MECHANISMS OF CARDIAC DYSFUNCTION IN SEPSIS

Abstract

Studies in animal models of sepsis have elucidated an intricate network of signaling pathways that lead to the dysregulation of myocardial Ca²⁺ handling and subsequently to a decrease in cardiac contractile force, in a sex- and model-dependent manner. After challenge with a lethal dose of LPS, male animals show a decrease in cellular Ca²⁺ transients (ΔCa_i), with intact myofilament function, whereas female animals show myofilament dysfunction, with intact ΔCa_i. Male mice challenged with a low, nonlethal dose of LPS also develop myofilament desensitization, with intact ΔCa_i. In the cecal ligation and puncture (CLP) model, the causative mechanisms seem similar to those in the LPS model in male mice and are unknown in female subjects. ΔCa_i decrease in male mice is primarily due to redox-dependent inhibition of sarco/endoplasmic reticulum Ca²⁺ ATP-ase (SERCA). Reactive oxygen species (ROS) are overproduced by dysregulated mitochondria and the enzymes NADPH/NADH oxidase, cyclooxygenase, and xanthine oxidase. In addition to inhibiting SERCA, ROS amplify cardiomyocyte cytokine production and mitochondrial dysfunction, making the process self-propagating. In contrast, female animals may exhibit a natural redox resilience. Myofilament dysfunction is due to hyperphosphorylation of troponin I, troponin T cleavage by caspase-3, and overproduction of cGMP by NO-activated soluble guanylate cyclase. Depleted, dysfunctional, or uncoupled mitochondria likely synthesize less ATP in both sexes, but the role of energy deficit is not clear. NO produced by NO synthase (NOS)-3 and mitochondrial NOSs, protein kinases and phosphatases, the processes of autophagy and sarco/endoplasmic reticulum stress, and β-adrenergic insensitivity may also play currently uncertain roles.