European Heart Journal Supplements (2003) 5 (Supplement G), G10—G14

Prognostic benefits of heart rate reduction in

cardiovascular disease
R. Ferrari1,2, S. Censi1, F. Mastrorilli1 and A. Boraso2
1Cattedra di Cardiologia, Università di Ferrara, Ferrara

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2Fondazione Salvatore Maugeri, IRCCS, Cardiovascular Pathophysiology Research Centre, Gussago,
Brescia, Italy

Increased heart rate is associated with high blood pressure and metabolic
KEYWORDS
Cellular energetic disturbances that lead to hypertension, atherosclerosis and increased cardiovascular
needs; morbidity and mortality. In this respect, elevated heart rate can be considered a
Heart rate; marker of risk. Whole body temperature and energy needs are controlled by heart
Metabolic rate; activity, and the ‘language’ employed by the heart could be considered its rate,
Life expectancy which, via the intensity and frequency of shear stress, it uses to regulate endothelial
function and vascular tone. A close link between body temperature, metabolism and
heart rate has been observed, and so heart rate may determine metabolic demand
and ‘control’ the duration of life. In mammals, the calculated number of heart beats
in a lifetime is remarkably constant, despite a 40-fold difference in life expectancy.
According to this view, a reduction in heart rate would increase life expectancy also
in humans. The heart produces and utilizes approximately 30 kg adenosine
triphosphate each day, and slowing its rate by 10 beats/min would result in a saving
of about 5 kg in a day. Considering that heart rate is a major determinant of oxygen
consumption and metabolic demand, heart rate reduction would be expected to
diminish cardiac workload. Clinical studies with beta-blockers have already shown a
reduction in mortality and improvement in outcome as a result of reduction in heart
rate.
© 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
rights reserved

Introduction mortality but also with decreased all-cause

In the past decade, several studies have shown
that resting heart rate is closely correlated to
blood pressure and is prospectively related to
atherosclerosis and other cardiovascular diseases,
including hypertension. Furthermore, epidemio-
logical studies suggest that low heart rate is not
only associated with decreased cardiovascular
Correspondence: Prof. Roberto Ferrari, Cattedra di
Cardiologia, University of Ferrara and Fondazione S. Maugeri,
IRCCS, Cardiovascular Pathophysiology Research Centre,
Corso Giovecca, 203, 44100 Ferrara, Italy.
mortality. Drugs that do not reduce heart rate
after myocardial infarction have not been found to
improve survival. A typical example is that of
calcium channel blockers; the dihydropyridines,
which increase heart rate, have no effect or could
even worsen prognosis,1,2 whereas verapamil and
diltiazem, which reduce heart rate, have a
favourable effect.3,4
Mounting evidence indicates that increased heart
rate is associated with high blood pressure and
metabolic disturbances that lead to hypertension,
atherosclerosis and increased cardiovascular
morbidity and mortality. In this respect, elevated

01520-765X/03/0G0010 + 05 $35.00/0 © 2003 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.
Benefits of heart rate reduction
heart rate, and in particular low heart rate
variability, can be considered a marker of risk and
an independent factor in the induction of risk (i.e.
for myocardial infarction). After myocardial
infarction, reduction in heart rate variability — a
measure of cardiac autonomic innervation by the
brain — is a strong predictor of death. Loss of
normal autonomic nervous system control of heart
rate and rhythm is, in fact, an important risk factor
for adverse cardiovascular events. The sympathetic
overactivity that follows may explain the increase
in heart rate and blood pressure, and metabolic
abnormalities. With heart rate being a major
determinant of oxygen consumption and metabolic
demand, a decrease in rate would be expected to
decrease cardiac workload.
High heart rate increases the pulsatile nature of
arterial blood flow and arterial stress.
Experimental studies in monkeys have shown that
heart rate can exert a direct atherogenic action on
the arteries through increased wall stress.5,6
The body’s metabolic demand is
controlled by heart rate
Whole body temperature and energy need are
controlled by heart activity, via its rate. The way in
which the heart sends ‘messages’ and ‘talks’ to the
whole body is through the circulatory system, with
the help of the endothelium. The ‘language’ chosen
by the heart is very probably its rate, via the
intensity and frequency of shear stress, thus
exerting an important regulatory role on endothelial
function and vascular tone.7 This particular effect
has been observed experimentally in monkeys, as
previously reported.5,6 The endothelium releases
nitric oxide and other vasoactive compounds in
response to shear stress, thus regulating the degree
of vasodilatation and therefore the amount of blood
and oxygen delivered to peripheral muscles. The
heart could be viewed as the connection between
the central nervous system and the periphery,
determining and regulating the activities of
peripheral muscles via its rate.
Physical activity regulates metabolic demand,
which is determined by heart rate itself. Regression
analysis on a logarithmic scale between body mass
and metabolic demand among animals yields a
straight line with the same slope as that between
body mass and heart rate.8 There is a close link
between temperature, metabolism and heart rate;
therefore, because heart rate determines
metabolic demand, a relationship between heart
rate and lifespan may be produced for the entire
animal kingdom, including humans.
G11
In a lifetime the total number of heart
beats is constant
Among mammals, it has been observed that the
calculated number of heart beats in a lifetime is
remarkably constant, despite a 40-fold difference
in life expectancy. When the number of heart
beats in a lifetime is plotted against body weight,
the range span is 0.5 million-fold, from hamster to
whale.9 This can be summarized by reference to
the fact that life and energy available are equally
important in evolution, and the intrinsic concept
can be interpreted as the less energy needed, the
longer the lifespan. Azbel10 stressed the concept
that smaller animals have a higher heart rate and
shorter lifespan than do larger animals, with a
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35-fold difference in heart rate and a 20-fold
difference in lifespan, and suggested that life
expectancy is predetermined by the basic
energetics of living cells and that the inverse
relationship between longevity and heart rate
reflects an epiphenomenon in which heart rate is
a marker for or a determinant of metabolic rate
and energetic needs.
In homeotherms a fall in body temperature is
prevented by an increase in metabolic rate,
which, as we know, is related to an increase in
heart rate. In hibernating animals, the fall in
metabolic rate is achieved by a drop in body
temperature and heart rate. In marmots, mean
heart rate drops to 3—5 beats/min in hibernation,
from 150 beats/min.
Following the observation of a constant total
number of heart beats in a lifetime in mammals,
there are good reasons to believe that this can be
extended to the whole animal kingdom. A
Galapagos tortoise has a heart rate of 6 beats/min
and a life expectancy of 177 years, with a total
number of heart beats of 5.6 × 108 in a lifetime.11
This figure is close to that obtained for a rat
(6.3 × 108), with a heart rate of 240 beats/min and
a life expectancy of about 5 years.
Is prolongation of lifespan possible?
In humans a reduction in heart rate could, in
theory, prolong lifespan. Below, we analyze this
possibility in detail.
Coburn et al.12 tested this hypothesis in mice;
those investigators fed the animals with digoxin
and observed a prolongation of life and a slower
heart rate in treated mice. However, treated mice
had a lower body weight; this, together with other
confounding factors, made it impossible to infer a
clear cause—effect relationship.
G12
Another aspect must be considered. With a
heart rate of 70 beats/min and a life expectancy
of 80 years, humans are already an exception to
the equation for heart rate and life expectancy in
mammals. The explanation is provided by a
fundamental metabolic theory based on heat loss
and production, the ratio of which increases as
body size decreases. However, it is true that in the
general population the risk for death for all
causes, including cardiovascular events, is higher
as resting heart rate increases. Several clinical
studies have demonstrated that heart rate is an
important risk factor for cardiovascular morbidity
and mortality, not only among patients with
established heart disease13 or well-known cardio-
vascular risk factors such as atherosclerosis14 and
hypertension,15 but also in the general
population.16
Contraction of the heart
The heart requires regular oscillations of
cytoplasmic calcium (the ultimate messenger of
contraction) and availability of energy [in the form
of adenosine triphosphate (ATP)] if it is to contract
continuously. The mechanisms that are involved
are finely regulated and result in a continuum of
systole and diastole (i.e. heart beats). During each
action potential cytoplasmic calcium transiently
increases and interacts with the contractile
elements, leading to contraction (i.e. systole), in
the process known as excitation—contraction
coupling.
During excitation—contraction coupling, two
different types of calcium channels are involved.
In the sarcolemma the L-type/dihydropyridine-
sensitive calcium channels are opened by
depolarization; this initiates the action potential,
causing flux of calcium ions, following their
electrochemical gradient, into the cytoplasm.17
However, the level of calcium reached is not
sufficient to initiate contraction in the heart, but
allows the release of further calcium from the
sarcoplasmic reticulum through the ryanodine-
sensitive/calcium-release channels, via a
mechanism known as calcium-induced calcium
release.17,18 This increase in intracellular calcium
concentration, to nearly millimolar levels, then
leads to contraction.
Other calcium channels have been identified in
the sarcolemma of myocytes in the conduction
system (e.g. the Purkinje fibres). The T-type
calcium channels (also referred to as low-
threshold or low-voltage-activated channels) play
a role in pacemaker activity and open in response
R. Ferrari et al.
to a smaller depolarization of the sarcolemma
(approximately —40 mV) than is required by the
L-type calcium channels (high-threshold or high-
voltage-activated channels), which require
depolarization to —20 mV from a resting potential
of —80/—100 mV, to open and sustain contraction.
T-type calcium channels (like sodium channels)
participate in the early stage of pacemaker
depolarization, and therefore they may contribute
to initiation of the heart beat.
Relaxation of the heart
During diastole three main proteins are involved
in the cell to lower calcium in the cytoplasm: the
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sodium—calcium exchanger and, with limited
capacity, a calcium pump in the sarcolemma; and
a more powerful calcium pump in the
sarcoplasmic reticulum. In cardiac muscle,
activity of the latter is regulated by a mechanism
involving phosphorylation/dephosphorylation of
phospholamban — a 27-kDa protein that is also
associated with the sarcoplasmic reticulum
membrane. Phospholamban phosphorylation leads
to a marked increase in calcium transport activity
across the sarcoplasmic reticulum membrane and,
therefore, to cardiac muscle relaxation.17
Only during pathological conditions are
mitochondria involved in removing calcium from
the cytoplasm. There is in fact competition
between mitochondrial calcium transport and ATP
production as the two processes utilize the same
electrochemical gradient.20
How the heart spends its energy
The primary source of energy in the heart is ATP,
which is used for electrical excitation,
contraction, relaxation and recovery of the resting
electrochemical gradients across membranes.
Although the heart may suddenly increase its
output by up to sixfold and so require a huge
amount of energy, unlike other tissues it stores low
quantities of ATP that are just sufficient to sustain
a few beats. However, the low ATP levels in the
heart are counterbalanced by a higher level of
creatine phosphate, which permits availability of
ATP from adenosine diphosphate in a
phosphorylation reaction that is catalyzed by
creatine kinase.21
In the myocyte ATP is synthesized in the
mitochondria from various aerobic substrates.22 At
rest ATP is generated from beta-oxidation of fatty
acids (60—70%) and catabolism of carbohydrates
Benefits of heart rate reduction
(30%), including exogenous glucose and lactate.
Amino acids and ketone bodies are less frequently
utilized as substrates.
In the presence of cardiac arrest or ventricular
fibrillation, oxygen uptake by the heart is reduced
by 60—70%. Therefore, most of the production of
high-energy phosphates (i.e. ATP and creatine
phosphate) via oxidative phosphorylation is used
for contractile activity. ATP is hydrolyzed by
myosin heads during contraction, but also in order
to effect the reuptake of calcium into the
sarcoplasmic reticulum and to remove it from the
cytoplasm,23 or to transport sodium, potassium
and calcium ions across the sarcolemma to
maintain the resting potential. The sodium—
potassium pump in the sarcolemma utilizes 10—
15% of total ATP and less than 5% is used for action
potential generation and conduction.24 A small
amount of ATP is also required for phosphorylation
of proteins via cyclic adenosine monophosphate
production or protein kinase activation. Further-
more, ATP is hydrolyzed to transport ions across
mitochondrial membranes and for processes that
maintain mitochondrial volume and structure,
synthesis of triglycerides and glycogen (among other
substances), and in futile cycles.23,24 However, of
the total ATP, most is converted into heat and only
20—25% is turned into mechanical work.
Benefits of heart rate reduction
In humans the heart beats on average 100,800
times per day. This figure corresponds to
36.8 × 106 in a year and 29 × 108 heart beats in a
lifetime (80 years on average). The heart produces
and consumes approximately 30 kg ATP every day,
such is its turnover, corresponding to nearly
11,000 kg per year and approximately 880,000 kg
in a lifetime. It follows that each heart beat has its
own cost — approximately 300 mg ATP.
Considering the equation between heart rate
and life expectancy in mammals,9 a decrease in
heart rate from 70 to 60 beats/min would
increase life expectancy from 80 to 93.3 years.
This means that slowing the heart rate by
10 beats/min would result in a saving of about
5 kg ATP in a day. To produce ATP the myocardium
needs oxygen, which is used by the mitochondria
in oxidative phosphorylation. Azbel10 calculated
that the basal oxygen consumption per body atom
of all animals is approximately 10 molecules of
oxygen in a lifetime. This figure corresponds to
approximately 10—8 molecules of oxygen per heart
beat.10 It is astonishing to see that the total
number of heart beats in a lifetime calculated
G13
using these data (10 × 108) is similar to the mean
value observed among mammals (7.3 × 108).7
In the final analysis, all of these considerations
lead back to heart rate, albeit using simplified
figures, and may provide an idea of what powerful
consequences heart rate reduction may yield at
the cellular level. Considering that oxygen
delivery to heart muscle occurs mainly during
diastole, via the coronary flow, it is important to
note the threat of reduced oxygen delivery in the
damaged heart, such as in ischaemic heart disease
and certain forms of heart failure. These
conditions improve if agents that lower heart rate
are administered.2,3,25—27 As noted at the start of
the present review, heart rate is a major
determinant of oxygen consumption and metabolic
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demand, and heart rate reduction would be
expected to diminish cardiac workload.
Conclusion
The use of beta-blockers would improve myocardial
energy balance and induce a less negative force—
frequency relationship. The saving of energy at
the myocardial level therefore represents just one
aspect of the equation between heart rate and life
expectancy, the other being a reduction in the
metabolic rate of the body. Interestingly, the
increase in mortality among people with a high
heart rate is mostly attributed to a higher risk for
death from coronary artery disease. Atrial
fibrillation, especially in the post-operative
period, is a common complication of cardiac
surgery, and a combination of beta-blockers and/
or calcium channel blockers would be a logical
treatment. Thus, the heart determines heart rate,
and heart rate itself can be harmful to the heart;
otherwise stated, the heart is the cause and the
target of the same paradigm.
At present, it is not clear whether a primary
reduction in heart rate may effectively prolong
life in patients, although many clinical studies
suggest that agents that decrease heart rate do
improve survival in patients with myocardial
infarction,28 hypertension and heart failure.29,30 A
controlled reduction in heart rate, without
altering the normal variability, is a worthy
therapeutic objective not only in the whole
population but also, and especially, in those
patients who are at risk for cardiovascular events.
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