Cardiac function in experimental septic and non-septic conditions with special reference to the endothelin system

Myocardial depression in sepsis has been intensely investigated for the past 30 years and still poses a considerable issue in the intensive care units. Both systolic and diastolic dysfunction is implicated, correlating with severity of illness and mortality The importance of the endothelin (ET) system in normal physiology has been extensively studied. ET is a powerful vasoconstrictive peptide, has cardio-regolatory effects and is released from the endothelium. In sepsis, ET levels are dramatically increased and correlate to severity of disease. Thus, ET has been proposed as a mediator of myocardial depression in sepsis. Another mechanism P, proposed for cardiac dysfunction is decreased myofilament sensitivity for calcium (Ca2+). Levosimendan, a Ca2+ sensitizing agent, has been used successfully in patients with severe heart failure and decreased myocardial Ca2+ sensitivity has been shown in septic conditions.

The major aims of this thesis was to, in a porcine model in vivo, investigate cardiovascular effects of levosimendan in experimental sepsis, to characterize the influence of the ET system on cardiac performance in the normal and septic heart. Also, to assess myocardial function in endotoxemia and effects of intervention in the ET system by load-independent analysis of the left ventricular pressure-volume relation (LVPVR) by conductance volumetry.

Endotoxin administration was associated with major cardiovascular effects, pulmonary hypertension and increased systemic oxygen extraction. Levosimendan attenuated all these effects and also evoked vasodilation which improved splanchnic blood flow.

Tezosentan, a dual (ETA/ETB) ET receptor antagonist, was administered in established, highvolume resuscitated endotoxemia and resulted in increased cardiac index, stroke volume index and LV end-diastolic volume by counteracting pulmonary hypertension and improving LV compliance. However, these effects were dose-dependent. When increasing the dose of tezosentan ten-fold, the initial beneficial response was not sustained. Exaggerated vasodilation and severely low coronary perfusion pressure is a possible mechanism for the increased mortality seen with the higher dose of tezosentan.

Effects of ET receptor activation in the healthy heart were evaluated by LVPVR following intra-coronary infusion of endothelin-1 (ET- 1) and sarafotoxin 6c (S6c, ETB receptor agonist). ET-1 caused dose-related increase and S6c a decrease in systolic function, possibly mediated via ETA receptors. Both ETA and S6c caused similar impairment in diastolic function, mediated via ETB receptors.

By the same methodology, effects of tezosentan were studied in endotoxemia, where endotoxin caused marred relaxation but not systolic dysfunction. Tezosentan caused impairment in parameters of systolic performance but significantly improved diastolic relaxation.

We conclude that, in endotoxemia, intervention with levosimendan is beneficial, markedly improving cardiovascular function and regional blood flow. Therefore, levosimendan is a promising drug in septic states and should be evaluated for specific cardiac effects and used in future clinical trials. Furthermore, the ET system contributes significantly to cardiac performance in both healthy and acute experimental septic conditions. Diastolic dysfunction and pulmonary hypertension are suitable targets for ET receptor antagonism. Bearing in mind the dose issue and the possible negative inotropic effects, antagonizing the much upregulated ET system in septic patients may well be meaningful to explore in the clinical setting

List of scientific papers

I. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M (2001). Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med. 29(11): 2185-93.
https://pubmed.ncbi.nlm.nih.gov/11700420

II. Konrad D, Oldner A, Rossi P, Wanecek M, Rudehill A, Weitzberg E (2004). Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock. Crit Care Med. 32(5): 1192-9.
https://pubmed.ncbi.nlm.nih.gov/15190972

III. Konrad D, Oldner A, Wanecek M, Rudehill A, Weitzberg E, Biber B, Johansson G, Haggmark S, Haney M (2005). Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo. Am J Physiol Heart Circ Physiol. 289(4): H1702-9.
https://pubmed.ncbi.nlm.nih.gov/15951343

IV. Konrad D, Haney M, Johansson G, Wanecek M, Weitzberg E, Oldner A (2006). Cardiac effects of endothelin receptor antagonism in endotoxemic pigs. [Submitted]