Cardiopulmonary exercise testing and echocardiographic exam: an useful interaction

CPET is considered an accurate method to assess aerobic performance for both healthy individuals and patients with cardiovascular and/or respiratory diseases, consistently driving the exercise prescription [17]. Pivotal data in exercise prescription are heart rate (HR) and VT. The exercise performed below VT is considered the sub-maximal level tolerated by an individual patient for a sustained amount of time. Moreover, HR values at different points through the exercise are reported (i.e. HR at rest, HR at VT) in order to refine aerobic exercise prescriptions.

Functional assessment measured by CPET gives pivotal information about maximal aerobic capacity, therapy management and exercise prescription in patients with chronic heart failure. In the majority of these patient, CPET shows reduced VO₂, VT < 40% of the predicted VO₂ curve, peak VO₂ < 85%, increased VE/VCO₂, but normal O₂ saturation [18]. Of interest, peak VO₂ < 14 mL/kg/min carries a poor prognosis, being considered as indication for heart transplant [19]. Combined all together, these parameters, along with wide oscillations in ventilation during exercise and low HR recovery during the first minute after peak stress, reflect the ventilatory and metabolic inefficiency and are of relevant impact on prognosis in heart failure patients [20]. A comprehensive analysis of these parameters can help in accurately predicting the mortality rate in these patients [21]. In a metanalysis of studies on patients with heart failure undergoing CPET, peak VO₂, VE/VCO₂ slope, OUES and periodic ventilation appeared to have a strong prognostic impact, predicting adverse cardiovascular events with odds ratios of 4.10 (CI: 3.16–5.33), 5.40 (CI: 4.17–6.99), 8.08 (CI: 4.19–15.58) and 5.48 (CI: 3.82–7.86), respectively [22]. Myers et al. produced a stratification score that integrates most of the above-mentioned parameters (Table 2). The score ranges from 0 to 20, with the first group (0–5) used as a reference. Patients with a score >  15 had a 3 years mortality of 12.2% [23]. Noteworthy, VT can be undetermined in patients with considerably reduced exercise tolerance, thus unidentifiable VT is also considered a negative prognostic factor in patients with end-stage heart failure [24]. Accordingly, CPET has class I recommendation and level A in patients with HFrEF being considered for heart transplantation or mechanical device implantation [6]. In heart failure with preserved ejection fraction (HFpEF), not only peak VO₂, but also the percent-predicted peak VO₂ appear not be able to predict adverse events, probably, because current algorithms work poorly in this clinical setting. However, VE/VCO₂ has shown the capability of predicting adverse events [25, 26] In particular, a VE/VCO₂ slope > 33.3 showed a sensitivity of 97% and a specificity of 40% in predicting mortality and cardiac-related hospitalization in patients left ventricular ejection fraction (LVEF) > 50% [13].

In the cases of unexplained dyspnoea, 4 different categories can be identified by combining CPET variables: cardiac, pulmonary, mixed and non-cardiopulmonary [27, 28]. Reduction in peak VO₂ is seen in both respiratory, cardiac and metabolic disease. Mainly, patients with respiratory diseases show a significant drop (i.e.,> 4% on peak exertion) in O₂ saturation and low breathing reserve (i.e.,< 20%) [29]. On the other hand, patients with exertion dyspnoea induced by cardiac diseases show reduced peak VO₂, early VT, high VE/CO₂ slope, reduced OUES [29]. Of note, OUES has gained a recognized prognostic value in patients undergoing submaximal exercise [6]. In both primary or thromboembolic pulmonary arterial hypertension (PAH), low peak VO₂ and high VE/Vco₂ ratio during exercise have demonstrated to be useful in establishing the severity of functional impairment [30]. Consistently, CPET can be of helpful for the physicians who must face patients complaining dyspnoea both in terms of differential diagnosis and symptoms classification. Table 3 summarizes abnormal CPET patterns in patients with dyspnoea.

CPET provides an integrated evaluation of cardiac, pulmonary, and metabolic function and may be used to identify the source of exercise limitation in congenital heart disease. Because CPET measurements have also been associated with outcome in adults with congenital heart disease, CPET is now considered as an important prognostic indicator and also useful for surgical stratification in this population [31].

Exercise stress echocardiography (ESE) and CPET can be considered an intriguing combination, possibly providing fundamental information on differential diagnosis and therapeutic management in patients suffering for exertion dyspnoea in different clinical settings, mainly in patients complaining heart failure symptoms and valve heart disease. The combination CPET-ESE can non-invasively evaluate multiple aspects of the cardiovascular system, offering a more personalised O₂ pathway analysis, which is otherwise obtainable only with invasive hemodynamic monitoring [32]. In this context, the CPET-ESE approach is particularly valuable in identifying non-cardiopulmonary causes of dyspnoea, which are mainly related to an impaired oxygen extraction (AVO₂diff) [5]. Different authors have demonstrated that the effort intolerance observed in HFpEF and heart failure with mid range LVEF could be related to an impaired AVO₂diff (peripheral component of Fick equation) and near-normal cardiac output [33‐35].

In some patients, complaining exertion dyspnoea, in particular if hypertensive, the early stages of HFpEF cannot be always detectable by the sole echocardiographic exam at rest since the simple quantification of LVEF often fails to predict functional capacity. Under these circumstances, the combination of speckle tracking echocardiography and CPET may provide additional information. Global longitudinal strain (GLS) is reduced in parallel with a reduced peak VO₂ response and was superior to LVEF in identifying patients with impaired peak VO₂ [36]. A comprehensive non-invasive evaluation of LV diastolic function – performed according to standardized ASE/EACVI recommendations [37] - has also a proved a diagnostic impact in predicting functional capacity in patients with HFpEF [34]. Since patients with normal LV filling pressures or even normal LV diastolic function at rest may reveal elevated LV filling pressures during effort [37‐41], diastolic stress testing is indicated when echo exam at rest does not explain the symptoms of heart failure or dyspnoea, especially with exertion [37]. An E/e’ ratio >  15 during exercise can be considered as an accurate marker of HFpEF in presence of cardiac symptoms [42‐45]. Accordingly, the combination of CPET results, in particular VE/CO₂ slope, and E/e’ ratio at peak stress may be highly demonstrative of HFpEF (Fig. 3) [46]. This is confirmed also in patients with ischemic heart failure in which E/e’ ratio at peak stress was the most useful parameter for identifying severe exercise intolerance, as indicated by peak oxygen uptake < 14 mL/kg/min (AUC of E/e’ ratio ≥ 18 = 0.92, sensitivity = 85.2%, specificity = 95.6%) [47]. Worthy of note, the integrated CPET-ESE approach proved to increase patient risk stratification also in HFrEF, thanks to possibility of directly studying both LV and right ventricular (RV) contractility [35, 48].

Given the complicated relationships existing between hemodynamic changes from resting condition to peak exercise in patients with valvular disease, new protocols combining ESE and CPET may give detailed information to better face the challenge in developing optimal individualized therapy [49]. ESE associated with CPET can provide crucial information on exercise intolerance in asymptomatic patients with hemodynamically significant mitral regurgitation (MR). Reduced peak VO₂ has an important prognostic value in patients with significant MR, although the mechanisms underlying this association are not well established. In this subset of patients, ESE can provide information about the hemodynamic response to effort by measuring mean pulmonary arterial pressure (PAPm), systolic pulmonary arterial pressure (PAPs), RV systolic function and cardiac output (CO). Recently, reduced values in pulmonary vascular reserve, measured by PAPm/CO slope, and in RV contractile reserve, expressed by tricuspid annulus plane systolic excursion (TAPSE)/PAPs changes between rest and peak effort, were found to predict a low peak VO₂ response during effort. Accordingly, this association may explain the etiology of impaired exercise tolerance in patients affected by asymptomatic but significant MR. The combination of low pulmonary vascular reserve, impaired RV contractile reserve and low peak VO₂ may also guide the optimal timing for mitral valve surgery [50]. Frequently, patients with mitral stenosis (MS) show reduced exercise tolerance that, in some cases, is out of proportion compared to the hemodynamic at rest [49]. It is conceivable that several factors could contribute to alter exercise response in MR. Indeed, a low peak exercise HR (chronotropic incompetence) and the absence of a significant rise in stroke volume (impaired contractile reserve), combined with a reduced respiratory reserve (restrictive lung function) have a critical impact on the exercise response in MS. Accordingly, by combining CPET with echocardiography it is possible to identify the different determinants of reduction of both exercise capacity and peak VO₂, thus improving patient selection for targeted treatment. Of note, Laufer-Perl et al. demonstrated that in patients with moderate-to-severe MS, restrictive lung function, chronotropic incompetence and limited contractile reserve had a greater impact on symptoms compared to MS severity itself, as expressed by the transvalvular gradient and the mitral valve area [51].

Another possible combination of CPET and echocardiography involves cardiomyopathies and, in particular, the differential diagnosis with the athlete’s heart. Echocardiography is largely used for diagnosis of hypertrophic cardiomyopathy (HCM), it allowing to characterize a disproportionate increase of LV wall thickness and a reduction of LV end-diastolic diameter [51]. However, maximal wall thickness ranging between 13 and 15 represents a grey zone which can occur in 4% of males and more frequently in black athletes [52]. In addition, diagnostic accuracy of echocardiography is limited by the lack of clear cut-off points stratified by ethnicity, gender and sport types. CPET can help the echo approach to appropriately diagnosing HCM in athletes [52]. VO₂max resulted to be substantially reduced in athletes with HCM than in healthy athletes; in particular, a pVO2 > 50 ml/kg/min or >  20% above the predicted maximum VO₂ differentiated athlete’s heart from HCM [53]. These results could open unexplored horizons in order to refine echocardiographic diagnosis of HCM in athletes.

In chronic thromboembolic PAH, a fast and accurate diagnosis is pivotal for successful treatment. Clinical symptoms/signs may be nonspecific and risk factors not always detectable. Echocardiography is the recommended first-line diagnostic tool and guidelines recommend non invasively estimation of PAPs (by peak velocity of tricuspid regurgitation and atrio-ventricular pressure gradient) and detection of indirect signs of PAH (RV and right atrial dilation, RV systolic dysfunction corresponding to a reduced TAPSE and standard Doppler derived abnormalities of RV outflow tract) [54, 55]. CPET may be complementary and help to identify patients with milder abnormalities and chronic thromboembolic disease. Patients with impaired ventilation due to pulmonary arterial obstruction show elevated alveolar-capillary gradients of O₂ and CO₂ [56]. In a retrospective report, CPET was able to identify chronic thromboembolic PAH, despite normal echo exam [57]. It is also worthy of note that In patients symptomatic for dyspnea, the occurrence of ΔVO₂/Δwork rate flattening, ie. the “hockey stick” pattern, demonstrated to reflect a significantly impaired functional phenotype whose major cardiac determinants are the excessive PAPs increase and the reduced TAPSE) [58].

In the setting of coronary artery disease, the combination of ESE and CPET performed in 110 patients, allowed to discriminate between coronary circulatory disease and de-conditioning (i.e., a decrease in the responsiveness of heart muscle occurring after long periods of weightlessness and corresponding to a blood volume reduction and blood pooling in the legs upon return to normal conditions) [59]. In fact, multiple gas exchange parameters obtained by CPET were associated, despite with low sensitivity, with abnormal echo-Doppler derived stroke volume response to stress, and VE/VCO₂ slope to peak VO₂ ratio was the best discriminator (≥2.7: AUC 0.79, p < 0.0001). These findings demonstrate that in patients with borderline results, a combined stress-echo with CPET, measuring stroke volume and A-VO₂ difference throughout effort may be helpful for diagnosing significant coronary artery disease. Furthermore, stress echo derived wall motion abnormalities of isolated coronary lesions other than anterior descending artery, may require particular effort due to poor endocardial visualization, particularly when dealing with significant lesion of the right coronary artery. Blunted physiological VO₂ increase and plateau in HR response during CPET has demonstrated to be indicative of myocardial ischemia of right coronary artery, anticipating ECG abnormalities [60]. Hence, we can speculate that combined analysis of CPET pattern and wall motion abnormalities during ESE may improve the accuracy level in diagnosing right coronary artery stenosis.

Table 4 reports the main echo-derived systolic and diastolic measurement which can be combined with CPET parameters.