndrome. Esta interaco tem um impacto substancial em termos clnicos e teraputicos(1). Outras enzimas para alm da ECA podem formar Ang II, nomeadamente a qumase, a cate psina G e a carboxipeptidase. No corao humano, aproximadamente 90% da Ang II formada localmente dependente da aco da qumase. Os nveis dessa enzima so superiores nos ventrculos, enquanto a aco da ECA predomina nas aurculas, o que sugere uma assimetria da distribuio das duas enzimas entre as cmaras cardacas. Apesar de, fisiologicamente, a qumase ter um papel significativo na formao da Ang II nos tecidos, na IC a via da ECA tecidual parece ser mais importante. O heptapeptdeo angiotensina 1-7 (Ang 1-7), formado a partir da Ang I ou da Ang II por vrias endopeptidases, parece ter uma aco vasodilatadora directa ou mediada pela libertao de NO ou por um aumento da resposta vasodilatadora da bradicinina(18). Estudos rea lizados sugerem um papel cardioprotector da Ang 1-7: num modelo de IC isqumica em ratos demonstrou-se que a sua administrao preserva a funo cardaca, melhora a perfuso coronria e a funo do endotlio artico(19). Estes resultados

in an ischemic HF model in rats, it preserved cardiac function and improved coronary perfusion and endothelial function in the aorta(19). These results suggest that Ang-(1-7) may contribute to the therapeutic effect of ACE inhibitors (ACEIs) and AT-1 receptor blockers (ARBs) in HF(20). Clinical trials with ACEIs and ARBs have shown reduced morbidity and mortality in HF, as well as in hypertension and myocardial infarction(17), which reflects the central role of Ang II in HF. In animal models, ACEIs and ARBs prevent the development of cardiac hypertrophy, and in hypertensive patients they lead to its regression(21). The results of studies on ARBs have been less clear. The ELITE-II study(22) showed that losartan presented a similar benefit to captopril in HF patients. Subsequently, the OPTIMAAL trial reported that the incidence of death from cardiovascular cause was higher in the group treated with losartan than in those treated with captopril(22). More recently, the Valsartan in Acute Myocardial Infarction Trial (VALIANT) demonstrated that valsartan had similar efficacy to captopril when administered to high-risk patients with left ventricular dysfunction or HF immediately after myocardial infarction(23). Endothelin Endothelin is a potent vasoconstrictor polypeptide that affects cell growth and phenotype(24). It is synthesized in blood vessels and the myocardium by various cell types, including vascular endothelial cells, ventricular myocytes and fibroblasts. There are at least three endothelin isoforms (endothelin 1, 2 and 3), which act by activating two receptors (ETA and ETB) belonging to the superfamily of G protein-coupled receptors (GPCRs). Endothelin-1 (ET-1) appears to be the most important isoform in cardiovascular regulation. High plasma concentrations of ET-1 and its precursor proendothelin correlate negatively with HF prognosis(25). ET-1 synthesis is stimulated by Ang II, which enhances transcription of the preproendothelin-1 gene through binding to AT-1 receptors and activation of protein kinase C(17). ET-1 has a greater affinity for ETA receptors, which are found in vascular smooth muscle, where they mediate vasoconstriction, increase myocardial contractility, promote renal sodium retention, and stimulate aldosterone and

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sugerem uma possvel contribuio da Ang 1-7 para o efeito teraputico dos inibidores da ECA (IECA) e dos antagonistas dos receptores AT-1 (ARA) na IC(20). Os ensaios clnicos com os IECA e os ARA demonstraram uma melhoria da morbilidade e mortalidade na IC congestiva, bem como na hipertenso arterial e no enfarte agudo do miocrdio,(17) o que espelha o papel fulcral da Ang II na IC. Em modelos animais, os IECA e os ARA previnem o desenvolvimento de hipertrofia cardaca, e em doentes hipertensos promovem a sua regresso(21). Relativamente aos ARA, os resultados dos estudos no tm sido to consensuais. O estudo ELITE-II(22) mostrou que o ARA losartan apresentava um efeito benfico semelhante ao captopril em doentes com IC. Posteriormente, o estudo OPTIMAAL revelou que a incidncia de mortes cardiovasculares era mais elevada com o grupo tratado com losartan do que com o captopril(22). Mais recentemente, o estudo VALIANT (valsartan in acute myocardial infarction trial) demonstrou uma eficcia do valsartan semelhante do captopril, quando administrados a doentes de alto risco com disfuno ventricular esquerda ou IC no perodo imediato a um enfarte do miocrdio(23). Endotelina A endotelina um potente polipeptdeo vaso constritor com efeitos no crescimento e fentipo celulares(24). sintetizada nos vasos e no miocrdio por diferentes tipos celulares, incluindo clulas endoteliais vasculares, cardio micitos ventriculares e fibroblastos. H pelo menos trs isoformas de endotelina (endotelinas 1, 2 e 3), que actuam atravs da activao de dois receptores pertencentes superfamlia dos receptores acoplados a protenas G (ETA e ETB). A endotelina-1 (ET-1) parece ser a isoforma mais importante na regulao cardiovascular. A presena de concentraes plasmticas elevadas de ET-1 e do seu percursor, pr-endotelina, correlacionam-se negativamente com o prognstico da IC(25). A sntese de ET-1 estimulada pela Ang II, a qual aumenta a transcrio do gene da pr-pro-endotelina-1 atravs da sua ligao aos receptores AT-1 e da activao da protena cnase C (PKC)(17). A ET-1 tem maior afinidade para os receptores ETA, presentes no msculo liso vascular, os

catecholamine secretion. This receptor subtype thus undoubtedly contributes to progression of HF, as well as causing the clinical manifestations of the syndrome(26). Activation of ETA receptors in vitro stimulates cardiomyocyte hypertrophy and expression of the fetal phenotype. ET-1 also has important effects on extracellular matrix synthesis and degradation(24). It may have cardiotoxic and arrhythmogenic properties, and has been shown to be a potent indicator of cardiac cell death(27). ETB receptor activation induces vasodilation through release of NO and prostacyclin and inhibits growth. Recent functional studies suggest that there are two subtypes present in the heart: ETB1, found in endocardial endothelium, which promotes negative inotropism; and EBT2, found in the myocardium, which promotes positive inotropism(28). A study on rabbit papillary muscles showed that the negative inotropic and lusitropic effects mediated by ETB receptor stimulation require the presence of intact endothelium; they are enhanced by ETA receptor blockade and mediated by the release of NO and prostaglandins. There may be an interaction between the two types of ET-1 receptor. These findings could have important implications in HF(29). Apelin Apelin is a recently discovered vasoactive peptide identified as the endogenous ligand of the APJ receptor of the GPCR family. It is found in many tissues, including the heart, lungs, gastric mucosa, Kupffer cells in the liver, brain (neurones of the supraoptic and paraventricular nuclei), mammary glands, and the endothelium of small arteries of various organs and the coronary circulation(30,31). Despite this wide distribution, the cardio vascular system appears to be the main target of apelin activity. It induces increased inotropism, reduced afterload and peripheral vasodilation(32). As with other vasoactive peptides, apelin causes endothelium-dependent vasodilation through the release of substances such as NO, via endothelial NO synthase (eNOS)(33). At the same time, recent studies have demonstrated that apelin acts as a substrate for ACE2(34), and so ACE2 inhibition could be a potential therapeutic target by preventing degradation of an agent with the inotropic and vasodilator properties of apelin.

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quais medeiam vasoconstrio, aumento da contractilidade miocrdica, reteno renal de sdio, estimulao da secreo de aldosterona e catecolaminas. Esse tipo de receptores contribui assim, indubitavelmente, para a progresso da sndrome, para alm de condicionar as mani festaes clnicas da IC(26). In vitro, a activao dos receptores ETA estimula a hipertrofia dos cardiomicitos e a expresso do fentipo fetal. Tem igualmente efeitos proeminentes na sntese e degradao da matriz extracelular(24). A ET-1 tem, possivelmente, propriedades cardiotxicas e arritmognicas, tendo ainda sido demonstrado que representa um potente indicador de morte celular cardaca(27). Relativamente aos receptores ETB, a sua estimulao induz vasodilatao, mediante a libertao de xido ntrico (NO) e prostaciclina, e inibe o crescimento. Estudos funcionais recentes sugerem a existncia de dois sub-tipos a nvel cardaco: ETB1, de localizao endote lial endocrdica e promotores de inotropismo negativo; e ETB2 de localizao miocrdica e promotores de inotropismo positivo(28). Num estudo efectuado em msculos papilares de coelhos, demonstrou-se que os efeitos inotrpico e lusitrpico negativos induzidos pela activao dos receptores ETB dependem da integridade do endotlio, so potenciados pela inibio dos receptores ETA e mediados pela libertao de NO e prostaglandinas. Constatou-se uma possvel interaco dos dois tipos de receptores da ET-1. Tais resultados destacam-se pelas suas potenciais implicaes na IC(29). Apelina A apelina um peptdeo vasoactivo recentemente descoberto e identificado como o ligando endgeno do receptor APJ pertencente famlia de receptores acoplados protena G (GPCRs). Est presente em muitos tecidos, incluindo o corao, os pulmes, a mucosa gstrica, as clulas Kupffer do fgado, o crebro (neurnios dos ncleos supra-ptico e paraventricular), as glndulas mamrias, o endotlio de pequenas artrias de vrios rgos e da circulao coronria(30,31). Apesar da sua extensa distribuio, o sistema cardiovascular parece ser o alvo fulcral da aco da apelina. Induz aumento do inotropismo, redu o da ps-carga e vasodilatao perifrica(32). De destacar que a apelina, tal como outros

Reduced apelin/APJ expression and activity has been suggested as one possible mechanism in the pathophysiology of HF(35). Significant differences have been found in the expression of apelin and its receptor between healthy individuals and patients with CHF, in whom apelin levels increase in the early stages but return to baseline values in more advanced stages of the syndrome(31). This decrease may reflect endothelial dysfunction, which affects apelin production(36), or it may be a compensatory mechanism in response to pressure overload(32). Unlike in normal individuals, in whom apelin expression appears to be limited to the coronary circulation, in patients with advanced HF apelin is also found in cardiomyocytes, which suggests an autocrine mechanism in this pathology(31). Studies have shown the potential of apelin as a therapeutic target, the benefits of which would include reduced peripheral vascular resistance, improved contractility and increased diuresis. However, though these findings are promising, further studies are required before such results can be extrapolated to clinical practice. Nitric oxide Nitric oxide produced and/or released by cardiac vascular, myocardial or nerve cells has many effects on the cardiovascular system, both autocrine and paracrine, including modulation of systolic and diastolic function, heart rate and cardiac metabolism(37). The expression and activity of the NO system is altered in HF. This powerful vasodilator is synthesized through a catalytic reaction of NO synthases (NOS) that converts L-arginine into L-citrulline and nitric oxide. There are two NOS isoforms in the heart: constitutive (NOS-III or cNOS, which includes eNOS); and inducible (NOS-II or iNOS), which is pathological, induced by inflammatory mediators and produces large quantities of toxic NO. The effects of NO depend on its levels in the circulation. Low concentrations, the result of cNOS activation, cause a physiological vasodilator response but also regulate vascular permeability, platelet aggregation and oxidative phosphorylation. It has additional functions in cardiomyocytes and sinus node cells, activating phosphodiesterase inhibitors, which enhances the effects of sympathetic stimulation and produces a small positive inotropic effect(38).

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peptdeos vasoactivos, provoca vasodilatao dependente do endotlio atravs da libertao de substncias como o NO, via a NO-sntase endotelial (eNOS)(33). A par disso, estudos recentes demonstraram que a apelina funciona como substrato da ECA tipo 2(34), pelo que a inibio da ECA 2 se afigura como um potencial alvo teraputico, ao impedir a degradao de um agente com as propriedades da apelina. A diminuio da expresso e actividade do sistema apelina/APJ tem sido sugerida como um dos possveis mecanismos fisiopatolgicos da IC(35). Recentemente, verificaram-se diferenas significativas nos nveis de expresso da apelina e respectivo receptor entre indivduos saudveis e doentes com ICC, nos quais os nveis de apelina esto aumentados nas fases precoces, regressando aos valores basais nas fases mais avanadas da sndrome(31). Esta diminuio pode reflectir disfuno endotelial, o que afecta a produo de apelina(36), ou, poder significar um mecanismo compensatrio despertado por uma sobrecarga de presso(32). Contrariamente ao que ocorre em indivduos normais, nos quais a expresso de apelina parece restringir-se circulao coronria, em doentes com IC em fases avanadas, verifica-se igual mente a presena de apelina nos cardiomicitos, o que sugere uma via de actuao autcrina nesse contexto(31). Os estudos desenvolvidos revelam a potencial utilizao da apelina como alvo teraputico, cujos benefcios incluiriam a reduo das resistncias vasculares perifricas, a melhoria da contractilidade e o aumento da diurese. Todavia, ainda que promissores, tais resultados carecem de mais estudos, no sendo linear a extrapolao clnica. xido ntrico (NO) O NO produzido e/ou libertado nas clulas cardacas (vasculares, miocrdicas ou nervosas) exerce uma multiplicidade de efeitos, autcrinos ou parcrinos, no sistema cardiovascular: modula a funo sistlica e diastlica, a frequncia e o metabolismo cardacos(37). Na IC, a expresso e a actividade do sistema do NO encontram-se alterados. Este poderoso vasodilatador sintetizado atravs de uma reaco catalizada pelas NOsntases (NOS) que convertem a L-arginina em L-citrulina. No corao, esto presentes

Higher NO concentrations have different effects: reduced contractility, inhibition of the positive inotropic and chronotropic effects of sympathetic stimulation, increased renal sodium excretion and inhibition of cell proliferation(37). NO thus plays an active role in the pathophysiology of HF and affects the course of the syndrome. The reduced bioavailability of NO, resulting from lower eNOS synthesis, decreased availability and/or increased degradation of its substrate, contributes to the endothelial dysfunction that is characteristic of HF. It is not clear whether eNOS expression in HF is increased or decreased(37). A study by Heymes et al.(39) showed that, by optimizing systolic and diastolic function, NO was potentially beneficial in HF. An inverse relation was also found in HF patients between eNOS expression and severity of left ventricular dysfunction. In addition, in vivo studies have demonstrated that there may be advantages to a transient release of small quantities of NO by eNOS, reducing myocyte hypertrophy and cardiac chamber dilatation(37). Increased iNOS expression and activity in cardiac tissue has been demonstrated in HF patients(40). The resulting increase in NO production, which then reacts with oxygen free radicals to form peroxynitrite, may increase the harmful effects of NO in the myocardium, notably cell apoptosis, contractile dysfunction and impaired regulation of heart rhythm and rate(41). Peroxynitrite is a toxic species that has important effects on the cardiovascular system, causing apoptosis of cardiomyocytes, vascular endothelial cells and smooth muscle cells as a result of mitochondrial damage, activation of caspases, calcium dysregulation and energy depletion(42). In human models of HF, the ability of NO to decrease muscle tone is impaired(43), which appears to be due to a weakened vasodilator response to NO. Many therapeutic strategies used in HF are aimed at regulating the availability and release of NO, particularly NO donors, ACEIs, neutral endopeptidase inhibitors, calcium channel blockers and NO synthase inhibitors(37). Bradykinin Most of bradykinins cardiovascular actions are mediated by activation of the kinin B2

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duas isoformas de NOS: a constitutiva (cNOS, NOS3 ou eNOS); e a induzida pelos mediadores inflamatrios, patolgica (iNOS ou NOS2), que produz grandes quantidades de NO txico. Os efeitos do NO relacionam-se com os nveis presentes em circulao. Baixas concentraes de NO, formado pela activao da cNOS, condicionam uma resposta vasodilatadora fisio lgica, mas tambm regulam a permeabilidade vascular, a agregao plaquetria e a fosforilao oxidativa. Nos cardiomicitos e nas clulas nodais tem ainda funes adicionais: activao dos inibidores da fosfodiesterase, com consequente aumento dos efeitos da estimulao simptica e discreto efeito inotrpico positivo(38). Quando em concentraes mais elevadas, o NO pode ter aces distintas: reduo da contractilidade, inibio dos efeitos inotrpico e cronotrpico positivos da estimulao simptica, promoo da excreo renal de sdio e inibio da proliferao celular(37). O NO participa, efectivamente, na fisio patologia da IC, influenciando a evoluo desta sndrome. A reduo da biodisponibilidade do NO (consequncia da diminuio da sntese pela eNOS, da reduo da disponibilidade de substrato e/ou aumento da sua degradao) contribui para a disfuno endotelial tpica da IC. No consensual se a alterao da expresso de eNOS na IC no sentido do seu aumento ou diminuio(37). Um estudo desenvolvido por Heymes e col(39) demonstrou os potenciais efeitos benficos do NO na IC, optimizando as funes sistlica e diastlica. Foi igualmente constatada a relao inversa entre a intensidade da expresso de eNOS e a gravidade da disfuno ventricular esquerda em doentes com IC. Paralelamente, estudos in vivo revelaram as consequncias, possivelmente vantajosas, da libertao tran sitria de baixos nveis de NO pela eNOS: reduo da hipertrofia miocitria e da dilatao das cmaras cardacas(37). Comprovou-se o aumento da actividade/ expresso da iNOS no tecido cardaco de doentes com IC(40). O consequente aumento da produo de NO e posterior reaco com radicais livres de oxignio, resultando na gerao de peroxinitritos, pode aumentar os possveis efeitos deletrios do NO no miocrdio, nomeadamente a apoptose celular, a disfuno contrctil e a regulao anormal do ritmo e frequncia cardaca(41). Os

receptor, which results in a significant vasodilator response mediated by at least three enzymes: cNOS, phospholipase A2 and adenyl-cyclase. Like Ang I, bradykinin is a substrate for ACE, which hydrolyzes and inactivates it. Thus, ACEIs have a twofold effect in reducing arte riolar tone by simultaneously inhibiting Ang II production and bradykinin degradation. Unlike Ang II, bradykinin inhibits cell growth, and so ACEIs have synergistic effects in this respect(18). Stimulation of NO synthesis by bradykinin may contribute to the inflammatory response in HF, which is discussed below. Adrenomedullin Adrenomedullin is a vasodilator peptide, originally isolated from human pheochro mocytoma(44). However, its mRNA is expressed physiologically in different organs, including the adrenals, kidneys, heart and blood vessels(45). Expression of the gene coding for this extra cellular messenger is enhanced by inflammation, hypoxia, oxidative and mechanical stress, and activation of the RAS and sympathetic nervous system. Systemic administration of adrenomedullin increases cardiac output in both healthy individuals and HF patients(46); this may be mediated primarily by dilation of the coronary arteries and reduced afterload(47). At the same time, it lowers pulmonary wedge pressure, with limited effect on heart rate, and increases urine output and urinary sodium excretion. It has other beneficial effects, including stimulation of NO production and inhibition of apoptosis(46). Some studies appears to show that adrenomedullin has a positive inotropic effect through increased levels of cAMP and activation of protein kinase A(48), but such a direct inotropic effect remains controversial and has not been corroborated by other studies. Plasma adrenomedullin is elevated in various pathological conditions, particularly hypertension, renal insufficiency and HF(49). In the latter, the increase is proportional to disease severity and is an independent predictor of mild to moderate HF(50). In studies on animal models, chronic administration of adrenomedullin slows pro gression of cardiac dysfunction and improves the prognosis of CHF in rats(51). Recent studies, also

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peroxinitritos so espcies txicas com efeitos relevantes no aparelho cardiovascular, incluindo a apoptose dos cardiomicitos, do endotlio vascular e das clulas musculares lisas, como consequncia da leso mitocondrial, da activao de caspases, da desregulao do clcio e do colapso energtico(42). Em modelos humanos de IC, a capacidade do NO promover a diminuio do tnus muscular est perturbada(43). Este efeito parece dever-se atenuao da resposta vasodilatadora ao NO. Muitas das estratgias teraputicas utilizadas na IC regulam a disponibilidade e libertao do NO. Destacam-se os dadores de NO, os IECAs, os inibidores das endopeptidases neutrais, os inibidores dos canais de clcio e os inibidores das sntases do NO(37). Bradicinina A maioria das aces cardiovasculares da bradicinina so mediadas pela activao do receptor B2 das cininas. A resposta resultante um considervel efeito vasodilatador mediado por pelo menos trs enzimas: NOSc, fosfolpase A2 e adenilcclase. A bradicinina um substrato para a ECA, tal como a angiotensina I, sendo hidrolisada e inactivada pela enzima. Desse modo, os IECAs tm um duplo efeito na reduo do tnus arteriolar: inibem simultaneamente a produo de Ang II e a degradao da bradicinina. Contrariamente Ang II, a bradicinina um inibidor do crescimento celular, pelo que os IECA apresentam efeitos sinrgicos a esse nvel(18). A estimulao da sntese de NO pela bra dicinina pode participar na resposta inflamatria da IC, exposta seguidamente neste trabalho. Adrenomedulina A adrenomedulina um peptdeo vasodilatador, originalmente isolado de feocromocitomas hu manos(44). Contudo, o seu RNAm expresso, fisiologicamente, em diferentes rgos: supra-renal, rins, corao e vasos sanguneos(45). A expresso do gene que codifica este mensageiro extracelular estimulada pela inflamao, hi pxia, stress oxidativo, stress mecnico, activao do SRA e do sistema nervoso simptico. A administrao sistmica de adrenomedu lina aumenta o dbito cardaco quer em indivduos saudveis quer nos doentes com IC(46). Possivelmente, esse aumento do dbito

in animals, have shown that adrenomedullin is involved in the pathophysiology of the transition from left ventricular hypertrophy to HF(52). Experimental and clinical studies indicate that systemic administration of adrenomedullin is promising as a treatment for acute HF, while pharmacological blockade of adrenomedullin catabolism may be a possible treatment strategy for chronic HF(47). Prostaglandins This family of polyunsaturated fatty acid derivatives, produced by membrane-associated cyclooxygenases, includes several members that have neurohumoral effects in HF, acting locally in a paracrine or autocrine manner. Some prostaglandins induce vasodilation, notably prostacyclin (PGI2) and prostaglandin E2 (PGE2), playing a counter-regulatory role in HF, while others induce vasoconstriction, such as thromboxane A2 (TxA2)(53). Prostaglandins also mediate the vasodilator effect of bradykinin and perhaps of other vasodilators used in HF such as nitrates and furosemide (with a rapid effect when administered intravenously). Cyclooxygenase induction may also play an active role in triggering the inflammatory response in HF(54), discussed below. 1.3) Increased cardiac stimulation Stimulation of the inotropic, chronotropic and lusitropic responses of the heart results in increased cardiac output and end-diastolic volume, and decreases end-systolic volume. When this response is sustained, it becomes harmful to the failing heart. Activation of the sympathetic nervous system plays a fundamental role in the hemodynamic defense reaction and is the main mechanism involved in cardiac stimulation. The regulatory and counter-regulatory effects of this stimulation are described below. Sympathetic nervous system Sympathetic activation is probably one of the first mechanisms of the hemodynamic defense reaction to be triggered, often occurring in patients with moderate left ventricular dysfunction. In HF, various mechanisms contribute to activation of the sympathetic system, the most important being the response of baroreceptors to falls in blood pressure. Metabolic changes,

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cardaco mediado primariamente pela dilatao das artrias coronrias e diminuio da ps-carga(47). A par disso, condiciona tambm uma reduo da presso de encravamento pulmonar, com reduzido efeito na frequncia cardaca, bem como aumento no volume de urina e da excreo urinria de sdio. Exerce ainda outros efeitos benficos, incluindo a estimulao da produo de NO e a inibio da apoptose(46). H estudos que atribuem adrenomedulina um efeito inotrpico positivo atravs do aumento do AMPc e da activao da protena cnase A(48). Contudo, este efeito inotrpico directo ainda permanece controverso, no sendo corroborado por outros estudos. Os nveis plasmticos de adrenomedulina esto aumentados em diferentes situaes pato lgicas, nomeadamente na hipertenso arterial, insuficincia renal e IC(49). Na IC, esse aumento proporcional gravidade da sndrome e constitui um indicador de prognstico independente de IC ligeira a moderada(50). Em estudos com modelos animais, a infuso crnica de adrenomedulina atenua a progresso da disfuno cardaca e melhora o prognstico da ICC em ratos(51). Estudos recentes, tambm em animais, revelaram que a adrenomedulina participa na fisiopatologia da transio da hipertrofia ventricular esquerda para a IC(52). Estudos experimentais e clnicos demonstram que a administrao sistmica de adrenome dulina deve ser uma teraputica promissora no tratamento da IC na fase aguda, enquanto que o bloqueio farmacolgico do catabolismo da adrenomedulina poder ser uma possvel estratgia para o tratamento crnico da IC(47). Prostaglandinas Esta famlia de derivados polinsaturados de cidos gordos, formados por ciclo-oxignases associadas membrana, engloba vrios membros, alguns dos quais exercem aces neurohumorais na IC, actuando localmente, de forma parcrina ou autcrina. Algumas prostaglandinas tm efeitos vaso di latadores, nomeadamente a prostaciclina (PGI2) e a prostaglandina E2 (PGE2), desempenhando um papel contrarregulador na IC; enquanto outras exercem efeitos vasoconstritores, como o tromboxano A2 (TxA2)(53). As prostaglandinas medeiam o efeito vasodilatador da bradicinina e possivelmente de outros vasodilatadores usados

particularly hypoxia, hypercapnia and acidosis, also lead to sympathetic activation mediated by arterial chemoreceptors. This results in raised plasma catecholamines (particularly norepi nephrine), mainly due to enhanced release from peripheral nerve endings, while only a small proportion of circulating norepinephrine originates in the heart(55). Plasma norepinephrine is the most thoroughly studied biochemical marker in patients with CHF. The receptors that mediate the cellular actions of norepinephrine belong to two major types: alpha-adrenergic receptors, which are responsible for the vasoconstrictor effects of sympathetic stimulation; and beta-adrenergic receptors, which induce vasodilation and cardiac stimulation. Alpha-1 receptors are found in vascular smooth muscle and in the heart. Their principal action in HF is to increase peripheral vascular resistance and promote fluid retention by the kidneys. Alpha-2 receptors are found mainly in vasomotor centers in the brainstem, where they inhibit sympathetic activity and thus play a counter-regulatory role. The most important receptor subtype in the heart is the beta-1 adrenergic receptor, which normally accounts for 70-80% of the total. In HF, chronic sympathetic stimulation is accompanied by depletion of myocardial norepinephrine, desensitization (tachyphylaxis) and reduced expression and activity of beta-1 adrenergic receptors(56). Various mechanisms contribute to the latter effect, including decreased synthesis, inactivation by phosphorylation, and internalization and proteolytic breakdown of phosphorylated receptors(1). Also involved in the desensitization of beta-adrenergic receptors are cytokines, which uncouple adenyl-cyclase receptors(57), and an intracellular protein, betaadrenergic receptor kinase. Together, these mechanisms help protect the failing heart from the adverse effects of sustained sympathetic stimulation, which is confirmed by the improved prognosis of HF patients medicated with beta-blockers(58). In a study assessing a large number of variables as potential prognostic indicators in HF, plasma norepinephrine was the only independent predictor of mortality in patients with moderate to severe congestive heart failure(59).

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na IC, como os nitratos e a furosemida (efeito precoce, com a administrao endovenosa). A induo das ciclo-oxignases pode ainda ter um papel activo no desenvolvimento da resposta inflamatria na IC(54), descrita mais frente neste trabalho. 1.3) Aumento da estimulao cardaca A estimulao das propriedades inotrpica, cronotrpica e lusitrpica do corao resulta em aumento do dbito cardaco e do volume telediastlico, com diminuio do volume telessistlico. Essa resposta, quando sustentada, torna-se nociva para o corao insuficiente. A activao do sistema nervoso simptico ocupa um papel primordial na resposta hemo dinmica de defesa e constitui o mecanismo que mais contribui para a estimulao car daca. Seguidamente so expostos os efeitos reguladores e contrarreguladores dessa estimulao. Sistema simptico A activao simptica, provavelmente, dos primeiros mecanismos da resposta hemodinmica de defesa a ser mobilizado, ocorrendo frequentemente em doentes com disfuno ventricular esquerda moderada. Na IC, vrios mecanismos contribuem para a activao do sistema nervoso simptico, o mais importante dos quais a resposta dos barorreceptores diminuio da presso arterial. As alteraes metablicas (sobretudo a hipxia, a hipercapnia e a acidose), tambm resultam em activao simptica mediada pelos quimiorreceptores arteriais. Dessa activao advm aumento das catecolaminas plasmticas (sobretudo noradrenalina) devido, principalmente, libertao excessiva ao nvel das terminaes nervosas perifricas, enquanto que apenas uma pequena proporo da noradrenalina circulante se origina no corao(55). A noradrenalina plasmtica o marcador bioqumico mais estudado em doentes com ICC. Os receptores que medeiam as aces celu lares da noradrenalina pertencem a dois grandes tipos: receptores -adrenrgicos, responsveis pelos efeitos vasoconstritores da estimulao simptica, e receptores -adrenrgicos, que causam vasodilatao e estimulao cardaca. Os 1-receptores localizam-se no ms culo liso vascular e tambm no corao. O

Parasympathetic nervous system It has recently become clear that autonomic nervous system dysfunction and immune activation are involved in the pathophysiology of CHF(60). These systems have traditionally been considered separately, but some authors have suggested an interaction between them. Jankowska et al.(61) formed the hypothesis that damage to cardiac muscle, resulting from ischemia or other pathological processes, triggers a reflex response that is transmitted by autonomic afferents to the central nervous system, which then induces structural and functional alterations, some of which are linked to inflammatory processes (Fig. 1). Dysfunction of autonomic centers results in reduced central parasympathetic tone, while diminished cho linergic (predominantly nicotinergic) signaling triggers generalized inflammation and stimulates an immune response. These two phenomena influence prognosis and are potential therapeutic targets in CHF. Depressed parasympathetic tone leads to inhibition of NO synthesis, endothelial dysfunction, vasoconstriction (in both systemic and coronary circulation) and increased oxidative stress(62). This dysregulation of the immune system will be discussed below. Renal dopaminergic system Dopamine has been recognized as one of the counter-regulatory mechanisms activated in HF since 1987, following demonstration of its natriuretic, diuretic and vasodilator effects(63). Renal dopamine is produced in epithelial cells of the proximal convoluted tubule from L-dihydroxyphenylalanine (L-dopa) by aromatic acid decarboxylase. Its natriuretic effect is produced through activation of specific receptors (DA1) found in different regions of the nephron, resulting in inhibition of ATPase Na+/K+ in the basolateral membrane and of the Na+/H+ exchanger in the apical membrane. Increased renal utilization of L-dopa has been demonstrated in HF patients, suggesting enhanced activation of the renal dopaminergic system as a compensatory response to stimulation, which results in increased water and salt reabsorption(64).
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LESO DO MIOCRDIO / MYOCARDIAL DAMAGE
via fibras autnomas / via autonomic fibers

SISTEMA NERVOSO CENTRAL / CENTRAL NERVOUS SYSTEM (ex: neuroinflamao microglial / (e.g. microglial inflammation)

TNUS PARASSIMPTICO PARASYMPATHETIC TONE

TNUS SIMPTICO SYMPATHETIC TONE

INFLAMAO E ACTIVAO IMUNE RESISTNCIA INSULINA VASOCONSTRIO PERIFRICA INFLAMMATION AND IMMUNE ACTIVATION INSULIN RESISTANCE PERIPHERAL VASOCONSTRICTION

Maioria dos tecidos corporais Most body tissues

Tecido adiposo / Adipose tissue Intestino / Intestine Pulmo / Lung

Fgado / Liver Gnadas / Gonads Suprarrenais / Adrenals

Msculo esqueltico Skeletal muscle

Desregulao do reflexo do controlo cardiorespiratrio Dysregulation of reflex cardiorespiratory control

Figura 1. O desequilbrio autonmico e a activao imune na insuficincia cardaca crnica- hipottico mecanismo explicativo. (Adaptado de Jankowska EA, 2006 (61)) Figure 1. Hypothetical mechanisms of autonomic imbalance and immune activation in chronic heart failure. (Adapted from (61))

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seu principal papel na IC o aumento da resistncia vascular perifrica e a promoo da reteno de fluidos pelo rim. Os 2-receptores localizam-se predominantemente nos centros vasomotores a nvel do tronco cerebral, onde inibem a actividade simptica, desempenhando um papel contrarregulador. O subtipo de receptor de maior relevo no corao o receptor 1-adrenrgico (normalmente corresponde a 70-80% dos receptores). Na IC, a estimulao simptica crnica acompanhada por depleo da noradrenalina miocrdica, dessensibilizao (taquifilaxia) e diminuio da expresso e actividade dos re ceptores 1-adrenrgicos(56). Para esse efeito contribuem diferentes mecanismos: diminuio da sntese dos -receptores, inactivao dos mesmos por fosforilao, internalizao e digesto proteoltica dos receptores fosforilados(1). Para a dessensibilizao dos receptores -adrenrgicos tambm contribui a aco das citocinas, por desligarem os receptores da adenilcclase(57), e de uma protena intracelular designada por ARK.

2) Inflammatory Response One of the characteristics of CHF is activation of the immune system with increased expression of pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-), interleukin (IL)-1, IL-6 and soluble CD14, both systemically(65) and locally in the myocardium(66). Activation of complement factors such as C5b-9 has also been implicated in the pathophysiology of HF(67). Nishimuras group(68) has shown that levels of IL-13, a profibrotic cytokine typically activated in allergic reactions, are also elevated in HF, correlating positively with plasma BNP and C-reactive protein (CRP) and negatively with left ventricular ejection fraction. Two mechanisms are involved in immune activation in CHF: direct antigenic stimulation, as occurs in acute myocarditis and the reaction to heart transplantation; and activation secondary to cardiac injury that exposes new antigens which trigger an immune response against the heart, as occurs following myocardial infarction(69). Pro-inflammatory cytokines have an adverse impact on left ventricular function: they have

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Em conjunto, estes mecanismos ajudam a proteger o corao insuficiente dos efeitos adversos da estimulao simptica sustentada. Esse efeito comprovado pela melhoria do prognstico nos doentes com IC medicados com bloqueadores -adrenrgicos(58). Num estudo que avaliou inmeras variveis como potenciais indicadores de prognstico na IC, a noradrenalina plasmtica foi o nico preditor independente de mortalidade entre doentes com ICC moderada a grave(59). Sistema parassimptico Recentemente, tornou-se evidente que a disfuno do sistema nervoso autnomo e a activao do sistema imune participam na fisiopatologia da ICC(60). Tradicionalmente, esses sistemas so considerados separadamente, contudo h autores como Jankowsha e col.(61) que sugerem uma interaco entre eles (Fig. 1). Formulam a hiptese de uma leso do msculo cardaco (quer seja resultante de isquemia ou de outros processos patolgicos) accionar uma resposta nervosa reflexa transmitida, atravs de aferentes autonmicos, ao Sistema Nervoso Central, onde condiciona alteraes estruturais e funcionais, em parte relacionadas com processos inflamatrios. A disfuno dos centros autonmicos expressa como reduo do tnus parassimptico central. A diminuio da sinalizao colinrgica (predominantemente nicotinrgica) activa a inflamao generalizada e estimula a resposta imune. Estes dois fenmenos fundamentais predizem o prognstico e podem representar um alvo teraputico na ICC. A depleo do tnus parassimptico resulta em inibio da sntese de NO, disfuno endotelial, vasoconstrio (demonstrada quer na circulao sistmica quer na coronria) e aumento do stress oxidativo(62). Adiante ser explanada a desregulao imune aqui referida. Sistema dopaminrgico renal Desde 1987, a dopamina tem sido includa nos mecanismos contrarreguladores activados na IC, com efeitos natriurtico, diurtico e vasodilatador(63). A dopamina de origem renal sintetizada pelas clulas epiteliais dos tbulos contornados proximais, a partir da L-dihidroxifenilalanina (L-DOPA) atravs da enzima descarboxilase

a negative inotropic effect(70), induce changes in cardiac metabolism and promote ventricular remodeling(60), resulting in cardiomyocyte hyper trophy, necrosis, apoptosis and alterations in the extracellular matrix of the myocardium (see below). Cytokines also contribute to cachexia, frequently found in patients with advanced HF, and to skeletal muscle myopathy(1). Changes in cardiac mechanical function modulated by pro-inflammatory cytokines appear in two stages. The early stage is characterized by rapid activation of cellular signaling mechanisms, which are extensively interrelated and involve sphingolipids, phospholipids, eNOS and NOdependent pathways. The result can be cardiac stimulation or depression, depending mainly on oxidative and metabolic states, the strength of extracardiac adaptive responses, and synergistic and/or counter-regulatory effects of the different cytokines involved. This initial response is followed by a long-term response marked by impaired contractility(71). Elevated levels of pro-inflammatory cytokines and their receptors are strong predictors of increased mortality in CHF patients, inde pendently of conventional prognostic markers(72). One study has shown that CRP can be used as an alternative marker to IL-6 and complement activation in moderate CHF, providing additional prognostic information, particularly in patients with high BNP levels(73). Furthermore, high levels of cytokines can be detected in the early stages of HF, even before neurohumoral activation(74). A recently published study has reported a promising new predictor of prognosis in HF, pentraxin 3 (PTX3). A member of the pentraxin superfamily, this compound, produced by endothelial cells, smooth muscle and macrophages, is a new marker for vascular inflammation. PTX3 levels are increased in HF patients, in proportion to worsening New York Heart Association (NYHA) functional class, and patients with abnormally elevated plasma PTX3 present more cardiac events than those with normal levels. PTX3 measurement provides independent diagnostic and prognostic information and is more sensitive than CRP(75). Interestingly, some of the biological actions of pro-inflammatory cytokines appear to protect the cardiovascular system. Activation of the IL-6/gp130 signaling pathway helps to maintain myocardial homeostasis by inhibiting

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dos cidos aromticos. A dopamina exerce efeito natriurtico pela activao dos receptores especficos (DA1) localizados em diferentes regies do nefrnio e consequente inibio da ATPase Na+/K+ da membrana basolateral e do trocador Na+/H+ da membrana apical. Recentemente, demonstrou-se que, em doentes com IC, h aumento da utilizao renal de L-DOPA sugerindo um aumento da activao do sistema dopaminrgico renal como resposta compensatria ao estmulo que condiciona aumento da reabsoro de sdio e gua(64). 2) Resposta inflamatria Uma das caractersticas da ICC a activao do sistema imunolgico com aumento da expresso das citocinas pr-inflamatrias, nomea damente do factor de necrose tumoral (TNF-), da interleucina 1 (IL-1), da interleucina 6 (IL-6) e do CD14 solvel, quer sistmica(65), quer localmente no miocrdio(66). A activao de factores do complemento, como o C5b-9, tambm tem sido implicada na fisiopatologia da IC(67). O grupo de Nishimura mostrou que os nveis de IL-13, uma citocina pr-fibrtica e tipicamente activada nas reaces alrgicas, tambm se encontram elevados na IC, correlacionando-se positivamente com os nveis plasmticos de BNP e de protena C reactiva (PCR) e negativamente com a fraco de ejeco ventricular esquerda(68). A activao imune na ICC inclui dois mecanismos: estimulao antignica directa, como ocorre na miocardite aguda e na reaco ao transplante cardaco; e activao secundria leso cardaca que expe novos antgenos capazes de despertar uma resposta imunolgica contra o corao, como a que ocorre aps um enfarte agudo do miocrdio(69). As citocinas pr-inflamatrias afectam nega tivamente a funo ventricular esquerda, exercem um efeito inotrpico negativo(70), induzem alteraes no metabolismo cardaco e promovem a remodelagem ventricular(60), resultando em hipertrofia dos cardiomicitos, necrose, apoptose e alteraes na matriz extracelular do miocrdio (ver adiante). As citocinas contribuem tambm para a caquexia, frequente em indivduos com IC avanada, e para a miopatia dos msculos esquelticos(1). A funo cardaca mecnica alterada pelas citocinas pr-inflamatrias de uma forma bifsica, dependente do tempo. A fase precoce

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doxorubicin-induced cardiomyocyte apoptosis and caspase-3 activity and preventing pro gression of cardiac hypertrophy to HF in the early stages of pressure overload(76). It is still not clear what triggers immune activation, although various hypotheses have been put forward in a series of studies. Some authors believe ischemic or overloaded myocardium to be the main source of cytokines(66). It is now known that virtually all types of nucleated cells in the myocardium, including cardiomyocytes, secrete pro-inflammatory cytokines in response to different forms of stress or injury(77). However, other studies point to circulating immune cells as the primary source. Niebauer et al.(78) suggested that the circulatory decompensation of HF results in increased translocation of bacteria and endotoxins, particularly lipopolysaccharides (LPS), from edematous or poorly perfused intestinal mucosa to the systemic circulation. LPS are a strong stimulus for cytokine production through their interaction with CD14 receptors of the monocyte-macrophage system, triggering a positive feedback mechanism(57). Another mechanism recently proposed to account for the inflammatory response in HF is central suppression of the parasympathetic nervous system, as described above(61). The harmful effects of cytokines have aroused interest in developing anticytokine therapies, including pentoxifylline (which suppresses TNF- synthesis), etanercept (a soluble receptor that inactivates TNF-) and infliximab (a TNF- specific antibody). However, clinical trials have failed to demonstrate that they are sufficiently efficacious to be introduced into clinical practice(26,57). Recent evidence also attributes a role in the development of HF to advanced glycation endproducts (AGEs). AGEs are molecules formed during a non-enzymatic reaction between proteins and sugar residues, called the Maillard reaction, the final stage of which involves reactive oxygen species. AGEs accumulate in the body with age, more rapidly in patients with diabetes. These compounds are thought to contribute to HF, and not only in diabetic patients, in two ways: they affect the physiological properties of extracellular matrix proteins; and they cause numerous vascular and myocardial changes through their interaction with AGE receptors. Their possible contribution to systolic, diastolic

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caracteriza-se pela rpida activao dos mecanismos de sinalizao celular, amplamente interrelacionados, e que envolvem esfingolpidos, fosfolpidos, eNOS e vias dependentes do NO. A resposta pode ser cardioestimuladora ou depressora, dependendo, em particular, do estado oxidativo e metablico, da magnitude das respostas adaptativas extra-cardacas e dos efeitos sinrgicos e/ou contrarreguladores das vrias citocinas em aco. Esta resposta inicial seguida por outra mais prolongada, marcada por uma depresso da contractilidade(71). A elevao dos nveis das citocinas pr-inflamatrias e respectivos receptores so fortes indicadores de aumento da mortalidade em doentes com ICC, independentemente dos marcadores de prognstico convencionais(72). Um estudo mostrou que a PCR pode ser usada como marcador alternativo da activao da IL-6 e do complemento, na ICC moderada. A quantificao da PCR fornece informao adicional sobre o prognstico, especialmente em doentes com nveis elevados de BNP(73). Alm disso, os nveis elevados de citocinas so detectados em estdios precoces da IC, mesmo antes da activao neurohumoral(74). Um trabalho recentemente publicado des vendou um promissor marcador de prognstico na IC: a pentraxina 3 (PTX3). Esse composto, produzido pelas clulas endoteliais, msculo liso e macrfagos, representa uma das superfamlias de pentraxinas e constitui um novo indicador de inflamao vascular. Os nveis de PTX3 encontram-se aumentados em doentes com IC, em consonncia com o agravamento da classe funcional NYHA (New York Heart Association). Os doentes com nveis plasmticos anormalmente elevados de PTX3 apresentam mais eventos cardacos do que aqueles com nveis normais. A PTX3 fornece informao diagnstica e prognstica de uma forma independente e mais sensvel do que a PCR(75). Curiosamente, algumas das aces biolgicas das citocinas pr-inflamatrias parecem ser protectoras para o sistema cardiovascular. A activao da via de sinalizao IL-6-gp130 deve contribuir para a manuteno da homeostasia miocrdica: inibe a apoptose dos cardiomicitos induzida pela doxorrubicina, inibe a caspase-3 e previne a progresso da hipertrofia cardaca para IC em estdios iniciais de sobrecarga de presso(76).

and vascular dysfunction makes AGEs a new and interesting therapeutic target in CHF. Drugs that degrade AGEs, such as ALT-711 (alagebrium), are currently under investigation(79). 3) Hypertrophic response and ventricular remodeling As explained above, biochemical stress and extracellular mediators of the neurohumoral response, together with the action of growth factors and cell adhesion molecules, promote ventricular hypertrophy. This response, initially adaptive, is an attempt to compensate for pressure and/or volume overload and is thus a consequence of HF, but later it actually contributes to progression of the disease and so is simultaneously a pathophysiological mechanism of HF. Biomechanical stress is transmitted through the cytoplasmic membrane of cardiomyocytes by mechanisms that have yet to be fully determined. Stretch-activated ion channels, integrins and other structural proteins may be involved in this process, together establishing a link between the extracellular matrix, the cytoskeleton, the sarcomere, proteins involved in calcium homeostasis and the nucleus(80). In cardiomyocytes, biomechanical stress such as that caused by chronic hypertension and pressure overload, activates multiple signaling pathways that act together to promote hypertrophy and apoptosis (Fig. 2). This induces the synthesis and secretion of potent growth factors, such as ET-1, insulin-like growth factor I (IGF-1) and Ang II. Mechanical stretch can activate Ang II receptors directly in cardiomyocytes, in the absence of Ang II(91). At the same time, biomechanical stress leads to induction of gp130-dependent ligands such as cardiotrophin 1. This cytokine, of the IL-6 family, binds to its receptor, the heterodimer gp130-LIF (leukemia inhibitory factor), which activates pathways that inhibit apoptosis. In the absence of gp130, the response of cardiomyocytes to biomechanical stress leads to apoptosis, with loss of functional cells and onset of HF(81). At the cellular level, biomechanical stress triggers various processes that lead to different patterns of hypertrophy. In the pressureoverloaded heart, new contractile-protein units are assembled in parallel, resulting in an increase in the width of individual myocytes and

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A origem da activao imunolgica per manece incerta, porm vrias hipteses tm sido formuladas na sequncia de uma srie de trabalhos. H autores que atribuem ao miocrdio isqumico ou em sobrecarga a principal fonte de citocinas(66). Alis, sabe-se actualmente que virtualmente todos os tipos de clulas ncleadas do miocrdio, incluindo os cardiomicitos, podem segregar citocinas pr-inflamatrias em resposta a vrias formas de stress e leso(77). Porm, h estudos que apontam as clulas imunes circu lantes como fonte primordial dessa libertao. Niebauer e col.(78) propuseram a hiptese de que a descompensao circulatria na IC resultaria num aumento da translocao bacteriana ou de endotoxinas (lipopolissacardeos, LPS), atravs de uma mucosa intestinal edemaciada e mal perfundida, para a circulao sistmica. Os LPS, interagindo com os receptores CD14 do sistema monocitomacrofgico, constituiriam um forte estmulo para a produo de citocinas, iniciando-se um mecanismo de retroaco positiva(57). Mais recentemente, foi proposto outro mecanismo accionador da resposta inflamatria na IC: a supresso central do sistema nervoso parassimptico, j mencionado anteriormente(61). Os efeitos prejudiciais das citocinas suscitaram interesse no desenvolvimento de intervenes teraputicas anti-citocinas, das quais de destacam a pentoxifilina (suprime a sntese de TNF-), o etanercept (receptor solvel do TNF- que promove a sua inactivao) e o infliximab (anticorpo especfico contra o TNF-). Porm, os ensaios clnicos realizados no demonstraram inequivocamente eficcia que permita introduzi-los na prtica clnica(26,57). A evidncia actual atribui tambm aos produtos finais de glicosilao avanada (AGEs) um papel no desenvolvimento da IC. Os AGEs so molculas formadas durante reaces no-enzimticas entre protenas e resduos de acares. a designada reaco de Maillard, na qual participam espcies reactivas de oxignio, na sua etapa final. Os AGEs vo-se acumulando no organismo com o decorrer da idade e de uma forma mais acentuada caso o doente apresente diabetes mellitus. Esses compostos devem contribuir para a IC, sem se restringir aos doentes diabticos, de duas formas: afectam as propriedades fisiolgicas das protenas da matriz extracelular; e causam mltiplas alteraes vasculares e miocrdicas, atravs da interaco

hence concentric hypertrophy, with a reduction in ventricular chamber volume. By contrast, the addition of new contractile-protein units in series leads to the eccentric hypertrophy that occurs in patients with volume overload, with a greater increase in myocyte length than in width(81). Hypertrophy is thus induced by various mechanisms, including rises in intracellular calcium (one of the first events to occur(82)) and cell activation induced by factors such as TGF-, ET-1, catecholamines and Ang II(83). Some of the early and late phenomena associated with Ang II through AT-1 receptor activation that are implicated in cardiac hypertrophy are now discussed. Early in the process, Ang II activates three members of the MAPK family: ERKs, JNK and p38(84). MAPK-dependent signaling pathways increase the expression of various immediate-early proto-oncogenes such as c-fos, c-myc and c-jun, which are involved in cell proliferation, differentiation and transformation as well as in apoptosis, and hence play a part in the pathophysiology of HF(17). In the long term, Ang II affects the chronic adaptations involved in vascular remodeling through sustained activation of MAPK, which phosphorylate targets involved in the production of growth factors and oxygen free radicals(15). Ang II also plays an important role in activating the predominant TGF- isoform in the cardiovascular system (TGF-1)(85). Gupta et al.(86) demonstrated the central role of activation of the nuclear factor (NF)B signaling cascade (involved in cell growth, fibrosis or apoptosis, depending on the context(87)) in triggering cardiac hypertrophy and subsequent progression to HF. They developed an animal model of transgenic mice (Myo-Tg) with enhanced expression of myotrophin (a factor isolated in human hypertrophied hearts that stimulates cardiomyocyte protein synthesis, thus inducing myocardial growth(88)) specifically in the heart, in order to induce hypertrophy and progression to HF. This led to new experiments aimed at exploring the effects of NF-B inhibition by direct genetic intervention via a vector, which resulted in regression of cardiac hypertrophy. Such molecular studies provide further evidence of the importance of NF-B in the pathogenesis of HF, and indicate a possible therapeutic target. Curiously, one of the intracellular signaling pathways of AT-1 and AT-2 receptors (common

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Figure 2. Signaling pathways involved in hypertrophy and apoptosis during the progression from cardiac hypertrophy to heart failure in response to biomechanical stress. (Adapted from (81))

com receptores de AGE. A sua possvel con tribuio para a disfuno sistlica, diastlica e vascular, torna os AGEs um novo e interessante alvo no tratamento da ICC. Em particular, o desenvolvimento de frmacos que degradam os AGEs, como o ALT-711 (Alagebrium), ainda se encontra em investigao(79). 3) A resposta hipertrfica e a remodelagem ventricular Como j tem vindo a ser exposto, o stress biomecnico e os mediadores extracelulares da resposta neurohumoral, conjuntamente com a aco de factores de crescimento e molculas de adeso celular, promovem hipertrofia ventricular. Esta resposta, inicialmente adaptativa, repre senta uma tentativa de compensar a sobrecarga de presso e/ou volume (portanto uma conse quncia da IC) mas, mais tarde, contribuir para a progresso e auto-agravamento da IC (logo, simultaneamente um dos seus mecanismos fisiopatolgicos). O stress biomecnico transmitido atravs da membrana citoplasmtica dos cardiomicitos por mecanismos ainda no cabalmente esclarecidos.

to both despite differences in action as explained above) activates the NF-kB pathway(87), which reflects the relationship between different mediators. Recent studies have shown that cardiac autophagy also contributes to the transition from hypertrophy to HF. Autophagy, a cellular mechanism that recycles proteins and organelles, is activated in failing cardiomyocytes as a response to biomechanical stress(89,90). Beclin-1, a protein necessary to the formation of autophagosomes, plays an essential role in this process and it has been demonstrated that inhibiting genetic expression of one of the alleles that code for beclin-1 reduces cardiac autophagy and remodeling induced by biomechanical stress(90). Ventricular remodeling refers to the progressive process of dilatation, hypertrophy, myocyte loss, increased interstitial fibrosis and ventricular dysfunction found in HF(91). The heart undergoes remodeling in response to a variety of stimuli, a reflection of its plasticity. Exercise, pregnancy and postnatal growth result in the physiological growth of the heart,

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Figura 2. Vias envolvidas na hipertrofia e apoptose durante a transio entre a hipertrofia cardaca e a insuficincia cardaca, em resposta ao stress biomecnico. (Adaptado de Hunter, 1999 (81))

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Possivelmente, os canais inicos sensveis ao estiramento, as integrinas e outras protenas estruturais participam nesse processo e, em conjunto, estabelecem uma ligao entre a matriz extracelular, o citoesqueleto, o sarcmero, as protenas envolvidas na homeostasia do clcio e o ncleo(80). Nos cardiomicitos, o stress biomecnico, como a hipertenso crnica e a sobrecarga de presso, activa mltiplos sinais em paralelo con vergentes que provocam hipertrofia e apoptose (Fig. 2). induzida a sntese e secreo de potentes factores de crescimento, como a ET-1, o insulin-like growth factor I (IGF-1) e a Ang II. O estiramento mecnico tem a capacidade de activar directamente os receptores de Ang II nos cardiomicitos, sem a presena de Ang II(91). Simultaneamente, o stress biomecnico tambm leva induo dos ligandos dependentes da gp130, como a cardiotropina 1. Esta citocina, da famlia da interleucina-6, liga-se ao seu receptor, que consiste no heterodmero gp130LIF (leukemia inhibitory factor), condicionando a activao de vias que bloqueiam a apoptose. Na ausncia da gp130, a resposta dos cardiomicitos

while hypertension and myocardial damage can lead to pathological hypertrophy, which, unlike physiological growth, increases the risk of HF and malignant arrhythmias(92). Mann(93) defined ventricular remodeling at both the microscopic and macroscopic level, and classified its different components as follows: 1) changes in myocyte biology (notably expression of fetal myosin heavy chain genes, myofilament loss, hypertrophy, myocytolysis and adrenergic desensitization); 2) alterations in myocardial structure at the cell level (myocyte loss through necrosis and apoptosis and changes in the extracellular matrix); and 3) changes in left ventricular geometry (left ventricular dilatation and wall thinning, increased sphericity, subendocardial fibrosis and mitral regurgitation). For ventricular remodeling to take place, cardiomyocytes must stretch and lengthen, as well as slide over each other (slippage). The links between mechanical, humoral and autocrine factors stimulate fibroblasts to express various types of mRNA (including of collagen and fibronectin), which together lead to fibrosis,

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ao stress biomecnico direccionada para a apo ptose, com perda de cardiomicitos funcionais e incio da IC(81). A nvel celular, o stress biomecnico exercido sobre os cardiomicitos inicia diferentes processos que conduzem a padres distintos de hipertrofia. No corao com sobrecarga de presso, as novas unidades de protenas-contrcteis so adicionadas em paralelo, resultando num aumento relativo da largura dos cardiomicitos individualmente e, portanto, na hipertrofia concntrica, com reduo do volume da cavidade do ventrculo. Por seu lado, a adio em srie de novas unidades de protenas-contrcteis caracteriza a hipertrofia excntrica que ocorre em doentes com sobrecarga de volume, com um aumento proporcionalmente maior no comprimento do que na largura dos cardiomicitos(81). A hipertrofia desenvolve-se, assim, a partir de alguns mecanismos indutores, a referir: o aumento dos nveis de clcio intracelular (um dos eventos iniciais neste processo(82)), a activao celular induzida por factores como o TGF-, a ET-1, as catecolaminas e a Ang II(83). Destacam-se aqui alguns dos fenmenos precoces e tardios da Ang II, atravs da activao de receptores AT-1, implicados no processo de hipertrofia cardaca. Assim, a Ang II activa, precocemente, trs membros da famlia das cnases de protenas activadas por mitognios (MAPK): ERKs, JNK e p38(84). As vias de sinalizao dependentes das MAPK aumentam a expresso de vrios proto-oncogenes de resposta rpida como c-fos, c-myc e c-jun e esto envolvidos na proliferao, diferenciao e transformao celulares, bem como na apoptose, da a sua participao na fisiopatologia da IC(17). A longo-prazo, a Ang II influencia as adaptaes crnicas envolvidas na remodelagem vascular, pela activao sustentada das cnases j mencionadas, que fosforilam alvos implicados, por exemplo, na produo de factores de crescimento e radicais livres de oxignio(15). A Ang II tambm desempenha um papel importante na activao da isoforma do TGF- predominante no sistema cardiovascular (TGF-1)(85). Gupta e col.(86) demonstraram o papel crucial da activao da cascata de sinalizao do factor nuclear NF-B (envolvido no crescimento celular, fibrose ou apoptose, dependendo do contexto envolvente(87)) na iniciao da hipertrofia cardaca e posterior progresso para IC. Para tal, desenvolveram um modelo animal de ratos

one element in ventricular remodeling(83). Cardiac fibrosis is associated with changes in the normal structure of the heart at the myocyte level, with excessive deposition of extracellular matrix proteins(85). Zeisberg et al.(94) recently demonstrated that in aortic-banded rats the TGF-1 pathway activates the endothelialto-mesenchymal transition, which in turn contributes to cardiac fibrosis. TGF-1 promotes this transition by activation of Smad2 and Smad3 molecules. Another member of the TGF family, bone morphogenic protein 7 (BMP-7), a TGF- pathway antagonist, inhibits this transition and hence protects against fibrosis. The study revealed the link between hypertrophy and fibrosis and identified a molecule that can prevent or reverse cardiac fibrosis. At the same time, various other factors are known to reduce myocardial fibrosis, including collagenases (MMP-1 and MMP-13), stromelysin (MMP-3) and gelatinases (MMP-2 and MMP-9)(83). Changes in gene expression are also involved in HF. It is now known that the expression of genes coding for proteins that regulate calcium kinetics is significantly altered(95). In the case of sarcoplasmic reticulum proteins, ryanodine receptors, SERCA2a and phospholamban may have reduced expression(83). SERCA2a is the main protein responsible for calcium (Ca2+) reuptake during cardiomyocyte relaxation, and decreased transcription of the gene coding for this protein has been clearly established in HF(95), leading to diastolic elevation of cytosolic Ca2+ concentrations and decreased Ca2+ release from the sarcoplasmic reticulum. It has been shown that adenoviral gene transfer of SERCA2a in isolated cardiomyocytes(96) and in vivo(97) prevents the contractile dysfunction associated with progression to HF. Expression of SERCA2a appears to prevent activation of signaling molecules such as calcineurin by reducing cytosolic Ca2+ concentrations. Thus, calcineurin, a calcium/calmodulin-dependent phosphatase, plays an important part in induction of cardiac hypertrophy, and its activity is increased in HF(98). There are homeostatic disturbances in different cell types in HF. In sarcomeres, there is a reduction in specific myosin ATPase activity, increased expression of fetal myosin chains, and appearance of myosin heavy chains. Expression of cytoplasmic membrane

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transgnicos (designado de Myo-Tg) no qual aumentaram a expresso da miotrofina (um factor isolado em coraes humanos hipertrofiados, que estimula a sntese proteica nos cardiomicitos, induzindo assim o crescimento miocrdico(88)), especificamente no corao, de forma a induzir a hipertrofia e gradualmente a IC. Esses resultados conduziram a novas experincias no intuito de explorar os efeitos da inibio do NF-B por uma interveno gnica directa, atravs de um vector, da qual resultou uma regresso da hipertrofia cardaca. Estes estudos moleculares suportam a evidncia do papel do NF-B na patognese da IC, anunciando um possvel alvo teraputico. Curiosamente, uma das vias de sinalizao intracelular dos receptores AT-1 e AT-2 (por sinal comum a ambos, apesar da disparidade das suas aces, vide supra) activa a via do factor NF-kB(87); facto que reflecte a relao entre os diferentes mediadores. Recentemente, comprovou-se que a autofagia cardaca um processo que tambm contribui para a transio da hipertrofia cardaca para a IC. A autofagia, um mecanismo celular de reciclagem de protenas e organelos, encontra-se activada nos cardiomicitos insuficientes, como resposta ao stress biomecnico(89,90). A beclina-1, uma protena necessria para a formao do autofagossoma, desempenha um papel primordial nesse processo. Demonstrouse que a inibio da expresso gnica de um dos alelos que codificam a beclina-1 diminui a autofagia dos cardiomicitos e a remodelagem induzida pelo stress biomecnico(90). A remodelagem ventricular diz respeito a um processo progressivo de dilatao, hipertrofia, perda de cardiomicitos, aumento da fibrose intersticial e disfuno ventricular(91), presente na IC. O corao sofre remodelagem como resposta a uma variedade de estmulos, facto que ilustra a sua plasticidade. O exerccio fsico, a gravidez e o crescimento ps-natal promovem o crescimento fisiolgico do corao, enquanto que a hipertenso e a leso miocrdica, por exemplo, podem condicionar uma hipertrofia patolgica. Esta ltima, contrariamente ao crescimento fisiolgico, pode aumentar o risco de IC e arritmias malignas(92). Mann(93) define remodelagem ventricular numa perspectiva global, a nvel microscpico e macroscpico. Assim, agrupa os diferentes componentes da remodelagem ventricular em: 1)

proteins can also be altered, with an increase in the Na+/Ca2+ exchanger and a decrease in beta-1 adrenergic and muscarinic (M2) receptors(83). There is experimental evidence that in physiological conditions the Na+/Ca2+ exchanger, a sarcolemmal protein involved in diastolic calcium release to the extracellular environment, also contributes to calcium uptake by cardiomyocytes during excitationcontraction coupling by working in reverse, albeit only to a limited extent(99). However, the characteristic prolongation of action potentials in HF favors the exchanger working in reverse, thus increasing myocyte calcium uptake(100). Furthermore, increased expression of the Na+/ Ca2+ exchanger may contribute to the genesis of cardiac arrhythmias(101). One of the primary objectives of HF treatment is to counteract the mechanisms involved in cardiac remodeling, thus preserving contractile p function and cardiomyocyte viability(102). Su pression of the hypertrophic process is seen as one way of preventing or delaying progression to HF(103). It is possible that physiological cardiac hypertrophy induced by exercise, phosphatidylinositol 3-kinase/Akt activation or growth hormone therapy may be beneficial in HF patients(104). However, for these hypothetical therapeutic strategies to be applied in practice, they would have to be shown to be superior to current therapies. The macrostructural changes of ventricular remodeling can be partially reversed by pharmacological agents (ACEIs and beta-blockers) and by various other interventions, including ventricular reconstruction surgery, resynchronization and left ventricular assist devices(2). CONCLUSION Current evidence reveals the complex pathophysiology of CHF, which involves dysfunction of various systems, including the cardiovascular, musculoskeletal, renal, neuroendocrine, homeostatic, immune and inflammatory systems (Fig. 3). Together they contribute to a common pathway that culminates in HF, resulting in many changes to the structure, biology and function of the heart. The strong interaction between the different systems involved in HF, with the creation of

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Figure 3. Overall view of the different mediators involved in the pathophysiology of heart failure. (Adapted from (105))

alteraes na biologia do micito (nomeadamente: expresso dos genes fetais das cadeias pesadas da miosina, perda de miofilamentos, hipertrofia; miocitlise e dessensibilizao adrenrgica); 2) alteraes estruturais miocrdicas a nvel celular (perda de cardiomicitos por necrose e apoptose e alteraes na matriz extracelular); e 3) alteraes na geometria da cmara ventricular esquerda (dilatao e adelgaamento da parede do ventrculo esquerdo, aumento da esfericidade, fibrose subendocrdica e insuficincia mitral). Para que se verifique remodelagem ven tricular necessrio que ocorra o estiramento e alongamento dos cardiomicitos, bem como o deslizamento de uns sobre os outros. A articulao de factores mecnicos, humorais e autcrinos estimula os fibroblastos a expressarem vrios tipos de RNAm (de colagnio, fibronectina, entre outros) que no seu conjunto conduzem fibrose

pathways that are to some extent redundant and the duality of the effects they produce, with different short- and long-term consequences that can be beneficial or harmful, constitutes a real challenge for an understanding of the syndrome. Functional and molecular characterization of progression to HF has contributed to this understanding and to the definition of new therapeutic targets. ACKNOWLEDGEMENTS This work was funded by Project PIC/ IC/82943/2007, through the Cardiovascular R&D Unit No. 51 of the Portuguese Foundation for Science and Technology.
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Figura 3. Viso integrada dos diferentes mediadores na fisiopatologia da insuficincia cardaca. (Adaptado de Pacher P, 2007 (105))

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elemento que acompanha a remodelagem ventricular(83). A fibrose cardaca est associada alterao da estrutura normal do corao ao nvel dos cardiomicitos e a uma deposio excessiva das protenas da matriz extracelular(85). Zeisberg e col.(94) demonstraram, recentemente, atravs da constrio artica em ratos, que a via do TGF-1 activa uma transio endotelial-mesenquimatosa, a qual, por sua vez, acciona a fibrose cardaca. O TGF-1 promove essa transio pela activao das molculas Smad2 e Smad3. Um outro membro da famlia do TGF, a bone morphogenic protein 7 (BMP-7), um antagonista da via do TGF-, inibe essa transio, pelo que tem uma aco protectora contra a fibrose. Este trabalho revelou a interligao entre hipertrofia e fibrose e identificou uma molcula que pode prevenir ou reverter a fibrose cardaca. Paralelamente,

so reconhecidos vrios factores que podem contribuir para a reduo da fibrose miocrdica, tais como colagenases (MMP-1; MMP-13), estromalisinas (MMP-3) e gelatinases (MMP-2; MMP-9)(83). Tambm ao nvel da expresso gnica se verificam alteraes. Sabe-se hoje que na IC a expresso dos genes que codificam as protenas reguladoras da cintica do clcio se encontra extensamente alterada(95). Ao nvel das protenas do retculo sarcoplasmtico, os receptores ria nodnicos, a SERCA2a e o fosfolamban podem ter a sua expresso diminuda(83). A SERCA2a a principal protena responsvel pela recaptao do io clcio (Ca2+) durante o relaxamento dos cardiomicitos. Est perfeitamente estabelecida na IC a diminuio da transcrio do gene que codifica essa protena(95), com consequente ele vao diastlica da concentrao citoslica

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Quadro I. Mediadores qumicos da resposta neurohumoral na Insuficincia Cardaca


Componentes reguladores Catecolaminas efeitos perifrico Angiotensina II Aldosterona Arginina Vasopressina Endotelina Tromboxano
(Adaptado de Katz AM, 2000 (1)

Componentes contrarreguladores Catecolaminas efeitos centrais Peptdeos natriurticos xido ntrico Bradicinina Dopamina Prostaglandinas vasodilatadoras Adrenomedulina

Table I Chemical mediators of the neurohumoral response in heart failure.


Regulatory components Catecholamines peripheral effects Angiotensin II Aldosterone Arginine vasopressin Endothelin Thromboxane
(Adapted from (1))

Counter-regulatory components Catecholamines central effects Natriuretic peptides Nitric oxide Bradykinin Dopamine Vasodilator prostaglandins Adrenomedullin

de Ca2+ e diminuio da libertao de Ca2+ a partir do retculo sarcoplasmtico. Demonstrouse que a transferncia gnica de SERCA2a (mediada por adenovrus) para cardiomicitos isolados(96) e in vivo(97), previne a disfuno contrctil que acompanha a progresso para a IC. A expresso de SERCA2a, ao diminuir a concentrao citoslica de Ca2+, parece prevenir a activao de molculas sinalizadoras como a calcineurina. Alis, tambm a calcineurina, uma fosftase dependente do clcio-calmodulina, desempenha um papel relevante na induo da hipertrofia cardaca. A sua actividade encontra-se aumentada na IC(98). Na IC h, efectivamente, uma perturbao da homeostasia de diferentes elementos celulares. Ao nvel dos sarcmeros, ocorre uma diminuio da actividade especfica da ATPase da miosina, um aumento da expresso de cadeias fetais da miosina, bem como o aparecimento de cadeias pesadas da miosina . A expresso de protenas da membrana citoplasmtica pode estar igual mente alterada, observando-se, nomeadamente, o aumento do trocador Na+/Ca2+ e a diminuio dos receptores 1-adrenrgicos e muscarnicos (M2) (83) . H evidncias expe ri mentais que sugerem que, em situaes fisiolgicas, o trocador Na+/Ca2+, uma protena do sarcolema envolvida na extruso diastlica do Ca2+ para o meio extracelular,

tambm contribui, ainda que de forma muito limitada, ao trabalhar de modo reverso, para a entrada de clcio nos cardiomicitos durante o acoplamento excitao-contraco(99). Porm, na IC, o caracterstico prolongamento do potencial de aco favorece o funcionamento do trocador no sentido reverso, favorecendo a entrada de clcio nos cardiomicitos(100). Adicionalmente, o aumento da expresso do trocador Na+/Ca2+ pode contribuir para a gnese de arritmias cardacas(101). Um dos objectivos primordiais do tratamento da IC mitigar os mecanismos que participam na remodelagem cardaca com preservao da funo contrctil e da viabilidade dos cardiomicitos(102). A supresso do processo hi per trfico vislumbrada como um possvel mecanismo para impedir ou atrasar a evoluo para IC(103). Pondera-se que a activao da hipertrofia cardaca fisiolgica atravs do exerccio, da activao da via de sinalizao da cnase-3 do fosfatidilinositol Akt ou do tratamento com hormona de crescimento seja benfica, em doentes com IC(104). Contudo, para que essas hipotticas estratgias teraputicas tenham aplicabilidade prtica tero de apresentar vantagens superiores s demonstradas pela teraputica actual. Nesse domnio, as alteraes macro-estruturais da remodelagem ventricular

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podem ser parcialmente revertidas por agentes farmacolgicos (IECAs e -bloqueadores) e por intervenes vrias onde se incluem a cirurgia de reconstruo ventricular, a ressincronizao e os dispositivos de assistncia ventricular esquerda(2), entre outros. CONCLUSO A evidncia cientfica actual revela a complexidade da fisiopatologia da ICC, que envolve a disfuno de vrios sistemas do organismo, incluindo o cardiovascular, musculoesqueltico, renal, neuroendcrino, hemosttico, imunolgico e inflamatrio (Fig.3). Em articulao, contribuem para a progresso de uma via final comum que culmina na IC, resultando em inmeras alteraes na estrutura, biologia e funo cardacas. A forte interaco entre os diversos sistemas que participam na IC, com criao de vias de certo modo redundantes, a dualidade de efeitos por eles despertados, com consequncias dis tintas a curto e longo prazos, ora vantajosas ora deletrias, constituem um verdadeiro desafio para a compreenso desta sndrome. A caracterizao funcional e molecular da progresso para a IC veio contribuir para essa compreenso bem como para a definio de novos alvos teraputicos.

AGRADECIMENTOS Trabalho subsidiado pelos Projecto n. PIC /IC/82943/2007, atravs da Unidade I&D Cardiovascular n 51 da FCT.

Pedido de separatas para: Address for reprints: Adelino F. Leite-Moreira Servio de Fisiologia da Faculdade de Medicina do Porto Al. Prof. Hernni Monteiro 4200-319 Porto, Portugal Tel. 22 5513644; Fax. 22 5513 e-mail: amoreira@med.up.pt

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