International Journal of Cardiology 321 (2020) 118–125

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Sympathomodulation in congestive heart failure: From drugs to devices

Guido Grassi a,⁎, Gino Seravalle a, Murray Esler b
a
Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
b
Baker IDI Heart and Diabetes Institute, Melbourne, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Indirect and direct approaches to assess sympathetic neural function in man have shown that congestive heart
Received 29 June 2020 failure is characterized by a marked adrenergic overdrive. Although compensatory in the initial phases of the dis-
Received in revised form 15 July 2020 ease, with time the sympathetic overactivity exerts adverse cardiovascular effects, favoring the disease progres-
Accepted 16 July 2020
sion and promoting the occurrence of non-fatal and fatal cardiovascular events. This explains why the adrenergic
Available online 29 July 2020
overactivity has become an important target of the therapeutic interventions adopted in the managementof the
Keywords:
disease. The present paper will examine the impact of therapeutic approaches, used in the management of heart
Heart failure failure, on the sympathetic activation characterizing the disease. After a brief mention of the sympathetic effects
Sympathetic activation of non-pharmacological interventions and procedural approches, particular emphasis will be given to the effects
ßeta-blockers of pharmacological interventions and device treatments (renal denervation and carotid baroreceptor stimula-
ACE-inhibitors tion), which became in recent years a promising tool for the management of the disease. The clinical implications
Angiotensin II receptor blockers as well as the unsolved aspects related to the sympathomodulatory interventions in heart failure management
Diuretics i inhibitors will be finally discussed.
Renal denervation
© 2020 Elsevier B.V. All rights reserved.
Carotid baroreceptor stimulation

1. Introduction syndrome, life-threathening cardiac arrhythmias and sudden death

The hypothesis that an activation of the sympathetic nervous system
(and more in general of the neurohumoral systems) physiologically reg-
ulating cardiovascular homeostasis might be implicated in the develop-
ment and progression of congestive heart failure dates back to more
than half a century ago [1–2]. Since then a consistent amount of infor-
mation has reinforced and strengthened such hypothesis, which be-
came throughout the years a well documented pathophysiological
hallmark of the disease. The main features of the heart failure-related
sympathetic activation include: 1) its detection in different cardiovascu-
lar ares, including the heart, the peripheral vessels, the skeletal muscle
district and the kidneys [3–4], 2) the close parallelism between the de-
gree of the sympathetic activation and the clinical severity of the heart
failure state [5–6], 3) the greater adrenergic abnormalities described
when the disease is characterized by a reduced rather than a preserved
ejection fraction [7], 4) its potentiation when other conditions also
displaying an adrenergic overdrive, such as hypertension, obesity, met-
abolic syndrome, obstructive sleep apnea syndrome and renal failure
are detected [8–10], 5) its dependance on reflex, metabolic as well as
humoral abnormalities, including insulin resistance and renin-
angiotensin system activation [6–7,11], 6) its clinical relevance particu-
larly for the occurrence of major complications such as cardiorenal
⁎ Corresponding author at: Clinica Medica, University of Milano-Bicocca, Via Pergolesi
33, 20052, Monza, Milano, Italy.
E-mail address: guido.grassi@unimib.it (G. Grassi).
[12–13], 7) its adverse prognostic significance [13–16] and 7) its revers-
ibility by therapeutic interventions which exert sympathomodulatory
properties [17].
The present paper will review the impact of therapeutic approaches,
used in the management of heart failure, on the sympathetic activation
characterizing the disease. After a brief mention of the neuroadrenergic
effects of non-pharmacological interventions and procedural
approches, particular emphasis will be given to the effects of pharmaco-
logical interventions and device treatments (renal denervation and ca-
rotid baroreceptor stimulation), which became in recent years a
promising tool in the management of the disease. This will be done by
discussing data collected almost exclusively in the clinical setting via in-
direct and direct approaches to assess human sympathetic function. The
paper will address a final issue, namely whether and to what extent the
above mentioned interventions might be capable of restoring to physi-
ological levels the sympathetic function. This question may have impor-
tant clinical implications given the already mentioned relevance of the
adrenergic overdrive for patients prognosis.
2. Effects of non-pharmacological approaches and procedures on
sympathetic cardiovascular function
Table 1 summarizes the non-pharmacological approaches and pro-
cedural interventions at present employed in the clinical setting avail-
able or still under investigation in the therapeutic approach to heart
failure. Although information on the impact of several procedures on

https://doi.org/10.1016/j.ijcard.2020.07.027
0167-5273/© 2020 Elsevier B.V. All rights reserved.
 G. Grassi et al. / International Journal of Cardiology 321 (2020) 118–125
Table 1
Non pharmacological interventions
and device-based approaches.
1. Physical exercise training
2. Continuous positive airway pressure
3. Extracorporeal ultrafiltration
4. Cardiac resynchronization therapy
5. Slowing breathing technique
6. Vagal nerve stimulation
7. Spinal cord stimulation
8. Transvenous phrenic nerve pacing
human autonomic function are still lacking, for some of them data are
available on their impact on sympathetic neural function. This is the
case, for example, for prolonged physical exercise training programs,
which have been shown to exert sympathoinhibitory effects along
with the improvement in the New York Heart Association functional
class, systemic haemodynamic and exercise capability [17–19].
Simiilarly, continuous positive airway pressure may improve the clinical
severity of the sleep apnea syndrome not rarely complicating a heart
failure condition and favoring a significant reduction in various
neuroadrenergic markers, such as venous plasma norepinephrine, sys-
temic and cardiac norepinephrine spillover and sympathetic nerve traf-
fic [17,19–23]. Sympathoinhibitory effects, documented by the decrease
in sympathetic nerve traffic, have been demonstrated during cardiac
resynchronization therapy via biventricular pacing [24]. It is likelly
that for all the above mentioned interventions the resulting
sympathoinhibition is triggered by reflex mechanisms, namely that it
depends on the restoration of the sympathomoderating effects exerted
by arterial baroreceptors and chemoreceptors (directly or indirectly ac-
tivated by the procedures) on adrenergic neural function [23,17].
3. Effects of pharmacological interventions on sympathetic cardio-
vascular function
3.1. Background
There appear to be multiple pathways by which chronic sympathetic
activation in heart failure promotes disease progression. Systemic sym-
pathetic activation in the resistance circulation, evident for example in
the increase in muscle sympathetic nerve activation recorded with clin-
ical microneurography [4,6–7], increases cardiac afterload, while ve-
nous constriction distributes blood volume centrally, contributing to
the characteristic cardiopulmonary overfilling of heart failure [5,13].
This venous neural pathophysiology can be reversed by acute splanch-
nic nerve block [25]. Activation of the renal sympathetic outflow causes
increased renal tubular reabsorption of sodium and renin secretion,
disturbing sodium and water homeostasis [26]. Activation of the cardiac
sympathetic outflow contributes to the development of atrial fibrilla-
tion and lethal ventricular arrhythmias [11,13,17]. Adverse cardiac re-
modelling, key in the downward spiral of progressive left ventricular
failure, is paralleled by reduction in myocardial sympathetic nerve nor-
epinephrine stores [27]. Whether this directly contributes to the remod-
elling changes of increased left ventricular mass and left ventricular
chamber dilatation is unclear.
The different classes of drugs employed in the treatment of heart
failure may favorably interfere with the sympathetic activation charac-
terizing the heart failure state are schematically depicted in Fig. 1 [17].
Some drugs used in the treatment of heart failure directly antagonize
this sympathetic activation. Some other heart failure drugs seem to do
this, but this is illusory. Haemodynamic improvement during the course
of heart failure treatment, achieved with any drug, is accompanied by
reflex reduction in sympathetic activation. Diuretics and vasodilator ni-
trate drugs, which are sympathoexcitatory, reduce sympathetic activity
119
Beta-blockers ACEI-inhibitors
CHF related
SNS activation
Anti-aldosterone Ag II receptor
drugs antagonists
Ag receptor-neprilysin inhibitor
Ivabradine
Fig. 1. Schematic drawing of the drugs commonly used in the treatment of congestive
heart failure (CHF) with documented sympathomodulatory properties. SNS:
sympathetic nervous system, ACE: angiotensin converting enzyme, Ag.angiotensin.
during heart failure therapy, but this is not a direct pharmacological ef-
fect [27]. Further confounding occurs when the plasma concentration of
norepinephrine is used as a marker of sympathetic activity, which was
common in the past. With an increase in cardiac output under therapy,
the clearance of norepinephrine from plasma increases and the plasma
concentration consequently falls [27]. But this is not sympathetic
inhibition.
3.2. ßeta-adrenoceptor blockers
A favorable response to propranolol was reported in several small
observational studies in heart failure patients treated with this ßeta
-blocker in the mid 1970s. More formal trials were done subsequently,
but these remained too underpowered to show benefit. There was a
strong theoretical foundation for persisting with ßeta -blocker testing.
ßeta 1-adrenoceptors were known to be selectively downregulated in
the failing heart [28], and norepinephrine release from cardiac sympa-
thetic nerves to be markedly increased [3,17]. Eventually large, ran-
domized ßeta -blocker trials were conducted, these demonstrating
clear prolongation of survival, for carvedilol [29], metoprolol [30]
and bisoprolol [31] in turn. In a clinical trial performed in elderly
heart failure patients, the Study on the Effects of Nebivolol Interven-
tion on Outcomes and Rehospiatlization in Seniors with Heart Failure
(SENIORS), nebivolol, i.e. another ßeta-blocking agent which combines
the action on ßeta receptors to additional effects, including the induc-
tion of nitiric oxide release from endothelial cells, improved cardiac
haemodynamics without however reducing the hospitalization rate
of the patients [32]. The improved survival achieved through reverse
cardiac remodelling and prevention of lethal ventricular arrhythmias
was from ßeta-adrenoceptor blockade. Bucindolol and xamoterol pro-
vided no benefit with long-term dosing [33,34]. The probable reason is
that these two drugs share the property of possessing intrinsic
Table 2
ßeta-blocking drugs in heart failure.
Beneficial in heart failure
Without sympathomimetic (intrinsic agonist) activity
Carvedilol
Metoprolol
Bisoprolol
Nebivolol
Not beneficial in heart failure
Possessing sympathomimetic activity
Bucindolol
Xamoterol
From References [29–34].
120 G. Grassi et al. / International Journal of Cardiology 321 (2020) 118–125

agonistic activity [33,34], which triggers adverse cardiac adrenergic
stimulation (Table 2). In general the ßeta-blocking agents which re-
ceived special attention related to the effects on sympathetic function
in heart failure patients have been carvedilol and metoprolol. As
shown in Fig. 2, carvedilol showed clearcut sympathoinhibitory effects
both when assessed via norepinephrine spillover, clinical
microneurography or metaiodibenzylguanidine scintigraphic neuro-
imaging technique, at variance from metoprolol which failed to dem-
onstrate inhibitory effects on neuroadrenergic function [35–42].
3.3. Aldosterone antagonists
Mineralocorticoid receptor blockade is beneficial in heart failure. In
randomized controlled trials both spironolactone [43] and the selective
mineralocorticoid antagonist eplerenone [44] increase survival in heart
failure patients. Mineralocorticoid receptor blockade is now universally
recommended heart failure therapy in international guidelines [19]. It is
likely that this clinical benefit derives at least in part from suppression
of the existing sympathetic activation in heart failure. Aldosterone acts
within the central nervous system to increase central sympathetic out-
flow [45–46]. The increased circulating plasma concentrations of aldo-
sterone in primary aldosteronism enter the central nervous system to
elevate adrenergic drive, demonstrable with microneurography records
of increased postganglionic sympathetic nerve traffic to the skeletal
muscle vasculature [47]. Spironolactone does inhibit sympathetic out-
flow in patients with essential hypertension. This has been demon-
strated both with sympathetic nerve recording [48] and
norepinephrine kinetics methodology [49]. In heart failure patients ev-
idence has been provided via the scintigraphic neuroimaging technique
that spironolactone, when administered alone or at the top of the con-
ventional drug treatment, may favor substantial reduction in myocar-
dial sympathetic neural drive [50–52].
3.4. Diuretic drugs
Diuretic therapy in heart failure is beneficial, in reducing symptoms
from fluid retention (breathlessness and oedema) but has not been
demonstrated to prolong survival [19]. Why there is no survival benefit
is not clear. Perhaps the not uncommon adverse effects of hypokalaemia
(predisposing to lethal cardiac arrhythmias) and excessive central vol-
ume depletion (predisposing to pre-renal renal failure) are important
in this [19]. Additionally, diuretics substantially increase central sympa-
thetic outflow [48–49]. This is potentially adverse in heart failure pa-
tients, who are at risk of adrenergic cardiac arrhythmias and
pathological myocardial remodelling. In addition diuretic treatment
may favor the development and progression of an insulin resistance
state, i.e. a condition which is closely linked to sympathetic activation
[52–53].
3.5. Centrally-acting sympatholytics
A logical extension of the ßeta-blocker trials was the evaluation
of central inhibition of sympathetic outflow in heart failure. Acute
dosing with clonidine in heart failure patients is well tolerated and
demonstrably reduces sympathetic outflow to the heart and kidneys
[54]. Longer-term dosing caused persisting sympathetic nervous
suppression, particularly when the drug was admistered via trans-
dermal patches [55] and clinical improvement, including an increase
in left ventricular ejection fraction [56]. Subsequent to these pilot
studies a pivotal randomized trial was performed with the centrally
acting imidazoline agent, moxonidine, the MOXonidine CONgestive
Heart Failure trial (MOXCON) [57], which has been shown to reduce
neurohumoral and sympathetic activation. Central sympathetic in-
hibition with moxonidine actually increased mortality in heart fail-
ure patients, for uncertain reasons [57]. Whether this was because
the central premise, that inhibition of central outflow would be

Carvedilol Metoprolol Carvedilol Metoprolol

6 6 300 * 300
CANESP (pmol/min)

CANESP (pmol/min)
TBNESP (nmol/min)

TBNESP (pmol/min)

4 4 200 200

2 2 100 100

0 0 0 0
C D C D C D C D

Carvedilol Metoprolol Carvedilol Metoprolol

70 70 60 60
**
MSNA (bs/min)

MSNA (bs/min)

**
TDS (a.u.)

TDS (a.u.)

50 ** 50 40 40 *

30 30 20 20

10 10 0 0
C D C D C D C D

Fig. 2. Effects of different ßeta-blocking drugs on various sympathetic markers in patients with congestive heart failure. TBNESP: total body norepinephrine spillover, CANESP: cardiac
norepinephrine spillover, MSNA: muscle sympathetic nerve traffic, TDS: total defect score. C: control, D: after drug administration, bs/min: bursts/minute, a.u.: arbitrary units. Data are
shown as means±standard error. Asterisks (*P < .05,**P < .01) refer to the statistical significance between C and D. Data from Ref [35–42].
 G. Grassi et al. / International Journal of Cardiology 321 (2020) 118–125 121

beneficial in heart failure was in fact false, or was a consequence of question. A general principle of antiadrenergic treatment in heart
faulty trial design, specifically the adoption of a fixed, forced titra- failure is that this should be “slow and gentle”, the dosing being in-
tion to high moxonidine doses, 5–6 times the maximum dose used stituted slowly, with careful dose titration. The MOXCON trial cer-
in the treatment of hypertension [57], remains an unsettled tainly did not adopt this clinical adage.

Enaprilat Captopril Losartan

1200 * 300 300

CANESP (pmol/min)

CANESP (pmol/min)
TBNESP (ng/min)

1000
200 200

800

100 100
600

400 0 0
C D C D C D

Benazepril Candesartan Valsartan

70 70 70
*
**

MSNA (bs/min)
MSNA (bs/min)
MSNA (bs/min)

50 50 50
*

30 30 30

10 10 10
C D C D C D

Enalapril Perindopril Valsartan

60 60 60
** **

40
TDS (a.u.)
TDS (a.u.)
TDS (a.u.)

40 40

20 20 20

0 0 0
C D C D C D

Fig. 3. Effects of different ACE-inhibitor and angiotensin II receptor antagonists drugs on various sympathetic markers in patients with congestive heart failure. TBNESP: total body
norepinephrine spillover, CANESP: cardiac norepinephrine spillover, MSNA: muscle sympathetic nerve traffic, TDS: total defect score. C: control, D: after drug administration, bs/min:
bursts/minute, a.u.: arbitrary units. Data are shown as means±standard error. Asterisks (*P < .05,**P < .01) refer to the statistical significance between C and D. Data from Ref [65–74].
122 G. Grassi et al. / International Journal of Cardiology 321 (2020) 118–125
3.6. Drugs acting on the renin-angiotensin system
In major clinical trials both ACE-inhibitors and angiotensin II receptor
antagonists have been shown to exert favorable effects in heart failure
patients, by ameliorating haemodynamic proflile, clinical status as well
as improving exercise capacity and patients' survival [19,58–64]. Many
of these effects depend on the sympathomodulatory effects exerted by
these drugs which are capable to remove the sympathoexitation exerted
by angiotensin II on central and peripheral adrenergic neural function.
Although some differences between drugs exist, in general it can be con-
cluded that independently on the approach used to assess sympathetic
function (norepinephrine spillover, metaiodobenzylguanidine, myocar-
dial scintigraphy or microneurographic nerve traffic recording) both
ACE-inhibitors and angiotensin Ii receptor antagonists are capable to ef-
fectively modulate in heart failure patients cardiac and peripheral adren-
ergic drive (Fig. 3) [65–74], with favorable clinical consequences for the
patients. Recently the angiotensin receptor neprilysin inhibitor sacubitril
combined with valsartan has been shown in the Prospectice Comparison
of ARN with ARB global oucomes in Heart Failure with preserved ejection
fraction (PARAGON-HF) trial to exert greater cardioprotective effects
than angiotensin II receptor antgonist alone [75]. Whether and to what
extent this effect is dependent on a direct or indirect action of the drug
on central sympathetic outflow remains to be seen.
3.7. Other drugs
Although today much less used in the clinical approach to the heart
failure condition digitalis glicosides have been shown in the past to be
effective in reducing the elevated sympathetic cardiovascular drive typ-
ical of heart failure patients. These effects have been documented via a
large variety of approaches to study human sympathetic function, i.e.
via plasma norepinephrine assay, cardiac and systemic norepinephrine
spillover and muscle sympathetic nerve traffic recording [76–77]. They
are likely to depend on the potentiation triggered by the drug of the
sympathomodulation exerted by reflexogenic areas which physiologi-
cally restrain neuroadrenergic ouflow, ie. the arterial and the cardiopul-
monary reflexes [17]. An additional mechanism claims that the drug
may exert direct sympathoinhibitory effects on central sympathetic
drive [76]. Sympathoinhibitory effects have been also reported in
heart failure patients for statins, which frequently are combined to
the main pharmacological approaches used in the heart failure state
[78–79]. A further class of drugs, very recently introduced in the treat-
ment of type 2 diabetes mellitus, is represented by sodium glucose co-
transport protein 2 inhibitors, which block reabsorption of glucose in
the kidney and therefore lower blood glucose levels [80]. These drugs,
also called gliflozins, exert, along with favorable metabolic outcomes,
clercut beneficial effects on the cardiovascular system, particularly in
the heart failure state [81–82]. Some of these effects might be mediated
by a favorable action of these drugs on endothelial and
neuroadrenergic function [81,83]. Finally, in recent years the drug
ivabradine which inhibits funny currents (If) acting on the sinoatrial
node, resulting in a reduction in heart rate, has been tested in heart fail-
ure patients with reduction of heart failure hospitalization or cardio-
vascular death in symptomatic patients (New York Heart Assocaition
class II-IV) with severe left ventricular systolic impairment (ejection
fraction ≤35%), in sinus rhythm with resting heart rate at least 70
beats per minute [84]. As just mentioned the drug exerts its
bradycardic effects throughout mechanisms largely independent on
the autonomic nervous system [85].
4. Renal nerves ablation and baroreflex activation therapy
Renewed interest for a role of the sympathetic nervous system not
only in the pathophysiology of the heart failure state but also as target
of the therapeutic interventions has been provided by the development
of two approaches which have as common link the inhibition of the
60 *
*
50
*
MSNA (bs/min)
40
NS
30
20
10
0
B 6 mo 21 mo 42 mo Controls
Fig. 4. Effects of carotid baroreceptor stimulation on muscle sympathetic nerve traffic
(MSNA) after 6, 21 and 42 months following implantation of the device. Note the
marked inhibition of MSNA compared to the values seen in the preimplantation state
(B). Following 42 months the MSNA values were superimposable to the ones seen in
age matched healthy controls. Asterisk (P < .05) refer to the statistical significance
between B and different time intervals. B: preimplantation, Mo: months, bs/min: bursts/
minute, NS: not significant. Data from Ref [103–105].
sympathetic overactivity of the heart failure patients, namely bilateral
ablation of renal nerves and carotid baroreceptor stimulation.
Percutaneous transluminal ablation of renal nerves has recently be-
come available for treatment of resistant hypertension. The results, al-
though initially promising [86–87], did not appear later on to be
supported by the results of a placebo-controlled clinical trial which
failed to demonstrate clearcut blood pressure lowering effects of the in-
tervention [88]. Recently, however, results of clinical trials performed in
mild-to-moderate hypertensive patients whose blood pressure values
were not adequately controlled by multiple antihypertensive drug
treatment have renewed the interest for the approach [89–91].
Based on the evidence that renal nerves ablation may lower sympa-
thetic activity [92–93] the attempt has been made to employ the proce-
dure in heart failure patients. The few clinical studies performed so far
did not produce univocal results, some showing benefits (particularly
quality of life), some no substantial advantages and others prematurely
stopped because encompassing difficulties in patients recruitment
[94–98]. Although a recent meta-analysis examining the results of four
major published studies provide evidence on the favorable effects of
the procedure on left ventricular function [99], further data are needed
to achieve conclusive information on the use of renal nerves ablation as
a potential therapeutic intervention for congestive heart failure [100].
A final approach which has been used for counteracting the heart
failure- related sympathetic overdrive, and the related baroreflex dys-
function, has been the so-called baroreflex activation therapy [17]. In-
deed the procedure, originally developed for treating elevated blood
pressure values in drug resistant hypertension (99), has been docu-
mented to be effective in heart failure patients. Recent studies have
shown that during the long-term follow-up period (on average more
than 3 years) unilateral electrical stimulation of the carotid barorecep-
tors via a pulse generator device, surgically positioned at the level of
the carotid body, is capable to improve in heart failure patients belong-
ing to class III-IV New York Heart Association left ventricular ejection
fraction, brain natriuretic petides, exercise cacity and quality of life
[101–104]. Many of these effects are likely to be mediated by the
sympathoinhibitory properties of the procedure, which are consistent
for magnitude, long-lasting and dependent on the restoration of the
modulatory effects of carotid baroreceptors on sympathetic neural
drive [105–107].
5. Conclusions
Despite the large number of information collected over the past
fifthy years on the impact of non-pharmacological and pharmacological
 G. Grassi et al. / International Journal of Cardiology 321 (2020) 118–125
interventions on heart failure-related sympathetic overdrive, several as-
pects still remain unclear. One of them refers to the question as to
whether the sympathoinhibitory effects exerted by different procedures
allow not only to reduce the adrenergic cardiovascular drive but also to
bring it back to “normal” values. Fig. 4 shows the data related to the
long-term effects of the baroreflex activation procedure on sympathetic
function, whose pattern of activity becomes almost indistinguishable
from the one typical of healthy controls after three and half years fol-
lowing the implantation of the device [107]. Whether this is the case
also for other pharmacological or non-pharmacological interventions,
employed alone or in combination, remains to be seen. A furher ques-
tion which remains unanswered is whether and to what extent the
sympathetic deactivation elicited by therapeutic interventions in heart
failure contributes to the prolonged survival of the patients under treat-
ment or whether haemodynamic improvements are in this context
more relevant. Finally, as above mentioned, it remains to be investigated
the impact of sodium glucose cotransport protein-2 inhibitors as well as
angiotensin receptor neprilysin inhibitors on adrenergic neural func-
tion. It can be thus anticipated that the research area related to the ther-
apeutic approaches to sympathetic neural activation in heart failure will
remain in the future a stimulating one with promising developments on
the horyzon.
Author statement
All authors should have made substantial contributions to all of the
following: (1) the conception and design of the study, or acquisition of
data, or analysis and interpretation of data, (2) drafting the article or re-
vising it critically for important intellectual content, (3) final approval of
the version to be submitted.
Declaration of Competing Interest
None.
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