review article - jst

REVIEW ARTICLE

Cardiopulmonary Exercise TestThe Most Powerful Tool to Detect Hidden Pathophysiology

Hitoshi Adachi,1 MD

SummaryThe cardiopulmonary exercise test (CPX) is an essential examination for detecting pathophysiological de-

rangement and determining treatment policy because it clarifies not only the changes of hemodynamics but also

abnormality in the whole body during exercise where heart disease patients often feel symptoms.

To utilize CPX effectively, we must understand each parameter, such as peak oxygen uptake (peak�O2),

peak�O2/HR, and�E/�CO2. In addition, comparison of each parameter, for example, peak�O2 and�E/�CO2,

and peak�O2 and peak�O2/HR, is useful to detect the pathophysiological abnormalities.

In this article, I will describe how CPX should be used in clinical settings.

(Int Heart J 2017; 58: 654-665)

Key words: Heart failure, Angina pectoris, Cardiac rehabilitation

The cardiopulmonary exercise test (CPX) is an ex-

ercise stress test with a long history. The test

clarifies the pathophysiological mechanism under-

lying various unfavorable symptoms or conditions. The

principles and technical procedures for CPX were mostly

established by Prof. K. Wasserman and his colleagues1) in

the 1970s.

The most important point to note is that only CPX

can elucidate the pathophysiological changes that occur

while performing an activity at various levels of difficulty.

Because symptoms, such as chest pain, shortness of

breath, and/or leg fatigue appear during exercise in heart

disease patients, we cannot disregard the possibility of

heart disease even if the results of the examination at rest

are negative. Therefore, for patients with such symptoms,

it is necessary to perform an exercise test.

However, CPX has obviously been underused to date.

It is only used to evaluate peak oxygen uptake in patients

with severely impaired cardiac functions, so as to deter-

mine whether the patient is a candidate for heart trans-

plantation, or to determine the anaerobic threshold (AT)

for exercise training. In this review, I would like to dis-

cuss why CPX is necessary for the management of the

complications in heart disease patients, and how CPX can

be used in the field of cardiology. I hope this will help

many readers to develop an interest in CPX and begin to

use this test routinely.

Principles of CPX

Preparation: A gas analyzer is the principal equipment

for CPX. A breath-by-breath gas analyzer is necessary in

a clinical setting. Additionally, a cycle-ergometer or tread-

mill ergometer, as an exercise load device, and an electro-

cardiograph are necessary. If the facility has many patients

with severe heart failure, a cycle-ergometer is required to

produce a sufficiently weak load because the exercise ca-

pability of these patients is very low.

What is calculated during gas exchange analysis?: The

gas analyzer measures the oxygen and carbon dioxide

content in a gas. Using inspired and expired gas, oxygen

uptake (�O2) and carbon dioxide output (�CO2) are calcu-

lated. The gas analyzer also measures tidal volume (TV)

and respiratory rate (RR). From these measurements, min-

ute ventilation (�E) is calculated. Using�O2,�CO2,�E,

and heart rate (HR),�E/�CO2,�E/�O2, R (gas exchange

ratio), and�O2/HR are calculated. A breath-by-breath gas

analyzer also measures the partial pressure of end-tidal

oxygen and carbon dioxide (PETO2 and PETCO2)).

Ramp exercise protocol: CPX is usually performed using

a ramp protocol (Figure 1). This protocol clarifies how

much oxygen uptake is required when various disorders

are induced. For example, we can confirm how much ex-

ercise intensity induces angina pectoris, and determine the

severity of the disorder. Then, we can specify how much

daily activity can be performed safely. For example, if the

ischemic threshold is above the anaerobic threshold (AT),

angina pectoris is not severe.

Cardiac scintigraphy is one of the most prevalent and

reliable examinations to detect myocardial ischemia. It can

detect myocardial ischemia in more than 90% of patients.

However, during exercise-stress scintigraphy, the patient is

forced to pedal until their peak performance capacity,

where they feel chest pain. Afterward, an isotope is in-

jected and a myocardial scintigraphy image is taken. That

is, cardiac scintigraphy only reveals whether myocardial

From the 1Department of Cardiology, Gunma Prefectural Cardiovascular Center, Gunma, Japan.

Address for correspondence: Hitoshi Adachi, MD, Department of Cardiology, Gunma Prefectural Cardiovascular Center, 3-12, Kameizumi, Maebashi,

Gunma 371-0004, Japan. E-mail: [email protected]

Received for publication May 12, 2017. Revised and accepted May 14, 2017.

Released in advance online on J-STAGE September 30, 2017.

doi: 10.1536/ihj.17-264

All rights reserved by the International Heart Journal Association.

654

Int Heart J

September 2017 655HOW TO INTERPRET AND HOW TO USE CPX

Figure　1.　Model of ramp protocol. Warm-up is usually 3 to 4 minutes. The ramp intensity is set to com-

plete the exercise test after 8 to 12 minutes. AT indicates anaerobic threshold; RCP, respiratory compensa-

tion point; and R, gas exchange ratio.

Table　I.　Comparison of CPX, Scintigraphy and Stress Echocardiography

Modality Comparison with activity intensity Skill

CPX Can compare with daily activity ++

Scintigraphy Only at the peak exercise intensity ++

Dobutamine-stress echocardiography Impossible +++

Table　II.　Determinant Factors for Oxygen Uptake (V4

O2)

Factor Representative disease

Pulmonary function COPD

Lung fibrosis

Pulmonary circulation CTEPH

PAH

Pleural effusion

Heart failure

Cardiac function Heart failure

IHD

Valve disease

Peripheral circulation PAD

Heart failure

Skeletal muscle function Heart failure

Muscle dystrophy

Autonomic nerve function Heart failure

Beta-adrenergic receptor blocker

Anemia Anemia

CTEPH indicates chronic thromboembolic pulmonary hyperten-

sion; PAH, pulmonary arterial hypertension; IHD, ischemic

heart disease; and PAD, pulmonary arterial disease.

ischemia occurs at the peak exercise intensity. If the sub-

ject does not require vigorous performance near their peak

capacity in daily life, the findings from cardiac scintigra-

phy are less useful.

Dobutamine-stress echocardiography is also recom-

mended to detect myocardial ischemia. The sensitivity of

the examination is excellent if the examiner is an expert.

However, we cannot evaluate the severity of angina pecto-

ris from this test because the dose of dobutamine does not

indicate the exercise intensity. We can only confirm the

presence or absence of myocardial ischemia.

On the other hand, CPX using a ramp protocol re-

veals the intensity at which myocardial ischemia occurs

(Table I).

Significance of Each Parameter

Oxygen uptake (�O2): Oxygen uptake is the principal

parameter obtained from CPX. Oxygen is necessary to

produce ATP in the working muscle. Oxygen uptake de-

creases in the event of alveolar hypoventilation, pulmo-

nary arterial flow limitation, cardiac dysfunction, periph-

eral vascular insufficiency, skeletal muscle dysfunction,

and blood flow redistribution.2) That is, this parameter re-

flects the pulmonary function, cardiac function skeletal

muscle function, pulmonary and peripheral vascular func-

tion, and autonomic nerve function (Table II).

During steady state exercise (Figure 2), a certain pe-

riod of time is necessary before oxygen uptake reaches a

steady state. This period is divided into two phases. Phase

I lasts for approximately 15 seconds, during which oxy-

gen uptake increases because the transport of blood from

the lungs to the periphery increases. Next, oxygen uptake

increases exponentially until it reaches a plateau in Phase

II. The duration required to reach the plateau depends on

the subject’s exercise tolerance. This length of time is

Int Heart J

September 2017656 Adachi

Figure　2.　Oxygen uptake during a constant stress test.

Figure　3.　Oxygen uptake pattern during a ramp protocol. The solid line is a normal pattern. When the ratio

of work rate (watt) to oxygen uptake (mL/minute) is 1/10, the slope of work load and oxygen uptake is paral-

lel. The small dotted line is the pattern for an obese subject. The thick dotted line is for a heart failure patient,

and the dashed line is for a myocardial ischemia patient.

called the “time constant (τ)”, and reflects the ability for

cardiopulmonary adjustment. Therefore, heart failure pa-

tients and older individuals have longer time constants.

This parameter predicts the prognosis for heart disease pa-

tients.3) After the oxygen uptake increases exponentially, it

reaches a plateau if the exercise intensity is beneath the

AT. This is called Phase III.

With an incremental exercise protocol, oxygen uptake

increases linearly during a ramp, and continues to increase

by 10.2±3.1 mL/minute for one watt.4)

There are three abnormal patterns of oxygen uptake

increase during ramp tests (Figure 3). One is an upward

displacement of oxygen uptake. This pattern is observed

in obese subjects, who have higher than expected�O2 val-

ues throughout the exercise. These subjects need more

oxygen to move their heavier legs, resulting in greater�O2

(Figure 3, line A).

As previously described, the steepness of oxygen up-

take is approximately 10 mL/minute.4) In patients with di-

minished oxidative enzyme activity in skeletal muscle

such as chronic heart failure or deconditioning, the steep-

ness of�O2 decreases (Figure 3, line B).

The third abnormal�O2 pattern is “the hockey stick

pattern”. With mild to moderate exercise intensity,�O2 in-

creases as usual, but abruptly stops increasing near the

peak intensity. This pattern is observed in patients with

myocardial ischemia, diastolic and/or systolic ventricular

dysfunction, mitral/tricuspid valve regurgitation, and other

disorders, under conditions of restricted heart rate increase

such as when taking beta-adrenergic receptor blockers5)

(Figure 3, line C).

Peak�O2 is one of the most powerful indicators of a

patient’s prognosis.6,7) In addition, it is one of the most

important parameters to determine whether the patient is a

candidate for heart transplantation.

Cardiac function during exercise -�O2/HR, �E/�CO2,PETCO2: Stroke volume can be evaluated using�O2/HR

(oxygen pulse).8) Since�O2 is the product of cardiac out-

put and the volume of oxygen utilization (c(A-V)O2 dif-

ference), and c(A-V)O2 difference at the peak exercise is

constant, peak�O2/HR is equal to the product of stroke

volume and a constant value. We can even calculate stroke

volume at a given work rate.8)

�O2/HR increases gradually during ramp exercise. At

Int Heart J


Figure　4.　Sample of V4

O2/HR, stroke volume, heart rate and cardiac output. SV indicates stroke volume;

and CO, cardiac output.

Table　III.　Mechanisms That

Reduce V4

O2 /HR Increase

Mechanisms

Myocardial ischemia

Diastolic dysfunction

Systolic dysfunction

Mitral/tricuspid regurgitation

approximately 50-60% of peak exercise intensity, the

steepness of the line decreases (Figure 4). When it stops

increasing and does not reach the predicted value, we

should consider the possibility that something occurred at

this point. Usually, this phenomenon occurs in patients

with cardiac diastolic dysfunction, systolic dysfunction,

moderate to severe myocardial ischemia, and/or mitral or

tricuspid valve regurgitation (Table III).

Myocardial ischemia induces cardiac dysfunction. If

coronary arterial stenosis is severe enough to induce myo-

cardial dysfunction,�O2/HR does not reach the standard

value. However, if coronary arterial stenosis is not so se-

vere for the myocardial ischemia to affect the whole ven-

tricular function,�O2/HR reaches a normal value. That is,

�O2/HR can be used to evaluate the severity of angina

pectoris.

Usually, when the heart rate increases, the diastolic

duration diminishes. Assuming the systolic duration (QT

interval on ECG) and PQ interval do not shorten during

exercise, and are fixed at 400 mseconds and 200 msec-

onds, respectively, when the heart rate reaches 100/min-

ute, there is no interval between the T wave and P wave.

That is, ventricular relaxation and atrial contraction occur

simultaneously. This phenomenon reduces the effect of the

atrial kick. A healthy heart can adjust to systolic and dia-

stolic agile movements. However, a diseased heart cannot

do so. As a result, the cardiac pump function decreases

when tachycardia occurs. That is, patients with diastolic

and systolic dysfunction sometimes show an early flatten-

ing of the slope during a ramp exercise.9) This flattening

often occurs at a heart rate of 110/minute (Figure 5).

�E/�CO2 and PETCO2 (Figure 6) are determined by

the degree of ventilation-perfusion mismatch (V/Q mis-

match). If patient does not have severe pulmonary dys-

function, these parameters are indicators of pulmonary ar-

terial perfusion and cardiac output.10) That is, when pul-

monary arterial perfusion decreases, V/Q mismatch in-

creases, and minute ventilation at a given work rate and�E/�CO2 become greater.11,12) In addition, when the volume

of the pulmonary arterial perfusion is small, or the

amount of carbon dioxide in the pulmonary arterial flow

becomes smaller, the partial pressure of alveolar CO2

(PACO2) diminishes. Since end-tidal gas primarily consists

of alveolar gas, PETCO2 is equal to PACO2. A smaller

amount of PETCO2 is an indicator of less CO2 production

in the body and/or pulmonary arterial perfusion, or in

other words, the cardiac output (Figure 7). Cardiac reha-

bilitation is reported to improve these parameters.13)

Because the heart rate is included in �O2/HR, the

collection of data during the use of beta-adrenergic recep-

tor blockers should be avoided. Further, as the maximum

and minimum values of�E/�CO2 and PETCO2 are ob-

tained at the respiratory compensation point (RCP), when

the examination is stopped before RCP, these parameters

do not indicate cardiac output. The characteristics of each

parameter are shown in Table IV.

Indicators of shortness of breath - TV-RR slope, Ti/Ttot, breathing reserve: Shortness of breath during exer-

cise is induced by pathological responses to exercise. Ex-

cessively rapid RR, excessively augmented minute ventila-

tion, and diminished breathing reserve are the main causes

(Table V).

Typically, the RR increases abruptly at the AT (Fig-

Int Heart J


Figure　5.　Tachycardia and diastolic function. In patients with impaired cardiac function, the re-

duction in QT and PQ interval during exercise is small. Therefore, in patients with tachycardia, ear-

ly diastole and late diastole increase while pump function decreases.

Figure　6.　V4

EE/V4

CO2, V4

E/V4

O2, PETCO2, and PETO2 during a ramp protocol. V4

E/V4

O2 and

PETO2 reach a nadir at AT. V4

E/V4

CO2 and PETCO2 start to rise or decrease at RCP.

ure 8A, B). However, if the RR at rest is faster than a

normal value and the rate of increase during lighter inten-

sity exercise is greater, this is called a “rapid and shallow

breathing pattern”, which is one of the main causes of

shortness of breath (Figure 8C). This condition often in-

duces shortness of breath during mild activity.14) A rapid

and shallow breathing pattern can be improved by cardiac

rehabilitation.15)

Ventilation is regulated by the sensitivity of respira-

tory chemoreceptors and the ergo reflex in skeletal mus-

cles. The sensitivity of respiratory chemoreceptors in-

creases when the sympathetic nerve is activated and/or

acidosis occurs. These conditions often occur in heart fail-

ure patients as well as in exceedingly sedentary individu-

als whose skeletal muscles are atrophic. These subjects

experience shortness of breath throughout mild to vigor-

ous activity.

Usually, subjects stop pedaling during CPX because

they experience severe leg fatigue or are unable to con-

tinue pedaling due to weak leg power. However, patients

with chronic obstructive pulmonary disease (COPD) or re-

strictive lung disease experience shortness of breath that is

more severe than the leg fatigue, and the shortness of

breath limits their results. These patients cannot perform

more intense activity because they literary cannot breathe

more.

In patients with lung disease, ventilatory limitations

sometimes determine exercise tolerance. In severe COPD

patients, the difference between maximal voluntary venti-

lation (MVV) and peak VE becomes so small (less than

Int Heart J


Figure　7.　Conception diagram showing how PETCO2 changes. In a normal alveolus (left panel, left alveolus), CO2

diffuses almost completely from the pulmonary artery (Pa) to the alveolus (A). While in insufficiently expanded and

with increased dead space between artery and alveolus (left panel, right alveolus), diffusion of CO2 is less. Combined

with these gases, PETCO2 near the mouth is approximately 40 mmHg. During exercise, CO2 production from the skel-

etal muscle, pulmonary arterial flow, and alveolar parameters related to breathing increase. Hence, PETCO2 increases.

Table　IV.　Comparison of Peak V4

O2/HR, VE/V4

CO2 at RCP, PETCO2 at RCP

Parameter Denotation Required condition

Peak V4

O2/HR Stroke volume Needs to perform peak exercise

BB affects the result

VE/V4

CO2 at RCP Cardiac output Needs to perform exercise until RCP

PETCO2 at RCP Cardiac output Needs to perform exercise until RCP

Muscle mass affects the results

BB indicates beta-adrenergic receptor blockers.

Table　V.　Causes of SOB and CPX Results

Parameter Value Basal disease

V4

E/V4

CO2 at RCP 34 Heart failure

Breathing pattern Rapid and shallow

TV/RR slope < 90 Heart failure

Cardiac surgery (Sternotomy)

Obesity

Breathing reserve Peak V4

E/MVV > 0.6-0.9 COPD

MVV - Peak V4

E < 11L/minute

Peak TV = IC Restrictive lung disease

Ti/Ttot Abrupt drop < 0.4 COPD (air trapping)

11 L/minute or 10-40% of the MVV) that the patient

finds it difficult to continue pedaling. On the other hand,

in restrictive lung disease patients, inspiratory capacity

(IC) and peak TV become so close that the patient cannot

continue pedaling. These parameters are called the breath-

ing reserve (BR) (Figure 9).

CPX also reveals how a subject breathes during exer-

cise. As was previously described, the TV-RR relationship

demonstrates the existence of the rapid and shallow

breathing pattern. The time trend graph for�O2,�CO2,

and�E sometimes shows an oscillatory pattern (Figure

10). This ventilation pattern is often seen in heart failure

patients. Exacerbated chemosensitivity, diminished blood

flow velocity, and decreased PaCO2 relate to this phe-

nomenon. In addition, if the cardiac function is severely

deteriorated, and depends on afterload instead of preload,

cardiac output rhythmically changes due to the fluctuation

of the diameter of the aorta. This leads to the oscillatory

patterns for�O2,�CO2, and�E. The prognosis for patients

with oscillatory ventilation is poor,16,17) but cardiac reha-

Int Heart J


Figure　8.　RR threshold and TV/RR relationship. The respiratory rate increases abruptly at the anaerobic threshold

(AT) and respiratory compensation point (RCP). RR indicates respiratory rate; and TV, tidal volume.

Figure　9.　Breathing reserve. BR indicates breathing reserve; MVV,

maximal voluntary ventilation; IC, inspiratory capacity; and V4

E, min-

ute ventilation.

bilitation improves oscillatory ventilation.18)

The ratio of inspiratory time to whole respiratory

time (Ti/Ttot) abruptly diminishes a few minutes before

the peak exercise intensity in patients with pulmonary em-

physema. Usually, Ti/Ttot is maintained between 0.4 and

0.5 in normal subjects (Figure 11A). However, in severe

emphysema patients, the ratio abruptly decreases to nearly

0.35, and these patients cannot continue pedaling because

of shortness of breath (Figure 11B).

Severity of heart failure - AT, peak�O2,�E/�CO2,�Eversus�CO2 slope, PETCO2, time constant (τ on): As

heart failure becomes more severe, exercise tolerance

worsens. That is, both the AT and peak�O2 diminish.19)

This is not only due to the impaired cardiac function but

also due to deteriorated skeletal muscle function and en-

dothelial cell function, as well as abnormal autonomic

nerve function. In addition, due to the increased

ventilation-perfusion (V/Q) mismatch, �E/�CO2 at RCP

and the�E versus�CO2 slope increases, while PETCO2 at

RCP decreases. Impaired cardiovascular response in heart

failure patients leads to a prolonged time constant (τ on)

and the prognosis for patients with abnormal parameters is

poor.20-22) CPX parameters related to the severity of heart

failure are shown in Table VI.

Detecting the state of autonomic function - Heart rateanalysis: In heart disease, the state of autonomic nerve

function is an important factor for determining the prog-

nosis. Therefore, clarifying how much the sympathetic

and parasympathetic nerve function is activated is useful

to treat patients.

At rest and during mild exercise, heart rate is regu-

lated by parasympathetic nerve function. Therefore, a

rapid heart rate at rest is a sign of attenuated parasympa-

thetic nerve function. During moderate to vigorous exer-

cise intensity, sympathetic nerve activity regulates the

heart rate. In other words, in the event of exaggerated

sympathetic nerve activity, ΔHR/ΔWR diminishes. This is

called “chronotropic incompetence.” Usually, the heart

rate increase during a ramp exercise is approximately 0.6

Int Heart J


Figure　10.　Oscillatory ventilation. Oscillation in V4

E is defined as follows: a cycle length of approximately 80 sec-

onds, amplitude > 15% of resting V4

E, and duration > 60% or 66% of exercise duration.

Figure　11.　Ti/Ttot. Ti/Ttot is the ratio of inspiratory rate (Ti)

against total ventilation period (Ttot).

beats/minute per watt (Figure 12A). In chronotropic in-

competence, this value becomes lower than 0.6. An im-

paired heart rate response to the exercise is another sign

of exaggerated sympathetic nerve function. Characteristi-

cally, this is often observed in heart failure patients (Fig-

ure 12B). Beta-adrenergic receptor blocker administration

results in a lower resting heart rate and a lower heart rate

response to exercise (Figure 12C). Exercise training for

chronic heart failure patients improves the heart rate at

rest and the chronotropic incompetence (Figure 12D).

Rarely, there exists a patient whose heart rate does

not increase during a ramp exercise although their auto-

nomic nerve activity does not change (Figure 13). In pa-

tients with pacemakers who have sick sinus syndrome or

some kind of arrhythmia such as atrial tachycardia, the

heart rate stays nearly constant. In patients with severe

heart failure, and those that have undergone open heart

surgery or heart transplantation, the increase of heart rate

during a ramp exercise is blunted (Table VII).

Comparison of Each Parameter

AT and peak�O2: Usually, AT and peak�O2 decrease

similarly. If %peak�O2 is lower than %AT, there are 4

possible mechanisms. One is patient motivation. If the

subject stops pedaling below the peak intensity, %peak

�O2 becomes smaller than %AT. The next mechanism is

the problem of the subject’s muscle power. When a pa-

tient’s muscle power is too weak, he/she sometimes can-

not pedal an ergometer sufficiently. As for the linearity of

the�O2 increase, oxygen uptake increases linearly during

the examination unless the subject’s pedaling speed de-

creases.23)

If the increase in stroke volume during exercise de-

creases, and the subject’s heart rate response is blunted

primarily due to beta-adrenergic receptor blocker admini-

stration, %peak�O2 also becomes smaller than %AT. De-

teriorated cardiac output improvement during exercise re-

duces the oxygen uptake by working skeletal muscle.

However, when the increase in stroke volume does not

match the oxygen demand of the working muscle, the

heart rate usually increases to increase the blood flow and

oxygen supply. Therefore, in cases of limited heart rate

increase, %peak�O2 becomes smaller than %AT. This is

the third mechanism.

Int Heart J


Figure　12.　Heart rate response to the exercise. The thick solid line

(A) is the heart rate response of normal subjects. In heart failure, the

resting heart rate increases and the response to exercise becomes

blunted (thin solid line B). When a beta-adrenergic receptor blocker is

used, line B moves to line C. After successful cardiac rehabilitation,

chronotropic incompetence is ameliorated (dashed line D). Dotted line

E is the heart rate response for patients who underwent heart transplan-

tation.

Table　VI.　CPX Parameters in Heart Failure

Parameter Without BB With BB With BB + CRP

Peak V4

O2 low low slightly low - normal

Anaerobic threshold low low slightly low - normal

V4

E/V4

CO2 at RCP high high slightly high - normal

V4

E versus V4

CO2 slope steep steep slightly steep - normal

Peak V4

O2/HR low normal - high normal - high

PETCO2 at RCP low low slight low - normal

HR at rest high normal - low normal - low

HR response to exercise low low slightly low - normal

Time constant prolonged prolonged slightly prolonged

Respiratory pattern rapid and shallow slightly rapid and shallow slightly rapid and shallow - normal

BB indicates beta-adrenergic receptor blockers; and CRP, cardiac rehabilitation program.

Additionally, if oxygenation enzyme activity deterio-

rates, oxygen uptake during exercise decreases. In particu-

lar, since oxygen consumption depends mainly on meta-

bolic improvement above AT, the slope of oxygen uptake

becomes shallower, resulting in the mismatch of %peak

�O2 and %AT.

A comparison of AT and peak�O2 is shown in Table

VIII.

Peak�O2 versus peak�O2/HR: Performing peak exer-

cise is dependent on many factors, including sufficient

cardiac, skeletal muscle, and vascular endothelial cell

functions. On the other hand, peak�O2/HR is regulated

mainly by cardiac function. Therefore, when %peak�O2/

HR is disproportionately smaller than %peak�O2, cardiac

function during exercise is assumed to be impaired. On

the other hand, when %peak�O2/HR is greater than %

peak�O2, the primary cause of impaired exercise toler-

ance is attributed to skeletal muscle dysfunction. Of

course, if the subject is taking beta-adrenergic receptor

blockers, this does not hold true, because beta-adrenergic

receptor blockers cause a higher than expected�O2/HR.24)

Peak�O2 and�E/�CO2 at RCP: As was described pre-

viously, the peak �O2 is affected not only by cardiac

pump function, but also by skeletal muscle function. On

the other hand,�E/�CO2 at RCP (minimum�E/�CO2) is

mainly determined by pulmonary blood flow in heart dis-

ease if the subject does not have severely impaired pulmo-

nary function. Therefore, we can determine whether the

impairment is in the heart or in the skeletal muscle.

The relationship between %peak�O2 and�E/�CO2 at

RCP is not linear, as is shown in Figure 14. A normal

subject is plotted with open circles as A. A typical heart

failure patient is plotted as B. The improvement of cardiac

function without skeletal muscle function such as when

using a left ventricular assist device changes the plot from

B to C.25) After exercise training, the plot changes from C

to D. When the V/Q mismatch is high, as seen in chronic

thromboembolic pulmonary hypertension (CTEPH), pul-

monary arterial hypertension (PAH), or pleural effusion,

the patient often presents as E.

Clinical Application

How to determine the appropriate AV delay: In cardiac

resynchronization therapy (CRT), the optimal atrioven-

tricular (AV) delay must be determined to obtain the most

favorable effect. If the patient can walk a little, the opti-

mal AV delay should be the value that results in the great-

est cardiac output during exercise. The parameters for car-

diac output and/or pulmonary blood flow during exercise

are�O2/HR and�E/�CO2. CPX can reveal the greatest

cardiac output during exercise. Because the exercise toler-

ance of a patient who requires CRT is very low, we use a

watt load of 0 to 10. These loads are 1.5 to 2.5 METs,

consistent with a highly sedentary daily activity. The set-

ting of AV delay that shows the greatest�O2/HR and low-

est�E/�CO2 at this intensity is adopted (Figure 15).

How to determine the best rate response for the pacingdevice: The rate response is an important function that

improves exercise tolerance. CPX is repeated a few times

with different rate response patterns. The rate response

setting that shows the greatest�O2 and lowest�E/�CO2 at

a given work rate is the best setting. Because CPX must

be performed repeatedly, CPX until exhaustion should be

avoided.

Beta-adrenergic receptor blocker or stimulator?: To

determine whether a beta-blocker or a beta-stimulator is

more favorable for patients who experience shortness of

breath, respiratory pattern, breathing reserve, Ti/Ttot at

peak exercise, peak�O2/HR, and peak�O2 are evaluated.

Int Heart J


Figure　13.　The heart rate response of patients after open heart surgery during. A ramp protocol.

Figure　14.　The graph of V4

E/V4

CO2 at RCP as a function of %peak V4

O2.

Table　VII.　Causes of Diminished

Heart Rate Response to Exercise

Causes

Heart failure

Beta-adrenergic receptor blocker

Open heart surgery

Transplanted heart

Pacemaker

Atrial flutter

Atrial Tachycardia

Supraventricular tachycardia

Table　VIII.　Comparison of %anaerobic Threshold (AT) and %peak

V4

O2

Variable

%AT > %peak V4

O2 Diminished muscle power/ metabolism

Rejection against CPX

Impaired cardiac function under condition

of BB usage

%AT < %peak V4

O2 After successful cardiac rehabilitation

BB indicates beta-adrenergic receptor blockers.

Int Heart J


Figure　15.　Response of V4

E/V4

CO2 and stroke volume to various AV delays. This is a sample from a pa-

tient with cardiac resynchronization therapy defibrillator (CRT) implantation. Her best AV delay was deter-

mined to be 200 mseconds/160 mseconds (Ap/As) through echocardiography measured on a bed in a recum-

bent position. We tested 3 AV delays to determine the most effective value during daily activity. When AV

delay was set to Ap/As 130 mseconds/100 mseconds, V4

E/V4

CO2 was lowest and stroke volume was highest.

Therefore, AV delay was set as 130/100. After that, her shortness of breath disappeared.

Using these parameters, we can determine whether the pa-

tient’s basal problem is in the lungs or in the heart. After

that, we can select a beta-adrenergic receptor blocker or

stimulator correctly.

Should ASV be discontinued or not?: Since the publica-

tion of SERVE-HF,26) the use of adaptive servo-ventilators

(ASV) is being discontinued, although the favorable effect

of ASV for Japanese heart failure patients was established

by the SAVIOR-C27) investigation. Following abrupt dis-

continuation of ASV usage, the exacerbation of heart fail-

ure is often experienced. To avoid inappropriate exacerba-

tion, CPX should be performed before the discontinuation

of ASV. If the patient still has an unstable respiratory pat-

tern such as oscillatory ventilation or irregular respiration,

and/or abnormal heart rate response, it means that the pa-

tient still has impaired cardiac function and severely de-

ranged autonomic nerve function. Because ASV can im-

prove these dysfunctions, ASV is determined to be sill

necessary. It is important to remember that the effect of

ASV for chronic heart failure is not only extinction of

sleep apnea but also increasing the exercise tolerance by

improving the cardiac output and autonomic nerve de-

rangement.

Determining the need for PCI for stable angina pecto-ris: If the patient has significant coronary arterial stenosis,

CPX should be performed. If ST depression, flattening of

�O2/HR due to myocardial ischemia, and a sensation of

chest pain occur during mild activity with optimal medical

treatment, PCI or coronary artery bypass grafting (CABG)

should be considered. If these responses are not observed

until AT, interventional treatment should be avoided, be-

cause coronary stenosis does not induce angina pectoris

during daily activity. Further, PCI sometimes induces new

lesions due to the catheters and/or wires used. It must be

kept in mind that diagnosis and determination of the se-

verity of angina pectoris should be achieved not with frac-

tional flow wire reserve (FFR) wires, but with symptoms

during exercise.

Acknowledgment

This article was carefully checked by Dr. Karlman

Wasserman who was formerly my boss, for which I am

very grateful.

Disclosures

Conflicts of interest: None.

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