Sympathoinhibitory effects of statins in chronic kidney disease

In Greek and Roman times, theriaca, a first century AD concoction, was considered as a panacea, a remedy good for all kind of illnesses. Statins are a sort of twenty-first century theriaca. Indeed drugs in this class represent not only the best treatment for hypercholesterolemia – at least in theory – but also a remedy potentially useful in a growing list of conditions including osteoporosis, Alzheimer's disease, depression, hypertension, sepsis, and cancer [1]. Such a wide therapeutic potential depends on the fact that statins impinge upon a series of signaling molecules (see below) which are fundamental for physiological cell functioning. Interference with these molecular mechanisms results in a variety of effects at organ or system level, like immune system and central nervous system (CNS) modulation, bone marrow progenitor cells mobilization and regulation of bone physiology and repair. Furthermore, beyond cholesterol lowering, vasculo-protection by statins depends also on other key mechanisms implicated in the atherosclerosis process, including endothelial dysfunction, atherosclerotic plaques stabilization, oxidative stress and inflammation, and the thrombogenic response to vascular injury [2]. Most of these pleiotropic effects are mediated by inhibition of isoprenoids, a fundamental series of compounds that serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins – including Rac, Rho, and Ras – whose proper membrane localization and function are dependent on isoprenylation, is considered as a central mechanism in mediating the pleiotropic effects of statins [3]. Statins and the sympathetic nervous system: experimental background Even though of primary scientific interest, the effects of statins on the CNS have attracted relatively little interest in cardiovascular medicine. The rostral ventrolateral medulla (RVLM) is a fundamental CNS center for reflex cardiovascular control. Nitric oxide and reactive oxygen species (ROS) are key compounds in the RVLM. Indeed in experimental models like the stroke-prone spontaneously hypertensive rat (SHRSP), an increase in nitric oxide levels in this center inhibits the activation of the sympathetic nervous system (SNS) while ROS exerts an opposite action. Some statins, like atorvastatin, upregulate nitric oxide synthases in the brain and thereby produce well documented nitric oxide-dependent sympathoinhibitory effects [4]. Administration of atorvastatin in animal models not only reduces SNS activity but also restores baroreflex controlof circulation [5] and these effects are at least in part mediated via reduction of ROS (Fig. 1). Overall, the interference of this statin with SNS control mechanisms in the RVML depends on the ability of these drugs to upregulate nitric oxide synthase on one side and by an attenuation of the scavenging effect of oxidative stress for nitric oxide on the other side. Accordingly, inhibition of rac-1, which in turn determines nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase (a process mainly driven by angiotensin II), downregulation and activation of superoxide dismutase are key factors for the reduction in sympathetic activity induced by chronic intracerebroventricular administration of atorvastatin in the SHRSP [4]. Interestingly, in the SHRSP, the hypotensive and sympatho-inhibitory effects and the attenuation in oxidative stress in the RVLM by atorvastatin are demonstrable also when this statin is administered orally. This phenomenon may be an expression of disrupted blood-brain barrier, which allows orally administered atorvastatin to reach the brain in a direct fashion, or may depend on the fact that this statin is a lipophilic compound. Yet, interference with SNS is not peculiar to atorvastatin nor confined to the SHRSP because simvastatin normalizes autonomic function in rabbits with heart failure, again an effect at least in part mediated via central NAD(P)H oxidase inhibition [6].Fig. 1: No captions available.As to human studies, two short-term small trials in hypertensive patients coherently suggest that atorvastatin may reduce SNS activity in this condition. Postganglionic muscle sympathetic nerve activity (MSNA) was lower after 3 weeks of atorvastatin treatment than after a 3 weeks placebo administration in a cross-over trial in 13 individuals with mild to moderate hypertension [7]. By the same token, the same statin produced a 25% reduction in MSNA and an amelioration in baroreflex control of heart rate in a group of 10 essential hypertensives with mild hypercholesterolemia, whereas did not modify the same outcome measures in a parallel group of eight healthy control patients [8]. These findings were recently confirmed in a larger double blind, randomized trial with simvastatin [9]. Of note, in none of these studies MSNA reduction was accompanied by a parallel decline in blood pressure (BP) and heart rate. Interference of statins with the autonomic system in humans is not confined to hypertension. Welzig et al. [10] in a study comparing pravastatin and simvastatin in patients with frank hypercholesterolemia or established coronary heart disease found that pravastatin but not simvastatin raised parasympathetic modulation of heart rate. Of interest, such an effect went in parallel with an increase in the expression of the α-subunit of the heterotrimeric Gαi2-protein (a critical component of the parasympathetic signalling pathway) in lymphocytes in pravastatin treated patients only. Similarly, atorvastatin improved frequency domain indices of heart rate variability in patients with heart failure [11], and this observation was replicated in a subsequent study in patients with systolic heart failure [12]. Statins and sympathetic nervous system in chronic renal failure Testing the effect of statins on SNS activity specifically in patients with chronic kidney disease (CKD) is a relevant undertaking to further explore the importance of this effect in human diseases. In this respect, patients with moderate to severe CKD represent an almost unique natural model of progressive activation of the SNS [13] associated with a gradually increasing risk for cardiovascular events [14]. In these patients, renal function loss is also accompanied by a progressively reduced nitric oxide bio-availability, a phenomenon mainly dependent on accumulation of endogenous inhibitors of nitric oxide synthase like asymmetric dimethyl arginine [15,16]. Last but not least, oxidative stress is a quite common alteration in these patients. Thus CKD patients display two critical derangements, reduced nitric oxide bio-availability and high oxidative stress, which appear of major relevance for the central regulation of SNS activity. In this issue of the Journal, Siddiqi et al.[17], for the first time describe the effect of a statin on sympathetic activity in patients with CKD. In this unblinded, randomized, crossover trial 10 stable stage 2–4 CKD patients, all well stabilized on chronic treatment with aliskiren, MSNA was assessed at baseline and after 6 weeks of treatment with atorvastatin. Due to background renin inhibition, baseline MSNA was remarkably normal in these patients (28 bursts/min), an average figure much lower than that reported in the three studies in untreated essential hypertensives (39 bursts/min in the first [18] and about 36 bursts/min in the other two [8,9]). Nonetheless, like in previous studies, treatment with atorvastatin produced a substantial fall in MSNA to 20 bursts/min, a 28% decline. At baseline mean arterial pressure was nicely controlled (average: 93 mmHg) and heart rate was fairly slow (55 beats/min) which likely explains why neither parameter was modified by atorvastatin treatment, an observation again in keeping with previous studies. Perhaps because of the short time durationof their study, Siddiqi et al. [17] did not assess biomarkers of cardiovascular involvement like left ventricular mass index or carotid intima–media thickness, i.e. two parameters which may be modified by interventions aimed at reducing SNS activity. Given the quite remarkable size effect of atorvastatin on MSNA reported in the studies performed so far, the lack of effect of atorvastatin on BP may appear as a surprising and apparently odd finding. Statins produce a small but measurable effect on BP. In a meta-analysis including almost the whole spectrum of statins currently applied in clinical practice, treatment with these drugs produced a 4 mmHg decrease in systolic pressure in patients with systolic BP above 130 mmHg [19]. Duration of treatment in most studies considered in this meta-analysis was longer than that in those discussed above, suggesting that long-term treatment may be a factor for the hypotensive effect of statins be apparent. Furthermore, as the effect of BP lowering interventions is strictly proportional to the level of baseline BP, individuals with normal or near normal BP and MSNA – like the patients in the Siddiqi et al. [17] study – are expected to manifest modest or no effect by drugs that impact upon BP. This is confirmed by the results of the Plaque Hypertension Lipid-Lowering Italian Study, in which the BP lowering effects of these compounds were absent in hypertensive patients in whom BP was effectively reduced by concomitant antihypertensive drugs [20]. Although a central effect of statins on the SNS seems to be well demonstrated, it appears unlikely that such an effect in CKD patients who had already achieved normotension and normal MSNA levels may translate into prevention of organ damage. In patients with MSNA was found closely associated with left ventricular mass index (shared variance about 60%) only in the mildly to highly elevated range, but it was unrelated to the same parameter in normotensive patients having normal MSNA [21], such as the patients in the present study. Patients with CKD frequently lack the nocturnal BP fall, a phenomenon which has been linked with high sympathetic activity triggered by sleep apnea [22–23]. Standard BP measurements in the clinic do not capture in full the risk of raised BP in these patients [24]. Therefore, the lack of systematic ambulatory blood pressure monitoring measurements and of estimates of the BP and heart rate variability is another relevant limitation of this study. In conclusion, the observations by Siddiqi et al. [17] further enlarge the spectrum of diseases where statins exert measurable effects on SNS activity, but they leave open the question as to whether this intriguing phenomenon may translate into real benefits in this high-risk population. Acknowledgement Conflicts of interest There are no conflicts of interest.