Ischemic heart disease refers to a set of syndromes intimately related but of diverse aetiology, characterised generically by an imbalance between supply and demand of oxygen and substrates in cardiac tissue. This imbalance leads to a production deficit of ATP, necessary for contraction, and excessive accumulation of metabolic waste products.
Generally, the obstruction of blood flow at the level of a coronary artery, caused by the deposition of atheromatous plaques on the walls of the vessel, appears at the base of this set of diseases that presents three clinical manifestations (Felker, 2002):
Angina pectoris. The blood supply decreases enough not to satisfy an eventual demand caused by a situation of stress or stress. It manifests as transient chest pain due to ischemia, but its effects are reversible at the tissue level if normal flow is restored.
Acute myocardial infarction. Blood flow is totally disrupted in a coronary artery causing permanent tissue ischemia. The myocardial tissue becomes necrotic, loses its normal contractile capacity and tissue damage becomes irreparable even when the blood supply is later restored.
Sudden cardiac death. Ischemic heart disease appears behind more than 50% of these events. After disruption of coronary blood flow, ventricular fibrillation causes the individual to die within the first hour after the obstruction.
Socio-economic impact of heart disease of ischemic origin.
Currently, in the non-industrialized regions a number of major infectious diseases cause more than twelve million deaths a year. In the industrialized regions, these account for less than two million and are equivalent to those derived from industrialization itself. In this heterogeneous scenario, it is striking that ischemic heart disease still accounts for 2.5 and 3.5 million annual deaths in developing and developed areas, respectively. Far from reducing these figures, future projections predict that increasing longevity and change in lifestyles will take these numbers increasingly higher.
In 2006, J. Leal et al. published one of the most comprehensive studies to date on the socioeconomic impact of cardiovascular diseases in the European Union (Leal, 2006). According to official data, cardiovascular diseases accounted for 12% of total health expenditure in 2003, of which more than a quarter were justified by heart disease of ischemic origin, a proportion that is maintained and even increased in other regions. This year, expenses and losses from heart disease of ischemic origin were estimated at 44,725 million euro for the whole European Union, and one third of this amount was due to production and productivity losses due to mortality and morbidity (Leal, 2006).
In the United States, with a population equivalent to 70% of the European population, heart diseases of ischemic origin underlie one of every five deaths, and the gross expense in cardiovascular diseases doubles that of Europe and is twice the internal expense derived from all types of Cancer (American Heart Association Statistics Committee and Stroke Statistics Subcommittee, 2010). In emerging countries such as India, China, Brazil, Mexico and South Africa, cardiovascular diseases are already an important socio-economic factor and together, 21 million years of future productive life are lost annually in these five countries (Gaziano, 2007). At present, sub-Saharan Africa is the only economic region in which this set of pathologies is not the leading cause of death. If current trends continue, it is estimated that cardiovascular diseases will be soon a significant factor of imbalance for many economies (Jaffer, 2003). It is not surprising that, year after year, a large part of the health budget is dedicated to the prevention, diagnosis, treatment and research of cardiovascular diseases and, in particular, heart diseases of ischemic origin.
Historical perspective of ischemic heart disease.
In 1768 William Heberden, with his essay on angina, published the first detailed study of a heart disease of ischemic origin. More than 140 years later, in 1912, James B. Herrick published the first paper describing a case of acute nonfatal myocardial infarction three years after the introduction of the electrocardiogram (ECG). In this paper, Herrick described myocardial infarction as a cardiac ischemia with frequent survival, and accompanied of a damage that was often not irreversible (Herrick, 1912). This study was perhaps the starting point or inspiration of works and technological advances that, during the 20th century, have contributed to enrich the knowledge about this set of affections. In the 1930s, it was introduced the ECG using precordial leads, one of the cornerstones in the early diagnosis of myocardial infarction. In the 1950s, it was introduced the use of external defibrillators and pacemakers, which were fundamental in the treatment of this disease, as well as the first coronary arteriographies. Previously, in 1948, 5,209 people in Framingham (United States) were recruited to be part of the first prospective study that sought to unravel common patterns in the development of cardiovascular diseases (Dawber, 1951). On December 3, 1967, Christiaan Barnard performed the first successful heart transplant among humans in Cape Town, South Africa. Cardiac transplantation was a tremendous advance in the care of patients with severe heart failure but nevertheless, it is an extremely risky surgery to replace an organ that has lost its functionality irreversibly, and therefore it is a solution for cases with no alternative. In the early 1970s, techniques that are still in use, such as reperfusion via catheterism and coronary bypass, were introduced into clinical practice aimed to restore blood flow in the region affected by the infarction. At the end of the same decade the use of the creatine phosphokinase test was established for diagnosis and β-blockers (β-adrenergic antagonists) began to be prescribed to patients who had undergone angina pectoris or myocardial infarction. Its use would be generalized during the following decade, alongside the introduction of coronary angioplasty and the use of thrombolytic agents. The 1990s would see the generalization of inhibitory agents of the renin-angiotensin system, the use of coronary stents and the implementation of blood such as the troponin T test.
Classic therapeutic strategies to myocardial infarction were characterized for their focus towards the arrest of the processes triggered after the event of ischemia, but none of them offered the restoration of the pre-ischemic state. These approaches have significantly reduced mortality and improved the quality of life of patients with myocardial infarction. Unfortunately, these patients continue to suffer from limitations that indicate that there is still a long way to go in the treatment of this disease. Several different strategies have been proposed to replace the heart or part of the affected heart tissue. The first of these is, as already mentioned, heart transplantation. Currently, an average of 3,500 heart transplants are performed every year, but some 800,000 people are still waiting for an organ transplant (Reiner Körfer [TV interview], 2007). Therefore, although subject to strong debate, the use of organs of animal origin, or xenotransplantation, has been proposed as an alternative to transplantation between humans. This option has been officially implemented in eleven occasions using hearts of different origins (Deschamps, 2005; Bailey, 1985). Immunological barriers and the ethical and ideological concerns underlying such practice, and the still not excluded possibility of xenozoonosis, have made this practice fall into oblivion from a clinical perspective.
In the late 1990s, with the development of molecular and cellular biology, cell therapy has been proposed as the first realistic strategy for restoration and regeneration of cardiac tissue (Melo, 2004). This practice postulates the use of cells of different origins that, after their injection into the cardiac environment, would act as restorative agents of the contractile function of the myocardium, thus avoiding cardiac failure. However, after a very optimistic beginning, the heterogeneity of the results and methods have made this practice questioned by many authors (Abbasi, 2011). In parallel, new tissue engineering technologies have already proposed the use of bio-artificial hearts, created from the ex vivo culture of cells with cardiomyocyte capacity on natural decellularized matrices of animal origin (Ott, 2008). With these strategies still in preclinical stages, their application as a realistic therapy is still a prospect for the future.
The advent and establishment of high performance molecular biology techniques since the late 1990s has also been one of the major advances in the diagnosis and molecular knowledge of the processes that underlie and follow myocardial infarction. The identification of protein markers present in the serum is useful for the rapid and efficient diagnosis of many patients, thus shortening the waiting times and refining the treatments.
Physiopathology of ischemic heart disease
If for any reason one of the coronary arteries is blocked, the myocardium runs out of blood and therefore becomes necrotic. The point at which the obstruction occurs will be determinant for the survival of the individual since the closer the aorta is, the greater the volume of tissue affected and the worse the prognosis (Lee, 1995; The GUSTO investigators, 1993).
Immediately after the interruption of the blood flow, the myocardium of the affected region stops contracting and in many cases compromises cardiac function. In an attempt to maintain organ homeostasis, the region affected by ischemia, but also the regions bordering it, will undergo a series of processes aimed at compensating the loss of contractile work in a process known as cardiac remodelling (Meijs, 2007).
Cardiomyocytes have an extremely limited division capacity, and following various autocrine and paracrine signals, become hypertrophic (Kessler-Icekson, 1984). Initially, cardiomyocyte hypertrophy contributes to the maintenance of cardiac function. However, this additional effort translates into increased oxidative stress and the entrance in a spiral that affects a growing area of tissue, eventually leading tissue to apoptosis and total loss of contractile function. Moreover, cardiomyocytes stay connected by gap junctions that allow for a rhythmic contractile work (Sheikh, 2009). If part of the tissue loses this capacity, the rest of the heart will find problems to maintain an adequate and coordinated rhythm, leading in many cases to fibrillation and new episodes of remodelling. In a final stage, the whole organ will lose its functionality (Rossini, 2010).
Cardiac fibroblasts, on the other hand, differentiate into myofibroblasts, proliferate and begin to synthesize proteins of the contractile apparatus and the propagation system of the electric impulse (Weber, 1997; Vasquez, 2011). The acquisition of myogenic potential allows them to temporarily contribute to the contraction, but in a damaged tissue environment, the coupling of these cells is deficient, eventually contributing to the appearance of severe arrhythmias that further compromise cardiac function (Rossini, 2010). In the area of focal damage, after an acute inflammatory process that extends over the first 3-4 days after ischemia (Matsui, 2010), the ventricular wall loses its contractile functionality, but also its robustness. At the risk of definitively compromising tissue contractibility, the myofibroblasts beging to synthesize the extracellular matrix that will constitute the fibrotic scar, in order to avoid rupture of the tissue and subsequent total organ failure.
When cardiac tissue is subjected to ischemia, the processes of arteriogenesis (i.e. remodeling of pre-existing vessels) and angiogenesis (i.e. proliferation of new capillaries) are activated. The activation of pro-angiogenic molecular pathways induced by hypoxia is a protective mechanism that ensures the supply of nutrients in the affected tissue (Cao, 2010). For example, HIFs (hypoxia inducible factors), are transcription factors whose expression is activated under conditions of hypoxic stress and are capable of inducing the expression of genes such as VEGF (vascular endothelial growth factor), that promote angiogenesis. However, when the tissue undergoes extreme aggressions, the mechanisms of homeostasis that are effective for normal tissue maintenance are insufficient. In fact, acute responses to tissue hypoxia may not necessarily be beneficial for functional tissue recovery. Thus, the proliferation of new vessels in response to hypoxia is accompanied by an increase in vasodilator factors such as nitric oxide and VEGF. These molecules increase vascular permeability and may lead to the formation of edema, a determinant mortality factor following myocardial infarction (Eriksson, 2003; Senger, 1986).
Molecular mechanisms of cardiac remodeling.
The renin-angiotensin system (RAS), the TGFß (transforming growth factor beta) signaling pathway and theß-adrenergic system are key mediators of the adaptation of the heart to hemodynamic overload, and are therefore critically involved in the pathogenesis of ischemic heart disease (Rosenkranz, 2004). These three regulatory pathways, and particularly the first two, do not act in isolation, but are coordinated within a common regulatory system that promotes cardiac remodeling. Thus, various experimental animal studies (Nakamura, 2003; Kim, 2001) and clinical trials (McMurray, 2003; Pfeffer, 2003) have shown that inhibition of angiotensin II (Ang II) by administration of angiotensin converting enzyme (ACE) inhibitors or antagonists of the type I angiotensin receptor (AT1) prevent, mitigate or reverse ventricular remodelling, and increase the survival of patients who have suffered myocardial infarction.
The effector molecule of RAS is angiotensin II, which sees increased expression in situations of mechanical stress such as hypertension or myocardial infarction. However, Ang II stimulates different responses in cardiomyocytes and cardiac fibroblasts, and several studies have concluded that this molecule is not the ultimate trigger of the responses observed in myocardial cells. In contrast, Ang II induces the expression of various growth factors such as TGFß, which acts locally through autocrine and paracrine activation of genes leading to cardiomyocyte growth, proliferation of fibroblasts and their transition to myofibroblasts, and the induction of the expression of extracellular matrix proteins (Rosenkranz, 2004 ; Wenzel, 2001). Additional studies have shown that knockout animals for TGFß do not develop cardiac hypertrophy in the presence of Ang II (Schultz, 2002).
The synthesis of Ang II requires the presence of a precursor peptide (angiotensin) that is processed by cathepsin or renin to Ang I. Finally, ACE catalyzes the hydrolysis Ang I Ang II (Sun, 2009). Following the recognition of Ang II by AT1R (Ang II receptor), the induction of TGFß expression, depends on the activation of protein kinase C (PKC), in a process studied in detail by Wenzel et al (Wenzel, 2001).
Although different types of cardiac cells can produce TGFβ, macrophages are the major producers during the earliest stages of repair. After the acute phase, this task is assumed by fibroblasts (Sun, 2009) and it will be the performance of this molecule on the same cells that triggers and leads to the process of fibrosis and extracellular matrix deposition that contribute to cardiac remodeling. TGFβ includes three isoforms with high homology (TGFβ1, 2 and 3), which are secreted in their inactive form. The active form of TGFß is a 12kDa molecule synthesized together with the latency-associated peptide (LAP), from which it will be released by proteolytic action of plasmin or thrombospondin 1 (Sun, 1998). Latent forms of TGFβ may also appear to be linked to other latency associated proteins such as LTBPs (Latent TGF-binding proteins) (Oklü, 2000).
The active form of TGFß binds to a membrane receptor complex formed by a heterodimer of TGFß receptors receptors type I and type II (TGFBR1 and 2). TGFBR1 possesses kinase activity and binding of TGFβ to the complex results in the phosphorylation of SMAD2 and SMAD3, known as receptor-activated SMADs (R-SMADs). Activated forms of SMAD2/3 bind to SMAD4 and are translocated to the nucleus where, in association with other general transcription factors (Sun, 2009) act as transcriptional activators of a large part of the genes involved in the post-ischemic remodelling of the myocardium. On the other hand, SMAD6 and SMAD7 compete with R-SMADs for binding to TGFBR1. This attenuates the transcriptional activation induced by TGFβ. Moreover, TGFβ is able to regulate its own action by transcriptional induction of SMAD7 (Sun, 2009; Yan, 2011).
TGFß activates other non-SMAD-dependent pathways (Zhang, 2009) and, in addition to the established TGFß-SMAD signalling pathway, it is known that TGFß and Ang II can cause even the activation of non-TGFBRs-dependent pathways (Bhattacharyya, 2009). These lead for example to the induction of the expression of CTGF (connective tissue growth factor), a growth factor that participates synergistically with TGFß in the fibrosis process and matrix generation in connective tissues (Mori, 1999).
In addition to TGFß, various chemokines, cytokines and growth factors play key roles in repairative cardiac fibrosis. Many of them, such as MCP-1 (monocyte chemoattractant protein 1), are essential regulators of the fibrotic process in moderate ischemic events, which do not cause the massive death of cardiomyocytes (Dobaczewski, 2009). In contrast, endothelial-derived fibroblasts are able to synthesize endothelin-1, which contributes to the recruitment of new fibroblasts by EndMT (endothelial to mesenchymal transition), exacerbating fibrosis (Widyantoro, 2010).
Strategies for the attenuation of the fibrotic response.
The ability to repair damaged tissues without subsequent scar formation would be ideal and is the ultimate therapeutic goal. However, even in tissues with considerable regenerative capacity, the repair of massive or chronic damage based solely on regeneration of parenchymal cells is not feasible. It is for this reason that the development of therapeutic strategies that minimize the progression of fibrosis and scar formation without affecting the total repair process would represent a great advance. Nevertheless, evidence demonstrates that, if fibrosis is advanced enough, restoring normal tissue architecture is not possible (Wynn, 2008).
One of the usual emergency strategies used in patients with acute ischemia is the reestablishment of blood flow through reperfusion of the obstructed artery. However, although it is an extremely effective procedure, re-entry of tissue into normoxia leads to a level of oxidative stress that can not be absorbed by cardiomyocytes, which enter into apoptosis. It has been demonstrated that the reperfusion process is responsible for part of the tissue damage of the organ and in fact, several studies have shown that local or remote ischemic preconditioning prior to the restoration of blood flow results in an attenuation of the reperfusion injury (Hausenloy, 2011).
One of the reasons that have been suggested as the cause of the inability to restore fibrotic tissues is that the advanced stages are frequently hypocellular (Gandhi, 2011). During the acute inflammation phase, the presence of macrophages ensures a continuous source of matrix metalloproteinases that maintain the equilibrium between synthesis and degradation of extracellular matrix (Navalta, 2006). When these inflammatory mediators disappear, the cardiac fibroblast (myofibroblasts) remain the only source of MMPs, causing extracellular matrix deposition to prevail on degradation. The affected tissue enters a chronic phase of irreversible scarring and the connective tissue causes an increasing isolation of the cells, until they enter into apoptosis (Müller, 2011). Treatments aimed at attenuating the fibroblast response to ischemic events may offer a realistic approach to ischemic heart disease and in fact, various drugs currently in use are capable of disrupting or modulating part of the fibroblast response. Unfortunately, their unspecificity, combined with important side effects, still make recommendable the development of new agents that improve the prognosis of patients suffering from this ischemic heart disease (Porter, 2009).
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