
==== Front
Int J Cardiol Cardiovasc Risk Prev
Int J Cardiol Cardiovasc Risk Prev
International Journal of Cardiology. Cardiovascular Risk and Prevention
2772-4875
Elsevier

S2772-4875(24)00089-8
10.1016/j.ijcrp.2024.200324
200324
Research Paper
Evaluation of myocardial work and exercise capacity in patients recovered from the severe form of COVID-19
Fagundes de Sousa Thiago Lins ab
Kluser Sales Allan Robson a
Martins Fagundes Juliana Góes ab
Barbosa Botelho Luis Fábio ab
Ribeiro de Souza Francis a
Fonseca Guilherme Wesley c
Pereira de Albuquerque André Luis a
Tavares de Melo Marcelo Dantas b
Alves Maria-Janieire de Nazaré Nunes janieire.alves@incor.usp.br
a⁎
a Heart Institute (InCor), University of São Paulo Medical School, Brazil
b Medical Sciences Center of the Federal University of Paraíba, Brazil
c School of Physical Education and Sport, University of São Paulo, Brazil
⁎ Corresponding author. Heart Institute (InCor), University of São Paulo Medical School, Av. Dr. Enéas de Carvalho Aguiar, 44 - Cerqueira Cesar - CEP: 05403-900 - São Paulo, Brazil. janieire.alves@incor.usp.br
19 8 2024
12 2024
19 8 2024
23 2003248 5 2024
8 8 2024
15 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

The impact of COVID-19 goes beyond its acute form and can lead to the persistence of symptoms and the emergence of systemic disorders, defined as long-term COVID.

Methods

We performed a cross-sectional study that included patients over 18 years of age who recovered from the severe form of COVID-19 at least 60 days after their discharge. Patients and controls were enrolled to undergo transthoracic echocardiography (TTE) using a more sensitive tool, myocardial work, in combination with cardiopulmonary exercise testing (CPET).

Results

A total of 52 patients and 31 controls were enrolled. Significant differences were observed in ejection fraction (LVEF; 62 ± 7 vs. 66 ± 6 %; p = 0.007), global longitudinal strain (LVGLS; −18.7 ± 2.6 vs. −20.4 ± 1.4 %; p = 0.001), myocardial wasted work (GWW; 152 ± 81 vs. 101 ± 54 mmHg; p = 0.003), and myocardial work efficiency (GWE; 93 ± 3 vs. 95 ± 2 %; p = 0.002). We found a significant difference in peak VO2 (24.4 ± 5.4 vs. 33.4 ± 8.8 mL/kg/min; p < 0.001), heart rate (160 ± 14 vs. 176 ± 11 bpm; p < 0.001), ventilation (84.6 ± 22.6 vs. 104.9 ± 27.0 L/min; p < 0.001), OUES% (89 ± 16 vs. 102 ± 22 %; p = 0.002), T ½ (120.3 ± 32 vs. 97.6 ± 27 s; p = 0.002) and HRR at 2 min (−36 ± 11 vs. −43 ± 13 bpm; p = 0.010).

Conclusion

Our findings revealed an increased wasted work, with lower myocardial efficiency, significantly reduced aerobic exercise capacity, and abnormal heart rate response during recovery, which may be related to previously described late symptoms. The reduction in functional capacity during physical exercise is partly associated with a decrease in resting myocardial work efficiency. These findings strongly indicate the need to determine whether these manifestations persist in the long term and their impact on cardiovascular health and quality of life in COVID-19 survivors.

Keywords

COVID-19
Myocardial work
Exercise
Heart rate recovery
Handling editor: D Levy
==== Body
pmc1 Introduction

Coronavirus disease (COVID-19) is associated with a high risk of death from a cardiovascular event, especially in the first weeks after infection, with the elderly and those with cardiovascular diseases being the most vulnerable [1]. Cardiovascular complications occur in approximately 18 % of hospitalized patients, resulting in a 45 % mortality rate compared to 13 % in those without such complications [2]. A study evaluating the Brazilian population (CoronaHeart) identified mechanical ventilation, a high level of C-reactive protein, and a high level of troponin as markers of in-hospital mortality [3].

Multiple mechanisms contribute to myocardial damage and the onset of numerous cardiovascular complications, including the rupture of inflammatory plaques, stent thrombosis, vascular dysfunction, stress related to the high cardiac output in septic patients, endotheliitis mediated by ACE receptor dysregulation, as well as hypoxemia resulting from severe pulmonary compromise and the potential toxic effects of treatment drugs [[4], [5], [6]]. The mechanism for persistent subclinical dysfunction remains unknown; some magnetic resonance imaging studies suggest adverse remodeling, while another potential mechanism is endothelial and vascular dysfunction leading to subclinical impairment of left ventricular function persisting after the acute event [7,8].

Although many patients remain symptomatic, dyspnoea is present in half of patients after three months of recovery, and several post-COVID studies have shown that even among those with severe acute infection, systolic impairment measured by traditional echocardiographic analysis is rare, affecting only 9–11 % of patients [9]. Most of these studies evaluated ejection fraction, which, although a strong predictor of cardiovascular events, has low sensitivity in detecting subclinical events.

Myocardial strain assessment is a more sensitive marker for the early detection of changes in myocardial systolic function [10]. Among the strain indices, left ventricular global longitudinal strain (LVGLS) has emerged as a precise and reproducible measure. Another method that has gained prominence is the analysis of myocardial work (MW). This new measure is being studied as an evaluator of LV systolic function. It is less influenced than LVGLS by overload conditions, as it incorporates deformation and load in its analysis [11,12]. A recent study demonstrated that the pressure–strain curve measured by echocardiography can estimate LV performance in an analogous manner to invasive haemodynamics [13]. MW is highly reproducible and provides additional value to LVGLS in predicting adverse events. However, there are still no studies in the literature that have evaluated the behaviour of myocardial work in the post-COVID context and its relationship with aerobic capacity.

Equally important, cardiopulmonary exercise testing (CPET) has enabled the identification of the physiological mechanisms that affect patients' exercise capacity. Multiple studies have shown a decrease in peak oxygen consumption following an acute episode [14,15]. The primary mechanism of this seems to be muscle deficiency (oxygen extraction deficiency), which manifests mainly as submaximal exercise or early onset of the 1st ventilatory threshold. Although uncommon, central cardiocirculatory involvement has been described in some case series, and its mechanism is still poorly understood [16,17].

This study is the first to report the use of a new and refined approach in echocardiographic measurement in combination with CPET, with the aim of evaluating the behaviour of MW and its potential mechanisms in the aerobic performance of patients recovered from COVID-19.

Our main objective was to evaluate MW through the two-dimensional echocardiogram and the assessment of functional capacity through the CPET to assess the possible impact on the cardiovascular system and lower aerobic capacity of patients recovered from severe COVID-19. As secondary objectives, we aimed to correlate the results of MW measurements with the variables of the CPET, as well as correlate clinical, radiological, and laboratory data and length of hospitalization with the CPET and MW variables.

2 Methods

2.1 Study population

This was a single-centre, cross-sectional, observational study that included patients between 18 and 70 years of age who had recovered from severe COVID-19 (defined as intensive-care unit (ICU) admission with the need for oxygen supplementation by invasive or noninvasive mechanical ventilation). Patients with preexisting cardiac disease (heart failure, coronary artery disease, valvular heart disease, uncontrolled arrhythmias or those taking more than two antihypertensive medications), active cancer, renal failure requiring haemodialysis, cirrhosis, chronic obstructive pulmonary disease requiring oxygen therapy, diabetes requiring insulin, pregnancy, ultrasonographic limitations that prevented strain analysis or orthopaedic limitations or other contraindications to exercise testing were excluded from the study. A control group, matched for sex and age, was recruited for comparative purposes. This group consisted of individuals who did not meet any exclusion criteria and had not experienced symptomatic COVID-19.

Prior to inclusion, all participants provided written informed consent. The study received approval from the ethics and research committee of our centre under the number CAAE 45809421.7.0000.8069. Data from the electronic medical record of each hospitalization were collected. Pulmonary involvement data were derived from examination reports. The Total Severity Score (TSS) tool was employed to quantify and standardize the extent of pulmonary findings in chest tomography. At 60 days after hospital discharge, both the patients and control group underwent a transthoracic echocardiogram with measurement of MW and a cardiopulmonary exercise test performed during a single visit, according to established protocols [[18], [19], [20]].

2.2 Echocardiography

Two-dimensional transthoracic echocardiography was performed at the bedside using the Vivid S70 (GE Vingmed Ultrasound, Horten, Norway) with a 3Sc 1.3–4.0 MHz transducer, always by the same echocardiographer. The examination was performed with the patient in the left lateral decubitus position, and all images and measurements were acquired in accordance with the recommendations of the American Society of Echocardiography [19]. Video images corresponding to 3 cardiac cycles showing the QRS complex were acquired. All patients underwent non-invasive blood pressure measurement during the examination.

Myocardial deformation was assessed by two-dimensional dynamic images (3 cycles) in two, three and four chambers, with a frequency varying between 50 and 80 frames/second, acquired for the calculation of LVGLS. The opening and closing of the aortic and mitral valve were identified from the pulsatile Doppler of the aortic valve acquired in the apical three-chamber window. The endocardial and epicardial tracings were automatically tracked, and the acquisition was performed (after verification and adjustment by the examiner, when necessary). Using a 17-segment model, the software calculated GLS from the weighted average of the peak systolic longitudinal strain of each of the segments. Participants were excluded from the study if they had more than one segment with inadequate acquisition.

2.3 Myocardial work acquisition

MW and its variables were noninvasively calculated using two-dimensional echocardiography with the GE Vivid S70 machine. Participants' systolic blood pressure was measured by a sphygmomanometer immediately before the test (in the supine position), which was used as an estimate of LV systolic pressure. The software performed a noninvasive reconstruction of the LV pressure curve adjusted according to the durations of the ejection, isovolumetric contraction, and relaxation phases, defined from the times of opening and closing of the mitral and aortic valves. LV strain and pressure data were then synchronized with the times of valve events and systolic blood pressure, generating the following data for analysis:

Global work index (GWI): total work corresponding to the area of the pressure x strain curve, from mitral valve closure to mitral valve opening.

Global constructive work (GCW): total work that contributes to ventricular ejection: negative strain in systole + positive strain in isovolumetric relaxation time.

Global wasted work (GWW): work that does not contribute to LV ejection: strain positive in systole + strain negative in isovolumetric relaxation time.

Global work efficiency (GWE): fraction of constructive work from total work: GWE = (GCW)/(GCW + GWW) [21,22].

2.4 Cardiopulmonary exercise test

Stepwise incremental treadmill exercise was performed for the CPET (Cortex Biophisik GmbH, Leipzig, Germany). A protocol that applied a linear increase in walking speed along with a curvilinear increase in treadmill inclination to produce a linear increase in work rate was used [23]. Before the exercise test, spirometry was performed for respiratory evaluation, according to the Brazilian guidelines for pulmonary function testing [24]. The following variables were evaluated: oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER = VO2/VCO2), end-expiratory pressure of carbon dioxide (PETCO2), minute ventilation (Ve), tidal volume (Vt), dead space volume (Vd), respiratory rate (RR), heart rate (HR), oxygen pulse (VO2/HR), load achieved, ventilatory equivalents (Ve/VCO2 and Ve/VO2), Ve/VCO2 slope, oxygen uptake efficiency slope (OUES), and the recovery time taken for VO2 to fall to 50 % of its peak value (T ½).

The reference values used for VO2 and ventilatory thresholds were from Hansen and Wasserman and that for OUES% (OUES as a percentage of predicted) was from Hollenberg [25,26]. Exercise intolerance was defined as a peak VO2 <85 % of the predicted value. Ventilatory limitation to exercise was defined when the breathing reserve was <15 %. The Wassermann flowchart was used to define circulatory limitation in participants when it led to a circulatory category, including ECG changes consistent with ischaemia or arrhythmia. Deconditioning was defined as a peak VO2 <85 % of predicted with normal breathing reserve and no evidence of cardiocirculatory pathology (assessed by ECG, Ve/VCO2 slope, and oxygen-pulse curve) [20].

2.5 Statistical analysis

Data are presented as the mean ± standard deviation or as median with lower and upper quartiles (95 % confidence interval) for continuous variables and as frequencies and percentages for categorical variables. To verify associations between categorical variables, the chi-square test was performed when applicable. In the case of numeric variables, we used Student's t-test or the Mann‒Whitney test for parametric and nonparametric variables, respectively. Correlations between variables were assessed by Pearson's or Spearman's test. A p value lower than 0.05 was defined as statistically significant. Statistical tests were performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA). The sample size was not calculated, as no studies in the literature have performed the same comparative analysis.

3 Results

3.1 Baseline characteristics

Between January 10, 2021 and May 31, 2021, a total of 113 patients were admitted to our ICU for COVID-19 treatment. Of them, 68 were discharged from the hospital and were then enrolled in the study. Of these, 52 were able to complete the study protocol (Fig. 1). We also selected a group of 31 individuals as a control group, matched for age and sex.Fig. 1 Flowchart of patient inclusion in the research. (ICU: Intensive Care Unit; COVID-19: Coronavirus-19 infection. CPET: Cardiopulmonary exercise test).

Fig. 1

The clinical characteristics of the study population are shown in Table 1. Participants with COVID-19 and the control group were similar in sex and age. Participants with COVID-19 had a higher body mass index than the control group. Regarding comorbidities, the most frequent in both the COVID and control groups was the presence of hypertension (27 vs. 19 %; p = 0.597). None of the participants were using more than 2 classes of drugs as antihypertensive treatment. Patients with COVID-19 had higher SBP and DBP.Table 1 Clinical characteristics of study participants.

Table 1	COVID-19 n = 52	Control n = 31	p value	
Age (years)	47 ± 8	46 ± 10	0.748	
Male, n (%)	34 (65.4)	20 (64.5)	0.936	
Height (cm)	170	170	0.844	
Weight (kg)	84.3	76.3	0.017	
Body mass index (kg·m−2)	29.2 ± 4.3	26.2 ± 3.4	0.002	
Systolic blood pressure (mmHg)	141 ± 17	126 ± 10	<0.001	
Diastolic blood pressure (mmHg)	83 ± 9	77 ± 6	0.001	
Comorbidities, n (%)
Arrhythmias
Asthma
Diabetes
Hypertension	15 (28)
4 (8)
2 (4)
14 (27)	6 (19)
0
0
6 (19)	0.436
0.292
0.526
0.597	
Maximum pneumonia extent on chest CT
−25–49 %
−50–74 %
- ≥75 %
- no data	24 (46.2 %)
14 (26.9 %)
11 (21.2 %)
3 (5.8 %)			

The median laboratory values upon admission to the ICU in the COVID-19 group were as follows: oxygenation index of 101.5 mmHg (95 % CI, 81–133.5), troponin I of 18.1 pg/mL (95 % CI, 9.1–58.8), lactic dehydrogenase of 723 U/L (95 % CI, 453–1027); C-reactive protein of 128 mg/L (95 % CI, 73.5–153); D-dimer of 905 μg/L (95 % CI, 315–2550.5); and lymphocytes of 1285 cells/mm3 (95 % CI, 841.5–1561.7). Thirty-one (60 %) patients required invasive mechanical ventilation, with an average duration of 6 days of invasive ventilation, and the hospital stay was mostly between 11 and 20 days. During the study period, we lacked access to novel antiviral medications, such as remdesivir. Given that all our patients received ventilatory support, the established treatment protocol encompassed systemic corticosteroid therapy for all. Among patients who required invasive mechanical ventilation, one patient received extracorporeal membrane oxygenation (ECMO) support, and this patient's total length of hospitalization was 80 days. Patients with COVID-19 were evaluated on average 83 ± 30 days after hospital discharge. All received assistance in the form of a rehabilitation program after discharge.

3.2 Echocardiographic features

The echocardiographic characteristics are presented in Table 2. There were no significant differences in morphological parameters between the groups. The Doppler method revealed a significant difference in tricuspid regurgitation velocity. Of the LV functional parameters, there were significant differences observed in ejection fraction, LVGLS, GWW and GWE (Fig. 2, Fig. 3).Table 2 Characteristics of the echocardiogram and cardiopulmonary exercise test of the patients.

Table 2Echocardiogram	COVID-19 (n = 52)	Control (n = 31)	p value	
LVEDD indexed (mm/m2)	26.5 ± 8.7	25.5 ± 7.5	0.611	
LV indexed mass (g/m2)	75.0 ± 18.1	72.4 ± 18.0	0.529	
LAVI (mL/m2)	24.6 ± 6.4	26,5 ± 7,8	0.237	
E/e'	6.8 ± 1.2	6.7 ± 1.5	0.838	
Tricuspid S’ (cm/s)	13.4 ± 2.1	13.3 ± 1.8	0.934	
TAPSE (mm)	21.5 ± 3.3	22.8 ± 3.3	0.098	
sPAP (mmHg)	22.1 ± 4.9	21.7 ± 5.5	0.784	
TRV (m/s)	2.2 ± 0.3	2.0 ± 0.3	0.011	
LVEF (%)	62 ± 7	66 ± 6	0.007	
LVGLS (%)	−18.7 ± 2.6	−20.4 ± 1.4	0.001	
GWI (mmHg)
GCW (mmHg)
GWW (mmHg)
GWE (%)	2308 ± 464
2515 ± 458
152 ± 81
93 ± 3	2253 ± 358
2442 ± 315
101 ± 54
95 ± 2	0.571
0.440
0.003
0.002	
Cardiopulmonary exercise test	
Peak VO2 (mL/min/kg)	24.4 ± 5.4	33.4 ± 8.8	<0.001	
Peak VO2 (% pred)	92 ± 20	112 ± 21	<0.001	
Work (watts)	227 ± 61	242 ± 81	<0.001	
RER	1.12 ± 0.09	1.18 ± 0.09	0.01	
Peak HR (bpm)	160 ± 14	176 ± 11	<0.001	
VO2/HR (mL/beats·min)	13.2 ± 4.1	14.6 ± 4.2	0.151	
VO2/HR (% pred)	96 ± 21	104 ± 23	0.103	
Peak Ve (L/min)	84.6 ± 22.6	104.9 ± 27	<0.001	
Breathing reserve (%)	29 ± 13	20 ± 13	0.014	
Slope Ve/VCO2	33.1 ± 5.9	33.5 ± 5.1	0.794	
OUES (L/min)	2.3 ± 0.7	2.5 ± 0.7	0.147	
OUES% (% of pred.)	89 ± 16	102 ± 22	0.002	
T 1/2 (s)	120.3 ± 32	97.6 ± 27	0.002	
HRR at 1 min (bpm)	−20 ± 10	−23 ± 15	0.265	
HRR at 2 min (bpm)	−36 ± 11	−43 ± 13	0.010	
E/e′: ratio between the peak of the mitral and tissue E wave; GCW: global constructive work; GWE: global work efficiency; GWI: global work index; GWW: global wasted work; HR: heart rate; HRR: heart rate decay in recovery from exertion; HR/VO2: relationship between heart rate and oxygen consumption; LAVI: left atrial volume index; LVEDD: left ventricle end-diastolic diameter; LVEF: left ventricle ejection fraction by Simpson; LVGLS: left ventricle global longitudinal strain; OUES: oxygen uptake efficiency slope; RER: respiratory exchange ratio (VCO2/VO2); Slope Ve/VCO2: slope of the ratio of minute ventilation and carbon dioxide production; sPAP: systolic pulmonary artery pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity; Ve: minute ventilation; VO2: oxygen consumption; T ½: recovery time for VO2 to drop to 50 % of its peak value.

Fig. 2 Comparison of myocardial work between COVID-19 and Control groups.

Fig. 2

Fig. 3 Myocardial work index bull's-eye mapping. (A) Representative patient of the control group with normal strain and myocardial work; (B) Representative patient of COVID-19 group with severe reduced global longitudinal strain, myocardial work index, and work efficiency.

Fig. 3

3.3 Exercise evaluation

The CPET results are presented in Tables 2 and in Fig. 4. The two groups differed in peak VO2, HR, Ve and RER. They also significantly differed in the number of patients with desaturation (14 vs. 0; p = 0.002). Although there was no significant difference in their oxygen pulse values (HR/VO2), the morphology of the curve (dynamic behaviour) was significantly altered, with the finding of an early plateau in the COVID-19 group (14 vs. 0; p = 0.002). Regarding oxygen kinetics, there was a significant difference in relation to OUES% and T ½. During recovery, there was a significant difference in the drop-in heart rate (HRR), which was better characterized in the second minute of recovery than in the first minute. The chronotropic index was lower for patients with COVID-19 than for controls (0.83 ± 0.20 vs. 1.03 ± 0.15; p < 0.0001).Fig. 4 Exercise capacity between COVID-19 and Control.

Fig. 4

3.4 Association between echocardiographic and spiroergometric results

In Fig. 5, we present the main correlations between the echocardiogram data and the CPET results. There was an association between higher GWW and the following CPET results: deficit in peak VO2 from predicted (r = −0.36; p = 0.001), reduction in minute ventilation (r = −0.30; p = 0.008), deficit in VO2/HR from predicted (r = −0.32; p = 0.004), and HRR at 2 min (r = −0.28; p = 0.012). There was also a correlation between increased GWE and increased peak VO2 in % predicted (r = 0.31; p = 0.004). None of the other echocardiographic variables showed a significant correlation with CPET data.Fig. 5 Correlations between echocardiogram and CPET data.

Fig. 5

4 Discussion

The main findings of this study revealed that most severe COVID-19 patients exhibited low LVGLS and GWE, accompanied by high GWW. They demonstrated lower exercise capacity, as evidenced by lower peak VO2, lower work achieved, and lower OUES% than the matched controls. These patients exhibited a prolonged time for heart rate recovery, as indicated by higher T1/2 and higher HRR at 2 min.

Since early studies involving MW and COVID-19, GWE has emerged as a crucial marker of subclinical cardiac dysfunction in hospitalized patients [12,27]. It has been investigated as a prognostic indicator of in-hospital mortality, even in those with normal LVEF [28,29]. In our study, although there were significant differences in LVEF between the groups, these values still fell within the normal range, having no clinical significance. Regarding MW, patients exhibited normal GWI values. This finding could be attributed to the timing of the examination (an average of 60 days after hospital discharge, with cardiac rehabilitation), the patients’ higher systolic blood pressure than the control group, the younger age of the patients compared to previously published studies, or survivor bias [30]. In our study, the patients demonstrated higher values of GWW and lower values of GWE and LVGLS, indicating the presence of subclinical cardiac dysfunction in patients with COVID-19. Some studies have suggested an improvement in some of these indices, particularly GWI and particularly in the acute phase [31]. However, there are still no prospective studies evaluating these parameters specifically related to COVID-19.

Despite the considerable heterogeneity among studies, aerobic capacity is often reduced in patients following COVID-19, significantly improving in the months of recovery from the acute phase [[32], [33], [34]]. Among the multiple factors underlying this, peripheral limitation has been considered the primary mechanism associated with anaemia, reduced oxygen extraction, impaired mechanical efficiency, and decreased muscle strength [[35], [36], [37], [38]]. In a study assessing the long-term evolution of aerobic capacity over the first year after COVID-19, the number of patients with cardiocirculatory limitation was even higher than that of patients with ventilatory limitation [17].

The persistence of reduced VO2 in a significant portion of patients, even after a long period of recovery, suggests that peripheral deconditioning alone does not explain this reduction. While there is no clear central cardiocirculatory mechanism (e.g., myocardial contractility deficit), there is a strong association between low VO2 and the presence of diastolic dysfunction, chronotropic incompetence, autonomic dysfunction, and peripheral vascular damage (i.e., endothelial dysfunction), which can limit oxygen delivery to muscles during exercise [[39], [40], [41]]. One way to assess autonomic dysfunction is through heart rate decline in the recovery phase, and chronotropic incompetence has been seen in association with an abnormal heart rate response during recovery [[42], [43], [44], [45]]. In our study, patients exhibited a blunted peak heart rate, increased T1/2, and reduced HRR in the second minute compared to the control group, potentially indicating impaired parasympathetic drive and possibly having prognostic implications for the reduced aerobic capacity of such patients, as high heart rate variability is a marker of a favourable chronotropic adaptation response seen in healthy individuals.

Previous studies have suggested evidence of mitochondrial dysfunction characterized by significant impairment in fat beta-oxidation and increased blood lactate accumulation during exercise in patients with post-acute sequelae of SARS-CoV-2 infection [46]. Furthermore, patients with COVID-19 exhibit exaggerated muscle sympathetic nerve activity and a blunted vasodilatory response to mental challenge compared to control adults [30]. Taken together, these alterations may contribute to exercise limitations in these patients.

To our knowledge, this is the first study to evaluate cardiac mechanics via myocardial work and establish correlations with CPET in patients who have recuperated from severe COVID-19. Shimoni et al. had previously demonstrated the association between reduced LVGLS and aerobic capacity assessed through the standard treadmill exercise stress test using the Bruce protocol. Although it was weak, we found an association between higher wasted myocardial work (GWW) and lower VO2% and an association between higher myocardial work efficiency (GWE) and higher peak VO2 values. GWE reflects regional myocardial oxygen metabolism when compared against measurements obtained by positron emission tomography using (18F) fluorodeoxyglucose [47,48]. Therefore, the reduction in GWE does not exclude a central cardiocirculatory component related to disturbances in myocardial metabolism that may occur in the context of increased systemic inflammation and may contribute to the reduced aerobic capacity of these patients.

Our study has some limitations. First, all patients had severe COVID-19 requiring ICU admission, so our findings may not be applicable to patients with long COVID outside this profile. Our patients had not received the COVID-19 vaccine due to the timing of the study, so our findings may not replicate in a vaccinated population. Another noteworthy aspect pertains to the control group. Given the stage of the pandemic during the study, we were unable to perform RT‒PCR testing for COVID-19 in the control group, as the Brazilian Ministry of Health protocol did not include testing for asymptomatic individuals. Therefore, we cannot exclude the possibility that some of the control group had asymptomatic COVID-19, which may still affect cardiovascular capacity. Another significant limitation in our study was the absence of a control group consisting of critically ill patients but with a different infectious cause other than COVID-19. Consequently, we cannot solely attribute the observed alterations in results to COVID-19 or to post-ICU care syndrome. Furthermore, we had no data on the patients' aerobic capacity prior to hospitalization, and since all the patients underwent cardiopulmonary rehabilitation, we cannot assess the impact of this intervention on their recovery. Cardiac output, arterial lactate and endothelial function were not assessed during exercise, and muscle biopsies were not conducted, which introduces some uncertainty in evaluating the degree of deconditioning.

5 Conclusion

Survivors of severe COVID-19 exhibit increased wasted work, with lower myocardial efficiency, significantly reduced aerobic exercise capacity, and abnormal heart rate response during recovery, which may be related to previously described late symptoms. The reduction in functional capacity during physical exercise is partly associated with a decrease in resting myocardial work efficiency. These findings strongly indicate the need to determine whether these manifestations persist in the long term and their impact on cardiovascular health and quality of life in COVID-19 survivors.

CRediT authorship contribution statement

Thiago Lins Fagundes de Sousa: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation. Allan Robson Kluser Sales: Resources, Data curation. Juliana Góes Martins Fagundes: Writing – review & editing, Writing – original draft. Luis Fábio Barbosa Botelho: Software, Formal analysis. Francis Ribeiro de Souza: Conceptualization, Formal analysis, Writing – review & editing. Guilherme Wesley Fonseca: Writing – review & editing, Software, Formal analysis, Data curation. André Luis Pereira de Albuquerque: Methodology, Investigation, Data curation. Marcelo Dantas Tavares de Melo: Writing – review & editing, Supervision, Project administration, Methodology, Data curation, Conceptualization. Maria-Janieire de Nazaré Nunes Alves: Writing – review & editing, Supervision, Project administration, Data curation.
==== Refs
References

1 Catapano F. Marchitelli L. Cundari G. Cilia F. Mancuso G. Pambianchi G. Galea N. Ricci P. Catalano C. Francone M. Role of advanced imaging in COVID-19 cardiovascular complications Insights into Imaging 12 2021 10.1186/s13244-021-00973-z
2 Ali A.S. Sheikh D. Chandler T.R. Furmanek S. Huang J. Ramirez J.A. Arnold F. Cavallazzi R. Cardiovascular complications are the primary drivers of mortality in hospitalized patients with SARS-CoV-2 community-acquired pneumonia Chest 163 2023 1051 1060 10.1016/j.chest.2022.11.013 36410493
3 Guimarães P.O. de Souza F.R. Lopes R.D. Bittar C. Cardozo F.A. Caramelli B. Calderaro D. Albuquerque C.P. Drager L.F. Feres F. Baracioli L. Feitosa Filho G. Barbosa R.R. Ribeiro H.B. Ribeiro E. Alves R.J. Soeiro A. Faillace B. Figueiredo E. Damiani L.P. do Val R.M. Huemer N. Nicolai L.G. Hajjar L.A. Abizaid A. Kalil Filho R. High risk coronavirus disease 2019: the primary results of the CoronaHeart multi-center cohort study IJC Heart & Vasculature 36 2021 100853 10.1016/j.ijcha.2021.100853
4 Kwenandar F. Japar K.V. Damay V. Hariyanto T.I. Tanaka M. Lugito N.P.H. Kurniawan A. Coronavirus disease 2019 and cardiovascular system: a narrative review IJC Heart and Vasculature 29 2020 10.1016/j.ijcha.2020.100557
5 L'Heureux M. Sternberg M. Brath L. Turlington J. Kashiouris M.G. Sepsis-induced cardiomyopathy: a comprehensive review Curr. Cardiol. Rep. 22 2020 10.1007/s11886-020-01277-2
6 Wu L. O'Kane A.M. Peng H. Bi Y. Motriuk-Smith D. Ren J. SARS-CoV-2 and cardiovascular complications: from molecular mechanisms to pharmaceutical management Biochem. Pharmacol. 178 2020 10.1016/j.bcp.2020.114114
7 Puntmann V.O. Carerj M.L. Wieters I. Fahim M. Arendt C. Hoffmann J. Shchendrygina A. Escher F. Vasa-Nicotera M. Zeiher A.M. Vehreschild M. Nagel E. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19) JAMA Cardiology 5 2020 1265 1273 10.1001/jamacardio.2020.3557 32730619
8 Shimoni O. Korenfeld R. Goland S. Meledin V. Haberman D. George J. Shimoni S. Subclinical myocardial dysfunction in patients recovered from COVID-19 disease: correlation with exercise capacity Biology 10 2021 1201 10.3390/biology10111201 34827194
9 Moody W.E. Liu B. Mahmoud-Elsayed H.M. Senior J. Lalla S.S. Khan-Kheil A.M. Brown S. Saif A. Moss A. Bradlow W.M. Khoo J. Ahamed M. McAloon C. Hothi S.S. Steeds R.P. Persisting adverse ventricular remodeling in COVID-19 survivors: a longitudinal echocardiographic study J. Am. Soc. Echocardiogr. 34 2021 562 566 10.1016/j.echo.2021.01.020 33539950
10 Chan J. Edwards N.F.A. Scalia G.M. Khandheria B.K. Myocardial work: a new type of strain imaging? J. Am. Soc. Echocardiogr. 33 2020 1209 1211 10.1016/j.echo.2020.05.004 32591249
11 Roemer S. Jaglan A. Santos D. Umland M. Jain R. Tajik A.J. Khandheria B.K. The utility of myocardial work in clinical practice J. Am. Soc. Echocardiogr. 34 2021 807 818 10.1016/j.echo.2021.04.013 33895250
12 Jaglan A. Roemer S. Jan M.F. Khandheria B.K. Myocardial work index: a glimmer of hope in COVID-19 European Heart Journal Cardiovascular Imaging 22 2021 228 10.1093/ehjci/jeaa181 32542341
13 Hubert A. Le Rolle V. Leclercq C. Galli E. Samset E. Casset C. Mabo P. Hernandez A. Donal E. Estimation of myocardial work from pressure–strain loops analysis: an experimental evaluation European Heart Journal Cardiovascular Imaging 19 2018 1372 1379 10.1093/ehjci/jey024 29529181
14 Cassar M.P. Tunnicliffe E.M. Petousi N. Lewandowski A.J. Xie C. Mahmod M. Samat A.H.A. Evans R.A. Brightling C.E. Ho L.-P. Piechnik S.K. Talbot N.P. Holdsworth D. Ferreira V.M. Neubauer S. Raman B. Symptom persistence despite improvement in cardiopulmonary health - insights from longitudinal CMR, CPET and lung function testing post-COVID-19 EClinicalMedicine 41 2021 101159 10.1016/j.eclinm.2021.101159
15 Mohr A. Dannerbeck L. Lange T.J. Pfeifer M. Blaas S. Salzberger B. Hitzenbichler F. Koch M. Cardiopulmonary exercise pattern in patients with persistent dyspnoea after recovery from COVID-19 Multidiscip Respir Med 16 2021 732 10.4081/mrm.2021.732 33623700
16 Rinaldo R.F. Mondoni M. Parazzini E.M. Pitari F. Brambilla E. Luraschi S. Balbi M. Sferrazza Papa G.F. Sotgiu G. Guazzi M. Di Marco F. Centanni S. Deconditioning as main mechanism of impaired exercise response in COVID-19 survivors Eur. Respir. J. 58 2021 2100870 10.1183/13993003.00870-2021
17 Ingul C.B. Edvardsen A. Follestad T. Trebinjac D. Ankerstjerne O.A.W. Brønstad E. Rasch-Halvorsen Ø. Aarli B. Dalen H. Nes B.M. Lerum T.V. Einvik G. Stavem K. Skjørten I. Changes in cardiopulmonary exercise capacity and limitations 3–12 months after COVID-19 Eur. Respir. J. 61 2023 2200745 10.1183/13993003.00745-2022
18 Francone M. Iafrate F. Masci G.M. Coco S. Cilia F. Manganaro L. Panebianco V. Andreoli C. Colaiacomo M.C. Zingaropoli M.A. Ciardi M.R. Mastroianni C.M. Pugliese F. Alessandri F. Turriziani O. Ricci P. Catalano C. Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis Eur. Radiol. 30 2020 6808 6817 10.1007/s00330-020-07033-y 32623505
19 Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. Flachskampf F.A. Foster E. Goldstein S.A. Kuznetsova T. Lancellotti P. Muraru D. Picard M.H. Rietzschel E.R. Rudski L. Spencer K.T. Tsang W. Voigt J.-U. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging J. Am. Soc. Echocardiogr. 28 2015 1 39.e14 10.1016/j.echo.2014.10.003 25559473
20 K Wasserman, J Hansen, D Sue, W Stringer, B Whipp, eds, Principles of Exercise Testing and Interpretation, fourth ed., Lippincott Williams & Wilkins, Philadelphia, USA, (n.d).
21 Chan J. Edwards N.F.A. Khandheria B.K. Shiino K. Sabapathy S. Anderson B. Chamberlain R. Scalia G.M. A new approach to assess myocardial work by non-invasive left ventricular pressure-strain relations in hypertension and dilated cardiomyopathy European Heart Journal Cardiovascular Imaging 20 2019 31 39 10.1093/ehjci/jey131 30247622
22 Manganaro R. Marchetta S. Dulgheru R. Ilardi F. Sugimoto T. Robinet S. Cimino S. Go Y.Y. Bernard A. Kacharava G. Athanassopoulos G.D. Barone D. Baroni M. Cardim N. Hagendorff A. Hristova K. López-Fernández T. De La Morena G. Popescu B.A. Penicka M. Ozyigit T. Rodrigo Carbonero J.D. Van De Veire N. Von Bardeleben R.S. Vinereanu D. Zamorano J.L. Rosca M. Calin A. Moonen M. Magne J. Cosyns B. Galli E. Donal E. Carerj S. Zito C. Santoro C. Galderisi M. Badano L.P. Lang R.M. Oury C. Lancellotti P. Echocardiographic reference ranges for normal non-invasive myocardial work indices: results from the EACVI NORRE study European Heart Journal Cardiovascular Imaging 20 2019 582 590 10.1093/ehjci/jey188 30590562
23 Porszasz J. Casaburi R. Somfay A. Woodhouse L.J. Whipp B.J. A treadmill ramp protocol using simultaneous changes in speed and grade Med. Sci. Sports Exerc. 35 2003 1596 1603 10.1249/01.MSS.0000084593.56786.DA 12972882
24 Carlos Alberto de Castro Pereira, José Manoel Jansen, Sérgio S. Menna Barreto, Jamocyr Marinho, Nara Sulmonett, Ricardo Marques Dias, Sérgio Roberto Nassif, Diretrizes para o teste de função pulmonar, J. Bras. Pneumol. 28:suplemento 3 (n.d.).
25 Hansen J.E. Sue D.Y. Wasserman K. Predicted values for clinical exercise testing Am. Rev. Respir. Dis. 129 1984 S49 S55 10.1164/arrd.1984.129.2P2.S49 6421218
26 Hollenberg M. Tager I.B. Oxygen uptake efficiency slope: an index of exercise performance and cardiopulmonary reserve requiring only submaximal exercise J. Am. Coll. Cardiol. 36 2000 194 201 10.1016/s0735-1097(00)00691-4 10898434
27 Lairez O. Blanchard V. Houard V. Vardon-Bounes F. Lemasle M. Cariou E. Lavie-Badie Y. Ruiz S. Cazalbou S. Delmas C. Georges B. Galinier M. Carrié D. Conil J.M. Minville V. Cardiac imaging phenotype in patients with coronavirus disease 2019 (COVID-19): results of the cocarde study Int. J. Cardiovasc. Imag. 37 2021 449 457 10.1007/s10554-020-02010-4
28 Minhas A.S. Gilotra N.A. Goerlich E. Metkus T. Garibaldi B.T. Sharma G. Bavaro N. Phillip S. Michos E.D. Hays A.G. Myocardial work efficiency, A novel measure of myocardial dysfunction, is reduced in COVID-19 patients and associated with in-hospital mortality Frontiers in Cardiovascular Medicine 8 2021 https://www.frontiersin.org/articles/10.3389/fcvm.2021.667721
29 Olsen F.J. Lassen M.C.H. Skaarup K.G. Christensen J. Davidovski F.S. Alhakak A.S. Sengeløv M. Nielsen A.B. Johansen N.D. Graff C. Bundgaard H. Hassager C. Jabbari R. Carlsen J. Kirk O. Lindholm M.G. Wiese L. Kristiansen O.P. Nielsen O.W. Lindegaard B. Tønder N. Ulrik C.S. Lamberts M. Sivapalan P. Gislason G. Iversen K. Jensen J.U.S. Schou M. Svendsen J.H. Aalen J.M. Smiseth O.A. Remme E.W. Biering‐Sørensen T. Myocardial work in patients hospitalized with COVID‐19: relation to biomarkers, COVID‐19 severity, and all‐cause mortality J. Am. Heart Assoc. 11 2022 e026571 10.1161/JAHA.122.026571
30 Faria D. Moll-Bernardes R. Testa L. Moniz C.M.V. Rodrigues E.C. Mota J.M. Souza F.R. Alves M.J.N.N. Ono B.E. Izaias J.E. Sales A.O. Rodrigues T.S. Salemi V.M.C. Jordão C.P. De Angelis K. Craighead D.H. Rossman M.J. Bortolotto L.A. Consolim-Colombo F.M. Irigoyen M.C.C. Seals D.R. Negrão C.E. Sales A.R.K. Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors Am. J. Physiol. Regul. Integr. Comp. Physiol. 325 2023 R269 R279 10.1152/ajpregu.00111.2023 37449870
31 Ikonomidis I. Lambadiari V. Mitrakou A. Kountouri A. Katogiannis K. Thymis J. Korakas E. Pavlidis G. Kazakou P. Panagopoulos G. Andreadou I. Chania C. Raptis A. Bamias A. Thomas K. Kazakou P. Grigoropoulou S. Kavatha D. Antoniadou A. Dimopoulos M.A. Filippatos G. Myocardial work and vascular dysfunction are partially improved at 12 months after COVID-19 infection Eur. J. Heart Fail. 24 2022 727 729 10.1002/ejhf.2451 35138689
32 Durstenfeld M.S. Sun K. Tahir P. Peluso M.J. Deeks S.G. Aras M.A. Grandis D.J. Long C.S. Beatty A. Hsue P.Y. Use of cardiopulmonary exercise testing to evaluate long COVID-19 symptoms in adults: a systematic review and meta-analysis JAMA Netw. Open 5 2022 e2236057 10.1001/jamanetworkopen.2022.36057
33 Mancini D.M. Brunjes D.L. Lala A. Trivieri M.G. Contreras J.P. Natelson B.H. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease JACC Heart Fail 9 2021 927 937 10.1016/j.jchf.2021.10.002 34857177
34 Pleguezuelos E. Del Carmen A. Llorensi G. Carcole J. Casarramona P. Moreno E. Ortega P. Serra-Prat M. Palomera E. Miravitlles M.M. Yebenes J.C. Boixeda R. Campins L. Villelabeitia-Jaureguizar K. Garnacho-Castaño M.V. Severe loss of mechanical efficiency in COVID-19 patients Journal of Cachexia, Sarcopenia and Muscle 12 2021 1056 1063 10.1002/jcsm.12739 34102017
35 Baratto C. Caravita S. Faini A. Perego G.B. Senni M. Badano L.P. Parati G. Impact of COVID-19 on exercise pathophysiology: a combined cardiopulmonary and echocardiographic exercise study J. Appl. Physiol. 130 2021 1470 1478 10.1152/japplphysiol.00710.2020 33764166
36 Clavario P. Marzo V.D. Lotti R. Barbara C. Porcile A. Russo C. Beccaria F. Bonavia M. Bottaro L.C. Caltabellotta M. Chioni F. Santangelo M. Hautala A.J. Ameri P. Canepa M. Porto I. Assessment of functional capacity with cardiopulmonary exercise testing in non-severe COVID-19 patients at three months follow-up 10.1101/2020.11.15.20231985 2020
37 Clavario P. De Marzo V. Lotti R. Barbara C. Porcile A. Russo C. Beccaria F. Bonavia M. Bottaro L.C. Caltabellotta M. Chioni F. Santangelo M. Hautala A.J. Griffo R. Parati G. Corrà U. Porto I. Cardiopulmonary exercise testing in COVID-19 patients at 3 months follow-up Int. J. Cardiol. 340 2021 113 118 10.1016/j.ijcard.2021.07.033 34311011
38 Singh I. Joseph P. Heerdt P.M. Cullinan M. Lutchmansingh D.D. Gulati M. Possick J.D. Systrom D.M. Waxman A.B. Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing Chest 161 2022 54 63 10.1016/j.chest.2021.08.010 34389297
39 Longobardi I. do Prado D.M.L. Goessler K.F. Meletti M.M. de Oliveira Júnior G.N. de Andrade D.C.O. Gualano B. Roschel H. Oxygen uptake kinetics and chronotropic responses to exercise are impaired in survivors of severe COVID-19 Am. J. Physiol. Heart Circ. Physiol. 323 2022 H569 H576 10.1152/ajpheart.00291.2022 35984763
40 Aparisi Á. Ladrón R. Ybarra-Falcón C. Tobar J. San Román J.A. Exercise intolerance in post-acute sequelae of COVID-19 and the value of cardiopulmonary exercise testing- a mini-review Front. Med. 9 2022 https://www.frontiersin.org/articles/10.3389/fmed.2022.924819
41 Serviente C. Decker S.T. Layec G. From heart to muscle: pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection J. Appl. Physiol. 132 2022 581 592 10.1152/japplphysiol.00734.2021 35019775
42 Schwendinger F. Knaier R. Radtke T. Schmidt-Trucksäss A. Low cardiorespiratory fitness post-COVID-19: a narrative review Sports Med. 53 2023 51 74 10.1007/s40279-022-01751-7 36115933
43 Faria D. Moll-Bernardes R.J. Testa L. Moniz C.M.V. Rodrigues E.C. Rodrigues A.G. Araujo A. Alves M.J.N.N. Ono B.E. Izaias J.E. Salemi V.M.C. Jordão C.P. Amaro-Vicente G. Rondon M.U.P.B. Ludwig K.R. Craighead D.H. Rossman M.J. Consolim-Colombo F.M. Angelis K.D. Irigoyen M.C.C. Seals D.R. Negrão C.E. Sales A.R.K. Sympathetic neural overdrive, aortic stiffening, endothelial dysfunction, and impaired exercise capacity in severe COVID-19 survivors: a mid-term study of cardiovascular sequelae Hypertension 2023 10.1161/HYPERTENSIONAHA.122.19958
44 Ribeiro C.M. Gomes R. de A. Monteiro C.B. de M. Dias R.M. Simcsik A.O. de Araújo L.V. Maia L.C.P. de Oliveira A.P. de Freitas B.L. Dawes H. Ferreira C. de Moraes Í.A.P. da Silva T.D. Heart rate variability during virtual reality activity in individuals after hospitalization for COVID-19: a cross-sectional control study Electronics 12 2023 1925 10.3390/electronics12081925
45 Shetler K. Marcus R. Froelicher V.F. Vora S. Kalisetti D. Prakash M. Do D. Myers J. Heart rate recovery: validation and methodologic issues J. Am. Coll. Cardiol. 38 2001 1980 1987 10.1016/S0735-1097(01)01652-7 11738304
46 E. de Boer, I. Petrache, N.M. Goldstein, J.T. Olin, R.C. Keith, B. Modena, M.P. Mohning, Z.X. Yunt, I. San-Millán, J.J. Swigris, Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome, Am. J. Respir. Crit. Care Med. 205 (n.d.) 126–129. 10.1164/rccm.202108-1903LE.
47 Russell K. Eriksen M. Aaberge L. Wilhelmsen N. Skulstad H. Remme E.W. Haugaa K.H. Opdahl A. Fjeld J.G. Gjesdal O. Edvardsen T. Smiseth O.A. A novel clinical method for quantification of regional left ventricular pressure–strain loop area: a non-invasive index of myocardial work Eur. Heart J. 33 2012 724 733 10.1093/eurheartj/ehs016 22315346
48 Patel J.J. Alzahrani T. Myocardial perfusion scan StatPearls 2023 StatPearls Publishing Treasure Island (FL) http://www.ncbi.nlm.nih.gov/books/NBK539772/
