Abstract

Aims

Mitral stenosis (MS) may exhibit a dynamic valvular reserve. When resting gradients and systolic pulmonary pressure (sPAP) do not reflect the real severity of the disease, a dynamic evaluation becomes necessary. The aim of the study was to assess the clinical utility of exercise echocardiography in symptomatic patients with apparently subcritical MS.

Methods and results

One hundred and thirty consecutive patients were referred for symptomatic MS. Patients with unimpressive resting MVA (>1–1.5 cm2) and mean PG (≥5–9 mmHg) underwent exercise echocardiography. Cardiac performance and mitral indices (MVA, peak/mean PG, sPAP) were measured. Exhaustion of valvular reserve capacity under exercise was defined as appearance of symptoms and sPAP > 60 mmHg. Forty-six patients (35%) (age: 53 ± 10 years; 74%, female) with resting MVA (1.2 ± 0.36 cm2), mean PG (6.8 ± 2.7 mmHg), and sPAP (38 ± 7 mmHg) inconsistent with symptoms underwent stress echocardiography. Exercise was stopped for dyspnoea (76%) or fatigue (24%). At peak workloads (57.2 ± 21.8 Watts), increased mean PG (17.2 ± 4.8 mmHg, P< 0.001) and sPAP (67.4 ± 11.4 mmHg; P< 0.0001) were observed, without change in MVA (1.25 ± 0.4 cm2; P= n.s.). At univariate analysis, predictors of adaptation to exercise were age (−0.345; P = 0.024), mean PG (0.339; P= 0.023), and sPAP (0.354; P= 0.024); at multivariate analysis, best predictor was resting mean PG, although correlation was poor (−0.339; P= 0.015).

Conclusion

In MS with limiting symptoms despite unimpressive findings at rest, valvular capacity exhaustion should be tested on a dynamic background, as no single resting index can predict potential haemodynamic adaptation to exercise. In such context, the contribution of exercise echocardiography remains extremely valuable.

Introduction

In developed countries, valvular heart disease predominantly afflicts the elderly, whereas in Africa it is encountered in the young.1–3 Despite the significant decrease in the western prevalence of rheumatic fever, mitral stenosis (MS) still accounts for 12% of native valvular disease4 and increasing prevalence is expected according to the new epidemiologic trends following immigratory flow.

For any given degree of anatomic mitral narrowing, the stenotic orifice shows a ‘dynamic reserve’ responsible for different functional NYHA class or specific adaptation under stress conditions.5–8 While resting values of mitral gradients and pulmonary arterial pressures do not always reflect the true severity of the disease, stress echocardiography may provide the necessary clues to determine the clinical and haemodynamic impact of MS.9,10 Significant increments of heart rate (HR), cardiac index, and systolic pulmonary pressure (sPAP) help identify subgroups of patients with a greater functional severity of MS, despite unimpressive transvalvular gradients at rest,11–17 and therefore guide decision-making. The current ACC/AHA guidelines18 have given a Class I recommendation (level of evidence: C) for stress echocardiography in patients with MS and discordance between symptoms and stenosis severity. There are important caveats in applying these recommendations in clinical practice because they are all based on a level C weight of evidence, the consensus being driven and not supported by evidence of sufficient clinical studies. Purpose of the present study was therefore to assess the clinical utility of exercise echocardiography in gauging the functional severity of apparently subcritical MS.

Methods

Between 2003 and 2010, 130 consecutive patients were referred to San Raphael Scientific Institute for surgical or percutaneous treatment of symptomatic rheumatic MS. If diagnostic discrepancies were encountered between symptoms and haemodynamics at rest by the Heart Team, patients underwent exercise stress echocardiography in order to clarify the functional severity of MS before surgical correction (Figure 1).

Figure 1

Operative flowchart concerning the diagnostic assessment of patients with rheumatic mitral stenosis referred to San Raffaele Scientific Institute.

Figure 1

Operative flowchart concerning the diagnostic assessment of patients with rheumatic mitral stenosis referred to San Raffaele Scientific Institute.

Echocardiography at rest

Transthoracic echocardiography was performed in all patients to assess: (i) planimetry of mitral valve area (MVA); (ii) mitral peak and mean pressure gradients (PG); (iii) sPAP; (iv) left ventricular (LV) performance indices, such as systemic blood pressure (SBP), HR, and LV ejection fraction (EF); (v) Wilkins score19 and the commissural morphology suitable for balloon valvuloplasty or mitral repair/replacement.

Doppler and 2-D echocardiographic measurements included: LVEF assessed by modified biplane Simpson's method and RV systolic function (assessed by tricuspid annulus TDI peak systolic velocity). In standard parasternal or apical views, MR was quantified by EROA according to the ASE criteria.

Measurement of mitral valve opening profile

Transmitral filling flow velocity was recorded by pulsed Doppler echocardiography, and peak and mean PGs were calculated using the modified Bernoulli equation as following: PG (mmHg) = 4 × velocity2 (m/s). Measurement of planimetry of MVA was achieved by conventional short-axis and off-axis views providing the best orifice cross-sectional plane. sPAP was determined by adding the systolic right ventricular pressure derived from the tricuspid regurgitation (average of 5 beats for patients in AF) to the estimated right atrial pressure.20

Transoesophageal echocardiography (TEE) was performed in all patients in order to: (i) rule out cardiac embolic sources from calcified valves as well as from left appendage in patients with atrial fibrillation; (ii) define the degree of associated MR or other significant valvulopathies; (iii) assess the appropriate valve morphology suitable for balloon valvuloplasty or mitral repair.

According to the clinical flow-chart adopted, the study population included patients with discrepancy between symptoms and haemodynamics at rest (MVA > 1–1.5 cm2 and mean PG ≥ 5–9 mmHg).

Dynamic assessment: stress echocardiography

Stress echocardiography was performed in order to assess the severity and clinical impact of MS. Exclusion criteria were: (i) severe chronic obstructive pulmonary disease or vasculopathy leading to inability to exercise; (ii) evidence of embolic sources at TEE; (iii) severe associated aortic or mitral regurgitation (defined by EROA ≥ 0.40 cm2); (iv) previously disclosed concomitant coronary artery disease.

Stress echocardiography was performed in all patients in the semisupine position using a bicycle stress protocol based on incremental workload of 10 Watts/min under regular monitoring of systemic arterial blood pressure and 12-lead ECG. No medications were stopped before the test in order to assess the real current NYHA class under optimal medical treatment. The patients were encouraged to exercise until exhaustion or symptoms appear. All echo-Doppler data were measured at rest and at peak exercise by the same cardiologist.

Valvular reserve capacity (VRC)

At peak exercise, main parameters of cardiac performance were calculated including SBP, HR, LVEF, and RV systolic function. Mitral valve function indices were measured including MVA, peak, and mean PGs and systolic pulmonary arterial pressure.

Valvular reserve capacity (VRC) may be considered the maximum capacity of the stenotic orifice able to sustain the exercise burden before clinical symptoms or haemodynamic impairment. For the purposes of the present study, the exhaustion of VRC was defined as the peak exercise workload (Watts/min) attained before one or more of the following criteria was fulfilled: (i) appearance of clinical symptoms (severe fatigue/dyspnoea) related to exercise-induced increase of PG and sPAP values according to AHA/ACC guidelines; (ii) critical pulmonary hypertension (sPAP > 60 mmHg) regardless of symptoms or haemodynamic impairment.

Statistical analysis

Statistical analysis has been conducted using the JMP 5.1.1 software (SAS institute Inc., Cary, NC, USA). Continuous variables are presented as mean ± SD or as median, and categorical variables are expressed as proportions. Differences between rest and exercise values were tested for significance by use of a paired two-sample t-test and ANOVA for parametric data. Linear regression analysis was used to determine the correlation between cardiac adaptation to exercise and non-invasive parameters of mitral valve reserve. The level of significance has been set at P= 0.05.

Results

Study population

According to the diagnostic flowchart (Figure 1), 46 patients (35.4% of 130 patients) entered in the register of stress echocardiography (Table 1). Mean age was 53 ± 10 years, 34 patients (74%) were female. Most patients (89%) were Italian-born white Caucasian, whereas 11% were first generation black immigrants, mostly from North Africa. All patients were symptomatic (NYHA II, 54%; NYHA III, 46%), in stable sinus rhythm (100%) at the time of admission and under optimized medical treatment with diuretics and beta-blockers. Previous heart surgery in 12 patients (26%) included mitral commissurotomy (10 patients, 21.7%) and aortic valve replacement (2 patients, 4.3%).

Table 1

Demographic characteristics of overall population

Variable n ± SD (%) 
N 46 
Age (years) 53 ± 10 
Sex (M/F) 12/34 (26/74) 
Ethnic provenance  
 Italians (white Caucasians) 41 (89) 
 Immigrants (Africa/Eastern Europe/South America) 5 (11) 
Clinical history of RHD 100 (100%) 
Previous cardiac surgery 12 (26%) 
 Mitral commissurotomy 10 (21.7) 
 Aortic valve replacement 2 (4.3) 
 CABG 
Variable n ± SD (%) 
N 46 
Age (years) 53 ± 10 
Sex (M/F) 12/34 (26/74) 
Ethnic provenance  
 Italians (white Caucasians) 41 (89) 
 Immigrants (Africa/Eastern Europe/South America) 5 (11) 
Clinical history of RHD 100 (100%) 
Previous cardiac surgery 12 (26%) 
 Mitral commissurotomy 10 (21.7) 
 Aortic valve replacement 2 (4.3) 
 CABG 

Data are expressed as mean ± SD or number of patients (%).

M, male; F, female; RHD, rheumatic heart disease; CABG, coronary artery bypass grafting.

Resting and stress echocardiographic data

Baseline echocardiographic parameters of 46 study patients are summarized in Table 2. Overall, rheumatic MS was associated with moderate MVA reduction (1.2 ± 0.36 cm2) and unimpressive resting mean PG (6.8 ± 2.7 mmHg) and sPAP values (38 ± 7 mmHg) apparently inconsistent with patients' symptoms (NYHA class ≥ II).

Table 2

Clinical and echocardiographic characteristics of study population

Variable n ± SD (%) 
N 46 
Age (years) 53 ± 10 
Sex (M/F) 12/34 (26/74) 
NYHA Functional Class 
 NYHA class II 25 (54) 
 NYHA class III 21 (46) 
Atrial fibrillation at the time of admission 
Mitral PG (mmHg) 
 Peak 15 ± 4.8 
 Mean 6.8 ± 2.7 
MVA (cm21.2 ± 0.36 
MVA indexed (cm2/m20.64 ± 0.16 
MR grade [1+/4+] 
 MR grade 0+ 24 (52.2) 
 MR grade 1 or 1–2+ 22 (47.8) 
Wilkins Score 
 ≤8 22 (47.8) 
 >8 24 (52.2) 
LA volume (mL) 120 ± 40 
LA thrombosis 
EF (%) 60 ± 4 
Resting sPAP (mmHg) 38 ± 7 
Right ventricular dysfunction 2 (4) 
TR grade [1+/4+] 
 TR grade 1–2+ 38 (83) 
 TR grade 3–4+ 8 (17) 
Variable n ± SD (%) 
N 46 
Age (years) 53 ± 10 
Sex (M/F) 12/34 (26/74) 
NYHA Functional Class 
 NYHA class II 25 (54) 
 NYHA class III 21 (46) 
Atrial fibrillation at the time of admission 
Mitral PG (mmHg) 
 Peak 15 ± 4.8 
 Mean 6.8 ± 2.7 
MVA (cm21.2 ± 0.36 
MVA indexed (cm2/m20.64 ± 0.16 
MR grade [1+/4+] 
 MR grade 0+ 24 (52.2) 
 MR grade 1 or 1–2+ 22 (47.8) 
Wilkins Score 
 ≤8 22 (47.8) 
 >8 24 (52.2) 
LA volume (mL) 120 ± 40 
LA thrombosis 
EF (%) 60 ± 4 
Resting sPAP (mmHg) 38 ± 7 
Right ventricular dysfunction 2 (4) 
TR grade [1+/4+] 
 TR grade 1–2+ 38 (83) 
 TR grade 3–4+ 8 (17) 

Data are expressed as mean ± SD or number of patients (%).

M, male; F, female; NYHA, New York Heart Association; MVA, mitral valve area; LA, left atrium; EF, ejection fraction; sPAP, systolic pulmonary artery pressure; MR, mitral regurgitation; AR, aortic regurgitation; TR, tricuspid regurgitation.

Individual changes of cardiac performance indices are described in Table 3. During stress echocardiography, peak workloads reached 57.2 ± 21.8 Watts and no major clinical complications were observed. The test was stopped because of dyspnoea in 35 patients (76%) and fatigue in 11 patients (24%). At peak exercise, the main cardiac performance indices significantly increased, including SBP (125 ± 15 vs. ±154 ± 25 mmHg, P< 0.0001), HR (71 ± 8 vs. 159 ± 18bpm; P< 0.0001), and LV EF (60 ± 4 vs. 67 ± 5; <0.0001).

Table 3

Individual changes of cardiac performance and mitral indices during exercise stress echocardiography

Variable Rest, n ± SD Stress echo, n ± SD P-value 
Workload (Watts)  57.2 ± 21.8  
Reason to stop    
 Fatigue  11 (24)  
 Dyspnoea  35 (76)  
SBP (mmHg) 125 ± 15 154 ± 25 <0.0001** 
HR (bpm) 71 ± 8 159 ± 18 <0.0001** 
EF (%) 60 ± 4 67 ± 5 <0.0001** 
MVA (cm21.2 ± 0.36 1.25 ± 0.4 n.s. 
Mitral mean PG (mmHg) 6.6 ± 2.1 17.2 ± 4.8 <0.001* 
sPAP  (mmHg) 38.3 ± 7.2 67.4 ± 11.4 <0.0001** 
 VRC exhaustion (Watts/min)  
 Early (≤50) Late (>50)  
sPAP (mmHg) 29.2 ± 10 34 ± 9.4 n.s. 
PG (mmHg) 9.6 ± 4.7 11.5 ± 3.3 n.s. 
HR (beats/min) 82 ± 14 86 ± 14 n.s. 
Variable Rest, n ± SD Stress echo, n ± SD P-value 
Workload (Watts)  57.2 ± 21.8  
Reason to stop    
 Fatigue  11 (24)  
 Dyspnoea  35 (76)  
SBP (mmHg) 125 ± 15 154 ± 25 <0.0001** 
HR (bpm) 71 ± 8 159 ± 18 <0.0001** 
EF (%) 60 ± 4 67 ± 5 <0.0001** 
MVA (cm21.2 ± 0.36 1.25 ± 0.4 n.s. 
Mitral mean PG (mmHg) 6.6 ± 2.1 17.2 ± 4.8 <0.001* 
sPAP  (mmHg) 38.3 ± 7.2 67.4 ± 11.4 <0.0001** 
 VRC exhaustion (Watts/min)  
 Early (≤50) Late (>50)  
sPAP (mmHg) 29.2 ± 10 34 ± 9.4 n.s. 
PG (mmHg) 9.6 ± 4.7 11.5 ± 3.3 n.s. 
HR (beats/min) 82 ± 14 86 ± 14 n.s. 

Data are expressed as mean ± SD or number of patients (%).

SBP, systolic blood pressure; sPAP, systolic pulmonary artery pressure; PG, pressure gradients; HR, heart rate; EF, ejection fraction; VCR, valvular reserve capacity.

Valvular reserve capacity

The haemodynamic profile of VRC during exercise stress echocardiography is shown in Figure 2. At peak exercise, significant increase in mean PG (6.6 ± 2.1 to 17.2 ± 4.8 mmHg, P< 0.001) and sPAP values (38.3 ± 7.2 vs. 67.4 ± 11.4 mmHg; P< 0.0001) was observed, without significant change in MVA (1.2 ± 0.36 vs. 1.25 ± 0.4 cm2; P= n.s.). The exhaustion of VRC was defined as the peak exercise workload (Watts/min) attained before the following criteria: (i) appearance of clinical symptoms related to exercise-induced increase in PG and sPAP values according to the AHA/ACC guidelines; (ii) critical pulmonary hypertension (sPAP > 60 mmHg) regardless of symptoms or haemodynamic impairment. VRC was found to be impaired in all population showing different cardiac adaptation to exercise: 23 patients (50%) developed ‘early’ exhaustion of VRC at peak workloads ≤ 50 Watts (▵sPAP = 29.2 ± 10 mmHg; ▵PG 9.6 ± 4.7 mmHg) and 23 patients (50%) showed a ‘late’ exhaustion of VRC at peak workloads > 50 Watts (▵sPAP = 34 ± 9.4 mmHg; ▵PG = 11.5 ± 3.3 mmHg). No significant difference in the HR trend under exercise was observed in both subgroups (▵HR 82 ± 14 vs. 86 ± 14; P = 0.3) (Table 3).

Figure 2

Haemodynamic profile of mitral valve indices during exercise stress echocardiography.

Figure 2

Haemodynamic profile of mitral valve indices during exercise stress echocardiography.

At univariate regression analysis, main predictors of peak exercise workloads (Watts/min) were: age (−0.345; P = 0.024), mean mitral PG (0.339; P= 0.023), and sPAP (0.354; P= 0.024); no significant correlation between peak workloads and MVA (P= 0.05; R2: 0.098) was found. A significant correlation between ▵sPAP and mean ▵PG under exercise was observed (P< 0.001; R2: 0.247). At multivariate regression analysis, mean PG at rest was found to best predict the cardiac response to exercise in terms of peak workloads, although correlation was suboptimal (−0.339; P= 0.015); no significant correlation with resting sPAP (−0.159; P= n.s.) o ▵sPAP under exercise was noted. Figure 3 shows a patient's profile under exercise highlighting the exhaustion of mitral valve reserve capacity.

Figure 3

Example of exhaustion of mitral VRC under exercise stress echocardiography. VCR, valvular reserve capacity.

Figure 3

Example of exhaustion of mitral VRC under exercise stress echocardiography. VCR, valvular reserve capacity.

Management

The results of surgical and percutaneous treatment are summarized in Table 4. Among treatment options, patients underwent mitral valve replacement surgery (32 patients; 70%), surgical repair (commissurotomy/papillary splitting) (12 patients; 26%), and percutaneous balloon valvuloplasty (2 patients; 4%). At 2-year follow up, 84.8% are in NYHA class I.

Table 4

Type of intervention and surgical outcome of study population

Variable n ± SD (%) 
N 46 
Type of cardiac intervention  
 Percutaneous balloon valvuloplasty 2 (4.4) 
 Surgical treatment 44 (95.6) 
Mitral surgery 
 Commissurotomy/papillary splitting 12 (27.3) 
 Mitral valve replacement 32 (72.7) 
Tricuspid surgery 
 Annuloplasty 17 (38.7) 
 Valve replacement 1 (2.3) 
CABG 2 (4.5) 
Surgical ablation of AF 13 (29.5) 
Clinical outcome: follow-up (years) (2.1 ± 0.9)  
 NYHA I 39 (84.8) 
 NYHA II 7 (15.2) 
Variable n ± SD (%) 
N 46 
Type of cardiac intervention  
 Percutaneous balloon valvuloplasty 2 (4.4) 
 Surgical treatment 44 (95.6) 
Mitral surgery 
 Commissurotomy/papillary splitting 12 (27.3) 
 Mitral valve replacement 32 (72.7) 
Tricuspid surgery 
 Annuloplasty 17 (38.7) 
 Valve replacement 1 (2.3) 
CABG 2 (4.5) 
Surgical ablation of AF 13 (29.5) 
Clinical outcome: follow-up (years) (2.1 ± 0.9)  
 NYHA I 39 (84.8) 
 NYHA II 7 (15.2) 

Data are expressed as mean ± SD or number of patients (%).

M, male; F, female; NYHA, New York Heart Association; CABG, coronary artery bypass grafting; AF, atrial fibrillation.

Discussion

The management of patients with MS is currently focused on the degree of severity and discrepancies between symptoms and haemodynamics may frequently affect the clinical decision-making. Stress echocardiography has been proposed to assess the haemodynamic reserve of MS.9–17 In the clinical setting, exercise echocardiography plays an essential role in defining the mitral reserve capacity,21–25 to confirm that asymptomatic patients have satisfactory effort tolerance and no critical symptoms during normal workload18,26–29 and to assess the prognostic value of exercise-induced pulmonary hypertension in mildly symptomatic patients.30,31 The sPAP's trend under stress conditions is known to represent a clinical predictor of the severity of MS22,23: for any given MVA, patients with reduced VRC show a significant increase in pulmonary arterial pressure during exercise. There are important caveats in applying the ACC/AHA guidelines in clinical practice because they are all based on a level C weight of evidence18 and the proposed cut-off values remain arbitrary, not supported by sufficient clinical studies. The current study highlights the clinical impact of apparently unimpressive MS, confirming that dynamic assessment is essential to define the real severity of the disease and its correlation with clinical symptoms.

Dynamic assessment

In our study population, the physiologic effects of HR sensitivity produced exercise-induced pulmonary hypertension and exertional dyspnoea. Of note, the main predictors of cardiac adaptation to exercise were: age (−0.345; P = 0.024), mean mitral PG (0.339; P= 0.023), and sPAP (0.354; P= 0.024); no significant correlation was found between peak workload and MVA (0.313; P = 0.049) or MVA index (0.361; P= n.s.). This finding highlights that the fixed components of MS, defined by valvular calcium score, commissural fusion and fibrosis and by MVA/MVA index, might not necessarily reflect the exclusive determinant of the clinical picture; it also points out the central role of reciprocal influence between cardiac performance indices and mean PG–sPAP under stress conditions as predictors of a greater degree of MS and clinical symptoms. It has to be stressed that any exercise able to accelerate mitral inflow without determining an attendant increase in pulmonary pressure or a systemic hypotension has to be considered a landmark to rule out a ‘critical’ or clinically relevant MS. As a matter of fact, a significant correlation between mitral ▵PG and ▵sPAP was demonstrated.

When valve-related dynamic factors were compared in the multivariate regression analysis, the best predictor of exercise peak workload was mean PG at rest, although correlation was poor (−0.339; P= 0.015); of note, no significant influence by resting sPAP (−0.159; P= n.s.) or ▵sPAP under exercise was seen. Therefore, in the clinical setting of unimpressive MS, mean PG at rest seems a stronger factor compared with sPAP when assessing cardiac response to exercise in terms of exercise peak workloads and increase in SBP and LVEF. Nevertheless, dynamic assessment by exercise testing remains critical, because of the poor predictive accuracy of resting PG.

Mitral valve ‘reserve capacity’

An important finding of the present study was the characterization of exercise-induced exhaustion of mitral reserve capacity related to progressive rheumatic heart disease. The mitral valve reserve allows the stenotic orifice to counterbalance different degrees of dynamic stressors without determining clinical symptoms. There is general agreement that MS is significant for MVA values <1.0 cm2, mean gradients >10 mmHg, or sPAP > 50 mmHg.18,27 Nevertheless, the clinical impact of MS is strongly determined by multifactorial background: planimetry of MVA remains subject to interobserver variability and challenging for inexperienced operators, as well as a significant orifice reduction may still coexist with preserved cardiac adaptation to exercise without clinical symptoms: the increased HR and flow acceleration might not be sufficient to determine a significant backward pressure transmission to right heart and pulmonary hypertension. Because several pathophysiologic factors, such as atrial reserve, PGs across the stenotic orifice and fluctuations of sPAP may affect cardiac adaptation to exercise, it appears very difficult to predict the real clinical cut-off of VRC exhaustion, potentially different for each patient. In our population study, 50% of patients showed an ‘early’ VRC exhaustion at peak workloads ≤50 Watts, whereas the remaining patients developed clinical symptoms or valve-related haemodynamic impairment at peak workloads >50 Watts, revealing a ‘late’ VRC exhaustion. Although MS gradients are well known to be HR-related, our findings did not appear to be influenced by maximum HR attained during exercise; indeed, there was no significant difference in HR between the subgroups with early and late response (82 ± 14 vs. 86 ± 14; P = 0.3), supporting an independent pathophysiological genesis and possibly reflecting the real exhaustion of VRC. Therefore, the question concerning MS assessment is other than numbers, the VRC being influenced by the multifactorial haemodynamic balance between the permanent fixed background and dynamic fluctuations.

Conclusions and study limitations

The current study confirms that the valvular capacity exhaustion should be tested on a dynamic background in MS patients, as no single resting index can predict potential haemodynamic adaptation to exercise. In all our patients with rheumatic MS and limiting symptoms despite unimpressive findings at rest, exercise echocardiography unmasked exhaustion of VRC, providing a rationale for invasive management and allowing attribution of symptoms to the valve defect. The efficacy of this approach is confirmed by the resolution of symptoms following surgical and percutaneous procedures. Stress echocardiography remains a primary tool necessary to define the real haemodynamic clinical impact of MS, always in need of clinical insights to address or postpone surgery according to new generations of ‘rheumatic immigrants’.

Conflict of interest: none declared.

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