Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca2+ removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan

Abstract

Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca(2+) sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca(2+) handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca(2+)-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca(2+) sensitivity, in vitro cellular Ca(2+) homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca(2+) recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca(2+) sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca(2+) transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca(2+) extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) to Ca(2+) transient diastole in LPS-evoked sepsis but rather depressed Na(+)/Ca(2+) exchanger and plasmalemmal Ca(2+) ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca(2+) extrusion pathways resulting in intracellular diastolic Ca(2+) overload. Levosimendan, apart from stabilizing Ca(2+)-troponin C complexes, potently improves cellular Ca(2+) extrusion in the septic heart.

The effect of HMGA1 in LPS-induced Myocardial Inflammation

“…It has been demonstrated that when endotoxin like LPS binds the receptor TLR4 that is expressed on cardiomyocytes and macrophages, it initiates the activation of NF-κB and permits NF-κB translocating into nucleus [23]. After undergoing LPS insult, both the macrophages and cardiomyocytes can release a great quantity of inflammatory mediator, such as MCP-1, GM-CSF, IL-1α, IL-1β, IL-6, IL-7, IL-8, and IL-12 [22,23].These inflammatory cytokines could give rise to imbalance of calcium homeostasis [24], disturbance of energy metabolism [25], impairment of adrenergic signaling [26], and excess production of nitric oxide [27], all of which facilitate decreased contractility, diastolic dysfunction, impaired ejection fraction and reduced cardiac index. The high mobility group A1 (HMGA1) has a significant impact on the proliferation, differentiation, activation and recruitment of inflammatory cells, as well as the secretion of inflammatory mediators and cytokines [28].…”

Pathophysiology of sepsis-induced myocardial dysfunction

“…CLP increased myocardial angiotensin II content, which may be associated with the disturbance of Ca 2+ transport in the cardiac SR [ 79 ]. LPS also specifically impaired sarcolemmal diastolic Ca 2+ extrusion pathways by depressing the function of the Na + /Ca 2+ exchanger and the plasmalemmal Ca 2+ ATPase, which in turn resulted in intracellular diastolic Ca 2+ overload [ 80 ]. This disruption of cellular Ca 2+ homeostasis in cardiomyocytes may contribute to SIMD.…”

Cellular Mechanisms of Myocardial Depression in Porcine Septic Shock

“…Similarly, the downstream cellular pathophysiology of myocardial depression is still obscure, although in experimental models, a number of contributing mechanisms have been reported. The cardiac cellular mechanisms include a reduction of L-type calcium current (I CaL ) ( Lew et al, 1996 ; Zhong et al, 1997 ; Stengl et al, 2010 ), altered calcium transients ( Ren et al, 2002 ), increased calcium leakage from the sarcoplasmic reticulum ( Zhu et al, 2005 ), impaired sarcolemmal diastolic calcium extrusion pathways ( Wagner et al, 2015 ), oxidation and subsequent activation of calcium and calmodulin-dependent protein kinase with phosphorylation of the ryanodine receptor ( Sepúlveda et al, 2017 ), altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins ( Wu et al, 2001 ), and/or mitochondrial dysfunction ( Levy et al, 2004 ; Watts et al, 2004 ).…”