Introduction

The development of electrocardiogram (ECG) stress testing was a major advance in clinical cardiology [1]. Feil and Siegel recognized that myocardial ischemia and, thus, coronary artery disease (CAD) could be diagnosed by ST depression during exercise. Master and Oppenheimer developed the first standardized exercise test, a 1.5-minute step test to evaluate cardiac capacity and cardiovascular disease. Bruce developed the multi-stage treadmill test, now termed the Bruce protocol. An outcome study of Ellestad demonstrated that 1 mm of ST depression predicted cardiac events and death. Following one hundred years of development, the ECG remains the foundation of exercise stress testing [2, 3]. In the seventies, stress-ECG was also the natural approach of first-generation exercise-independent testing, such as dipyridamole [4, 5] or dobutamine stress [6], later popularized with cardiac imaging. In the cardiac imaging era, ECG stress testing progressively lost ground in favor of other markers of ischemia, more sensitive and earlier in the classical ischemic cascade of events in the presence of epicardial CAD [7–9]. In the last decade, it became progressively more obvious that even in the imaging era, ECG changes can offer surprisingly important diagnostic and prognostic information. Ischemia has multiple phenotypes in the real world [10], including ECG changes without cardiac imaging abnormality. The present narrative review will address the added value of ECG changes during stress in the cardiac imaging era, with a special focus on the different patterns of ECG changes (ST-segment depression, ST-segment elevation) in the presence of cardiac imaging normal or abnormal findings, the prevalence and meaning of arrhythmias during stress, and the pathophysiological and prognostic meaning of chronotropic incompetence during physical stress testing and during pharmacological stress testing where stress ECG is rarely use.

ST-segment depression and new regional wall motion abnormalities during stress echocardiography

In about 50% of patients with anatomically verified epicardial CAD and stress imaging positivity [with perfusion changes or regional wall motion abnormality (RWMA)], a diagnostic ST-segment depression develops during stress. In 178 patients with dipyridamole stress echo positivity, Cortigiani et al. [11] found that 59% of patients showed concomitant ST-segment depression, and these patients were 2 times more likely to have 3-vessel or left main CAD and 3 times more likely to have major adverse events in a 3-year follow-up. In the SE2030 study, Kobal et al. [12] found that stress-induced ischemic ECG changes during physical or pharmacological stress testing are associated with more extensive RWMA and blunted global left ventricular contractile reserve, with reduced coronary flow velocity reserve in the left anterior descending artery. These data were observed with different types of stress (exercise, dobutamine, vasodilators) and with the recruitment of 641 patients from 39 different sites in 10 countries, increasing the generalizability of the findings [12].

Heart rate reserve: a simple predictor of mortality

Heart rate reserve is one of the simplest markers of risk during stress. It is easy to acquire since a simple one-lead ECG on the echo monitor is sufficient to obtain all the information needed. It is extraordinarily simple to analyze, since only the rest and peak value of the heart rate are utilized, and the heart rate is displayed automatically online in the echo monitor. It has an impressive amount of evidence behind its clinical use since it was first shown to predict all-cause death in 1975 by the father of stress testing, Ellestad. In a landmark paper published in Circulation, Ellestad and Wan [35] assembled follow-up data in 2,700 patients with exercise stress tests and showed that those with chronotropic incompetence had a high incidence of coronary events even though the ECG response to exercise was normal. This finding was confirmed over the subsequent decades [36, 37], and progressively extended to models beyond CAD such as heart failure [38, 39] or hypertrophic cardiomyopathy [40, 41] or transthyretin amyloidosis [42] and to stresses other than exercise such as dobutamine [43, 44] and vasodilators [45–53]. A blunted heart rate reserve is a strong predictor of all cause-death, especially of sudden death, and its value is additive and incremental over cardiac stress imaging information provided by perfusion defect or wall motion abnormality [54, 55].

Insufficient heart rate increase due to chronotropic incompetence is considered a major contributor to exercise and functional intolerance in heart failure, resulting from an imbalanced autonomic nervous system, which is chronically shifted toward sympathetic overactivation, leading to down-regulation and desensitization of cardiac β-receptors [56, 57].

It is addictive because it focuses on a specific vulnerability, different from critical epicardial coronary artery stenosis or coronary microvascular dysfunction. It is the cardiac sympathetic reserve, elicited by endogenous catecholamines or exogenous catecholamines such as dobutamine or endogenous or exogenous adenosine accumulation stimulating A2a receptors present on the carotid body and increasing efferent sympathetic efflux to the heart, eventually increasing heart rate [58–62]. The greater the increase in heart rate, the higher the cardiac sympathetic reserve, and this problem is a universal feature of vulnerability across all types of disease (Figure 1). This simple parameter has 100% feasibility, 0% variability, and prognostic strength higher than RWMA and coronary flow velocity reserve, and much more user-friendly than all methods used to assess cardiac autonomic function in the clinical arena [63, 64].

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Figure 1. 

HRR as a marker of sympathetic dysfunction in several cardiovascular conditions. ECG: electrocardiogram; HRR: heart rate reserve

Conclusions

In the 2016 joint recommendation of the European Association of Cardiovascular Imaging and the American Society of Echocardiography of stress echo applications beyond CAD, chronotropic incompetence during exercise is considered an alternative explanation for symptoms of exercise and an exclusion criterion for the correct diagnosis of heart failure with preserved ejection fraction [65]. Before including this diagnosis, one should exclude exercise-induced ischemia with new wall motion abnormalities, dynamic severe mitral regurgitation during stress, development of left ventricular outflow tract obstruction, and insufficient increase in heart rate. In the recently released 2024 recommendations of European Association of Cardiovascular Imaging on the clinical use of stress echocardiography, heart rate reserve is incorporated as a pillar of the ABCDE protocol, with E standing for ECG-based assessment of chronotropic incompetence measured with heart rate reserve with all stresses in all patients, from chronic coronary syndromes to heart failure and hypertrophic cardiomyopathy [9]. Guidelines of the European Society of Cardiology on chronic coronary syndromes, in individuals with an initially low (> 5–15%) likelihood of obstructive CAD, exercise ECG, and detection of atherosclerotic disease in non-coronary arteries may be considered to adjust the pre-test likelihood estimate (IIb C). For the diagnosis of disease progression in patients with established chronic coronary syndrome, with new or worsening symptoms, it is now recommended to use stress imaging (I C). The second, still legitimate, choice of using “alternatively, exercise ECG”—present in the 2019 ESC recommendations, has been deleted. For the initial evaluation of patients with chest pain, exercise-ECG is recommended “in selected patients” [66]. Guidelines state that “Exercise ECG testing may modify the likelihood of obstructive CAD and can be used in patients with low (> 5%–15%) clinical likelihood, in whom a negative test allows reclassification to the very low (≤ 5%) clinical likelihood group with a favorable prognosis. Exercise ECG testing has a lower diagnostic performance of obstructive CAD compared with modern functional imaging and CCTA, which, therefore, should be preferred as a first-line test in subjects with suspected CCS.”

Exercise ECG is recommended in selected patients for the assessment of exercise tolerance, symptoms, arrhythmias, blood pressure response, and event risk. Interestingly, guidelines completely miss the information on heart rate reserve. However, if we consider the value (outcome/cost) [67] and even more, the sustainability (outcome/cost + radiation + carbon footprint) of testing, as we probably should [68], exercise ECG is the first-line obligatory cornerstone of diagnosis and risk stratification of the patient with known or suspected chronic coronary syndromes. Exercise is the only physiologic and by far the safest stress, and is fundamental not only for diagnosis but also for risk stratification. A maximal exercise ECG assesses ischemic vulnerability (with ST-segment and angina), arrhythmic vulnerability, hemodynamic vulnerability (with excessive hypertension or blood pressure drop), and cardiac autonomic system vulnerability (with heart rate reserve for sympathetic reserve and heart rate recovery for parasympathetic reserve) (Figure 2).

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Figure 2. 

The many functional vulnerabilities identified by a simple exercise-ECG test. HR: heart rate; ECG: electrocardiogram

Even in modern cardiology, it is difficult to obtain so much with so little investment of time and money.

Our review provides an overview of the diagnostic and prognostic role of ECG during stress in the new cardiac imaging era. With the advances in cardiac imaging in both functional and anatomic fronts and the existing limitations of exercise stress testing, this modality appears less favoured worldwide, as reflected in recent guidelines. Instead, the combination of stress-ECG and imaging modalities provides the clinician a wealth of information to identify different phenotypes of inducible ischemia and to better risk-stratify patients (Figure 3). Chronotropic incompetence is another important marker of vulnerability that can emerge during stress. Heart rate reserve is a strong predictor of outcomes, especially sudden death, not only in CAD but in many other cardiovascular conditions, especially heart failure. In summary, the ECG represents a ubiquitous, noninvasive, and low-cost functional test for a comprehensive risk assessment in patients with CAD and other cardiac conditions. This improves patient management by guiding treatment decisions and preventive strategies.

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Figure 3. 

Central illustration. An example of a patient with positive ABCDE dipyridamole stress: induced ST-segment depression, new wall motion abnormalities (WMSI, step A positive), B lines at peak stress (step B positive), abnormal left ventricular contractile reserve (LVCR, step C positive) reduced coronary flow velocity reserve (CFVR, step D positive). RWMA: regional wall motion abnormality; LVCR: left ventricular contractile reserve; CFVR: coronary flow velocity reserve; CFR: coronary flow reserve; HRR: heart rate reserve; AWMSI: average wall motion score index; WMSI: wall motion score index; HR: heart rate