Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock

Groeneveld, A. B. Johan; Lambalgen, A.A. van; Bos, G. C. van den; Bronsveld, W; Nauta, J. J. P.; Thijs, L. G.

doi:10.1093/cvr/25.1.80

Cited by 71 publications

(39 citation statements)

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“…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).…”

Section: Alterations Of Microvasculaturementioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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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...

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Section: Alterations Of Microvasculaturementioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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“…Because LTs apparently do not directly suppress heart muscle contractile function (37), the most reasonable explanation is a maldistribution of regional perfusion caused by the vasoconstrictor potency of the cys-LTs. Such a phenomenon, characterized by the coexistence of under-and overperfused capillaries in close vicinity, has long been considered as a pathogenetic mechanism in septic heart failure (7,12,22). Interestingly, similar abnormalities were also observed in rat hearts undergoing high-dose ␣-toxin challenge, with thromboxane being implicated as the predominantly responsible vasoconstrictor agent under these conditions.…”

Section: Discussionmentioning

confidence: 88%

“…Cardiodepressant effects of cytokines, predominantly tumor necrosis factor-␣ and interleukin-1␤, have been implicated in the development of cardiac depression in sepsis (26,27). In addition, experimental data suggest that-despite preserved coronary blood flow in sepsis (10)-impairment of coronary vasoregulation and myocardial regional perfusion may also depress cardiac performance (7,13,22,40). Moreover, there is recent experimental evidence that recruitment and activation of polymorphonuclear neutrophils (PMN) may also contribute to the development of septic myocardial failure.…”

mentioning

confidence: 99%

Staphylococcal α-toxin provokes neutrophil-dependent cardiac dysfunction: role of ICAM-1 and cys-leukotrienes

Grandel

Reutemann

Kiss

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Staphylococcal ␣-toxin provokes neutrophil-dependent cardiac dysfunction: role of ICAM-1 and cysleukotrienes. Am J Physiol Heart Circ Physiol 282: H1157-H1165, 2002; 10.1152/ajpheart.00165.2001.-The role of polymorphonuclear neutrophils (PMN) in septic myocardial dysfunction is presently unknown. Staphylococcus aureus infections are frequently associated with septic sequelae. Therefore, we perfused isolated rat hearts with low doses of ␣-toxin, the major staphylococcal exotoxin, followed by application of human PMN, N-formyl-methionyl-leucylphenylalanine, and arachidonic acid. In contrast to shamperfused hearts (no ␣-toxin), a rise in coronary perfusion pressure (CPP) and a reduction of contractile function were noted, and cardiac expression of intercellular adhesion molecule (ICAM)-1 was detected by immunohistochemical methods and real-time PCR. Histological analysis and myeloperoxidase activity indicated cardiac PMN accumulation in ␣-toxin-challenged hearts. Major quantities of cysteinyl (cys)-leukotrienes (LT), LTB4, and 5-hydroxyeicosatetraenoic acid (5-HETE) were found in the perfusate of ␣-toxin-exposed hearts. With an anti-ICAM-1 antibody, neutrophil accumulation, leukotriene (LT) synthesis, coronary vasoconstriction, and the accompanying cardiodepression were suppressed. Similarly, the lipoxygenase inhibitor MK-886 blocked LT synthesis and maintained cardiac function. We conclude that low-dose ␣-toxin provokes coronary endothelial ICAM-1 expression and neutrophil accumulation, with subsequent synthesis of cys-LTs, LTB4, and 5-HETE under conditions of appropriate stimulation. This response is linked with coronary vasoconstriction and contractile dysfunction, with cys-LT synthesis and maldistribution of perfusion offered as likely underlying mechanisms. bacterial exotoxins; septic heart dysfunction; neutrophil mediators PROGRESSIVE MYOCARDIAL dysfunction, characterized by dilatation and reduced ejection fractions of both ventricles (33, 34), contributes to the cardiocirculatory abnormalities of septic shock. Despite the clinical importance of this disease (35), the pathogenetic mechanisms leading to the loss of myocardial function in sepsis are still not fully elucidated. Cardiodepressant effects of cytokines, predominantly tumor necrosis factor-␣ and interleukin-1␤, have been implicated in the development of cardiac depression in sepsis (26,27). In addition, experimental data suggest that-despite preserved coronary blood flow in sepsis (10)-impairment of coronary vasoregulation and myocardial regional perfusion may also depress cardiac performance (7,13,22,40). Moreover, there is recent experimental evidence that recruitment and activation of polymorphonuclear neutrophils (PMN) may also contribute to the development of septic myocardial failure. In endotoxemic animals PMN have been shown to accumulate in the myocardium (3, 14), and very recently it was demonstrated that leukocytes originating from endotoxemic rabbits are retained in the coronary circulation of isolated hearts and cause contractile dysfu...

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“…Among these, notable mechanisms include alterations and dysfunction of cardiac calcium channels, 4 cardiomyocyte damage caused by excessive nitrous oxide, 5 cytokines including IL-1, TNF-alpha and IL-6, 1 oxidative stress 6 and, to some extent, microvascular myocardial ischemia. 7 However, it is worth emphasizing that unlike earlier hypotheses had suggested, decrease in coronary perfusion is usually not seen in sepsis and in fact, there might be an increase in global coronary perfusion. 8 Methodology suggested in the literature regarding diagnosis of myocardial dysfunction in sepsis is inconsistent.…”

Section: Sepsis and Cardiac Dysfunctionmentioning

confidence: 89%