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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Cardiopulmonary Exercise TestingWhat Is its Value?

Marco Guazzi, MD, PHD,a Francesco Bandera, MD, PHD,a Cemal Ozemek, PHD,b David Systrom, MD,c,d

Ross Arena, PHDb

ABSTRACT

Fro

Mi

Sci

Me

Ce

rel

Ma

Compared with traditional exercise tests, cardiopulmonary exercise testing (CPET) provides a thorough assessment of

exercise integrative physiology involving the pulmonary, cardiovascular, muscular, and cellular oxidative systems. Due to

the prognostic ability of key variables, CPET applications in cardiology have grown impressively to include all forms of

exercise intolerance, with a predominant focus on heart failure with reduced or with preserved ejection fraction. As

impaired cardiac output and peripheral oxygen diffusion are the main determinants of the abnormal functional response

in cardiac patients, invasive CPET has gained new popularity, especially for diagnosing early heart failure with preserved

ejection fraction and exercise-induced pulmonary hypertension. The most impactful advance has recently come from the

introduction of CPET combined with echocardiography or CPET imaging, which provides basic information regarding

cardiac and valve morphology and function. This review highlights modern CPET use as a single or combined test that

allows the pathophysiological bases of exercise limitation to be translated, quite easily, into clinical practice.

(J Am Coll Cardiol 2017;70:1618–36) © 2017 by the American College of Cardiology Foundation.

I n cardiopulmonary disorders, exercise intoler-ance is a major clinical feature from early stages,and becomes a source of symptoms and the

reason for referral to a physician. Exercise limitationis one of the most disabling problems experiencedby patients with heart failure (HF) (1). Its quantifica-tion may be approximated by several methods, but athorough analysis of the organ systems and pathwaysinvolved in the impaired physiological response isobtained by exercise gas exchange analysis withcardiopulmonary exercise testing (CPET). Thistechnique enables the clinician to scrutinize reasonsfor dyspnea and fatigue to precisely differentiatecardiac from pulmonary disorders, optimize thedecision-making process and outcome prediction,and objectively determine targets for therapies (2).Furthermore, CPET has become a reproducible (3)and safe technique (4).

m the aUniversity of Milan, Cardiology University Department, Heart Fai

lanese, Milan, Italy; bDepartment of Physical Therapy, Department of K

ences, University of Illinois at Chicago, Chicago, Illinois; cDivision of Pu

dicine, Brigham and Women’s Hospital and Harvard Medical School, B

nter, Brigham and Women’s Hospital, Boston, Massachusetts. The auth

evant to the contents of this paper to disclose.

nuscript received August 1, 2017; accepted August 2, 2017.

Despite this attractive evidence base and the clinicalpotential of CPET, the question put forth in the title ofthe present review (i.e., what is the value of CPET), isnot trivial, and the definitive response requiresmentioning a few historical notes and passages.

The idea of a CPET application in cardiology wasintroduced in the early 1980s byWeber et al. (5), whosework allowed the landmark classification of patientswith HF with reduced ejection fraction (HFrEF) basedon peak oxygen consumption (VO2), from A (peak VO2

> 20 ml $ kg�1 $ min�1) to D (peak VO2 < 10 ml $ kg�1 $

min�1) through B (peak VO2<20 to>15ml $kg�1 $min�1)and C (peak VO2 < 15 and 10 ml $ kg�1 $ min�1).

A few years later, Mancini et al. (6), in their seminal1991 paper, demonstrated that VO2 measured at peakexercise stratifies the risk of cardiovascular (CV) deathat 1 year in ambulatory patients with advanced HF.These remarkable findings were subsequently

lure Unit, IRCCS Policlinico San Donato, San Donato

inesiology and Nutrition, College of Applied Health

lmonary and Critical Care Medicine, Department of

oston, Massachusetts; and the dHeart and Vascular

ors have reported that they have no relationships

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AB BR E V I A T I O N S

AND ACRONYM S

CaO2 = arterial oxygen content

CO = cardiac output

CPET = cardiopulmonary

exercise testing

CvO2 = venous oxygen content

EOV = exercise oscillatory

ventilation

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

HFrEF = heart failure with

reduced ejection fraction

PETCO2 = end-tidal pressure of

carbon dioxide

PETO2 = end-tidal pressure

of oxygen

tau = time constant

VCO2 = volume of carbon

dioxide released

VD = dead space

VE = ventilation

VO2 = peak oxygen

consumption

tidal volume

J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7 Guazzi et al.S E P T E M B E R 2 6 , 2 0 1 7 : 1 6 1 8 – 3 6 Cardiopulmonary Exercise Testing

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validated and reproduced by several laboratories (7,8).This solid evidence perhaps led to a quite paradoxicalstatic vision of CPET applications for a long period (i.e.,until the 2000s), with a single parametric approachfocused just on advanced HF.

In the last 15 years, the utility of CPET has beenincreasingly recognized by both extending medical in-terest to the physiological bases of many variables thatwere previously under-recognized and by aligning evi-dence for a multivariable approach, including primarilyabnormalities in ventilation and its control (1). In HF, thecombined use of variables has led to the generation ofalgorithms (9) and risk scores (10–12) covering the entireset of HF stages. This process has been witnessed andvalidated by a significant number of official documentsand statements definitively (1,2,13) entering exercise gasexchange variables as study endpoint in the assessmentof the effects of emerging pharmacological therapies(14,15) and in interventional trials (16,17). Along with themain developments in HF, the role of routine CPET incardiology has been extended to specific patient pop-ulations, including those with suspected ischemic heartdisease (18), congenital heart defects (19), valve diseases(20), hypertrophic cardiomyopathy (21), suspected orconfirmed pulmonary arterial hypertension (PAH) (22),and left-sided pulmonary hypertension (PH) (23).

In this paper, the modern key applications of CPETin CV diseases, with primary emphasis on HF, arediscussed, starting from the principles that precipi-tate reduced exercise performance and impairedventilation, and highlighting the most recent de-velopments on combining exercise invasive hemo-dynamic and stress echocardiography with gasexchange evaluation. The large body of evidence onthe established pathophysiological clinical and prog-nostic impact of CPET-derived variables will beemphasized, making a continuum of value fromphysiological bases to their translation into thepractical applications. Accordingly, CPET is hereproposed as a technique that may provide significantand synergistic advancements in the process ofprecision medicine and phenotyping.

GAS EXCHANGE ANALYSES AND

THE PRINCIPAL BASES FOR

EXERCISE LIMITATION IN HF

OXYGEN TRANSPORT AND USE. The body underphysical stress behaves as a perfect machine that in-tegrates and harmonizes the functional responses ofmultiple organs and pathways. In this process, thedelivery of oxygen (O2) to mitochondria is essential toperform at aerobic capacity (24). Optimal O2 deliverydepends on a set of elegant biological interactions

between the functional components of the O2

transport chain, which requires oxygenationof the blood in the lung (alveolar diffusion),normal O2-carrying capacity of the bloodby adequate cardiac output (CO), yieldingto its redistribution to working muscles(delivery or convection) and adequate O2

release, diffusion from capillaries to cells,and tissue extraction from the blood(Central Illustration).

HF represents the typical condition wheremost of these pathways exhibit a maladaptiveresponse, impeding attainment of maximalVO2 because of the reduction in muscle O2

supply simultaneous with increasing de-mands for O2. Maximal performance istherefore defined by VO2 at peak exercise,conventionally measured as the VO2 averagedover a 20- to 30-s period at maximal effort,pending attainment of a respiratory exchangeratio (RER) >1.15 (1).

Measuring peak VO2 and, especially, thepercentage predicted, normalized to age-,sex-, and weight-based normative values, isthe gold standard to objectively assess func-tional limitations in cardiac patients (1).

What are the major pathophysiological reasons fora low peak VO2 in cardiac patients? These can bedescribed by analyzing the framework of the Fickprinciple (i.e., VO2 ¼ CO � [CaO2 � CvO2], where CO iscardiac output [stroke volume � heart rate], CaO2 isarterial oxygen content, CvO2 is venous oxygen con-tent, and [CaO2 � CvO2] is the arteriovenous [a-v]difference in O2).

On the basis of this equation, delivery or convec-tion and extraction are the 2 physiological processesthat convey O2 use through cellular pathways.O2 delivery is not only described by CO distribution,but is also the O2 content and the mechanismsinvolved in O2 dissociation from hemoglobin (Hb).O2 content is 1.34 (which corresponds to the ml of O2

carried by each gram of Hb) � O2 saturation � Hbconcentration.

Extraction is the net result of the chain of O2

transport and use, and depends on the ability of O2 todiffuse from capillaries to cells and on mitochondriafunction.

Normal, healthy adults can increase VO2 up to6-fold during exercise. The relative contributionof Fick’s equation determinants to VO2 changes isapproximately 1.2-, 2.5-, and 2.5-fold for strokevolume, heart rate, and CaO2 � CvO2, respectively.

Landmark pioneering studies (5,25) performed inpatients with HFrEF first demonstrated that low peak

VT =

CENTRAL ILLUSTRATION Determinants of the O2 Transport and Utilization Chain Framed on the Fick Principle

Guazzi, M. et al. J Am Coll Cardiol. 2017;70(13):1618–36.

Optimal O2 delivery depends on the optimal biological interaction between functional components of the O2 transport chain. This requires oxygenation of the blood in

the lung (alveolar diffusion), normal O2 carrying capacity of the blood by adequate CO; CO redistribution to working muscles (delivery or convection), and efficient O2

release, diffusion from capillaries to cells, and tissue extraction from the blood. The arteriovenous O2 difference reflects the extraction of O2 from mitochondria by

muscle cells. ATP ¼ adenosine triphosphate; CaO2 � CvO2 ¼ the arteriovenous difference in oxygen; CO ¼ cardiac output; Hb ¼ hemoglobin; HFpEF ¼ heart failure

with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; O2 ¼ oxygen; VO2 ¼ peak oxygen consumption.

Guazzi et al. J A C C V O L . 7 0 , N O . 1 3 , 2 0 1 7

Cardiopulmonary Exercise Testing S E P T E M B E R 2 6 , 2 0 1 7 : 1 6 1 8 – 3 6

1620

VO2 is tightly related to a limited CO increase andquite reasonably preserved peripheral O2 use. Whendata were stratified according to functional impair-ment, even Weber class D patients, despite having noincrease in CO, were still able to maintain theirCaO2 � CvO2 difference within the lower-normalrange (12 to 16 ml/dl). The underlying pathophysi-ology needs, of course, to be complemented with theconcept that along with reduced CO, several patientswith HF may have anemia and a lower O2 concen-tration, thus further impairing O2 delivery andchallenging the a-v O2 difference, irrespective of theability to efficiently extract O2 (1).

Intriguingly, observations have suggested thatiron deficiency in nonanemic patients with HF isresponsible for worse exercise performance andexercise gas exchange phenotypes (26). Theseobservations have been confirmed over time byseveral studies proving that in HFrEF, the capability

to extract O2 remains preserved thanks to an “opti-mized” peripheral blood flow redistribution and highmitochondrial activity (27–29), and that the cause ofan inadequate increase in CO is predominant, eventhough likely not exclusive. An additional set ofremarkable works aimed at assessing how much animpaired O2 diffusion may be involved in the lowaerobic performance (30), on the basis of Fick’s lawof diffusion: VO2 ¼ D � K � (PaO2 � PvO2), where D isequal to the O2 diffusive capacity (D), K is a constant,which is the ratio between arterial and venous O2

partial pressure (which is approximately 2), and(PaO2 � PvO2) is the capillary mitochondrial differ-ence, assuming an intracellular partial pressure of O2

close to 0.The relation of delivery or convection (Fick prin-

ciple) and diffusion (Fick’s law) can be represented ona diagram relating VO2 and PvO2, which are commonto both equations (Figure 1A).

FIGURE 1 The Relationship Between O2 Diffusion and Convection

3500

3000

2500 Peak

Peak

A

E

Controlpeak VO2

Fick law lines

Fick principle lines

C

D

B

30 W 30 W 30 W

RestRestCONVECTION

CONVECTION: VO2 = Q x [CaO2 – CvO2]

DIFFUSION

DIFFUSION: VO2 = D x k x PvO2

VO2 peak

2000

1500

1000

500

001009080706050403020100 2

Controls HFpEF HFrEF

4 6 8 10CvO2 in ml/dl

VO2 i

n m

l/min

Leg

VO2 (

ml/m

in)

Muscle Venous PO2 (Torr)

4000

A B C

3000

2000

1000

0

Oxyg

en C

onsu

mpt

ion

ml/m

in

Muscle Venous PO2, mm Hg12 14 16 18

(A) Scheme of the 2 relationships of delivery or convection (Fick principle) and diffusion (Fick’s law) in the diagram relating VO2 and in venous O2 pressure, which are

common to both equations (30). (B) Relative impairment of convection versus diffusion by 2 different exercise modalities, incremental test at maximum (A and B)

versus local isolated knee extension (C and D) (28). (C) VO2 and PvO2 relationship in a group of patients with HFrEF, HFpEF, and controls, showing a limitation in either

diffusion and convection (33). CaO2 ¼ arterial oxygen content; CvO2 ¼ venous oxygen content; D ¼ the O2 diffusive capacity; HFpEF ¼ heart failure with preserved

ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; K ¼ a constant (the ratio between arterial and venous O2 partial pressure, which is

approximately 2); O2 ¼ oxygen; PO2 ¼ oxygen pressure; PVO2 ¼ venous oxygen pressure; Q ¼ cardiac output; VO2 ¼ peak oxygen consumption.


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As proposed by Wagner (30), the diagram relatesVO2 to the muscle-venous PO2 from rest to peakexercise, with the lines of convection and diffusioncrossing the axes and intercepts, and whose slopevaries according to the muscle-venous PO2, with anupper and leftward shift representing the best diffu-sion, whereas the point of intersection between the 2lines represents the VO2 max (i.e., the resultant ofconvection and diffusion).

In a set of elegant, controlled experiments per-formed in HFrEF (28), the relative impairment ofconvection versus diffusion was assessed by testingthe same patients with 2 different exercise modal-ities: an incremental test at maximal exercise (needfor CO increase, central challenge) versus a localisolated knee extension (need for increase in O2

extraction, peripheral challenge) (Figure 1B). Theseexperiments were paralleled by the analysis of mus-cle fiber type, mitochondria volume, and thecapillary-to-fiber ratio.

Interestingly, skeletal muscle and mitochondriacontributed minimally to O2 limitation, in agreementwith the concept that mitochondrial oxidativecapacity largely exceeds O2 delivery at peak VO2 (31).Rather, patients with HF, compared with controls,exhibited an attenuation of convective and diffusivecomponents of O2 transport, both during maximalexercise and knee extension.

How do these concepts adapt to HF with preservedejection fraction (HFpEF) syndrome? Whereas some

pathophysiology overlaps between the 2 HF pheno-types, there is more uncertainty and unequivocaldefinition on the O2 transport/utilization-limitingsteps involved in the functional response of patientswith HFpEF. These patients are elderly and anemic ina high rate of cases, and exhibit a decreased totalcirculating red blood cell volume in 9 of 10 patientsaffected by Hb-based anemia, thus presenting withimpaired blood O2 carrying capacity (32). In addition,they may show a defect in O2 diffusion and lower(a-v) O2 (Figure 1C) (33).COMPLEMENTARY CPET-DERIVED MEASURES OF

AEROBIC EFFICIENCY. Although peak VO2 describesthe net limitation in exercise capacity, an even morecomprehensive idea of aerobic efficiency is obtainedby measuring the VO2 at the first ventilatory threshold(VT). VO2 at first VT reflects the metabolic conditionabove which blood lactate and pH start to increase anddecrease, respectively, generating isocapnic compen-satory acidotic buffering by bicarbonate (HCO3

�).There are 3 CPET-derived methods for detecting VO2 atthe first VT: the V-slope (i.e., the point at which theincremental volume of carbon dioxide [CO2] released[VCO2] becomes higher, as compared with VO2, due tothe additional CO2 produced by lactic acid buffering);the end-tidal CO2 (PETCO2) versus the end-tidal O2

(PETO2) method (when a divergent kinetic point of thesevariables occurs with PETO2 progressively increasingand the PETCO2 slightly decreasing) and the minuteventilation (VE)/VO2 versus VE/VCO2 ratio change in

FIGURE 2 VO2/WR Relationship and the Phenotypes Encountered in Cardiac Failure

VO2

BA

DC

WR

shallow

VO2

WR

downsloping

35 sec

VO2/WR slopearound 10 ml/min x watt

WR

peak VO2(average 30 sec)

VO2

WR

flattening

VO2

(A) In normal individuals, the increase in the VO2/WR relationship is 10 ml/kg/min irrespective of the ramp protocol. Physical deconditioning

and initial cardiac limitation to exercise make this relationship shallow (B). Two patterns have been described in patients with advanced heart

failure: VO2 flattening (C) (i.e., loss of linearity from a certain point of exercise) and downsloping (D), which is tightly related to an acute drop

in cardiac output and blood pressure. VO2 ¼ peak oxygen consumption; WR ¼ work rate.



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pattern of increase (identifying the point of contin-uous increase in VE/VO2 and stable VE/VCO2 kinetics).The lack of VO2 at the first VT determination by any ofthese methods occurs in around 10% of patients withHF and carries a strong independent prognostic role(34). Measuring gas exchange during submaximalexercise response to constant workload is the goldstandard for studying the early VO2 kinetic timeconstant (tau) during exercise or recovery of exerciseO2 kinetics, which corresponds to 63% of the D _VO2

from rest to steady state (exercise) or vice versa(recovery) during a constant workload.

Tau provides additional objective information onthe mechanisms that control the ability to adapt toand recover from exercise indicative of daily lifeactivity (35). Along with an impaired tau, VO2 maytypically fail to linearly increase relative to energydemands as the work rate (WR) is increased (VO2/WR),resulting in delayed post-exercise recovery from amaximal test. During a maximal test, VO2/WR accu-rately reflects the extent of aerobically regeneratedadenosine triphosphate. In physiological conditionsand nonobese people, the VO2/WR linearity corre-sponds to a 10 ml/min increase per watt,

independently of the load imposed and slightlychanging according to exercise duration (Figure 2A).These assumptions, however, are not true in CV dis-orders, such as HF, and the pattern of VO2 increasemay change in a shallow downward shift (Figure 2B)or by VO2 flattening at a given WR (Figure 2C). There isthen an alarming, rare condition with VO2 down-sloping associated with an acute drop in blood pres-sure and CO (Figure 2D).

The last 2 patterns of VO2 generally match with asimilar O2 pulse, which is the ratio of VO2 to heart rateand reflects the amount of O2 extracted per heartbeat. The O2 pulse provides an estimate of left ven-tricular (LV) stroke-volume changes during exercise,assuming that C(a-v)O2 is maximal and no anemia orhypoxia is present. As the relative contribution ofstroke volume to CO is predominant during the initialand intermediate phases of exercise, the O2 pulse hasa typical hyperbolic profile, with a rapid rise duringthe initial stages of exercise and a slow approach to anasymptotic value at the end of exercise. Thus, onceVO2/WR changes in linearity, a flattening or even adownward displacement of O2 pulse kinetics duringprogressive CPET would very likely reflect a


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cardiogenic, rather than a peripheral vascular perfu-sion/extraction, limitation to exercise performance.Finally, the addition of systolic blood pressure to thepeak VO2, as circulatory power, has been proposedas having the potential to better investigate thecirculatory impairment (36).VENTILATORY EFFICIENCY AND LUNG MECHANICS.

Cardiac patients may exhibit a lung mechanical–related mechanism of exercise limitation, which istightly related to restrictive physiology due tocongestion and physical interaction between theheart and the lung (37). However, detection of lungmechanical dysfunction is often overlooked becausepatients with HF often display a normal breathingreserve, which is described by the relationshipbetween exercise VE and maximal breathing capacity,as estimated by resting maximal voluntary ventila-tion. Values <15% suggest a ventilatory limitation,and may help to discriminate between patients withHF and those with comorbid chronic obstructivepulmonary disease (COPD) (38).

The impaired breathing reserve would, however,be insensitive to mechanical ventilatory constraintscaused by differences in lung mechanics during ex-ercise compared to the maximal voluntary ventilationmaneuver. For this reason, the most recent consensusdocuments have introduced the use of flow-volumeloops as standard for the assessment of mechanicalVE limitation in cardiac versus lung disorders (2).Indeed, flow-volume loops supplement basic breath-ing mechanics information by identification of expi-ratory airflow limitation and changes in operationallung volumes during exercise.

Assessment of VE efficiency during CPET perhapsprovides the most relevant clues for addressing thepathophysiological changes behind the impairedexercise performance in HFrEF and HFpEF, especiallywhen associated with PH and right ventricular (RV)dysfunction (39,40). Similar reasoning may, in part,be applied to cases of post-embolic or idiopathic PAH.

An inefficient VE typically translates into anabnormal rate of increase in the slope of VE increaseversus VCO2 production. This relationship shows anear-linear increasing pattern that is determined by 3factors: the amount of CO2 produced; the physiolog-ical dead space/tidal volume ratio (VD/VT); and thearterial carbon dioxide partial pressure (PaCO2). Thisrelationship can be explained using the modifiedalveolar equation:

VE ¼ 863 � VCO2/(PaCO2 � [1 � VD/VT])For low and moderate intensities of work, the VE

response is tightly regulated by the PaCO2. At higherwork intensities, VE is affected by the increasedamount of VT over VD and the development of lactic

acidosis and proton (Hþ) production from theprevailing anaerobic metabolism, which furtherincreases CO2 release and the consequent amount ofVE. In HF, 3 different orders of mechanisms mediatean impaired VE requirement for a given CO2 produc-tion: increased waste ventilation (41,42); earlyoccurrence of decompensated acidosis (41,43); andabnormal chemoreflex and/or metaboreflex control(44). Recent findings obtained in HFpEF document aprimary role of increased VD/VT in causing a steepVE/VCO2 slope (45). In cases of a comorbid conditionwith COPD or COPD in isolation, high VD/VT mayprevail as a functional gas exchange abnormalitysustaining dyspnea sensation and hyperpnea (46).

The oxygen-uptake efficiency slope (OUES) is anunderused variable that reflects the global (pulmo-nary, CV, and skeletal muscle) functional impairmentby combining VO2 and VE/VCO2 slope. OUES is calcu-lated on the logarithmic transformation of VE data inliters/min (plotted on the x-axis), creating a linearrelationship with VO2 (plotted on the y-axis, whereVO2 ¼ log10 [VE þ b]). Given the tight linear relation-ship the OUES creates between VE and VO2

throughout a progressive exercise test (47), thiscalculation requires only submaximal effort.

Finally, an additional VE pattern at CPET evalua-tion, which is typically unmasked by gas exchangeanalysis, is an exercise oscillatory ventilatory (EOV)pattern (Figure 3) and consists of a cyclic fluctuationof VE and expired gas kinetics of variable amplitude,frequency, and duration detectable in up to 30% ofsymptomatic patients with HF (48). The source of thisventilatory abnormality is still controversial, but itsominous clinical and prognostic significance is clear(49,50). At variance with PAH, this pattern seemstypical of HF and pulmonary interstitial congestion,and a delayed circulatory transit time may explain theobserved differences (51).

APPLICATIONS OF CPET IN

CLINICAL PRACTICE

EVIDENCE INPREVENTIVEMEDICINEANDREHABILITATION

PROGRAMS. Application of CPET to primary andsecondary prevention is challenging. Interestingly, arole for CPET-derived data in detecting abnormal gasexchange pattern phenotypes has been just recentlyexplored in the general population at CV risk.An example is the European Exercise (EURO-EX)population-based trial, whose preliminary data havehighlighted some cases of EOV, typically occurring inthe phenotype of elderly diabetic women (52).

Overall, despite a wealth of persuasive evidenceand numerous statements supporting the utility of

FIGURE 3 9-Plot CPET Report of a Case of HFrEF With EOV

Time (sec)

VE (L

/min

) 0 100 200 300

0

20

40

60

80

Time (sec)0 100 200 300

0.0

0.5

1.0

1.5

0.0

0.5

1.0

1.5

VO2 (L/min)

HR (b

pm)

0.0 0.4 0.8 1.20

20

40

60

80

100

120

VCO2

VE (L

/min

)

0.0 0.4 0.8 1.20

20

40

60

80

Time (sec)

VE/V

O 2

VE/VCO2

0 100 200 3000

2

4

6

8

10

0

20

40

60

80

100

Time (sec)

HR (b

eats

/min

)

VO2 /HR

0 50 100 150 200 25060

70

80

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100

0.0

0.1

0.2

0.3

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VE (L/min)

V T (L) RR

0 20 40 60 800.0

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2.0

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Time (sec)

P ETO 2 (

mm

Hg)

PET CO

2 (mm

Hg)

0 100 200 30080

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40

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VO2 (

mL/

min

)

VCO 2 (

L/m

in) VO

2 (L/min)

0 10 20 30 400.0

0.5

1.0

1.5

EOV is a specific VE abnormal phenotype occurring in approximately 30% of patients with mid-to-late manifestations of chronic heart failure, characterized by

cyclic fluctuation of VE and expired gas kinetics of variable amplitude, frequency, and duration. Because oscillatory manifestations may occur even in normal

subjects, criteria for an abnormal definition are an oscillatory pattern at rest that persists for $60% of the exercise test at an amplitude of $15% of the average

resting value (2). CPET ¼ cardiopulmonary exercise testing; EOV ¼ exercise oscillatory ventilation; HR ¼ heart rate; PETCO2 ¼ partial pressure of end-tidal carbon

dioxide; PETO2 ¼ partial pressure of end-tidal oxygen; RR ¼ respiratory rate; VCO2 ¼ volume of carbon dioxide released; VE ¼ ventilation; VO2 ¼ peak oxygen

consumption; VT ¼ tidal volume.



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CPET in prevention and in early HF stages, practi-tioners have not generally adopted a portfolio ofvariables that provides a 3-dimensional view ofcardiorespiratory fitness with diagnostic and prog-nostic applicability, and an effective means to eval-uate therapeutic benefits.

In the realm of patient care, exercise testingwithout the simultaneous collection of expired gaseshas seemingly taken on a static role, with the singular

(but not exclusive) purpose of evaluating signs andsymptoms of coronary insufficiency (53). However,despite observations pointing out the high sensitivityand specificity of gas exchange analysis in detectingsuspected myocardial ischemia (53,54), few of themrecognize a CPET role.

Implementation of rehabilitation and exercisetraining (ET) programs is a Class I (55) to IIa (56) guide-line recommendation. In this context, implementation


1625

of CPET is 3-fold: 1) to plan correct exercise intensitylevel or domain; 2) to assess benefits of exerciseprescription by monitoring gas exchange variables andtheir related phenotypes; and 3) to identify subjectswho, despite adherence to the program, are non- or poorresponders to this multilevel intervention.

Although guidelines recommend the application ofobjective exercise prescriptions using CPET data (57),it is commonplace for programs without CPET capa-bilities or with limited resources to establish exerciseintensity on the basis of resting heart rate (e.g.,exercising heart rate threshold set 20 or 30 beats/minabove the resting heart rate). This simple method hasbeen criticized and demonstrated to be inadequate bymany. For example, Reed et al. (58) reported that only26% and 38% of participants were exercising at therecommended exercise intensity of 40% to 60% ofheart rate reserve (confirmed by CPET) when usingresting heart rate þ 20 and 30 beats/min, respectively.Patients exercising at 30 beats/min or above theirresting heart rates experienced significantly greaterincreases in 6-min walk distances comparedwith patients exercising at 20 to 29 beats/minabove resting heart rate, suggesting that the imple-mentation of CPET as a standard tool in cardiacrehabilitation programs can really help to optimizehealth-related outcomes.

Accordingly, the recent joint European Associationfor Cardiovascular Prevention & Rehabilitation(EACPR)/American Association of Cardiovascular andPulmonary Rehabilitation Statement provideddirections on the identification of ET intensitydomains by using constant WR exercise tests, lookingat the different kinetic responses to VO2 (57), which,although it may be impractical in most cases, remainsthe most accurate physiology-based approach. Briefly,VO2 kinetics during a constant WR exercise reflect 3phases of adaptation of the organ systems and factorsinvolved in the alveolar-to-cell O2 coupling. The 3phases are identified as: phase I, or cardiodynamic,during which the increase in VO2 is mediated by theimmediate increase in CO and pulmonary blood flow atthe start of exercise; phase II, or cell respiration,reflecting the decreased O2 content (muscle extrac-tion) and increased venous CO2 content secondary toincreased cell respiration, as well as a further increasein CO; and phase III, or the eventual steady-statephase, during which an equilibrium is reached be-tween O2 extraction and the CO2 production rate. If theWR is above the subject’s first VT, the rate of increaseduring phase III is not steady and correlates tightlywith the magnitude of lactate increase.

This background applies and allows for the preciseidentification of 4 exercise training domains whose

intensity is based on the physiology of O2 uptakekinetics: light to moderate; moderate to high;high to severe; and severe to extreme. The light-to-moderate– and moderate-to-high–intensity programsare performed by continuous exercise, a conditionthat is not sustainable for high-to-severe and severe-to-extreme protocols, requiring an interval exerciseapproach. Intensity domains of light to moderateencompass the corresponding WR that engenders aVO2 steady-state value below the corresponding firstVT. During this constant workload range and in thisdomain, a VO2 steady state is attained relativelyrapidly following the onset of exercise, and lactate isnot produced. For this reason, exercise can be verywell tolerated and is generally sustainable for longperiods of time (30 to 40 min) with only a mild senseof fatigue and breathlessness. The moderate-to-high–intensity domain corresponds to workloads betweenthe first and second VTs.

An improvement in functional capacity is the mostimmediate and objective result of an effective ETprogram. Although functional capacity is governed byan integrated response of multiple organ systems thatare wholly or partly involved in this response, benefitsof ET interventions are generally quantified as changesin VO2. The physiological background behind exercisecapacity response and the progressive familiarizationof the cardiac rehabilitation personnel with the gasexchange analysis technique points, however, to astep forward that is a more in-depth analysis andcomprehensive interpretation of exercise interventiontrials. Indeed, attention to the determinants of exer-cise improvement that may add to peak VO2, andpotentially result in even more remarkable demon-stration of efficacy, seems quite timely.

One example of this reasoning is the unexplored,but perhaps intriguing, question of how much ET mayimprove VO2 kinetics (tau and VO2/WR linearity),rather than peak VO2. Specifically, looking at favor-able modifications that ET may induce in patterns ofVO2/WR (i.e., shallow, typical of deconditioned car-diac patients, flattening, or downsloping associatedwith acute drop in blood pressure and CO) (Figure 2).Thus, an analysis of the effects of different exercisetraining programs may be of value when consideringthe potential to modify these abnormal patterns, evenwhen changes in peak VO2 per se are not remarkable.DIAGNOSTIC ROLE OF CPET IN HF. As the severity ofCV disease advances, the role of CPET in the diag-nostic setting of HF is not completely recognized. The2013 American College of Cardiology (ACC)/AmericanHeart Association (AHA) guidelines for the manage-ment of HF highlight the subjective nature of the ACCFoundation/AHA stages of HF and the New York



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Heart Association functional classification system.These are primarily based on patient interviews per-taining to the “severity and triggers of dyspnea andfatigue, presence of chest pain, exercise capacity aswell as physical and sexual activity” (59), and arethen followed by objective procedures for character-ization of LV structure/function and evaluation ofdiagnostic blood markers. Despite evidence of CPETas a strong predictor of future HF development, itsconsideration as a primary diagnostic tool iscautioned, mainly due to the manifestations commonto other chronic conditions (e.g., PAH, congenitalheart defects, and interstitial lung disease) (60).However, it seems more appropriate to use CPETvariables to guide the diagnosis of secondary patho-physiological consequences of HF, irrespective ofetiology. Assessment of exercise ventilatory patternsis particularly attractive in identifying left-sided PHdue to its physiological link with ventilation-perfusion matching. Identification of left-sided PH isparticularly important, given that it is prevalent inroughly 30% to 50% patients with overt HF andcarries a poor prognosis (61). The VE/VCO2 slope, thePETCO2, and the presence of EOV hold a high level ofprognostic utility (9). In a study of parallel evaluationof pulmonary pressure, a VE/VCO2 slope of </$36 wasfound to be the strongest predictor (odds ratio [OR]:12.1; p < 0.001) of a pulmonary artery pressure(PAP) $40 mm Hg, followed by peak exercise PETCO2

(</$36 mm Hg; OR: 3.8; p < 0.001), and presence ofEOV (OR: 3.2; p < 0.001) in patients with HFrEF. Morecompelling was the greater predictive utility whenall measures were considered together (OR: 16.7;p < 0.001) (9). There have been significantly fewerstudies evaluating the relationship between diseaseseverity and CPET variables in patients with HFpEF,although most recent observations have shed newlight on VE efficiency (45,62). Considering that theVE/VCO2 relationship possesses prognostic value atsubmaximal levels of effort, this observation in-creases the feasibility of implementing CPET forprognostic purposes, particularly in an elderly popu-lation that is likely not accustomed to exercise or maybe hesitant to provide maximal effort.

Collectively, the aforementioned CPET indexesshould not be thought of as markers to identifyspecific pathophysiological conditions associatedwith HF, but rather for use of objective CPET data tohelp guide characterization of the HF disease state,which is staged, in part, by subjective determinants.Interpreting CPET outcomes in this manner helpsconfirming HF and identifying secondary issues andmay provide a clear objective in deciding the bestcourse of patient treatment.

MONITORING THERAPEUTIC EFFICACY WITH CPET. TheACC/AHA stages of HF provide a comprehensiveoutline of patient characteristics that define the stageof HF, as well as respective therapies and their asso-ciated goals. Many, if not all, therapeutic goals aim tomitigate HF-related symptoms (e.g., dyspnea at restand/or upon exertion, fatigue), reduce hospitalreadmission rates, and improve survival. The acuteefficacy of a number of therapeutic regimens aretypically verified by standard follow-up visits thatassess the patient’s resting blood pressure, weight,blood markers, and patient-reported changes insymptom severity/presence. This system of patientmanagement is generally considered to be adequatein most clinical settings, and therefore leaves manypractitioners with a lack of clarity as to the addedvalue of CPET. However, an important considerationis that follow-up visit examinations are done at rest,thus providing no information on symptoms andon hemodynamic measures during physical exertion(when symptoms typically become evident).Furthermore, the main aim of any intervention is toimprove prognosis, limit morbidity, and increase thequantity of years a patient is able to live a higherquality of life, all of which are markers associatedwith high peak VO2 values and lower VE/VCO2 slopes.

Furthermore, the current ACC/AHA guidelinesrecognize the therapeutic benefits of various phar-macological interventions to improve cardiorespira-tory fitness. Angiotensin-converting enzyme (ACE)inhibitors or angiotensin II receptor blockers (ARBs)significantly improve peak VO2 on their own and haveled to greater enhancements when taken together(63). These improvements also translate to reductionsin the VE/VCO2 slope with ACE inhibitor therapy;however, there are conflicting outcomes with ARBtherapy (64). The effects of b-blockers on exerciseperformance have been extensively studied, andCPET application has garnered relevant information,in terms of influence of different types of b-blockerson gas exchange (65). Moreover, decreases in PAP,with concomitant decreases in the VE/VCO2 slope (66)and some reversal of EOV (67), have been demon-strated with sildenafil therapy in patients withHFrEF. By contrast, CPET outcomes in response toACE inhibitor, ARB, or sildenafil therapy in patientswith HFpEF have not been as favorable (68–70). Thesame seems to be true for ivabradine (71).

Given the associated improvements in key prog-nostic CPET variables with the initiation of pharma-cological therapy in certain patient populations, itmay be interesting to explore the feasibility oftitrating medications based on CPET “responders” or“nonresponders” in future clinical trials. Peak VO2 is


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an endpoint in trials of cardiac resynchronizationtherapy, LV assist device implantation, and valvesurgical or percutaneous treatments, even thoughCPET-derived variables are not standardized criteriafor these indications (2).

The frequency at which a patient should performCPET evaluation to monitor the effectiveness ofinterventions is not well-defined. Certainly, in clini-cally stable patients, CPET should be considered at2- to 4-year intervals, whereas in patients with signsand symptoms, the test should occur in a time framethat has been reported to cause significant improve-ments in the variable of interest (2).PROGNOSTIC UTILITY OF CPET. Among the exten-sive list of criteria for determining candidates fortransplantation, CPET variables are recognized tohelp refine the selection process. At time of Manciniet al.’s investigation (6), demonstrating a higher1-year survival rate in HF patients with peak VO2

>14 ml $ kg�1 $ min�1 compared with patients withpeak VO2 #14 ml$kg�1$min�1, and a similar 1-yearsurvival rate of transplanted patients compared withthose above the 14 ml$kg�1$min�1 threshold,b-blocker therapy was not part of routine clinicalmanagement of patients with HF, as it became in theearly 2000s. Despite the marginal effects ofb-blockers on peak VO2, survival rates were signifi-cantly improved, and therefore prompted reconsid-eration of Mancini et al.’s proposed cutoff fortransplantation. Consequently, a threshold of10 ml$kg�1$min�1 was proposed to be the optimalprognostic threshold for transplantation consider-ation for b-blocked patients with HFrEF (72). Inaddition to these landmark studies, a continuingwealth of evidence has fortified the prognosticstrength of peak VO2, so much so that the Interna-tional Society for Heart Lung Transplantation pro-vides a Class I, Level of Evidence: B recommendationfor inclusion of maximal CPET (RER > 1.05) to guidetransplant listing, with peak VO2 #14 ml$kg�1$min�1

(Class I, Level of Evidence: B) in the absence of ab-blocker and a peak VO2 #12 ml$kg�1$min�1 (Class I,Level of Evidence: B) in its presence (73). However, anequally impressive and convincing body of publishedreports identifies ventilatory efficiency (e.g., theVE/VCO2 slope and EOV) as a more powerful prog-nostic index than peak VO2 (74). Despite the growingbody of evidence highlighting the greater prognosticutility of the VE/VCO2 slope, current ACC/AHA guide-lines recognize peak VO2 as the sole CPET outcome fortransplant consideration. Similarly, the InternationalSociety for Heart Lung Transplantation recommendedthat the VE/VCO2 slope be reserved (slope >35; ClassIIb, Level of Evidence: C) for CPET performances with

a submaximal effort (RER <1.05). Both sets of rec-ommendations are also similar in that they recom-mend the use of one of the CPET parameters, eventhough there is strong evidence for the increaseddiscriminatory power of the VE/VCO2 slope and othervariables considered together (2,10,75).Mult iparametr i c CPET data table . It is evidentthat across the years, there has been a surge of CPETvariables, making it difficult for clinicians to identifyand interpret measures of interest. To ameliorate thisconcern, early efforts by Wasserman (24) (Figure 3)provided 9 visually friendly panel plots incorporatingthe CPET variables of interest in a single-page report.A potential disadvantage of this method, however,was the lack of guidance or references to variablethresholds pertinent to CPET clinical application.Accordingly, Arena et al. (76) developed an earlyiteration of the figures by proposing color-codedinterpretive tables applied to different diseases. Anexample is shown in Table 1 (for HF), where the list ofCPET variables (the VE/VCO2 slope, peak VO2, EOV,resting PETCO2) was separated into primary (e.g., theVE/VCO2 slope and peak VO2) and secondary (e.g., EOVand resting PETCO2) CPET measures of interest, alongwith respective categories of risk. Furthermore,instructions were provided to help with guiding theinterpretation of multivariable CPET results. Thisapproach took valuable initial steps towardcondensing a large amount of CPET-related informa-tion into a single table that could be used by cliniciansin patient management. Many modifications weremade and subsequently integrated and presented inthe 2012 EACPR/AHA Scientific Statement (1). Thecolor-coded tables now provide striking visual cluesto facilitate the interpretation of CPET. Normal re-sponses are identified in green, whereas intensifyingabnormalities are highlighted in yellow, orange, andred. Expanded clinical recommendations for theoverall severity of the patient’s condition are pro-vided, based on the frequency of color occurrence inthe table. Of note, the decision to include therespective CPET variables in the outcome tables wasbased on the available evidence, summarized inTable 2, for the predictive application of each measureindependently, but more importantly, collectivelyacross populations. Moreover, these tables weredeveloped with the objective of being applicable andrelevant to the qualifications for CPET (e.g., prog-nosis, therapeutic efficacy, and diagnosis) in orderto promote their use. As such, the AHA, and EACPRhave made an effort to increase the visibility of amultivariable paradigm that implements visual cluesto trigger appropriate actions. Because no studieshave yet tested the feasibility of this model’s

TABLE 1 Clinical Stratification for Patients With HF

Primary CPET Variables

VE/VCO2 Slope Peak VO2 EOV PETCO2

Ventilatory Class I

VE/VCO2 slope <30.0

Ventilatory Class A

Peak VO2 >20.0 ml$kg�1$min�1

Not Present Resting PETCO2

$33.0 mm Hg3–8 mm Hg increase during ET

Ventilatory Class II

VE/VCO2 slope 30.0–35.9

Ventilatory Class B

Peak VO2 ¼ 16.0–20.0 ml$kg�1$min�1

Ventilatory Class III

VE/VCO2 slope 36.0–44.9

Ventilatory Class C

Peak VO2 ¼ 10.0–15.9 ml$kg�1$min�1

Present Resting PETCO2

<33.0 mm Hg<3 mm Hg increase during ET

Ventilatory Class IV

VE/VCO2 slope $45.0

Ventilatory Class D

Peak <10.0 ml$kg�1$min�1

Standard ET Variables

Hemodynamics ECG HRR

Rise in systolic BP during ET No sustained arrhythmias, ectopic foci, and/or ST-segmentchanges during ET and/or in recovery

>12 beats at 1 min recovery

Flat systolic BP response during ET Altered rhythm, ectopic foci, and or ST-segment changes duringET and/or in recovery: did not lead to test termination

#12 beats at 1 min recovery

Drop in systolic BP during ET Altered rhythm, ectopic foci, and/or ST-segment changes duringET and/or in recovery: led to test termination

Patient Reason for Test Termination

Lower extremity muscle fatigue Angina Dyspnea

Interpretation

� All variables in green: excellent prognosis in the next 1–4 years ($90% event-free)B Maintain medical management and retest in 4 years

� Greater number of CPET and standard ET variables in red/yellow/orange indicative of progressively worse prognosis.B All CPET variables in red: risk for major adverse event extremely high in next 1–4 years (>50%)

� Greater number of CPET and standard ET variables in red/yellow/orange indicative of increasing HF disease severity.B All CPET variables in red: expected significantly diminished cardiac output, elevated neurohormones, higher potential for secondary PH.

� Greater number of CPET and standard ET variables in red/yellow/orange warrants strong consideration of more aggressive medicalmanagement and surgical options.

Example of a color-coded table for clinical stratification that applies to patients with either HFrEF or HFpEF. A list of evidence-based CPET variables (the VE/VCO2 slope, peak VO2,EOV, resting PETCO2) are separated into primary (e.g., the VE/VCO2 slope and peak VO2) and secondary (e.g., EOV and resting PETCO2) measures of interest, along with respectivecolor-code categorizations of risk (2).

BP ¼ blood pressure; CPET ¼ cardiopulmonary exercise testing; ECG ¼ electrocardiogram; EOV ¼ exercise oscillatory ventilation; ET ¼ exercise testing; HF ¼ heart failure;HFrEF ¼ heart failure with reduced ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HRR ¼ heart rate recovery; PETCO2 ¼ partial pressure of end-tidalcarbon dioxide; PH ¼ pulmonary hypertension; VE/VCO2 ¼ minute ventilation/carbon dioxide production; VO2 ¼ oxygen consumption.



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implementation in a clinical setting, as well as itseffect on patient management, future studies areencouraged to do so.

REAPPRAISAL OF INVASIVE CPET

Invasive CPET (iCPET) allows better characterizationof the hemodynamic reasons for exercise limitations,precisely dissecting central and peripheral mecha-nisms. As this approach has the potential to accu-rately phenotype cardiopulmonary disorders, it hasbeen reappraised since its initial use in early 1980s asa routine approach in more laboratories (77).Measuring pulmonary hemodynamics, LV fillingpressures, Fick CO, and a-v difference in O2, becomeessential in cases of unexplained exercise-induceddyspnea (78) and in the evaluation of exercise-induced PH of either idiopathic or secondary origin (79).

A recent analysis documented that iCPET allowsto considerably shorten the time lag from manifes-tations of unexplained exercise-induced dyspnea toan organ-specific diagnosis. Conditions that can beultimately diagnosed with iCPET are HFpEF, mito-chondrial myopathy, and confirmation of decondi-tioning (78).

Pulmonary hemodynamic measurements duringexercise, especially of PAP and pulmonary arterialwedge pressure (PAWP), have incremental prognosticvalue compared with evaluation at rest (79).

Borlaug et al. (80) first reported the potential todiagnose HFpEF in symptomatic euvolemic patientswith normal levels of B-type natriuretic peptide andwithout clear signs and symptoms of HF at rest. Inone-half of cases, looking at the PAWP and end-diastolic LV pressure increase, the observed increasein PAWP during exercise was diagnostic for HFpEF.

TABLE 2 Class Recommendation and Level of Evidence for CPET Applications in HF

ClassificationLevel ofEvidence

Prognostic Recommendations

CPET should be performed in patients with HFrEF beingconsidered for heart transplantation or mechanical deviceimplantation. However, CPET provides robust prognosticinformation in all patients with HFrEF and therefore is alsorecommended in those not being considered for end-stagesurgical management.

Class I A

Primary CPET variables, including the VE/VCO2 slope, peak VO2,and EOV, are strong predictors of adverse events. Theresponse of these 3 CPET variables is recommended to formthe basis of the prognostic assessment in patients withHFrEF. A combination of a VE/VCO2 slope $45.0, peakVO2 #10 ml$kg�1$min�1, and the presence of EOV carries aparticularly poor prognosis.

Secondary CPET variables, including PETCO2, O2 pulse, systolicblood pressure, and the ECG response to exercise, areadditional predictors of adverse events and can be usefulduring the prognostic assessment in patients with HFrEF. Aresting PETCO2 <33 mm Hg, a rise in PETCO2 <3 mm Hg duringexercise, a drop in systolic blood pressure during exercise,and/or ECG abnormalities warranting termination of exerciseindicate a worse prognosis.

Class IIa B

Prognostic value in patients with HFpEF is showing initialpromise, in particular, the VE/VCO2 slope, peak VO2, and EOV.These variables can be useful in providing prognosticinformation also in patients with HFpEF.

Class IIa B

Use of a multivariate model composed of key CPET variables andthresholds, as illustrated in Figure 4, can be useful inimproving prognostic resolution in patients with HFrEF incomparison with variables assessed independently.

Class IIa B

Recommendations for Gauging Therapeutic Efficacy

Primary CPET variables, including the VE/VCO2 slope and peakVO2, are responsive to numerous pharmacological, surgical,and exercise interventions in patients with HFrEF. As such,assessment of the change in the VE/VCO2 slope and peak VO2

is recommended when gauging therapeutic efficacy inpatients with HFrEF in both clinical and research settings.

Class I A

Reversal of EOV also may occur with pharmacological andexercise interventions in patients with HFrEF. Therefore,assessing for reversal of EOV as a gauge of therapeuticefficacy can be useful in both clinical and research settings.

Class IIa B

Primary CPET variables, including the VE/VCO2 slope and peakVO2, may be responsive to pharmacological, surgical, andexercise interventions in patients with HFpEF. As such, theVE/VCO2 slope and peak VO2 can be useful as core variableswhen gauging therapeutic efficacy in patients with HFpEF inboth clinical and research settings.

Class IIa C

Diagnostic Recommendations

CPET variables reflecting ventilatory efficiency, including theVE/VCO2 slope, EOV, and PETCO2 at rest and during exercise,may be considered in detecting left-sided PH in patients withHFrEF and HFpEF. If all 3 of these variables are in theirrespective red zones, as illustrated in Table 1, the suspicionthat the patient has left-sided PH may be reasonable. Aprimary indication of CPET for diagnostic purposes cannot berecommended at this time. Diagnostic assessments may beconsidered in patients with HF and suspicion of PH.

Class IIb B

Abbreviations as in Table 1.


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These data were reproduced by others, showingthat in patients with normal biventricular function, anincreased mean PCWP >20 mm Hg at peak exercise, inthe absence of elevations in pulmonary vascularresistance, suggests exercise-induced HFpEF (81).Patients with early stages of PAH and still normalcardiopulmonary hemodynamics at rest demonstrateincreased mean PAP >30 mm Hg and pulmonaryvascular resistance >80 to 120 dyne $ s $ cm5 oniCPET (82).

Exertional intolerance may be associated with pre-load–dependent limitations to stroke volume and CO(83). In this patient population, failure to augmentright atrial pressure on exercise is observed despiteabnormally decreased CO. Finally, impaired systemicO2 extraction indicates left-to-right shunting or amitochondrial myopathy. An algorithm for diag-nosing these conditions was recently proposed byHuang et al. (78).

Accurate assessment of the pressure-flow relation-ship during exercise by plotting mean PAP versus COprovides robust indication of abnormalities in RV topulmonary circulation coupling (79). A mean PAP/COrelationship >3 mm Hg/l/min is reflective of a PHresponse, which combines with an elevated VE/VCO2

slope (39). Evenmore, occurrence of RV-to-pulmonarycirculation (PC) uncoupling is responsible for adelayed VO2 on kinetics during early exercise (84).

The most relevant limitations to this approach areits invasive nature and technical inaccuracies inobtaining reliable pulmonary hemodynamic tracingsduring high respiratory frequencies, despite aver-aging of repeated measures.

CPET IMAGING: A NEW FRONTIER

CPET imaging is a quite recent and valuable testingmodality, which is receiving attention for its potentialto combine exercise physiological data with noninva-sive recordings of cardiac function by measures ofchamber volumes and geometry, valvular status, andsystolic and diastolic function, including the evalua-tion of left atrium (LA) function (85). In addition, theassessment of cardiac “functional reserve” by CPETimaging is greatly improved by the study of the path-ophysiological response of the pulmonary circulationto exercise, whose clinical implications appear com-plementary to and synergistic with the informationobtained with iCPET (86,87). A typical example of thisconcept is the identification of a basic role of RV topulmonary circulation uncoupling in determining theflattening of the DVO2/DWR relationship (88).

On a methodological basis, there is not yet stan-dardization, but the semirecumbent position is

suggested for a better Doppler evaluation of param-eters that are strictly dependent on workload (i.e.,systolic pulmonary pressure, transvalvular gradients,LV outflow gradients) and decline quickly during thefirst seconds of recovery. Feasibility is strictlydependent on the acoustic window and its variability



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during exercise caused by breath, body motion, andheart movements.

Incremental ramps at low increasing workload (8 to15 W/min) are preferable for fully acquiring imagesevery 2 min. Loop storage of adequate duration (3 to 5beats) is required in order to perform the averagingof measures, especially for Doppler parameters,accounting for physiological respiratory variations.Figure 4 summarizes the main parameters providedby CPET imaging, pointing out their applications tospecific cardiac diseases, with some illustrative casesof HFrEF, HFpEF, mitral valve insufficiency, andhypertrophic cardiomyopathy.HF WITH REDUCED EJECTION FRACTION. There aremultiple applications of CPET imaging in HF. First, agood discrimination between circulatory ratherdeconditioning limitation is signaled by the inabilityto reach an exercise stroke volume >50 ml/m2 (89).The importance of measuring CO reserve (90,91) inparallel with LV compliance and filling pressures iswell-established (92). Furthermore, estimation of O2

peripheral extraction by CPET imaging using theechocardiographic-derived Fick equation is an im-mediate method to explore the role of the periphery(90). Assessment of functional mitral regurgitation(MR) is of basic relevance as a marker of severity andadverse outcome (93), which, in early stages, may bedetectable just during exercise (20). Exercise-inducedMR determines the same extent of exercise limitationobserved in patients with severe MR at rest. DynamicPH is a further limiting mechanism, also induced byMR, and is associated with specific ventilatory phe-notypes of gas exchange, such as EOV (20). Inadvanced HFrEF, assessment of exercise-induced RVcontractile reserve may be investigated by CPETimaging. In a study of 97 patients with advancedHFrEF, RV exercise contractile reserve and RV-to-PCcoupling response to maximal exercise wereanalyzed through the relationships of systolic pul-monary arterial pressure (sPAP) to tricuspid annularpeak systolic excursion (TAPSE) and sPAP to CO usingstress echocardiography and CPET. Categorizationinto 3 groups based on TAPSE at rest$16 mm (group A,n ¼ 60) and patients with TAPSE at rest <16 mm,who were further divided into 2 subgroups (group B,n ¼ 19; group C, TAPSE <15.5 mm, n ¼ 18) according towhether their respective median TAPSE was higher orlower than 15.5 mm at peak exercise. Group B, atvariance with group C, showed an upward shift of theTAPSE versus sPAP relationship and some degree offavorable coupling adaptation during exercise. Thus,severely impaired RV function at rest may still beassociated with the capacity to improve RV-to-PCcoupling during exertion in a proportion of the

patients with HFrEF (87). Interestingly, the worstRV-to-PC coupling pattern was associated with thehighest rate of exercise ventilation inefficiency. Thisanalysis appears useful for unmasking different rightheart phenotypes not detectable with rest evaluation.

Most recent findings suggest that impaired LAdynamics, estimated by LA strain response duringmaximal exercise and during the recovery phase,plays a central hemodynamic role in triggering RV toPC uncoupling and ventilatory inefficiency, especiallywhen LV systolic function is reduced (85).HF WITH PRESERVED EJECTION FRACTION. HFpEFis a syndrome whose diagnostic process and limitedtherapeutic options remain major challenges (94).The expanding body of published reports on CPETimaging in this syndrome is based on several points:to uncover unexplained dyspnea and suspectedHFpEF; to confirm HFpEF diagnosis in subjects notmeeting the criteria required at rest; and to stratifyCV risk once a true diagnosis is established.

Recently, the American Society of Echocardiogra-phy/European Association of Cardiovascular Imagingrecommendations on diastolic function evaluationadvocated the use of the exercise E/e0 ratio to detectdiastolic dysfunction (95) and, for the past severalyears, changes in E/e0 were taken as a reference tointerpret unexplained dyspnea and suspected HFpEF(96,97). In a study by Nedelikovic et al. (98), per-formed in 87 patients with dyspnea unexplained byexercise and hypertension, gas exchange and Doppleranalysis led to the ultimate diagnosis of HFpEF in theminority of patients presenting with a combinationof E/e0 >15 at peak exercise, along with an elevatedVE/VCO2 slope.

A parallel number of observations have focused onhow exercise E/e0 may add to the clinical follow-up ofestablished HFpEF, especially looking at the associ-ated changes in pulmonary pressure during effort(99,100). Interestingly, CPET imaging with immedi-ately post-exercise echocardiographic assessment hasdocumented that in about 1 of 3 patients with HFpEF,exercise elevation of LV filling pressure (E/e0

EXE >13)can be absent, but associated with reduced contrac-tile reserve and ventriculoarterial coupling, as well aswith a mild degree of functional impairment (101).However, a similar approach has shown that peakE/e0 >15 occurred in 9% of hypertensive patientswith exertional dyspnea and normal resting LVfunction, being associated with lower peak VO2 andsignificantly impaired ventilator efficiency (higherVE/VCO2), compared with patients with normalexercise E/e0 (98).

The intrinsic value of exercise echocardiographyhas been recently confirmed in an elegant

FIGURE 4 Example of CPET Imaging Applied to Different Cardiac Diseases

The figure shows the semirecumbent approach (center), allowing for simultaneous echocardiography and expired-gas analysis. The yellow table on the right lists the

main parameters provided by exercise echocardiography; the disease-specific tables indicate prognostic parameters to collect during the test. The blue table on the

left lists the main CPET parameters; the “red flags” table (left) points out CPET pathological patterns with prognostic impact. The 4 panels in blue depict cases of iCPET

with the main CPET (left blue frame) and echocardiographic (right red frames) findings. (Upper left) A case of HFrEF due to post-ischemic LV dysfunction with a very

abnormal functional phenotype; CPET frames show pronounced exercise oscillatory ventilation and severe impairment of ventilatory efficiency; echocardiographic

frames show end-diastolic and end-systolic apical 4-chamber views with apical aneurysmatic evolution and severely reduced ejection fraction, transmitral pulsed wave

Doppler, and annular TDI displaying grade III diastolic dysfunction and transtricuspid continuous wave Doppler demonstrating severe pulmonary hypertension at rest

and during exercise. (Upper right) A case of HCM with preserved functional phenotype, despite the evidence of severe left ventricular outflow obstruction; CPET

frames show normal ventilatory response; echocardiographic frames show left ventricular outflow tract continuous wave Doppler demonstrating severe rest dynamic

obstruction, enhanced by the Valsalva maneuver and by post-exercise period (when afterload is decreasing, but adrenergic inotropic drive is still present). (Bottom

right) A case of HFpEF with typical abnormal functional phenotype characterized by chronotropic incompetence; CPET frames show the flattening of the DVO2/DWR

relationship, expression of blunted cardiac output during exercise, and the reduced chronotropic response related to VO2 consumption; echocardiographic frames show

transmitral pulsed wave Doppler and annular TDI displaying rest grade II diastolic dysfunction with worsening during exercise, transtricuspid continuous wave

Doppler demonstrating a borderline rest gradient with a severe exercise-induced increase, and left ventricular outflow tract pulsed wave Doppler evidencing a slight

increase of flow during exercise, consistent with abnormal stroke volume reserve. (Bottom left) A case of moderate left ventricular systolic dysfunction characterized by

exercise-induced mitral regurgitation with mild exercise oscillatory ventilation. CPET frames show mild exercise oscillatory ventilation with preserved ventilatory

efficiency; echocardiographic frames show rest and exercise midsystolic color Doppler apical 4-chamber views with severe exercise-induced mitral regurgitation and

transtricuspid continuous wave Doppler demonstrating normal rest gradient with abnormal exercise-induced increase, reflecting dynamic pulmonary hypertension.

AT ¼ anaerobic threshold; AVA ¼ aortic valve area; CO2 ¼ carbon dioxide; EDA ¼ end-diastolic area; EDV ¼ end-diastolic volume; ERO ¼ effective regurgitant orifice;

ESA ¼ end-systolic area; ESV ¼ end-systolic volume; EXE ¼ exercise; FAC ¼ fractional area change; GLS ¼ global longitudinal strain; HCM ¼ hypertrophic cardio-

myopathy; iCPET ¼ invasive cardiopulmonary exercise testing; iEDV ¼ indexed end-diastolic volume; iESV ¼ indexed end-systolic volume; LVEF ¼ left ventricular

ejection fraction; MPG ¼ mean pressure gradient; MG ¼ mean gradient; MR ¼ mitral regurgitation; PG ¼ peak gradient; RegVol ¼ mitral regurgitant volume;

RER ¼ respiratory exchange ratio; RV ¼ right ventricular; SPAP ¼ systolic pulmonary artery pressure; SV ¼ systolic volume; TAPSE ¼ tricuspid annular plane systolic

excursion; TDI ¼ tissue Doppler imaging; WMSI ¼ wall motion score index; other abbreviations as in Figures 1 to 3.


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simultaneous invasive and echocardiographic studyreporting increased sensitivity, but compromisedspecificity of guideline-recommended use of theexercise E/e0 ratio (77), proposing a screening role ofexercise echocardiography aimed at ruling out thepresence of HF.

VALVULAR DISEASES. Exercise echocardiography isextensively used for the evaluation of valvular dis-eases, as recently stated in the European Associationof Cardiovascular Imaging/American Society ofEchocardiography recommendations (95). Specificprotocols and target parameters have been estab-lished according to the valve disease and the clinicalquestion (102). The main goal of physical stress is tomeasure the “valve reserve” (i.e., the entity ofexercise-induced worsening of valve disease) and thedirect pathophysiological consequences (i.e.,exercise-induced PH, LV transient systolic dysfunc-tion, increase in transvalvular gradients). The mainindication for testing patients with valvular disease isan unclear clinical presentation. Considering theadvanced age of people with valvular disease andtheir high prevalence of dyspnea (103), it is quitecommon to experience some difficulties in under-standing the origin of self-reported dyspnea. In thedecision process for surgical treatment, what appearspivotal is the recognition of how much symptoms arerelated to the valve disease or reflective of otherconditions, in order to optimize surgical timing. Ofnote, CPET imaging was recently used in patientswith rheumatic mitral stenosis, providing evidencethat functional limitation has a complex origin.Restrictive lung function, chronotropic incompe-tence, limited stroke volume reserve, and peripheralfactors equally contributed to reduce ability to exer-cise (104). Interestingly, patients with attenuatedfunctional responses showed the expected exercise-induced PH; however, this was not the mainlimiting factor. A similar combined approach has beenused in functional MR to demonstrate that exercise-induced severe MR limits patients with HFrEF,mainly causing exercise PH. The rationale for usingCPET imaging in valvular disease is strong; however,systematic data are still lacking and future in-vestigations are desirable for defining surgical risk,especially in the assessment of complex conditions,such as paradoxical low-flow–low-gradient severeaortic stenosis (105).

HYPERTROPHIC CARDIOMYOPATHY. Hypertrophiccardiomyopathy (HCM) is commonly associated withexercise intolerance, and CPET analysis is helpful forimproving prognostic stratification (106). Mechanismsunderlying abnormal gas exchange during exercise

can differ according to the predominant echocardio-graphic phenotype (107). CPET imaging allows theidentification of LV outflow obstruction and diastolicdysfunction assessment during exercise, as well asobjective measurement of functional limitations.In 156 patients with HCM evaluated with both CPETand noninvasive hemodynamic assessment, a highprevalence of exercise intolerance and ventilatoryinefficiency has been reported (108). Impaired peakVO2 (<80% of predicted) was associated with peakcardiac index, age, male sex, and RV end-diastolicarea, whereas ventilatory inefficiency (VE/VCO2 >34)was related to E/e0 and to indexed LA volume. Bothfunctional parameters were predictive of increasedrisk of major events in the short-term follow-up.

The role of diastolic dysfunction as a limiting factorof functional response has been reinforced by a recentpaper using iCPET imaging in 197 patients with HCM(109). Multivariate analysis showed that LV obstruc-tion, LA dilation, and especially rest or latentdiastolic dysfunction were the main determinants ofexercise intolerance.

According to the European guidelines (110), CPEThas a Class IIa indication in patients with HCM,irrespective of symptoms reported, and a Class Iaindication when consistent symptoms are present.Simultaneous exercise echocardiography has theadvantage of evaluating LV outflow tract obstructionand weighing all potential causes of exercise intoler-ance, such as diastolic dysfunction, dynamic MR, andPH. An additive value of CPET imaging has beensuggested for monitoring therapeutic response toseptal reduction, looking at the linearity of the DVO2/DWR relationship, which can be flattened in case ofsevere obstruction and normalize after septal reduc-tion (111).SUSPECTED OR CONFIRMED PH. CPET imaging andexercise echocardiography have independent, spe-cific roles in the diagnostic work-up, functionalevaluation, and clinical management of patients withconfirmed PH, irrespective of disease origin (95).Nonetheless, the combination of both tests in asingle-step evaluation has the advantage of confirm-ing suspected PH, making an early diagnosis, identi-fying secondary causes of PH, and improving overallpatient characterization. Systolic pulmonary pressureduring exercise is one of the most important variablesto collect during exercise echocardiography in severalclinical settings because it reflects the main mecha-nism of effort intolerance. Nonetheless, in thecontext of Group 1 or PAH, the role of exercise echo-cardiography in the diagnostic work-up is stilldebated and it is not recommended for diagnosis andclinical purposes (112).


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The role of CPET imaging has been validated inseveral conditions for determining exercise-inducedPH, however no prospective studies have tested theincremental value of this combined approach in thediagnostic work-up of PAH.

CONCLUSIONS

CPET now has a definitive place in the armamen-tarium of the practicing clinician for the evaluation ofcardiopulmonary disorders, primarily HF. It providesa thorough assessment of the integrative multiorganphysiological response to exercise. A revival of

invasive CPET and introduction of CPET imaging havenow extended the amount of pathophysiologicaland clinical information, providing new insights insystemic and pulmonary hemodynamics, along withdirect knowledge of cardiac, valve, and functionaldata.

ADDRESS FOR CORRESPONDENCE: Dr. Marco Guazzi,University of Milano, Department of Biomedical Sciencesfor Health, Heart Failure Unit, University CardiologyDepartment, IRCCS Policlinico San Donato, Piazza E.Malan 2, 20097 San Donato Milanese, Milan, Italy.E-mail: [email protected].

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KEY WORDS exercise, gas exchangeanalysis, heart failure, oxygen consumption






























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