Molecular Events in the Cardiomyopathy of Sepsis

Abstract

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. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne 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 MicrovasculatureThere 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 MediatorsAnother 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 an...

Quels sont les signes indirects de sepsis sévère en tomoscintigraphie par émission de positons au 18-désoxy-fluoroglucose ?

“…Les mitochondries des cardiomyocytes présentent des dommages structuraux et un transport réduit des électrons par les complexes enzymatiques de la chaîne respiratoire mitochondriale, réduisant ainsi la production d'ATP. Le phénomène d'hibernation décrit lors du choc septique constituerait une réponse adaptative, en diminuant les dépenses énergétiques dans ce contexte de production énergétique réduite [24].…”

Sepsis and Septic Shock: Pathophysiological and Cardiovascular Background as Basis for Therapy

“…It also plays an important role in myocardial depression (11,13,14). High doses of NO have been shown to induce contractile dysfunction by depressing myocardial energy generation: NO 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) (3,16,17). The adverse effects of NO might also, in part, be related to interactions between NO and superoxide anions with subsequent excessive production of peroxynitrite (ONOO -) (18).…”

“…The adverse effects of NO might also, in part, be related to interactions between NO and superoxide anions with subsequent excessive production of peroxynitrite (ONOO -) (18). The latter has been shown to impair cardiac muscle contraction during sepsis and, like NO, depress mitochondrial respiration during experimental sepsis (17,19).…”

Pathomechanismen des Organversagens

“…Weitere Faktoren, die zur Entstehung der septischen Kardiomyopathie beitragen, umfassen Veränderungen der intrazellulären Kalziumflüsse, der Signaltransduktion an β-Adrenozeptoren sowie die Aktivierung von Matrixmetalloproteinasen [27].…”