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Cytokines are small, nonstructural proteins with a molecular weight ranging from 8 40 KDa that are secreted by cells in response to a variety of different inducing stimuli. Two classes of cytokines are known, namely proinflammatory- and anti-inflammatory cytokines. These proinflammatory cytokines are named inflammatory regulators, namely due to their function to produce inflammation, fever, tissue destruction and, in some cases, shock and death in response to stress or immune activation. Several studies have data suggesting that susceptibility to cardiac disease is genetically determined by the balance or expression of proinflammatory cytokines (1 new).
The myocardium's ability to adapt successfully to superimposed environmental stress, caused by myocardial ischemia or hemodynamic overloading, determines whether the heart fails or maintains preserved function. The three important mechanisms in the heart to overcome damage due to stress, seen as psychological or immunological, or tissue damage are cardiac hypertrophy, cardiac repair and myocyte cytoprotective responses (Figure 1). These processes are crucial for maintaining myocardial homeostasis, therefore preventing myocardial damage. Stress and inflammation are combined regulators of inflammatory cytokines, and should not be seen as two different entities. However, the molecules that mediate this myocardial response (inflammation) to stress remain poorly understood (1). Therefore, the role that proinflammatory cytokines play as autocrine/paracrine factors, responsible for integrating, and maintaining the myocardial response to stress are focused.
Figure 1 The coordination of the three mechanisms involved in myocardial homeostasis. The maintenance of homeostasis in the myocardium is crucial in protecting the heart from myocardial damage, due to external factors, e.g. stress (psychological) and inflammation (tissue injury or pathogen entry) via induction of proinflammatory cytokines.
2. Stress- activated proinflammatory cytokines in the heart: Psychological Contribution to Inflammation
2.1 Adaptive effects of stress-activated cytokines in the heart
The proinflammatory cytokines involved in the heart includes interleukin-1 (IL-1), interleukin- 6 (IL-6) and tumour necrosis factor (TNF). The molecules were believed to be derived only in the immune system and the primarily function was to initiate inflammation. However, it is now well known that cytokines are expressed by all nucleated cells located in the myocardium, including the cardiac myocyte itself in response to stress. (2, 3) This latter observation has let to an increased questioning on the biological role that proinflammatory cytokines play in the heart.
Recent studies of proinflammatory cytokine gene regulation have produced two important themes, namely the first is that proinflammatory cytokines are not constitutively expressed in the heart (2, 3). The second theme suggests that cytokines are consistently and rapidly expressed in response to different types of myocardial injury. The observation that proinflammatory cytokine gene expression is observed in all forms of cardiac injury, suggests that cytokines constitute part of an intrinsic or innate cardiac response system. Therefore, the role that proinflammatory cytokines play as effector molecules in the innate system, relates to act as an early warning sign in the heart to permit the myocardium to respond rapidly to tissue injury. However, growing body of evidence suggests that short-term expression of proinflammatory cytokines is beneficial. Sustained and/or dysregulated expression of proinflammatory cytokines, e.g., chronic depression, is sufficient to produce tissue injury and to trigger overt cardiac decompensation. (1)
Table 1 cardiac pathophysiological conditions related to
Acute viral myocarditis ()1
Cardiac allograft rejection ()
Cardiopulmonary bypass ()
Myocardial reperfusion injury ()
Myocardial infarction ()
Unstable angina ()
1 Numbers in parentheses refer to reference
2 Indicates conditions that are not traditionally associated with immunologically mediated inflammation.
The first line of evidence in support of the beneficial role for proinflammatory cytokines in the heart comes from a series of "gain-of-function" studies showing that proinflammatory cytokines present cytoprotective responses in the heart. (1) The first study to prove this potential beneficial effect of cytokines showed that pre-treating Wistar rats with TNF-inflammatory cytokine protected the heart from ischemic reperfusion injury ex vivo (1). Subsequently inducing ischemia reperfusion injury, the TNF-pretreated hearts of the animals had a approximately threefold reduction in the amount of lactate dehydrogenase release (18) and showed a definite increase in recovery of the left ventricular pressure when compared with control hearts (19). According to Terracio (1988) (20) and Maulik (1993) (21) IL-1 can also protect the rat hearts against ischemia reperfusion injury in vitro (20, 21) The demonstration of in vitro and ex vitro studies have proven that physiological levels of TNF are sufficient to protect cardiac myocytes against either hypoxic or ischemic injury, respectively (22). Furthermore, the cytoprotective effects of TNF can be mimicked by stimulating either type 1 (TNFR1) or the type 2 (TNFR2) receptor, which imply that the cytoprotective effects of TNF are mediated by activating TNFR1 or TNFR2. Although, the previous study did not identify the mechanism responsible for these findings, proinflammatory cytokines are known to upregulate the expression of two sets of protective proteins in the heart, namely the free radical scavenger manganese superoxide dismutase (MnSOD) (18, 23) and the cytoprotective heat shock proteins (HSPs) (24, 25) Significant to this discussion is the finding that TNF-induced MnSOD induction is rapid (< 1h) and requires low levels of TNF (0.1 ng/ml) constant with the proposed homeostatic role for these proteins. The contracting myocardial cells are continually susceptible to oxygen-derived free radicals; therefore TNF and IL-1 may play important roles in protecting the heart against oxidative stress during ischemia and reperfusion injury. TNF has also shown in studies that it upregulate the expression of heat shock protein 72 (HSP72) (24), a protein considered to protect the heart against ischemia and reperfusion injury (26, 27). Adding to this discussion, proinflammatory cytokines such as TNF and IL-1Î² can activate the cytoprotective transcription factor nuclear factor-kappa B (NF-ÎºB), presumably through upregulation of one or more cytoprotective genes, that include MnSOD, inhibitors of apoptosis 1 and 2 (c-IAP1 and cIAP2), and the Bcl-2 family, including Bfl-1 and Bcl-xL (28, 29).
Parallel findings have been obtained in the gain-of-function studies for the IL-6 family of cytokines, which include leukemia inhibitory factor (LIF), cardiotropin-1 (CT-1) IL-11, ciliary neurotrophic factor (CNTF) and oncostatin M (OSM). These cytokines target downstream signaling pathways in cardiac myocytes, through the heterodimarization of gh130 or the homodimarization of the gp130 receptor with a related transmembrane receptor. Studies with CT-1 have revealed that it blunts serum deprivation-induced apoptosis in isolated cardiac myocytes through a pathway that is dependent on activation of mitogen-activated protein kinase (MAPK) pathway. These specific studies, transfection of a MAP kinase 1 (MEK1) dominant-negative mutant cDNA into myocardial cells or treatment of a MEK- specific inhibitor blocked the anti-apoptotic effects of CT-1, ultimately indicating a requirement of the MAP kinase pathway for survival of CT-1. Comparable studies have shown that LIF grant cytoprotective responses in isolated myotubes and also in intact myocardial tissue (19). However, the cytoprotective mechanisms for LIF-mediated cytoprotective effects appear to be more complex that those stated for CT-1.
The second line of evidence in support of a beneficial role for proinflammatory cytokines in the heart comes from a series of "loss-of-function" studies in mice lacking proinflammatory cytokine receptor-mediated signaling. The study is conducted by targeting disruption of gp130; evidence shows that the homozygous null mice (gp130-/-) died between 12.5 days postcoitum and term. The ventricular myocardium developed normally until 14.5 days postcoitum; however, after 16.5 days postcoitum, the gp130-/- mice demonstrated a markedly hypoplastic ventricle with an abnormally thin ventricular wall (34, 35)
Current studies in mice doubly deficient for type 1 and type 2 TNF receptors (TNFR1-/-/TNFR2-/-) have revealed an increase in infarct size in response to ischemic injury (36). Data summarized by Douglas (2003) (1) shows that infarct size was the same in wild-type, TNFR1-/- mice and TNFR2-/- mice; however infarct size was 40% greater in the TNFR1-/-/TNFR2-/- mice. This increase was secondary to accelerated apoptosis in the TNFR1-/-/TNFR2-/- mice, as opposed to increased myocyte necrosis. The observation that the deletion of both TNFR1 and TNFR2 is necessary to provoke increased tissue injury suggests that TNFR1 and TNFR2 activate redundant cytoprotective signaling pathways in the heart (1). Although, the complete portfolio of cytoprotective signaling pathways that are common to both TNFR1 and TNFR2 is not known, it is motivating to note that NF-ÎºB activation is downstream from both TNF receptors (37). As discussed previously, NF-ÎºB activation can be cytoprotective in specific settings. Taken jointly, the above gain-of-function and loss-of-function studies for gp130- and TNF-mediated signaling suggest that proinflammatory cytokines play a tremendously important role in the orchestration and the timing of the myocardial stress response by providing early anti-apoptotic cytoprotective signals that are responsible for delimiting tissue injury but also supplying delayed signals that facilitate tissue repair and / or tissue remodeling once myocardial tissue damage has supervened. Adding to this latter point of view, previous studies have revealed that CT-1, LIF and TNF are all sufficient to provoke modest hypertrophic growth response in cardiac myocytes (38) and that TNF is sufficient to lead to degradation and remodeling of the extracellular matrix in the heart (39).
2.2 Maladaptive effects of stress-activated cytokines in the heart
Although the self-limited expression of stress-activated cytokines can provide the heart with an adaptive response to environmental injury, this protective response can lead to upregulation of unwanted deleterious effects that can occur when cytokines are elaborated for sustained periods of time or when cytokines are expressed at pathological levels. As shown in Table 2, a considerable body of evidence suggests that the continuous expression of cytokines may produce frank maladaptive effects in the heart. Although it is clear from several studies that proinflammatory cytokine expression becomes dysregulated; e.g. sustained in the heart, the mechanisms responsible for this sustained expression are not known. Consequently, in the following section, focus will be placed on maladaptive downstream consequences of sustained proinflammatory cytokine expression, with an emphasis on the adverse consequences of cytokines on cardiac function and remodeling.
Table 2 Maladaptive cardiovascular effects of stress-activated cytokines
Produces LV dysfunction ()1
Produces cardiomyopathy in humans ()
Promotes LV remodeling experimentally ()
Produces abnormalities in myocardial metabolism
1 Numbers in parentheses refer to reference
2.2.1 Effects of stress-activated cytokines on heart function
It is evident that proinflammatory cytokines are capable of modulating LV function following a series of experimental studies showing that direct injections of TNF produce hypotension, hemoconcentration, metabolic acidosis and death within minutes, therefore mimicking the cardiac/ hemodynamic response seen during endotoxin-induced septic shock (40) Furthermore, the injections of TNF antibodies were subsequently shown to attenuate the hemodynamic collapse seen in endotoxic shock. The significance of TNF in the clinical setting has been suggested by studies in which injection of endotoxin into humans resulted in elevated TNF levels and neglected LV ejection performance (41) and by studies in which TNF was infused in patients undergoing antitumour therapy resulted in profound systemic hypotension (42-44). With relation to the potential mechanisms for TNF-induced LV dysfunction, the literature insinuate that TNF modulates myocardial function through at least two different pathways; namely an immediate pathway that is manifest within minutes and secondly, a delayed pathway that requires hours to days to develop, respectively.
The delayed effects of proinflammatory cytokines on myocardial function were first established in important early studies in neonatal cardiomyocytes showing that although continuous exposure (72 h) to TNF and IL-1Î² did not alter the baseline contractile function, these proinflammatory cytokines did blunt the positive inotropic response to isoproterenol, additionally the cytokine-mediated effects were entirely reversible (45-47). This delayed effect of cytokines on myocardial contractility have also been observed in dogs in vivo, in which a single infusion of TNF resulted in abnormalities of systolic functions within the first 24 h (49-50). Comparable findings with respect to the delayed onset for the functional effects of cytokines have been confirmed for IL-1 which produces a delayed reduction in myocardial contractility in vitro (53), as well as chronotropism (spontaneous beating) in isolated rat cardiomyocytes (55). See Table 3
Table 3 The effect of proinflammatory cytokines on LV remodeling (1)
Alterations in the extracellular matrix
Degradation of the matrix
Alterations in the cardiomyocyte's biology
Fetal gene expression
Progressive cardiomyocytes loss
The latest studies in the adult heart have suggested that TNF, IL-2 and IL-6 also manufacture immediate negative inotropic effects (51). Fascinatingly, however, IL-1Î² had no immediate effects on cardiac contractility (57). According studies in thin strips of myocardial tissue from Syrian hamsters (57) illustrated that high concentrations of TNF (>900U/ml-1), IL-6 (>500U/ ml-1) and IL-2 (>60 U/ ml-1) were adequate to produce an immediate (2-3 min) concentration-dependant decrease in myocardial contractility, which was entirely reversible upon cytokine removal. These results have been confirmed at the cellular level for TNF (58) and IL-6 (59), respectively, in isolated chick cardiomyocytes and contracting feline cardiomyocytes (1). Additionally to the cellular mechanism for the immediate inotropic effects of TNF, a recent study in isolated adult feline cardiomyocytes has revealed that the negative inotropic effects of TNF are the direct result of alterations in intracellular calcium homeostasis (58). I this study, treatment with >50U/ml-1 TNF created a 25% decrease in the progress of cell shortening and a 40% decrease in peak intracellular calcium levels. Additionally, whole-cell patch-clamp studies shows that the decrease in intracellular calcium was not the consequence of changes in the voltage-sensitive inward calcium current, therefore indicating that TNF-induced changes in intracellular calcium homeostasis were secondary to alterations in the sarcoplasmic reticular managing of calcium (58). Studies in isolated avian cardiomyocytes have shown that stimulation with >500U/ ml-1 IL-6 caused immediate negative chronotropic and inotropic effects, as well as a decline in peak systolic levels of intracellular calcium (59). In summary, the literature implies that cytokines produce instantaneous and delayed negative inotropic effects in the heart.
2.2.2 Effects of stress-activated cytokines on left ventricular remodeling
Left ventricular remodeling has been used to described multitude of modifications that occur in cardiac size, shape and composition in the failing heart that are not directly related to a pre-load-mediated raise in sarcomere length (62). As revealed in Table 3, proinflammatory cytokines have a number of vital effects on myocardial physiology that may directly contribute to LV remodeling- process, including alterations in fetal gene expression (63), myocyte hypertrophy (38), contractile defects and progressive cardiomyocytes loss through myocyte apoptosis (65). In addition to the above effects, several recent lines of evidence indicate that TNF may promote LV remodeling through adjustment in the extracellular matrix component of the myocardium. Initially, human volunteers were administered endotoxin (a potent stimulus for TNF production) intravenously, resulting in a ~20% increase in LV end-diastolic volume within 5h (41). Secondly, a recent experimental study indicates that when TNF concentration observed in patients with heart failure, there was a time-dependent change in LV dimension, which was attended by advanced degradation of the extracellular matrix (39). Third, transgenic mice that overexpress TNF in cardiomyocytes developed LV dilation that is accompanied by activation of matrix metalloproteinases (MMP), and also an increased denaturation of collagen (66, 67). As indicated in this experimental study, there was progressive loss of fibrillar collagen and increased levels of MMP activation in the hearts of the transgenic mice overexpressing TNF. It will be expected that the dissolution of the fibrillar collagen weave that surrounds the individual cardiac myocytes and links the cardiomyocytes together would allow for rearrangement of the myofibrillar bundles within the ventricular wall (68). However, according to Douglas Mann (2003), long-term stimulation (9-13 weeks) with TNF resulted in an increased fibrillar collagen content that was accompanied by decreased levels of MMP activity and amplified expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) (1). Altogether, these observations imply that sustained myocardial inflammation trigger time-dependant changes in the balance between MMP and TIMP activity. Specifically, during the early stages of inflammation there in amplification in the ratio of MMP activity to TIMP levels ultimately leading to LV dilation. However, with chronic inflammation there is time-dependant increase in TIMP levels, with a consequential increase in myofibrillar content. Studies in experimental models of chronic injury/inflammation in an range of different organs, including lung, liver and kidney (wherein an primary increase in MMP expression is superseded by increased TIMP expression and advanced tissue fibrosis) have implicated the increased expression of TGF-Î² (69, 70). Therefore excessive activation of proinflammatory cytokines may contribute to LV remodeling through a range of different mechanisms that involve both myocyte and nonmyocyte components in the heart.
2.3 Psychology and inflammatory responses in the heart
Depression is a mood disturbance characterized by sleep and appetite disturbances and the alterations of mood and libido that may seriously impact the individual's ability to function at work or in personal relationships (199). Depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as IL-6 and IL-1, may play a fundamental role in the immune and acute phase response in depression (400).
2.3.1 The psychological killer, depression, and inflammation in the heart
Several studies have linked depression to heart disease, both a precursor to and as a risk factor for poor outcomes amoung patients with existing heart failure. Elevated levels of proinflammatory cytokines have been proposed as a potential link between depression and morbidity and mortality associated with heart disease. Proinflammatory cytokines exert negative effects on cardiac function as mentioned previously. Heart failure patients have been found to have considerably higher levels of IL-6 and TNFÎ±, compared to healthy controls (300).
Elevated levels of proinflammatory cytokines, especially IL-6, TNFÎ± and IL-1Î², have been repeatedly associated with major depressive disorder (20-28). Additional to the studies that have assessed the levels proinflammatory cytokines in patients diagnosed with major depressive disorder, various reports have focused on individuals who have elevated symptoms of depression, rather than a diagnosis of major depression. Suarez et al (30) found that symptoms of depression, measured using Beck Depression Inventory BDI), were considerably associated with levels of TNFÎ± and IL-1Î². XXXXXOOO (32) reported the relation between depressive symptoms and levels of TNFÎ± and IL-1Î² in an elderly sample.
Amy Ferketich et al (300) compared heart failure patients with and without symptoms of depression with respect to the proinflammatory cytokines IL-6, TNFÎ± and IL-1Î². The results indicated that heart failure patients who have elevated levels of depressive symptoms according to the BDI score have significantly higher levels of the proinflammatory cytokine TNFÎ± compared with their nondepressed counterparts. Additionally, there was no difference in the levels of IL-6 and IL-1Î² between patients with and patients without depressive symptoms (300).This suggests that there might be a true link between depression and TNFÎ± in heart failure patients.
3. Immune- activated proinflammatory cytokines in the heart
Inflammation is a defensive response to microbial infections or tissue injury and is crucial for the survival of higher organisms in contaminated environments. However, while serving their protective role, inflammatory responses nearly invariably contribute to tissue damage. Most diseases are caused by dysregulation of inflammatory responses that are initiated in the absence of danger or continue even after resolution of the infection or injury. Inflammation is a common event in most tissue with epithelial interfaces with the outside world, and these tissues are frequently able to sustain the damaging effects of acute and chronic inflammation without compromising their essential function. Our capability to tolerate inflammation in various tissues indicates many factors, including regenerative capacity (e.g., in the skin, liver and gastrointestinal tract), internal redundancy (e.g., the biological reserve of the kidney and liver with several independently functioning glomeruli or lobules, respectively) and external redundancy (i.e., paired organs).The heart is a organ without regenerative capacity and without internal or external redundancy. Continuous, uncompromised heart function is, off course, required to sustain life. Although inflammatory processes arise in the heart in different disease states, these are not well tolerated, and a healthy heart rarely harbors any foci of inflammation.
3.1 Beneficial effects of innate immune responses in the heart
The extent of the inflammatory responses is a critical determinant of the host's outcome. Recent evidence suggests that the innate immune response may constitute a component of cardiology that is actually adaptive in the short term. Fundamental to this topic is the finding that proinflammatory cytokines- which are rapidly involved in response to virtually any insult ultimately leading to myocardial damage, including infarction, hypertension, unstable angina, reperfusion injury and heart failure- may constitute a form of postconditioning in the heart (222). Proinflammatory cytokines, namely TNF, IL-1 and IL-6 are synthesized not only by cells of the immune system, but also by cardiomyocytes in response to ischemia or mechanical stretch (35, 36)Additional to the way that these proinflammatory cytokines serve as effectors of innate immunity (functioning as an early warning system to discriminate potential pathogens), expression of these proinflammatory cytokines in the heart may allow the myocardium to respond rapidly to tissue injury as part of an early warning sign coordinating several local homeostatic responses.
This topic is supported by several studies in which pretreatment of rats with TNFÎ± or IL-1Î² present protection for the heart against ischemic reperfusion injury (37-39). This late-phase protection result within 12-24 h of ischemic stress, lasting for approximately 4 days and is similar to that observed with sublethal stressors such as hyperthermia, transient ischemia or exercise (40-42). Supporting this finding, neutralizing antibodies to both TNFÎ± and IL-1Î² eliminated the protective preconditioning induced by transient cardiac ischemia (43). One potential mechanism, earlier mentioned, involves MnSOD, which was induced in the heart during infusion of these proinflammatory cytokines but was blocked in the neutralization studies. Inhibition of MnSOD using oligodeoxynucleotide eliminates the predicted cardioprotective effect following ischemic preconditioning (43). Recently, a protective role for the proinflammatory cytokine IL-6 was demonstrated when mice lacking IL-6 failed to show cardioprotective effects associated with ischemic preconditioning. This loss of preconditioning effect paradigm decreases in activation of the JAK-STAT pathway and reduced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX 2) (44). In fact, the inflammatory cytokines TNFÎ±, IL-6 and IL-1Î² promote reduction in cardiac contractility (45, 46), which may comprise an adaptive strategy to limit myocardial energy demand in an ischemic site. These cytokines also promote early wound repair, including resorption of tissue debris and phagocytosis, synthesis and degradation of matrix components such as integrins and collagens, angiogenesis and proliferation of myofibroblasts and to a partial extent, progenitor cell proliferation (47-49). In supporting of the above statement, anti IL-1Î² treatment early postinfarction leads to reduced wound healing and delayed collagen deposition (50), as does steroid treatment prior to myocardial infarction (51).
The Toll-like receptor (TLR)-IRAK1 signaling pathway is another innate immune system linked to IL-1 pathway that may have cardioprotective properties under certain circumstances. Lipopolysaccharides (LPS), which signal through TLR4, can protect the heart from ischemic injury, and TLR4 signaling can protect cardiomyocytes from apoptosis (52, 53). Therefore, indirectly, IL-1 has beneficial effects in protecting the cardiomyocytes against apoptosis. Contradictory, TLR4-deficient mice are more resistant to ischemic reperfusion injury in the myocardium (54). Additionally, indirectly, IL-1-deficient mice are prone to resistance to ischemic reperfusion injury in the heart. These distinct findings highlight the complexity in isolating beneficial effects of the innate immune response from the maladaptive effects discussed in the following section.
3.2 Maladaptive effects of innate immune responses in the heart
Although the transient, self-limited expression of inflammatory cytokines may serve a essentially cardioprotective role in the acute setting by promoting cell survival and wound healing, there is increasing evidence that these inflammatory mediators promote lethal effects in the heart over time (222). Persistent expression of proinflammatory cytokines, e.g., as a result of an immense infarct or sustained robust host responses, can lead to a second signal of cytokine upregulation that may extend to involve noninfarcted regions and contribute to remodeling of the entire myocardium (55-57). Activation of additional inflammatory-cell signaling can contribute to considerable myocyte hypertrophy, which helps maintain cardiac output following cardiomyocytes loss, but can chronically lead to ventricular dysfunction (58). This is remarkably illustrated in several murine transgenic models of cardiac-specific overexpression of TNFÎ±. Consistently; these animals display myocardial hypertrophy resulting in interstitial fibrosis, inflammatory-cell infiltration and DCM (59-61).
Increased fibrosis results as the infracted myocardium is replaced by scar tissue. It is crucial that chronic, continuous presence of cytokines, which activate matrix metalloproteinases, also promotes interstitial fibrosis and deposition in noninfarcted zones. This ultimately leads to irregular acceleration in extracellular remodeling as the initial degradation gives way to new fiber deposition and redistribution of integrins at the interface between matrix and myocyte (47). Cardiac fibroblasts seem to hold unique properties relative to other fibroblast types, and the mechanisms that direct resolution of acute injury responses versus the switch to chronic activation of cardiac fibroblasts are poorly understood. Fascinatingly, these cells are particularly responsive to IL-1Î², which induces iNOS and tissue growth factor-beta 1(TGFÎ²1) with consequent promotion of matrix remodeling and other pleiotropic effects in the heart (62). Although adaptive at various levels, excessive scar development critically diminishes myocardial compliance, which contributes to diastolic and ultimately systolic dysfunction, disrupts myocyte-to-myocyte electrical connectivity, and further aggravates the cycle of ischemic stress-inflammatory-stress.
Despite intriguing reports suggesting the persistent renewal of a small subpopulation of cardiomyocytes derived from differentiating cardiac stem cells, infracted myocardium is replaced tremendously with scar tissue (5, 6, 63, and 64). Several reports with positive TUNEL assay staining in hearts following acute myocardial infarction implies that apoptosis is prominent (65, 66)
Interestingly, the detrimental cycle of cytokine amplification that contributes to myocardial remodeling can be managed significantly with timely interventions of angiotensin-converting enzyme inhibitors, statins, or Î²-blockers. (69-75). These therapies show reassurance in improving morbidity and mortality from heart failure, potentially associated to their increasingly recognized pleiotropic effects as anti-inflammatory modulators (76-78).While the revolutionary description of elevated inflammatory cytokines in patients with heart failure in 1990, there has been mounting appreciation of the pathophysiologic consequences of continuous inflammation in the heart. Nonetheless, clinical trials targeting neutralization of TNF in patients with significant heart failure were stopped prematurely due to worsening heart failure (79, 80). These findings underscore the inflammatory contributions of the innate immune response to cardiac function.
3.3 Metabolic contributions to inflammation
The obese gene product, leptin, plays a central role in food intake and energy metabolism. Evidence has imply that leptin play a specific role in the intricate of cardiovascular events, in addition to its well-established metabolic effects. Released by adipose tissue, leptin is considered the hormonal signal linking the peripheral adipose tissue to the central nervous system (CNS) for the control of appetite and energy expenditure (1441). Leptin has structural homology to TNFÎ±, IL-6 and other cytokine family proteins, and is therefore considered a cytokine-like substance (1234). Plasma leptin levels are associated with the propensity of certain cardiac damage in patients with acute myocardial infarction (701).
While acute, over a span of 90 min, leptin infusion failed significantly to alter the heart rate, but contrasting chronic leptin treatment over one week elicited a significant increase in heart rate along with an increase in sympathetic nervous system activity (399). A surprising positive correlation between hyperleptinemia and tachycardia was confirmed in mildly obese or mildly hypertensive human subjects (401). Additionally, an increase in heart rate may enhance cardiac output and provide short-term beneficial effects; sustained tachycardia may lead to cardiac hypertrophy and ultimately result in heart failure. The individuals with a higher heart rate will impose a greater myocardial workload and therefore predispose the heart to pathophysiological changes, leading to congestive heart failure and myocardial infarction (402).
Other signaling pathways have also been focused in the leptin- induced cardiac effect. Specifically, the adenylate cyclase complex has been shown to be affected by leptin in the H9c2 cardiac cell line. Differences in adenylate cyclase activity after short- and long- term exposure to leptin and the interaction between leptin and sympathetic nervous system catecholamine neurotransmitters is believed to play a central role in the development of hypertension and congestive heart failure in obese patients (403).
Leptin has also been demonstrated to activate fatty acid oxidation and decrease triglyceride levels without affecting glucose oxidation over a 60-min perfusion period (403). Although leptin did not affect cardiac work, it increased oxygen consumption and decreased cardiac efficiency (404). Patients with advanced congestive heart failure exhibit elevated plasma levels of leptin, indicating that leptin may participate in the catabolic state leading to the development to cardiac cachexia (405). Therefore; a high concentration of plasma leptin levels can be detrimental in the cardiac setting, in promote cardiac inefficiency.
3.4 Immunology and inflammatory responses in the heart
The body's ability to protect itself from viruses, bacteria and other disease-causing entities is known as immunity. The immune system consists of the lymphoid tissue of the body, the immune cells, and the chemicals that coordinate and execute immune functions. The immune system serves three major functions, namely; it protects the body from disease-causing invaders (pathogens), it removes dead or damaged cells and it tries to recognize and remove abnormal cells, respectively. Detection, identification and the attack on the invader all depend on the signal molecules, cytokines. If incorrect responses occur, it can lead to the formation of an autoimmune disease (199)
3.4.1 Proinflammatory cytokine genes are constitutively overexpressed in Systemic Lupus Erythematosus: Autoimmune disease and inflammation
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of the unknown etiology, accompanied by the involvement of the heart in approximately 50% of all cases (1-5). Although all mortality cases due to SLE-related illness have declined during the last 2 decades; the risk of cardiovascular morbidity in lupus has remained unchanged (6-8). Lupus may affect the endocardium, pericardium, myocardium, heart valves, coronary arteries and conduction system (9, 10). Independently of the site anatomical participation or its etiology, inflammation is thought to play a critical role in the pathogenesis of cardiovascular disease in SLE. Thus, endocarditis, pericarditis, myocarditis and coronary arteritis typically occur in the highly active lupus and coronary heart disease in SLE is more observed in poorly controlled disease (12, 13).
Peripheral inflammation is mirrored in part by the production of acute phase reactants such as serum amyloid A (SAA) and C-reactive protein (CRP). Elevated systemic levels of these proinflammatory markers are associated with adverse prognoses in unstable angina and appear to predict consequent cardiac events (14-17). The synthesis of SAA and CRP by hepatocytes is transcriptionally upregulated by proinflammatory cytokines, most outstandingly IL-6, TNFÎ± or IL-1Î². These cytokines have been found in functionally and structurally damaged areas of the heart and have been implicated in the pathogenesis of this disease (125).
In diseases characterized by leukocytic infiltration, such as monocytes, macrophages, myocarditis and T-cells are conventionally thought to account for the spectrum of cytokines found in the heart (23). In artherosclerotic cardiovascular disease, mononuclear cells are also potential sources of cytokine production.
On theoretical grounds, cytokine production in the heart may originate not only from infiltrating leukocytes but also from cardiomyocytes. In this relation multiple cytokines cascades have been shown to be activated within the myocardium in experimental pathological states, namely myocardial infarction and in an experimental model of congestive heart failure, cardiomyocytes from both the atria and ventricle were found to produce leukemia inhibitory factor (LIF) , a cytokine capable of instigate cardiac hypertrophy (29, 30). Michiyo et al (2004) (125) main reason in this experimental topic was to explore the possibility that cardiomyocytes may be involved in cytokine production in the setting of inflammation, therefore they examined constitutive gene expression in the heart of MRL/MpJ-Tnfrs6lrp (MRL-lpr/lpr ) mice, a murine model of SLE. These mice spontaneously developed autoimmune syndrome characterized clinically by arthritis and immune-complex glomeruloephritis, immunologically by deregulated cytokines in multiple tissue, and serologically by autoantibodies to Smith antigen and native DNA, which are pathognomonicod human lupus (35).These mice resist atherosclerosis unless given a diet high in saturated fat.
The results indicated that ventricular myocytes from autoimmune MRL-lpr/lpr mice express high levels of genes that encode proinflammatory cytokines (IL-2 and IL-10) in the absence of atherosclerosis or mononuclear cell infiltrates (125). Implied in the findings is suggestion that under chronic systemic inflammation, as occur in many connective tissue diseases, mediators derived from the myocardium may contribute to the pathogenesis of heart disease. Genes encoding TNFÎ± was not amoung those that were overexpressed in MRL-lpr/lpr cardiomyocytes. TNFÎ± drives inflammation in rheumatoid arthritis (RA), has been associated with vascular injury in chronic inflammatory states, and may induce the production of both IL-6 and IL-1Î² (125). Alternatively, the genes encoding TNFÎ± was equally expressed in autoimmune and normal cardiac myocytes, enhanced expression of IL-6 and IL-1Î² was observed only in the setting of autoimmunity. One promising explanation for this finding is that TNFÎ± mRNA is differentially regulated posttranscriptionally in autoimmune and normal hearts.
This finding may be particular significant to disease such as SLE and RA, which are typically accompanied by elevated plasma levels of proinflammatory cytokines when clinically active (44). These connective tissue diseases are correlated with a significant incidence of cardiovascular disease. These observations described here suggest that systemic inflammation, a consequence of poorly controlled disease activity in SLE and RA, may be accompanied by the production of proinflammatory cytokines by the cardiomyocytes. Hypothetically, these cytokines may act in a paracrine or autocrine manner to promote the generation of pro-oxidant molecules, such as nitric oxide and superoxide, and eventually generate damaging free radicals, such as peroxynitrite and hydroxyl ions. In these patients, proinflammatory cytokines originating from the heart, such as IL-6 and IL-1Î², if produced in sufficient amount may enter the periphery and transcriptionally upregulate hepatocytes to produce CRP.
I have summarized from researched papers that activation of proinflammatory cytokines in the heart following acute cardiac injury may have beneficial or detrimental consequences for the host, depending on the degree and duration of proinflammatory cytokine exposure. Specifically, short-term expression of proinflammatory cytokines, due to response to stress or immune activation, may be beneficial by upregulating the expression of families of protective proteins in the heart, as well as by incorporating the various components of the myocardial stress response, i.e., cardiac remodeling, cardiac repair and cardiac hypertrophy. Regardless of this statement, the short-term beneficial effects of proinflammatory cytokine activation may be lost if myocardial expression of these molecules becomes either sustained and/or excessive, in which case the beneficial effects of these proteins may be contravened by their known deleterious effects.