statins and the autonomic nervous system

Clinical Science (2014) 126, 401–415 (Printed in Great Britain) doi: 10.1042/CS20130332

Statins and the autonomic nervous systemPhilip J. MILLAR* and John S. FLORAS*

*University Health Network and Mount Sinai Hospital Division of Cardiology, University of Toronto, Toronto, Ontario, Canada

AbstractStatins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improveendothelium-dependent vasodilation, inflammation and oxidative stress. A ‘pleiotropic’ property of statins receivingless attention is their effect on the autonomic nervous system. Increased central sympathetic outflow anddiminished cardiac vagal tone are disturbances characteristic of a range of cardiovascular conditions for whichstatins are now prescribed routinely to reduce cardiovascular events: following myocardial infarction, and inhypertension, chronic kidney disease, heart failure and diabetes. The purpose of the present review is to synthesizecontemporary evidence that statins can improve autonomic circulatory regulation. In experimental preparations,high-dose lipophilic statins have been shown to reduce adrenergic outflow by attenuating oxidative stress in centralbrain regions involved in sympathetic and parasympathetic discharge induction and modulation. In patients withhypertension, chronic kidney disease and heart failure, lipophilic statins, such as simvastatin or atorvastatin, havebeen shown to reduce MNSA (muscle sympathetic nerve activity) by 12–30%. Reports concerning the effect ofstatin therapy on HRV (heart rate variability) are less consistent. Because of their implications for BP (bloodpressure) control, insulin sensitivity, arrhythmogenesis and sudden cardiac death, these autonomic nervous systemactions should be considered additional mechanisms by which statins lower cardiovascular risk.

Key words: blood pressure, nitric oxide, oxidative stress, sympathetic nervous system, statin

INTRODUCTION

Statins or HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) re-ductase inhibitors act competitively on the mevalonate pathwayto reduce endogenous production of cholesterol. Depending uponthe dose and type of statin prescribed, reductions in total choles-terol between 15 and 40 % and in LDL (low-density lipoprotein)-cholesterol between 20 and 55 % can be achieved [1]. Large-scale trials, whether alone or integrated into meta-analyses, havedemonstrated that statins reduce cardiovascular morbidity andmortality in high-risk populations [2–6] and the risk of majorvascular events in low-risk populations [7]. As a consequence,statins have become one of the most prescribed classes of med-ication worldwide.

These clinical effects, proportionate to patients’ risk pro-file [7], have been credited principally to total-cholesterol- and

Abbreviations: AngII, angiotensin II; AT1 receptor, angiotensin type 1 receptor; BP, blood pressure; DBP, diastolic BP; ET-1, endothelin-1; GABA, γ -aminobutyric acid; HF, high-frequency;HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HR, heart rate; HRV, heart rate variability; icv, intracerebroventricular; LDL, low-density lipoprotein; LF, low-frequency; L-NAME,NG-nitro-L-arginine methyl ester; L-NMMA, NG-monomethyl-L-arginine; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; MIBG, metaiodobenzylguanidine; MSNA, musclesympathetic nerve activity; NE, noradrenaline; NOS, nitric oxide synthase; eNOS, endothelial NOS; nNOS, neuronal NOS; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA,New York Heart Association; O2

−, superoxide anion; pNN50, percentage of consecutive normal RR intervals that differ by more than 50 ms; RMSSD, square root of the mean squaredifference of successive RR intervals; ROCK, Rho-associated kinase; ROS, reactive oxygen species; RSNA, renal sympathetic nerve activity; RVLM, rostral ventrolateral medulla; SBP,systolic BP; SDNN, S.D. of consecutive normal R-wave to R-wave intervals; SHRSP, stroke-prone spontaneously hypertensive rat; SOD, superoxide dismutase; Mn-SOD, manganeseSOD; TBARS, thiobarbituric acid-reactive substance; WKY rat, Wistar–Kyoto rat.

Correspondence: Dr John S. Floras (email [email protected]).

LDL-cholesterol-lowering [8]; however, statins have been shownalso to improve concurrently vascular function, inflammation andoxidative stress, actions that should contribute to their overall car-diovascular benefit [9,10]. An established mechanism for theseadditional ‘pleiotropic’ actions is via the inhibition of isoprenoidintermediates necessary for small G-protein function that alsoare synthesized through the mevalonate pathway [11]. At the in-tracellular level, small G-proteins, such as Ras, Rac1 and RhoA,participate in several signalling pathways with cardiovascularimplications (see [9]). These pathways are involved in modulat-ing the production of ROS (reactive oxygen species), throughNADPH oxidase [12] and ET-1 (endothelin-1) [13,14], and, bydestabilizing and uncoupling eNOS [endothelial NOS (nitric ox-ide synthase)] mRNA, the availability of the antioxidant vas-odilator NO (nitric oxide) [15]. They can also regulate AT1 re-ceptor (angiotensin type 1 receptor) gene expression [16]. AT1

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P. J. Millar and J. S. Floras

receptor stimulation via AngII (angiotensin II), a bioactive pep-tide up-regulated in hypertension and heart failure, also increasesROS production [17,18].

Statins exert additional effects on NO bioavailability by activ-ating PI3K (phosphoinositide 3-kinase)/Akt signalling, increas-ing eNOS phosphorylation [19] and by reducing caveolin-1, astructural membrane protein that binds and inhibits NOS function[20]. The changes in the production and availability of ROS andNO observed with statin therapy are thought to be one mechanismresponsible for increasing conduit artery endothelium-dependentvasodilation, promoting angiogenesis, inhibiting vascular smoothcell proliferation, and reducing oxidative stress and inflammation[8–10,21].

The possibility that statins also reduce cardiovascular risk byrectifying the disturbed neural control of the heart and circulationpresent in many disease conditions has received less attention.The purpose of the present review is to focus on the effects ofstatin therapy on the autonomic nervous system, with particularemphasis on human studies measuring post-ganglionic efferentMSNA (muscle sympathetic nerve activity) and HRV (heart ratevariability).

EXPERIMENTAL BACKGROUND

In addition to the vasculature, the small G-proteins describedabove are also present and functionally active in central neuralsites involved in the generation of sympathetic and parasympath-etic outflow, such as the RVLM (rostral ventrolateral medulla),nucleus tractus solaritius and paraventricular nucleus. In exper-imental models of hypertension or heart failure, one or more ofthese central brainstem regions exhibit elevated oxidative stresswith increased ROS [e.g. TBARS (thiobarbituric acid-reactingsubstance) levels and O2

− (superoxide anion)] [18,22–25], andreduced NO [26,27] and antioxidant defences [22,28], all poten-tial targets of statin therapy. Increased ROS, such as O2

−, inactiv-ate NO, an important signalling molecule in the brain [29], andproduce the highly reactive and cytotoxic peroxynitrate [30]. ROSalso balance excitatory and inhibitory amino acids in the RVLM[31], facilitating premotor sympathetic neuron input modulation[32]. As one consequence, inhibitory GABA (γ -aminobutyricacid) is reduced in the RVLM of hypertensive rats [33,34].

One mechanism responsible for such increased central ox-idative stress may be the pathological activation of the RAAS(renin–angiotensin–aldosterone system), which up-regulates andacts on central AT1 receptors to increase NADPH oxidase andmitochondrion-produced ROS [18,24,25,35–37]. Pharmacolo-gical interventions designed to inhibit the central effects of aldos-terone, AngII or AT1 receptor binding each reduce sympatheticoutflow [38–43]. Inflammatory cytokines produced by brain pe-rivascular macrophages may also be involved [44], increasingNADPH oxidase and O2

−, and up-regulating AT1 receptor activ-ity [45].

A causal role for the central neural imbalance between ROSand NO/antioxidants as a mediator of augmented sympatheticoutflow and cardiac vagal tone has been tested similarly us-

ing an icv (intracerebroventricular) infusion to exclude the in-volvement of peripheral afferent neural mechanisms. In animalmodels of hypertension icv infusion of an NADPH oxidase in-hibitor or tempol, a SOD (superoxide dismutase) mimetic givento reduce central ROS production, decreases both RSNA (renalsympathetic nerve activity) and BP (blood pressure) [24,34,46].Reductions in RSNA with icv tempol involve NO-mediated re-lease of GABA within the RVLM [34,47]. Conversely, reducingNO by icv NOS inhibition using L-NMMA (NG-monomethyl-L-arginine) increases sympathetic outflow [34]. In healthy rats, theincreased RSNA and BP elicited by icv L-NMMA is abolished bytransecting the spinal cord at C1 to C2, or by intravenous infusionof L-arginine, a precursor to NO [48,49].

Thus, if brain penetration is achieved, statins could exertsympathetic inhibitory actions centrally by reducing the ROS-mediated central oxidative stress and by increasing production oravailability of NO [50,51]. If so, these auxiliary properties couldhave important applications for patients with conditions such ashypertension, post-myocardial infarction, chronic kidney disease,heart failure and diabetes in whom elevated sympathetic activityand decreased vagal HR (heart rate) modulation are present, andare associated with increased risk of ventricular hypertrophy [52],impaired endothelium-dependent and -independent vasodilation[53–55], insulin resistance [56,57], arrhythmias [58] and prema-ture mortality [59–61].

Individual statins differ with respect to lipophilicity, whichinfluences their tissue-selectivity. Hydrophilic statins such asrosuvastatin and pravastatin undergo primarily hepatic uptake bya carrier-mediated organic anion transport polypeptide, whereaslipophilic statins (simvastatin, atorvastatin, fluvastatin and lovast-atin) are able to diffuse passively across extrahepatic cell mem-branes [62]. Consequently, lipophilic statins have a greater po-tential to cross the blood–brain barrier and interact with centralbrain regions involved in the generation or modulation of effer-ent sympathetic and parasympathetic activity. To date, becausethe majority of studies investigating potential autonomic effectshave administered lipophilic statins, data concerning hydrophilicstatins are limited.

EXPERIMENTAL STUDIES

The effects of statin therapy on autonomic nervous system func-tion have been studied thus far in experimental models of humanhypercholesterolaemia, diabetes, the metabolic syndrome, hyper-tension, myocardial infarction and heart failure.

HypercholesterolaemiaIn genetically dyslipidaemic apoE (apolipoprotein E)− / − mice,2 weeks of oral rosuvastatin (80 mg/kg of body weight per day)had no effect on LDL-cholesterol, but the HF (high-frequency)power of HRV, BP and HR reverted to values of control mice[20]. Rosuvastatin also increased the HR response to atropineand the SBP (systolic BP) response to NOS inhibition, suggestingincreased arterial baroreflex modulation.

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Autonomic effects of statins

DiabetesIn streptozotocin-induced diabetic rats, 2 weeks of oral high-dose fluvastatin (10 mg/kg of body weight per day) did not al-ter total cholesterol, but normalized cardiac sympathetic MIBG(metaiodobenzylguanidine) scintigraphy [63]. Compared withhealthy control animals, MIBG accumulation was reduced inuntreated diabetic animals, but normalized with fluvastatin, al-though the two groups exhibited a similar washout rate, a markerof decreased NE (noradrenaline) turnover and thus cardiac sym-pathetic activity [64]. The difference in MIBG accumulation maythen be related to impaired NE neural uptake. Fluvastatin did notalter BP but reduced markers of oxidative stress, plasma levelsof lipid peroxides, and mRNA expression of myocardial 8-iso-prostaglandin F2α and NADPH oxidase subunit p22phox [63].

Metabolic syndromeSilva et al. [65] reported that 2 weeks of oral simvastatin (5 mg/kgof body weight per day) altered HR responses to methylatropineand propanolol in rats with the metabolic syndrome: the increasein HR following methylatropine was augmented and the decreasein HR following propanolol was diminished, suggesting increasedcardiac vagal tone and reduced sympathetic HR modulation. Sim-vastatin improved insulin resistance but did not change BP.

HypertensionIn SHRSPs (stroke-prone spontaneously hypertensive rats),30 days of high-dose oral atorvastatin (50 mg/kg of body weightper day) reduced 24-h urinary NE excretion and mean arterialpressure [66]. These effects were not observed in control WKY(Wistar–Kyoto) rats even though atorvastatin reduced total cho-lesterol and LDL-cholesterol in both groups. Atorvastatin in-creased the expression of eNOS (cortex, cerebellum, hypothal-amus, brainstem and aorta) and inducible NOS (cortex, hypothal-amus, brainstem and aorta) in both the SHRSP and WKY groups,but no effect on nNOS (neuronal NOS) was detected. The sametreatment reduced the elevated TBARS levels in the RVLM andwhole brain of SHRSPs, but had no effect in WKY animals [67].

By contrast, when this group were orally administered ator-vastatin at 20 mg/kg of body weight per day for 28 days theyfound no effects on 24-h urinary NE excretion or BP in SHR-SPs [68]. They did report that TBARS levels in the RVLM werelower and arterial baroreflex sensitivity of HR increased com-pared with untreated SHRSP controls, although both measureswere not normalized to control WKY animals. This neutral resultsuggests that high doses of lipophilic statins may be necessaryfor efferent autonomic actions to be detected.

Interestingly, 28 days of low-dose atorvastatin (20 mg/kg ofbody weight per day) reduced 24-h urinary NE excretion and HRwhen combined with amlodipine (5 mg/kg of body weight perday) [69]. Combination therapy also reduced TBARS levels andNADPH oxidase activity, while increasing the antioxidant activityof Mn-SOD (manganese SOD) in the RVLM and hippocampus.No effects were reported for atorvastatin or amlodipine alone.Amlodipine, a lipophilic dihydropyridine, is thought also to exertcentral autonomic actions and can reduce RSNA and urinary NEexcretion [70,71], possibly by blocking mitochondrial calcium-mediated ROS production [72]. The autonomic actions exerted

by combined low doses of atorvastatin and amlodipine may bemediated by synergistic improvements in central oxidative stress.

Kishi et al. [73] also reported that after 14 days of icv atorvast-atin (40 μg/ml) SHRSPs exhibited lower 24-h urinary NE excre-tion, and LF (low-frequency) power spectra for SBP, MAP (meanarterial pressure) and HR as compared with vehicle-treated anim-als. The effects on urinary NE excretion and BP were similar tothose achieved with 50 mg/kg of body weight per day orally [67].Animals treated with icv atorvastatin exhibited lower TBARSlevels, NADPH oxidase activity and Rac1 activity, in concert withincreased Mn-SOD activity in the RVLM. As NADPH oxidaseactivity was lower in atorvastatin-treated SHRSPs, microinjec-tion of apocynin, an NADPH oxidase inhibitor, into the RVLMcaused a smaller reduction in MAP compared with untreatedSHRSPs [73].

By comparison, in SHRs (spontaneously hypertensive rats),2 weeks of pravastatin [100 mg/l (in drinking water)], a hydro-philic statin, did not alter plasma cholesterol or BP, but reducedHR [74]. An accompanying in vitro study of the right atriumfound that pravastatin diminished the release of pre-loaded tracer-labelled [3H]-NE to that of the WKY control rats. The AT1 re-ceptor antagonist losartan reduced [3H]-NE release similarly;blockade of NOS [L-NAME (NG-nitro-L-arginine methyl ester)]did not reverse this effect of pravastatin. This suggests a pos-sible NO-independent effect of pravastatin on NE release, andreaffirms the central autonomic role for NO during in vivo stud-ies. Pravastatin did not alter protein levels of nNOS or eNOS,guanylate cyclase, NADPH oxidase subunits gp91phox and p40phox

or the AT1 receptor, but did reduce cardiac tissue AngII by re-ducing the protein expression of ACE1 and ACE2 (angiotensin-converting enzymes 1 and 2 respectively).

Post-myocardial infarctionIn an experimental rat model of myocardial infarction, 4 weeksof pravastatin (5 mg/kg of body weight per day) did not alter totalcholesterol or NE (plasma or tissue), but reduced cardiac sym-pathetic neural re-innervation and pacing-induced ventricular ta-chyarrhythmias compared with vehicle-treated infarcted animals[75].

Heart failureFollowing 3 weeks of oral simvastatin at a dose of 1.5 or 3 mg/kgof body weight per day (but not 0.3 mg/kg of body weight perday), Pliquett et al. [76] reported lower RSNA and plasma NEconcentrations in normolipidaemic rabbits with pacing-inducedheart failure compared with a vehicle-treated group. The arter-ial baroreflex modulation of RSNA and of HR in response tosodium nitroprusside (but not phenylephrine) infusion were alsonormalized in the simvastatin-treated group (1.5 mg/kg of bodyweight per day and 3 mg/kg of body weight per day). Fractionalshortening remained depressed. The 3 mg/kg of body weight perday dose restored both time [SDNN (S.D. of consecutive nor-mal R-wave to R-wave intervals)] and frequency (total spectralpower) domain measures of HRV in the heart failure group tovalues obtained in control animals [77].

Briefer durations of statin therapy may also be sufficient toachieve such autonomic effects. In an experiment by Gao et al.

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Table 1 Effects of statin therapy on MSNA burst incidence in humansPercentage change values are reported as group means. ∗Not statistically significant; †trend for a reduction (P = 0.06).C, cross-over; CKD, chronic kidney disease; CON, controlled; HC, hypercholesterolaemia; CHF, chronic heart failure; HTN,hypertension; n/a, not available; RPCC, randomized placebo-controlled cross-over; RCT, randomized-controlled trial; S, statin;SN, statin-naıve; UC, uncontrolled.

Trial Study Study Subjects Change Change

reference population design (n) Intervention (dose; duration) in LDL in MSNA

[91] HTN + HC CON S: 10 Atorvastatin (20 mg/day; 8 weeks) ↓41% ↓17%

C: 8 None ↓7% ↑ 8%

[92] HTN + HC RCT S: 15 Simvastatin (40 mg/day; 8 weeks) ↓31% ↓18%

C: 16 Placebo ↓4% ↓1%

[93] HTN RPCC 13 Atorvastatin (80 mg/day; 3 weeks) ↓48% ↓10%

[94] HTN + SN RPCC 14 Simvastatin (80 mg/day; 4 weeks) ↓48% ↓22%

[100] CKD + HTN RCT S: 10 Atorvastatin (20 mg/day; 6 weeks) ↓13 %† ↓30%

C: 10 None n/a ↓4%

[103] CHF C 8 Atorvastatin or simvastatin (40 mg/day; 4 weeks) ↓51% ↓29%

[104] CHF RCT S: 9 Atorvastatin (10 mg/day; 12 weeks) ↓37% ↓16 %∗

C: 9 Placebo 0% ↓3%

[105] CHF UC 7 Simvastatin (40 mg/day; 4 weeks) ↓42% ↓12%

CHF RPCC 6 Simvastatin (40 mg/day; 4 weeks) ↓37% ↓24%

[78] again involving normolipidaemic heart failure rabbits, 7 daysof simvastatin (3 mg/kg of body weight per day) resulted in lowerRSNA and total peripheral resistance. Mean LVEF (left ventricu-lar ejection fraction) was 78 % in non-heart failure controls, 32 %in rabbits with heart failure given placebo and 52 % in thosetreated with simvastatin (P < 0.05 compared with placebo). Sim-vastatin also increased arterial baroreflex gain for both RSNAand HR modulation, and reduced the RSNA and BP responses toacute icv AngII. Resting BP and HR were unchanged. In the an-imals treated with simvastatin, RVLM AT1 receptor and NADPHoxidase subunit (gp91phox, p47phox and p40phox) mRNA and pro-tein expression, and NADPH-oxidase-dependent O2

− productionwere reduced. No significant adaptations were found in animalstreated with both simvastatin and icv AngII.

In a subsequent study involving normolipidaemic rabbits withheart failure, 7 days of icv simvastatin infusion (5 μg/0.5 μl perh) reduced RSNA and increased the arterial baroreflex gain ofRSNA [51]. There was no effect on LVEF. Central NOS inhibitionwith icv L-NAME prevented these RSNA responses. Simvastatintreatment increased nNOS protein expression in the RVLM. Theauthors provided in vitro confirmation that 0.1 and 1 μM, butnot 10 mM, simvastatin increased nNOS mRNA expression; thiseffect was blocked by co-administration of upstream isoprenoidintermediates L-mevalonate, farnesyl pyrophosphate or geranyl-geranyl pyrophosphate, and was replicated by administration ofa ROCK (Rho-associated kinase) inhibitor. These observationsdemonstrate that simvastatin inhibits the mevalonate pathwayand implicate the RhoA/ROCK pathway in statin-induced up-regulation of nNOS. Recent work with icv fasudil, a ROCKIIinhibitor, confirms an NO-dependent improvement in parasym-pathetic and sympathetic modulation in rabbits with heart failure[79].

In a rat model of chronic heart failure, 15 days of oral fluvast-atin (10 mg/kg of body weight per day) increased arterial barore-flex control of HR and cardiac output compared with untreated

animals [80]. Although HR and BP were unchanged, fluvast-atin decreased cardiac hypertrophy and normalized markers ofoxidative stress (decreased serum malondialdehyde and reducedglutathione; increased SOD) and inflammation (decreased TNF-α (tumour necrosis factor-α)].

Collectively, these results suggest that high-dose lipophilicstatins can alter autonomic function in a variety of experimentalmodels of human disease. These effects appear to be mediated byimprovements in central oxidative stress through their actions onROS production and antioxidant defences. The increased sensitiv-ities of arterial baroreflex regulation of RSNA and HR describedby several investigators [51,68,76,78] could also implicate anafferent peripheral statin mechanism, for example via increasedvascular NO bioavailability improving conduit artery complianceand baroreceptor signal transduction. However, overexpression ofeNOS or nNOS by gene transfer into the RVLM also improvesthe baroreflex control of HR and RSNA in hypertensive and heartfailure animals [81,82], and, since augmentation of the reflex con-trol of RSNA was effected by icv infusion of simvastatin [51], acentral neural reduction in oxidative stress may be sufficient toaccount for this finding. With evidence that low-dose simvastatin(0.25 mg/kg of body weight) can improve the 28-day survival ofmice subjected to myocardial infarction [83], further work shouldbe directed to establishing whether autonomic effects contributeto this benefit.

HUMAN STUDIES

The autonomic effects of statin therapy have been investigatedin patients with hypercholesterolaemia, hypertension, coronaryartery disease, chronic kidney disease and heart failure. Thesedata are summarized in Tables 1 and 2.



Table 2 Effects of statin therapy on HRV in humansC, control; CAD, coronary artery disease; CKD, chronic kidney disease; CON, controlled; HC, hypercholesterolaemia; CHF,chronic heart failure; HF, HF power; HTN, hypertension; LF, LF power; OC, observation control; R, randomized; RC, randomizedcross-over; RPCC, randomized placebo-controlled cross-over; RCT, randomized-controlled trial; S, statin; SN, statin-naıve; TP,total power; UC, uncontrolled; VLF, very-LF.

Study Subjects

Trial reference Population design (n) Intervention (dose; duration) Major HRV findings

[84] HC RC 29 Atorvastatin (10 mg/day; 10 weeks) ↑SDNN, RMSSD, TP and VLF

[88] HC UC 74 Atorvastatin (40 mg/day; 56 weeks) No change in HRV

[89] HC R 31 Simvastatin (20 mg/day; 6 weeks) No change in HRV

30 Simvastatin + omega-3 No change in HRV

[90] HC RC 26 Pravavastatin (20 mg/day; 8 weeks) ↑Night time HF power

Simvastatin (20 mg/day; 8 weeks) No change in HRV

[93] HTN RPCC 13 Atorvastatin (80 mg/day; 3 weeks) No change in HRV

[94] HTN + SN RPCC 14 Simvastatin (80 mg/day; 4 weeks) No change in HRV

[95] HC +− CAD CON S: 40 Atorvastatin (20 mg/day; 112 weeks) ↑SDNN, pNN50, RMSSD and TP, and ↓LF andLF/HF ratioC: 20 None

[96] CAD RPCC 10 Atorvastatin (80 mg/day; 4 weeks) Trend for ↓LF/HF ratio

[97] CAD OC S: 29 Any statin ↑SDNN

C: 44 None

[98] CAD RPCC 80 Simvastatin (80 mg/day; 6 weeks) No change in HRV

[99] CAD OC S: 54 Any statin No change in HRV

C: 32 None

[102] CKD RPCC 10 Simvastatin (40 mg/day; 4 weeks) No change in HRV

[106] CHF RCT S: 40 Atorvastatin (10 mg/day; 12 weeks) ↑ SDNN and RMSSD

C: 40 None

[107] CHF RCT S: 12 Atorvastatin (40 mg/day; 12 weeks) ↓LF and LF/HF ratio

C: 9 Placebo

[111] CHF RPCC 15 Atorvastatin (80 mg/day; 12 weeks) No change in HRV

[112] CHF UC 25 Simvastatin (20 mg/day; 6 weeks) No change in HRV

HypercholesterolaemiaIn a randomized cross-over trial of 29 patients with hypercho-lesterolaemia, Melenovsky et al. [84] compared the effects of10 weeks of low-dose atorvastatin (10 mg/day) or fenofibrate(200 mg/day) on HRV. Both atorvastatin and fenofibrate reducedtotal cholesterol and increased time domain [SDNN and RMSSD(square root of the mean square difference of successive RRintervals)] and frequency domain (total spectral power and very-LF power) measures of HRV. However, interpretation of thesefindings is limited by the lack of a placebo control group. Ator-vastatin also increased the arterial baroreflex sensitivity of HR,as did 6 weeks of diet plus atorvastatin (10 mg/day) in a smallcross-over trial of ten otherwise healthy men with elevated totalcholesterol [85]. In a controlled study of 30 hypercholestero-laemic patients with Type 2 diabetes, 12 months of simvastatin(40 mg/day) reduced total cholesterol and LDL-cholesterol, andincreased HR recovery, a marker of parasympathetic potency[86], 1 min following a maximal exercise test [87].

In contrast, in an uncontrolled trial of 74 hypercholestero-laemic men, 12 months of atorvastatin (40 mg/day) reduced totalcholesterol and LDL-cholesterol, but did not affect time or fre-quency domain measures of HRV [88]. Similar neutral resultshave been observed following 6 weeks of simvastatin (20 mg/day)

or simvastatin (20 mg/day) plus omega-3 fatty acid supplement-ation [89]. However, both studies are again confounded by theabsence of a control group.

Interestingly, in a randomized cross-over trial of 26 hyperlip-idaemic patients, night-time HF power, a marker of parasympath-etic modulation, was increased following 8 weeks of pravastatin(20 mg/day), but not simvastatin (20 mg/day) [90], suggesting asinoatrial action of this more hydrophilic statin at a time of lowcardiac sympathetic tone.

HypertensionThe most consistent evidence in humans for a sympathoinhib-itory role of statins arises from patients with primary hyper-tension. Sinski et al. [91] studied ten hypercholesterolaemicessential hypertensive men and found that, compared with anuntreated control group, 8 weeks of atorvastatin (20 mg/day) re-duced MSNA burst incidence and frequency by 17 % (46.5 +− 6.2to 38.4 +− 5.5 bursts/100 heart beats; 36.0 +− 6.6 to 28.6 +− 4.8bursts/min), without altering BP or heart rate. Subsequentlythis group conducted a larger randomized double-blind placebo-controlled study of simvastatin (40 mg/day for 8 weeks) in 31 hy-percholesterolaemic hypertensive men [92]. Those receiving sim-vastatin (n = 15) exhibited significant reductions in MSNA burst

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Figure 1 Representative mean voltage neurograms in two participants of MSNA acquired after 4 weeks of placebo(left-hand panels) or simvastatin (80 mg/day) (right-hand panels)MSNA burst frequency (bursts/min) and incidence (bursts/100 cardiac cycles) are reported below each. This Figure wasdrawn from data reported in [94].

incidence (18 %; 47.8 +− 8.4 to 39.4 +− 8.3 bursts/100 heart beats)and burst frequency (24 %; 36.5 +− 5.4 to 27.8 +− 5.8 bursts/min),and HR (8 %; 77 +− 7 to 71 +− 5 beats/min). BP was unchanged.None of these variables changed significantly in the placebogroup. In both studies the statin treatment was reported to in-crease arterial baroreflex sensitivity of HR, a marker of reflexcardiac vagal modulation [91,92].

Using a more stringent randomized double-blind placebo-controlled cross-over study design, Gomes et al. [93] reportedsignificant mean 10 % and 11 % reductions in MSNA burst in-cidence (64.7 +− 3.0 to 58.5 +− 2.0 bursts/100 heart beats) andburst frequency (39.2 +− 1.5 to 35.0 +− 2.0 bursts/min) following3 weeks of atorvastatin (80 mg/day) in 13 primary hypertensivepatients. Neither 24-h ambulatory BP nor resting HR or HRVwas affected. Of note, because four out of their 13 patients haddiscontinued pre-existing therapy before their participation, thesevalues may have been affected by a residual central neural statinaction.

To avoid potential confounding effects of hypercholestero-laemia or previous statin therapy we conducted a randomizeddouble-blind placebo-controlled cross-over study investigatingthe effects of 4 weeks of simvastatin (80 mg/day) on MSNA in 14essential hypertensive normolipidaemic statin-naıve patients whootherwise would not have received statin therapy [94]. Simvast-atin lowered mean MSNA burst incidence (55 +− 23 to 43 +− 17

bursts/100 heart beats) and burst frequency (32 +− 12 to 25 +− 9bursts/min) by 22 %. Representative tracings from two patientsare demonstrated in Figure 1. Simvastatin did not alter HRV orarterial baroreflex sensitivity of HR and MSNA, ruling out aneffect on efferent sinoatrial node discharge or afferent peripheralmechanisms of action. These results are in agreement with exper-imental findings suggesting a central autonomic action of statins.

In three patients, simvastatin reduced atrial or ventricular ec-topy by 55 %. There were no significant effects on the homoeo-static model assessment of insulin resistance, BP or HR. Inter-estingly, with simvastatin a trend was observed for a reduction inDBP (diastolic BP) (81 +− 10 to 77 +− 8; P = 0.055), a responsewhich should normally trigger reflexive increases in MSNA. Sim-vastatin increased also endothelium-independent vasodilation,possibly as a result of less neurogenic constraint, but did notalter endothelium-dependent (flow-mediated) vasodilation.

Coronary artery diseaseIn a controlled trial of 40 hypercholesterolaemic patients withand without coronary artery disease, 24 months of atorvastatin(20 mg/day) reduced total cholesterol and LDL-cholesterol, andaltered time domain [increased SDNN, RMSSD and pNN50(percentage of consecutive normal RR intervals that differ bymore than 50 ms)] and frequency domain (increased total spec-tral power and HF power; decreased LF power and the LF/HF



ratio) measures of HRV [95]. Atorvastatin did not change HR orBP.

In a smaller randomized double-blind placebo-controlledcross-over study of ten patients with documented coronary arterydisease, 4 weeks of atorvastatin (80 mg/day) reduced restingplasma NE and demonstrated a trend towards a reduced LF/HFratio of HRV [96]. These authors reported no significant changein plasma NE or HRV responses to supine tilt (80◦) or in pressoror HR responses to a cold pressor test. Unfortunately, these sub-jects were not statin-naıve but underwent a 4-week medicationwashout period prior to participation. Increased HRV has alsobeen reported in a controlled observational study of 29 post-infarct patients on statins [97].

In contrast, in a larger randomized double-blind placebo-controlled cross-over trial of 80 patients with diagnosed coronaryartery disease, 6 weeks of high-dose atorvastatin (80 mg/day) re-duced total cholesterol and LDL-cholesterol, but did not altertime domain HRV [98]. Similar neutral HRV results have beenobserved in a controlled observational study of 54 coronary arterydisease patients with an implanted cardioverter defibrillator onstatins [99].

Chronic kidney diseaseIn a randomized-controlled trial of ten hypertensive patientswith chronic kidney disease, Siddiqi et al. [100] observedthat, compared with usual-care controls, 6 weeks of atorvastatin(20 mg/day) reduced MSNA burst incidence by 30 % (50 +− 13to 35 +− 12 bursts/100 heart beats) and burst frequency by29 % (28 +− 8 to 20 +− 6 bursts/min). Atorvastatin did not lowerLDL-cholesterol or total cholesterol, BP or HR. It is conceiv-able that greater MSNA reductions might have been detectedhad these patients not been pre-treated for hypertension withaliskiren, a renin inhibitor known to reduce MSNA in thispopulation [101].

In contrast, in a randomized double-blind placebo-controlledcross-over study, 4 weeks of simvastatin (40 mg/day) loweredLDL-cholesterol, but did not affect time domain measures ofHRV in ten chronic haemodialysis patients [102].

Chronic heart failureIn comparison with the consistent reductions in RSNA in exper-imental preparations [51,76,78], thus far studies in human heartfailure have yielded less conclusive results. Gomes et al. [103]prospectively examined eight heart failure patients [NYHA (NewYork Heart Association) classes II–IV and LVEF <40%] beforeand 8 weeks after discontinuation of atorvastatin or simvastatin(40 mg/day). They reported a significant increase in mean MSNAburst incidence (56 +− 5 to 73 +− 4 bursts/100 heart beats) and fre-quency (32 +− 3 to 42 +− 3 bursts/min). Values returned to baselinelevels 4 weeks after statins were re-prescribed (burst incidence,52 +− 6 bursts/100 heart beats; frequency, 28 +− 3 bursts/min).

In a double-blind randomized-controlled trial of 18 statin-naıve non-ischaemic systolic heart failure patients (LVEF<35 %), Horwich et al. [104] studied the effects of 12 weeksof low-dose atorvastatin (10 mg/day) (n = 9) or placebo (n = 9)on MSNA. Atorvastatin lowered both LDL-cholesterol andtotal cholesterol, but did not produce a statistically signific-

ant reduction in MSNA, although burst incidence (62 +− 6 to52 +− 6 bursts/100 heart beats) and frequency (43 +− 3 to 36 +− 5bursts/min) fell by 16 % with statin therapy compared with ∼3 %reductions in the placebo group. Inspection of the individual datademonstrates that this mean MSNA change was driven primarilyby one subject with a very large reduction (>30 bursts/min). Dis-crepancy in these published findings suggest that the autonomiceffects of statins are not universal in heart failure, but are un-related to clear-cut cholesterol reductions. They may also raiseimportant questions regarding a dose threshold for the autonomiceffects of statins in a heart failure population.

More recently, Deo et al. [105] reported the findings of aseries of investigations in patients with idiopathic dilated car-diomyopathy (NYHA classes I–III and LVEF <40 %). In bothgroups, simvastatin reduced both LDL-cholesterol and total cho-lesterol. In the initial proof-of-concept study involving seven pa-tients, 4 weeks of simvastatin (40 mg/day) reduced mean MSNAburst incidence and frequency by 12–13 % (75 +− 5 to 65 +− 5bursts/100 heart beats; 50 +− 4 to 44 +− 5 bursts/min), and alsoMAP. In a subsequent double-blind placebo-controlled cross-over study of six patients, simvastatin reduced mean MSNAburst incidence (24 %; 59 +− 5 bursts/100 heart beats in placeboto 45 +− 6 bursts/100 heart beats in statin-treated) and frequency(27 %; 44 +− 6 bursts/min in placebo to 32 +− 5 bursts/min in statin-treated), and also total ROS and O2

−, as estimated from plasmaby electron paramagnetic spin resonance. These findings are con-sistent with the concept that reductions in sympathetic activitywith lipophilic statins occur secondarily to a reduction in oxidat-ive stress.

In a randomized-controlled trial, Vrtovec et al. [106] repor-ted that heart failure patients (LVEF <30 %) receiving 3 monthsof atorvastatin (10 mg/day; n = 40) had increased time domainHRV (SDNN and RMSSD) and QT interval variability com-pared with controls. They reported that these effects were inde-pendent of the reductions in total cholesterol. In a single-blindrandomized-controlled trial of 21 systolic heart failure patients(LVEF <45 %), Hamaad et al. [107] reported that 12 weeks ofatorvastatin (40 mg/day) reduced the LF power of HRV, and con-sequently the LF/HF ratio. The significance of this finding isunknown in so far as there is an inverse relationship betweenMSNA and LF spectral power as heart failure progresses [108],and in a multivariate analysis involving heart failure patients re-duced daytime LF power of HR was an independent predictorof increased risk of sudden cardiac death [109]. In a controlledstudy, 3 months of fluvastatin (80 mg/day) reduced total cho-lesterol and LDL-cholesterol, and increased HR recovery at 1and 3 min following a maximal exercise test in 29 hyperlipid-aemic patients with ischaemic cardiomyopathy (LVEF <40 %)[110].

In contrast, in a randomized double-blind placebo-controlledcross-over study of 15 non-ischaemic cardiomyopathy patients(LVEF <40 %), 12 weeks of atorvastatin (80 mg/day) reducedLDL-cholesterol, but did not alter HRV [111]. Similar neutralHRV results have been reported in an uncontrolled trial of 25 pa-tients with non-ischaemic dilated cardiomyopathy (LVEF <40 %)following 6 weeks of simvastatin (20 mg/day) [112]. However,this group did report an intriguing correlation, with an inverse

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relationship between the changes in baseline LDL-cholesterolfollowing simvastatin therapy and the changes in LF power dur-ing a Valsalva stress.

In the only head-to-head trial of a lipophilic compared with ahydrophilic statin, Tsutamoto et al. [113] compared 6 months oflow-dose atorvastatin (5 mg/day) or rosuvastatin (2.5 mg/day) onseveral end points in non-diabetic patients with dilated cardiomy-opathy (LVEF <45 %). Total cholesterol and LDL-cholesterolwere reduced equally in both groups. Although plasma NEwas unchanged, in the atorvastatin group cardiac sympatheticimaging using MIBG scintigraphy detected an increased H/M(heart/mediastinum) ratio (a marker of increased NE uptake orcardiac adrenoreceptor density [114]) and a decreased washoutrate. Additionally, the atorvastatin group reported increasedLVEF and reduced plasma NT-proBNP (N-terminal pro-B-typenatriuretic peptide) and oxidized LDL-cholesterol concentra-tions. A trend for reduced hsCRP (high-sensitivity C-reactiveprotein) was also observed.

DISCUSSION AND IMPLICATIONS

The available human evidence indicates that several statins arecapable of exerting autonomic effects. The most consistent find-ing is that of a significant reduction in efferent sympatheticoutflow, measured as MSNA, with lipophilic statins in sub-jects with normal ventricular function. Simvastatin and atorvast-atin, across a wide range of doses, reduced MSNA by 10–24 %in patients with hypertension (Table 1). Low-dose atorvastatinfailed to reduce MSNA in one study of heart failure patients[104], although overall, when studied in heart failure, MSNA fellby 12–29 %.

In contrast with these generally concordant findings, only∼50 % of the studies published reported a significant change inHRV with statin therapy. This lack of consensus probably resultsfrom differences between investigative laboratories with respectto the time and frequency domain methods they use to infervagal and sympathetic HR modulation; differences in the qualityof study designs (Table 2); the sample size implication of theskewed (non-parametric) distribution of such variables withingroups (i.e. some studies may have lacked the statistical power todemonstrate true differences) [115]; the impact of heart failureon the congruence of MSNA and LF spectral power [108,116];the confounding potential of background medication with effecton sinoatrial discharge rates, such as β-adrenoceptor antagonists[116–118]; and differences in statin dosage. For example, a pro-spective trial involving 359 subjects reported significant positivecorrelations between statin dose and the time domain indices ofvagal HR modulation (SDNN and RMSSD) studied [119].

Although limited mechanistic human data are available, basedon experimental evidence, the autonomic effects appear to bemediated by a reduction in central oxidative stress, secondaryto changes in NO and ROS production and availability. Penet-ration of statins into brain regions associated with generatingand modulating sympathetic and parasympathetic outflow maybe dependent on statin lipophilicity. However, the effects of hy-

drophilic statins on MSNA or HRV have not been thoroughlytested.

The published literature raises several important questions asto the clinical implications of the autonomic changes effected bystatin therapy.

Is there a relationship between MSNA and BP orinsulin resistance?Notable in these small clinical trials demonstrating a fall inMSNA has been the absence of reductions in resting or am-bulatory BP. This has raised the question as to whether this effectof lipophilic statins on MSNA is clinically relevant [120]. In arandomized double-blind placebo-controlled trial of 973 healthynormotensive subjects, 6 months of simvastatin (20 mg/day) orpravastatin (40 mg/day) both reduced SBP and DBP equally (de-crease of 2.4–2.8 mmHg) [121]. Meta-analyses have confirmedlong-term statin usage can produce modest reductions in rest-ing BP (decrease by ∼2–4/1–2 mmHg), with the largest effectsobserved in patients with elevated BP [122,123]. These reduc-tions also appear to be independent of changes in plasma lipids[124]. Current studies of autonomic effects of statins have beenprimarily of small cohorts of patients receiving anti-hypertensivemedications or with normal BP, i.e. groups unlikely to demon-strate substantive reductions in BP. Future investigations of thisquestion would benefit from longer treatment periods and ad-equate statistical power to detect modest BP changes.

A relationship between sympathetic activity and insulin res-istance has been demonstrated in a number of well-controlledinterventional studies. Insulin resistance is reduced with acuteincreases in MSNA in healthy normotensive men [125] and im-proved following treatment with α-adrenergic blockers [126,127]or central-acting sympatholytics in heart failure or hypertensivepopulations [128–130]. Indeed, positive correlations have beenreported between MSNA and insulin resistance in obese patients[57]. Given that statins can be a robust stimulus to lower MSNA(Table 1), the reported longitudinal observation that statins alsoincrease the risk of diabetes [131] appears contradictory. Onepossibility is that statins exert several qualitatively distinct ef-fects with metabolic consequences. In patients with the metabolicsyndrome, 16 weeks of moxonidine, a central sympatholytic, pro-duced the largest reductions in OGTT (oral glucose tolerance test)plasma insulin responses in those with high sympathetic activity[129]. This could mean that patients with low baseline sympath-etic activity, and thus presumably less likely to experience largereductions in MSNA, are more susceptible to a statin-mediatedincrease in insulin resistance. Interestingly, in the only study tosimultaneously examine MSNA and insulin sensitivity with statintherapy, McGowan et al. [94] found no change in insulin resist-ance after 4 weeks of simvastatin in normolipidaemic primaryhypertensive patients, even though MSNA was reduced. The in-teractive autonomic and metabolic consequences of statin therapyrequires further study.

Are the mechanisms responsible for the autonomiceffects cholesterol-independent?The experimental evidence suggests that statins exert autonomiceffects via non-cholesterol-mediated or ‘pleiotropic’ actions on



central oxidative stress. However, not all human studies havebeen designed specifically to test whether MSNA reductions areindeed cholesterol-independent. Although the majority of studies(Table 1) have observed parallel reductions in LDL-cholesteroland MSNA, one study reported reductions in LDL-cholesterolwithout corresponding reductions in MSNA [104], while anotherreported significant reductions in MSNA, but only a trend towardscholesterol-lowering [100]. Correlation analyses have also failedto detect a significant association between the changes in LDL-cholesterol or total cholesterol and MSNA, but the individualstudy sample sizes are small.

Acute lipid infusion can increase MSNA in both young andold participants [132,133]. One group has reported a positive sig-nificant correlation between total cholesterol and MSNA burstincidence (r = 0.50) [93]. Treatment with a α1-adrenoreceptorinhibitor has been shown to lower total cholesterol and LDL-cholesterol in hypertensive patients [134], whereas 4 weeks ofpost-ganglionic sympathetic neuron blockade with debrisoquinecaused significant, correlated, changes in plasma NE and totalcholesterol in essential hypertensive patients, but not healthycontrols [135]. McGowan et al. [94] found the change in MSNAelicited by simvastatin to correlate with pre-treatment total cho-lesterol and LDL-cholesterol (r = 0.56 and 0.59; i.e. the higherbaseline total cholesterol or LDL-cholesterol the greater thechange in MSNA). However, whether this relationship was causalor coincidental could not be determined definitively. Total cho-lesterol and LDL-cholesterol have been found to associate neg-atively with HRV [136], whereas the sympathetically mediatedmorning surge in BP [137] correlates positively with plasmaLDL-cholesterol concentrations [138]. Further work is requiredto confirm the cholesterol-independence of the observed statinautonomic effects.

Do these actions influence cardiovascular endpoints?Both increased MSNA and decreased HRV have been linked toadverse cardiovascular events [59–61]. Thus impaired neurogeniccirculatory regulation may be an additional mechanism by whichstatins reduce cardiovascular morbidity and mortality. However,several large-scale trials [e.g. GISSI-HF (Gruppo Italiano per loStudio della Streptochinasi nell’Infarto Miocardico-Heart Fail-ure), CORONA (Controlled Rosuvastatin Multinational Studyin Heart Failure) and AURORA (A Study to Evaluate the Useof Rosuvastatin in Subjects On Regular Haemodialysis: an As-sessment of Survival and Cardiovascular Events) in heart failureor chronic kidney disease populations have reported that stat-ins do not improve cardiovascular events despite lowering LDL-cholesterol and total cholesterol [139–141]. Interestingly, in eachof these large neutral trials the statin tested was rosuvastatin, a hy-drophilic statin. Lipophilicity may be the key to these neutral out-comes. In a study involving patients with dilated cardiomyopathy,6 months of atorvastatin, but not rosuvastatin, improved cardiacMIBG scintigraphy parameters, LVEF, NT-proBNP and oxidizedLDL-cholesterol concentrations [113]. In contrast, in a recentlypublished 4-year follow-up of Japanese patients with chronicheart failure, pitavastatin, a lipophilic statin, at 2 mg/day (equi-valent to simvastatin at approximately 20 mg/day or atorvastatin

at approximately 10 mg/day) did not improve cardiac mortalityand hospitalization for worsening heart failure [142]. Predefinedsubgroup analysis did demonstrate improvements in patients witha LVEF >30 %, suggesting a possible statin–ventricular functioninteraction. A limitation of that study is that, although the dosewas sufficient to reduce LDL-cholesterol, it may not have beenhigh enough to permit adequate penetration of central neural sitesand produce autonomic effects. Indeed, the only human trial notto demonstrate a statistically significant reduction in MSNA useda similar dose of atorvastatin (10 mg/day) [104]. The concept thathigher doses of lipophilic agents may be required to act on centralneural sites has been put forth for AT1 receptor blockers [143].The issue of lipophilicity and statin penetration is complicated byevidence that hydrophilic statins are capable of reducing circulat-ing isoprenoid levels as a result of hepatic HMG-CoA reductaseinhibition [144]. Future work is required to elucidate possible dif-ferences in clinical benefits of lipophilic and hydrophilic statins.

Alternatively, the neutral finding of lipophilic statin therapyin human heart failure may represent the net of concurrent posit-ive and deleterious actions. Evidence for an adverse role of lowcholesterol has been documented in heart failure, with mortal-ity increasing 25 % for each mmol/l decrease in total cholesterol[145,146]. Lipophilic statin therapy may also attenuate adapta-tions in cardiorespiratory fitness following aerobic exercise train-ing [147], a significant predictor of mortality [148,149]. Thus, insome patient populations, the overall statin effect may be thebalance of its beneficial and adverse properties.

One likely mechanism by which statin-mediated autonomiceffects may improve cardiovascular outcomes is by reducingthe risk of arrhythmias and sudden cardiac death. Sympath-etic activity has been identified as an important trigger to in-crease the dispersion of repolarization or the generation of after-depolarizations [58]. Likewise reduced autonomic tone, as as-sessed by decreased HRV, is associated with ventricular ar-rhythmias and sudden cardiac death [60,150,151]. Statin therapyhas been associated with reduced sudden cardiac death in a num-ber of prospective trials [LIPID (Long-term Intervention withPravastatin in Ischaemic Disease) and 4S (Scandinavian Simvast-atin Survival Study), while meta-analyses (>110 000 patients) re-port that statin therapy decreased the risk of sudden cardiac deathby 10 % and non-sudden cardiac deaths by 20 % [152,153], butdid not affect the risk of ventricular tachyarrhythmias or cardiacarrest [154]. These improvements also appear to occur independ-ently of the reductions in LDL-cholesterol.

In contrast, other analyses have reported significant reductionsin ventricular tachyarrhythmias with statin therapy [155,156].Lipophilic, but not hydrophilic, statin therapy can also produce adose-independent reduction in the incidence and risk of reoccur-rence for atrial fibrillation [157]. Statin lipophilicity may explainthe discrepancy in some meta-analytic results [158].

Another potential benefit of attenuating central sympatheticoutflow in both heart failure and hypertension is reducing renalsodium retention [159]. If this were the case, it might account forreductions in post-acute coronary syndrome hospitalizations forheart failure with atorvastatin reported in the PROVE IT-TIMI22 (Pravastatin or Atorastatin Evaluation and Infection Trial-Thrombolysis in Myocardial Infarction 22) trial [160].

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CONCLUSIONS

Conventionally, the benefits of statin therapy have been ascribedprincipally to their effects on plasma cholesterol. However, inconditions characterized by exaggerated sympathoexcitation andelevated oxidative stress, lipophilic statin therapies have demon-strated a consistent capacity to reduce direct efferent sympath-etic outflow in both animal and human studies. In experimentalpreparations, these reductions appear to be mediated by quench-ing oxidative stress in central brain regions involved in gener-ating or modulating autonomic activity, as a result of reducedROS and increased NO production. In humans, resting levelsof efferent sympathetic activity are associated with mortality insome populations, but the clinical significance of the observedreductions in MSNA with statins remain largely unknown, asthey, for example, have not been accompanied by parallel de-creases in BP or HR. Future research should be directed atdetermining mechanisms responsible for statin-mediated sym-pathoinhibition in humans and to establish its potential clinicalimpact.

FUNDING

P.J.M. is supported by a Canadian Institutes of Health ResearchPostdoctoral Fellowship. J.S.F. holds the Canada Research Chairin Integrative Cardiovascular Biology. Our work was supported byoperating grants from the Canadian Institutes of Health Research[grant number MOP85052] and the Heart and Stroke Foundationof Ontario [grant number NA6298].

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Received 27 June 2013/27 August 2013; accepted 10 September 2013

Published on the Internet 15 November 2013, doi: 10.1042/CS20130332

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statins and the autonomic nervous system

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