Molecular mechanisms autonomic dysfunction and impaired cardiac contractility in critical illness

Abstract

Objectives: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (NADPH oxidase-dependent) oxidative stress resulting in increased expression of G-protein coupled receptor kinase (GRK)-2, a key negative regulator of cardiac function. Design: Laboratory/clinical investigations. Setting: University laboratory/medical centers. Subjects: Adult rats; wild-type/NAPDH oxidase subunit-2 (NOX-2) deficient mice; elective surgical patients. Interventions: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (BD, sino-aortic denervation) in rats and mice. Immunoblots assessed GPCR recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardio-pulmonary exercise testing, time/frequency measures of parasympathetic parameters were related to the presence/absence of BD (defined by spontaneous baroreflex sensitivity of <6ms.mmHg(-1)). The associations of BD with intraoperative cardiac function and outcomes were assessed. Measurements and Main Results: Experimental BD in rats and mice resulted in impaired cardiac contractility and upregulation of GRK-2 expression. In mice, genetic deficiency of gp91 NADPH-oxidase (NOX-2) subunit prevented upregulation of GRK-2 expression in conditions of BD and preserved cardiac function. BD was present in 81/249 (32.5%) patients, and was characterized by lower parasympathetic tone and increased GRK-2 expression in mononuclear leukocytes. BD in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with BD (relative risk: 1.66 [95%CI:1.16-2.39]; p=0.006). Conclusions: Reduced baroreflex sensitivity is associated with NOX-2 mediated upregulation of GRK-2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.