Hypertension

REVIEW

Individualized Beta-Blocker Treatment for

High Blood Pressure Dictated by Medical
Comorbidities: Indications Beyond the 2018
European Society of Cardiology/European
Society of Hypertension Guidelines
Giuseppe Mancia , Sverre E. Kjeldsen , Reinhold Kreutz , Atul Pathak , Guido Grassi , Murray Esler

ABSTRACT: Several hypertension guidelines have removed beta-blockers from their previous position as first-choice drugs for
the treatment of hypertension. However, this downgrading may not be justified by available evidence because beta-blockers
lower blood pressure as effectively as other major antihypertensive drugs and have solid documentation in preventing
cardiovascular complications. Suspected inconveniences of beta-blockers such as increased risk of depression or erectile
dysfunction may have been overemphasized, while patients with chronic obstructive pulmonary disease or peripheral artery
disease, that is, conditions in which their use was previously restricted, will benefit from beta-blocker therapy. Besides,
evidence that from early to late phases, hypertension is accompanied by activation of the sympathetic nervous system makes
beta-blockers pathophysiologically an appropriate treatment in hypertension. Beta-blockers have favorable effects on a variety
of clinical conditions that may coexist with hypertension, making their use either as specific treatment or as co-treatment
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potentially common in clinical practice. Guidelines typically limit recommendations on specific beta-blocker use to cardiac
conditions including angina pectoris, postmyocardial infarction, or heart failure, with little or no mention of the additional
cardiovascular or noncardiovascular conditions in which these drugs may be needed or preferred. In the present narrative
review, we focus on multiple additional diseases and conditions that may occur and affect patients with hypertension, often
more frequently than people without hypertension, and that may favor the choice of beta-blocker. Notwithstanding, beta-
blockers represent an in-homogenous group of drugs and choosing beta-blockers with documented effect in prevention and
treatment of disease is important for first choice in guidelines.

Key Words:  antihypertensive drugs ◼ beta-blockers ◼ blood pressure ◼ heart rate ◼ hypertension

I
n recent years, several hypertension and cardiovas-
cular prevention guidelines1–4 have removed beta-
blockers from their previous position as first-choice
drugs for the treatment of hypertension, recommending
their use only for some specific clinical conditions or, in
absence of or insufficient blood pressure (BP) lower-
ing response to initially administered agents, as a later
treatment step. However, this downgrading may not be
justified by the available evidence because beta-block-
ers lower elevated BP as effectively as all other major
antihypertensive drugs.5 Furthermore, beta-blockers
have been shown to sizably reduce the risk of cardio-
vascular outcomes in placebo-controlled trials.6 Finally,
with 2 exceptions,7,8 in several randomized clinical tri-
als (RCTs), beta-blockers have shown an association
with cardiovascular outcomes similar to that of other

 
The opinions expressed in this article are not necessarily those of the editors nor the American Heart Association.
Correspondence to: Sverre E. Kjeldsen, Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway, Email s.e.kjeldsen@medisin.uio.no or Reinhold
Kreutz, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and
Toxicology, Berlin, Germany, Email reinhold.kreutz@charite.de
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.122.19020.
For Sources of Funding and Disclosures, see page 1164.
© 2022 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp

Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020 June 2022   1153

 Mancia et al Beta-Blockers in Hypertension

blood flow autoregulation. (3) Beta-blockers substan-

Nonstandard Abbreviations and Acronyms tially reduce the risk of stroke in placebo-controlled tri-
als on hypertensive patients.17 On the other side, recent
ACE angiotensin-converting observations provide evidence that favors the use of
Review

enzyme beta-blockers. That is, inconveniences of beta-blockers

ASCOT Anglo-Scandinavian
Cardiac Outcomes Trial
COPD chronic obstructive
pulmonary disease
EMPEROR-PRESERVED Empagliflozin in Heart
Failure With a Pre-
served Ejection Fraction
ESC European Society of
Cardiology
ESH European Society of
Hypertension
HF heart failure
HFpEF heart failure with pre-
served ejection fraction
I-PRESERVE Irbesartan in Heart
Failure With Preserved
Systolic Function Trial
LV left ventricular
PARAGON Angiotensin-neprilysin
inhibition in heart failure
with preserved ejection
fraction.
LIFE Losartan Intervention
for End Point Reduction
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such as increased risk of depression20 or erectile dys-
function21 seem to be overemphasized.
These drugs now have been shown to be protective
and safe in conditions such as chronic obstructive pul-
monary disease (COPD) and peripheral artery disease,
for which their use has been traditionally restricted or
even regarded as contraindicated.22,23 Importantly, from
early to late phases, hypertension and related diseases
and conditions such as heart failure (HF), ischemic
heart disease, obesity, or obstructive sleep apnea are
accompanied by activation of the sympathetic nervous
system,24 which makes beta-blockers pathophysiologi-
cally an appropriate treatment in individuals with ele-
vated BP.
Further important advantages of beta-blockers are
their favorable effects on a large variety of clinical con-
ditions that may coexist with hypertension, thus making
their use either as specific treatment or as co-treatment
potentially common in clinical practice. Although in line
with the growing tendency to personalize medical treat-
ments, this is not or only partly, addressed by most guide-
lines. Guidelines limit recommendations on beta-blocker
use typically to cardiac conditions including angina pec-
toris, heart rate control, postmyocardial infarction or HF,

in Hypertension with little or no mention of several additional cardiovas-

NORDIL Nordic Diltiazem
MRA mineralocorticoid
receptor antagonist
SENIORS Study of the Effects
of Nebivolol Interven-
tion on Outcomes and
Rehospitalization in
Seniors With Heart
Failure
SGLT2i sodium glucose
cotransporter 2 inhibitor
major antihypertensive drugs,9–14 with a superimposable
or an only slightly less evident overall protective effect
in trial meta-analyses.6,15,16 As mentioned by the 2018
guidelines of the European Society of Cardiology (ESC)
and the European Society of Hypertension (ESH),1
the observation that beta-blockers are less protective
against stroke than other drugs in meta-analyses of
RCTs17 should be interpreted with caution for several
reasons. (1) This difference may have originated from
between-trial small differences in achieved BP, which
can hardly be neutralized by adjustment procedures
and to which stroke is especially sensitive.8,18,19 (2) No
evidence has ever been obtained of a direct damag-
ing effect of beta-blockers on cerebral tissue and its
cular or noncardiovascular conditions in which these
drugs may be needed or preferred. In the present narra-
tive review, we aim to focus on these additional diseases
and conditions, which may occur and affect patients with
hypertension, often more frequently than people with-
out hypertension, favoring a beta-blocker in the choice
of drug treatment. A more detailed assessment of BP
lowering effects of beta-blockers in monotherapy in
uncomplicated, essential hypertension is discussed in
the Supplemental Material S1. Because some of us are
also members of the European Guidelines Committee,
we have in the Supplemental Material S2 added a short
organizational explanation for why the present review is
needed. We have further elaborated on our motivation
and the general use of beta-blockers in medicine in the
Supplemental Material S3 and the benefits of combina-
tions RAS-blocker/calcium channel blocker/diuretic in
Supplemental Material S4. Our focus is on chronic con-
ditions where comorbid hypertension should often, inci-
dentally and/or as consequence of comorbid disease‚ be
treated with a beta-blocker as a preferable choice com-
pared to other antihypertensive drugs. In this context, we
find it too extensive to discuss the sympatholytic effects
of other antihypertensive drugs such as the indirect
effects of blockers on the renin-angiotensin-aldosterone
system or α-blockers.

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 Mancia et al
THE 2018 GUIDELINES AND TREATMENT
WITH BETA-BLOCKERS
The 2018 ESC/ESH Hypertension Guidelines stated
the following recommendations regarding the usage
of beta-blocker.1 Beta-blockers have been shown to
be particularly useful for the treatment of hypertension
in specific situations such as symptomatic angina, for
heart rate control, postmyocardial infarction, HF with
reduced ejection fraction and as an alternative to ACE
(angiotensin-converting enzyme) inhibitors or ARBs in
younger hypertensive women planning pregnancy or
of child-bearing potential.” Treatment with beta-block-
ers is recommended by the European guidelines in
the text describing prevention and treatment of atrial
fibrillation, and in case of aortic dissection. These
comorbidities (Table 1) are well-recognized indications
for treatment of hypertension with beta-blocker and
therefore not discussed further in detail in the pres-
ent article‚ with 2 exceptions namely benefits of heart
rate lowering and HF with preserved ejection fraction
(HFpEF).
Beta-Blockers and Heart Rate Reduction
Elevated resting heart rate values are detectable in a
consistent fraction of hypertensive patients as schemat-
ically illustrated in Figure 1, particularly young or mid-
dle-aged mild-to-moderate hypertensive patients with
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a so-called hyperkinetic circulation.24,25 Elevated heart
rate in hypertensive patients has detrimental effects on
the cardiovascular system, increasing cardiac work and
myocardial oxygen demand, augmenting arterial wall
stress, decreasing arterial distensibility and facilitat-
ing coronary plaque disruption.26 Taken together, these
adverse effects explain why increased heart rate rep-
resents an independent risk factor in the hypertensive
population, associated with an elevated probability of
development of fatal and nonfatal cardiovascular events
Table 1.  The 2018 ESC/ESH Hypertension Guidelines Men-
tion Beta-Blocker Treatment if Hypertensive Patients Suffer
the Following Concomitant Diseases or Conditions
Symptomatic angina
Postmyocardial infarction
HFrEF
Women with childbearing potential/planning pregnancy
Heart rate control (<80 beats/min)
Atrial fibrillation
 Prevention
  Rhythm control
  Heart rate (frequency) control
Aortic dissection
ESC indicates European Society of Cardiology; ESH, European Society of
Hypertension; and HFrEF, Heart failure with reduced ejection fraction.
Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
as well as target organ damage, particularly at cardiac
level.26 Evidence has been also provided that elevated
heart rate values at rest depend on the alteration in car-
diac autonomic regulation of sinus node activity, reflect-
Review
ing in particular an increased sympathetic function and
a reduced parasympathetic tone to the heart. This is
supported by the recent finding that in hypertensive
patients heart rate values greater than 80 beats/min-
utes, a value indicated by recent ESC/ESH guidelines,1
reflect an increased sympathetic cardiovascular drive,
as assessed by the microneurographic technique and
the assay of the circulating venous plasma levels of the
neuro-adrenergic transmitter noradrenaline.27 In hyper-
tensive patients with an elevated heart rate the cardiac
sympathetic outflow is specifically activated, evident in
increased cardiac noradrenaline spillover values.28 As
far as the therapeutic intervention is concerned, despite
the lack of direct Randomized Clinical Trial evidence,
ESC/ESH guidelines recommend beta-blockers as first
choice drug treatment of the hypertensive patients with
resting heart rate values >80 beats/min. The guidelines
are recognizing the clinical relevance of reducing ele-
vated heart rate in this group of patients for decreasing
cardiac sympathetic overdrive and the related increase
in cardiovascular risk.1
The Use of Beta-Blocker Treatment in Patients
With HF With Mid-Range and Preserved Ejection
Fraction
The 2018 ESC/ESH Hypertension Guidelines1 did not
discuss HF with mid-range (heart failure with medium
range ejection fraction) or HFpEF while the ESC HF
guidelines make the point that there is no specific drug
treatment for HFpEF.29 However, the SENIORS (Study
of the Effects of Nebivolol Intervention on Outcomes
and Rehospitalisation in Seniors With HF)30 investi-
gated nebivolol versus placebo in unselected patients
with HF in whom low ejection fraction was not a selec-
tion criterion, and the results were positive for the pri-
mary end point (composite of hospitalization for HF and
death). In a prespecified sub-group analysis, there was
no difference in outcome (primary end point) in patients
with reduced compared to patients with preserved ejec-
tion fraction.31
Though no RCT of beta-blocker treatment on com-
posite death and HF has been performed in patients
with HFpEF, there is an extensive use of free add-
on beta-blockers in all RCTs performed in this group
of HF patients in whom hypertension is typically
extremely common. Up to 96% of the study partici-
pants had hypertension irrespective of which HF agent
was investigated in the RCTs.32
Figure 2 illustrates more in detail the use of beta-
blockers in RCTs in HFpEF patients. Beta-blocker
treatment was given as free add-on to >55% of all
June 2022   1155
 Mancia et al Beta-Blockers in Hypertension
Review

Figure 1. Schematic relationship

between plasma catecholamines,
heart rate, and blood pressure in
hypertension.
Adr indicates adrenaline; BP, blood
pressure; HR, heart rate; and NA,
noradrenaline.

patients groups irrespective of placebo or active drug.
In I-PRESERVE (Irbesartan in HF With Preserved
Systolic Function Trial),33 the use of beta-blocker
increased to 72% of the patients during the course of
the trial. In PARAGON (Angiotensin-Neprilysin Inhi-
bition in HF With Preserved Ejection Fraction)34 as
many as 80% were on beta-blockers at baseline. In
EMPEROR-PRESERVED (Empagliflozin in HF With
a Preserved Ejection Fraction),35 87% were taking
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concomitant medications were not included in other
publications.34,35 Thus, dedicated HF trial investiga-
tors treat most of the patients with typical hyperten-
sive HF (HFpEF) with beta-blockers. We have briefly
commented upon this issue also in the Supplemental
Material S5.
Moreover, a recent individual patient-level analysis of
RCTs indicated that beta-blocker therapy improved left
ventricular (LV) ejection fraction, all-cause mortality and

beta-blocker at baseline in the placebo group and cardiovascular mortality in patients with mid-range/mildly
86% in the empagliflozin treatment group. Percent- reduced ejection fraction (LV ejection fraction 40%–
ages at study end were probably higher as it was 49%) in patients in sinus rhythm to a similar extent as in
shown in I-PRESERVE33 although follow-up data on patients with HF with reduced ejection fraction.36

Figure 2. Overview of the use of beta-blockers on clinical indications in the randomized clinical trials of patients with heart
failure with preserved ejection fraction (HFpEF).
ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor blocker neprilysin
inhibitor; CHARM-PRES, Candesartan in patients with chronic heart failure and preserved left ventricular ejection fraction; EMPEROR-PRES,
empagliflozin in heart failure with a preserved ejection fraction; HFpEF, heart failure with preserved ejection fraction; I-PRESERVE, Irbesartan in
patients with heart failure and preserved ejection fraction; MRA, mineralocorticoid receptor antagonist; PARAGON, Prospective Comparison of
ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure;
RCT, randomized clinical trial; SGLT2i, sodium glucose cotransporter inhibitor; and TOPCAT, Treatment of Preserved Cardiac Function Heart
Failure With an Aldosterone Antagonist.

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 Mancia et al
OTHER CARDIAC INDICATIONS FOR BETA-
BLOCKER TREATMENT
There is a number of other cardiac indications for
beta-blocker treatment not covered in the 2018
ESC/ESH Hypertension Guidelines (Table 2). These
concomitant diseases or conditions are complica-
tions of hypertension or they occur more frequently
in patients with hypertension than in normotensive
people.
Acute and Chronic Coronary Syndromes
Chronic coronary syndrome relates to the indication
of beta-blocker treatment in postmyocardial infarc-
tion and symptomatic angina pectoris, described in
the hypertension guidelines.1,37 The postmyocardial
infarction RCTs were performed before fibrinolytic
treatment and invasive treatment with PCI and implan-
tation of stents were introduced,38,39 and beta-blocker
treatment was effective in preventing sudden cardiac
death. All these trials have reinforced the indication
for beta-blocker treatment of postmyocardial infarc-
tion in presence of additional conditions. If there is
hypertension, tachycardia, angina, arrhythmias, HF,
or ischemia because of incomplete myocardial revas-
cularization beta-blockers are indicated. This is the
case also for an unstable acute coronary syndrome
with persistent ischemia, angina pectoris, or arrhyth-
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mias, usually showing ischemia on ECG or leakage of
troponins into blood. In these patients, beta-blockers
are first-choice treatment regardless whether patients
have hypertension or not. In postmyocardial infarction
patients in stable conditions and without any of these
strong indications for beta-blocker treatment several
ongoing RCTs may clarify the beta-blocker indication.
Table 2.  Other Cardiac Indications for Treatment With Beta-
Blockers
Acute coronary syndrome
Chest pain
LQTS
HOCM, subaortic stenosis, septal thickness
Uncontrolled rapid atrial fibrillation combined with diltiazem or verapamil to
avoid toxic amiodarone
Paroxysmal supraventricular arrhythmias, ventricular arrhythmias, other
arrhythmias
Post ICD implantation
Attacks of tachycardia after PM implantation for tachy-brady syndrome
After CABG, valve and other major cardiac surgery, consider in HF with
medium range (HFmrEF) and HFpEF
Unpleasant palpitations
CABG indicates coronary artery bypass graft; ICD, implantable cardioverter
defibrillator; HF, heart failure; HFpEF, heart failure with preserved ejection frac-
tion; HOCM, hypertrophic obstructive cardiomyopathy; LQTS, long QT syndrome;
and PM, pacemaker.
Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
Unspecific Chest Pain, Reduced Coronary
Reserve, and Myocardial Infarction With
Nonobstructive Coronary Arteries
Review
Beta-blockers may be indicated for uncharacteristic or
atypical chest pain, which may not necessarily be related
to macrovascular coronary disease. In a number of
patients, main epicardial coronary arteries are open and
normal, but chest pain still has a cardiac origin because
of extensive structural alterations of the microcircula-
tion. This is typically associated with hypertension, which
increases the wall thickness and wall-to-lumen ratio of
small precapillary arteries and causes capillary rarefac-
tion (The Hallmark of Hypertension).40 Compromised
arterial microcirculation is compatible with reduced coro-
nary reserve41—these days referred to as myocardial
infarction with non-obstructive coronary arteries,42 a term
used to describe patients with a diagnosis of myocardial
infarction who are found to have nonobstructive or normal
coronary arteries following coronary angiography. With
these conditions chest pain has been more common in
nonbeta-blocker arms of large outcome trials, justifying
the indication for beta-blocker treatment. For example,
in the close out phase of the LIFE (Losartan Intervention
for End point Reduction in Hypertension) Study,7 patients
were recommended further treatment with both losar-
tan and atenolol irrespective of in-trial blinded medica-
tion. One of the reasons beside insufficient BP control
was reports of significantly more unspecific chest and
back pains on losartan (23%) versus the atenolol (20%)
treated patients with LV hypertrophy.7
Long QT Syndrome
Long QT syndrome is an abnormal feature of the heart’s
electrical system that can lead to a potentially life-threat-
ening arrhythmia called torsades de pointes. Torsades
de pointes may result in ventricular fibrillation, syncope
(fainting), or sudden cardiac death. Catecholaminergic
polymorphic ventricular tachycardia may for example
benefit from nadolol versus others beta-blockers.43 When
Long QT syndrome is diagnosed, it is important to remove
any triggering mechanism including drugs that prolong
QT and may cause the condition. Long QT syndrome may
have a genetic nature but even when acquired it may be
difficult to resolve. Thus, antiarrhythmic drugs as beta-
blockers maybe indicated,44 especially in people with
hypertension. Some patients may nevertheless need a
pacemaker or an implantable cardiodefibrillator.45
LV Outflow Tract Obstruction
Various cardiac conditions are characterized by a LV outflow
tract obstruction towards the aortic valve. One of them may
be due to extensive thickness or hypertrophy of the septum,
a condition common in patients with hypertension,46 or to a
June 2022   1157
 Mancia et al
classic subaortic stenosis with loud and high frequent sys-
tolic murmur. Alternatively, the cause can be a hypertrophic
obstructive cardiomyopathy at an advanced stage.47 Treat-
ment with beta-blockers will slow down heart rate, increase
Review
the length of diastole, and thus improve ventricular filling.48
Auscultation of patients with subaortic stenosis soon after
initiation of beta-blocker therapy may reveal their effects by
demonstrating that the preceding systolic murmur is weaker
or even absent. This is a sign of successful treatment.
Uncontrolled Rapid Atrial Fibrillation
and Combination of Beta-Blocker and
Nondihydropyridine Calcium Antagonist
Rapid atrial fibrillation is treated with a beta-blocker or a
nondihydropyridine calcium channel blocker such as dil-
tiazem or verapamil, although beta-blocker is the option
of choice if HF with reduced ejection fraction is involved,
because of the pronounced negative-inotropic effect of
nondihydropyridine CCBs.29 Moreover, unlike beta-block-
ers, drug interactions must be considered when using
verapamil or diltiazem, due to their inhibitory effect on drug
transport mediated by P-glycoprotein and metabolism by
the cytochrome P 450 3A4 enzyme. The latter may affect
several other cardiovascular and noncardiovascular drugs‚
including direct oral anticoagulants for which co-admin-
istration with nondihydropyridines would result in higher
drug levels and thereby increase bleeding risk.49
However, there are patients who do not respond sat-
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isfactorily to separate treatment with either drug class, in
which a cautious use of their combination may be indicated.
This is particularly the case when single agent treatment
reduces heart rate to 110 to 120 beats/min or less, but
patients are still short of breath, complain of palpitations, or
feel uncomfortable. The combination of beta-blocker with
diltiazem or verapamil may also be a treatment alternative
to avoid the toxic side effects of amiodarone. Their admin-
istration alone or in combination may reduce symptoms
and improve well-being in hypertensive patients with high
risk of atrial fibrillation who may have an increased LV mass
or LV hypertrophy, that is, conditions in which slowing heart
rate down to <100 beats/min or lower (ideally <84 beats/
min) improves filling of the LV in diastole.
One may wonder whether the combination of beta-
blocker and nondihydropyridine CCB may cause an
excessive reduction of heart rate or even cardiac arrest.
However, in the NORDIL (Nordic Diltiazem) study, about
700 patients took this drug combination (mostly because
of crossover between open treatment arms) and syncope
or need for pacemaker implantation was not reported.50
Because crossover between randomized study arms was
foreseen, the NORDIL investigators assessed the safety
issue on beforehand. The question was whether the com-
bination could cause severe bradycardia and/or cardiac
arrest. However, in clinical practice, the beta-blocker plus
diltiazem or plus verapamil combination treatment had not
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Beta-Blockers in Hypertension
been reported to cause severe bradycardia with the subse-
quent need for pacemaker treatment in the NORDIL coun-
tries (Norway and Sweden) except for a very few patients.51
It should nevertheless be mentioned that worsening of HF
could happened in selected patients because of excessive
negative inotropic and chronotropic effects, in which case
amiodarone would be the remaining treatment choice of
therapy usually combined with beta-blocker.29
Other Arrhythmias, Cardiac Devices,
Palpitations, and Cardiac Surgery
There are various paroxysmal supraventricular arrhythmias,
ventricular arrhythmias, and other tachy-arrhythmias with an
indication for beta-blocker treatment not specifically men-
tioned or described in the 2018 ESC/ESH hypertension
guidelines.1 Patients are routinely given beta-blockers after
cardiodefibrillator implantation and in tachy-bradycardia syn-
drome (after PM implantation) to suppress the attacks of
tachycardia and unneeded device activity. In absence of heart
disease, some people are bothered by unpleasant palpita-
tions, which may be associated with findings of X-systolic
beats or not, at the work up of the cardiologist. Although, no
prognostic documentation is available, treatment with beta-
blockers may relieve symptoms. In the first days or even
longer after coronary artery by-pass graft surgery (CABG),
valve surgery or other major cardiac surgery the myocardium
maybe particular sensitive to arrhythmias and beta-blocker
treatment has to be frequently used—whether patients have
hypertension or not. Cardiology textbooks provide further
details on the conditions mentioned in this paragraph.
NONCARDIAC INDICATIONS FOR BETA-
BLOCKER TREATMENT RELATED TO THE
PERIPHERAL CIRCULATION
There is a number of indications for beta-blocker treat-
ment related to the peripheral circulation (Table 3).
Emergency, Urgency, and Parenteral
Administration of Labetalol
For simplicity reasons, it is referred to textbooks.
Perioperative Hypertension and Major
Noncardiac Surgery
The 2017 ACC/AHA defines perioperative hyperten-
sion as a BP ≥160/90 mm Hg or a systolic BP eleva-
tion ≥20% of the preoperative value that persists for
longer than 15 minutes. Beta-blockers is a first treat-
ment choice in patients undergoing vascular procedures
or in those with an intermediate or high risk of cardiac
complications.52 Postcarotid endarterectomy hyperten-
sion is a well-recognized phenomenon closely related to
 Mancia et al
Table 3.  Indication for Beta-Blocker Treatment Related to
Peripheral Circulation
Emergency, urgency, and parenteral administration of labetalol
Perioperative hypertension
Major noncardiac surgery
Excessive pressor response to exercise and stress
Hyperkinetic heart syndrome
POTS
Orthostatic hypertension
Obstructive sleep apnea syndrome
Peripheral arterial disease with claudication
Portal hypertension, cirrhosis-related oesophageal varices and recurrent
variceal bleeding
Pregnancy related disorders (eclampsia, preeclampsia)
POTS indicates postural orthostatic tachycardia syndrome.
surgical complications in which the perioperative use of
beta-blockers protects against the BP elevation and con-
tributes to stabilizing the postoperative peak systolic BP
for days after the intervention.53 Beta-blocker treatment
is also widely used for any type of major noncardiac sur-
gery associated with an increased response to the stress-
ful condition or environment, which can make the body
vulnerable to untoward outcomes. Beta-blockers attenu-
ate this stress response, resulting in a slowing of heart
rate and a fall in BP. On one side, such effects are desir-
able to fight the stress response, but the same effects,
if pronounced, may cause very low BP and heart rate.54
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Thus, beta-blocker use for major noncardiac surgery is
controversial unless patients have known cardiac disease
including history and findings by presurgical assessment.
Excessive Pressor Response to Exercise
and Mental Stress and Hyperkinetic Heart
Syndrome
Excessive elevations of BP induced by physical exercise
and/or mental stress and beta-blocker treatment may be
a good choice.55
Hyperkinetic heart syndrome may occur in some hyper-
tensive individuals who have a higher heart rate and stroke
volume at rest and thus a higher cardiac output than hyper-
tensive patients without this particular syndrome. There-
fore, BP is high although peripheral resistance is lower
than normal. After beta-adrenergic blockade,56 heart rate
and cardiac output decrease, whereas peripheral resis-
tance increases. Mean BP mostly remains unchanged.
Postural Orthostatic Tachycardia Syndrome and
Orthostatic or Postural Hypertension
Postural orthostatic syndrome is characterized by an exces-
sive tachycardia, quantified as either an increase of 30 beats
per minute or as a rate of >120 beats per minutes after up to
half an hour of standing. Distressing symptoms are common
Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
and so is beta-blocker prescribing. Orthostatic or postural
hypertension is a less well-known form of hypertension that
occurs abruptly when someone moves into an upright posi-
tion. An increase in BP of 20 mm Hg or more when standing
Review
is the diagnostic criterion. In severe cases, orthostatic hyper-
tension can result in patients experiencing the same compli-
cations that they would with regular hypertension. However,
in the majority of patients with orthostatic hypertension,
symptoms are only present in the upright position. Beta-
blocker is a natural choice for treating postural orthostatic
tachycardia syndrome57,58 while beta-blockers are used with
much less justification in the other orthostatic intolerance
variants including nonpostural orthostatic syndrome forms
of orthostatic hypertension. In other words, beta-blockers
do not directly influence orthostatic intolerance per se apart
from postural orthostatic tachycardia syndrome.
Obstructive Sleep Apnoea Syndrome
This syndrome is of interest to various medical fields. It
is certainly of interest in the present context because
obstructive sleep apnoea is common in obese hyper-
tensive patients in whom it further activates the sym-
pathetic nervous system. This justifies treatment with
beta-blockers.
Peripheral Arterial Disease with Claudication
Peripheral arterial disease with claudication, the smokers’
leg, is a common condition characterized by ischemia of
skeletal muscle tissue in the lower limbs, caused by exten-
sive arterial atherosclerosis. Beta-blocker treatment achieve
anti-ischemic effects and relieve pain.23,59 Dihydropyridine
CCBs may have similar anti-ischemic effects and combine
with beta-blocker on this indication. Smokers frequently
have COPD. One should always be alert regarding wors-
ening of pulmonary function (increased airway resistance)
when treating patients with peripheral artery disease with
beta-blockers (Table 5). Nonselective beta-blockers such as
propranolol or timolol seem to be worse compared to the
selective beta-1 blockers, or alpha-beta blockers. We refer
to the section on COPD in the text below.
Portal Hypertension, Liver Cirrhosis–Related
Oesophageal Varices, and Recurrent Variceal
Bleeding
Treatment with beta-blockers is widely recommended
because these drugs lower the portal pressure and pre-
vent life-threatening bleedings.60
Pregnancy-Related Disorders (Eclampsia,
Preeclampsia)
In hypertension in pregnancy and pregnancy-related dis-
orders (eg, preeclampsia and eclampsia), blockers of the
June 2022   1159
 Mancia et al
renin-angiotensin system and diuretics are not recom-
mended,1 while alpha-methyldopa, nifedipine, and the
unique beta-blocker labetalol with an additional alpha-
blocking mode of action are recommended as first treat-
Review
ment choice.61 However, as recently emphasized, these
therapeutic options are based on small individual investi-
gations and recommendations vary between national and
international guidelines, while there is no clear evidence
that one drug is preferable to another.1 This applies also
to other beta-blockers including metoprolol and bisopro-
lol, which are considered to be safe in pregnancy and are
used in many European countries, particularly in countries
in which labetalol is not available (eg, Germany), due to
its hepatotoxic effect that may also occur in pregnancy.62
INDICATIONS FOR BETA-BLOCKER
TREATMENT NOT DIRECTLY RELATED
TO THE HEART OR PERIPHERAL
CIRCULATION
There is a number of indications for beta-blocker treat-
ment not directly related to the heart or peripheral circu-
lation (Table 4).
Chronic Obstructive Pulmonary Disease
As a general warning, one should always be alert for
worsening of pulmonary function with increased airway
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resistance when giving beta-blockers to patients with
pulmonary diseases (Table 5).
Patients with COPD frequently have coronary heart
disease or peripheral arterial disease because of their
smoking habits. However, patients with COPD have
frequently been excluded from treatment with beta-
blockers, because of the unjustified fear that block-
ing beta2-receptors in the bronchial system could put
these patients at risk. This was pointed out many years
ago22,63 and reiterated more recently.51 Importantly, a
recent meta-analysis64 demonstrated that the use of
Table 4.  Other Indications for Beta-Blocker Treatment Not
Directly Related to the Heart or Peripheral Circulation
COPD
Diabetes
Thyrotoxicosis, hyperthyroidism, thyroiditis, and Graves’ disease
Hyperparathyroidism in uremia
Migraine headache
Essential tremor
Glaucoma
Performance anxiety and anxiety disorders
Olympic sports (negative) as doping and sabotage
Psychiatric disorders (posttraumatic stress)
COPD indicates chronic obstructive pulmonary disease.
1160   June 2022
Beta-Blockers in Hypertension
Table 5.  Various Problems With the Use of Beta-Blockers to
Treat Concomitant Diseases and Disorders in the Treatment
of Hypertension
Nonselective beta- Worsening of bronchial asthma (increased airway resis-
blockers tance) (also with low beta-1 selectivity as for atenolol)
Nonselective beta- Male impotency—may choose vasodilating beta-
blockers blocker
Nonselective beta- Lower HDL cholesterol, increase TG, may cause
blockers type-2 diabetes
Nonselective timolol Bradycardia, occasional need for pacemaker, in gen-
eral lowering heart rate too much in the elderly with
beta-blocker treatment may cause serious adverse
event (Supplemental Material S7)
Nonselective sotalol Occasional proarrhythmic effect limits the use
Intrinsic sympatho- Insufficient reduction of heart rate, no beneficial
mimetic activity effect in heart failure
Hydrophilic beta- Do not pass blood-brain barrier, alternative if
blockers unpleasant dreaming
Beta-1 selective Ultra-short acting, emergency use only
esmolol
Beta-1 selective Inferior in 2 RCTs (vs losartan, LIFE, and vs amlo-
atenolol dipine, ASCOT) and untoward metabolic effects like
nonselective beta-blockers indicated above
Beta-blockers in May mask symptoms of hypoglycemia and thus
type-1 diabetes impair awareness particularly in patients with type-1
diabetes or patients treated with insulin
Beta-blockers in Labetalol and metoprolol considered safe
pregnancy
ASCOT indicates Anglo-Scandinavian Cardiac Outcomes Trial; HDL, high-
density lipoprotein; LIFE, Losartan Intervention for End Point Reduction in Hyper-
tension; RCT, randomized controlled trial; and TG, triglycerides.
beta-blockers (including both beta1- selective and non-
selective agents) in patients with COPD and cardiovas-
cular disease is not only safe but also reduces their all
cause and in-hospital mortality. Of interest, this analy-
sis indicated also that beta1-selective beta-blockers
may even reduce COPD exacerbations.65 In addition,
cardio-selective beta-blockers do not affect the action
of bronchodilators but reduce the heart rate accel-
eration caused by their use.65 It should be mentioned,
however, that patients with classical pulmonary asthma
may worsen their condition by use of nonselective beta-
blockers or agents with low beta1-selectivity.
Diabetes
Patients with diabetes may occasionally experience
hypoglycemia and thus impaired awareness particularly
in patients with type 1 diabetes or patients treated with
insulin (Table 5). Beta-blockers in general may mask
symptoms of hypoglycemia, which are activation of the
sympathetic nervous system including tachycardia. How-
ever, patients with diabetes may because of neuropathy,
have silent ischemia in their myocardium and elsewhere
and may benefit from beta-blocker treatment. Because of
an extensive destruction of the microcirculation type 2 dia-
betes is also a main cause of HF and, though not proven
specifically, probably the cause of the high prevalence
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 Mancia et al
of type-2 diabetes in patients with HFpEF and one of
the reasons for the increasing concomitant use of beta-
blockers in RCTs of HFpEF medications (Figure 2).
First and second generation beta-blockers are asso-
ciated with increased incidence of new onset diabetes
shown in several RCTs including in LIFE7 and ASCOT
(Anglo-Scandinavian Cardiac Outcomes Trial).8 The
importance of such findings is uncertain as it could sim-
ply be earlier de-masking of latent type-2 diabetes which
would then receive more intensified preventive treat-
ment. First- and second-generation beta-blockers are
also associated with apparently unfavorable changes in
blood lipids (Table 5).
Thyrotoxicosis, Hyperthyroidism, Thyroiditis,
and Grave’s Disease
In patients with thyrotoxicosis (thyroid storm) or symp-
tomatic hyperthyroidism, thyroiditis, and Graves’ disease,
the excess of thyroid hormone production and secretion
may result in increased heart rate, tremor, and nervous-
ness. Propranolol is the most widely studied nonselec-
tive beta-blocker to treat the increased heart rate and
tremor under these circumstances.65 Beta-blocker may
additionally reverse some of the reduced systemic vas-
cular resistance associated with the hormonal disease
and inhibit the peripheral conversion of T4 to the more
biologically active hormone, T3.66 The American Asso-
ciation of Clinical Endocrinologists Medical Guidelines
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for the Evaluation and Treatment of Hyperthyroidism
and Hypothyroidism67 have for many years discussed
the use of beta-blockers in conditions characterized by
an excess of thyroid hormones without specifically rec-
ommending one beta-blocker over another.
Hyperparathyroidism in Uremia
Various beta-blockers suppress PTH secretion in patients
with uremia and hyperparathyroidism.68
Migraine Headache
Beta-blockers may prevent migraine or reduce the sever-
ity of attacks. Efficacy has been established for metopro-
lol, propranolol, and timolol, it is probable for atenolol and
nadolol, and possible for nebivolol and pindolol. Timo-
lol and propranolol are Food and Drug Administration
approved for migraine prevention69 while off label (unap-
proved) use of metoprolol is also common.
Essential Tremor
Propranolol has been used to treat essential tremor for
more than 40 years. Other beta-blockers, for example,
metoprolol, may also be effective depending on the
case.70
Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
Glaucoma
Topical beta-blockers reduce intraocular pressure by
decreasing the production of aqueous humor. Oral beta-
Review
blockers also reduce intraocular pressure, but they are
not used primarily to treat or prevent glaucoma because
of the systemic effects. If used for other indications, for
example, hypertension or cardiac disease, lower intraocu-
lar pressure may be a major additional benefit especially
in the elderly. However, in the elderly both topical and
systemic co-administration of beta-blockers is frequently
observed71 and may result in additive effects including
the risk of bradycardia. Hence, topical administration of
timolol eye drops72 is a potent treatment for glaucoma
that may cause bradycardia and other systemic effects.
Some patients with a strong need of timolol against glau-
coma may even need pacemaker implantation because
of the associated bradycardia.
Anxiety Disorders and Performance Anxiety
In psychiatry, beta-blockers are used in the treatment of
anxiety disorders with somatic manifestations such as
palpitations, sweating, and tremor.73 As such, performance
anxiety that may affect public speakers, musicians, or
those taking an examination also seem to be well suited
for beta-blocker treatment. Beta-blockers have a relaxing
effect on muscle function, gaining the drug class a popular
reputation as illegal, performance-enhancement drugs for
athletes who benefit from the adrenaline-blocking effects
of the medication. Some athletes use propranolol specifi-
cally for its anxiety-reducing effects, resulting in steadier
hands, an even heart rate and an increased ability to focus.
From 2010, beta-blockers were banned by the World Anti-
Doping Agency for all Olympic sports, including archery,
gymnastics, shooting, and golf.74 Athletes who need beta-
blockers for other indications must therefore stop taking
this treatment for several days (depending on the halflife
of agents) before competition. Further, regarding sport
activities, timolol eye drops are so potent that mixed in
sport drinks they ruin chances of high-level performance
(and for example Olympic medals in runners).
Panic Disorder
In panic disorder, beta-blockers are commonly pre-
scribed75 for symptom relief, combined with cognitive
behavior therapy and/or a selective serotonin reuptake
inhibitors and/or a benzodiazepine. This joins perfor-
mance anxiety as a psychiatric comorbidity treated with
beta-blockade.
Posttraumatic Stress Disorder
The National Institute of Mental Health (Bethesda,
MD) reports that approximately 5.2 million Americans
experience posttraumatic stress disorder each year.76
June 2022   1161
 Mancia et al
Posttraumatic stress disorder can be severely debilitat-
ing and diminish quality of life for patients and those
who care for them. Studies have indicated that beta-
blocker treatment reduces consolidation of emotional
Review
memory. When administered immediately after a psy-
chic trauma, it is efficacious as a prophylactic for post-
traumatic stress disorder.77
DISCUSSION
We have scrutinized the medical field for diseases and
conditions for which beta-blocker treatment is indicated
in patients with hypertension. Tables 1 to 4 summarize
our findings‚ that there are roughly 50 different diseases
and conditions documented to benefit from beta-blocker
treatment. Thus, an overwhelming number of diseases
and conditions needs consideration for beta-blocker
treatment in patients with hypertension compared with
those few key indications mentioned up front in the
guidelines.1 In general, as a thumb rule, beta-blockers
with higher beta1-selectivity are indicated in a large num-
ber of cardiovascular diseases while nonselective beta-
blockers are indicated for endocrine diseases, anxiety,
and other psychiatric disorders and more when the aim
of the beta-blocker treatment is to target noncardiovas-
cular tissue in general. However, this is not always so
clear-cut and we have not aimed to discuss this topic in
detail as we feel it is beyond the question of beta-blocker
as first choice in the treatment of hypertension.
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There are also problems related to treatment with
beta-blockers, which are important to highlight, and which
we have touched upon in this review. We have summa-
rized the most common problems in Table 5 and partly
also mentioned how to resolve them when they appear.
Although observational data from the RCTs clearly show
morbidity and mortality benefits of keeping heart rate
below approximately 80 to 84 beats/min, lowering heart
rate further below 70 toward 60 beats/min in the elderly
hypertensive patients may be related to serious adverse
and even cardiovascular events and should be prohibited
(Supplemental Material S6).
Our main point is that beta-blocker treatment is
indicated for numerous diseases and conditions that
patients may suffer from concomitant with hyperten-
sion. In a time developing toward personalized medi-
cine, there are multiple opportunities for targeting both
hypertension and the concomitant disease with the
same treatment namely a beta-blocking drug. Hyper-
tension is a risk factor for more or less all cardiac and
vascular diseases, which we have reviewed, and hyper-
tension may result from some of the other diseases
such as hyperthyroidism. This means that more patients
with hypertension have these concomitant diseases
and conditions than have people with normal BP. This is
a general statement from our side, which we have not
attempted to support with exact data in as much as this
1162   June 2022 Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
point does not affect the main message of this article.
However, it could be of interest in the future to inves-
tigate in details fractions of hypertensive patients who
suffer from the various concomitant diseases.
It is quite striking that beta-blocker treatment is indi-
cated in common diseases such as COPD22,63–65 and
peripheral arterial disease. For many years, physicians
and the RCTs that were performed excluded patients with
these diseases from therapy with beta-blockers. Rea-
sons could be for example lack of separation between
pulmonary asthma and COPD—2 very different diseases
of the lungs.
Overall‚ beta-blockade is a key principle of treatment
in medicine. Beta-blockers inhibit the actions of adrena-
line and noradrenaline in various organs and systems as
schematically shown in Figure 3. This holds true from
classic physiology with the fright, fight, and flight reac-
tion to mostly chronic diseases on which beta-receptor
stimulation has a worsening effect. Beta-blocker treat-
ment has been investigated in hypertension and heart
disease RCTs together with numerous other cardiovas-
cular drugs that lower BP at the same time, which we
have illustrated in Figure 4. Beta-blockers provide docu-
mented cardiovascular prevention together with several
other drugs and in particular together with diuretics of
the thiazide/thiazide-like type. In fact, the overwhelm-
ing evidence for combination therapy with beta-blockers
comes from beta-blockers plus diuretics (Supplemental
Material S7). It is also good clinical practice to combine
beta-blockers with other cardiovascular drugs, for exam-
ple, dihydropyridine CCBs by buffering reflex tachycar-
dia. There is usually close connection with drugs that
work in HF with those drugs that provide cardiovas-
cular prevention in hypertension. Angiotensin receptor
blocker neprilysin inhibitor, mineralocorticoid receptor
antagonist, and SGLT2i (sodium glucose cotransporter
2 inhibitor) are drug classes that never have been inves-
tigated for end point prevention in patients with hyper-
tension without HF or diabetes; however, all these drugs
lower BP substantially, and they have powerful protec-
tive effects in HF of mostly hypertensive etiology. The
Food and Drug Administrations in the United States has
approved angiotensin receptor blocker neprilysin inhibi-
tor, mineralocorticoid receptor antagonist, and SGLT2i
for treatment of HF irrespective of LV ejection fraction. It
means that these drugs lower hospitalizing and mortality
in patients with HFpEF, related to hypertension in 90%
of these patients or more. Beta-blockers have been less
studied in HFpEF but as shown in Figure 2 the heart
specialist investigators in the HF RCTs gave almost all
the study participants concomitant beta-blocker treat-
ment on clinical indications.
Regarding the 2018 ESC/ESH Hypertension
Guidelines,1 it intuitively feels incorrect that beta-
blocker treatment was removed from the first-
choice treatment in the core-treatment strategy for
 Mancia et al
uncomplicated hypertension, that is, in patients without
specific indications including cardiac conditions and in
younger women with or planning pregnancy.1 There are
numerous additional indications for beta-blocker treat-
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ment in hypertension, which need assessment before
any decision of not giving beta-blocker for hyperten-
sion. Frequently, the choice would then be that the
physicians will prescribe beta-blocker, and we wonder
whether a more positive attitude for beta-blocker as
first choice should be indicated up front in the guide-
lines.1 Beta-blocker may be combined with all other
BP lowering drugs; regarding the nondihydropyridine
Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020
Beta-Blockers in Hypertension
Review
Figure 3. Schematic overview of
sympathetic transmitter activity
in which adrenaline facilitates
noradrenaline release.
Adr indicates adrenaline; and NA,
noradrenaline.
CCBs diltiazem and verapamil care should be taken if
suspected HF is involved because of combined nega-
tive chronotropic and inotropic effects, but for heart
rate control in uncontrolled rapid atrial fibrillation, a
common cause of hospitalization, this combination may
be excellent.50,51
Regarding hypertension and renal disease, it is well
known that beta-blockers are well tolerated and do not
deteriorate renal function. It has not been extensively
investigated, but some data suggest that renal tissue
oxygenations improves if patients with hypertension and
renal artery stenosis are treated with beta-blocker.78
Figure 4. Overview of drugs classes
suited as first choice combination
treatments of hypertension. Solid
lines connect drug classes in
combinations documented to prevent
cardiovascular complications in
hypertension, or hospitalization
and death in randomized placebo
controlled clinical trials in patients
with heart failure with predominantly
hypertensive etiology.
ACEi indicates angiotensin-converting
enzyme inhibitor; ARB, angiotensin
receptor blocker; ARNi, angiotensin
receptor blocker neprilysin inhibitor;
DH-CCB, dihydropyidin calcium channel
blocker (calcium-antagonist); MRA,
mineralocorticoid receptor antagonist; and
SGLT2i, sodium glucose cotransporter
inhibitor.
June 2022   1163
 Mancia et al
In conclusion, we suggest that beta-blockers as
a group of BP lowering medication should again be
included in the first choice armamentarium of available
antihypertensive drugs by the guidelines.
Review
ARTICLE INFORMATION
Affiliations
University of Milano-Bicocca, Milan, Italy (G.M., G.G.). Department of Cardiology,
University of Oslo, Ullevaal Hospital, Norway (S.E.K.). Charité – Universitätsmed-
izin Berlin, Institute of Clinical Pharmacology and Toxicology, Germany (R.K.).
Department of Cardiology, Centre Hospitalier Princesse Grace, Monte Carlo,
Monaco (A.P.). Human Neurotransmitters Laboratory, Baker Heart and Diabetes
Institute, and Monash University, Melbourne, Australia (M.E.).
Acknowledgments
We thank the Centre Hospitalier Princesse Grace, Monte Carlo, Monaco for gen-
erously paying for author payment charges.
Sources of Funding
The present work had no funding or secretarial assistance.
Disclosures
G. Mancia has received honoraria from Astra Zeneca, Boehringer Ingelheim,
Daiichi Sankyo, Medtronic, Menarini, Merck, Novartis, Recordati, Sandoz, Sanofi
and Servier. S.E. Kjeldsen reports lecture honoraria from Getz Pharma, Merck
Healthcare KGaA, Sanofi-Aventis and Vector-Intas. R. Kreutz reports support for
research by Bayer, honoraria for lectures from Bayer, Berlin-Chemie/Menarini,
Daiichi Sankyo, Ferrer, Merck, Sanofi and Servier. A. Pathak has received hono-
raria from Ablative Solution, Air Liquide, Astra Zeneca, Boehringer Ingelheim,
Medtronic, Menarini, Merck, Novartis, Recordati, Recor Medical, Sanofi and Ser-
vier. G. Grassi has received honoraria for lectures from Medtronic, Merck Health-
care KGaA, and Servier. M. Esler reports honoraria for participating in the Renal
Denervation advisory boards of Medtronic (United States) and SyMap (China).
Downloaded from http://ahajournals.org by on June 26, 2023
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