Exercise Stress Testing in Clinical Cardiology: Practical Guide

Review
Exercise Stress Testing in Clinical Cardiology: A Practical Guide
to Performance and Interpretation
Chiara Carluccio 1 , Francesco Bressan 1 , Matteo Pizzolato 1 , Amedeo De Antoni 1 , Simone Ungaro 1 ,
Dorottya Balla 2,3 , Alberto Cipriani 1 , Manuel De Lazzari 1 , Martina Perazzolo Marra 1 , Hajnalka Vago 2,3 ,
Domenico Corrado 1 , Alessandro Zorzi 1 and Francesca Graziano 1,2,3, *
1
2
3
*
Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Via Giustiniani 2,
35128 Padua, Italy; [email protected] (C.C.); [email protected] (F.B.);
[email protected] (A.D.A.); [email protected] (S.U.);
[email protected] (A.C.); [email protected] (M.D.L.);
[email protected] (M.P.M.); [email protected] (D.C.);
[email protected] (A.Z.)
Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary;
[email protected] (D.B.); [email protected] (H.V.)
Department of Sports Medicine, Semmelweis University, 1122 Budapest, Hungary
Correspondence: [email protected]; Tel.: +39-0498212322
Abstract
Exercise stress testing remains one of the most widely used and cost-effective diagnostic
tools in clinical cardiology. Beyond the traditional evaluation of induced ischemia, it provides valuable information on functional capacity, blood pressure response and arrhythmic
behavior during exercise. In particular, the test plays a crucial role in assessing and interpreting exercise-induced arrhythmias, including tachyarrhythmias, such as premature
ventricular beats (PVBs) and bradyarrhythmias, as well as corroborating the suspicion of
some ion channel diseases. The usefulness of exercise testing is also highlighted in patients
with devices, where it can help evaluate their function and exercise adaptation, as well as
in specific conduction disorders, such as Wolff–Parkinson–White syndrome. This practical
guide summarizes the key aspects of performing and interpreting the exercise stress test,
focusing on hemodynamic and arrhythmic findings and their clinical implications, and
includes several illustrative clinical cases.
Keywords: exercise stress testing; functional capacity; inducible ischemia; arrhythmias;
premature ventricular beats; ion channel disease; ventricular pre-excitation
1. Introduction
Academic Editor: Fabian
Sanchis-Gomar
Received: 29 January 2026
Revised: 17 February 2026
Accepted: 19 February 2026
Published: 22 February 2026
Copyright: © 2026 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Exercise stress testing (EST) has been used for decades as a non-invasive procedure
to provide diagnostic and prognostic information in patients with known or suspected
heart disease. The procedure entails continuous 12-lead electrocardiographic monitoring
while the patient undergoes physical exercise, typically on a treadmill or cycle ergometer,
according to standardized protocols. Concomitantly, blood pressure is monitored at regular
intervals, and clinical symptoms are recorded.
EST is the most widely available functional test, relatively low-cost and easy to administer. Traditionally, EST has been employed to assess for inducible ischemia in patients with
suspected coronary artery disease (CAD) [1–4]. However, its diagnostic accuracy for detecting obstructive CAD is modest. Beyond ischemia detection, EST represents a fundamental
Attribution (CC BY) license.
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clinical tool to provide information on exercise capacity, chronotropic and blood pressure
(BP) response to exercise, detection of exercise-induced arrhythmias and conduction disorders, to assess the effectiveness of cardiovascular (CV) therapy and exercise response in
patients with cardiac implantable electronic devices (CIEDs) [4,5].
This review examines the physiological basis of exercise, EST methodologies, the
indications and specific clinical applications and provides a practical, easy-to-consult guide
to EST performance and interpretation.
2. Physiology of Cardiovascular Response to Exercise
The ability to perform physical exercise is enabled by a progressive increase in oxygen
uptake (VO2 ). Maximal oxygen uptake (VO2 max) is defined as the greatest amount of
oxygen a subject can consume during dynamic exercise and represents an excellent measure
of CV fitness and functional capacity. The amount of oxygen required during rest, per unit
mass of 1 Kg body weight and time, is defined as the metabolic equivalent (MET) and is
equal to 3.5 mL O2 /Kg/min. Functional capacity is typically expressed as estimated METs,
which represent multiples of the basal rate of oxygen consumption at rest [6–8].
VO2 , as defined by the Fick equation, is the product of cardiac output and peripheral
arteriovenous oxygen difference. During the initial phases of exercise, the increase in
cardiac output is driven by an increase in peripherical oxygen extraction, a rise in stroke
volume (mediated through the Frank–Starling mechanism) and by an increase in HR. Conversely, during maximal aerobic exercise, the continued rise in VO2 is mainly due to an
increase in HR, as stroke volume reaches a plateau at 50–60% of VO2 max. HR is, at any moment, the result of a dynamic balance between sympathetic and parasympathetic nervous
system influences [8,9]. In healthy subjects, an average resting HR of 60–80 beats per minute
(bpm) reflects a basal predominance of parasympathetic tone. As exercise progresses, the
increase in sympathetic discharge and the inhibition of parasympathetic stimulation result
in a positive chronotropic and inotropic response, leading to a progressive increase in HR
and myocardial contractility. At submaximal workloads below the lactate or ventilatory
threshold (i.e., the exercise intensity at which lactate production and buffering begin to
exceed clearance capacity), HR, cardiac output, blood pressure, and ventilation increase
proportionally to workload and remain physiologically regulated. Although anaerobic
metabolism contributes at all exercise intensities, this threshold reflects the point at which
glycolytic pathways become progressively predominant, leading to systemic lactate accumulation and a disproportionate increase in ventilation. As exercise intensity surpasses
this threshold, sympathetic discharge further increases, promoting peripheral vasoconstriction in most vascular beds (except exercising muscle and the cerebral and coronary
circulations) and enhanced oxygen extraction [7]. In patients with heart failure, reduced
beta-adrenergic receptor density and desensitization may contribute to chronotropic incompetence and impaired exercise capacity. Nevertheless, VO2 peak reduction is multifactorial
and phenotype-dependent, reflecting both central hemodynamic limitations and peripheral
abnormalities in oxygen extraction [8].
The maximal HR achieved during exercise is strongly influenced by age and agerelated hormonal and autonomic factors, although recent evidence suggests a substantial
heritable genetic component [10,11]. The maximal HR (HR max) could be predicted from
one of several available equations. The most straightforward and commonly used equation
[predicted HR max = 220 − age in years] is burdened by high intersubject variability and
tends to overestimate HR max in younger women but tends to underestimate it in older
women. Newer equations have been proposed to predict the HR max more accurately [7,12]:
Men: HR max = 208 − (0.7 × Age)
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Women: HR max = 206 − (0.88 × Age)
Alternatively, exercise intensity can be expressed as a percentage of a person’s HR
reserve (predicted maximum HR − resting HR) using the Karvonen formula [5].
Immediately after exercise interruption, sympathetic withdrawal and increased
parasympathetic tone cause a rapid decline in HR, defined as HR recovery (HRR). In
routine clinical practice, HRR is conventionally assessed at 1 min after exercise cessation,
and less frequently at 2 min. In contrast, earlier time points (e.g., 10–30 s) are primarily used
in research settings and in athletic populations to better characterize autonomic reactivation.
Highly trained athletes often exhibit a rapid drop in HR of 30–50 bpm during the first
minute of recovery due to parasympathetic overactivity [9,13,14]. Conversely, the Multiple
Risk Factor Intervention Trial (MRFIT) demonstrated that a delayed HR recovery (<50 bpm
after 3 min) was an independent predictor of all-cause death in asymptomatic men [15].
It was recently reported that decreased HR recovery at 10 s after cessation of exercise is a
superior predictor of outcome compared with the same indicator at later time intervals [16].
Generally, the HR should decrease by at least 12 beats in the first minute of recovery [17].
HR variability during exercise and recovery from exercise is an important physiological marker reflecting vagal and sympathetic nerve activity. If high HR variability is
associated with healthy conditions, low HR variability reflects an underlying pathological
substrate [18]. As a result, imbalances in autonomic control of CV activity both during
and after exercise are strongly associated with increased risk of adverse CV outcomes and
sudden death [15,19,20].
Under physiologic conditions, systolic blood pressure (BP) increases linearly with
exercise intensity, reflecting increased cardiac output to meet metabolic demands, whereas
diastolic pressure usually remains stable or is moderately decreased because of vasodilatation of the vascular bed [7]. BP usually increases by 5–10 mmHg/MET [21] during a
progressive exercise test, while diastolic BP exhibits little or no change (<10 mmHg) due to
peripheral vasodilatation. Moreover, in healthy and highly trained individuals, the more
pronounced CV adaptation to intensive long-term endurance training leads to a greater
increase in cardiac output, with a greater increase in volume overload and systolic BP
during exercise, while diastolic BP usually remains unchanged due to extensive peripheral
vasodilation [22,23].
Following maximal exercise, systolic BP rapidly declines as cardiac output decreases,
usually reaching resting levels or lower within 6 min. However, stopping exercise abruptly
can cause precipitous drops in pressure due to venous pooling and a delayed increase
in vascular resistance. To mitigate these hemodynamic risks, an active cool-down period
is strongly recommended [7]. Several factors, including age, sex, sex-related hormonal
modulation, cardiorespiratory fitness, training level, and cardioactive medication, influence BP response to exercise [24–26]. An exaggerated hypertensive response or an inadequate/hypotensive SBP response during exercise has been associated with masked
hypertension and an increased risk of future CV events, although no universally accepted
definition is currently provided in European hypertension guidelines [24].
The index derived from the product of HR and systolic BP obtained during graded
exercise is defined as Rate-Pressure Product (RPP) or Double Product. It is a derived hemodynamic index that serves as a non-invasive surrogate of myocardial oxygen consumption
(MVO2 ). In healthy subjects, RPP increases progressively with exercise intensity, reflecting
the augmenting cardiac work required to meet peripheral metabolic needs. Peak RPP
values in healthy individuals typically range between 20,000 and 35,000 mmHg·bpm. This
peak value characterizes the maximal aerobic performance of the CV system. By contrast, a
failure to raise the systolic BP or HR adequately (low peak RPP) is associated with increased
risk of adverse CV events and poor hemodynamic reserve [7].
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3. Indications and Contraindications of Exercise Stress Testing
The broad indications of EST encompass diagnosis, prognosis, functional assessment,
and evaluation of therapeutic interventions.
Exercise stress testing is recommended for assessing exercise tolerance and inducible ischemia during the initial diagnostic evaluation of patients with suspected chronic coronary
syndrome [4,5,27,28]. In asymptomatic master athletes, although EST is a poor predictor of CAD, it could help identify previously unrecognized medical conditions such as
hypertension or exercise-induced ventricular arrhythmias, guiding subsequent clinical
management [29,30].
Although CPET remains the preferred tool for comprehensive evaluation of exercise
physiology in patients with heart failure and cardiomyopathy, EST may still be considered
in selected cases for functional assessment and arrhythmic risk evaluation, particularly
when CPET is not available [5].
EST is indicated for detecting exercise-induced arrhythmias, diagnosing chronotropic
incompetence, frequency-induced atrioventricular and bundle branch blocks, and assessing
exertional symptoms in both sedentary individuals and athletes during pre-participation
screening [31]. It is also recommended for the diagnosis and assessment of therapy response
in patients with suspected or proven adrenergic-dependent rhythm disturbances (e.g.,
catecholaminergic polymorphic ventricular tachycardia) [32,33]. In addition, assessment
of the QTc interval during exercise and recovery may aid in the diagnosis of long QT
syndrome (LQTS) [33]. It is also widely used as a non-invasive tool for risk stratification in
patients with asymptomatic ventricular pre-excitation.
It can diagnose CIED-mediated chronotropic incompetence and provide HR targets to
optimize pacemaker programming.
The specific applications of EST will be detailed in the following sections. Common
contraindications are listed in Table 1 [7].
Table 1. Absolute and relative contraindications to exercise testing.
Absolute Contraindications
■
■
■
■
■
■
■
■
■
■
■
Acute myocardial infarction within 2 days
Hish-risk unstable angina
Uncontrolled cardiac arrhythmia with hemodynamic compromise
Active endocarditis
Symptomatic severe aortic stenosis
Decompensated heart failure
Acute pulmonary embolism or pulmonary infarction
Acute myocarditis or pericarditis
Acute aortic dissection
Acute pneumothorax
Physical disability that precludes safe and adequate testing
Relative Contraindications
Known obstructive left main coronary artery stenosis
Moderate aortic stenosis with uncertain relation to symptoms
■
Tachyarrhythmias with uncontrolled ventricular rates
■
Acquired complete heart block
■
Hypertrophic obstructive cardiomyopathy with severe resting gradient
■
Recent stroke or transient ischemic attack
■
Mental impairment with limited ability to cooperate
■
Severe resting hypertension
■
Uncorrected medical conditions, such as significant anemia, important electrolyte imbalance, and
hyperthyroidism
Adapted from “Exercise standards for testing and training: a scientific statement from the American Heart
Association” [7].
■
■
How to Define a Maximal Exercise Testing and When to Stop It
Historically, the indications for EST termination were established based on populations
with ischemic heart disease. In this clinical context, an HR threshold of 85% of Maximal
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Theoretical Heart Rate (MTHR) was set to ensure safe training below the individual ischemic threshold. Consequently, this cut-off became the standard parameter for defining
an EST “maximal” in pathological conditions. Nevertheless, the indications for EST terminations in subjects without known CV disease are not unequivocally established. Evidence
suggests that, in healthy individuals, 85% of MTHR is ineffective at quantifying patients’
maximal exertion during EST [34]. Sirico et al. demonstrated that the majority of healthy
subjects exceeded 85% of MTHR, reporting only moderate perceived exertion (typically
around 14 in the Rating of Perceived Exertion Borg Scale), indicative of submaximal effort.
Moreover, almost half of the recorded ECG events (both ischemic and arrhythmic) occurred
at HR > 85% of MTFR; thus, terminating EST at 85% of MTHR limits diagnostic accuracy in
detecting ECG abnormalities [35]. Therefore, EST is defined as maximal when performed
until physical exhaustion, as indicated by a Rating of Perceived Exertion Scale > 17 [35].
In patients receiving beta-blocker therapy, the negative chronotropic effect may blunt the
HR response to exercise, preventing the attainment of 85% of MTHR. However, if the EST
is conducted until physical exhaustion, it can be considered maximal and diagnostic.
By contrast, in deconditioned patients, an exaggerated HR response to physical exertion may occur early; also, in this case, EST should continue until symptom-limited exertion.
EST should be terminated at the onset of typical angina, ST-segment elevation
(>1.0 mm in leads other than aVR, aVL, or V1, and without Q waves due to prior myocardial
infarction), or complex ventricular arrhythmias with hemodynamic compromise. Further
absolute and relative indications for EST termination are listed in Table 2 [7]. Nonetheless,
the safety of exercise testing is well established, and the overall risk of adverse events is
low, though it depends on the study population’s characteristics [7].
Table 2. Absolute and relative indications for terminating the exercise testing.
Absolute indications for termination
■
■
■
■
■
■
■
■
■
ST elevation (>1.0 mm) in leads without Q waves due to prior MI (other than aVR, aVL, or V1)
Drop in systolic BP of >10 mm Hg, despite an increase in workload, when accompanied by any other
evidence of ischemia
Typical angina
Central nervous system symptoms (e.g., ataxia, dizziness, or near syncope)
Signs of poor perfusion (cyanosis or pallor)
Complex ventricular arrhythmias or other arrhythmias that interferes with normal maintenance of
cardiac output during exercise
Technical difficulties monitoring the ECG or systolic BP
Patient’s request to stop
Exaggerated hypertensive response (systolic blood pressure >250 mm Hg and/or diastolic blood
pressure >115 mm Hg) *
Relative indications for termination
Marked ST displacement (horizontal or downsloping of >2 mm) in a patient with suspected ischemia
Drop in systolic BP of >10 mm Hg (persistently below baseline) despite an increase in workload, in the
absence of other evidence of ischemia
■
Increasing chest pain
■
Fatigue, shortness of breath, wheezing, leg cramps, or claudication
■
Development of bundle branch block that cannot be distinguished from ventricular tachycardia
Adapted from “Exercise standards for testing and training: a scientific statement from the American Heart
Association” [7]. * BP thresholds should be interpreted within the clinical context. In highly trained athletes, SBP
values above 250 mmHg may occur at very high workloads without clear evidence of acute risk; therefore, test
termination should not rely solely on absolute BP values but also on symptoms and ECG findings. In patients
with known aortic disease or heritable connective tissue disorders, exercise testing should be individualized and
often limited to submaximal protocols with conservative BP limits.
■
■
4. Exercise Testing Procedure
4.1. Patient Preparation
Before performing an EST, a comprehensive clinical assessment is essential to confirm
the indication for testing, to ensure the appropriateness of the selected protocol, evaluate the
patient’s ability to perform exercise, and identify any contraindications (Table 1). In selected
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patients with unexplained symptoms, suspected structural heart disease, significant valvular abnormalities, cardiomyopathy, or aortic pathology, transthoracic echocardiography
should be considered prior to exercise testing to better define baseline cardiac structure and
function. The pre-test evaluation should integrate information from the patient’s medical
history supplemented by a focused physical examination. A current resting 12-lead ECG is
crucial to assess HR, rhythm, conduction abnormalities, and evidence of prior myocardial
infarction, and, when available, it should be compared with previous ECGs. Resting BP
measurement should be performed to screen for baseline hypertension/hypotension and
assess the safety and feasibility of the EST.
Patients should be advised to wear comfortable exercise clothing and supportive
footwear. Dietary restrictions include abstaining from significant food intake for two to
three hours before testing, while adequate hydration is encouraged. Furthermore, patients
must avoid caffeine, alcohol, and tobacco before the procedure [7].
Medication management should be tailored to the clinical objective. It is recommended
to continue usual therapy when EST is performed to evaluate the efficacy of cardioactive
drugs, such as for controlling exercise-induced arrhythmias, BP response to exercise, or
to determine their functional and hemodynamic effects. Conversely, cardioactive drugs
(especially β-blockers) should be withheld for 24 h prior to the EST if the purpose is to
evaluate the exercise response without medication. In patients with a diagnosis of CAD,
cardioactive drugs should generally be maintained.
In patients with CIEDs, device type, programming, rate responsiveness, and pacing
limits must be reviewed in advance. Specifically, for patients with implantable cardioverterdefibrillators (ICDs), information about ICD rhythm detection and therapy thresholds
should be identified to ensure that peak exercise HR remains safely below programmed
intervention zones [12]. If possible, continuous device telemetry monitoring should be
performed during the test to verify appropriate sensing and rhythm discrimination at
increasing workloads. These precautions apply regardless of the underlying cardiac disease.
Before EST, the patient should be familiarized with the symptom rating scales used to
monitor perceived effort and symptoms during the procedure. The most used are the Borg
Rating of Perceived Exertion (RPE) and the Borg Category-Ratio 10 (CR10) scale. The Borg
RPE scale ranges from 6 to 20, with each number corresponding to the perceived exertion,
from 6 (no exertion at all) to 20 (maximal exertion). The scale was initially designed to
correspond to HR when multiplied by 10. The Borg CR10 scale ranges from 0 (no exertion)
to 10 (maximal exertion) [12].
During EST, ECG is monitored continuously. To obtain a high-quality 12-lead ECG
acquisition, meticulous skin preparation, including hair removal and mild abrasion of the
superficial epidermal layers, is required.
Furthermore, the Mason–Likar modification of the standard 12-lead ECG is routinely
employed to reduce motion-induced artifacts by relocating the limb electrodes to the
torso. In this configuration, the arm electrodes are positioned at the distal aspects of the
infraclavicular fossae, while the leg electrodes are placed on stable sites above the iliac
crests (Figure 1).
Blood pressure should be assessed at baseline, at 2 min intervals during exercise or
according to necessity, and at least twice during the recovery period. During exercise
stress testing, blood pressure measurement should preferably be performed manually
using the auscultatory method, particularly during treadmill protocols, since motion
artifacts and patient movement may reduce the reliability of non-validated oscillometric
devices. Automated devices specifically validated for exercise conditions can be acceptable,
especially during cycle ergometer testing, but abnormal readings should be confirmed
manually [36].
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Figure 1. Representation of lead placement for noise reduction during ECG-EST. LA, left arm; LL, left
leg; RA, right arm; RL, right leg.
4.2. Exercise Testing Room
The testing room should be large enough to ensure patient privacy and provide adequate space around exercise ergometers for staff movement and immediate access for
emergency equipment. Climate control is essential to prevent heat-related complications;
the guidelines recommend maintaining a cool temperature (ideally 20 ◦ C to 22 ◦ C) and
adequate ventilation [7,37]. Crucially, a fully equipped emergency crash cart containing appropriate drugs and a defibrillator must be immediately accessible. Figure 2 schematically
illustrates the characteristics of a testing room and the patient assessment process.
b.
a.
c.
Figure 2. Schematic representation of a clinical exercise testing laboratory. (a) Patient intake and
preparation, resting ECG acquisition. (b) Supervised exercise testing. (c) Post-test recovery with vital
signs assessment and report generation.
4.3. Exercise Testing Protocols and Modality
Treadmill and cycle ergometer testing are the primary modalities for dynamic EST
in clinical practice. The choice of testing modality and protocol should be guided by the
patient’s estimated functional capacity, considering factors such as age, physical fitness,
and underlying disease.
Treadmill and cycle ergometer EST can be conducted using either stepped or continuous ramp protocols. Stepped protocols typically increase work rate by 1 to 2.5 METs per
stage. Ramp protocols, in contrast, use smaller, constant-workload increments with stages
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lasting no longer than 1 min, aiming for the patient to achieve peak exercise capacity within
8 to 12 min [37].
The most used stepped treadmill protocols are the Bruce, modified Bruce, and
Naughton protocols, which offer standardized workload progression for a broad spectrum of functional capacities. The metabolic cost in METs of the treadmill work rate can be
estimated from the speed and grade of elevation using standardized equations [12,38]. The
standard Bruce treadmill protocol, first described by Robert Bruce in 1973 [39], is widely
used in healthy individuals. It is a maximal, multistage protocol consisting of 3 min stages,
designed to allow the achievement of steady-state conditions before the workload increases.
Compared with the ramp protocol, the Bruce protocol exhibited higher sensitivity for
detecting myocardial ischemia, owing to higher HR and a higher Double Product at peak
exercise, favoring its use in screening settings [40]. In older adults and in patients with
cardiac-related exercise limitations, a modified version including two initial 3 min warm-up
stages at 2.4 km/h with 0% and 5% incline is commonly employed. A major limitation of
the Bruce protocol is the relatively large increment in VO2 between stages and the increased
energetic cost of running in later stages. In contrast, the Naughton and Weber protocols,
which use shorter stages (1–2 min) with smaller workload increments of approximately
1 MET per stage, are better suited for patients with reduced exercise tolerance, including
those with stable chronic heart failure [12].
Cycle ergometry is a suitable alternative to treadmill testing, especially for patients
with orthopedic, peripheral vascular, or neurological impairments that limit weight-bearing
capacity. The cycle ergometer EST utilizes incremental workloads calibrated in watts
(W) or kilogram-meters per minute (kg·m/min), with 1 W equivalent to approximately
6 kg·m/min. In mechanically braked cycle ergometers, workload is determined by the
applied resistance and pedaling distance, necessitating that the patient maintain a constant
cadence, typically 60–80 revolutions per minute (rpm). Electronically braked cycle ergometers, by contrast, maintain a constant workload regardless of variations in pedaling cadence
and are therefore less reliant on patient cooperation. Most cycle ergometer protocols commence at a workload of 10 or 25 W (approximately 150 kg·m/min), with incremental
increases of 25 W every 2 or 3 min until predefined or symptom-limited endpoints are
achieved. For younger or more physically fit individuals, protocols may begin at 50 W,
with subsequent increments of 50 W every 2 min. Ramp protocols differ from stepped
protocols by initiating with some minutes of unloaded pedaling, followed by a continuous
and uniform increase in workload, typically by 5 to 30 W per minute, based on the patient’s
anticipated exercise capacity [41,42].
Regardless of the specific protocol chosen, EST should be individualized to achieve
a fatigue-limited exercise duration of ≈8 to 12 min. Any EST duration of less than 8 min
typically results in a 10% reduction in maximal VO2 , with a nonlinear relationship between
VO2 and work rate. By contrast, a protocol exceeding 12 min may lead to test termination
due to muscle fatigue or orthopedic factors rather than cardiopulmonary end points [43,44].
Accurate prediction of peak work rate is important to bring subjects to their maximal
performance within the recommended 8–12 min; several predictive equations have been
developed to estimate peak work rate using weight, height, sex, and ethnicity as variables;
however, none of these is adapted and validated to the subject’s fitness and training
level [45,46]. For this reason, the expertise of the clinicians in individualizing the right
protocol, given the fitness level of the patient, is essential. Indeed, in high-performance
athletes, longer or sport-specific protocols may be required to accurately characterize
exercise capacity and to inform individualized training recommendations. In selected
endurance disciplines, lactate steady-state testing may be necessary to precisely define
training intensity domains.
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Physiological demands vary significantly between testing modalities; notably, VO2
max achieved with cycle ergometer EST is generally reduced by 5% to 20% compared
to treadmill protocols [7]. When serial testing is performed for follow-up or training
monitoring, the same testing modality and protocol should be maintained to ensure valid
intraindividual comparison.
5. Exercise Testing in Clinical Practice
5.1. Inducible Ischemia
EST has long been a key non-invasive tool in traditional clinical cardiology for assessing inducible ischemia in patients with suspected CAD. However, its diagnostic accuracy
for detecting CAD is lower than that of modern functional or anatomical imaging modality,
with sensitivity and specificity ranging from 60% to 77%. Nevertheless, EST remains a
valuable method for prognostic assessment and risk stratification [47–49].
Exercise stress testing is recommended for assessing inducible ischemia during the
initial diagnostic evaluation of patients with suspected chronic coronary syndrome. It is
particularly useful for individuals with a low (5–15%) pre-test likelihood of obstructive
CAD, as it can facilitate reclassification into the very low likelihood category, in whom
further testing can be deterred [4,27].
Moreover, several position statements recommend CV screening with EST in athletes over 35 years and in sedentary individuals at high CV risk who plan to undertake
high-intensity exercise in order to early detect CAD, potentially at risk of sudden cardiac
death [5,28].
Exercise-induced angina is a key predictor of the presence and severity of CAD.
Christman et al. [50] demonstrated that exercise-induced typical angina, occurring during
EST, independently predicts CV events, irrespective of ECG abnormalities.
During EST, ST-T changes may suggest CAD and warrant further evaluation.
The usual criterion to define pathological ST-segment depression is the presence of a
horizontal (0.7–1 mV/s) or downsloping ST depression of 0.10 mV (1 mm) or greater in
at least three consecutive beats. ST-segment evaluation should be read at 80 ms from the
J-point and at 60 ms from the J-point when HR is greater than 130 bpm (Figure 3) [51].
J-point depression is a normal finding during maximal exercise. Rapid upsloping ST
depression (>1 mV/s) of <0.15 mV, read 80 ms after the J-point, is usually a normal response
to exercise and gradually returns to pre-exercise values during recovery [7]. Conversely,
slowly upsloping (0.5–1.0 mV/s) ST-segment depression of >0.15 mV is abnormal and is
typically seen in patients with known obstructive CAD [48,51].
ST-segment depression observed exclusively during the recovery phase of EST has
diagnostic and prognostic significance comparable to that observed during the active
exercise phase [52]. Furthermore, the persistence of ST-segment changes beyond 1 min of
recovery is tied to a worse prognosis and more extensive CAD. Conversely, the resolution
of ECG abnormalities within 1 min of recovery indicates a lower likelihood and severity of
obstructive CAD [53].
The earlier ST-segment depression appears during EST and the longer it persists into
recovery, the greater the probability of CAD.
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How to measure ST-segment depression
At HR < 130 bpm: ST-segment depression
Types of pathologic ST-segment depression
(a) Downsloping ST-segment depression
should be measured 80 ms after J-point
80 ms
1
2
1
2
≥ 0.1mV
3
3
(b) Horizontal ST-segment depression
1
2
At HR ≥ 130 bpm: ST-segment depression
should be measured 60 ms after J-point
≥ 0.1mV
3
(c) Slowly upsloping ST-segment depression
60 ms
1
≥ 0.15mV
2
1
2
3
4
Figure 3. Definition of ST-segment depression changes during exercise. On the left column, example
of how to correctly measure ST-segment depression. On the right column, abnormal ST-segment
responses to EST: horizontal (a) and downsloping (b) ST-segment depression ≥ 1 mV and slowly
upsloping (0.5–1.0 mV/s) ST-segment of >0.15 mV (c). Define the isoelectric line (1); define the j-point
(2); measure the ST-segment depression after 80 msec from the j-point (3), or 60 msec (4) according to
the heart rhythm (HR).
Exercise-induced ST elevation of 0.1 mV (1 mm) or greater in at least three consecutive
beats is a marker of inducible ischemia. In particular, the presence of ST-segment elevation
in lead aVR is a sensitive predictor of left main CAD or multivessel CAD [54,55].
In individuals with Wolff–Parkinson–White (WPW) syndrome, abnormal ventricular
activation and repolarization, due to the accessory pathway, frequently lead to ST-segment
depression or T-wave inversion, which can be misinterpreted as ischemic changes [56].
Furthermore, chronic treatment with digitalis glycosides can compromise ST-segment
assessment. Digitalis administration typically induces a prominent J-point depression
and, less commonly, ST-segment depression. Notably, these changes are often evident
at rest but can be accentuated during exercise [57]. Therefore, ECG-EST evaluation in
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patients taking digitalis is associated with a higher risk of false-positive results and reduced
diagnostic value.
When evaluating exercise-induced ST-segment depression, it should be recognized
that exaggerated atrial repolarization waves during exercise may produce an apparent
downsloping ST depression, particularly in inferior leads, even without underlying ischemia. Consequently, isolated inferior ST-segment depression is frequently a false positive
resulting from atrial repolarization artifacts [58].
The presence of resting ECG abnormalities prevents ST-segment evaluation during
EST; these conditions include LBBB, ventricular pacing, ventricular pre-excitation, and
resting ST depression ≥ 0.1 mV. In patients with established CAD, the test may still be
considered to assess functional status and symptom onset, complementing the overall
clinical assessment [4].
5.2. Functional Capacity
As explained in Section 2, functional capacity is a strong predictor of mortality and
nonfatal CV outcomes in both patients with and without CAD.
It was reported that each 1-MET increase in functional capacity is associated with a
17–20% reduction in the risk of CV mortality, regardless of the indication for EST [59].
Predicted functional capacity adjusted for age and sex could be estimated by a simple
regression equation [7]: predicted METs = 18 − (0.15 × Age) in men or 14.7 − (0.13 × Age)
in women.
The two fundamental physiologic parameters that provide relevant information concerning functional capacity and prognosis are HR and BP responses to exercise.
5.2.1. Chronotropic Incompetence and Heart Rate Recovery
Chronotropic incompetence is defined as the inability of the heart to increase its rate
adequately to meet the body’s metabolic demand during exertion. This condition significantly contributes to exercise intolerance and is an independent predictor of CV events
and mortality. Failure to achieve maximal predicted HR, inadequate submaximal HR,
or HR instability during exertion are all examples of impaired chronotropic response [8].
In patients with HF, the mechanism underlying chronotropic incompetence involves reduced β-adrenergic receptor density and sensitivity secondary to increased sympathetic
drive [8,60,61]. Chronotropic incompetence is also relatively common in patients with sick
sinus syndrome, atrioventricular block and CAD. In patients with cardiac amyloidosis,
impairment of the chronotropic response has been increasingly recognized. In a recent
multicentre cohort study, chronotropic incompetence was prevalent and significantly correlated with reduced exercise capacity, suggesting that analysis of exercise-induced HRR
may contribute to the clinical assessment in this population [62].
The diagnosis of chronotropic incompetence should be considered when a subject
fails to achieve 80% of age-predicted maximum HR. However, the traditional formula
(220 − Age) is not suitable for patients with CV disease or individuals taking negative chronotropic medications. Consequently, it is recommended to use an equation
derived from a population that closely resembles the target group (e.g., Tanaka et al.
equation in apparently healthy persons, Brawner et al. equation in those with suspected
CV disease) [8,61].
Another method for evaluating chronotropic response is to measure chronotropic
index (Wilkoff method). It is calculated by dividing the HR response (defined as the
difference between resting HR and the maximal HR achieved during maximal exertion) by
the difference between resting HR and age-predicted maximum HR. A chronotropic index
< 80% is indicative of chronotropic incompetence and predicts a poor prognosis [61].
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A delayed recovery of HR after exertion is another parameter associated with an increased risk of CV events, all-cause mortality, and death, independently of the peak HR [63]
and regardless of age, gender, exercise capacity and left ventricular systolic function [64].
The physiological basis of HR recovery has been described previously (Section 2). While
many methods have been used to define HR recovery cut-off, an abnormal HR recovery is
generally defined as a reduction from the peak HR of <12 bpm/min (or <18 bpm/min if
recovery was “active,” e.g., unloaded cycling or slow walking) in the first minute of passive
supine recovery and of <42 bpm after 2 min of recovery [65,66]. A recent meta-analysis
showed that, for every 10 bpm/min decrement in HR recovery rate, the risk of CV events
and all-cause mortality was increased by 13% and 9%, respectively. Moreover, it showed
that 1 min and 2 min HR recovery rates were equally effective at predicting all-cause
mortality while the 2 min HR recovery rate appeared more sensitive for predicting CV
events [63].
5.2.2. Blood Pressure Response
The BP response during EST can provide important diagnostic and prognostic information [67].
Current guidelines provide conflicting opinions regarding normal values of BP response to exercise: the American Heart Association recommends that maximal systolic BP
should not exceed 210 mmHg in men and 190 mmHg in women, whereas the European Society of Cardiology sets higher thresholds of 220 mmHg for men and 200 mmHg for women
and the American College of Sports Medicine advises a universal systolic BP threshold of
225 mmHg, applicable to all genders [7,68,69]. Moreover, the applicability of these guidelines to highly trained athletes is not clearly defined. To address this gap, Caselli et al. [22]
derived athlete-specific reference values from a large cohort of elite athletes, identifying upper systolic BP thresholds of 220 mmHg in men and 200 mmHg in women and diastolic BP
upper limits of 85 mmHg in men and 80 mmHg in women. Interestingly, the small subset
of healthy athletes with BP values above the 95th percentile included those with superior
physical performance, endurance training, and more pronounced cardiac remodeling [22].
Evidence from systematic reviews and meta-analyses highlights a complex and sometimes conflicting association between systolic BP responses to exercise and mortality [70].
Notably, in individuals with high fitness levels, a higher systolic BP during exercise is
associated with greater external workload and a lower incidence of CV events [21]; by
contrast, other investigations have shown that an exaggerated BP responses to exercise
predicts the future onset of hypertension and may trigger atherosclerotic plaque rupture,
potentially leading to acute CV events [71]. As a result, the use of an absolute threshold of
peak systolic BP to define an abnormal BP response to exercise may be misleading, mainly
in populations with higher fitness and low CV risk. In high-performance athletes, peak SBP
values may exceed guideline-defined thresholds at extreme workloads, likely reflecting
elevated cardiac output rather than pathological vascular response [70].
Consistently, recent data in endurance athletes have shown that peak SBP alone
demonstrates modest diagnostic accuracy in identifying hypertension on 24 h ambulatory
blood pressure monitoring, whereas workload-indexed parameters provide improved
discrimination [72]. To overcome these limitations, workload-indexed metrics such as
the SBP/MET slope have been proposed. This parameter reflects the increase in SBP
relative to achieved metabolic demand. Hedman et al. [21] demonstrated that an SBP/MET
slope > 10 mmHg/MET was associated with increased long-term mortality, whereas the
prognostic significance of peak SBP varied according to baseline cardiovascular risk.
The SBP/MET slope is also a valuable index for assessing CV adaptation in elite
athletes. In this population, an elevated SBP/MET slope (>6.2 mmHg/MET [21]) has been
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associated with increased left ventricular thickness (even in the absence of systolic/diastolic
dysfunction), reduced exercise capacity and higher risk of developing arterial hypertension
and mortality compared with their counterparts. Accordingly, an elevated SBP/MET slope
may represent an early marker of long-term CV risk and the initial manifestation of a
maladaptive cardiac response [73].
Moreover, workload-indexed parameters such as the SBP/workload ratio have also
demonstrated prognostic value in patients with heart failure, further supporting the concept
that indexing systolic BP to external workload may provide incremental risk stratification
beyond peak SBP alone [74,75]. Consistent with previous analysis [76,77], systolic BP
assessed at a predefined submaximal workload demonstrates superior prognostic value
compared with peak systolic BP and more effectively identifies individuals at increased
risk of CV disease.
In contrast to hypertensive responses, a drop in systolic BP by ≥20 mmHg despite
increasing workload is a pathological finding. When accompanied by other evidence of
ischemia, this finding is an absolute indication to terminate the EST. A sustained, exerciseinduced decrease in peak systolic BP is predictive of poor prognosis and often related to
evidence of severe, multivessel CAD. This phenomenon is best explained by acute left
ventricular pump failure secondary to extensive myocardial ischemia [78]. The clinical
significance is greatest when hypotension occurs at low workloads and is accompanied by
other ischemic features (e.g., ST-segment depression or angina). Beyond ischemia, exerciserelated hypotension may be observed in a variety of other clinical scenarios, including
cardiomyopathy, LV outflow tract obstruction, enhanced vagal tone, hypovolemia, the use
of antihypertensive medications, and arrhythmias.
5.3. Ventricular Pre-Excitation
Ventricular pre-excitation is a cardiac conduction disorder characterized by the persistence of an abnormal accessory pathway that conducts electrical impulses from the atria
to the ventricles, bypassing the normal atrioventricular node-His bundle axis. The Wolff–
Parkinson–White (WPW) syndrome refers to the presence of an overt accessory pathway in
combination with symptomatic, usually recurrent, tachyarrhythmias [79]. During sinus
rhythm, the typical electrocardiographic pattern of a ventricular pre-excitation in WPW
syndrome includes: a short PR interval (≤120 ms); a slurring of the initial segment of
the QRS complex (delta wave); and a wide QRS complex (>120 ms). Delta wave may be
particularly evident in highly trained athletes who exhibit an increased vagal tone and
prolonged atrioventricular node conduction time. Among patients with WPW, atrioventricular reentrant tachycardia (AVRT), either orthodromic or antidromic, is the most common
arrhythmia, followed by atrial fibrillation.
The capability of the accessory pathway to allow a rapid non-decremental atrioventricular conduction exposes subjects with WPW syndrome to an increased risk of malignant arrhythmic events and SCD, also in athletes [80,81]. Consequently, a proper risk
stratification is essential in these subjects, especially in athletes, to identify those with
high-risk accessory pathways able to sustain rapid conduction and potentially leading to
life-threatening ventricular arrhythmias (Figure 4—Clinical Box).
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Figure 4—Clinical Box
40-year-old male with no significant past medical history presented with sudden
onset exertional palpitations. The resting ECG showed sinus rhythm with HR 57 bpm,
PR at the upper normal limit and incomplete right bundle branch block, early repolarization (a).
An EST was performed using a stepped protocol and documented the onset of intermittent ventricular pre-excitation suggestive of a left lateral accessory pathway at a
workload of 150 W (b).
At HR >130 bpm (175 W) 1:1 antidromic conduction via accessory pathway was observed (c). Notably, EST revealed diffuse 3–4 mm downsloping ST-segment depression
and T-wave inversion only in pre-excited beats; at the same workload, normal ventricular
repolarization was detectable in not pre-excited beats (b). This finding is not indicative of
myocardial ischemia but a direct consequence of conduction over the accessory pathway
that results in aberrant depolarization and repolarization. Normal atrioventricular nodal
conduction was resumed during recovery phase and coincided with ST-segment normalization.
After EST, the patient was referred for electrophysiology study which confirmed the
presence of a left lateral accessory pathway and ultimately underwent radiofrequency
ablation.
(a)
150 W
175 W
(b)
(c)
Figure 4. Clinical Box. (a) Resting ECG. (b) Intermittent ventricular pre-excitation (blue line) and
normal atrioventricular conduction (red line). (c) Shows 1:1 antidromic conduction via accessory
pathway (blue line) and secondary ST-segment depression (light blue area).
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Current guidelines recommend performing an electrophysiological study in asymptomatic patients and professional athletes with ventricular pre-excitation. A non-invasive
evaluation with EST should also be considered for asymptomatic subjects without high-risk
occupations/hobbies [79].
The identification, during EST, of a sudden loss of ventricular pre-excitation, with the
disappearance of the delta wave and complete normalization of the PR interval, is accepted
as a low-risk predictor of malignant arrhythmias [82,83]. The disappearance of ventricular
pre-excitation during exercise implies a long refractory period of the accessory pathway,
even during adrenergic stimulation, identifying a low-risk pathway [84]. Evidence of an
intermittent ventricular pre-excitation at rest is not necessarily indicative of a low-risk
pattern, as exercise-dependent adrenergic stimulation can markedly improve accessory
pathway conduction and refractoriness [85].
EST may provide additional diagnostic value by unmasking hidden accessory pathways; during the recovery phase, the physiological increase in vagal tone slows down
the atrioventricular nodal conduction, making the conduction over the accessory pathway more evident. Moreover, evidence of multiple accessory pathways with different
pre-excited morphologies on resting ECG or EST is defined as a marker of high risk.
Interpretation of EST in patients with ventricular pre-excitation may be challenging,
leading to incorrect diagnoses and improper risk assessment. During exercise, sympathetic
stimulation enhances atrioventricular nodal conduction and reduces the degree of ventricular pre-excitation, potentially leading to an apparent disappearance of the delta wave
and a misdiagnosis of a low-risk accessory pathway. On the other hand, intermittent preexcitation during exercise, with alternating presence and absence of the delta wave, could
mimic other arrhythmic conditions such as atrial fibrillation or multifocal atrial tachycardia
intermittent conduction [84]. Moreover, the accessory pathway causes abnormal ventricular
activation and repolarization, responsible for ST-segment depression or T-wave inversion,
which can be misinterpreted as ischemic changes. These electrocardiographic alterations,
particularly in young healthy patients, are typically not associated with underlying CAD
but may serve as an indication for the presence of an accessory pathway, even when a
delta wave is not clearly visible (Figure 4—Clinical Box). Usually, the WPW-related ST-T
alterations are deflected in the opposite direction with respect to the delta wave vector,
the ST-segment change is nonhorizontal, and the T-wave inversion is nonsymmetrical. By
contrast, when WPW syndrome coexists with an ischemic ST-T alteration, the ST-segment
is horizontal, in accordance with the delta wave vector, the T-wave inversion is symmetrical
and ST-T changes appear in two or more contiguous leads with angina symptoms [56].
To date, however, the role of EST for risk stratification in patients with ventricular preexcitation remains controversial. This is because abrupt loss of ventricular pre-excitation
during EST is observed in only a minority of patients, and the overall accuracy of EST
in excluding high-risk accessory pathways appears to be moderate [83]. When EST does
not allow confirmation of a low-risk accessory pathway, or when the presence of multiple
accessory pathways is suspected, invasive evaluation with an electrophysiological study
is recommended.
5.4. Ventricular Arrhythmias
PVBs are a common finding in the general population with a similar prevalence in
sedentary subjects and athletes, and no substantial differences according to the training
volume and sport type [86–88]. PVBs are observed during EST in approximately 5–10%
of athletes, and their prevalence increases with age [89]. In most cases, ventricular arrhythmias occur in the absence of an underlying heart disease; however, in a minority of
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individuals, PVBs may represent the only manifestation of a pathological substrate at risk
of SCD [90–94].
A careful evaluation of PVBs’ features and their behavior during EST is essential to
accurately stratify the risk of pathological substrate, and the need for further investigations.
Key aspects to assess include: PVB morphology, complexity and coupling interval, response
to exercise, and reproducibility in different moments at the same type of examination or
during a Holter ECG.
The assessment of the morphologic features of PVBs revealed during EST helps to
identify the anatomical site of origin of the arrhythmia and infer the associated risk of an
underlying cardiac disorder. Idiopathic PVBs usually occur in the absence of underlying
structural heart disease and have a benign prognosis. The two most common sites of
origin of idiopathic PVBs are the ventricular outflow tracts (“infundibular PVBs”) and the
fascicular specialized cardiac conduction system. Infundibular morphology is characterized
by a left bundle branch block (LBBB) pattern in V1 and inferior axis; the precordial transition
beyond V3 identifies the origin from the right ventricle outflow tract while an earlier
transition in V1–V2 denotes PVBs from the left ventricular outflow tract. Infundibular PVBs
are usually monomorphic, appear in isolated beats and rarely in couplets or short runs of
non-sustained ventricular tachycardia. This ventricular ectopy is usually very frequent
during the day but typically decreases or disappears at peak of exercise and reappears
during recovery [86,95]. Fascicular PVBs are another manifestation of benign idiopathic
ventricular arrhythmias. The fascicular pattern is characterized by a typical right bundle
branch block (RBBB) with a narrow QRS (<130 ms). A specific ECG pattern identifies
PVBs with an origin from the posterior fascicle (RBBB and left anterior fascicular block
morphology) or anterior fascicle (RBBB and left posterior fascicular block morphology).
Both fascicular and infundibular PVBs generally arise from automatic ventricular foci.
Ventricular ectopy originating from structures other than ventricular outflow tracts or
fascicles displays different QRS patterns, is less frequent and should be carefully evaluated
because it can to be associated with a cardiac disease [96]. Figure 5 schematically represents
the main sites of origin of PVBs and their 12-lead electrocardiographic features. Among
these, the most concerning pattern involves suggesting an origin from the lateral LV wall,
the typical site of non-ischemic left ventricular scar (NILVS) [96]. A multicenter study
by Muser et al. highlighted that PVBs with RBBB morphology and particularly those
with superior axis (consistent with an origin from the inferolateral wall of the LV) were
more frequently associated with myocardial abnormalities identified on cardiac magnetic
resonance. Moreover, the presence of multifocal PVBs was associated with a pathological
substrate and resulted in an independent predictor of a worse long-term outcome [97–100].
Calò et al. examined the electrocardiographic features of PVBs with RBBB morphology
in apparently healthy athletes and demonstrated that PVBs exhibiting RBBB morphology,
superior or intermediate axis and qR pattern in leads aVR and V1 are strongly associated
with the absence of underlying structural disease [101]. Therefore, while PVCs with RBBB
morphology and superior or intermediate axis often raise clinical concern, the additional
presence of a qR pattern in aVR or V1 and a short intrinsicoid deflection time (<80 ms)
suggests a favorable prognosis.
The complexity of PVBs, and hence the occurrence of couplets or runs of non-sustained
ventricular tachycardia, may reflect the propensity of the arrhythmia to self-perpetuate,
becoming sustained and potentially malignant. The evidence of short-couplet PVBs or
R-on-T phenomena are warning signs for myocardial electrical instability which may predispose to malignant ventricular arrhythmia, independent from the PVB’s morphology [102]
(Figure 6—Clinical Box).
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Figure 5. Premature ventricular beats morphology and probable site of origin. Schematic representation of the main sites of origin of PVBs and their ECG features. RV = right ventricle. LVOT = left
ventricle outflow tract; NCC = non-coronary aortic cusp.
EST is essential for evaluating PVBs response to exercise. Typically, PVCs that are
present during the warm-up phase but are suppressed as the workload increases suggest a
benign etiology. Conversely, ectopy that emerges or intensifies in frequency and complexity
during high-intensity effort is consistently associated with an increased risk of structural
heart disease [103].
Evaluating the PVBs’ reproducibility at repeated EST may facilitate risk stratification
for underlying heart disease. Reproducibility is established when 3 or more PVBs with
the same pattern and the same exercise-inducibility of a previous EST are recorded [92].
Therefore, when evaluating an individual with PVBs, particularly when isolated and not
associated by other suspicious findings, it may be reasonable to repeat EST in order to
improve risk stratification and to avoid unnecessary second-level investigations [96].
Corrado et al. proposed a simplified classification that distinguishes between “common” PVBs, generally idiopathic and benign, and “uncommon” PVBs, associated with
higher likelihood of underlying heart disease. Common PVBs typically display infundibular or fascicular morphologies, often occur as isolated, are monomorphic and are suppressed
by exercise. On the other hand, uncommon PVBs are characterized by RBBB morphology
with a wide QRS complex (>130 ms) or LBBB morphology with a superior axis; “uncommon” PVBs are more frequently repetitive and polymorphic and tend to persist or increase
in number and complexity with exertion. The evidence, during EST, of PVBs with “uncommon” characteristics should launch a cascade of CV evaluation in order to confirm or rule
out the suspected cardiac pathology [102].
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Figure 6—Clinical Box
44-year-old man, with no significant past medical history and no family history of
cardiopathy or SCD, was admitted to the Intensive Care Unit following an aborted sudden cardiac arrest due to idiopathic ventricular fibrillation.
On admission, the resting ECG was unremarkable. Transthoracic echocardiography demonstrated normal biventricular dimensions and preserved systolic function.
The coronarography showed no significant CAD. Cardiac magnetic resonance imaging
confirmed the absence of morpho-functional abnormalities.
Subsequent EST documented frequent fascicular PVBs including complex ectopy
with very short coupling intervals. Ectopic beats occasionally occurred as R-on-T phenomena, potentially triggering degeneration into ventricular fibrillation. The patient
underwent a successful ablation.
Figure 6. Clinical Box. In blue the fascicular premature ventricular beats realizing the R-on-T
phenomenon, and organized in a triplet.
The following section outlines the diagnostic role of EST in specific conditions.
Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited cardiac channelopathy characterized by life-threatening polymorphic ventricular arrhythmias
adrenergically triggered. A missed diagnosis could lead to cardiac arrest during exertion.
CPVT is mostly associated with the mutation of cardiac ryanodine receptor (RyR2)
or calsequestrin 2 genes (CASQ2). Other pathogenic variants involved CALM1, CALM2,
CALM3, KCNJ2, TECRL and TRDN genes. These mutations resulted in the dysregulation
of the intracellular calcium homeostasis, predisposing to triggered-activity polymorphic
ventricular arrhythmias favored by adrenergic stimulation. Genetic testing identifies a
pathogenic variant in almost 60–70% of probands [103].
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The diagnosis of CPVT is often challenging, as this condition is typically associated
with a normal resting ECG and structurally normal heart; therefore, the EST (or a Holter
ECG with an exercise session) is the only diagnostic tool able to detect this condition [104].
The hallmark of CPVT is the onset of ventricular ectopy during EST. PVBs progressively increase in number and complexity as HR rises, evolving from isolated monomorphic PVBs to PVBs in bigeminy or couplets to bidirectional or polymorphic ventricular
tachycardia, which may degenerate into ventricular fibrillation if exercise is not promptly
discontinued, and the disappearance of the arrhythmias when the HR decreases (an on/off
mechanism) [104]. Moreover, in patients with CPVT, ventricular arrhythmias are usually
reproducible in different ESTs and elicited at the same HR.
EST plays a pivotal role in the follow-up of patients with established CPVT. It is
essential for assessing the efficacy of ongoing medical therapy, optimizing drug choice
and titration, and identifying patients who are refractory to combination medical therapy
who may be candidates for ICD implantation or cardiac sympathetic denervation [105].
Furthermore, EST allows the identification of the HR at which ventricular arrhythmias
are reproducibly induced, which may serve as a pragmatic reference to guide individualized exercise recommendations. However, this value should not be interpreted as a
definitive safety threshold, as arrhythmic events may occur at lower intensities depending
on adrenergic fluctuations and individual susceptibility.
5.5. Long QT Syndrome
Long QT Syndrome (LQTS) is an inherited cardiac channelopathy, characterized by
prolongation of the QT interval and by a predisposition to ventricular arrhythmias and
SCD [106]. LQTS is caused by pathogenic variants in multiple genes encoding cardiac
ion channels. Each genetic subtype is associated with a relatively characteristic clinical
phenotype and a distinct pattern of electrocardiographic features [106].
The upper normal value limits of the of QTc (with correction for HR according to
Bazett’s formula) are 440 ms in men and 460 ms in women, and 480 msec in male athletes [107].
In LQTS, QTc prolongation often accompanies specific and bizarre morphologic
changes in ventricular repolarization that may help predict the genotype. Notched Twaves are common in patients with LQTS type 2 and serve as an arrhythmic risk marker
due to early after-depolarization; T-wave alternans is also a red flag of electrical instability,
which can precede the onset of malignant ventricular arrhythmias usually triggered by
adrenergic stimulation.
LQTS is easily diagnosed when a clear QTc prolongation of ≥ 480 ms is accompanied
by syncope. However, up to 25% of “silent” mutation carriers have a normal resting QTc
because of low penetrance and the dynamic nature of QT prolongation [108]. Therefore, in
asymptomatic patients with borderline resting ECG features, EST and diagnostic scoring
systems (e.g., LQTS Diagnostic Criteria [109]) could aid in identifying this condition.
In patients with normal or borderline resting QTc and suspected LQTS, EST is recommended to assess the QT behavior during active exercise and the recovery phase. During
exercise and early recovery, QT measurement should be performed in the lead with the
clearest T-wave morphology, typically lead II or lateral precordial leads (e.g., V5), avoiding leads with prominent U waves or significant motion artifacts. At rest, QT correction
using Bazett’s formula remains widely adopted in clinical practice; however, during exercise and recovery, when the HR is >90 bpm, Fridericia’s correction may provide a more
reliable estimate due to reduced heart rate-related overcorrection [110]. It was demonstrated that a prolonged QTc >480 ms during late recovery (the 4th minute after exercise)
is a highly specific predictor of LQTS and a more sensitive marker than resting QT pro-
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longation. Notably, a lower cut-off of 445 ms yields reduced specificity (approximately
90%) but increased sensitivity (approximately 90%) for distinguishing mutation carriers
from non-carriers [33,109,111]. Therefore, the combination of resting QTc with QTc at 4
min recovery could predict a positive genetic result in subjects with suspected LQTS and
borderline features.
Although exaggerated QTc prolongation during exercise is characteristic of LQTS
and a robust predictor of LQT1, its utility is only modest, perhaps reflecting the technical
difficulty of measuring QT accurately at peak exercise [111].
However, EST can provoke characteristic T-wave abnormalities at peak exercise,
thereby serving as a valuable tool to unmask this diagnostic feature. A recent analysis
conducted by Boeri et al. demonstrated that the evidence, at peak exercise of EST, of a
complete fusion of the T- and P-wave (TP-fusion) in all precordial leads except V1 predicted
an 88% probability of being affected by LQTS even in subjects with normal baseline
QTc [112]. This novel variable is defined when a broad positive T-wave ends just before
the onset of the QRS deflection, completely incorporating the P-wave. TP-fusion appeared
concomitantly with an increased peak HR (>145 bpm) and longer peak QTc (>450 ms) in all
LQTS genotypes and, interestingly, in 55% of patients with genotype-positive and baseline
QTc < 450 ms, highlighting the usefulness of TP-fusion as a marker of “likely LQTS” in
otherwise normal or borderline subjects [112].
5.6. Conduction Disorders
5.6.1. Sinoatrial Node Dysfunction and Atrioventricular Block
In selected patients presenting with exercise-related symptoms or resting seconddegree Mobitz type I atrioventricular (AV) block at rest, EST is recommended to clarify
the diagnosis [107,113,114]. Furthermore, EST is valuable for differentiating exerciseinduced symptoms associated with chronotropic incompetence from those resulting from
conduction disorders.
Under physiological conditions, an enhanced vagal tone, as observed during sleep
or pain, leads to slower conduction through the AV node and decreased pacing rate of
the sinoatrial node; by contrast, adrenergic activation, such as that induced by exercise,
shortens the effective refractory period and increases conduction velocity as the sinoatrial
node pacing rate increases. On the surface ECG, this physiological facilitation manifests as
a shortening of the PR interval as the HR increases.
Therefore, in patients with Mobitz 1 or 2:1 AV block, EST can be valuable for noninvasively identifying the site of the conduction disorder. Improvement or resolution of AV
conduction abnormalities during exercise, due to increased sympathetic activation, typically
indicates a supra-hisian block that usually does not require intervention. By contrast, a
worsening of AV block during exercise and the development of tachycardia-related exerciseinduced second-degree or complete AV block suggest an infra-hisian disease that predicts
progression to permanent AV block [113,115]. Patients with infra-hisian AV block often
show intraventricular conduction abnormalities on resting ECG, but a normal resting ECG
has also been reported. In such cases, EST should be performed with caution and in centers
equipped for advanced cardiac monitoring and immediate management of high-grade
AV block.
While uncommon in patients with normal AV conduction at rest, exercise-induced
second-degree AV block can lead to exercise intolerance, sometimes requiring a PM implantation. This condition could be associated with congenital heart disease or underlying
myocardial ischemia [116].
In athletes who participate in high-volume endurance sports, sinus bradycardia (even
extreme), moderate prolongation of the PR interval, and first- or second-degree Mobitz type
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I AV block are traditionally considered physiological and reversible phenomena, usually
disappearing with increased HR [117]. The main mechanisms behind this are the trainingrelated increase in vagal tone and a decrease in the intrinsic pacemaker rate [118,119], even
if some epigenetic mechanisms have been proposed. When sinoatrial node dysfunction is
suspected, a short detraining period may be necessary to differentiate it from physiological
bradycardia induced by exercise [107].
However, some individuals with a long history of sports activity remain bradycardic
even after stopping training. This may be due to two additional factors: stress-related
damage to the sinoatrial and AV tissues and post-transcriptional downregulation of ion
channel genes influencing AV and sinoatrial node activity. In athletes or former athletes
with bradycardia and AV block at rest, EST is useful to determine whether the conduction
disorder is a training adaptation or indicates a pathological condition. Recent data indicate
that intense physical activity, mainly endurance training, can speed up the development of
sinus node dysfunction and AV node dysfunction [119,120].
5.6.2. Bundle Branch Block
In patients with left bundle branch block (LBBB), EST can be useful to evaluate
functional capacity and chronotropic response to physical exercise, as well as the potential
presence of exercise-induced ventricular arrhythmias. By contrast, the assessment of
ventricular repolarization abnormalities is compromised by LBBB, making the evaluation
of ST-T alterations less accurate. Therefore, in patients with LBBB in whom ischemic heart
disease is suspected, stress testing with imaging may be considered [91].
Exercise-induced LBBB is a rare phenomenon, with a prevalence of approximately
0.5–1%. Exercise-induced LBBB has distinct prognostic implications depending on the
HR at onset [121,122]. Vasey et al. found no coronary disease in patients who developed
exercise-induced LBBB at a heart rate > 125 bpm, whereas the incidence of coronary artery
disease was significantly higher when the LBBB developed at lower HR [123].
In patients without structural heart disease, exercise-induced LBBB is attributed to
rate-dependent aberrant conduction due to delayed recovery of LBB. As HR increases
with exercise, electrical impulses reach the proximal conduction system before the fascicle
has fully repolarized, thereby precipitating bundle branch block. In a subset of patients,
exercise-induced LBBB can lead to exertional intolerance characterized by atypical chest
pain and palpitations upon exceeding the threshold of onset. In this setting, EST is essential
to correlate the patient’s exertional symptoms with the onset of the conduction disturbance,
to assess repolarization abnormalities before the development of LBBB and to identify the
HR of LBBB appearance. It was reported that regular training shortens the repolarization
phase 3 of the action potential, thereby increasing the rate at which LBBB occurs and
improving exertional intolerance [122].
Exercise-induced right bundle branch block (RBBB) is an infrequent finding during
EST. Similarly to exercise-induced LBBB, it is caused by a frequency-dependent delayed
recovery of RBBB and is not related to an increased risk of cardiovascular events [117].
5.7. Assessment of Cardiac Implantable Electronic Device Function During Exercise
Exercise testing plays a crucial role in optimizing pacing responses during exercise
and identifying the mechanisms of exercise intolerance. The optimal strategy involves
performing EST while analyzing the electrogram on the CIED programmer to detect possible exercise-related device dysfunction and verify the effectiveness of any parameter
reprogramming. In pacemaker-dependent patients, the chronotropic incompetence is the
main cause of exercise intolerance. Rate-responsive pacing (RRP) was developed to improve exercise capacity in patients with chronotropic incompetence. This pacing mode
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is particularly important in patients with HF, in which the exercise-related increase in
cardiac output is strongly dependent on HR, because of reduced stroke volume. Inadequate
rate-adaptive settings may lead to persistent chronotropic incompetence, contributing to
the worsening of functional capacity. Conversely, an excessive increase in HR may result in
an improper rise in oxygen demand, ischemia, and a worsening of HF. Standard settings
for RRP do not adequately mimic physiological sinoatrial node behavior; therefore, it is
recommended to tailor CIED setup, mainly in highly active patients, using a meticulous
approach with simultaneous maximum-effort exercise and device monitoring [124]. Assessment of the RRP profile during EST is essential to verify whether the chronotropic response
is appropriate and to guide the modification of CIEDs parameters such as accelerometer
response factor, accelerometer reaction time and recovery time, maximum tracking rate, or
medical therapy optimization [124].
Based on cardiopulmonary exercise testing and pacemaker stress echocardiography,
Serova et al. introduced a novel algorithm for optimal RRP programming in patients with
HF and demonstrated that, in selected patients, a tailored RRP optimization improves
exercise tolerance, LV diastolic function, and quality of life [125].
Another CIED-dependent mechanism of exercise intolerance is the inadequate adaptation of the AV delay during exercise. Under physiological conditions, the PR interval
shortens during exercise; this adaptation reduces atrial systole duration while extending diastolic filling time and increasing end-diastolic volume, stroke volume, and cardiac output.
In modern CRT devices, dynamic AV delay optimization algorithms are developed to mimic
this physiological response. By contrast, if a static AV delay is programmed and the intrinsic
PR interval shortens below this value during exercise, intrinsic conduction will override,
resulting in progressive loss of biventricular synchronization and, ultimately, complete
loss of effective left ventricular capture. It was demonstrated that an individualized device
programming with dynamic AV delay improves left ventricular reverse remodeling and
systolic function compared with biventricular pacing at fixed atrioventricular delay [126].
Therefore, assessment of CRT performance during EST allows clinicians to verify the appropriateness of dynamic AV delay settings, ensuring that optimal biventricular capture is
maintained up to maximal HR.
Additionally, in dual-chamber pacing mode, exercise intolerance may be attributed
to the device’s “Wenckebach behavior”. As the atrial rate increases, ventricular pacing
cannot exceed the programmed maximum tracking rate, resulting in progressively longer
AV delay until a P-wave falls in the refractory period and is not tracked. However, if the
total atrial refractory period is excessively prolonged and the intrinsic atrial rate exceeds the
programmed maximum tracking rate during exercise, an abrupt 2:1 block may occur, resulting in a sudden slowing of the ventricular rate and exercise intolerance (Figure 7—Clinical
Box). This condition is more frequent in young patients, in whom the physiologic increase
in sinoatrial pacing rate during exercise requires a higher maximal tracking rate [127].
Moreover, exercise-induced augmentation of T-wave amplitude can result in T-wave
oversensing and double-counting of the cardiac cycle. This may lead to the erroneous
detection of a tachyarrhythmia, triggering inappropriate therapy delivery.
Therefore, EST is useful for verifying adequate sensing during exercise, particularly
in young patients with subcutaneous implantable defibrillators, because the ability to
discriminate ECG morphology is lower.
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Figure 7—Clinical Box
52-year-old man, endurance athlete, presented with exercise intolerance and exertional presyncope. Two years prior to presentation, the patient underwent dual-chamber
pacemaker implantation because of a III-degree AV block complicating a SAVR (surgical
aortic valve replacement) reoperation in bicuspid aortic valve stenosis.
On presentation, the pacemaker was programmed to DDD 50–165 bpm mode. Atrial
and ventricular sensing and pacing threshold were within normal values. The average
atrial and ventricular pacing percentages were 28% and 99.9%.
The resting ECG showed atrial-sensed ventricular paced rhythm with an HR of 75
bpm (a).
EST was performed using a 20 W/min ramp protocol and during pacemaker monitoring. At a workload of 100 W, the atrial rhythm was correctly sensed with appropriate
rate-responsive ventricular pacing at a HR of 110 bpm (b). At a workload of 180 W, EST
was terminated due to an abrupt drop in HR from 150 to 75 bpm, caused by the onset of
2:1 conduction accompanied by dizziness and presyncope. Intracavitary EGM analysis
revealed T-wave oversensing, which caused the intrinsic P-waves to fall within the postventricular blanking period, resulting in a loss of atrial tracking (c). The pacemaker was
reprogrammed by reducing ventricular sensitivity. A repeat EST confirmed the resolution of the issue, demonstrating normal conduction even at high HR.
(a)
At rest
(b)
100 W
(c)
180 W
EGM
monitoring
Figure 7. Clinical Box. (a) Atrial-sensed ventricular paced rhythm at rest. (b) Normal atrial tracking at
100 W workload. (c) T-wave oversensing (red arrow) resulting in loss of atrial tracking (2:1 behavior).
P-waves are highlighted by blue circles; ventricular paced beats are indicated by red lines.
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6. Limitations and Critical Considerations
Although the strengths and clinical applications of EST are well established, its limitations should be recognized. The diagnostic accuracy for obstructive CAD remains inferior
to contemporary imaging techniques, and the interpretation of ECG changes may be influenced by baseline abnormalities, pharmacologic therapy, and training status. Moreover,
heterogeneity in guideline-recommended cut-offs for blood pressure response, CI, and
HRR reflects ongoing uncertainty regarding optimal thresholds, particularly in athletes.
Finally, exercise-induced arrhythmias require cautious interpretation, as isolated findings
may have low predictive value in otherwise healthy individuals. Therefore, EST findings
should always be integrated within the overall clinical and demographic context.
7. Conclusions
EST is a widely available and cost-effective tool for evaluating hemodynamic and
arrhythmic responses under physiological adrenergic stimulation. It provides integrated,
dynamic data on functional capacity and exercise-inducible ischemia without the need for
ionizing radiation or pharmacological stressors.
This review outlines practical guidelines (Table 3) regarding the execution and multifaceted applications of EST, integrating updated evidence with illustrative figures and
exemplary clinical cases. Specifically, we explored the utility of EST in assessing BP response, advocating for a shift beyond the static cut-offs of current guidelines toward
novel prognostic markers. Furthermore, EST remains pivotal in the evaluation of patients
with brady- and tachyarrhythmias, and conduction disordes. Finally, in patients with
CIEDs, EST represents a pragmatic tool for verifying the adaptation of device settings to
real-life demands.
Table 3. Practical summary of key parameters for exercise stress testing interpretation.
Parameter
Normal Target
Abnormal Findings
Clinical Interpretation
Symptom-limited test
Test duration < 8 min or Borg
RPE < 14
Reduced diagnostic reliability:
consider repeat EST or
alternative stress modality
Test performance
Exercise duration and effort
scale (Borg RPE)
Borg RPE ≥ 17
Recommended duration
8–12 min
Functional capacity
Peak workload (METs)
Predicted METs = 18 − 0.15 ×
age in males; 14.7 − 0.13×age
in females
Peak METs < 85% of predicted
values or marked reduction
compared with prior testing
Strong predictor of
cardiovascular events and
all-cause mortality
Age-predicted maximum HR
220 − age; 208 − 0.7 × age
(Tanaka et al. equation in
apparently healthy persons);
164 − 0.7 × age (Brawner et al.
equation in those with
suspected
cardiovascular disease)
Failure to reach ≥ 80%
of predicted HR
Suggests autonomic
dysfunction, sinus node
disease, heart failure, or
drug effect
Chronotropic index
CI = HR response/(resting
HR − age-predicted
maximum HR) %
CI < 80%
Indicative of chronotropic
incompetence and poor
prognosis
Heart Rate Recovery
≥12 bpm at 1 min (passive
recovery); ≥42 bpm at 2 min
HR decrease < 12 bpm at 1 min
(or <18 bpm with active
recovery) or <42 bpm at 2 min
→ delayed HR recovery
Predictor of risk of
cardiovascular events and
all-cause mortality
Chronotropic response
•
Blood pressure response
Peak SBP; SBP/MET slope;
SBP/W; SBP drop
SBP increase
≈ 5–10 mmHg/MET; no
significant SBP fall
•
•
Exaggerated SBP
response
(≥220 men/≥200 women;
guideline-dependent)
Elevated SBP/MET
slope (>10 mmHg/MET;
>6.2 in elite athletes)
SBP drop ≥ 20 mmHg
(or >10 mmHg with
ischemia), especially at
low workload
Hypertensive response may
indicate masked hypertension
or maladaptive response to
training; hypotension suggests
severe CAD, LV dysfunction,
or other cardiovascular
pathology, and poor prognosis
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Table 3. Cont.
Parameter
Normal Target
Abnormal Findings
•
Ischemic ECG changes
ST-segment deviation
symptoms
No pathological ST-segment
changes
•
•
•
•
Ventricular Arrhythmias
Conduction disorders
PVB morphology, complexity,
response to exercise,
reproducibility
AV and intraventricular
conduction
Isolated, monomorphic PVBs;
infundibular or fascicular
(common) morphology;
suppression or reduction with
exercise
PR interval shortens with
exercise; stable AV conduction
•
•
•
•
•
•
Disease-specific patterns
QTc, pre-excitation, CPVT
features
QTc shortens during exercise;
abrupt loss of pre-excitation
with increasing HR
•
•
CIED assessment
Rate response and AV delay
(CIED electrocardiogram
analysis during exercise)
Appropriate HR adaptation;
preserved AV synchrony;
stable ventricular tracking
during exercise
Horizontal or
downsloping ST
depression ≥ 1 mm in
≥3 consecutive beats
Slowly upsloping ST
depression > 0.15 mV
ST elevation ≥ 1 mm in
≥3 beats
Persistence into
recovery (>1 min)
Indicates inducible myocardial
ischemia
Uncommon
morphology
Polymorphic
Complex
Increase in frequency or
complexity with
workload
R-on-T phenomenon;
Reproducibility on
repeated EST
Higher likelihood of structural
heart disease or
channelopathy; requires
second-level investigations
Worsening AV block during
exercise (new or advanced
second/third-degree block);
occurrence of bundle branch
block
•
•
•
•
Clinical Interpretation
Suggests infra-Hisian disease
or ischemia; may require EP
evaluation or pacing.
QTc: QTc ≥ 480 ms at
4th minute recovery;
peak TP-fusion.
Persistence or
appearance of
pre-excitation during
exercise or multiple
accessory pathways →
potentially high-risk.
CPVT: progressive
increase in PVB
complexity and number
as HR rises with
suppression during
recovery
Suggestive of LQTS, CPVT, or
high-risk accessory pathway.
Mandates targeted evaluation
and therapy
Chronotropic
incompetence despite
RRP
2:1 tracking
Loss of biventricular
capture
T-wave oversensing
Device-related exercise
intolerance; requires
reprogramming
AV, atrioventricular; bpm, beats per minute; CAD, coronary artery disease; CI, chronotropic index; CIED,
cardiac implantable electronic devices; CPVT, catecholaminergic polymorphic ventricular tachycardia; ECG,
electrocardiogram; EP, electrophysiological; EST, exercise stress testing; HR, heart rate; LQTS, long QT syndrome;
LV, left ventricular; MET, metabolic equivalent; PVB, premature ventricular beat; QTc, corrected QT interval; RPE,
rating of perceived exertion; RRP, rate-responsive pacing; SBP, systolic blood pressure.
In summary, this review serves as an updated, accessible guide, underscoring the
enduring and versatile role of EST in contemporary clinical practice.
Author Contributions: Conceptualization, F.G., A.Z. and D.C.; methodology, F.G. and C.C.; literature
search, data interpretation, and manuscript drafting, C.C.; literature search and data interpretation,
F.B., M.P., A.D.A., S.U., D.B., A.C., M.D.L., M.P.M. and H.V.; writing—review and editing, F.G., A.Z.
and D.C.; supervision, F.G. and A.Z. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created.
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Acknowledgments: During the preparation of this manuscript, the authors used ChatGPT (version 5.2) as support for checking the text for clarity, grammar, and language, and for generating
schematic images.
Conflicts of Interest: The authors declare no conflicts of interest.
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https://doi.org/10.3390/jcm15041656