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- justified by the available evidence because beta-block-
cular prevention guidelines1–4 have removed beta- ers lower elevated BP as effectively as all other major
blockers from their previous position as first-choice antihypertensive drugs.5 Furthermore, beta-blockers
drugs for the treatment of hypertension, recommending have been shown to sizably reduce the risk of cardio-
their use only for some specific clinical conditions or, in vascular outcomes in placebo-controlled trials.6 Finally,
absence of or insufficient blood pressure (BP) lower- with 2 exceptions,7,8 in several randomized clinical tri-
ing response to initially administered agents, as a later als (RCTs), beta-blockers have shown an association
treatment step. However, this downgrading may not be 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 such as increased risk of depression20 or erectile dys-
Cardiac Outcomes Trial function21 seem to be overemphasized.
COPD chronic obstructive These drugs now have been shown to be protective
pulmonary disease and safe in conditions such as chronic obstructive pul-
EMPEROR-PRESERVED Empagliflozin in Heart monary disease (COPD) and peripheral artery disease,
Failure With a Pre- for which their use has been traditionally restricted or
served Ejection Fraction even regarded as contraindicated.22,23 Importantly, from
ESC European Society of early to late phases, hypertension and related diseases
Cardiology and conditions such as heart failure (HF), ischemic
ESH European Society of heart disease, obesity, or obstructive sleep apnea are
Hypertension accompanied by activation of the sympathetic nervous
HF heart failure system,24 which makes beta-blockers pathophysiologi-
HFpEF heart failure with pre- cally an appropriate treatment in individuals with ele-
served ejection fraction vated BP.
I-PRESERVE Irbesartan in Heart Further important advantages of beta-blockers are
Failure With Preserved their favorable effects on a large variety of clinical con-
Systolic Function Trial ditions that may coexist with hypertension, thus making
LV left ventricular their use either as specific treatment or as co-treatment
PARAGON Angiotensin-neprilysin potentially common in clinical practice. Although in line
inhibition in heart failure with the growing tendency to personalize medical treat-
with preserved ejection ments, this is not or only partly, addressed by most guide-
fraction. lines. Guidelines limit recommendations on beta-blocker
LIFE Losartan Intervention use typically to cardiac conditions including angina pec-
for End Point Reduction toris, heart rate control, postmyocardial infarction or HF,
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in Hypertension with little or no mention of several additional cardiovas-

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

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 Mancia et al Beta-Blockers in Hypertension

THE 2018 GUIDELINES AND TREATMENT as well as target organ damage, particularly at cardiac
level.26 Evidence has been also provided that elevated
WITH BETA-BLOCKERS heart rate values at rest depend on the alteration in car-
The 2018 ESC/ESH Hypertension Guidelines stated diac autonomic regulation of sinus node activity, reflect-

Review
the following recommendations regarding the usage ing in particular an increased sympathetic function and
of beta-blocker.1 Beta-blockers have been shown to a reduced parasympathetic tone to the heart. This is
be particularly useful for the treatment of hypertension supported by the recent finding that in hypertensive
in specific situations such as symptomatic angina, for patients heart rate values greater than 80 beats/min-
heart rate control, postmyocardial infarction, HF with utes, a value indicated by recent ESC/ESH guidelines,1
reduced ejection fraction and as an alternative to ACE reflect an increased sympathetic cardiovascular drive,
(angiotensin-converting enzyme) inhibitors or ARBs in as assessed by the microneurographic technique and
younger hypertensive women planning pregnancy or the assay of the circulating venous plasma levels of the
of child-bearing potential.” Treatment with beta-block- neuro-adrenergic transmitter noradrenaline.27 In hyper-
ers is recommended by the European guidelines in tensive patients with an elevated heart rate the cardiac
the text describing prevention and treatment of atrial sympathetic outflow is specifically activated, evident in
fibrillation, and in case of aortic dissection. These increased cardiac noradrenaline spillover values.28 As
comorbidities (Table 1) are well-recognized indications far as the therapeutic intervention is concerned, despite
for treatment of hypertension with beta-blocker and the lack of direct Randomized Clinical Trial evidence,
therefore not discussed further in detail in the pres- ESC/ESH guidelines recommend beta-blockers as first
ent article‚ with 2 exceptions namely benefits of heart choice drug treatment of the hypertensive patients with
rate lowering and HF with preserved ejection fraction resting heart rate values >80 beats/min. The guidelines
(HFpEF). are recognizing the clinical relevance of reducing ele-
vated heart rate in this group of patients for decreasing
Beta-Blockers and Heart Rate Reduction cardiac sympathetic overdrive and the related increase
in cardiovascular risk.1
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- The Use of Beta-Blocker Treatment in Patients
dle-aged mild-to-moderate hypertensive patients with With HF With Mid-Range and Preserved Ejection
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a so-called hyperkinetic circulation.24,25 Elevated heart Fraction

rate in hypertensive patients has detrimental effects on The 2018 ESC/ESH Hypertension Guidelines1 did not
the cardiovascular system, increasing cardiac work and discuss HF with mid-range (heart failure with medium
myocardial oxygen demand, augmenting arterial wall range ejection fraction) or HFpEF while the ESC HF
stress, decreasing arterial distensibility and facilitat- guidelines make the point that there is no specific drug
ing coronary plaque disruption.26 Taken together, these treatment for HFpEF.29 However, the SENIORS (Study
adverse effects explain why increased heart rate rep- of the Effects of Nebivolol Intervention on Outcomes
resents an independent risk factor in the hypertensive and Rehospitalisation in Seniors With HF)30 investi-
population, associated with an elevated probability of gated nebivolol versus placebo in unselected patients
development of fatal and nonfatal cardiovascular events with HF in whom low ejection fraction was not a selec-
tion criterion, and the results were positive for the pri-
Table 1.  The 2018 ESC/ESH Hypertension Guidelines Men- mary end point (composite of hospitalization for HF and
tion Beta-Blocker Treatment if Hypertensive Patients Suffer death). In a prespecified sub-group analysis, there was
the Following Concomitant Diseases or Conditions no difference in outcome (primary end point) in patients
Symptomatic angina with reduced compared to patients with preserved ejec-
Postmyocardial infarction tion fraction.31
HFrEF
Though no RCT of beta-blocker treatment on com-
Women with childbearing potential/planning pregnancy
posite death and HF has been performed in patients
with HFpEF, there is an extensive use of free add-
Heart rate control (<80 beats/min)
on beta-blockers in all RCTs performed in this group
Atrial fibrillation
of HF patients in whom hypertension is typically
 Prevention extremely common. Up to 96% of the study partici-
  Rhythm control pants had hypertension irrespective of which HF agent
  Heart rate (frequency) control was investigated in the RCTs.32
Aortic dissection Figure 2 illustrates more in detail the use of beta-
ESC indicates European Society of Cardiology; ESH, European Society of
blockers in RCTs in HFpEF patients. Beta-blocker
Hypertension; and HFrEF, Heart failure with reduced ejection fraction. treatment was given as free add-on to >55% of all

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

OTHER CARDIAC INDICATIONS FOR BETA- Unspecific Chest Pain, Reduced Coronary
BLOCKER TREATMENT Reserve, and Myocardial Infarction With
There is a number of other cardiac indications for Nonobstructive Coronary Arteries

Review
beta-blocker treatment not covered in the 2018 Beta-blockers may be indicated for uncharacteristic or
ESC/ESH Hypertension Guidelines (Table 2). These atypical chest pain, which may not necessarily be related
concomitant diseases or conditions are complica- to macrovascular coronary disease. In a number of
tions of hypertension or they occur more frequently patients, main epicardial coronary arteries are open and
in patients with hypertension than in normotensive normal, but chest pain still has a cardiac origin because
people. 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
Acute and Chronic Coronary Syndromes small precapillary arteries and causes capillary rarefac-
Chronic coronary syndrome relates to the indication tion (The Hallmark of Hypertension).40 Compromised
of beta-blocker treatment in postmyocardial infarc- arterial microcirculation is compatible with reduced coro-
tion and symptomatic angina pectoris, described in nary reserve41—these days referred to as myocardial
the hypertension guidelines.1,37 The postmyocardial infarction with non-obstructive coronary arteries,42 a term
infarction RCTs were performed before fibrinolytic used to describe patients with a diagnosis of myocardial
treatment and invasive treatment with PCI and implan- infarction who are found to have nonobstructive or normal
tation of stents were introduced,38,39 and beta-blocker coronary arteries following coronary angiography. With
treatment was effective in preventing sudden cardiac these conditions chest pain has been more common in
death. All these trials have reinforced the indication nonbeta-blocker arms of large outcome trials, justifying
for beta-blocker treatment of postmyocardial infarc- the indication for beta-blocker treatment. For example,
tion in presence of additional conditions. If there is in the close out phase of the LIFE (Losartan Intervention
hypertension, tachycardia, angina, arrhythmias, HF, for End point Reduction in Hypertension) Study,7 patients
or ischemia because of incomplete myocardial revas- were recommended further treatment with both losar-
cularization beta-blockers are indicated. This is the tan and atenolol irrespective of in-trial blinded medica-
case also for an unstable acute coronary syndrome tion. One of the reasons beside insufficient BP control
with persistent ischemia, angina pectoris, or arrhyth- was reports of significantly more unspecific chest and
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mias, usually showing ischemia on ECG or leakage of back pains on losartan (23%) versus the atenolol (20%)
troponins into blood. In these patients, beta-blockers treated patients with LV hypertrophy.7
are first-choice treatment regardless whether patients
have hypertension or not. In postmyocardial infarction
patients in stable conditions and without any of these Long QT Syndrome
strong indications for beta-blocker treatment several Long QT syndrome is an abnormal feature of the heart’s
ongoing RCTs may clarify the beta-blocker indication. electrical system that can lead to a potentially life-threat-
ening arrhythmia called torsades de pointes. Torsades
Table 2.  Other Cardiac Indications for Treatment With Beta- de pointes may result in ventricular fibrillation, syncope
Blockers (fainting), or sudden cardiac death. Catecholaminergic
polymorphic ventricular tachycardia may for example
Acute coronary syndrome
benefit from nadolol versus others beta-blockers.43 When
Chest pain
Long QT syndrome is diagnosed, it is important to remove
LQTS
any triggering mechanism including drugs that prolong
HOCM, subaortic stenosis, septal thickness QT and may cause the condition. Long QT syndrome may
Uncontrolled rapid atrial fibrillation combined with diltiazem or verapamil to have a genetic nature but even when acquired it may be
avoid toxic amiodarone
difficult to resolve. Thus, antiarrhythmic drugs as beta-
Paroxysmal supraventricular arrhythmias, ventricular arrhythmias, other
blockers maybe indicated,44 especially in people with
arrhythmias
hypertension. Some patients may nevertheless need a
Post ICD implantation
pacemaker or an implantable cardiodefibrillator.45
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 LV Outflow Tract Obstruction
Unpleasant palpitations
Various cardiac conditions are characterized by a LV outflow
CABG indicates coronary artery bypass graft; ICD, implantable cardioverter tract obstruction towards the aortic valve. One of them may
defibrillator; HF, heart failure; HFpEF, heart failure with preserved ejection frac-
tion; HOCM, hypertrophic obstructive cardiomyopathy; LQTS, long QT syndrome; be due to extensive thickness or hypertrophy of the septum,
and PM, pacemaker. a condition common in patients with hypertension,46 or to a

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 Mancia et al Beta-Blockers in Hypertension

classic subaortic stenosis with loud and high frequent sys- been reported to cause severe bradycardia with the subse-
tolic murmur. Alternatively, the cause can be a hypertrophic quent need for pacemaker treatment in the NORDIL coun-
obstructive cardiomyopathy at an advanced stage.47 Treat- tries (Norway and Sweden) except for a very few patients.51
ment with beta-blockers will slow down heart rate, increase It should nevertheless be mentioned that worsening of HF
Review

the length of diastole, and thus improve ventricular filling.48 could happened in selected patients because of excessive
Auscultation of patients with subaortic stenosis soon after negative inotropic and chronotropic effects, in which case
initiation of beta-blocker therapy may reveal their effects by amiodarone would be the remaining treatment choice of
demonstrating that the preceding systolic murmur is weaker therapy usually combined with beta-blocker.29
or even absent. This is a sign of successful treatment.
Other Arrhythmias, Cardiac Devices,
Uncontrolled Rapid Atrial Fibrillation Palpitations, and Cardiac Surgery
and Combination of Beta-Blocker and There are various paroxysmal supraventricular arrhythmias,
Nondihydropyridine Calcium Antagonist ventricular arrhythmias, and other tachy-arrhythmias with an
Rapid atrial fibrillation is treated with a beta-blocker or a indication for beta-blocker treatment not specifically men-
nondihydropyridine calcium channel blocker such as dil- tioned or described in the 2018 ESC/ESH hypertension
tiazem or verapamil, although beta-blocker is the option guidelines.1 Patients are routinely given beta-blockers after
of choice if HF with reduced ejection fraction is involved, cardiodefibrillator implantation and in tachy-bradycardia syn-
because of the pronounced negative-inotropic effect of drome (after PM implantation) to suppress the attacks of
nondihydropyridine CCBs.29 Moreover, unlike beta-block- tachycardia and unneeded device activity. In absence of heart
ers, drug interactions must be considered when using disease, some people are bothered by unpleasant palpita-
verapamil or diltiazem, due to their inhibitory effect on drug tions, which may be associated with findings of X-systolic
transport mediated by P-glycoprotein and metabolism by beats or not, at the work up of the cardiologist. Although, no
the cytochrome P 450 3A4 enzyme. The latter may affect prognostic documentation is available, treatment with beta-
several other cardiovascular and noncardiovascular drugs‚ blockers may relieve symptoms. In the first days or even
including direct oral anticoagulants for which co-admin- longer after coronary artery by-pass graft surgery (CABG),
istration with nondihydropyridines would result in higher valve surgery or other major cardiac surgery the myocardium
drug levels and thereby increase bleeding risk.49 maybe particular sensitive to arrhythmias and beta-blocker
However, there are patients who do not respond sat- treatment has to be frequently used—whether patients have
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isfactorily to separate treatment with either drug class, in hypertension or not. Cardiology textbooks provide further
which a cautious use of their combination may be indicated. details on the conditions mentioned in this paragraph.
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 NONCARDIAC INDICATIONS FOR BETA-
feel uncomfortable. The combination of beta-blocker with BLOCKER TREATMENT RELATED TO THE
diltiazem or verapamil may also be a treatment alternative
to avoid the toxic side effects of amiodarone. Their admin-
PERIPHERAL CIRCULATION
istration alone or in combination may reduce symptoms There is a number of indications for beta-blocker treat-
and improve well-being in hypertensive patients with high ment related to the peripheral circulation (Table 3).
risk of atrial fibrillation who may have an increased LV mass
or LV hypertrophy, that is, conditions in which slowing heart
Emergency, Urgency, and Parenteral
rate down to <100 beats/min or lower (ideally <84 beats/
min) improves filling of the LV in diastole. Administration of Labetalol
One may wonder whether the combination of beta- For simplicity reasons, it is referred to textbooks.
blocker and nondihydropyridine CCB may cause an
excessive reduction of heart rate or even cardiac arrest.
However, in the NORDIL (Nordic Diltiazem) study, about
Perioperative Hypertension and Major
700 patients took this drug combination (mostly because Noncardiac Surgery
of crossover between open treatment arms) and syncope The 2017 ACC/AHA defines perioperative hyperten-
or need for pacemaker implantation was not reported.50 sion as a BP ≥160/90 mm Hg or a systolic BP eleva-
Because crossover between randomized study arms was tion ≥20% of the preoperative value that persists for
foreseen, the NORDIL investigators assessed the safety longer than 15 minutes. Beta-blockers is a first treat-
issue on beforehand. The question was whether the com- ment choice in patients undergoing vascular procedures
bination could cause severe bradycardia and/or cardiac or in those with an intermediate or high risk of cardiac
arrest. However, in clinical practice, the beta-blocker plus complications.52 Postcarotid endarterectomy hyperten-
diltiazem or plus verapamil combination treatment had not sion is a well-recognized phenomenon closely related to

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 Mancia et al Beta-Blockers in Hypertension

Table 3.  Indication for Beta-Blocker Treatment Related to and so is beta-blocker prescribing. Orthostatic or postural
Peripheral Circulation hypertension is a less well-known form of hypertension that
Emergency, urgency, and parenteral administration of labetalol occurs abruptly when someone moves into an upright posi-
tion. An increase in BP of 20 mm Hg or more when standing

Review
Perioperative hypertension
Major noncardiac surgery is the diagnostic criterion. In severe cases, orthostatic hyper-
Excessive pressor response to exercise and stress
tension can result in patients experiencing the same compli-
cations that they would with regular hypertension. However,
Hyperkinetic heart syndrome
in the majority of patients with orthostatic hypertension,
POTS
symptoms are only present in the upright position. Beta-
Orthostatic hypertension
blocker is a natural choice for treating postural orthostatic
Obstructive sleep apnea syndrome tachycardia syndrome57,58 while beta-blockers are used with
Peripheral arterial disease with claudication much less justification in the other orthostatic intolerance
Portal hypertension, cirrhosis-related oesophageal varices and recurrent variants including nonpostural orthostatic syndrome forms
variceal bleeding
of orthostatic hypertension. In other words, beta-blockers
Pregnancy related disorders (eclampsia, preeclampsia) do not directly influence orthostatic intolerance per se apart
POTS indicates postural orthostatic tachycardia syndrome. from postural orthostatic tachycardia syndrome.

surgical complications in which the perioperative use of

beta-blockers protects against the BP elevation and con- Obstructive Sleep Apnoea Syndrome
tributes to stabilizing the postoperative peak systolic BP This syndrome is of interest to various medical fields. It
for days after the intervention.53 Beta-blocker treatment is certainly of interest in the present context because
is also widely used for any type of major noncardiac sur- obstructive sleep apnoea is common in obese hyper-
gery associated with an increased response to the stress- tensive patients in whom it further activates the sym-
ful condition or environment, which can make the body pathetic nervous system. This justifies treatment with
vulnerable to untoward outcomes. Beta-blockers attenu- beta-blockers.
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,
Peripheral Arterial Disease with Claudication
if pronounced, may cause very low BP and heart rate.54 Peripheral arterial disease with claudication, the smokers’
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Thus, beta-blocker use for major noncardiac surgery is leg, is a common condition characterized by ischemia of
controversial unless patients have known cardiac disease skeletal muscle tissue in the lower limbs, caused by exten-
including history and findings by presurgical assessment. 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
Excessive Pressor Response to Exercise with beta-blocker on this indication. Smokers frequently
and Mental Stress and Hyperkinetic Heart have COPD. One should always be alert regarding wors-
Syndrome ening of pulmonary function (increased airway resistance)
Excessive elevations of BP induced by physical exercise when treating patients with peripheral artery disease with
and/or mental stress and beta-blocker treatment may be beta-blockers (Table 5). Nonselective beta-blockers such as
a good choice.55 propranolol or timolol seem to be worse compared to the
Hyperkinetic heart syndrome may occur in some hyper- selective beta-1 blockers, or alpha-beta blockers. We refer
tensive individuals who have a higher heart rate and stroke to the section on COPD in the text below.
volume at rest and thus a higher cardiac output than hyper-
tensive patients without this particular syndrome. There- Portal Hypertension, Liver Cirrhosis–Related
fore, BP is high although peripheral resistance is lower
Oesophageal Varices, and Recurrent Variceal
than normal. After beta-adrenergic blockade,56 heart rate
and cardiac output decrease, whereas peripheral resis- Bleeding
tance increases. Mean BP mostly remains unchanged. Treatment with beta-blockers is widely recommended
because these drugs lower the portal pressure and pre-
vent life-threatening bleedings.60
Postural Orthostatic Tachycardia Syndrome and
Orthostatic or Postural Hypertension
Postural orthostatic syndrome is characterized by an exces-
Pregnancy-Related Disorders (Eclampsia,
sive tachycardia, quantified as either an increase of 30 beats Preeclampsia)
per minute or as a rate of >120 beats per minutes after up to In hypertension in pregnancy and pregnancy-related dis-
half an hour of standing. Distressing symptoms are common orders (eg, preeclampsia and eclampsia), blockers of the

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 Mancia et al Beta-Blockers in Hypertension

renin-angiotensin system and diuretics are not recom- Table 5.  Various Problems With the Use of Beta-Blockers to
mended,1 while alpha-methyldopa, nifedipine, and the Treat Concomitant Diseases and Disorders in the Treatment
of Hypertension
unique beta-blocker labetalol with an additional alpha-
blocking mode of action are recommended as first treat- Nonselective beta- Worsening of bronchial asthma (increased airway resis-
Review

blockers tance) (also with low beta-1 selectivity as for atenolol)

ment choice.61 However, as recently emphasized, these
Nonselective beta- Male impotency—may choose vasodilating beta-
therapeutic options are based on small individual investi-
blockers blocker
gations and recommendations vary between national and
Nonselective beta- Lower HDL cholesterol, increase TG, may cause
international guidelines, while there is no clear evidence blockers type-2 diabetes
that one drug is preferable to another.1 This applies also Nonselective timolol Bradycardia, occasional need for pacemaker, in gen-
to other beta-blockers including metoprolol and bisopro- eral lowering heart rate too much in the elderly with
lol, which are considered to be safe in pregnancy and are beta-blocker treatment may cause serious adverse
event (Supplemental Material S7)
used in many European countries, particularly in countries
in which labetalol is not available (eg, Germany), due to Nonselective sotalol Occasional proarrhythmic effect limits the use

its hepatotoxic effect that may also occur in pregnancy.62 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

INDICATIONS FOR BETA-BLOCKER blockers unpleasant dreaming

Beta-1 selective Ultra-short acting, emergency use only
TREATMENT NOT DIRECTLY RELATED esmolol
TO THE HEART OR PERIPHERAL Beta-1 selective Inferior in 2 RCTs (vs losartan, LIFE, and vs amlo-

CIRCULATION atenolol dipine, ASCOT) and untoward metabolic effects like

nonselective beta-blockers indicated above
There is a number of indications for beta-blocker treat- Beta-blockers in May mask symptoms of hypoglycemia and thus
ment not directly related to the heart or peripheral circu- type-1 diabetes impair awareness particularly in patients with type-1
diabetes or patients treated with insulin
lation (Table 4).
Beta-blockers in Labetalol and metoprolol considered safe
pregnancy

Chronic Obstructive Pulmonary Disease ASCOT indicates Anglo-Scandinavian Cardiac Outcomes Trial; HDL, high-
density lipoprotein; LIFE, Losartan Intervention for End Point Reduction in Hyper-
As a general warning, one should always be alert for tension; RCT, randomized controlled trial; and TG, triglycerides.
worsening of pulmonary function with increased airway
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resistance when giving beta-blockers to patients with beta-blockers (including both beta1- selective and non-
pulmonary diseases (Table 5). selective agents) in patients with COPD and cardiovas-
Patients with COPD frequently have coronary heart cular disease is not only safe but also reduces their all
disease or peripheral arterial disease because of their cause and in-hospital mortality. Of interest, this analy-
smoking habits. However, patients with COPD have sis indicated also that beta1-selective beta-blockers
frequently been excluded from treatment with beta- may even reduce COPD exacerbations.65 In addition,
blockers, because of the unjustified fear that block- cardio-selective beta-blockers do not affect the action
ing beta2-receptors in the bronchial system could put of bronchodilators but reduce the heart rate accel-
these patients at risk. This was pointed out many years eration caused by their use.65 It should be mentioned,
ago22,63 and reiterated more recently.51 Importantly, a however, that patients with classical pulmonary asthma
recent meta-analysis64 demonstrated that the use of may worsen their condition by use of nonselective beta-
blockers or agents with low beta1-selectivity.
Table 4.  Other Indications for Beta-Blocker Treatment Not
Directly Related to the Heart or Peripheral Circulation Diabetes
COPD Patients with diabetes may occasionally experience
Diabetes hypoglycemia and thus impaired awareness particularly
Thyrotoxicosis, hyperthyroidism, thyroiditis, and Graves’ disease in patients with type 1 diabetes or patients treated with
Hyperparathyroidism in uremia insulin (Table 5). Beta-blockers in general may mask
Migraine headache symptoms of hypoglycemia, which are activation of the
Essential tremor
sympathetic nervous system including tachycardia. How-
ever, patients with diabetes may because of neuropathy,
Glaucoma
have silent ischemia in their myocardium and elsewhere
Performance anxiety and anxiety disorders
and may benefit from beta-blocker treatment. Because of
Olympic sports (negative) as doping and sabotage
an extensive destruction of the microcirculation type 2 dia-
Psychiatric disorders (posttraumatic stress) betes is also a main cause of HF and, though not proven
COPD indicates chronic obstructive pulmonary disease. specifically, probably the cause of the high prevalence

1160   June 2022 Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020

 Mancia et al Beta-Blockers in Hypertension

of type-2 diabetes in patients with HFpEF and one of Glaucoma

the reasons for the increasing concomitant use of beta-
Topical beta-blockers reduce intraocular pressure by
blockers in RCTs of HFpEF medications (Figure 2).
decreasing the production of aqueous humor. Oral beta-
First and second generation beta-blockers are asso-

Review
blockers also reduce intraocular pressure, but they are
ciated with increased incidence of new onset diabetes
not used primarily to treat or prevent glaucoma because
shown in several RCTs including in LIFE7 and ASCOT
of the systemic effects. If used for other indications, for
(Anglo-Scandinavian Cardiac Outcomes Trial).8 The
example, hypertension or cardiac disease, lower intraocu-
importance of such findings is uncertain as it could sim-
lar pressure may be a major additional benefit especially
ply be earlier de-masking of latent type-2 diabetes which
in the elderly. However, in the elderly both topical and
would then receive more intensified preventive treat-
systemic co-administration of beta-blockers is frequently
ment. First- and second-generation beta-blockers are
observed71 and may result in additive effects including
also associated with apparently unfavorable changes in
the risk of bradycardia. Hence, topical administration of
blood lipids (Table 5).
timolol eye drops72 is a potent treatment for glaucoma
that may cause bradycardia and other systemic effects.
Thyrotoxicosis, Hyperthyroidism, Thyroiditis, Some patients with a strong need of timolol against glau-
and Grave’s Disease coma may even need pacemaker implantation because
of the associated bradycardia.
In patients with thyrotoxicosis (thyroid storm) or symp-
tomatic hyperthyroidism, thyroiditis, and Graves’ disease,
the excess of thyroid hormone production and secretion Anxiety Disorders and Performance Anxiety
may result in increased heart rate, tremor, and nervous- In psychiatry, beta-blockers are used in the treatment of
ness. Propranolol is the most widely studied nonselec- anxiety disorders with somatic manifestations such as
tive beta-blocker to treat the increased heart rate and palpitations, sweating, and tremor.73 As such, performance
tremor under these circumstances.65 Beta-blocker may anxiety that may affect public speakers, musicians, or
additionally reverse some of the reduced systemic vas- those taking an examination also seem to be well suited
cular resistance associated with the hormonal disease for beta-blocker treatment. Beta-blockers have a relaxing
and inhibit the peripheral conversion of T4 to the more effect on muscle function, gaining the drug class a popular
biologically active hormone, T3.66 The American Asso- reputation as illegal, performance-enhancement drugs for
ciation of Clinical Endocrinologists Medical Guidelines
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athletes who benefit from the adrenaline-blocking effects

for the Evaluation and Treatment of Hyperthyroidism of the medication. Some athletes use propranolol specifi-
and Hypothyroidism67 have for many years discussed cally for its anxiety-reducing effects, resulting in steadier
the use of beta-blockers in conditions characterized by hands, an even heart rate and an increased ability to focus.
an excess of thyroid hormones without specifically rec- From 2010, beta-blockers were banned by the World Anti-
ommending one beta-blocker over another. Doping Agency for all Olympic sports, including archery,
gymnastics, shooting, and golf.74 Athletes who need beta-
Hyperparathyroidism in Uremia blockers for other indications must therefore stop taking
this treatment for several days (depending on the halflife
Various beta-blockers suppress PTH secretion in patients
of agents) before competition. Further, regarding sport
with uremia and hyperparathyroidism.68
activities, timolol eye drops are so potent that mixed in
sport drinks they ruin chances of high-level performance
Migraine Headache (and for example Olympic medals in runners).
Beta-blockers may prevent migraine or reduce the sever-
ity of attacks. Efficacy has been established for metopro- Panic Disorder
lol, propranolol, and timolol, it is probable for atenolol and
In panic disorder, beta-blockers are commonly pre-
nadolol, and possible for nebivolol and pindolol. Timo-
scribed75 for symptom relief, combined with cognitive
lol and propranolol are Food and Drug Administration
behavior therapy and/or a selective serotonin reuptake
approved for migraine prevention69 while off label (unap-
inhibitors and/or a benzodiazepine. This joins perfor-
proved) use of metoprolol is also common.
mance anxiety as a psychiatric comorbidity treated with
beta-blockade.
Essential Tremor
Propranolol has been used to treat essential tremor for Posttraumatic Stress Disorder
more than 40 years. Other beta-blockers, for example, The National Institute of Mental Health (Bethesda,
metoprolol, may also be effective depending on the MD) reports that approximately 5.2 million Americans
case.70 experience posttraumatic stress disorder each year.76

Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020 June 2022   1161

 Mancia et al Beta-Blockers in Hypertension

Posttraumatic stress disorder can be severely debilitat- point does not affect the main message of this article.
ing and diminish quality of life for patients and those However, it could be of interest in the future to inves-
who care for them. Studies have indicated that beta- tigate in details fractions of hypertensive patients who
blocker treatment reduces consolidation of emotional suffer from the various concomitant diseases.
Review

memory. When administered immediately after a psy- It is quite striking that beta-blocker treatment is indi-
chic trauma, it is efficacious as a prophylactic for post- cated in common diseases such as COPD22,63–65 and
traumatic stress disorder.77 peripheral arterial disease. For many years, physicians
and the RCTs that were performed excluded patients with
these diseases from therapy with beta-blockers. Rea-
DISCUSSION sons could be for example lack of separation between
We have scrutinized the medical field for diseases and pulmonary asthma and COPD—2 very different diseases
conditions for which beta-blocker treatment is indicated of the lungs.
in patients with hypertension. Tables 1 to 4 summarize Overall‚ beta-blockade is a key principle of treatment
our findings‚ that there are roughly 50 different diseases in medicine. Beta-blockers inhibit the actions of adrena-
and conditions documented to benefit from beta-blocker line and noradrenaline in various organs and systems as
treatment. Thus, an overwhelming number of diseases schematically shown in Figure 3. This holds true from
and conditions needs consideration for beta-blocker classic physiology with the fright, fight, and flight reac-
treatment in patients with hypertension compared with tion to mostly chronic diseases on which beta-receptor
those few key indications mentioned up front in the stimulation has a worsening effect. Beta-blocker treat-
guidelines.1 In general, as a thumb rule, beta-blockers ment has been investigated in hypertension and heart
with higher beta1-selectivity are indicated in a large num- disease RCTs together with numerous other cardiovas-
ber of cardiovascular diseases while nonselective beta- cular drugs that lower BP at the same time, which we
blockers are indicated for endocrine diseases, anxiety, have illustrated in Figure 4. Beta-blockers provide docu-
and other psychiatric disorders and more when the aim mented cardiovascular prevention together with several
of the beta-blocker treatment is to target noncardiovas- other drugs and in particular together with diuretics of
cular tissue in general. However, this is not always so the thiazide/thiazide-like type. In fact, the overwhelm-
clear-cut and we have not aimed to discuss this topic in ing evidence for combination therapy with beta-blockers
detail as we feel it is beyond the question of beta-blocker comes from beta-blockers plus diuretics (Supplemental
as first choice in the treatment of hypertension. Material S7). It is also good clinical practice to combine
Downloaded from http://ahajournals.org by on June 26, 2023

There are also problems related to treatment with beta-blockers with other cardiovascular drugs, for exam-
beta-blockers, which are important to highlight, and which ple, dihydropyridine CCBs by buffering reflex tachycar-
we have touched upon in this review. We have summa- dia. There is usually close connection with drugs that
rized the most common problems in Table 5 and partly work in HF with those drugs that provide cardiovas-
also mentioned how to resolve them when they appear. cular prevention in hypertension. Angiotensin receptor
Although observational data from the RCTs clearly show blocker neprilysin inhibitor, mineralocorticoid receptor
morbidity and mortality benefits of keeping heart rate antagonist, and SGLT2i (sodium glucose cotransporter
below approximately 80 to 84 beats/min, lowering heart 2 inhibitor) are drug classes that never have been inves-
rate further below 70 toward 60 beats/min in the elderly tigated for end point prevention in patients with hyper-
hypertensive patients may be related to serious adverse tension without HF or diabetes; however, all these drugs
and even cardiovascular events and should be prohibited lower BP substantially, and they have powerful protec-
(Supplemental Material S6). tive effects in HF of mostly hypertensive etiology. The
Our main point is that beta-blocker treatment is Food and Drug Administrations in the United States has
indicated for numerous diseases and conditions that approved angiotensin receptor blocker neprilysin inhibi-
patients may suffer from concomitant with hyperten- tor, mineralocorticoid receptor antagonist, and SGLT2i
sion. In a time developing toward personalized medi- for treatment of HF irrespective of LV ejection fraction. It
cine, there are multiple opportunities for targeting both means that these drugs lower hospitalizing and mortality
hypertension and the concomitant disease with the in patients with HFpEF, related to hypertension in 90%
same treatment namely a beta-blocking drug. Hyper- of these patients or more. Beta-blockers have been less
tension is a risk factor for more or less all cardiac and studied in HFpEF but as shown in Figure 2 the heart
vascular diseases, which we have reviewed, and hyper- specialist investigators in the HF RCTs gave almost all
tension may result from some of the other diseases the study participants concomitant beta-blocker treat-
such as hyperthyroidism. This means that more patients ment on clinical indications.
with hypertension have these concomitant diseases Regarding the 2018 ESC/ESH Hypertension
and conditions than have people with normal BP. This is Guidelines,1 it intuitively feels incorrect that beta-
a general statement from our side, which we have not blocker treatment was removed from the first-
attempted to support with exact data in as much as this choice treatment in the core-treatment strategy for

1162   June 2022 Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020

 Mancia et al 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.

uncomplicated hypertension, that is, in patients without CCBs diltiazem and verapamil care should be taken if
specific indications including cardiac conditions and in suspected HF is involved because of combined nega-
younger women with or planning pregnancy.1 There are tive chronotropic and inotropic effects, but for heart
numerous additional indications for beta-blocker treat- rate control in uncontrolled rapid atrial fibrillation, a
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ment in hypertension, which need assessment before common cause of hospitalization, this combination may
any decision of not giving beta-blocker for hyperten- be excellent.50,51
sion. Frequently, the choice would then be that the Regarding hypertension and renal disease, it is well
physicians will prescribe beta-blocker, and we wonder known that beta-blockers are well tolerated and do not
whether a more positive attitude for beta-blocker as deteriorate renal function. It has not been extensively
first choice should be indicated up front in the guide- investigated, but some data suggest that renal tissue
lines.1 Beta-blocker may be combined with all other oxygenations improves if patients with hypertension and
BP lowering drugs; regarding the nondihydropyridine 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.

Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020 June 2022   1163

 Mancia et al Beta-Blockers in Hypertension

In conclusion, we suggest that beta-blockers as a randomised trial against atenolol. Lancet. 2002;359:995–1003. doi:
10.1016/S0140-6736(02)08089-3
a group of BP lowering medication should again be 8. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M,
included in the first choice armamentarium of available Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al; ASCOT Inves-
antihypertensive drugs by the guidelines. tigators. Prevention of cardiovascular events with an antihypertensive
Review

regimen of amlodipine adding perindopril as required versus atenolol

adding bendroflumethiazide as required, in the Anglo-Scandinavian Car-
diac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a
ARTICLE INFORMATION multicentre randomised controlled trial. Lancet. 2005;366:895–906. doi:
10.1016/S0140-6736(05)67185-1
Affiliations
9. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P,
University of Milano-Bicocca, Milan, Italy (G.M., G.G.). Department of Cardiology, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, et al;
University of Oslo, Ullevaal Hospital, Norway (S.E.K.). Charité – Universitätsmed- INVEST Investigators. A calcium antagonist vs a non-calcium antago-
izin Berlin, Institute of Clinical Pharmacology and Toxicology, Germany (R.K.). nist hypertension treatment strategy for patients with coronary artery
Department of Cardiology, Centre Hospitalier Princesse Grace, Monte Carlo, disease. The International Verapamil-Trandolapril Study (INVEST):
Monaco (A.P.). Human Neurotransmitters Laboratory, Baker Heart and Diabetes a randomized controlled trial. JAMA. 2003;290:2805–2816. doi:
Institute, and Monash University, Melbourne, Australia (M.E.). 10.1001/jama.290.21.2805
10. Wilhelmsen L, Berglund G, Elmfeldt D, Fitzsimons T, Holzgreve H, Hosie J,
Acknowledgments Hörnkvist PE, Pennert K, Tuomilehto J, Wedel H. Beta-blockers versus diuret-
We thank the Centre Hospitalier Princesse Grace, Monte Carlo, Monaco for gen- ics in hypertensive men: main results from the HAPPHY trial. J Hypertens.
erously paying for author payment charges. 1987;5:561–572. doi: 10.1097/00004872-198710000-00009
11. Wikstrand J, Warnold I, Tuomilehto J, Olsson G, Barber HJ, Eliasson K,
Sources of Funding Elmfeldt D, Jastrup B, Karatzas NB, Leer J. Metoprolol versus thiazide diuret-
The present work had no funding or secretarial assistance. ics in hypertension. Morbidity results from the MAPHY Study. Hypertension.
1991;17:579–588. doi: 10.1161/01.hyp.17.4.579
Disclosures 12. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year fol-
G. Mancia has received honoraria from Astra Zeneca, Boehringer Ingelheim, low-up of intensive glucose control in type 2 diabetes. N Engl J Med.
Daiichi Sankyo, Medtronic, Menarini, Merck, Novartis, Recordati, Sandoz, Sanofi 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470
and Servier. S.E. Kjeldsen reports lecture honoraria from Getz Pharma, Merck 13. Hansson L, Lindholm LH, Ekbom T, Dahlöf B, Lanke J, Scherstén B,
Healthcare KGaA, Sanofi-Aventis and Vector-Intas. R. Kreutz reports support for Wester PO, Hedner T, de Faire U. Randomised trial of old and new anti-
research by Bayer, honoraria for lectures from Bayer, Berlin-Chemie/Menarini, hypertensive drugs in elderly patients: cardiovascular mortality and mor-
Daiichi Sankyo, Ferrer, Merck, Sanofi and Servier. A. Pathak has received hono- bidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet.
raria from Ablative Solution, Air Liquide, Astra Zeneca, Boehringer Ingelheim, 1999;354:1751–1756. doi: 10.1016/s0140-6736(99)10327-1
Medtronic, Menarini, Merck, Novartis, Recordati, Recor Medical, Sanofi and Ser- 14. Medical Research Council Working Party. MRC trial of treatment of
vier. G. Grassi has received honoraria for lectures from Medtronic, Merck Health- mild hypertension: principal results. Br Med J. 1985;291:97–104. doi:
care KGaA, and Servier. M. Esler reports honoraria for participating in the Renal 10.1136/bmj.291.6488.97
Denervation advisory boards of Medtronic (United States) and SyMap (China). 15. Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C,
Chalmers J, Fagard R, Gleason A, et al; Blood Pressure Lowering Treat-
Downloaded from http://ahajournals.org by on June 26, 2023

ment Trialists’ Collaboration. Blood pressure-lowering treatment based

on cardiovascular risk: a meta-analysis of individual patient data. Lancet.
REFERENCES 2014;384:591–598. doi: 10.1016/S0140-6736(14)61212-5
1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, 16. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J,
Clement DL, Coca A, de Simone G, Dominiczak A, et al; Authors/Task Force Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention
Members. 2018 ESC/ESH Guidelines for the management of arterial hyper- of cardiovascular disease and death: a systematic review and meta-analysis.
tension: The Task Force for the management of arterial hypertension of the Lancet. 2016;387:957–967. doi: 10.1016/S0140-6736(15)01225-8
European Society of Cardiology and the European Society of Hypertension: 17. Thomopoulos C, Bazoukis G, Tsioufis C, Mancia G. Beta-blockers in hyper-
the Task Force for the management of arterial hypertension of the European tension: overview and meta-analysis of randomized outcome trials. J Hyper-
Society of Cardiology and the European Society of Hypertension. J Hyper- tens. 2020;38:1669–1681. doi: 10.1097/HJH.0000000000002523
tens. 2018;36:1953–2041. doi: 10.1097/HJH.0000000000001940 18. Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C,
2. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Chalmers J, Fagard R, Gleason A, et al; Blood Pressure Lowering Treat-
Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, ment Trialists’ Collaboration. Effects of different regimens to lower blood
et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ pressure on major cardiovascular events in older and younger adults:
NMA/PCNA Guideline for the prevention, detection, evaluation, and meta-analysis of randomised trials. Br Med J. 2008;336:1121–1123. doi:
management of high blood pressure in adults: a report of the american 10.1136/bmj.39548.738368.BE
college of cardiology/american heart association task force on clini- 19. Mancia G, Zanchetti A; European Society of Hypertension-European Soci-
cal practice guidelines. J Am Coll Cardiol. 2018;71:e127–e248. doi: ety of Cardiology. Choice of antihypertensive drugs in the European Society
10.1016/j.jacc.2017.11.006 of Hypertension-European Society of Cardiology guidelines: specific indica-
3. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez tions rather than ranking for general usage. J Hypertens. 2008;26:164–
A, Schlaich M, Stergiou GS, Tomaszewski M, et al. 2020 International soci- 168. doi: 10.1097/HJH.0b013e3282f52fa8
ety of hypertension global hypertension practice guidelines. Hypertension. 20. Riemer TG, Villagomez Fuentes LE, Algharably EAE, Schäfer MS,
2020;75:1334–1357. doi: 10.1161/HYPERTENSIONAHA.120.15026 Mangelsen E, Fürtig MA, Bittner N, Bär A, Zaidi Touis L, Wachtell K, et al.
4. Jones NR, McCormack T, Constanti M, McManus RJ. Diagnosis and man- Do β-blockers cause depression? Systematic review and meta-analysis
agement of hypertension in adults: NICE guideline update 2019. Br J Gen of psychiatric adverse events during β-blocker therapy. Hypertension.
Pract. 2020;70:90–91. doi: 10.3399/bjgp20X708053 2021;77:1539–1548. doi: 10.1161/HYPERTENSIONAHA.120.16590
5. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination 21. Farmakis IT, Pyrgidis N, Doundoulakis I, Mykoniatis I, Akrivos E,
treatment with blood pressure lowering drugs: analysis of 354 randomised Giannakoulas G. Effects of major antihypertensive drug classes on erectile
trials. BMJ. 2003;326:1427. doi: 10.1136/bmj.326.7404.1427 function: a network meta-analysis [published online May 4, 2021]. Cardio-
6. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on vasc Drugs Ther. doi: 10.1007/s10557-021-07197-9. https://link.springer.
outcome incidence in hypertension: 4. Effects of various classes of antihy- com/article/10.1007/s10557-021-07197-9
pertensive drugs–overview and meta-analyses. J Hypertens. 2015;33:195– 22. Hawkins NM, Petrie MC, Macdonald MR, Jhund PS, Fabbri LM,
211. doi: 10.1097/HJH.0000000000000447 Wikstrand J, McMurray JJ. Heart failure and chronic obstructive pulmonary
7. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, disease the quandary of Beta-blockers and Beta-agonists. J Am Coll Cardiol.
Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, et al; 2011;57:2127–2138. doi: 10.1016/j.jacc.2011.02.020
LIFE Study Group. Cardiovascular morbidity and mortality in the Losar- 23. Espinola-Klein C, Weisser G, Jagodzinski A, Savvidis S, Warnholtz A,
tan Intervention For Endpoint reduction in hypertension study (LIFE): Ostad MA, Gori T, Munzel T. β-Blockers in patients with intermittent

1164   June 2022 Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020

 Mancia et al Beta-Blockers in Hypertension

claudication and arterial hypertension: results from the nebivolol or meto- 41. Olsen MH, Wachtell K, Meyer C, Hove JD, Palmieri V, Dige-Petersen H,
prolol in arterial occlusive disease trial. Hypertension. 2011;58:148–154. Rokkedal J, Hesse B, Ibsen H. Association between vascular dysfunction and
doi: 10.1161/HYPERTENSIONAHA.110.169169 reduced myocardial flow reserve in patients with hypertension: a LIFE sub-
24. Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ study. J Hum Hypertens. 2004;18:445–452. doi: 10.1038/sj.jhh.1001716
Res. 2014;114:1804–1814. doi: 10.1161/CIRCRESAHA.114.302524 42. Sucato V, Testa G, Puglisi S, Evola S, Galassi AR, Novo G. Myocardial infarc-

Review
25. Grassi G, Mark A, Esler M. The sympathetic nervous system altera- tion with non-obstructive coronary arteries (MINOCA): Intracoronary imag-
tions in human hypertension. Circ Res. 2015;116:976–990. doi: ing-based diagnosis and management. J Cardiol. 2021;77:444–451. doi:
10.1161/CIRCRESAHA.116.303604 10.1016/j.jjcc.2021.01.001
26. Mancia G, Masi S, Palatini P, Tsioufis C, Grassi G. Elevated heart rate and 43. Leren IS, Saberniak J, Majid E, Haland TF, Edvardsen T, Haugaa KH. Nado-
cardiovascular risk in hypertension. J Hypertens. 2021;39:1060–1069. doi: lol decreases the incidence and severity of ventricular arrhythmias during
10.1097/HJH.0000000000002760 exercise stress testing compared with β1-selective β-blockers in patients
27. Grassi G, Quarti-Trevano F, Seravalle G, Dell’Oro R, Facchetti R, with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm.
Mancia G. Association between the European Society of Cardiology/Euro- 2016;13:433–440. doi: 10.1016/j.hrthm.2015.09.029
pean Society of Hypertension heart rate thresholds for cardiovascular 44. Kaufman ES, Eckhardt LL, Ackerman MJ, Aziz PF, Behr ER, Cerrone M,
risk and neuroadrenergic markers. Hypertension. 2020;76:577–582. doi: Chung MK, Cutler MJ, Etheridge SP, Krahn AD, et al. Management of con-
10.1161/HYPERTENSIONAHA.120.14804 genital long-QT syndrome: commentary from the experts. Circ Arrhythm Elec-
28. Esler M, Lambert G, Esler D, Ika Sari C, Guo L, Jennings G. Evalua- trophysiol. 2021;14:e009726. doi: 10.1161/CIRCEP.120.009726
tion of elevated heart rate as a sympathetic nervous system biomarker 45. Wang M, Peterson DR, Rosero S, McNitt S, Rich DQ, Seplaki CL, Polonsky B,
in essential hypertension. J Hypertens. 2020;38:1488–1495. doi: Goldenberg I, Zareba W. Effectiveness of implantable cardioverter-defibrilla-
10.1097/HJH.0000000000002407 tors to reduce mortality in patients with long QT syndrome. Am Coll Cardiol.
29. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, 2021;78:2076–2088. doi: 10.1016/j.jacc.2021.09.017
Burri H, Butler J, Čelutkienė J, Chioncel O, et al; ESC Scientific Document 46. Loncaric F, Nunno L, Mimbrero M, Marciniak M, Fernandes JF, Tirapu L,
Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and Fabijanovic D, Sanchis L, Doltra A, Cikes M, et al. Basal ventricular septal
chronic heart failure. Eur Heart J. 2021;42:3599–3726. doi: 10.1093/ hypertrophy in systemic hypertension. Am J Cardiol. 2020;125:1339–1346.
eurheartj/ehab368 doi: 10.1016/j.amjcard.2020.01.045
30. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, 47. Anderson JL. Treatment of cardiac myopathies with beta blockers. What
Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, et al; SENIORS do we know, where do we go from here? Postgrad Med. 1988;Spec
Investigators. Randomized trial to determine the effect of nebivolol No:104–112.
on mortality and cardiovascular hospital admission in elderly patients 48. Dybro AM, Rasmussen TB, Nielsen RR, Andersen MJ, Jensen MK,
with heart failure (SENIORS). Eur Heart J. 2005;26:215–225. doi: Poulsen SH. randomized trial of metoprolol in patients with obstructive
10.1093/eurheartj/ehi115 hypertrophic cardiomyopathy. J Am Coll Cardiol. 2021;78:2505–2517. doi:
31. Ambrosio G, Flather MD, Böhm M, Cohen-Solal A, Murrone A, Mascagni F, 10.1016/j.jacc.2021.07.065
Spinucci G, Conti MG, van Veldhuisen DJ, Tavazzi L, et al. β-blockade with 49. Fauchier L, Boriani G, de Groot JR, Kreutz R, Rossing P, Camm AJ. Medical
nebivolol for prevention of acute ischaemic events in elderly patients with therapies for prevention of cardiovascular and renal events in patients with
heart failure. Heart. 2011;97:209–214. doi: 10.1136/hrt.2010.207365 atrial fibrillation and diabetes mellitus. Europace. 2021;23:1873–1891. doi:
32. Kjeldsen SE, von Lueder TG, Smiseth OA, Wachtell K, Mistry N, 10.1093/europace/euab184
Westheim AS, Hopper I, Julius S, Pitt B, Reid CM, et al. Medical thera- 50. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH,
pies for heart failure with preserved ejection fraction. Hypertension. Syvertsen JO, Lanke J, de Faire U, Dahlöf B, Karlberg BE. Randomised
Downloaded from http://ahajournals.org by on June 26, 2023

2020;75:23–32. doi: 10.1161/HYPERTENSIONAHA.119.14057 trial of effects of calcium antagonists compared with diuretics and beta-
33. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, blockers on cardiovascular morbidity and mortality in hypertension: the
Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, et al; I-PRE- Nordic Diltiazem (NORDIL) study. Lancet. 2000;356:359–365. doi:
SERVE Investigators. Irbesartan in patients with heart failure and pre- 10.1016/s0140-6736(00)02526-5
served ejection fraction. N Engl J Med. 2008;359:2456–2467. doi: 51. Kjeldsen SE, Syvertsen JO, Hedner T. Cardiac conduction with diltiazem
10.1056/NEJMoa0805450 and beta-blockade combined. A review and report on cases. Blood Press.
34. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, 1996;5:260–263. doi: 10.3109/08037059609078057
Martinez F, Packer M, Pfeffer MA, Pieske B, et al; PARAGON-HF Inves- 52. Diercks DB, Ohman EM. Hypertension with acute coronary syndrome
tigators and Committees. Angiotensin-neprilysin inhibition in heart failure and heart failure. Ann Emerg Med. 2008;51(Suppl 3):S34–S36. doi:
with preserved ejection fraction. N Engl J Med. 2019;381:1609–1620. doi: 10.1016/j.annemergmed.2007.11.012
10.1056/NEJMoa1908655 53. Teng L, Fang J, Zhang Y, Liu X, Qu C, Shen C. Perioperative baseline β-blockers:
35. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, an independent protective factor for post-carotid endarterectomy hyperten-
Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, et al; sion. Vascular. 2021;29:270–279. doi: 10.1177/1708538120946538
EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with 54. Blessberger H, Lewis SR, Pritchard MW, Fawcett LJ, Domanovits H,
a preserved ejection fraction. N Engl J Med. 2021;385:1451–1461. doi: Schlager O, Wildner B, Kammler J, Steinwender C. Perioperative beta-block-
10.1056/NEJMoa2107038 ers for preventing surgery-related mortality and morbidity in adults undergo-
36. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, ing non-cardiac surgery. Cochrane Database Syst Rev. 2019;9:CD013438.
Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, et al; Beta- doi: 10.1002/14651858.CD013438
blockers in Heart Failure Collaborative Group. Beta-blockers for heart 55. François B, Cahen R, Gravejat MF, Estrade M. Do beta blockers prevent
failure with reduced, mid-range, and preserved ejection fraction: an indi- pressor responses to mental stress and physical exercise? Eur Heart J.
vidual patient-level analysis of double-blind randomized trials. Eur Heart J. 1984;5:348–353. doi: 10.1093/oxfordjournals.eurheartj.a061667
2018;39:26–35. doi: 10.1093/eurheartj/ehx564 56. Frohlich ED. Beta adrenergic blockade in the circulatory regulation of
37. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck- hyperkinetic states. Am J Cardiol. 1971;27:195–199. doi: 10.1016/
Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, et al; ESC Scientific 0002-9149(71)90258-x
Document Group. 2019 ESC Guidelines for the diagnosis and manage- 57. Abed H, Ball PA, Wang LX. Diagnosis and management of postural ortho-
ment of chronic coronary syndromes. Eur Heart J. 2020;41:407–477. doi: static tachycardia syndrome: a brief review. J Geriatr Cardiol. 2012;9:61–67.
10.1093/eurheartj/ehz425 doi: 10.3724/SP.J.1263.2012.00061
38. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality 58. Benowitz NL, Zevin S, Carlsen S, Wright J, Schambelan M, Cheitlin M. Ortho-
and reinfarction in patients surviving acute myocardial infarction. N Engl J static hypertension due to vascular adrenergic hypersensitivity. Hyperten-
Med. 1981;304:801–807. doi: 10.1056/NEJM198104023041401 sion. 1996;28:42–46. doi: 10.1161/01.hyp.28.1.42
39. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Málek I, Nyberg G, Rydén L, 59. Radack K, Deck C. β-Adrenergic blocker therapy does not worsen intermit-
Swedberg K, Vedin A, Waagstein F, et al; Effect on mortality of metopro- tent claudication in subjects with peripheral arterial disease. Arch Intern Med.
lol in acute myocardial infarction. A double-blind randomised trial. Lancet. 1991;151:1769–1776. doi: 10.1016/0741-5214(93)90757-D
1981;2:823–827. doi: 10.1016/s0140-6736(81)91101-6 60. Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, Austin A,
40. Freis ED. Hemodynamics of hypertension. Physiol Rev. 1960;40:27–54. Ferguson JW, Olliff SP, Hudson M, et al; Clinical Services and Standards
doi: 10.1152/physrev.1960.40.1.27 Committee of the British Society of Gastroenterology. U.K. guidelines

Hypertension. 2022;79:1153–1166. DOI: 10.1161/HYPERTENSIONAHA.122.19020 June 2022   1165

 Mancia et al Beta-Blockers in Hypertension

on the management of variceal haemorrhage in cirrhotic patients. Gut. 68. Makdassi R, Decourcelle PH, Moriniere P, Coevoet B, de Fremont JF,
2015;64:1680–1704. doi: 10.1136/gutjnl-2015-309262 Kassouf J, Roussel A, Gheerbrand JD, Andrejak M, Fournier A. Blockers of
61. Garovic VD, Dechend R, Easterling T, Karumanchi SA, McMurtry Baird S, beta and H2 receptors and secondary hyperparathyroidism in uraemia. Proc
Magee LA, Rana S, Vermunt JV, August P; American Heart Associa- Eur Dial Transplant Assoc. 1981;18:642–647.
tion Council on Hypertension; Council on the Kidney in Cardiovascular 69. Danesh A, Gottschalk PCH. Beta-blockers for migraine prevention: a
Review

Disease, Kidney in Heart Disease Science Committee; Council on Arte- review article. Curr Treat Options Neurol. 2019;21:20. doi: 10.1007/
riosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and s11940-019-0556-3
Cardiometabolic Health; Council on Peripheral Vascular Disease; and 70. Haubenberger D, Hallett M. Essential tremor. N Engl J Med. 2018;378:1802–
Stroke Council. Hypertension in pregnancy: diagnosis, blood pressure 1810. doi: 10.1056/NEJMcp1707928
goals, and pharmacotherapy: a scientific statement from the american 71. Huber M, Kölzsch M, Stahlmann R, Hofmann W, Bolbrinker J, Dräger
heart association. Hypertension. 2022;79:e21–e41. doi: 10.1161/HYP. D, Kreutz R. Ophthalmic drugs as part of polypharmacy in nursing home
0000000000000208 residents with glaucoma. Drugs Aging. 2013;30:31–38. doi: 10.1007/
62. Whelan A, Izewski J, Berkelhammer C, Walloch J, Kay HH. Labetalol-induced s40266-012-0036-x
hepatotoxicity during pregnancy: a case report. AJP Rep. 2020;10:e210– 72. Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, Wormald R,
e212. doi: 10.1055/s-0040-1713789 Dickersin K. Comparative effectiveness of first-line medications for primary
63. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality open-angle glaucoma: a systematic review and network meta-analysis.
among high-risk and low-risk patients after myocardial infarction. N Engl J Ophthalmology. 2016;123:129–140. doi: 10.1016/j.ophtha.2015.09.005
Med. 1998;339:489–497. doi: 10.1056/NEJM199808203390801 73. Lader M. Beta-adrenoceptor antagonists in neuropsychiatry: an update. J
64. Dransfield MT, Voelker H, Bhatt SP, Brenner K, Casaburi R, Come CE, Clin Psychiatry. 1988;49:213–223.
Cooper JAD, Criner GJ, Curtis JL, Han MK, et al; BLOCK COPD Trial Group. 74. Barnes KP, Rainbow CR. Update on banned substances 2013. Sports
Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Health. 2013;5:442–447. doi: 10.1177/1941738113478546
Med. 2019;381:2304–2314. doi: 10.1056/NEJMoa1908142 75. Das M. Panic disorder: propranolol and behavioural therapy. Br Med J.
65. Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL. Association 2006;332:1094. doi: 10.1136/bmj.332.7549.1094
of β-blocker use with survival and pulmonary function in patients with 76. Henry M, Fishman JR, Youngner SJ. Propranolol and the prevention of post-
chronic obstructive pulmonary and cardiovascular disease: a system- traumatic stress disorder: is it wrong to erase the “sting” of bad memories?
atic review and meta-analysis. Eur Heart J. 2020;41:4415–4422. doi: Am J Bioeth. 2007;7:12–20. doi: 10.1080/15265160701518474
10.1093/eurheartj/ehaa793 77. Brunet A, Saumier D, Liu A, Streiner DL, Tremblay J, Pitman RK. Reduc-
66. Sharma A, Stan MN. Thyrotoxicosis: diagnosis and management. Mayo Clin tion of PTSD symptoms with pre-reactivation propranolol therapy: a
Proc. 2019;94:1048–1064. doi: 10.1016/j.mayocp.2018.10.011 randomized controlled trial. Am J Psychiatry. 2018;175:427–433. doi:
67. Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, 10.1176/appi.ajp.2017.17050481
Segal RL; American Association of Clinical Endocrinologists. American 78. Hall ME, Rocco MV, Morgan TM, Hamilton CA, Jordan JH, Edwards MS,
Association of Clinical Endocrinologists medical guidelines for clinical prac- Hall JE, Hundley WG. Beta-blocker use is associated with higher renal tis-
tice for the evaluation and treatment of hyperthyroidism and hypothyroidism. sue oxygenation in hypertensive patients suspected of renal artery stenosis.
Endocr Pract. 2002;8:457–469. Cardiorenal Med. 2016;6:261–268. doi: 10.1159/000445302
Downloaded from http://ahajournals.org by on June 26, 2023

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