Role of Elevated Heart Rate in the Development of Cardiovascular Disease in

Hypertension
Paolo Palatini

Hypertension 2011, 58:745-750: originally published online September 6, 2011

doi: 10.1161/HYPERTENSIONAHA.111.173104
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 Brief Review
Role of Elevated Heart Rate in the Development of
Cardiovascular Disease in Hypertension
Paolo Palatini
● Online Data Supplement
T hat elevated heart rate (HR) is a risk factor for cardio-
vascular morbidity and mortality in healthy people as
well as in patients with cardiac diseases is supported by
numerous epidemiological association studies.1– 4 Increased
HR has been recognized as a negative prognostic factor
independent of many other clinical parameters that can
influence the HR, including physical activity scores, left
ventricular function, or use of ␤-blockers. Thus, HR appears
to satisfy all epidemiological criteria for being considered as
a true risk factor, and its predictive value for cardiovascular
disease appeared to be as strong as that of most important
cardiovascular risk factors. This is particularly true for the
results obtained in hypertensive patients. Elevated HR is a
common feature among hypertensive individuals.1 Among
the young hypertensive subjects participating in the HAR-
VEST study, ⬎15% had a baseline resting HR ⱖ85 bpm and
27% had a HR ⱖ80 bpm.5 According to the Tensiopulse
study, which evaluated 38 145 patients cared for by 2000
general practitioners all across Italy, ⬎30% of the hyperten-
sive patients had a resting HR ⱖ80 bpm.6 In a large French
population, untreated hypertensive subjects had approxi-
mately a 6-bpm faster HR than normotensive individuals.7
Elevated HR is frequently associated with high blood pres-
sure (BP) and metabolic disturbances and increases the risk of
new onset hypertension and diabetes.1 Many experimental
data obtained both in animals and in human beings support
the importance of HR as a true risk factor for atherosclerosis
and cardiovascular disease, providing convincing evidence
for this pathogenetic mechanism.1–3 The pathogenetic con-
nection between HR and cardiovascular disease has been
discussed in several reports1–3,8,9 and is beyond the scope of
this review.
High HR as a Precursor of Hypertension, Obesity,
and Diabetes
Numerous studies have demonstrated that tachycardia is
frequently associated with hypertension in both sexes and that
this relationship is present at all ages and all BP levels.1,10
This association remains significant even after taking into
account several confounding factors, such as body mass index
Received March 10, 2011; first decision April 10, 2011; revision accepted August 11, 2011.
From the Department of Clinical and Experimental Medicine, University of Padova, Padua, Italy.
Correspondence to Paolo Palatini, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. E-mail palatini@unipd.it
(Hypertension. 2011;58:745-750.)
© 2011 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
Downloaded from http://hyper.ahajournals.org/
745
(BMI), age, and metabolic parameters. HR has also emerged
as a risk factor for future development of hypertension. The
first study to demonstrate a longitudinal relationship between
HR and BP dates back to 1945, when an American army
doctor11 observed that transient tachycardia detected during
routine examination could predict the development of stable
hypertension later in life. The predictive power of HR for the
development of hypertension has been confirmed in numer-
ous other studies. In a Japanese cohort, normotensive men
and women with an HR in the upper quartile had a 60%
higher 3-year risk of developing hypertension than persons in
the bottom quartile.12 This longitudinal association has been
demonstrated not only for baseline HR but also for the change
in HR over time. In the HARVEST study, both baseline and
follow-up HRs were potent predictors of subsequent devel-
opment of hypertension needing drug therapy.5 In many
cross-sectional analyses, high HR was found to be associated
with increased BMI, higher glucose and lipid abnormalities,
and was considered as a key component of the metabolic
syndrome.10 However, it was unclear whether higher HR in
metabolic syndrome was a cause, consequence, or simply an
epiphenomenon. The results of 2 recent longitudinal analyses
have shown that elevated HR may predispose to the devel-
opment of obesity and diabetes mellitus.13,14 In the Chicago
study, higher resting HR was prospectively associated with
diabetes claims in older age, and this association was only
due in part to BMI and concurrently measured glucose.15 In
the Atherosclerosis Risk in Communities Study (ARIC),
higher HR and lower HR variability were both associated
with an increased likelihood of developing diabetes over 9
years of follow-up, even when concurrent BMI and physical
activity levels were taken into account.16 Thus, measurement
of HR can be of help for identifying subjects who are most
likely to develop hypertension, obesity, the metabolic syn-
drome, and diabetes.
The longitudinal association between increased HR, obe-
sity, and metabolic abnormalities probably reflects persistent
sympathetic stimulation.1,9,13,14 In longitudinal studies, it has
been demonstrated that plasma noradrenaline concentrations
predict both future BP elevation and weight gain in lean
normotensives.17 Previous results from our laboratory
showed that a sympathovagal balance in favor of sympathetic
activity against a background of reduced HR variability
DOI: 10.1161/HYPERTENSIONAHA.111.173104
by guest on October 28, 2011
746 Hypertension November 2011
promotes an increase in BMI, BP, and total cholesterol,
leading to increased susceptibility to vascular complications
early in life.18 Downregulation of adrenoceptor-mediated
thermogenic responses may be the mechanism by which
longstanding sympathetic overactivity may favor weight gain
in subjects with elevated sympathetic tone.19 In a previous
study, we demonstrated that both plasma and urinary nor-
adrenaline negatively correlated with HR response to isopro-
terenol bolus and with systolic BP and energy expenditure
responsiveness to isoproterenol infusion.20 The thermogenic
effect of sympathetic activity represents a physiological
compensatory mechanism against weight gain. This thermo-
genic effect is exerted through norepinephrine release with
stimulation of all 3 ␤-adrenoceptor subtypes, and an impair-
ment of this mechanism may be important in promoting and
maintaining excess body weight.19 The experimental evi-
dence for the linkage between increased sympathetic tone and
insulin resistance was provided by numerous studies. Epi-
nephrine infusion induces acute insulin resistance in healthy
volunteers, and this can be blocked by propranolol.21 In animals
chronically infused with epinephrine, a shift in skeletal muscle
fibers was observed, with an increase in rapidly contracting
fibers, which is associated with insulin resistance.22 Vasocon-
striction produced by ␣-adrenergic stimulation also induces
insulin resistance. This has been observed in studies con-
ducted by Jamerson et al23 on the forearm with infusion of
insulin into the brachial artery and determination of glucose
utilization. In this model, central sympathetic activation
elicited by thigh-cuff inflation was able to decrease glucose
utilization in the forearm. This points to a specific role of
vasoconstriction induced by sympathetic overactivity in de-
termining insulin resistance, probably diverting capillary
blood flow away from nutritional beds.
HR as a Determinant of Target Organ Damage
In the International Survey Evaluating Microalbuminuria
Routinely by Cardiologists in Patients with Hypertension
(I-SEARCH), investigating 21 050 patients with high-risk
hypertension, elevated HR was an independent predictor of
microalbuminuria.24 In a Japanese study, subjects with a
higher HR had higher frequencies of proteinuria, although
they were all normotensive, indicating that subjects with
elevated HR are likely to have early-stage vascular damage,
even if they are normotensive.25 In hypertensive patients
assessed with 24-hour ambulatory monitoring, Facila et al26
showed that patients with nocturnal HR ⱖ65 bpm (41.3%)
had a higher prevalence of target organ damage compared
with those with HR ⬍65 bpm. HR was also shown to be a
main determinant of arterial stiffness. Benetos et al,27 in a
6-year longitudinal study, found that increased HR was one of
the most powerful predictors of accelerated progression in
pulse-wave velocity. Interestingly, the greatest influence of
HR on the acceleration of arterial stiffness was observed in
the hypertensive segment of the population. In a recent report,
Tomiyama et al28 found that both HR at the baseline exam-
ination and changes in HR during the follow-up period were
significantly associated with the corresponding changes in
pulse-wave velocity during a 5-year follow-up. These rela-
tionships held true also after adjustment for a variety of
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atherogenic risk factors. In keeping with the above data, in a
group of young to middle-aged subjects with stage 1 hyper-
tension, Saladini et al29 found that high baseline HR and
increase in HR over time were independent determinants of
evolution of arterial stiffness.
HR as a Cardiovascular Risk Factor in
General Populations
A review of the literature showed that 33 articles had been
published on the prognostic significance of elevated HR for
cardiovascular and/or all-cause mortality in general popula-
tions. All but 1 article reported a significant association
between all-cause mortality and fast HR in men or women.1
After adjustment for confounders, 3 other studies failed to
reach the level of statistical significance for cardiovascular
mortality.1 However, in a more recent analysis of the Chicago
Heart Association Project Cohort, a significant relationship
between HR and cardiovascular mortality was found for men
and women 40 to 59 years of age, independent of other risk
factors.30 Likewise, a longer follow-up of the Paris Prospec-
tive Study showed an independent association of HR with
sudden death and fatal myocardial infarction after adjustment
for many confounders.31 In all the other studies performed in
subjects free of disease, the association of HR with total
and/or cardiovascular mortality remained significant after
adjustment for traditional risk factors for atherosclerosis and
other possible confounders. It should be pointed out that in
some of those studies the predictive power of HR for
mortality was higher than that of cholesterol and/or BP.1
HR as a Cardiovascular Risk Factor
in Hypertension
A systematic review of the literature identified 12 articles
encompassing 11 studies on the association between HR and
mortality in hypertension4,32– 42 (see the online Data Supple-
ment, available at http://hyper.ahajournals.org). Details of the
11 studies are shown on Table S1 (please see http://hyper.
ahajournals.org). The size of these studies varied from 2293
to 60 343 patients (overall number, 184 157 patients), with
duration of follow-ups from 2.5 to 36 years. Mean patient age
ranged from 51 to 70.2 years and was ⬎65 years in 5 studies.
The percentage of men ranged from 33% to 77% in 10 studies
and was 100% in 1 study. One cohort study enrolled subjects
with prehypertension and 4 cohort studies recruited subjects
with hypertension. The 6 clinical trials were performed in
elderly patients with systolic hypertension (n⫽1), patients
with hypertension associated with coronary artery disease
(CAD, n⫽1) or left ventricular hypertrophy (n⫽1), and
patients with high-risk hypertension (n⫽3). In the individuals
with prehypertension from the ARIC study,32 subjects with
HR ⱖ80 bpm had 50% higher all-cause mortality than people
with lower resting HR, which was essentially unchanged after
controlling for several confounders and other risk factors. In
the Framingham Study,4 the relative risk of cardiovascular
death adjusted for age and BP was 1.68 among men and 1.70
among women, for an increase in HR of 40 bpm. The
relationship of HR with all-cause mortality rate was even
stronger, with ⬎100% increase in the adjusted relative risk.
In the placebo arm of the Systolic Hypertension in Europe
 Palatini
(Syst-Eur) trial,35 patients with HR ⬎79 bpm had a 1.89 times
greater risk of all-cause mortality and a 1.60 greater risk of
cardiovascular mortality than subjects with HR below that
level. In the INternational VErapamil-SR/trandolapril STudy
(INVEST) study36 in patients with hypertension and CAD
treated with either verapamil or atenolol, a 5-bpm increment
in resting HR was associated with a 6% excess risk in adverse
outcome (all-cause death, nonfatal myocardial infarction, or
nonfatal stroke). The HR-mortality association was not linear
for follow-up HR, as a tendency to an upturn in mortality was
observed for the low HRs with a nadir at 59 bpm. In the LIFE
study in hypertensive patients with ECG left ventricular
hypertrophy treated with losartan- or atenolol-based regi-
mens,37 a 10 bpm higher HR was associated with a 25%
increased risk of cardiovascular death and a 27% greater risk
of all-cause mortality. Persistence or development of a HR
ⱖ84 bpm during the follow-up was associated with an 89%
greater risk of cardiovascular death and a 97% increased risk
of all-cause mortality. Interestingly, there was a significant
interaction between in-trial HR and baseline HR. For a 10
bpm higher in-trial HR, there was a 44% increase in risk of
cardiovascular death in patients with a baseline HR ⱖ84 as
opposed to only a 12% increase in risk in patients with a
baseline HR ⬍84 bpm. In the Glasgow Blood Pressure Clinic
Study,38 hypertensive patients with persistently elevated HR
(⬎80 bpm) had an increased risk of all-cause and cardiovas-
cular mortality. The highest risk of all-cause mortality was
associated with a final HR of 81 to 90 bpm, and the lowest
risk was associated with a final HR of 61 to 70 bpm. In the
ASCOT-BPLA study, baseline HR predicted all-cause, non-
cardiovascular, and cardiovascular mortality that occurred
during the follow-up but not nonfatal cardiovascular events.39
However, follow-up accumulated mean levels of HR were
better predictors of cardiovascular events than baseline HR.40
Similar results were obtained in a recent analysis of the
VALUE study,41 in hypertensive patients treated with either
valsartan- or amlodipine-based therapy. Both baseline and
in-trial HRs ⬎79 bpm were powerful predictors of the
composite cardiovascular outcome after adjustment for other
risk factors. In ONTARGET and TRANSCEND, the risk of
cardiovascular death increased by 41% to 58% (depending on
the risk-adjusted model used) among the patients with HR
ⱖ70 bpm and by 77% in those with HR ⬎78 bpm.42 In
conclusion, across the 10 studies that reported data for
all-cause death4,33,34,36 – 43 and the 9 studies that reported data
for cardiovascular mortality,4,33–35,37– 42 HR was found to be
independently associated with outcome after adjustment for
comorbid risk factors as well as for cardiac-slowing drugs. In
addition, a significant association between baseline or
follow-up HR and CAD was observed in the 8 studies in
which this information was available.4,32,33,35,38 – 42 However,
in the study by Benetos et al,33 no HR-mortality association
was found among the hypertensive women. The 6 studies that
also analyzed follow-up HRs showed that follow-up HR may
add prognostic information over and above HR measured at
baseline.36 – 42 This may be due to the fact that HR recorded
during follow-up is a more stable trait than baseline HR and
thus may be more representative of the overall hemodynamic
bulk on the arterial wall over time. At least 2 studies have
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Resting Heart Rate in Hypertension 747
shown that the increase in cardiovascular risk related to high
HR is even higher in hypertensive than in normotensive
subjects, suggesting that HR and BP may act synergistically
in the development of cardiovascular complications.4,41 Al-
though the above studies have shown that high HR is strongly
associated with mortality, a reason for concern is that in some
individuals tachycardia may be due to an underlying disease
that is not yet clinically manifest, such as incipient cardiac
failure or a chronic disorder, especially in elderly people. In
that case, an elevated HR is an indicator of poor physical
health, and the association between high HR and cardiovas-
cular events might be explained by reverse causality. To
account for this, several studies excluded patients who died
within the initial years of follow-up and then repeated the
survival analyses, showing that the association between high
HR and risk of mortality or cardiovascular events remained
robust and did not deviate substantially from that observed in
the entire cohort.4,41
Predictive Value of Ambulatory HR
HR measured out of the office with the ambulatory measure-
ment might be more representative of a subject’s usual HR.
Indeed, a study performed in 839 hypertensive subjects
showed that the reproducibility of HR was better for the
ambulatory than the office measurement.43 However, only a
few studies examined the association between ambulatory
HR and total or cardiovascular mortality. Recent results from
the Ohasama study have shown that neither daytime nor
nighttime HR predicted cardiovascular disease mortality,
whereas both predicted noncardiovascular disease mortal-
ity.44 In a recent analysis of 6 populations, 24-hour HR
predicted total and noncardiovascular mortality but not car-
diovascular mortality or any of the fatal combined with
nonfatal events.45 The above data are in agreement with
previous results obtained in the PAMELA46 and Syst-Eur
cohorts35 and indicate that HR measured with ambulatory
recording is of little use for stratifying the cardiovascular risk.
No conclusive explanation has yet been provided for the lack
of association of ambulatory HR with cardiovascular mortal-
ity. This might be related to the different nature of HR
measured for 24 hours outside the medical environment
compared with clinic HR. HR measured in the office may
reflect the sympathetic activation associated with the alerting
reaction induced by the medical environment. Ambulatory
HR is affected by a number of confounders related to the
different daily life behaviors, as exemplified by the degree of
physical activity habits, which may greatly differ from
subject to subject. On such a background, the better relation-
ship of clinic rather than of ambulatory HR with cardiovas-
cular events might thus reflect its greater ability to more
specifically reflect an underlying sympathetic overactivity.
The ␤-Blocker Controversy
If HR is an important independent risk factor in hypertension,
drugs that decrease BP and HR such as nondihydropyridine
calcium antagonists or ␤-blockers might be beneficial in
hypertensive patients with high HR. ␤-Blockers cause a
marked reduction of HR and theoretically should be a
first-choice treatment in these patients. However, in interven-
748 Hypertension November 2011
tion trials the efficacy of ␤-blocking therapy in hypertensive
subjects was lower than that predicted on an epidemiological
basis.47 It should be pointed out that in some trials a
considerable number of patients on ␤-blockers were with-
drawn because of a low HR, which was a sign of effective
␤-blockade.48 According to a recent meta-analysis of 147
randomized trials of BP-lowering drugs, the reduction in
incidence of stroke was smaller with ␤-blockers (17%) than
with other classes of antihypertensive drugs (29%).49 How-
ever, in that analysis, 37 trials of ␤-blockers in patients with
history of CAD were excluded, and in those 37 studies, the
risk reduction of recurrent CAD events was 29% compared
with 15% in trials of other antihypertensive drugs.49 A recent
meta-analysis of ⬎34 000 patients with hypertension in 9
large ␤-blocker trials showed that a lower HR achieved from
␤-blockade compared with other antihypertensives or placebo
was associated with an increase in all-cause mortality, car-
diovascular mortality, myocardial infarction, stroke, and heart
failure.50 In the ASCOT-BPLA dataset, the authors found no
evidence that the superiority of amlodipine-based therapy
over atenolol-based therapy for patients with hypertension
uncomplicated by CAD was attenuated with higher baseline
HR.39 This evidence led many authors to conclude that
␤-blockers will remain as indicated for heart failure, for after
myocardial infarction, and for tachyarrhythmias but no longer
for hypertension in the absence of these compelling indica-
tions. The disappointing effects of ␤-blockers in hypertension
have been attributed to their unfavorable effects on the lipid
profile and insulin sensitivity.51 The higher central BP with
␤-blocker– based therapy compared with a calcium entry
blocker–ACE-inhibitor association, recently found in the
CAFE (Conduit Artery Function Evaluation) study, is another
possible cause of the unsatisfactory effect of ␤-blockers in
noncardiac patients.52 The effect on central pressure was
attributed mainly to a shift of the reflected wave into late
systole due to the reduction in ejection duration at lower HRs
and to the vasoconstrictor effect of ␤-blockers on the periph-
eral circulation that increases pulse-wave reflection. The
results of the above study were certainly provocative. On the
other hand, in the ASCOT-BPLA study there was a signifi-
cant association of attained HR at 6 weeks after random
assignment with myocardial infarction and fatal coronary
outcome.40 This indicates that a low final achieved HR (lower
on atenolol) actually had a favorable effect on cardiovascular
outcomes, as it did in the INVEST study. It should be noted
that the great majority of the patients enrolled in past clinical
trials were prescribed atenolol,49 and it is possible that
atenolol and not all ␤-blockers are associated with the
untoward effects mentioned above. It is possible that atenolol
exerts a beneficial effect on the cardiovascular system due to
the HR-lowering action and a detrimental one due to its
untoward effects on metabolic variables and central BP. The
newer ␤-blockers such as carvedilol and nebivolol have a
more favorable effect on the lipid profile and insulin resis-
tance compared with older ␤-blockers.53 In contrast with
traditional ␤-blockers, carvedilol was shown to decrease
vascular resistance, with little effect on cardiac output.53 In
addition, a neutral effect on insulin sensitivity and a decrease
in central aortic pressure have been observed with vasodila-
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tory ␤-blockers.53 ␤-Blockers might have advantages over
other antihypertensive drugs in individuals with elevated HRs
and activation of the sympathetic nervous system, as shown
by experimental studies in monkeys.54 Unfortunately, in no
clinical trial was ␤-blocker efficacy in preventing coronary
events tested as a function of HR. Also, no data are available
on long-term cardiovascular morbidity and mortality in hy-
pertension for vasodilatory ␤-blockers. Controlled clinical
trials performed with third-generation ␤-blockers may shed
more light on this controversial issue. If the disappointing
effects of ␤-blockers are mainly due to their negative hemo-
dynamic effects, drugs that reduce HR without altering
central hemodynamics should provide better results in pa-
tients with high HR. Sharman et al55 showed that the strongest
predictor of central systolic BP augmentation is the duration
of systolic ejection (accounting for 78% of the variance)
rather than HR itself. ␤-Blockers decrease the HR by causing
a disproportionate increase in the duration of systole that
might be responsible for the augmentation of central systolic
pressure.56 At variance with ␤-blockers, the selective HR-
reducing agent ivabradine reduces HR chiefly by prolonging
diastole and does not induce ␣-adrenergic vasoconstriction.57
These properties will have beneficial effects on the relative
timing of reflected pressure waves in the proximal conduit
arteries.56 In addition, the greater increase in diastolic time
caused by ivabradine facilitates myocardial perfusion.56 Thus,
the impact of HR reduction on outcome may depend on the
means by which HR is lowered.
Normalcy Limits
As a result of the epidemiological evidence, the 2007 Euro-
pean Society of Hypertension/European Society of Cardiol-
ogy guidelines suggested including elevated HR when assess-
ing the cardiovascular risk profile of a hypertensive patient or
a person with high-normal BP.58 However, the same guide-
lines still raise some doubts about the clinical utility of
measuring resting HR because no precise cutoff can be
offered to the practicing physician for increasing the accuracy
of risk stratification. The lack of official normal values should
not discourage the physician from measuring HR in hyper-
tensive patients. For most cardiovascular risk factors, the
relationship between the factor and the level of risk is a
continuous one and limits of normality have been identified
arbitrarily. In most epidemiological studies, the upper normal
limit for resting HR was identified from the lower limit of the
top HR quintile, because in this group a remarkable increase
in the risk of morbidity and/or mortality was invariably
observed. In most studies, this limit was between 80 and 85
bpm, and there is no doubt that a HR ⱖ80 to 85 bpm implies
a noticeable increase in risk. Also, the results of the interven-
tion trials in post–myocardial infarction patients or in subjects
with congestive heart failure suggest that the limit of normal-
ity of HR should be set at this level.59
Perspectives
Today, there is a body of evidence to suggest that tachycardia
should no longer be viewed as an innocent clinical feature.
Given the high prevalence of fast HR among patients with
hypertension, treatment of elevated HR might have a major
 Palatini
public health significance in this clinical setting. However, no
results of clinical trials specifically designed to investigate
the clinical value of cardiac slowing in hypertensive patients
without cardiovascular disease are available, and, in the
absence of evidence from prospective trials, no specific
treatment recommendations can be made. Lifestyle changes
including a program of regular aerobic exercise and the
reduction of caffeine and alcohol consumption should be
recommended to any hypertensive patient with elevated HR.
Smoking and stimulating drugs should be avoided. Effective
drugs for the treatment of elevated HR, some provided with
antihypertensive effects and some with a neutral effect on BP,
are available and might be of help. A final answer to whether
these conceptual advantages can be translated into clinical
benefit can come only from future prospective studies in
hypertensive patients with tachycardia.
Disclosures
None.
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KEY WORDS: heart rate 䡲 cardiovascular 䡲 risk 䡲 prognosis 䡲 mortality
ONLINE SUPPLEMENT

Role of elevated heart rate in the development of cardiovascular disease in hypertension

By Palatini P

Department of Clinical and Experimental Medicine

University of Padova, Padua, Italy

Running title: Resting heart rate in hypertension

Word count: 5927

Correspondence to:

Professor Paolo Palatini, M.D.,

Clinica Medica 4 - University of Padova

via Giustiniani, 2- 35128 Padova (Italy)

Phone: +39-049-8212278

Fax: +39-049-8754179

e-mail: palatini@unipd.it

Downloaded from http://hyper.ahajournals.org/ by guest on October 28, 2011

Search strategy and selection of articles

An electronic bibliographic search was conducted in PubMed taking into account articles published
from 1966 to the present. The keywords for the searches were: heart rate, risk, mortality,
hypertension. Variants for all keywords were used to increase the number of studies returned by the
search. The references in the identified or related articles were then manually reviewed in the search
for other relevant citations. Only studies in which cardiovascular mortality or total mortality was
available as outcome measure were included. Articles were rejected if they were as follows: gave
insufficient data, used other outcomes, were duplicate articles, studies were performed in non
hypertensive subjects, in general populations, in patients with diabetes, acute myocardial infarction,
or heart failure. Relevant articles were then checked in full to confirm eligibility and extract data.
The search was performed in May 2011 and yielded 516 articles. Of these, 366 were excluded on
initial screen of title and abstract. The remaining 150 articles were retrieved for detailed analysis
and a further 140, including 32 review papers, were excluded because of ineligibility or
overlapping subject cohorts from a previous publication. A further 2 studies in the form of abstract
were identified from a manual review of references, giving a total of 12 publications, including 6
randomized clinical trials and 5 cohort studies. For the ASCOT study, the data were drawn from a
full article (1) and from a reply letter (2).

1. Poulter NR, Dobson JE, Sever PS, Dahlöf B, Wedel H, Campbell NR; ASCOT
Investigators. Baseline heart rate, antihypertensive treatment, and prevention of cardiovascular
outcomes in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). J Am Coll Cardiol.
2009;54:1154-1161.
2. Poulter NR, Dobson JE, Sever PS, Dahlöf B, Wedel H, Campbell NR. Elevated heart rate in
hypertension :A target for treatment ? Reply. J Am Coll Cardiol. 2010;55 :931-932.

Downloaded from http://hyper.ahajournals.org/ by guest on October 28, 2011 2

 Table S1. Resting heart rate and adverse outcome in one pre-hypertensive and ten hypertensive populations.

Author Baseline FU HR Patient Age Male sex Treatment FU Outcome Increased Clinical

(Study) HR (bpm) (bpm) number (years) (%) length variables risk for setting

(years) high HR*

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King 13.1%≥80 n. av. 3275 M: n. av. 49 No 10.1 Total Mort Yes Pre-

(ARIC) R: 45-64 CV Mort n. av. hypertension

CHD Yes†

Gillman M:78.6 n. av. 4530 M: 56.2 45 No 36 Total Mort Yes Hypertension

(Framingham) CV Mort Yes‡

CHD Mort Yes‡

Benetos 1999 n. av. n. av. 19386 M: ma=51 63 Yes 18.2 Total Mort Yes‡ Hypertension

(French study) fe=52 CV Mort Yes‡

CHD Mort Yes‡

Thomas 20%>80 n. av. 60343 Middle- 100 Yes 14 Total Mort n. av. Hypertension

(French study) age and CV Mort Yes

elderly CHD Mort n.av.

Palatini 73.0 -0.4║ 2293 M: 70.2 33 No 4 Total Mort Yes Isolated

3
 (Syst-Eur) CV Mort Yes systolic

CHD Mort n. av. hypertension

Kolloch 75.7 At: 69.2 22192 M: 65.9 48 Yes (At vs 2.7 Total Mort Yes¶ Hypertension

(INVEST) Ver: 72.8 ver) or non-fatal with CHD

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MI, or non-

fatal stroke

Paul 77.0 74.0 4065 M: 52 47 Yes 2.5 Total Mort Yes# Hypertension

(Glasgow CV Mort Yes#

Clinic) CHD Mort Yes#

Okin 20%≥ 84 At: -4.1║ 9190 M: 67 46 Yes (At vs 4.8 Total Mort Yes§ Hypertension

(LIFE) los) CV Mort Yes§ with LVH

Los: -0.5║
CHD Mort n. av.

Poulter 73.8 At:-12.0║ 12159 M: 62.9 77 Yes (At vs 5.5 Total Mort Yes Hypertension

(ASCOT) amlo) CV Mort Yes with 3 CV

Amlo:-1.3║
CHD Yes§ risk factors

Julius 69.1 70.2 15193 M:67.2 58 Yes (Val vs 4.2 Total Mort Yes High risk**

(VALUE) amlo) Comp EP° Yes hypertension

4
 Rambihar 68.0 n. av. 31531 66.5 70 Yes (Tel vs 5.0 Total Mort Yes High risk

(ONTARGET/ ram vs CV Mort Yes patients$

TRANSCEND) combination) Comp EP& Yes

M indicates mean; R, range; FU, follow-up; CHD, coronary heart disease; CV, cardiovascular; n. av., not available; Mort., mortality; MI,
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myocardial infarction; LVH, left ventricular hypertrophy; At, atenolol; Ver, verapamil; Amlo, amlodipine; Val, valsartan; *for fully adjusted

models; †only in women; ‡only in men; §for follow-up heart rate; ║change from baseline; ¶for both baseline and follow-up heart rates; #for

subjects with high heart rate at baseline and follow-up visits; **age>50 years and presence of cardiovascular risk factors or disease according to an

algorithm based on age and sex; °a composite of sudden cardiac death, fatal myocardial infarction, death during or after percutaneous coronary

intervention or coronary artery bypass graft, death due to heart failure, and death associated with recent myocardial infarction on autopsy, heart

failure requiring hospital management, non-fatal myocardial infarction, or emergency procedures to prevent myocardial infarction. & a composite of

cardiovascular death, myocardial infarction, stroke, and congestive heart failure. $hypertension in 70%.