266

REVIEW / SYNTHÈSE

Impaired regulation of cardiac function in sepsis,

SIRS, and MODS1
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by University of Western Ontario on 11/14/14

Karl Werdan, Hendrik Schmidt, Henning Ebelt, Klaus Zorn-Pauly, Bernd Koidl,
Robert Sebastian Hoke, Konstantin Heinroth, and Ursula Müller-Werdan

Abstract: In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a
severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympatheti-
cally and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the
nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial
cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels,
which mediate the pacemaker current If and play an important role in transmitting sympathetic and vagal signals on heart
rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endo-
toxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the
autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory re-
flex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppres-
sion of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed
For personal use only.

therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of
statins, b-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.
Key words: Autonomic dysfunction, heart rate variability (HRV), endotoxin, HCN channel, cardiac pacemaker current If,
sepsis, systemic inflammatory response syndrome (SIRS), multiorgan dysfunction syndrome (MODS), statins, b-blockers,
angiotensin-converting enzyme inhibitors (ACEI), multiorgan failure (MOF).
Résumé : La sepsie, le syndrome de réponse inflammatoire systémique (SRIS) et le syndrome de défaillance multiviscé-
rale (SDMV) sont associés à un grave dysfonctionnement d’intérêt diagnostique de la fonction autonome cardiaque, qui
est illustré par une forte atténuation de la variabilité de la fréquence cardiaque (VFC), véhiculée par voie sympathique et
vagale. Les mécanismes à l’origine de cette atténuation ne se limitent pas au système nerveux. Ils incluent aussi des modi-
fications des cellules régulatrices du rythme cardiaque au niveau cellulaire. Comme démontré dans les cardiomyocytes au-
riculaires humains, l’endotoxine interagit avec les canaux (HCN) activés par l’hyperpolarisation, modulés par les
nucléotides cycliques et non sélectifs aux cations, qui médient le courant de pacemaker If et jouent un rôle important dans
la transmission des signaux sympathiques et vagaux sur la fréquence cardiaque et sa variabilité. De plus, l’endotoxine sen-
sibilise les canaux HCN aux signaux sympathiques. Ces résultats identifient l’endotoxine comme un modulateur pertinent
de la régulation nerveuse autonome de la fonction cardiaque. Dans le SDMV, la voie vagale du système nerveux autonome
en particulier est affaiblie, entraı̂nant une atténuation du réflexe cholinergique anti-inflammatoire. La stimulation de l’ac-
tivité vagale semble être une cible thérapeutique prometteuse afin d’obtenir la suppression de l’inflammation et, par consé-
quent, un meilleur pronostic chez les patients SDMV. Les premiers résultats préliminaires révèlent des bénéfices
thérapeutiques (augmentation des taux de survie et stimulation de l’activité vagale déprimée) de l’administration de stati-
nes, de bêta-bloquants et d’inhibiteurs de l’enzyme de conversion de l’angiotensine chez les patients souffrant du SDMV.

Received 21 August 2008. Accepted 25 November 2008. Published on the NRC Research Press Web site at cjpp.nrc.ca on 3 April 2009.
K. Werdan,2 H. Schmidt, H. Ebelt, R.S. Hoke, K. Heinroth, and U. Müller-Werdan. Department of Medicine III, Martin Luther
University Halle-Wittenberg, Ernst-Grube Str. 40, D-06097 Halle (Saale), Germany.
K. Zorn-Pauly and B. Koidl. Institute of Biophysics, Department of Physiological Medicine, Medical University of Graz, Graz, Austria.
1This article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health
(published in part 2 of a 2-part Special Issue).
2Corresponding author (e-mail: karl.werdan@medizin.uni-halle.de).

Can. J. Physiol. Pharmacol. 87: 266–274 (2009) doi:10.1139/Y09-012 Published by NRC Research Press
 Werdan et al.
Mots-clés : dysfonctionnement autonome, variabilité de la fréquence cardiaque (VFC), endotoxine, canal HCN, courant pa-
cemaker If, sepsie, syndrome de réponse inflammatoire systémique (SRIS), syndrome de défaillance multiviscérale
(SDMV), statines, bêta-bloquants, inhibiteurs de l’enzyme de conversion de l’angiotensine (IECA), défaillance polyviscé-
rale (DFV).
[Traduit par la Rédaction]
______________________________________________________________________________________
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Sepsis, SIRS, and MODS—major problems in
intensive care medicine
Sepsis, noninfectious systemic inflammatory response
syndrome (SIRS), and multiorgan dysfunction syndrome
(MODS) (Fig. 1) pose tremendous problems in our health
care system. In Germany, about 150 000 patients annually
suffer from sepsis, severe sepsis (with organ failure), and
septic shock, and about 65 000 patients die from septic states
(Engel et al. 2007), nearly as many as from myocardial in-
farction. In Europe, every third intensive care unit (ICU) pa-
tient suffers from sepsis (Vincent et al. 2006). At least half
of the high mortality rates (30%–80%) of severe sepsis, sep-
sis, and MODS can be attributed to the impairment of the
cardiovascular system (Parrillo 1989).
Impaired regulation of cardiac function in
For personal use only.
sepsis, SIRS, and MODS
Cardiac function is severely impaired in sepsis and
MODS (Parrillo 1989) and, to a lesser extent, in severe
SIRS. In sepsis, echocardiographic studies have demon-
strated both systolic and diastolic dysfunction (Jafri et al.
1990; Munt et al. 1998; Poelaert et al. 1997). In septic
MODS, only 40% of patients have a normal cardiac function
(i.e., >80% of normal), while 40% have a moderate reduc-
tion in pump function (60%–80% of normal), and 20% have
a severe to very severe reduction in pump function (£40% of
normal) (A. Oelke and K. Werdan, unpublished results). Im-
pairment of cardiac function clearly leads to a worse out-
come (A. Oelke and K. Werdan, unpublished results;
Parrillo 1989; Parrillo et al. 1990). At present, scientific re-
search into cardiac impairment in sepsis and MODS focuses
on myocardial depression due to bacterial toxins (e.g., endo-
toxin) and sepsis mediators (Merx and Weber 2007; Müller-
Werdan et al. 2006). However, it is often forgotten that a
real problem in sepsis and SIRS is not only myocardial de-
pression, but also the strongly impaired regulation of cardiac
function due to extensive alterations of the cardiovascular
autonomic nervous system (Heinroth et al. 1999; Schmidt et
al. 2008a, 2008b). The development of MODS is character-
ized by an activation of the innate immunity resulting in an
overshooting release of inflammatory mediators (Fig. 1) that
leads to cell damage of parenchymal organs and to inflam-
matory, metabolic, and neuroendocrine disturbances (Godin
and Buchman 1996). Increasing evidence suggests that auto-
nomic dysfunction contributes substantially to the develop-
ment of MODS. Physiologic homoeostasis depends on
continuous communication between all vital organs through
signals of the autonomic nervous system (Godin and Buch-
man 1996). An ‘uncoupling’ of these neurally mediated or-
gan interactions in MODS and sepsis may alter neural
reflexes and thus cause a disruption of appropriate inter-or-
267
gan communication, thereby advancing single organ dys-
function into MODS. Diminished organ reactivity to
vegetative signals may also play a role (Fig. 2). Dysfunc-
tional cardiomyocyte responses, blunted by inflammatory
mediators, possibly contribute to the compromised cardiac
regulation by the autonomic nervous system (Müller-Werdan
et al. 1996) (Fig. 2).
This cardiac autonomic dysfunction in sepsis and MODS
can be measured by parameters of the 24-hour heart rate
variability (HRV), which shows a strong impairment in both
the sympathetically and the vagally mediated nervous sig-
nals (Table 1). HRV measurement describes cerebral control
of the heart, whereas baroreflex sensitivity (BRS) character-
izes communication between heart and vascular system, and
chemoreflex sensitivity (CRS) describes the interaction be-
tween the respiratory system and the heart. As the conven-
tional measurement of CRS—hypoxemia provocation by
breathing oxygen-poor air and recording of the consecutive
rise in heart rate—cannot be applied to ventilated intensive
care patients, we developed a method for CRS measurement
in intensive care patients by increasing inspiratory oxygen
fraction and determining the consecutive fall in heart rate
(Schmidt et al. 2004) (Table 2). All indicators of HRV,
BRS, and CRS are severely impaired in sepsis and MODS
(Schmidt et al. 2005) (Table 2).
Consequences of impaired regulation of
cardiac function in sepsis and MODS
The consequences of impaired regulation of cardiac func-
tion in sepsis and MODS are manifold (Table 3): besides
impaired cardiac contractility (Calvin et al. 1981; Müller-
Werdan et al. 2006; Parker et al. 1984; Ren et al. 2002), it
is particularly the resulting chronotropic incompetence that
yields a reduced HRV and an increased heart rate, both of
which are associated with an unfavourable prognosis (Hein-
roth et al. 1999; Schmidt et al. 2005, 2008a, 2008b) (Fig. 3).
Finally, depression of the cholinergic activity dampens the
antiinflammatory cholinergic reflex (AICR) and conse-
quently allows overshooting of the inflammatory state, with
its detrimental consequences on survival (Borovikova et al.
2000; Libert 2003; Pavlov et al. 2006; Saeed et al. 2005;
Tracey 2002, 2007; Wang et al. 2004, 2003).
Possible mechanisms of impaired regulation
of cardiac function in sepsis and MODS—the
HCN channels as targets
Intravenously applied endotoxin induces a reversible heart
rate ‘stiffness’ in healthy volunteers and thus causes myo-
cardial autonomic dysfunction (Godin et al. 1996). With
this in mind, one can speculate that endotoxin contributes to
Published by NRC Research Press
 268
Fig. 1. Sepsis and systemic inflammatory response syndrome
(SIRS): common final pathways. Both infectious (e.g., bacterial
toxins) and noninfectious triggers can activate inflammatory cells
like macrophages (Ma.) and leucocytes (Leu.) to synthesize and re-
lease a number of aggressive (pro)inflammatory mediators such as
cytokines (tumor necrosis factor-a, interleukin-1 and -6), reactive
oxygen species, and nitric oxide. From a teleologic point of view,
these mediators are synthesized to destroy and inactivate bacteria
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by University of Western Ontario on 11/14/14
and bacterial toxins and to fight against infectious as well as non-
infectious overshooting inflammation. These mediators are so ag-
gressive, however, that they may damage the organs of the patient
as well, thereby contributing considerably—in addition to direct
toxin effects on the organs—to the development of multiorgan dys-
function syndrome (MODS).
For personal use only.
the impaired cardiac autonomic function seen in patients
with sepsis and MODS. The decrease in HRV observed in
sepsis and MODS patients is most likely due to a mitigated
heart rate regulation either by the rate-increasing sympa-
thetic activity, the rate-decreasing vagal activity, or both.
The efferent sympathetic and vagal signals to the heart start
in the brain, run through the sympathetic chain and the va-
gus nerve, respectively, and then use binding of the neuro-
transmitters norepinephrine to cardiac adrenoceptors and
acetylcholine to muscarinic receptors. Receptor binding trig-
gers signal transduction pathways in the cardiac pacemaker
cells that finally result in a modulation of the pacemaker
current. This pacemaker current is mainly conducted
through the If (‘funny’ current) (Baruscotti et al. 2005). If
is the result of ion flux through the hyperpolarization-acti-
vated cyclic nucleotide-gated (HCN) channel (Biel et al.
2002). The channel is controlled by direct interaction with
cyclic adenosine monophosphate and hence contributes to
sympathetic and parasympathetic regulation of heart rate
(Ludwig et al. 1998). Four HCN channels (HCN 1–4)
have been characterized to date (Ludwig et al. 1999). In
human sinus nodes, HCN4 is the dominantly expressed
HCN isoform.
In principle, autonomic impairment can occur at all the
levels illustrated in Fig. 2. The experiments by Godin et al.
(1996), however, do not elucidate whether the heart rate
stiffness observed is due to an endotoxin-induced alteration
of the brain, the autonomic nervous system, or the pace-
maker cell itself. Because we were able to demonstrate that
endotoxin also reduces HRV in spontaneously beating cul-
Can. J. Physiol. Pharmacol. Vol. 87, 2009
Fig. 2. Autonomic cardiac dysfunction in the patient with sepsis,
SIRS, and MODS. Autonomic function and especially cardiac auto-
nomic function is severely impaired in patients with sepsis, SIRS,
and MODS. This impairment is most likely due to the action of
bacterial toxins and sepsis and SIRS mediators, which interfere
with autonomic nerve signals in the brain, with neuronal transmis-
sion, or with the target cell (e.g., cardiomyocyte pacemaker and
ventricular cells). In the target cell, this interference can, in princi-
ple, be found at the level of receptors, signal transduction path-
ways, or ion channels. In the case of the heart, the consequences
are myocardial depression, increased heart rate, and strongly de-
pressed heart rate variability (HRV), all indicating an unfavourable
prognosis (Schmidt et al. 2005). CNS, central nervous system; NO,
nitric oxide; ROS, reactive oxygen species.
tured neonatal rat heart cells (Schmidt et al. 2007), we hy-
pothesized that endotoxin-induced heart rate stiffness is
mediated, at least in part, by a direct interaction of endo-
toxin with the signal transduction pathways and ion channels
in the cardiac pacemaker cells. A likely target for endotoxin
is the pacemaker current If, which is mainly driven by HCN
channels (see above). Indeed, in our whole-cell patch-clamp
experiments with isolated human myocytes from right atrial
appendages, endotoxin (at concentrations of 1 and 10 mg/
mL) significantly and specifically impaired If (Figs. 4 and
5) by suppressing the current at membrane potentials posi-
tive to –80 mV and by slowing down current activation, but
did not affect peak current (Zorn-Pauly et al. 2007) (Figs. 4
and 5). Furthermore, the response of If to b-adrenergic stim-
ulation (1 mmol/L isoproterenol) was significantly larger in
endotoxin-incubated cells than in control cells: half-maximal
activation voltage shifted to more positive potentials by 10
mV in control cells but by 14 mV in lipopolysaccharide-
treated cells (Zorn-Pauly et al. 2007). Using a spontaneously
active sinoatrial cell model (Kurata et al. 2002), we demon-
strated that endotoxin-induced If impairment reduces the re-
sponsiveness of the model to fluctuations of autonomic input
(Zorn-Pauly et al. 2007).
In summary, our experiments demonstrate both a direct
inhibitory effect of endotoxin on If and a sensitizing of If
to b1-adrenergic catecholamines (Fig. 6). These phenomena
trigger a narrowing of HRV and therefore might contribute
to the autonomic cardiac dysfunction (reduced HRV) seen
in patients with sepsis, SIRS, and MODS. Consequently,
autonomic dysfunction is the result not only of an altera-
tion of the autonomic nervous system, but also of an im-
pairment of the signal transduction pathways and (or) ion
channels mediating the autonomic nervous signals in the
Published by NRC Research Press
 Werdan et al. 269

Table 1. Autonomic dysfunction in patients with MODS (n = 85).

Autonomic component
HRV parameter mainly represented Normal value Value in MODS patients p value
SDNN, ms T 141±39 57.7±30.7 ; <0.001
pNN50, % V 9±7 4.8±8.4 ; <0.001
LF, ms2 S/V 791±563 129±405 ; <0.001
HF, ms2 V 229±282 112±267 ; <0.001
VLF, ms2
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V 1782±965 191±661 ; <0.001

LF/HF, ms2 S/V 4.61±2.33 1.1±0.9 ; <0.001
BRS, ms/mm Hg — >6.1 1.6±1.5 ; <0.001
CRS, ms/mm Hg — 0.9±0.5 0.5±0.4 ; <0.001
Note: A strongly impaired autonomic cardiac regulation—measured by 24-hour heart rate variability (HRV)—can
be observed in both septic and nonseptic multiorgan dysfunction syndrome (MODS); ; = below normal. Not only is
total activity (T) affected, but the sympathetic (S) and vagal (V) components as well. The following variables of the
time and frequency domains of HRV are internationally standardized: SDNN, standard deviation of all normal-to-
normal RR intervals; pNN50, percentage of consecutive NN intervals varying >50 ms from the preceding NN inter-
val; LF, low-frequency power domain; HF, high-frequency domain; VLF, very low frequency domain; LF/HF = LF
divided by HF. These variables indicate, at least to some degree, either sympathetically or parasympathetically mod-
ified HRV. Not only HRV but also baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) are significantly
compromised. Data from Schmidt et al. 2005.

Table 2. How to analyse autonomic function in the ventilated critically ill patient.
Autonomic function Method
Brain $ heart Heart rate variability Measure 24-hour heart rate by telemetry
Heart $ vascular system Baroreflex sensitivity Increase blood pressure by application of phenylephrine and determine
For personal use only.

heart beat interval reduction

Lungs $ heart Chemoreflex sensitivity Non-ICU: Decrease alveolar oxygen concentration and determine in-
crease in heart rate
ICU: Increase inspiratory oxygen concentration and determine heart beat
interval reduction
Note: For further explanation see text and Schmidt et al. 2004, 2005.

Table 3. Consequences of cardiac autonomic dysfunction in sepsis, SIRS,

and MODS.

Effect of reduced sympathetic tone and vagal tone Prognosis

Chronotropic dysfunction
Narrowing of heart rate variability unfavourable
Inadequately high heart rate unfavourable
Myocardial dysfunction unfavourable
Dampening of the antiinflammatory cholinergic reflex unfavourable
Note: In sepsis, SIRS, and MODS, sympathetic and vagal regulation of heart func-
tion are strongly impaired. As a result, chronotropic and inotropic dysfunction occur,
and dampening of the antiinflammatory cholinergic reflex (AICR) further triggers
systemic and regional inflammation. All these consequences of impaired cardiac auto-
nomic function add to the unfavourable prognosis of these patients.

heart itself. As HCN channels are expressed both in the
heart and in the brain (Baruscotti et al. 2005), the effects
of endotoxin on noncardiac HCN channels remain to be
investigated.
One point, however, needs clarification: endotoxin-in-
duced blockade of If lowers heart rate, whereas in patients
with sepsis, SIRS, and MODS, heart rate is usually inap-
propriately high. The combination of a markedly attenuated
vagal tone (Table 1), a massive endogenous catecholamine
release, exogenous catecholamine treatment, and the in-
creased catecholamine sensitivity of HCN channels might
override the bradycardic endotoxin blockade of If in vivo
and thus account for this apparent discrepancy.
Can we restore the depressed vagal activity
in MODS patients and thereby improve
prognosis?
As shown in Table 1, vagal activity is strongly suppressed
in MODS, and this depression correlates with an unfavoura-
ble prognosis (Fig. 3). Nicotine patches, acupuncture, and
vagus stimulation devices have been suggested to stimulate
the impaired AICR, but have not been tested in clinical tri-
als to date (Tracey 2002).
We chose another approach: we asked whether specific
medications improve autonomic function (as measured by
HRV) in patients with septic and nonseptic MODS, and if

Published by NRC Research Press

 270 Can. J. Physiol. Pharmacol. Vol. 87, 2009

Fig. 3. Impaired HRV correlates with unfavourable prognosis in patients with MODS. The Kaplan–Meier plot for cumulative 28-day survi-
val is given for 85 patients with MODS, depending on the HRV parameter VLF (given as lnVLF), a marker of vagal activity to the heart
(data from Schmidt et al. 2005). In this prospective cohort study, MODS was defined as an APACHE II score ‡ 20. In patients with
lnVLF £ 3.9 lnms2, cumulative survival is significantly lower (0.53) than that of patients with lnVLF > 3.9 lnms2 (0.79), p = 0.012. VLF,
very low frequency power domain.
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Fig. 4. Effects of endotoxin on If and the corresponding activation curves in isolated human myocytes from right atrial appendages, as
measured by the whole-cell patch-clamp technique. Current recordings (left) and activation curves (right) from an untreated cell (A and B)
and from two endotoxin-incubated cells at 1 mg/mL LPS (C and D) or 10 mg/mL LPS (E and F). Hyperpolarizing steps were applied from a
holding potential of –40 to –140 mV (10 mV increment). The 3 cells had comparable maximal conductance values (gf) of approximately 90
pS/pF. If, cardiac pacemaker current mediated by HCN channels (‘funny’ current); LPS, lipopolysaccharide. (From Zorn-Pauly et al. 2007,
For personal use only.

reproduced with permission of Shock, Vol. 28, p. 656, # 2007 the Shock Society.)

Published by NRC Research Press

 Werdan et al.
Fig. 5. Absolute mean current density values of control and lipopo-
lysaccharide (LPS)-incubated isolated human myocytes from right
atrial appendages, as measured by the whole-cell patch-clamp tech-
nique. Absolute mean current density values I are measured by ap-
plication of different hyperpolarization voltage steps Vm in LPS-
treated cells (1 mg/mL or 10 mg/mL) and control cells. At a mem-
brane potential of –60 mV, If can be detected only in untreated
myocytes. If current densities at –70 mV were significantly higher
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in control and in 1 mg/mL LPS-treated cardiomyocytes than in
10 mg/mL LPS-treated cardiomyocytes. At –80 mV, current densi-
ties were found to be significantly higher in control group com-
pared with 10 mg/mL LPS-treated group. At test potentials more
negative than –80 mV, If densities were not significantly different
between control and LPS-incubated myocytes. *, Significant at p <
0.05. If, ‘funny’ current (mediated by HCN channels). (From Zorn-
Pauly et al. 2007, reproduced with permission of Shock, Vol. 28, p.
657, # 2007 the Shock Society.)
For personal use only.
so, whether this HRV improvement correlates with a better
survival rate. To test this hypothesis we analysed the sur-
vival rates of MODS patients who were either treated or un-
treated in the initial phase of MODS with statins, b-blockers,
or angiotensin-converting enzyme inhibitors (ACEI). These
medications were chosen because the beneficial effects of
the drugs coincide with an improvement of depressed HRV
in patients with coronary artery disease or heart failure, the
latter being prevalent underlying conditions of medical
MODS patients.
Statins
Besides their cholesterol-lowering properties, statins pos-
sess antiinflammatory and immunomodulatory pleiotropic
characteristics. These properties appear to be beneficial in
reducing cardiovascular events in patients with coronary ar-
tery disease and also, surprisingly, in preventing sepsis and
exo- and endotoxic shock (Almog et al. 2004; Kruger et al.
2006; Merx et al. 2004; Pruefer et al. 2002). These beneficial
phenomena of statins go along with an increased parasympa-
thetic modulation of the heart rate (Welzig et al. 2003).
In a recent retrospective case–control study, we analysed
survival data of MODS patients (Schmidt et al. 2006). MODS
was defined as an APACHE (acute physiology and chronic
health evaluation) II score at ICU admission ‡20. Forty
MODS patients with prior or ongoing statin therapy and 80
age- and sex-matched MODS patients without statin therapy
271
Fig. 6. Effects of endotoxin on HCN channels and adrenergic
HCN-channel stimulation in human atrial cardiomyocytes. Endo-
toxin inhibits If but also intensifies b-adrenoceptor-mediated stimu-
lation of If (Zorn-Pauly et al. 2007). If inhibition by endotoxin is
specific, as the L-type calcium current (ICa,L) is not inhibited by
endotoxin. :, stimulation; ;, inhibition; AC, adenylyl cyclase;
cAMP, cyclic adenosine monophosphate; Gi, inhibitory G protein;
Gs, stimulatory G protein; HCN channel, hyperpolarization-acti-
vated cyclic nucleotide-gated ion channel; If, ‘funny’ current
(mediated by HCN channels); ICa,T, T-type calcium current;
ICa,L, L-type calcium current.
were included. The 28-day mortality was significantly lower
in the statin group than in the control group (Fig. 7 and Ta-
ble 4). Cholesterol levels were not significantly different in
the 2 groups (Fig. 7). However, the parasympathetically medi-
ated variable lnVLF (logarithm of very low frequency power,
an index of HRV derived from power spectral analysis of the
ECG signal) was better preserved in the statin group (Fig. 7
and Table 4). Hence, statin therapy might influence short-
term mortality in MODS patients by restoring or preserving
parasympathetic tone and thereby reducing the inflammatory
response in MODS via the antiinflammatory cholinergic path-
way. Alternatively, other pleiotropic statin effects, such as at-
tenuation of overshooting inflammation, have been discussed
as possible contributors to the beneficial effects of statins in
patients with sepsis, SIRS, and MODS (Almog et al. 2004;
Kruger et al. 2006; Merx et al. 2004; Pruefer et al. 2002).
b-blockers
Administration of b-blockers has been proven to increase
HRV among patients with coronary artery disease, chronic
heart failure, and diabetes. These drugs mainly act indirectly
by attenuating the sympathetic tone, but direct effects of
parasympathetic modulation have also been described.
Moreover, b-blockers have been shown to increase BRS, a
major source of vagal activity (Parati et al. 1994), and to
blunt increased CRS (Agostoni et al. 2006), thus reducing
sympathetic tone. These effects might restore an appropriate
sympathetic–vagal balance and thus attenuate inflammation.
Angiotensin-converting enzyme inhibitors
ACEI can reduce mortality of cardiac patients with re-
duced left ventricular function (SOLVD Investigators 1991;
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 272 Can. J. Physiol. Pharmacol. Vol. 87, 2009

Fig. 7. Kaplan–Meier survival estimates in patients with MODS with or without prior or ongoing statin treatment, and role of improvement
of autonomic cardiac dysfunction, in particular vagal tone. Cumulative 28-day survival is shown for 40 MODS patients with prior or on-
going statin therapy (‘on statin’) and 80 MODS patients without statin therapy (‘no statin’) in this retrospective case–control study (data
from Schmidt et al. 2006). MODS (including septic and nonseptic and cardiac and noncardiac origin) was defined as an APACHE II score ‡
20 (Schmidt et al. 2005, 2006). MODS patients with prior or ongoing statin treatment had a significantly higher survival rate (0.68) than
MODS patients without statin therapy (0.48), p = 0.041. This beneficial effect is not due to a cholesterol-lowering effect. Interestingly,
statin-treated patients not only had better survival, but also had higher lnVLF values, indicative of a less severely impaired cardiac vagal
autonomic function.
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Table 4. Effects of statins, b-blockers, and ACEI on survival and autonomic cardiac regulation in patients with MODS,
as measured by the vagal component lnVLF (see Table 1) of HRV measurements.
For personal use only.

Number of patients 28-day survival, % HRV (lnVLF in ms2)

Drug Drug Drug
Drugs + – + – p value + – p value
Statins 40 80 67 47 0.03 4.1±1.4 3.1±1.3 0.009
b-blockers 86 108 64 49 <0.001 4.5±1.7 3.4±1.4 <0.001
ACEI 68 110 78 45 <0.001 4.5±1.9 3.5±1.3 <0.001
Note: In retrospective case–control studies in patients with MODS, the effect of prior or ongoing medication with statins, b-blockers,
and angiotensin-converting enzyme inhibitors (ACEI) was tested with respect to survival and autonomic cardiac regulation, the latter
measured as HRV. All 3 medications coincide with a higher 28-day survival and also with a higher vagal cardiac autonomic tone, as
shown by the higher lnVLF values in HRV analysis (see Table 1). Data from Schmidt et al. 2006, 2008b, and previously unpublished
results.

CONSENSUS Trial Study Group 1987). Additionally, in
patients with chronic heart failure and coronary artery dis-
ease, these inhibitors restore autonomic function (especially
vagal activity) and have antiinflammatory features (Ferrario
and Strawn 2006; Routledge et al. 2002). A blockade of the
angiotensin II receptor may be even more effective, since
angiotensin II enhances the afferent drive of the carotid
chemoreceptors and thus acts sympathomimetically (Li et
al. 2006). In conclusion, ACEI and angiotensin-receptor
blockers might be capable of modifying important features
of autonomic dysfunction characterizing MODS; however,
this hypothesis has yet to be tested.
MODS survival and vagal activity
The aforementioned examples show that statins, b-block-
ers, and ACEI exert beneficial effects on autonomic dys-
function. Nevertheless, it is unclear whether these effects
contribute to an improved survival rate. At least in our ret-
rospective case–control studies, MODS patients treated ei-
ther with statins, b-blockers, or ACEI not only had a
higher survival rate than MODS patients without these
medications, but also had a higher vagal activity, as shown
by the higher lnVLF values (Table 4) (Schmidt et al. 2006,
2008b).
Conclusions
In sepsis, SIRS, and MODS our therapeutic efforts focus
on the support of failing organs such as lungs, cardiovascu-
lar system, and kidneys. MODS, however, is constituted not
only by the sum of all failing organs, but also by a severe
impairment of inter-organ communication. The impaired in-
ter-organ communication contributes to the unfavourable
prognosis of these patients. This ‘‘uncoupling of biological
oscillators’’ (Godin and Buchman 1996) is the consequence
of a profound disturbance of the neuroendocrine system,
particularly the autonomic nervous system, leading to a dys-
regulation of organ function itself. In this review, we illus-
trated the impaired regulation of cardiac function. We
showed that autonomic cardiac regulation by the sympa-
thetic and parasympathetic nervous system is highly de-
pressed, and we pointed out that this impairment coincides
with an unfavourable prognosis of critically ill patients. We
further demonstrated that endotoxin, a trigger of sepsis,

Published by NRC Research Press

 Werdan et al.
SIRS, and MODS, can induce autonomic cardiac dysfunc-
tion both by inhibiting the cardiac pacemaker If and by sen-
sitizing the pacemaker current to sympathetic stimuli. As
autonomic function and inflammation are linked by the
AICR, improvement of the autonomic nervous activity, es-
pecially the vagal component, could potentially contribute
to better survival of these patients. First observations from
retrospective case–control studies with MODS patients are
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by University of Western Ontario on 11/14/14
encouraging: MODS patients treated with statins, b-blockers,
or ACEI before or during MODS show a higher survival rate
that parallels the improvement seen in autonomic function. It
will be interesting to see whether improved autonomic car-
diac function in these patients goes along with better cardiac
pump function and (or) a lower systemic inflammatory state.
If this should be the case, the attractive concepts of ‘‘uncou-
pling of biological oscillators’’ postulated by Godin and
Buchman (1996) and that of the AICR described by Tracey
(2002) would gain interest beyond pathophysiology of sepsis,
SIRS, and MODS, representing a qualitatively new, additive
approach to possibly better treat these disastrous conditions.
Acknowledgements
We are indebted to the Deutsche Forschungsgemeinschaft
(SCHM 1398) for support and to Biotest AG, Dreieich,
Germany, for an unrestricted research grant.
For personal use only.
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Abbreviation list
ACEI Angiotensin-converting enzyme inhibitor
AICR Antiinflammatory cholinergic reflex
APACHE Acute Physiology and Chronic Health Evaluation
BRS Baroreflex sensitivity
CRS Chemoreflex sensitivity
HCN Hyperpolarization-activated cyclic nucleotide-activated
ICU Intensive care unit
MODS Multiple organ dysfunction syndrome
SIRS Systemic inflammatory response syndrome
VLF Very low frequency
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