Molecular Medicine

, Volume 14, Issue 5–6, pp 327–336 | Cite as

Molecular Events in the Cardiomyopathy of Sepsis

  • Michael A. Flierl
  • Daniel Rittirsch
  • Markus S. Huber-Lang
  • J. Vidya Sarma
  • Peter A. WardEmail author
Open Access
Review Article


Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression.


Early pioneering reports sought to distinguish between two distinct clinical profiles of septic shock and associated “warm shock” with warm, dry skin, a pounding pulse despite hypotension, and high cardiac output. This was observed in the initial phase of hospitalization due to septic shock. In contrast, “cold shock” seemed to be related to low cardiac output and was correlated with the later clinical stages of septic shock before patients succumbed to sepsis (1, 2, 3). Based on these findings, it was concluded that patients during septic shock initially encountered an early hyperdynamic phase from which they either recovered or declined into a hypodynamic phase associated with myocardial depression, heart failure, and death (4). This principle was initially supported by experimental models, demonstrating that septic shock associated with reduced cardiac output and elevated systemic vascular resistance led to the death of animals (5,6). However, these concepts were substantially challenged when Wilson et al. (7) linked septic shock in humans with normal, or even elevated, cardiac output (and very rarely with low cardiac output) and decreased systemic vascular resistance in adequately resuscitated septic patients. Subsequent studies using pulmonary artery catheters confirmed that sufficient fluid resuscitation in septic shock patients manifested a hyperdynamic circulatory state with high cardiac output, decreased systemic vascular resistance, normal stroke volume, and high heart rate (8, 9, 10, 11)—even in nonsurvivors (12). Therefore, it was concluded that the initial depiction of cold shock-associated decreased cardiac output was likely related to hypovolemia due to inadequate volume loading of septic shock patients, rather than being involved in mechanisms leading to lethality.

First evidence for myocardial suppression in patients with septic shock was published in 1984 (13). All observed patients presented with high cardiac output maintained their stroke volume index, and displayed decreased systemic vascular resistance. It was further reported that 75% of patients exhibited decreased left ventricular ejection fraction after the onset of septic shock over a two-day period. However, one of the most striking findings in the study was that depression of the left ventricular ejection fraction, as well as the observed acute left ventricular dilatation, were reversible and returned to normal levels after 7 to 10 days in surviving patients (13). This was later confirmed in further patient studies and experimental settings (14, 15, 16, 17). In more recent studies, predominantly using echocardiography, cardiac dysfunction during sepsis and septic shock has been confirmed (18, 19, 20, 21). To date, it is now generally accepted that, after adequate volume resuscitation, patients develop a hyperdynamic circulatory state associated with high cardiac output, decreased systemic vascular resistance, and biventricular dilatation. Here, we describe supracellular, systemic, and various molecular mechanisms that might be involved in septic cardiomyopathy, such as circulating cardiosuppressing mediators, alterations of calcium flux in cardiomyocytes, involvement of nitric oxide and peroxynitrite, as well as mitochondrial dysfunction and apoptosis.

Systemic, Supracellular Mechanisms

Decreased Coronary Blood Flow

One of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined.

Alterations of Microvasculature

There is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31).

Cardiosuppressing Circulating Proinflammatory Mediators

Another hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis and have been found to directly depress myocardial contractility in vitro (34, 35, 36). It is noteworthy that cardiomyocytes are able to generate TNF-α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage migration inhibitory factor (MIF), and high-mobility group box (HMGB)-1 during endotoxemia, sepsis, and burn injury (37, 38, 39). This is a seemingly paradoxical phenomenon because such cardiomyocyte products would impair cardiomyocyte performance (Figure 1). Our understanding of this negative feedback loop to date remains elusive, but in many respects it is analogous to products of the inflammatory response that are tissue-damaging as opposed to products that are tissue-protective (40). During sepsis the complement anaphylatoxin C5a has been described to be involved in immuno-paralysis (41), multiple organ failure (42), thymocyte apoptosis (43), and imbalance of the coagulation system (44). Recently, C5a has also been found to play a major role in septic cardiomyopathy (36). Following experimental sepsis, reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro, both of which could be reversed by in vivo administration of a blocking antibody to C5a (Figure 2). in vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and septic cardiomyocytes, suggesting that excessive in vivo generation of C5a during sepsis causes dysfunction of cardiomyocytes (36).
Figure 1

Flowchart of the presumed intracellular signaling in cardiomyocytes leading to myocardial production of cardiodepressant mediators.

Figure 2

Myocardial contractile dysfunction sepsis might, in part, be triggered by C5a. Question marks illustrate open, to date unanswered, questions.

Despite all these findings, isolated rabbit papillary muscles or rat cardiomyocytes harvested during the acute phase of sepsis and ex vivo studies show a persistent decrease in contractility in spite of the absence of direct contact with septic plasma (36,45,46). This raises questions as to whether cardiodepressant factors in serum represent an exclusive pathophysiological mechanism of sepsis-associated cardiomyopathy.

Metabolic Changes

Various profound metabolic changes have been described in the cardiomyocyte during sepsis and septic shock. Patients in severe sepsis and septic shock display a 30% increase of oxygen consumption and baseline metabolism compared with normal basal values, but both are markedly reduced compared with “uncomplicated” sepsis (47). Once organ dysfunction develops, however, oxygen consumption and resting metabolic rate decrease, suggesting that, during multiple organ failure, patients seem to tolerate lower values of oxygen supply (48). Moreover, prolonged sepsis has been found to be associated with progressive increase in tissue oxygen tension paralleling the severity of illness (49,50). It has therefore been speculated whether, during severe sepsis, cells utilize less oxygen, rather than suffering from a defective oxygen delivery to tissues. Whereas sepsis is generally associated with increased blood levels of lactate, septic human hearts exhibited a net lactate extraction between arterial and coronary sinus blood (22). In a recent human autopsy study of patients who had succumbed to severe sepsis, buildup of lipids was found inside cardiomyocytes (51). During sepsis, human cardiomyocytes have also displayed diminished uptake of ketone bodies, free fatty acids, and glucose (23). In parallel, septic mice presented with increased intracardiomyocyte deposits of glycogen (52).

Autonomic Dysfunction

Septic shock has been found to be associated with neuronal and glial apoptosis within cardiovascular autonomic centers (53,54), raising the question whether failure of cardiac modulation by the autonomic nervous system might contribute to septic cardiomyopathy. Other reports linked high levels of circulating catecholamines with the onset of septic shock but found impaired sympathetic modulation on heart and vessels, suggesting that central autonomic regulatory impairment contributes to circulatory failure (55). Moreover, impaired function of the autonomic nervous system is associated with an increased risk for death from critical illness (56). Thus, innovative pathophysiologic concepts targeting autonomic dysfunction in life-threatening disease emerge as a new clinical and scientific challenge (57, 58, 59, 60).

Cellular Molecular Mechanisms

In addition to the circulating cardiodepressing factor theory, a second concept was developed, focusing on intrinsic alterations in the myocardium as a predominant mechanism of septic cardiomyopathy (see below). It remains to be determined if and to what extent cytokines, chemokines, and C5a participate in the initiation of these intracellular events, which would link the two hypotheses.

Calcium Flux and Cardiomyofilaments

There is now increasing evidence that sepsis induces significant alterations in the myocardial calcium homeostasis in two ways. First, abnormalities in the myocardial calcium current have been described in endotoxemic guinea pigs (61), as well as in cultured rodent cardiomyocytes exposed to the cardiodepressive IL-1β (62). In line with these findings, myocardial L-type calcium channels have been found to be decreased during endotoxemia (63). Second, a reduction in myofilament calcium sensitivity has been reported in endotoxemic rabbits (64,65). The exact mechanisms of these observations are only partially understood, but the decreased response of myofilaments to calcium may be involved in the impaired myocardial contractility and depression of systolic function in septic patients. Indeed, reduced calcium sensitivity of myofilaments seems to be associated with increased cardiomyocyte length and increased ventricular distensibility (66). Recently, scattered foci of disruptions in the actin-myosin contractile apparatus were described in septic human hearts (51). Moreover, myocardial Ca2+ transport across membranes of the sarcoplasmic reticulum (SR) plays a central role in cardiac contraction-relaxation sequence (Figure 3). The density of the calcium release-triggering ryanodine receptor is decreased on the SR during experimental sepsis, associated with subsequent impairment of Ca2+ release from the sarcoplasmic reticulum (67). Transient increases of intracellular Ca2+ activate myofilament proteins to cause myocardial contraction. The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) subsequently translocates cytoplasmatic Ca2+ back into the SR, a process that is tightly controlled by a closely associated SR membrane protein, phospholamban (PLB) (68). Dephosphorylated PLB activates and enhances SERCA2 activity, whereas phosphorylation of PLB greatly diminishes SERCA2 functionality and myocardial relaxation (68,69). Thus, PLB and SERCA2 interactions play a primary role in regulating cardiac contractility and relaxation. Calcium uptake by sarcoplasmic reticulum has been shown to be impaired during the hypodynamic phase of sepsis in the rat heart (70). The resulting decrease in myocardial contractility during the hypodynamic phase might also, in part, be induced by a decrease in phospholamban phosphorylation, which leads to decreased Ca2+ transport across the SR (71). In sharp contrast, during the early hyperdynamic phase of sepsis, the interaction between phospholamban phosphorylation and Ca2+ transport across the SR seems to be largely disrupted, represented by an increase in phospholamban phosphorylation (71).
Figure 3

Physiologic regulation of calcium flux in cardiomyocytes.

Toll-like Receptors and CD14

Toll-like receptors (TLRs) have been identified as primary receptors of innate immunity that distinguish between different patterns of pathogens and evoke a rapid innate immune response (72). To date, nine TLRs have been identified and characterized (72). Various studies have identified the expression of human TLRs, including TLR2, TLR4, and TLR6 in the heart (73, 74, 75). The importance of myocardial TLR signaling was established when TLR4 or IRAK1 (IL-1 receptor-associated kinase 1; a downstream signaling component of TLR4) deficient mice were found to be protected from LPS-induced cardiac dysfunction, as determined by echocardiogram (76,77). When mice were subjected to LPS challenge, the rapid and robust induction of NF-κB, subsequent increase of TNF and IL-1β mRNA, and protein expression in cardiomyocytes were significantly ameliorated and delayed in TLR4-mutant mice (78). These findings indicate that TLR4 signaling is responsible, at least in part, for the induction of myocardial proinflammatory mediators during endotoxemia.

CD14 is a 55-kD glycosylphosphati-dylinositin-anchored receptor that binds LPS with affinity and is critically involved in mediating LPS responses (79). Subsequently, CD14-deficient mice were shown to be protected against LPS-induced septic shock (80). Cardiomyocytes from CD14-deficient mice exhibited decreased activation of NF-κB, blunted consequent downstream expression of myocardial mRNA, and protein levels of TNF and IL-1β during endotoxemia (81). Moreover, endotoxemic CD14-/- mice maintained normal cardiac function, whereas wild-type littermates displayed decreased left ventricular shortening and diminished velocity of circumferential shortening and left ventricular pressure/time (dP/dtmax) (81). Because CD14 lacks a transmembrane domain, however, the exact mechanism by which LPS binding to CD14 induces cell activation remains to be determined.

β-Adrenergic Receptors

Catecholamines are known to increase cardiac contractility and heart rate via interaction with β-adrenoceptors expressed on the myocardium. However, if these receptors are excessively stimulated or engaged over an extended period of time, myocardial damage by calcium overload and subsequent cell necrosis have been reported (82). Septic patients are known to be exhibit increased levels of catecholamines (55,83,84). These findings have been confirmed in various animal studies (85,86). In a murine model of sepsis, decreased density of β-adrenoceptors on the myocardium was reported (87,88). However, other reports linked the myocardial contractile dysfunction to cytokine stimulation, as β-adrenoceptor density was found to be normal (89). Importantly, there seems to be significant disruption of the myocardial signal transduction following β-adrenoceptor stimulation. Endotoxemic rabbits displayed decreased levels of stimulatory G-proteins (90), and septic rats exhibited increased expression of inhibitory G-protein (91), which was also reported in the myocardium of human nonsurvivors of septic shock (92). These events are likely to decrease the activity of the adenylyl cyclase, resulting in decreased intracellular levels of cyclic adenosine monophosphate (cAMP), paralyzing the cardiomyocyte. Thus, it remains to be determined whether a blunted β-adrenoceptor stimulation, disruption of the signaling cascades further downstream, or a combination of both are involved in septic cardiomyopathy.

MAPK Signaling Cascades

Many extracellular stimuli recognized by mammalian cells engage a highly complex intracellular signaling network, at the center of which are involved the mitogen-activated protein kinases (MAPKs). The most extensively studied members of the MAPKs are extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK) (93). In cardiomyocytes, MAPK activation has been linked to a wide array of cellular events, including apoptosis (94,95), ischemia/reperfusion injury (96), and ischemic heart failure (97). It remains to be determined if myocardial MAPK activation also occurs during sepsis (Figure 1), and if MAPKs are also engaged in other myocardial defects like disturbance of sarcoplasmic calcium flux, etc. (see above).

Matrix Metalloproteinases

Matrix metalloproteinases (MMPs) comprise a large family of zinc-dependent endopeptidases that have been recognized for their ability to degrade components of the extracellular matrix. Increased MMP activity has been associated with a wide variety of cardiovascular pathologies, including acute and chronic heart failure and atherosclerosis (98, 99, 100, 101). MMP-2 activation and release has been found to mediate acute cardiac failure following ischemia-reperfusion injury through cleavage of troponin I (102,103). Recent studies have also demonstrated an important role for MMPs during septic cardiomyopathy. Endotoxemic rats were found to have significantly depressed cardiac function, loss of ventricular 72-kD MMP-2, and release of MMP-9 (104). MMP inhibitors significantly preserved cardiac function during LPS-induced septic shock and reversed these observations (104). In an ovine sepsis study, cardiac MMP-2 and MMP-9 activity positively correlated with heart rate and negatively correlated with left ventricular stroke work index, and increased MMP-2 and MMP-9 activities were positively correlated with cardiomyocyte apoptosis (105).

Nitric Oxide and Peroxynitrite

Excessive production of nitric oxide (NO) is an important player during hypotension and catecholamine resistance in septic shock (106). However, its role and impact on septic cardiomyopathy is still a matter of debate. Whereas disproportionate levels of NO sustain the ability of the left ventricle to fill during diastole, and thereby crucially support adequate myocardial perfusion (107,108), cardiodepressant activity of proinflammatory cytokines also seems to involve NO synthase (NOS): exposure of rat cardiomyocytes to septic sera depressed contractility (see below), but NOS inhibition restored contractility to control levels (109). Moreover, intracoronary infusion of the NO donor sodium nitroprusside impaired systolic pressure development despite improved diastolic relaxation and distensibility (110). Finally, deficiency or selective blockade of inducible NOS (iNOS) protected against the development of cardiac dysfunction in endotoxemic mice (111,112). In a cecal ligation and puncture (CLP) sepsis model, genetic iNOS deletion or pharmacological iNOS blockade enhanced cardiac norepinephrine responsiveness associated with improved systolic function, but seemed to be associated with compromised left ventricular relaxation (113). In septic patients, administration of a nonspecific NOS inhibitor increased arterial pressure but decreased cardiac output (114). The adverse effects of NO might also, in part, be related to interactions between NO and superoxide anions with subsequent production of peroxynitrite. Peroxynitrite, rather than NO per se, has been shown to impair muscle contractility during sepsis by its ability to denature proteins, perturb calcium flux, and depress mitochondrial respiration during experimental sepsis (115,116). In contrast, neutralization of peroxynitrite improved cardiac dysfunction in a rodent model of sepsis (117). In human septic hearts, increased expression of iNOS and significant amounts of peroxynitrite were found (51). Finally, NO, produced in large amounts during sepsis, can bind to complex IV of the respiratory chain and then compete with oxygen, inhibiting this complex and increasing production of reactive oxygen species (ROS) (3). High concentrations of NO also seem to block other complexes of the respiratory chain. Peroxynitrite can also be very toxic for the respiratory chain and particularly inhibits complexes I, II, and III (3).

Mitochondrial Dysfunction

Sepsis and septic shock severely impair the “cellular power plants,” mitochondria (118,119). Recent evidence suggests that the severity of myocardial dysfunction and maybe even severity and outcome of sepsis (120) could be related to mitochondrial dysfunction (121, 122, 123). During sepsis, myocardial mitochondria display ultrastructural damages in rodents (124,125) and humans (126). Septic animal hearts exhibited reduced activities of mitochondrial electron transport chain enzyme complexes (127, 128, 129). The increased mitochondrial production of superoxide and NO (130) in combination with the depletion of intramitochondrial antioxidants during sepsis might severely inhibit oxidative phosphorylation and ATP generation (120). This acquired defect in oxidative phosphorylation prevents cells from using molecular oxygen for ATP production and potentially causes sepsis-induced organ dysfunction (131). This concept has been termed “cytopathic hypoxia” (132,133). Interestingly, mitochondrial DNA seems to be more receptive to LPS-induced damage than nuclear DNA (124,134). Finally, the mitochondrial permeability transition pore seems to be involved in sepsis-induced mitochondrial damage in the myocardium, because its inhibition significantly improved cardiac function and reduced mortality in rodents (135).


There is now increasing evidence that apoptosis is involved in septic cardiomyopathy (136, 137, 138). Activation of various caspases, the effectors of apoptosis, and mitochondrial cytochrome c release have been reported in cardiomyocytes following septic challenge (139, 140, 141). Caspase 3 activation via endotoxin might also be associated with altered calcium myofilament responses, cleavage of contractile proteins, and sarcomere disorganization (142). Therefore, it is not surprising that anti-apoptotic strategies have reversed cardiac dysfunction (inhibition of caspases [particularly caspase 3] averted endotoxin-induced cardiac dysfunction and heart apoptosis) (137,143). Cyclosporin A, which inhibits mitochondrial permeability transition and cytochrome c release, or overexpression of anti-apoptotic Bcl-2 both prevented sepsis-induced myocardial dysfunction (135,144,145). Yet, there seem to be additional parameters involved in the caspase inhibitor-mediated cardioprotection, besides decreasing apoptotic cell death. Blockade of caspase activation may decrease cytokine/chemokine production and indirectly influence intracellular calcium homeostasis (3). However, the time course of septic cardiomyopathy in humans (potential recovery after 7 to 20 days) profoundly challenges a central role of apoptotic cell death as a major cause of myocardial impairment. We need to understand more precisely the involvement of apoptosis in this setting.


Although tremendous research efforts have attempted to uncover the molecular mechanisms resulting in septic cardiomyopathy (Figure 4), various pieces of the puzzle so far fail to come together as a big picture. Why? Despite the identification of various mechanisms contributing to sepsis-induced cardiac dysfunction (such as cardiodepressant mediators, mitochondrial dysfunction, or apoptosis), we are far from understanding their exact impact. Each theory has a major flaw that challenges its principles. Cardiodepressant mediators, such as TNF-α, IL-1β, IL-6, MIF, etc., are known to be elevated early during sepsis, but return to normal levels within 2 to 3 days. Thus, cytokine/chemokine involvement in early cardiodepression seems possible. However, because cardiodepression is usually reversed only 7 to 10 days after sepsis onset in humans, myocardial suppression by cytokines/chemokines during the late stages of sepsis seems highly unlikely, unless these mediators are predominantly stored inside cardiomyocytes and exert their functions mainly without being secreted. However, this would infer functions of mediators without their interactions with surface receptors. Moreover, if apoptosis is a driving force in cardiac dysfunction during sepsis, as various studies suggest, we have yet to understand how septic cardiosuppression can be reversible after 7 to 10 days. Thus, is apoptosis signaling somehow stopped at a pre-apoptotic level; and if so, by what molecular mechanisms? It seems that the abnormalities leading to contractile myocardial dysfunction during sepsis are transient and that a “corrective switch” exists, once profound sepsis is overcome, reversing cardiomyopathy.
Figure 4

A depiction of supracellular, systemic, and molecular events involved in the cardiomyopathy of sepsis. See text for details.

The explanations for all of these questions and challenges might lie in the fact that the sepsis-induced depressed cardiac performance recapitulates the changes that occur during cardiac hibernation, an adaptive and reversible response otherwise seen in ischemia and hypoxia (52). Although these changes occurred in the setting of preserved arterial oxygen tension and myocardial perfusion, sepsis-associated myocardial depression might in fact be a form of cardiac hibernation, triggered by the same metabolic changes (increased glucose uptake, glycogen deposits, and increased steady-state levels of GLUT4) that have been described during ischemia and hypoxia (52). Hibernation is currently considered not only as a simple consequence of an oxygen deficit, but rather as an adaptive response to maintain cardiomyocyte viability in the setting of reduced blood flow (146). In stunning parallel with septic cardiomyopathy, the hibernating myocardium exhibits reduced calcium responsiveness (147), ultrastructural changes including loss of myofibrils (148), loss of mitochondria (149), and apoptosis-induced cell loss (150,151). Moreover, there is evidence that TNF-α and iNOS contribute to myocardial hibernation (152). Interestingly, these changes seem to be dose dependent, with moderate increases leading to reversible myocardial dysfunction, and greater increases resulting in irreversible injury (148). Thus, a crucial question is whether exceeding a certain threshold level of TNF-α, iNOS, or further unidentified mediators triggers the conversion from reversible to irreversible myocardial dysfunction. This remains to be determined.



We are indebted to Robin Kunkel for her excellent assistance in the composition of the illustrations. We also thank Beverly Schumann and Sue Scott for their assistance in the preparation of this manuscript.

This study was supported by NIH grants GM29507, GM61656, and HL-31963 (P.A.W.) and Deutsche Forschungsgemeinschaft grants DFG HU 823/2-2 and HU 823/2-3 (M.H.-L).


  1. 1.
    MacLean LD, Mulligan WG, McLean AP, Duff JH. (1967) Patterns of septic shock in man: a detailed study of 56 patients. Ann. Surg. 166:543–62.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Waisbren BA. (1951) Bacteremia due to gramnegative bacilli other than the Salmonella; a clinical and therapeutic study. AMA. Arch. Intern. Med. 88:467–88.CrossRefPubMedGoogle Scholar
  3. 3.
    Rabuel C, Mebazaa A. (2006) Septic shock: a heart story since the 1960s. Intensive. Care. Med. 32:799–807.CrossRefPubMedGoogle Scholar
  4. 4.
    Clowes GH Jr, Vucinic M, Weidner MG. (1966) Circulatory and metabolic alterations associated with survival or death in peritonitis: clinical analysis of 25 cases. Ann. Surg. 163:866–85.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Maclean LD, Spink WW, Visscher MB, Weil MH. (1956) Studies on the circulatory changes in the dog produced by endotoxin from gram-negative microorganisms. J. Clin. Invest. 35:1191–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Postel J, Schloerb PR. (1977) Cardiac depression in bacteremia. Ann. Surg. 186:74–82.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wilson RF, Sarver EJ, LeBlanc PL. (1971) Factors affecting hemodynamics in clinical shock with sepsis. Ann. Surg. 174:939–43.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Packman MI, Rackow EC. (1983) Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic shock. Crit. Care Med. 11:165–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Gunnar RM, Loeb HS, Winslow EJ, Blain C, Robinson J. (1973) Hemodynamic measurements in bacteremia and septic shock in man. J. Infect. Dis. 128(Suppl):295–8.CrossRefGoogle Scholar
  10. 10.
    Winslow EJ, Loeb HS, Rahimtoola SH, Kamath S, Gunnar RM. (1973) Hemodynamic studies and results of therapy in 50 patients with bacteremic shock. Am. J. Med. 54:421–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Krausz MM, Perel A, Eimerl D, Cotev S. (1977) Cardiopulmonary effects of volume loading in patients in septic shock. Ann. Surg. 185:429–34.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE. (1987) Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit. Care Med. 15:923–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Parker MM, et al. (1984) Profound but reversible myocardial depression in patients with septic shock. Ann. Intern. Med. 100:483–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. (1990) Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 97:126–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Ellrodt AG, et al. (1985) Left ventricular performance in septic shock: reversible segmental and global abnormalities. Am. Heart. J. 110:402–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Natanson C, et al. (1989) Role of endotoxemia in cardiovascular dysfunction and mortality: Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J. Clin. Invest. 83:243–51.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Natanson C, et al. (1989) Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J. Exp. Med. 169:823–32.CrossRefPubMedGoogle Scholar
  18. 18.
    Jones AE, Craddock PA, Tayal VS, Kline JA. (2005) Diagnostic accuracy of left ventricular function for identifying sepsis among emergency department patients with nontraumatic symptomatic undifferentiated hypotension. Shock 24:513–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Jardin F, et al. (1999) Persistent preload defect in severe sepsis despite fluid loading: a longitudinal echocardiographic study in patients with septic shock. Chest 116:1354–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA. (1997) Left ventricular systolic and diastolic function in septic shock. Intensive Care Med. 23:553–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Charpentier J, et al. (2004) Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit. Care Med. 32:660–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. (1986) The coronary circulation in human septic shock. Circulation 73:637–44.CrossRefPubMedGoogle Scholar
  23. 23.
    Dhainaut JF, et al. (1987) Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 75:533–41.CrossRefPubMedGoogle Scholar
  24. 24.
    Wu AH. (2001) Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med. 27:959–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Lanone S, et al. (2000) Muscular contractile failure in septic patients: role of the inducible nitric oxide synthase pathway. Am. J. Respir. Crit. Care Med. 162:2308–15.CrossRefPubMedGoogle Scholar
  26. 26.
    Groeneveld AB, et al. (1991) Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc. Res. 25:80–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Solomon MA, et al. (1994) Myocardial energy metabolism and morphology in a canine model of sepsis. Am. J. Physiol. 266:H757–68.PubMedGoogle Scholar
  28. 28.
    Madorin WS, et al. (2004) Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC. Circ. Res. 94:944–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Chagnon F, Bentourkia M, Lecomte R, Lessard M, Lesur O. (2006) Endotoxin-induced heart dysfunction in rats: assessment of myocardial perfusion and permeability and the role of fluid resuscitation. Crit. Care Med. 34:127–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Yu P, et al. (1997) Myocardial collagen changes and edema in rats with hyperdynamic sepsis. Crit. Care Med. 25:657–62.CrossRefPubMedGoogle Scholar
  31. 31.
    Hotchkiss RS, et al. (1991) Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am. J. Physiol. 261:R965–72.PubMedGoogle Scholar
  32. 32.
    Wangensteen SL, Geissinger WT, Lovett WL, Glenn TM, Lefer AM. (1971) Relationship between splanchnic blood flow and a myocardial depressant factor in endotoxin shock. Surgery 69:410–8.PubMedGoogle Scholar
  33. 33.
    Parrillo JE, et al. (1985) A circulating myocardial depressant substance in humans with septic shock: septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J. Clin. Invest. 76:1539–53.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kumar A, et al. (1996) Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J. Exp. Med. 183:949–58.CrossRefPubMedGoogle Scholar
  35. 35.
    Finkel MS, et al. (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257:387–9.CrossRefGoogle Scholar
  36. 36.
    Niederbichler AD, et al. (2006) An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J. Exp. Med. 203:53–61.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Carlson DL, Willis MS, White DJ, Horton JW, Giroir BP. (2005) Tumor necrosis factor-alpha-induced caspase activation mediates endotoxin-related cardiac dysfunction. Crit. Care Med. 33:1021–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Garner LB, et al. (2003) Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor. Am. J. Physiol. Heart. Circ. Physiol. 285:H2500–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Maass DL, White J, Horton JW. (2002) IL-1beta and IL-6 act synergistically with TNF-alpha to alter cardiac contractile function after burn trauma. Shock 18:360–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Gao H, Neff T, Ward P.A. (2006) Regulation of lung inflammation in the model of IgG immune-complex injury. Annu. Rev. Pathol. Mech. Dis. 1:215–42.CrossRefGoogle Scholar
  41. 41.
    Huber-Lang MS, et al. (2002) Complement-induced impairment of innate immunity during sepsis. J. Immunol. 169:3223–31.CrossRefPubMedGoogle Scholar
  42. 42.
    Huber-Lang M, et al. (2001) Role of C5a in multiorgan failure during sepsis. J. Immunol. 166:1193–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Riedemann NC, et al. (2002) C5a receptor and thymocyte apoptosis in sepsis. FASEB J. 16:887–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Laudes IJ, et al. (2002) Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. Am. J. Pathol. 160:1867–75.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Abi-Gerges N, et al. (1999) Sequential changes in autonomic regulation of cardiac myocytes after in vivo endotoxin injection in rat. Am. J. Respir. Crit. Care. Med. 160:1196–204.CrossRefPubMedGoogle Scholar
  46. 46.
    Mebazaa A, et al. (2001) Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide. Circulation 104:3137–44.CrossRefPubMedGoogle Scholar
  47. 47.
    Kreymann G, et al. (1993) Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit. Care Med. 21:1012–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Rudiger A, Singer M. (2007) Mechanisms of sepsis-induced cardiac dysfunction. Crit. Care Med. 35:1599–608.CrossRefPubMedGoogle Scholar
  49. 49.
    Boekstegers P, Weidenhofer S, Kapsner T, Werdan K. (1994) Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit. Care Med. 22:640–50.CrossRefPubMedGoogle Scholar
  50. 50.
    Boekstegers P, Weidenhofer S, Pilz G, Werdan K. (1991) Peripheral oxygen availability within skeletal muscle in sepsis and septic shock: comparison to limited infection and cardiogenic shock. Infection 19:317–23.CrossRefPubMedGoogle Scholar
  51. 51.
    Rossi MA, Celes MR, Prado CM, Saggioro FP. (2007) Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. Shock 27:10–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Levy RJ, et al. (2005) Evidence of myocardial hibernation in the septic heart. Crit. Care Med. 33:2752–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Sharshar T, et al. (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362:1799–805.CrossRefPubMedGoogle Scholar
  54. 54.
    Sharshar T, et al. (2004) The neuropathology of septic shock. Brain Pathol. 14:21–33.CrossRefPubMedGoogle Scholar
  55. 55.
    Annane D, et al. (1999) Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am. J. Respir. Crit. Care Med. 160:458–65.CrossRefPubMedGoogle Scholar
  56. 56.
    Korach M, et al. (2001) Cardiac variability in critically ill adults: influence of sepsis. Crit. Care Med. 29:1380–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Schmidt HB, Werdan K, Muller-Werdan U. (2001) Autonomic dysfunction in the ICU patient. Curr. Opin. Crit. Care 7:314–22.CrossRefPubMedGoogle Scholar
  58. 58.
    Borovikova LV, et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–62.CrossRefPubMedGoogle Scholar
  59. 59.
    Huston JM, et al. (2007) Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit. Care Med. 35: 2762–8.PubMedGoogle Scholar
  60. 60.
    Tracey KJ. (2002) The inflammatory reflex. Nature 420:853–9.CrossRefGoogle Scholar
  61. 61.
    Zhong J, Hwang TC, Adams HR, Rubin LJ. (1997) Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am. J. Physiol. 273:H2312–24.PubMedGoogle Scholar
  62. 62.
    Liu S, Schreur KD. (1995) G protein-mediated suppression of L-type Ca2+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am. J. Physiol. 268:C339–49.CrossRefPubMedGoogle Scholar
  63. 63.
    Lew WY, Yasuda S, Yuan T, Hammond HK. (1996) Endotoxin-induced cardiac depression is associated with decreased cardiac dihydropyridine receptors in rabbits. J. Mol. Cell Cardiol. 28:1367–71.CrossRefPubMedGoogle Scholar
  64. 64.
    Tavernier B, Garrigue D, Boulle C, Vallet B, Adnet P. (1998) Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin-treated rabbits. Cardiovasc. Res. 38:472–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Tavernier B, et al. (2001) Phosphorylation-dependent alteration in myofilament Ca2+ sensitivity but normal mitochondrial function in septic heart. Am. J. Respir. Crit. Care Med. 163:362–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Shah AM. (1996) Paracrine modulation of heart cell function by endothelial cells. Cardiovasc. Res. 31:847–67.CrossRefPubMedGoogle Scholar
  67. 67.
    Dong LW, Wu LL, Ji Y, Liu MS. (2001) Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock 16:33–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Hagemann D, Xiao RP. (2002) Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc. Med. 12:51–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Vangheluwe P, Raeymaekers L, Dode L, Wuytack F. (2005) Modulating sarco(endo)plasmic reticulum Ca2+ ATPase 2 (SERCA2) activity: cell biological implications. Cell Calcium 38:291–302.CrossRefPubMedGoogle Scholar
  70. 70.
    Wu LL, Ji Y, Dong LW, Liu MS. (2001) Calcium uptake by sarcoplasmic reticulum is impaired during the hypodynamic phase of sepsis in the rat heart. Shock 15:49–55.PubMedGoogle Scholar
  71. 71.
    Wu LL, Tang C, Dong LW, Liu MS. (2002) Altered phospholamban-calcium ATPase interaction in cardiac sarcoplasmic reticulum during the progression of sepsis. Shock 17:389–93.CrossRefPubMedGoogle Scholar
  72. 72.
    Takeda K, Kaisho T, Akira S. (2003) Toll-like receptors. Annu. Rev. Immunol. 21:335–76.CrossRefPubMedGoogle Scholar
  73. 73.
    Frantz S, et al. (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J. Clin. Invest. 104:271–80.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Frantz S, Ertl G, Bauersachs J. (2007) Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat. Clin. Pract. Cardiovasc. Med. 4:444–54.CrossRefPubMedGoogle Scholar
  75. 75.
    Frantz S, Kelly RA, Bourcier T. (2001) Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J. Biol. Chem. 276:5197–203.CrossRefPubMedGoogle Scholar
  76. 76.
    Nemoto S, et al. (2002) Escherichia coli LPS-induced LV dysfunction: role of Toll-like receptor-4 in the adult heart. Am. J. Physiol. Heart Circ. Physiol. 282:H2316–23.CrossRefPubMedGoogle Scholar
  77. 77.
    Thomas JA, et al. (2003) IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. Am. J. Physiol. Heart Circ. Physiol. 285:H597–606.CrossRefPubMedGoogle Scholar
  78. 78.
    Baumgarten G, et al. (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of Tolllike receptor-4. J. Infect. Dis. 183:1617–24.CrossRefPubMedGoogle Scholar
  79. 79.
    Ferrero E, et al. (1993) Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide. Proc. Natl. Acad. Sci. U. S. A. 90:2380–4.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Haziot A, et al. (1996) Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity 4:407–14.CrossRefPubMedGoogle Scholar
  81. 81.
    Knuefermann P, et al. (2002) CD14-deficient mice are protected against lipopolysaccharide-induced cardiac inflammation and left ventricular dysfunction. Circulation 106:2608–15.CrossRefPubMedGoogle Scholar
  82. 82.
    Opie LH. Receptors and Signal Transduction. Lippincott Williams & Wilkins, London, 2004, p. 186–220.Google Scholar
  83. 83.
    Bocking JK, Sibbald WJ, Holliday RL, Scott S, Viidik T. (1979) Plasma catecholamine levels and pulmonary dysfunction in sepsis. Surg. Gynecol. Obstet. 148:715–9.PubMedGoogle Scholar
  84. 84.
    Bernardin G, Strosberg AD, Bernard A, Mattei M, Marullo S. (1998) Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans. Intensive Care Med. 24:1315–22.CrossRefPubMedGoogle Scholar
  85. 85.
    Hahn PY, et al. (1995) Sustained elevation in circulating catecholamine levels during polymicrobial sepsis. Shock 4:269–73.CrossRefPubMedGoogle Scholar
  86. 86.
    Iwase M, et al. (2001) Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor. Crit. Care Med. 29:609–17.CrossRefPubMedGoogle Scholar
  87. 87.
    Tang C, Liu MS. (1996) Initial externalization followed by internalization of beta-adrenergic receptors in rat heart during sepsis. Am. J. Physiol. 270:R254–63.PubMedGoogle Scholar
  88. 88.
    Shepherd RE, Lang CH, McDonough KH. (1987) Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin. Am. J. Physiol. 252:H410–6.PubMedGoogle Scholar
  89. 89.
    Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. (1989) Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte betaadrenergic responsiveness. Proc. Natl. Acad. Sci. U. S. A. 86:6753–7.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Matsuda N, et al. (2000) Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits. Anesthesiology. 93:1465–73.CrossRefPubMedGoogle Scholar
  91. 91.
    Wu LL, et al. (2003) G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis. Shock 19:533–7.CrossRefPubMedGoogle Scholar
  92. 92.
    Bohm M, Kirchmayr R, Gierschik P, Erdmann E. (1995) Increase of myocardial inhibitory G-proteins in catecholamine-refractory septic shock or in septic multiorgan failure. Am. J. Med. 98:183–6.CrossRefPubMedGoogle Scholar
  93. 93.
    Kyriakis JM, Avruch J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81:807–69.CrossRefPubMedGoogle Scholar
  94. 94.
    Baines CP, Molkentin JD. (2005) STRESS signaling pathways that modulate cardiac myocyte apoptosis. J. Mol. Cell. Cardiol. 38:47–62.CrossRefPubMedGoogle Scholar
  95. 95.
    Liu Q, Hofmann PA. (2004) Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes. Am. J. Physiol. Heart. Circ. Physiol. 286:H2204–12.CrossRefPubMedGoogle Scholar
  96. 96.
    Bogoyevitch MA, et al. (1996) Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart: p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ. Res. 79:162–73.CrossRefPubMedGoogle Scholar
  97. 97.
    Cook SA, Sugden PH, Clerk A. (1999) Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease. J. Mol. Cell Cardiol. 31:1429–34.CrossRefPubMedGoogle Scholar
  98. 98.
    Creemers EE, Cleutjens JP, Smits JF, Daemen MJ. (2001) Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ. Res. 89:201–10.CrossRefPubMedGoogle Scholar
  99. 99.
    Weber KT, Pick R, Janicki JS, Gadodia G, Lakier JB. (1988) Inadequate collagen tethers in dilated cardiopathy. Am. Heart. J. 116:1641–6.CrossRefPubMedGoogle Scholar
  100. 100.
    Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF Jr. (1996) Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross-links. Am. J. Pathol. 148: 1639–48.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Galis ZS, Khatri JJ. (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ. Res. 90:251–62.CrossRefPubMedGoogle Scholar
  102. 102.
    Cheung PY, et al. (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101:1833–9.CrossRefPubMedGoogle Scholar
  103. 103.
    Wang W, et al. (2002) Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106:1543–9.CrossRefPubMedGoogle Scholar
  104. 104.
    Lalu MM, Gao CQ, Schulz R. (2003) Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9. Mol. Cell. Biochem. 251:61–6.CrossRefPubMedGoogle Scholar
  105. 105.
    Wohlschlaeger J, et al. (2005) Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model. Pathol. Res. Pract. 201:809–17.CrossRefPubMedGoogle Scholar
  106. 106.
    Boyle WA 3rd, et al. (2000) iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice. Circ. Res. 87:E18–24.CrossRefPubMedGoogle Scholar
  107. 107.
    Belcher E, Mitchell J, Evans T. (2002) Myocardial dysfunction in sepsis: no role for NO? Heart 87:507–9.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Cotton JM, Kearney MT, Shah AM. (2002) Nitric oxide and myocardial function in heart failure: friend or foe? Heart 88:564–6.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Kumar A, et al. (1999) Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am. J. Physiol. 276:R265–76.PubMedGoogle Scholar
  110. 110.
    Paulus WJ, Vantrimpont PJ, Shah AM. (1994) Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans: assessment by bicoronary sodium nitroprusside infusion. Circulation 89:2070–8.CrossRefPubMedGoogle Scholar
  111. 111.
    Ullrich R, et al. (2000) Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice. Circulation 102:1440–6.CrossRefPubMedGoogle Scholar
  112. 112.
    Ichinose F, et al. (2003) A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice. Am. J. Physiol. Heart Circ. Physiol. 285:H2524–30.CrossRefPubMedGoogle Scholar
  113. 113.
    Barth E, et al. (2006) Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit. Care Med. 34:307–13.CrossRefPubMedGoogle Scholar
  114. 114.
    Grover R, et al. (1999) An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group. Crit. Care Med. 27:913–22.CrossRefPubMedGoogle Scholar
  115. 115.
    Ishida H, Ichimori K, Hirota Y, Fukahori M, Nakazawa H. (1996) Peroxynitrite-induced cardiac myocyte injury. Free Radic. Biol. Med. 20:343–50.CrossRefPubMedGoogle Scholar
  116. 116.
    Xie YW, Kaminski PM, Wolin MS. (1998) Inhibition of rat cardiac muscle contraction and mitochondrial respiration by endogenous peroxynitrite formation during posthypoxic reoxygenation. Circ. Res. 82:891–7.CrossRefPubMedGoogle Scholar
  117. 117.
    Lancel S, et al. (2004) Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats. J. Am. Coll. Cardiol. 43:2348–58.CrossRefPubMedGoogle Scholar
  118. 118.
    Crouser ED. (2004) Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4:729–41.CrossRefPubMedGoogle Scholar
  119. 119.
    Gellerich FN, et al. (2002) Mitochondrial dysfunction in sepsis: evidence from bacteraemic baboons and endotoxaemic rabbits. Biosci. Rep. 22:99–113.CrossRefPubMedGoogle Scholar
  120. 120.
    Brealey D, et al. (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219–23.CrossRefPubMedGoogle Scholar
  121. 121.
    Brealey D, et al. (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286:R491–7.CrossRefPubMedGoogle Scholar
  122. 122.
    Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. (2002) Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit. Care Med. 30:276–84.CrossRefPubMedGoogle Scholar
  123. 123.
    Crouser ED, et al. (2004) Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit. Care Med. 32:478–88.CrossRefPubMedGoogle Scholar
  124. 124.
    Suliman HB, Welty-Wolf KE, Carraway M, Tatro L, Piantadosi CA. (2004) Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc. Res. 64:279–88.CrossRefPubMedGoogle Scholar
  125. 125.
    Watts JA, Kline JA, Thornton LR, Grattan RM, Brar SS. (2004) Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J. Mol. Cell Cardiol. 36:141–50.CrossRefPubMedGoogle Scholar
  126. 126.
    Soriano FG, et al. (2006) Potential role of poly(adenosine 5′-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit. Care Med. 34:1073–9.CrossRefPubMedGoogle Scholar
  127. 127.
    Levy RJ, Vijayasarathy C, Raj NR, Avadhani NG, Deutschman CS. (2004) Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis. Shock 21:110–4.CrossRefPubMedGoogle Scholar
  128. 128.
    Gellerich FN, et al. (1999) Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock 11:336–41.CrossRefPubMedGoogle Scholar
  129. 129.
    Trumbeckaite S, Opalka JR, Neuhof C, Zierz S, Gellerich FN. (2001) Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function. Eur. J. Biochem. 268:1422–9.CrossRefPubMedGoogle Scholar
  130. 130.
    Taylor DE, Ghio AJ, Piantadosi CA. (1995) Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch. Biochem. Biophys. 316:70–6.CrossRefPubMedGoogle Scholar
  131. 131.
    Levy RJ. (2007) Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock 28:24–8.CrossRefPubMedGoogle Scholar
  132. 132.
    Fink MP. (2002) Bench-to-bedside review: cytopathic hypoxia. Crit. Care 6:491–9.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Fink MP. (2002) Cytopathic hypoxia: is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration? Crit. Care Clin. 18:165–75.CrossRefPubMedGoogle Scholar
  134. 134.
    Suliman HB, Carraway, MS, Piantadosi CA. (2003) Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am. J. Respir. Crit. Care Med. 167:570–9.CrossRefPubMedGoogle Scholar
  135. 135.
    Larche J, et al. (2006) Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J. Am. Coll. Cardiol. 48:377–85.CrossRefPubMedGoogle Scholar
  136. 136.
    Bergmann MW, Loser P, Dietz R, von Harsdorf R. (2001) Effect of NF-kappa B inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes. J. Mol. Cell Cardiol. 33:1223–32.CrossRefPubMedGoogle Scholar
  137. 137.
    Fauvel H, Marchetti P, Chopin C, Formstecher P, Neviere R. (2001) Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. Am. J. Physiol. Heart Circ. Physiol. 280:H1608–14.CrossRefPubMedGoogle Scholar
  138. 138.
    McDonald TE, Grinman MN, Carthy CM, Walley KR. (2000) Endotoxin infusion in rats induces apoptotic and survival pathways in hearts. Am. J. Physiol. Heart Circ. Physiol. 279: H2053–61.CrossRefPubMedGoogle Scholar
  139. 139.
    Carlson D, Maass DL, White DJ, Tan J, Horton JW. (2006) Antioxidant vitamin therapy alters sepsis-related apoptotic myocardial activity and inflammatory responses. Am. J. Physiol. Heart Circ. Physiol. 291:H2779–89.CrossRefPubMedGoogle Scholar
  140. 140.
    Buerke U, et al. (2007) Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock. Aug 2;Publish Ahead of Print.Google Scholar
  141. 141.
    Kumar A, et al. (2005) Human serum from patients with septic shock activates transcription factors STAT1, IRF1, and NF-kappaB and induces apoptosis in human cardiac myocytes. J. Biol. Chem. 280:42619–26.CrossRefPubMedGoogle Scholar
  142. 142.
    Lancel S, et al. (2005) Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction. Circulation 111: 2596–604.CrossRefGoogle Scholar
  143. 143.
    Neviere R, Fauvel H, Chopin C, Formstecher P, Marchetti P. (2001) Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis. Am. J. Respir. Crit. Care Med. 163:218–25.CrossRefPubMedGoogle Scholar
  144. 144.
    Fauvel H, et al. (2002) Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats. Am. J. Respir. Crit. Care Med. 165:449–55.CrossRefPubMedGoogle Scholar
  145. 145.
    Lancel S, et al. (2005) Expression of apoptosis regulatory factors during myocardial dysfunction in endotoxemic rats. Crit. Care Med. 33:492–6.CrossRefPubMedGoogle Scholar
  146. 146.
    Heusch G, Schulz R. (2000) The biology of myocardial hibernation. Trends Cardiovasc. Med. 10: 108–14.CrossRefPubMedGoogle Scholar
  147. 147.
    Heusch G, Rose J, Skyschally A, Post H, Schulz R. (1996) Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart: inotropic responses to postextrasystolic potentiation and intracoronary calcium. Circulation 93:1556–66.CrossRefPubMedGoogle Scholar
  148. 148.
    Sawyer DB, Loscalzo J. (2002) Myocardial hibernation: restorative or preterminal sleep? Circulation 105:1517–9.CrossRefPubMedGoogle Scholar
  149. 149.
    Vanoverschelde JL, et al. (1997) Chronic myocardial hibernation in humans: from bedside to bench. Circulation 95:1961–71.CrossRefPubMedGoogle Scholar
  150. 150.
    Elsasser A, et al. (1997) Hibernating myocardium: an incomplete adaptation to ischemia. Circulation 96:2920–31.CrossRefPubMedGoogle Scholar
  151. 151.
    Elsasser A, et al. (2004) Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death. J. Am. Coll. Cardiol. 43:2191–9.CrossRefPubMedGoogle Scholar
  152. 152.
    Kalra DK, et al. (2002) Increased myocardial gene expression of tumor necrosis factor-alpha and nitric oxide synthase-2: a potential mechanism for depressed myocardial function in hibernating myocardium in humans. Circulation 105:1537–40.CrossRefPubMedGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Michael A. Flierl
    • 1
  • Daniel Rittirsch
    • 1
  • Markus S. Huber-Lang
    • 2
  • J. Vidya Sarma
    • 1
  • Peter A. Ward
    • 1
    Email author
  1. 1.Department of PathologyThe University of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Trauma, Hand and Reconstructive SurgeryUniversity of Ulm Medical SchoolUlmGermany

Personalised recommendations