Pleiotropic effects of atorvastatin in experimental sepsis: preservation of β1-adrenoreceptor signaling in the heart.

Sepsis-induced cardiomyopathy is a common complication of sepsis with myocardial depression occurring in up to 60% of septic patients (1) that correlates with severity and outcome in sepsis. A large spectrum of alterations in left (and right) ventricular systolic and diastolic function can be observed in septic shock, including the typical echocardiographic sign(s) of a hypokinetic left ventricle (1, 2). Pathophysiologic mechanisms leading to this manifestation are not yet fully understood, but it is assumed that the intrinsic septic myocardial depression represents a part of the general inflammatory response to infection and is primarily triggered by cytokineand nitric oxide (NO)Ymediated alterations, including the attenuation of adrenergic response at the cardiomyocyte level (2). Lacking specific therapeutic strategies for this condition, the recommended treatment is mainly supportive in nature, aiming at an optimization of preload and afterload with sufficient fluid resuscitation and catecholamine therapy to improve organ perfusion (3). The current clinical characterization of sepsisinduced cardiomyopathy and the underlying pathophysiologic mechanisms were recently discussed in a highly informative review article by Zaky et al. (2) in Shock. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or statins, are among the most frequently prescribed drugs worldwide. Clinical studies revealed that a continuous therapy with statins, initially used for lowering lipid levels in patients with hyperlipidemias and cardiovascular disease, is also accompanied with a number of beneficial effects on cardiovascular diseases, including reducing the risk of myocardial infarction and prolonging life. The pleiotropic effects of statins have been the subject of intense research in cancer and infection during recent years, and there is some evidence from observational studies and preclinical studies that statins might be associated with an improved outcome in sepsis. Numerous studies suggest that these pleiotropic effects of statins are related to a modulation of both, innate and adaptive immune system (4, 5), including anti-inflammatory effects through inhibition of proinflammatory cytokine production and chemokine expression (5). Moreover, statins seem to play a role in counteracting the adverse effects on the activation of the coagulation system associated with sepsis (6). However, randomized clinical trials demonstrated equivocal results, but did not reveal the improvement of prognosis suggested by basic research and observational studies (6). Kandasamy et al. (7) have recently reported in Shock that pretreatment of mice with atorvastatin that were subsequently subjected to sepsis (secondary to cecal ligation and puncture) abolished the reduced vascular contractility to norepinephrine Bvasoplegia[ observed ex vivo in aortic rings obtained from these animals. This beneficial effect of atorvastatin was associated with attenuation of overproduction of NO, reduced inducible NO synthase expression, and increased ! (1D)adrenoreceptor expression. Following up on these results, the same group convincingly demonstrates in this issue of Shock that pretreatment of septic mice with atorvastatin improves the sepsis-induced decrease in left ventricular contractility (measured in the isolated heart perfused according to Langendorff) by preservation of "1-adrenoreceptor signaling (8). Specifically, the authors have shown that the attenuation of impaired left ventricular function by pretreatment with atorvastatin is associated with preserved "1-AR mRNA and protein expressions, an attenuation of the sepsis-induced decrease of cardiac tissue cAMP content, an attenuation of the sepsis-induced refractoriness to dobutamine stimulation, and an inhibition of the sepsis-induced increase in the cardiac GRK-2 protein expression, protein kinase A activity, and plasma catecholamines. This article represents a very interesting report of research with emerging clinical significance. Myocardial dysfunction as well as resistance to catecholamines and vasopressors is one of the major problems in septic patients that determines poor outcome. Clearly, the presented data are fundamental in improving our understanding of the pathophysiology of sepsis-induced cardiomyopathy and further elucidate important mechanistic pathways responsible for the potential beneficial effects of atorvastatin treatment in this condition, such as recently reported in 2 different single-center phase II randomized double-blind placebo-controlled trials by Patel et al. (9) and Kruger et al. (10). Patel et al. (9) found that acute atorvastatin administration (40 mg daily) in statin-naive patients with sepsis may prevent sepsis progression, reflected in a significantly lower conversion rate to severe sepsis in the atorvastatin arm compared with placebo. However, in this study, they observed no significant differences in length of hospital stay, critical care unit admission, or mortality (9). These latter findings are in line with the study by Kruger and colleagues (10) that revealed no significant changes in the atorvastatin group (20 mg daily) compared with placebo in all parameters assessed (such as length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge). One could argue that the current study by Thangamalai et al. (8) has its limitations, as the authors have not investigated the