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Abstract

Aims

In atrial functional mitral regurgitation (aFMR), a considerable proportion of patients displays a discrepancy between symptoms and echocardiographic findings at rest. Exercise testing plays a substantial role in assessing the haemodynamic relevance of mitral regurgitation (MR) and is recommended by current guidelines. Here, we aimed to assess the prevalence, extent, and prognostic impact of exercise-induced changes in patients with aFMR.

Methods and results

Patients with at least mild MR who underwent handgrip exercise echocardiography at the University Hospital Duesseldorf between January 2019 and September 2021 were enrolled. Patients were followed up for 1 year to assess clinical outcomes. Eighty patients with aFMR were included [median age: 80 (77–83) years; 53.8% female]. The median N-terminal pro-brain natriuretic peptide level was 1756 (1034–3340) ng/L. At rest, half of the patients (53.8%) had mild MR, 20 patients (25.0%) had moderate MR, and 17 patients (21.2%) had severe MR. In approximately every fifth patient (17.5%) with non-severe MR at rest, the MR became severe during exercise. Handgrip exercise led to a reclassification of MR severity in 28 patients (35.0%). At 1-year follow-up, adverse events occurred more often in patients with severe MR at rest (76.5%) and exercise-induced dynamic severe MR (66.7%) than in those with non-severe MR (28.6%; P < 0.001).

Conclusion

Handgrip exercise during echocardiography revealed exercise-induced changes in aFMR in every third patient. These data may have implications for therapeutic decision-making in symptomatic patients with non-severe aFMR at rest.

(Top) Echocardiographic images of a patient with mild atrial functional mitral regurgitation at rest and a marked exercise-induced increase in mitral regurgitation severity during handgrip exercise. (Bottom) The leaflet-to-annulus index is determined by summing the length of the anterior and posterior mitral valve leaflet and dividing it through the mitral annulus diameter. AML, anterior mitral leaflet; AP diameter, anterior–posterior diameter; LAI, leaflet-to-annulus index; PML, posterior mitral leaflet.
Graphical Abstract

(Top) Echocardiographic images of a patient with mild atrial functional mitral regurgitation at rest and a marked exercise-induced increase in mitral regurgitation severity during handgrip exercise. (Bottom) The leaflet-to-annulus index is determined by summing the length of the anterior and posterior mitral valve leaflet and dividing it through the mitral annulus diameter. AML, anterior mitral leaflet; AP diameter, anterior–posterior diameter; LAI, leaflet-to-annulus index; PML, posterior mitral leaflet.

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atrial functional mitral regurgitation, dynamic mitral regurgitation, exercise testing, transcatheter edge-to-edge repair

See the editorial comment for this article ‘Functional mitral regurgitation, a dynamic disease: lobbying for greater adoption of handgrip echocardiography!', by E. Donal et al., https://doi.org/10.1093/ehjci/jeae007.

Introduction

In recent years, ‘atrial functional mitral regurgitation’ (aFMR) has become an increasingly recognized entity, which is associated with heart failure with preserved ejection fraction (HFpEF), and atrial fibrillation.1 In aFMR, the left ventricular (LV) size and systolic function are typically normal, while isolated mitral annular dilatation and inadequate leaflet adaption are considered to be the culprits.1–3 In the clinical setting, a significant proportion of patients presents with a discrepancy between symptoms and echocardiographic findings at rest. This may occur when mitral regurgitation (MR) may be mild or moderate at rest and severe during exercise. Exercise-induced dynamic MR is reportedly seen in 20–50% of patients with primary or secondary aetiology.4–6 However, the prevalence, pathophysiological mechanisms, and prognostic relevance of dynamic aFMR have yet to be studied.2,7 The current European Society of Cardiology (ESC) and American (ACC/AHA) Society of Cardiology guidelines recommend exercise echocardiography in patients with MR to unmask symptoms in asymptomatic patients, identify the origin of dyspnoea, and gain additional prognostic information.8,9 Currently, no recommendations exist concerning exercise modalities. Bicycle exercise may not always be feasible for older patients with comorbid conditions. Isometric handgrip exercise, which can be easily performed during echocardiography, may serve as an alternative.10–12

We hypothesize that handgrip exercise during echocardiography may unmask dynamic MR in a significant proportion of patients with aFMR, which could potentially alter therapeutic decision-making. Thus, we aimed to assess the prevalence, predictors, and prognostic impact of exercise-induced changes in aFMR during isometric handgrip exercise.

Methods

Study population

A total of 447 consecutive patients who underwent exercise echocardiography at the University Hospital Duesseldorf, Germany, between January 2019 and September 2021 were screened. Of those, 80 patients with aFMR were included in the current study. Echocardiography at rest and during handgrip exercise was performed according to a standardized protocol in all patients. Exercise echocardiography was performed in patients with heart failure (HF) symptoms and at least mild MR, particularly when there was a discrepancy between the symptoms and the echocardiographic findings at rest. The study was approved by the ethics committee of Heinrich-Heine University Duesseldorf and executed in accordance with the Declaration of Helsinki.

Echocardiographic examination

Echocardiographic examinations were conducted by using a Vivid E90 (General Electrics, Chicago, IL, USA) and iE33 (Philips, Amsterdam, Netherlands). All echocardiographic examination data were stored on a workstation for offline analysis (IntelliSpace Cardiovascular Version 3.2; Philips). LV volumes and LV ejection fraction (LVEF) were measured using Simpson’s biplane method. Systolic pulmonary artery pressure (SPAP) was measured from the tricuspid regurgitation (TR) jet. Fractional area change (FAC) and tricuspid annulus plane systolic excursion (TAPSE) were used according to current recommendations for the assessment of right ventricular (RV) function. MR assessment was performed according to current ESC guidelines.9 MR was classified as aFMR in patients with isolated atrial fibrillation despite normal LV function (LVEF ≥50%) and no degenerative change in the mitral valve (MV), and if there was no sign of ischaemic or any other cardiomyopathy, that could explain the presence of MR. Furthermore, these patients showed normal leaflet motion (Carpentier Class I) and a left atrial volume index (LAVi) ≥30 mL/m2.1,2,13,14

An integrative approach using semi-quantitative and quantitative parameters was used to analyse the MR severity, which was classified as mild, moderate, or severe. The cut-offs for severe MR were as follows: effective regurgitant orifice area (EROA) ≥40 mm2 and regurgitation volume (RVol) ≥60 mL. Under low-flow conditions (e.g. effective LV stroke volume index <35 mL/m2 or cardiac index <2.0 L/min/m2), lower cut-offs were used for the definition of severe MR (EROA ≥30 mm2 and/or RVol ≥45 mL).9,15,16 For semi-quantitative assessment, the vena contracta (VC) width was measured in the apical four-chamber view. In the case of atrial fibrillation, MR severity at rest and during exercise was assessed at least in three to five cardiac cycles in each patient. Interobserver variability for quantitative measures of MR severity are given in Supplementary data online, Figure S1. The mitral annulus was analysed at end-diastole and mid-systole in the parasternal long-axis view and apical four-chamber view and was then averaged. The anterior mitral leaflet (AML) and posterior mitral leaflet (PML) lengths were measured at mid-systole in the parasternal long-axis view. The leaflet-to-annulus index (LAI) was determined by adding the AML and PML lengths and dividing it by the mitral annulus diameter (Graphical Abstract).

Isometric exercise protocol

Following the comprehensive echocardiographic examination at rest, handgrip exercise testing was performed according to a standardized protocol using a handgrip dynamometer (Jamar® Hydraulic Hand Dynamometer; Sammons Preston Inc., Warrenville, IL, USA). The patient lay on their left side at rest and during exercise. After recording blood pressure and heart rate at rest, the patient was asked to push the dynamometer with one hand with maximum effort for a short period to assess the maximal handgrip strength. Subsequently, the handgrip exercise was performed with one hand at 30% maximal force for 3 min. Dedicated medical staff observed the grip strength. Echocardiographic images were obtained after 2 min of exercise until peak exercise. Blood pressure and heart rate were recorded during peak exercise. Medical therapy was continued for the exercise test.

Follow-up

The clinical course was monitored by follow-up examinations and phone calls to the referring cardiologists, primary physicians, or the patients themselves. We assessed a composite of all-cause mortality, HF-associated hospitalizations, MV surgery, and transcatheter edge-to-edge repair (TEER) during follow-up as the combined endpoint.

Statistical analysis

The normality distribution of continuous variables was assessed using the Kolmogorov–Smirnov test. The categorical variables were compared between the two groups using the χ2 test (or Fisher’s exact test). Differences in the continuous variables were compared between the two groups using a two-tailed paired t-test. To assess differences among the three groups, analysis of variance or the Kruskal–Wallis test was performed for continuous variables. Categorical variables are reported as percentages, and continuous variables are reported as medians with inter-quartile ranges (IQRs) or means ± standard deviations. To examine the incremental predictive power of exercise echocardiography, changes in the χ2 values were analysed using the likelihood ratio test. Harrell’s c-index was used as a measure of discrimination to predict MV surgery/TEER during follow-up. The Kaplan–Meier analysis was used to evaluate the event-free rate. For all analyses, P-values <0.05 were considered to be statistically significant. All analyses were performed using Sigma Plot (version 11.0; Systat Software Ltd. Inpixon GmbH, Duesseldorf, Germany) and GraphPad Prism (version 7; GraphPad Software, San Diego, CA, USA).

Results

Study population

We screened 541 patients who had undergone echocardiography at rest and during handgrip exercise. After excluding 94 patients [poor image quality (n = 50), non-feasible handgrip exercise (n = 22), severe aortic stenosis (n = 2), severe mitral stenosis (n = 1), and previous MV repair (n = 19)], the study cohort included 447 patients. Of these, 80 patients (17.9%) presented with aFMR, irrespective of the degree of MR at rest. A consort diagram is shown in Figure 1. In this aFMR cohort, the median age was 80 (IQR 77–83) years, and 53.8% of the patients were females. All patients had pre-existing atrial fibrillation. The median NT-pro brain natriuretic peptide (NT-proBNP) level was 1756 (IQR 1034–3340) ng/L. Most of the patients presented with advanced HF symptoms (Table 1). There was no difference in the New York Heart Association (NYHA) functional class among patients with mild, moderate, and severe MR at rest (Table 1). Three of four patients (75%) had an H2FPEF score ≥6, demonstrating a probability of HFpEF >90%. Patient characteristics are provided in Table 1.

Consort diagram. DMR, degenerative MR; VFMR, ventricular functional MR.
Figure 1

Consort diagram. DMR, degenerative MR; VFMR, ventricular functional MR.

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Table 1
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Patient characteristics

VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Demographics
 Sex female, n (%)43 (53.8)30 (58.8)6 (50.0)7 (41.2)0.432
 BMI (kg/m2)25.5 (23.0–29.3)27.0 (23.0–30.1)23.9 (21.3–25.7)26.2 (23.8–28.2)0.134
 Age (years)80 (77–83)80 (77–84)81 (78–84)80 (76–81)0.748
 Diabetes mellitus, n (%)21 (26.6)17 (34.0)1 (8.3)3 (17.7)0.138
 Hypertension, n (%)71 (88.8)46 (90.2)10 (83.3)15 (88.2)0.793
 Smoking, n (%)12 (15.2)8 (15.7)1 (8.3)3 (17.7)0.767
 CAD, n (%)57 (71.3)37 (72.6)8 (66.7)12 (70.6)0.919
 NYHA class0.328
  NYHA 1, n (%)7 (8.8)7 (13.7)0 (0.0)0 (0.0)
  NYHA 2, n (%)29 (36.3)18 (35.3)4 (33.3)7 (41.2)
  NYHA 3, n (%)44 (55.0)26 (51.0)8 (66.7)10 (58.8)
 Atrial fibrillation, n (%)80 (100.0)51 (100.0)12 (100.0)17 (100.0)>0.999
 H2FPEF score6.0 (5.3–6.0)6.0 (5.0–7.0)6.0 (6.0–6.0)6.0 (5.5–6.0)0.595
H2FPEF score ≥6 points60 (75.0)37 (72.5)10 (83.3)13 (76.5)0.731
Medication
 β-Blocker, n (%)67 (85.9)44 (86.3)10 (83.3)13 (76.5)0.637
 ACE-I/AT-1 blocker, n (%)63 (78.8)42 (82.4)8 (66.7)13 (76.5)0.474
 m antagonist, n (%)15 (18.8)8 (15.7)2 (16.7)5 (29.4)0.446
 Sacubitril/valsartan, n (%)4 (5.0)3 (5.9)0 (0.0)1 (6.3)0.690
 Diuretic, n (%)72 (90.0)47 (92.2)10 (83.3)15 (94.1)0.242
Laboratory markers
 Creatinine (mg/dL)1.1 (0.9–1.5)1.1 (0.9–1.6)1.1 (0.9–1.4)1.2 (0.9–1.7)0.636
 Haemoglobin (mg/dL)12.7 (11.7–14.0)12.4 (10.5–14.0)13.0 (11.9–14.1)12.6 (9.5–14.2)0.497
 NT-proBNP (ng/mL)1756 (1034–3340)1882 (994–3074)1620 (1020–2608)1768 (1175–3973)0.638
VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Demographics
 Sex female, n (%)43 (53.8)30 (58.8)6 (50.0)7 (41.2)0.432
 BMI (kg/m2)25.5 (23.0–29.3)27.0 (23.0–30.1)23.9 (21.3–25.7)26.2 (23.8–28.2)0.134
 Age (years)80 (77–83)80 (77–84)81 (78–84)80 (76–81)0.748
 Diabetes mellitus, n (%)21 (26.6)17 (34.0)1 (8.3)3 (17.7)0.138
 Hypertension, n (%)71 (88.8)46 (90.2)10 (83.3)15 (88.2)0.793
 Smoking, n (%)12 (15.2)8 (15.7)1 (8.3)3 (17.7)0.767
 CAD, n (%)57 (71.3)37 (72.6)8 (66.7)12 (70.6)0.919
 NYHA class0.328
  NYHA 1, n (%)7 (8.8)7 (13.7)0 (0.0)0 (0.0)
  NYHA 2, n (%)29 (36.3)18 (35.3)4 (33.3)7 (41.2)
  NYHA 3, n (%)44 (55.0)26 (51.0)8 (66.7)10 (58.8)
 Atrial fibrillation, n (%)80 (100.0)51 (100.0)12 (100.0)17 (100.0)>0.999
 H2FPEF score6.0 (5.3–6.0)6.0 (5.0–7.0)6.0 (6.0–6.0)6.0 (5.5–6.0)0.595
H2FPEF score ≥6 points60 (75.0)37 (72.5)10 (83.3)13 (76.5)0.731
Medication
 β-Blocker, n (%)67 (85.9)44 (86.3)10 (83.3)13 (76.5)0.637
 ACE-I/AT-1 blocker, n (%)63 (78.8)42 (82.4)8 (66.7)13 (76.5)0.474
 m antagonist, n (%)15 (18.8)8 (15.7)2 (16.7)5 (29.4)0.446
 Sacubitril/valsartan, n (%)4 (5.0)3 (5.9)0 (0.0)1 (6.3)0.690
 Diuretic, n (%)72 (90.0)47 (92.2)10 (83.3)15 (94.1)0.242
Laboratory markers
 Creatinine (mg/dL)1.1 (0.9–1.5)1.1 (0.9–1.6)1.1 (0.9–1.4)1.2 (0.9–1.7)0.636
 Haemoglobin (mg/dL)12.7 (11.7–14.0)12.4 (10.5–14.0)13.0 (11.9–14.1)12.6 (9.5–14.2)0.497
 NT-proBNP (ng/mL)1756 (1034–3340)1882 (994–3074)1620 (1020–2608)1768 (1175–3973)0.638

BMI, body mass index; CAD, coronary artery disease.

Table 1
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Patient characteristics

VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Demographics
 Sex female, n (%)43 (53.8)30 (58.8)6 (50.0)7 (41.2)0.432
 BMI (kg/m2)25.5 (23.0–29.3)27.0 (23.0–30.1)23.9 (21.3–25.7)26.2 (23.8–28.2)0.134
 Age (years)80 (77–83)80 (77–84)81 (78–84)80 (76–81)0.748
 Diabetes mellitus, n (%)21 (26.6)17 (34.0)1 (8.3)3 (17.7)0.138
 Hypertension, n (%)71 (88.8)46 (90.2)10 (83.3)15 (88.2)0.793
 Smoking, n (%)12 (15.2)8 (15.7)1 (8.3)3 (17.7)0.767
 CAD, n (%)57 (71.3)37 (72.6)8 (66.7)12 (70.6)0.919
 NYHA class0.328
  NYHA 1, n (%)7 (8.8)7 (13.7)0 (0.0)0 (0.0)
  NYHA 2, n (%)29 (36.3)18 (35.3)4 (33.3)7 (41.2)
  NYHA 3, n (%)44 (55.0)26 (51.0)8 (66.7)10 (58.8)
 Atrial fibrillation, n (%)80 (100.0)51 (100.0)12 (100.0)17 (100.0)>0.999
 H2FPEF score6.0 (5.3–6.0)6.0 (5.0–7.0)6.0 (6.0–6.0)6.0 (5.5–6.0)0.595
H2FPEF score ≥6 points60 (75.0)37 (72.5)10 (83.3)13 (76.5)0.731
Medication
 β-Blocker, n (%)67 (85.9)44 (86.3)10 (83.3)13 (76.5)0.637
 ACE-I/AT-1 blocker, n (%)63 (78.8)42 (82.4)8 (66.7)13 (76.5)0.474
 m antagonist, n (%)15 (18.8)8 (15.7)2 (16.7)5 (29.4)0.446
 Sacubitril/valsartan, n (%)4 (5.0)3 (5.9)0 (0.0)1 (6.3)0.690
 Diuretic, n (%)72 (90.0)47 (92.2)10 (83.3)15 (94.1)0.242
Laboratory markers
 Creatinine (mg/dL)1.1 (0.9–1.5)1.1 (0.9–1.6)1.1 (0.9–1.4)1.2 (0.9–1.7)0.636
 Haemoglobin (mg/dL)12.7 (11.7–14.0)12.4 (10.5–14.0)13.0 (11.9–14.1)12.6 (9.5–14.2)0.497
 NT-proBNP (ng/mL)1756 (1034–3340)1882 (994–3074)1620 (1020–2608)1768 (1175–3973)0.638
VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Demographics
 Sex female, n (%)43 (53.8)30 (58.8)6 (50.0)7 (41.2)0.432
 BMI (kg/m2)25.5 (23.0–29.3)27.0 (23.0–30.1)23.9 (21.3–25.7)26.2 (23.8–28.2)0.134
 Age (years)80 (77–83)80 (77–84)81 (78–84)80 (76–81)0.748
 Diabetes mellitus, n (%)21 (26.6)17 (34.0)1 (8.3)3 (17.7)0.138
 Hypertension, n (%)71 (88.8)46 (90.2)10 (83.3)15 (88.2)0.793
 Smoking, n (%)12 (15.2)8 (15.7)1 (8.3)3 (17.7)0.767
 CAD, n (%)57 (71.3)37 (72.6)8 (66.7)12 (70.6)0.919
 NYHA class0.328
  NYHA 1, n (%)7 (8.8)7 (13.7)0 (0.0)0 (0.0)
  NYHA 2, n (%)29 (36.3)18 (35.3)4 (33.3)7 (41.2)
  NYHA 3, n (%)44 (55.0)26 (51.0)8 (66.7)10 (58.8)
 Atrial fibrillation, n (%)80 (100.0)51 (100.0)12 (100.0)17 (100.0)>0.999
 H2FPEF score6.0 (5.3–6.0)6.0 (5.0–7.0)6.0 (6.0–6.0)6.0 (5.5–6.0)0.595
H2FPEF score ≥6 points60 (75.0)37 (72.5)10 (83.3)13 (76.5)0.731
Medication
 β-Blocker, n (%)67 (85.9)44 (86.3)10 (83.3)13 (76.5)0.637
 ACE-I/AT-1 blocker, n (%)63 (78.8)42 (82.4)8 (66.7)13 (76.5)0.474
 m antagonist, n (%)15 (18.8)8 (15.7)2 (16.7)5 (29.4)0.446
 Sacubitril/valsartan, n (%)4 (5.0)3 (5.9)0 (0.0)1 (6.3)0.690
 Diuretic, n (%)72 (90.0)47 (92.2)10 (83.3)15 (94.1)0.242
Laboratory markers
 Creatinine (mg/dL)1.1 (0.9–1.5)1.1 (0.9–1.6)1.1 (0.9–1.4)1.2 (0.9–1.7)0.636
 Haemoglobin (mg/dL)12.7 (11.7–14.0)12.4 (10.5–14.0)13.0 (11.9–14.1)12.6 (9.5–14.2)0.497
 NT-proBNP (ng/mL)1756 (1034–3340)1882 (994–3074)1620 (1020–2608)1768 (1175–3973)0.638

BMI, body mass index; CAD, coronary artery disease.

Echocardiographic parameters at rest and during exercise

At rest, half of the patients had mild MR (53.8%), 20 patients (25.0%) had moderate MR, and 17 patients (21.2%) had severe MR. LV function was preserved (LVEF ≥50%) in all patients; the mean LVEF was 58 ± 8% (Table 2). LV volumes were in the normal range [LV end-diastolic volume index (LVEDVi), 54 ± 17 mL/m2 and LV end-systolic volume index (LVESVi), 23 ± 9 mL/m2], while the left atria were severely dilated (LAVi, 61 ± 20 mL/m2; Table 2). Approximately half of the patients (46.3%) presented with concomitant moderate or severe TR, and the estimated SPAP (43 ± 13 mmHg) was elevated in most patients (Table 2).

Table 2
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Echocardiographic parameters at rest

VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Heart rate (bpm)67 ± 1569 ± 1665 ± 863 ± 120.350
Systolic BP (mmHg)126 ± 17126 ± 20131 ± 15121 ± 170.383
Diastolic BP (mmHg)69 ± 1370 ± 1766 ± 968 ± 130.737
RPP (mmHg × min−1)8391 ± 20938549 ± 20558462 ± 13257532 ± 12880.140
LAVi (mL/m2)61 ± 2059 ± 1959 ± 1972 ± 240.055
LVEDVi (mL/m2)54 ± 1753 ± 1858 ± 1957 ± 120.540
LVESVi (mL/m2)23 ± 923 ± 1025 ± 924 ± 70.789
LVSVi (mL/m2)31 ± 931 ± 934 ± 1032 ± 80.420
LVEF (%)58 ± 858 ± 759 ± 1058 ± 70.892
Forward LVSVi (mL/m2)37 ± 1237 ± 1539 ± 833 ± 70.495
Cardiac index (L/min/m2)2.3 ± 0.82.4 ± 0.92.5 ± 0.72.1 ± 0.60.387
RAVi (mL/m2)50 ± 2646 ± 2544 ± 1161 ± 340.128
RVEDDi (mm/m2)22 ± 521 ± 422 ± 424 ± 60.097
TAPSE (mm)19 ± 519 ± 521 ± 518 ± 50.266
FAC (%)42 ± 942 ± 937 ± 744 ± 100.232
SPAP (mmHg)43 ± 1342 ± 1446 ± 1341 ± 110.588
MR<0.001
 Mild, n (%)43 (53.8)40 (78.4)3 (25.0)0 (0.0)
 Moderate, n (%)20 (25.0)11 (21.6)9 (75.0)0 (0.0)
 Severe, n (%)17 (21.2)0 (0.0)0 (0.0)17 (100.0)
MR VC (mm)5.0 ± 1.44.6 ± 1.24.7 ± 1.16.6 ± 1.0<0.001a,b
MR EROA (cm2)0.18 ± 0.60.15 ± 0.040.18 ± 0.030.28 ± 0.05<0.001a,b,c
MR vol (mL)30 ± 1026 ± 736 ± 847 ± 11<0.001a,b,c
Annulus systole (mm)36 ± 434 ± 436 ± 439 ± 4<0.001a
Annulus diastole (mm)38 ± 433 ± 338 ± 441 ± 3<0.001a
Annulus fractional change (%)5.6 ± 6.06.4 ± 5.96.2 ± 3.63.8 ± 5.00.226
AML length (mm)27 ± 527 ± 527 ± 528 ± 30.532
PML length (mm)15 ± 315 ± 313 ± 316 ± 30.129
LAI1.12 ± 0.21.17 ± 0.181.05 ± 0.151.08 ± 0.10.039c
Symmetric tethering, n (%)66 (82.5)42 (82.4)10 (83.3)14 (82.4)0.997
AML angle (°)158.8 ± 7.7158.9 ± 8.0160.0 ± 6.7157.5 ± 7.70.677
PML angle (°)154.1 ± 8.7154.0 ± 8.5154.0 ± 10.2154.4 ± 8.50.985
TR grade (n)0.767
 No TR, n (%)8 (10.0)5 (10.0)1 (7.7)2 (11.8)
 Mild, n (%)34 (42.5)22 (43.1)5 (46.2)7 (35.3)
 Moderate, n (%)21 (26.3)13 (25.5)5 (30.8)3 (29.4)
 Severe, n (%)15 (18.8)9 (18.0)1 (15.4)5 (30.8)
VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Heart rate (bpm)67 ± 1569 ± 1665 ± 863 ± 120.350
Systolic BP (mmHg)126 ± 17126 ± 20131 ± 15121 ± 170.383
Diastolic BP (mmHg)69 ± 1370 ± 1766 ± 968 ± 130.737
RPP (mmHg × min−1)8391 ± 20938549 ± 20558462 ± 13257532 ± 12880.140
LAVi (mL/m2)61 ± 2059 ± 1959 ± 1972 ± 240.055
LVEDVi (mL/m2)54 ± 1753 ± 1858 ± 1957 ± 120.540
LVESVi (mL/m2)23 ± 923 ± 1025 ± 924 ± 70.789
LVSVi (mL/m2)31 ± 931 ± 934 ± 1032 ± 80.420
LVEF (%)58 ± 858 ± 759 ± 1058 ± 70.892
Forward LVSVi (mL/m2)37 ± 1237 ± 1539 ± 833 ± 70.495
Cardiac index (L/min/m2)2.3 ± 0.82.4 ± 0.92.5 ± 0.72.1 ± 0.60.387
RAVi (mL/m2)50 ± 2646 ± 2544 ± 1161 ± 340.128
RVEDDi (mm/m2)22 ± 521 ± 422 ± 424 ± 60.097
TAPSE (mm)19 ± 519 ± 521 ± 518 ± 50.266
FAC (%)42 ± 942 ± 937 ± 744 ± 100.232
SPAP (mmHg)43 ± 1342 ± 1446 ± 1341 ± 110.588
MR<0.001
 Mild, n (%)43 (53.8)40 (78.4)3 (25.0)0 (0.0)
 Moderate, n (%)20 (25.0)11 (21.6)9 (75.0)0 (0.0)
 Severe, n (%)17 (21.2)0 (0.0)0 (0.0)17 (100.0)
MR VC (mm)5.0 ± 1.44.6 ± 1.24.7 ± 1.16.6 ± 1.0<0.001a,b
MR EROA (cm2)0.18 ± 0.60.15 ± 0.040.18 ± 0.030.28 ± 0.05<0.001a,b,c
MR vol (mL)30 ± 1026 ± 736 ± 847 ± 11<0.001a,b,c
Annulus systole (mm)36 ± 434 ± 436 ± 439 ± 4<0.001a
Annulus diastole (mm)38 ± 433 ± 338 ± 441 ± 3<0.001a
Annulus fractional change (%)5.6 ± 6.06.4 ± 5.96.2 ± 3.63.8 ± 5.00.226
AML length (mm)27 ± 527 ± 527 ± 528 ± 30.532
PML length (mm)15 ± 315 ± 313 ± 316 ± 30.129
LAI1.12 ± 0.21.17 ± 0.181.05 ± 0.151.08 ± 0.10.039c
Symmetric tethering, n (%)66 (82.5)42 (82.4)10 (83.3)14 (82.4)0.997
AML angle (°)158.8 ± 7.7158.9 ± 8.0160.0 ± 6.7157.5 ± 7.70.677
PML angle (°)154.1 ± 8.7154.0 ± 8.5154.0 ± 10.2154.4 ± 8.50.985
TR grade (n)0.767
 No TR, n (%)8 (10.0)5 (10.0)1 (7.7)2 (11.8)
 Mild, n (%)34 (42.5)22 (43.1)5 (46.2)7 (35.3)
 Moderate, n (%)21 (26.3)13 (25.5)5 (30.8)3 (29.4)
 Severe, n (%)15 (18.8)9 (18.0)1 (15.4)5 (30.8)

BP, blood pressure; RPP, rate pressure product; LVSVi, LV stroke volume index; RAVi, right atrial volume index; RVEDDi, RV end-diastolic diameter index; vol, volume; .

aNon-severe MR vs. severe MR at rest.

bDynamic severe MR vs. severe MR at rest.

cNon-severe MR vs. dynamic severe MR.

Table 2
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Echocardiographic parameters at rest

VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Heart rate (bpm)67 ± 1569 ± 1665 ± 863 ± 120.350
Systolic BP (mmHg)126 ± 17126 ± 20131 ± 15121 ± 170.383
Diastolic BP (mmHg)69 ± 1370 ± 1766 ± 968 ± 130.737
RPP (mmHg × min−1)8391 ± 20938549 ± 20558462 ± 13257532 ± 12880.140
LAVi (mL/m2)61 ± 2059 ± 1959 ± 1972 ± 240.055
LVEDVi (mL/m2)54 ± 1753 ± 1858 ± 1957 ± 120.540
LVESVi (mL/m2)23 ± 923 ± 1025 ± 924 ± 70.789
LVSVi (mL/m2)31 ± 931 ± 934 ± 1032 ± 80.420
LVEF (%)58 ± 858 ± 759 ± 1058 ± 70.892
Forward LVSVi (mL/m2)37 ± 1237 ± 1539 ± 833 ± 70.495
Cardiac index (L/min/m2)2.3 ± 0.82.4 ± 0.92.5 ± 0.72.1 ± 0.60.387
RAVi (mL/m2)50 ± 2646 ± 2544 ± 1161 ± 340.128
RVEDDi (mm/m2)22 ± 521 ± 422 ± 424 ± 60.097
TAPSE (mm)19 ± 519 ± 521 ± 518 ± 50.266
FAC (%)42 ± 942 ± 937 ± 744 ± 100.232
SPAP (mmHg)43 ± 1342 ± 1446 ± 1341 ± 110.588
MR<0.001
 Mild, n (%)43 (53.8)40 (78.4)3 (25.0)0 (0.0)
 Moderate, n (%)20 (25.0)11 (21.6)9 (75.0)0 (0.0)
 Severe, n (%)17 (21.2)0 (0.0)0 (0.0)17 (100.0)
MR VC (mm)5.0 ± 1.44.6 ± 1.24.7 ± 1.16.6 ± 1.0<0.001a,b
MR EROA (cm2)0.18 ± 0.60.15 ± 0.040.18 ± 0.030.28 ± 0.05<0.001a,b,c
MR vol (mL)30 ± 1026 ± 736 ± 847 ± 11<0.001a,b,c
Annulus systole (mm)36 ± 434 ± 436 ± 439 ± 4<0.001a
Annulus diastole (mm)38 ± 433 ± 338 ± 441 ± 3<0.001a
Annulus fractional change (%)5.6 ± 6.06.4 ± 5.96.2 ± 3.63.8 ± 5.00.226
AML length (mm)27 ± 527 ± 527 ± 528 ± 30.532
PML length (mm)15 ± 315 ± 313 ± 316 ± 30.129
LAI1.12 ± 0.21.17 ± 0.181.05 ± 0.151.08 ± 0.10.039c
Symmetric tethering, n (%)66 (82.5)42 (82.4)10 (83.3)14 (82.4)0.997
AML angle (°)158.8 ± 7.7158.9 ± 8.0160.0 ± 6.7157.5 ± 7.70.677
PML angle (°)154.1 ± 8.7154.0 ± 8.5154.0 ± 10.2154.4 ± 8.50.985
TR grade (n)0.767
 No TR, n (%)8 (10.0)5 (10.0)1 (7.7)2 (11.8)
 Mild, n (%)34 (42.5)22 (43.1)5 (46.2)7 (35.3)
 Moderate, n (%)21 (26.3)13 (25.5)5 (30.8)3 (29.4)
 Severe, n (%)15 (18.8)9 (18.0)1 (15.4)5 (30.8)
VariableAll patients (N = 80)Non-severe MR (N = 51)Dynamic severe MR (N = 12)Severe MR at rest (N = 17)P-value
Heart rate (bpm)67 ± 1569 ± 1665 ± 863 ± 120.350
Systolic BP (mmHg)126 ± 17126 ± 20131 ± 15121 ± 170.383
Diastolic BP (mmHg)69 ± 1370 ± 1766 ± 968 ± 130.737
RPP (mmHg × min−1)8391 ± 20938549 ± 20558462 ± 13257532 ± 12880.140
LAVi (mL/m2)61 ± 2059 ± 1959 ± 1972 ± 240.055
LVEDVi (mL/m2)54 ± 1753 ± 1858 ± 1957 ± 120.540
LVESVi (mL/m2)23 ± 923 ± 1025 ± 924 ± 70.789
LVSVi (mL/m2)31 ± 931 ± 934 ± 1032 ± 80.420
LVEF (%)58 ± 858 ± 759 ± 1058 ± 70.892
Forward LVSVi (mL/m2)37 ± 1237 ± 1539 ± 833 ± 70.495
Cardiac index (L/min/m2)2.3 ± 0.82.4 ± 0.92.5 ± 0.72.1 ± 0.60.387
RAVi (mL/m2)50 ± 2646 ± 2544 ± 1161 ± 340.128
RVEDDi (mm/m2)22 ± 521 ± 422 ± 424 ± 60.097
TAPSE (mm)19 ± 519 ± 521 ± 518 ± 50.266
FAC (%)42 ± 942 ± 937 ± 744 ± 100.232
SPAP (mmHg)43 ± 1342 ± 1446 ± 1341 ± 110.588
MR<0.001
 Mild, n (%)43 (53.8)40 (78.4)3 (25.0)0 (0.0)
 Moderate, n (%)20 (25.0)11 (21.6)9 (75.0)0 (0.0)
 Severe, n (%)17 (21.2)0 (0.0)0 (0.0)17 (100.0)
MR VC (mm)5.0 ± 1.44.6 ± 1.24.7 ± 1.16.6 ± 1.0<0.001a,b
MR EROA (cm2)0.18 ± 0.60.15 ± 0.040.18 ± 0.030.28 ± 0.05<0.001a,b,c
MR vol (mL)30 ± 1026 ± 736 ± 847 ± 11<0.001a,b,c
Annulus systole (mm)36 ± 434 ± 436 ± 439 ± 4<0.001a
Annulus diastole (mm)38 ± 433 ± 338 ± 441 ± 3<0.001a
Annulus fractional change (%)5.6 ± 6.06.4 ± 5.96.2 ± 3.63.8 ± 5.00.226
AML length (mm)27 ± 527 ± 527 ± 528 ± 30.532
PML length (mm)15 ± 315 ± 313 ± 316 ± 30.129
LAI1.12 ± 0.21.17 ± 0.181.05 ± 0.151.08 ± 0.10.039c
Symmetric tethering, n (%)66 (82.5)42 (82.4)10 (83.3)14 (82.4)0.997
AML angle (°)158.8 ± 7.7158.9 ± 8.0160.0 ± 6.7157.5 ± 7.70.677
PML angle (°)154.1 ± 8.7154.0 ± 8.5154.0 ± 10.2154.4 ± 8.50.985
TR grade (n)0.767
 No TR, n (%)8 (10.0)5 (10.0)1 (7.7)2 (11.8)
 Mild, n (%)34 (42.5)22 (43.1)5 (46.2)7 (35.3)
 Moderate, n (%)21 (26.3)13 (25.5)5 (30.8)3 (29.4)
 Severe, n (%)15 (18.8)9 (18.0)1 (15.4)5 (30.8)

BP, blood pressure; RPP, rate pressure product; LVSVi, LV stroke volume index; RAVi, right atrial volume index; RVEDDi, RV end-diastolic diameter index; vol, volume; .

aNon-severe MR vs. severe MR at rest.

bDynamic severe MR vs. severe MR at rest.

cNon-severe MR vs. dynamic severe MR.

Handgrip exercise provoked a significant haemodynamic response: heart rate, systolic blood pressure, diastolic blood pressure, and rate pressure product increased by 13 ± 15 bpm, 14 ± 17 mmHg, 4 ± 15 mmHg, 2850 ± 2926 mmHg × bpm, respectively (all P < 0.05; Table 3). MR severity increased by 1 grade in 17 patients (21.3%) and by 2 grades in 3 patients (3.8%). Seven patients (8.8%) showed a decrease in MR severity during the handgrip exercise (Figure 2). Eleven patients (17.5%) with non-severe MR at rest developed severe MR during exercise. Handgrip exercise led to a reclassification of MR severity in 28 patients (35.0%). This was accompanied by a more advanced increase in LVESVi (+6 ± 12 mL; P = 0.008) than in LVEDVi (+4 ± 15 mL; P = 0.147) and led to a subsequent decrease in LV systolic function (LVEF −6 ± 12%; P < 0.001; Table 3). SPAP also increased from rest to exercise (+8 ± 10 mmHg; P < 0.001); however, there was no effect on RV volumes or function.

Distribution of MR severity at rest and during handgrip exercise.
Figure 2

Distribution of MR severity at rest and during handgrip exercise.

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Table 3
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Exercise-induced changes in echocardiographic parameters according to the presence of dynamic MR

VariableAll patients (n = 80)Non-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)P-value
Δ Heart rate (bpm)13 ± 1511 ± 1414 ± 1720 ± 170.134
Δ Systolic BP (mmHg)14 ± 1715 ± 1916 ± 1013 ± 140.876
Δ Diastolic BP (mmHg)4 ± 154 ± 165 ± 107 ± 140.759
Δ RPP (mmHg × min−1)2850 ± 26282667 ± 25803079 ± 32883522 ± 22910.503
Δ LAVi (mL/m2)0 ± 200 ± 182 ± 14−3 ± 290.815
Δ LVEDVi (mL/m2)5 ± 156 ± 166 ± 103 ± 150.810
Δ LVESVi (mL/m2)6 ± 127 ± 145 ± 65 ± 80.664
Δ LVSVi (mL/m2)−1 ± 14−2 ± 141 ± 11−1 ± 110.852
Δ LVEF (%)−6 ± 12−7 ± 12−3 ± 11−5 ± 110.489
Δ Forward LVSVi (mL/m2)−3 ± 9−4 ± 10−2 ± 9−2 ± 50.617
Δ Cardiac index (mL/min/m2)0.2 ± 0.90.1 ± 0.80.4 ± 1.20.5 ± 0.60.442
Δ RAVi (mL/m2)0 ± 171 ± 155 ± 7−6 ± 240.183
Δ RVEDDi (mm/m2)1 ± 41 ± 42 ± 4−1 ± 40.099
Δ TAPSE (mm)0 ± 3−1 ± 31 ± 30 ± 30.676
Δ FAC (%)−2 ± 10−1 ± 10−4 ± 13−5 ± 110.563
Δ SPAP (mmHg)8 ± 109 ± 125 ± 77 ± 60.418
Δ MR VC (mm)0.7 ± 1.20.5 ± 1.02.0 ± 1.30.3 ± 1.4<0.001a,b
Δ MR EROA (mm2)0.3 ± 0.050.02 ± 0.040.07 ± 0.040.03 ± 0.070.025a
Δ MR vol (mL)7 ± 104 ± 815 ± 108 ± 140.005a
Δ Annulus systole (mm)1 ± 31 ± 40 ± 30 ± 30.739
Δ Annulus diastole (mm)1 ± 21 ± 30 ± 21 ± 30.517
VariableAll patients (n = 80)Non-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)P-value
Δ Heart rate (bpm)13 ± 1511 ± 1414 ± 1720 ± 170.134
Δ Systolic BP (mmHg)14 ± 1715 ± 1916 ± 1013 ± 140.876
Δ Diastolic BP (mmHg)4 ± 154 ± 165 ± 107 ± 140.759
Δ RPP (mmHg × min−1)2850 ± 26282667 ± 25803079 ± 32883522 ± 22910.503
Δ LAVi (mL/m2)0 ± 200 ± 182 ± 14−3 ± 290.815
Δ LVEDVi (mL/m2)5 ± 156 ± 166 ± 103 ± 150.810
Δ LVESVi (mL/m2)6 ± 127 ± 145 ± 65 ± 80.664
Δ LVSVi (mL/m2)−1 ± 14−2 ± 141 ± 11−1 ± 110.852
Δ LVEF (%)−6 ± 12−7 ± 12−3 ± 11−5 ± 110.489
Δ Forward LVSVi (mL/m2)−3 ± 9−4 ± 10−2 ± 9−2 ± 50.617
Δ Cardiac index (mL/min/m2)0.2 ± 0.90.1 ± 0.80.4 ± 1.20.5 ± 0.60.442
Δ RAVi (mL/m2)0 ± 171 ± 155 ± 7−6 ± 240.183
Δ RVEDDi (mm/m2)1 ± 41 ± 42 ± 4−1 ± 40.099
Δ TAPSE (mm)0 ± 3−1 ± 31 ± 30 ± 30.676
Δ FAC (%)−2 ± 10−1 ± 10−4 ± 13−5 ± 110.563
Δ SPAP (mmHg)8 ± 109 ± 125 ± 77 ± 60.418
Δ MR VC (mm)0.7 ± 1.20.5 ± 1.02.0 ± 1.30.3 ± 1.4<0.001a,b
Δ MR EROA (mm2)0.3 ± 0.050.02 ± 0.040.07 ± 0.040.03 ± 0.070.025a
Δ MR vol (mL)7 ± 104 ± 815 ± 108 ± 140.005a
Δ Annulus systole (mm)1 ± 31 ± 40 ± 30 ± 30.739
Δ Annulus diastole (mm)1 ± 21 ± 30 ± 21 ± 30.517

Abbreviations as in Table 2.

aNon-severe MR vs. dynamic severe MR.

bDynamic severe MR vs. severe MR at rest.

Table 3
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Exercise-induced changes in echocardiographic parameters according to the presence of dynamic MR

VariableAll patients (n = 80)Non-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)P-value
Δ Heart rate (bpm)13 ± 1511 ± 1414 ± 1720 ± 170.134
Δ Systolic BP (mmHg)14 ± 1715 ± 1916 ± 1013 ± 140.876
Δ Diastolic BP (mmHg)4 ± 154 ± 165 ± 107 ± 140.759
Δ RPP (mmHg × min−1)2850 ± 26282667 ± 25803079 ± 32883522 ± 22910.503
Δ LAVi (mL/m2)0 ± 200 ± 182 ± 14−3 ± 290.815
Δ LVEDVi (mL/m2)5 ± 156 ± 166 ± 103 ± 150.810
Δ LVESVi (mL/m2)6 ± 127 ± 145 ± 65 ± 80.664
Δ LVSVi (mL/m2)−1 ± 14−2 ± 141 ± 11−1 ± 110.852
Δ LVEF (%)−6 ± 12−7 ± 12−3 ± 11−5 ± 110.489
Δ Forward LVSVi (mL/m2)−3 ± 9−4 ± 10−2 ± 9−2 ± 50.617
Δ Cardiac index (mL/min/m2)0.2 ± 0.90.1 ± 0.80.4 ± 1.20.5 ± 0.60.442
Δ RAVi (mL/m2)0 ± 171 ± 155 ± 7−6 ± 240.183
Δ RVEDDi (mm/m2)1 ± 41 ± 42 ± 4−1 ± 40.099
Δ TAPSE (mm)0 ± 3−1 ± 31 ± 30 ± 30.676
Δ FAC (%)−2 ± 10−1 ± 10−4 ± 13−5 ± 110.563
Δ SPAP (mmHg)8 ± 109 ± 125 ± 77 ± 60.418
Δ MR VC (mm)0.7 ± 1.20.5 ± 1.02.0 ± 1.30.3 ± 1.4<0.001a,b
Δ MR EROA (mm2)0.3 ± 0.050.02 ± 0.040.07 ± 0.040.03 ± 0.070.025a
Δ MR vol (mL)7 ± 104 ± 815 ± 108 ± 140.005a
Δ Annulus systole (mm)1 ± 31 ± 40 ± 30 ± 30.739
Δ Annulus diastole (mm)1 ± 21 ± 30 ± 21 ± 30.517
VariableAll patients (n = 80)Non-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)P-value
Δ Heart rate (bpm)13 ± 1511 ± 1414 ± 1720 ± 170.134
Δ Systolic BP (mmHg)14 ± 1715 ± 1916 ± 1013 ± 140.876
Δ Diastolic BP (mmHg)4 ± 154 ± 165 ± 107 ± 140.759
Δ RPP (mmHg × min−1)2850 ± 26282667 ± 25803079 ± 32883522 ± 22910.503
Δ LAVi (mL/m2)0 ± 200 ± 182 ± 14−3 ± 290.815
Δ LVEDVi (mL/m2)5 ± 156 ± 166 ± 103 ± 150.810
Δ LVESVi (mL/m2)6 ± 127 ± 145 ± 65 ± 80.664
Δ LVSVi (mL/m2)−1 ± 14−2 ± 141 ± 11−1 ± 110.852
Δ LVEF (%)−6 ± 12−7 ± 12−3 ± 11−5 ± 110.489
Δ Forward LVSVi (mL/m2)−3 ± 9−4 ± 10−2 ± 9−2 ± 50.617
Δ Cardiac index (mL/min/m2)0.2 ± 0.90.1 ± 0.80.4 ± 1.20.5 ± 0.60.442
Δ RAVi (mL/m2)0 ± 171 ± 155 ± 7−6 ± 240.183
Δ RVEDDi (mm/m2)1 ± 41 ± 42 ± 4−1 ± 40.099
Δ TAPSE (mm)0 ± 3−1 ± 31 ± 30 ± 30.676
Δ FAC (%)−2 ± 10−1 ± 10−4 ± 13−5 ± 110.563
Δ SPAP (mmHg)8 ± 109 ± 125 ± 77 ± 60.418
Δ MR VC (mm)0.7 ± 1.20.5 ± 1.02.0 ± 1.30.3 ± 1.4<0.001a,b
Δ MR EROA (mm2)0.3 ± 0.050.02 ± 0.040.07 ± 0.040.03 ± 0.070.025a
Δ MR vol (mL)7 ± 104 ± 815 ± 108 ± 140.005a
Δ Annulus systole (mm)1 ± 31 ± 40 ± 30 ± 30.739
Δ Annulus diastole (mm)1 ± 21 ± 30 ± 21 ± 30.517

Abbreviations as in Table 2.

aNon-severe MR vs. dynamic severe MR.

bDynamic severe MR vs. severe MR at rest.

Characteristics of patients with ‘dynamic severe MR’ and ‘severe MR at rest’

Patients were divided into three groups according to the MR severity at rest and during exercise: 51 patients (63.8%) had non-severe MR, 12 patients (15.0%) had dynamic severe MR (non-severe MR at rest and severe MR during exercise), and 17 patients (21.3%) had severe MR at rest. There were no differences in baseline patient characteristics among the three groups (Table 1). Patients with severe MR at rest had a larger mitral annulus diameter than those without severe MR (systolic diameter: 39 ± 4 vs. 33 ± 4 mm, P < 0.001; diastolic diameter: 41 ± 3 vs. 34 ± 3 mm, P < 0.001; Table 2). In line with this, LAVi tended to be more dilated in patients with ‘severe MR at rest’ than in those without severe MR (72 ± 24 vs. 59 ± 19 mL/m2; P = 0.055). Furthermore, patients with dynamic severe MR had a reduced LAI compared with patients with non-severe MR (1.05 ± 0.15 vs. 1.17 ± 0.18; P = 0.039; Figure 3). As expected, exercise-induced increases in MR severity were more advanced in patients with dynamic severe MR than in those in the other groups (Table 3).

Comparison of the LAI according to MR severity at rest and during exercise and in dependence of the presence of dynamic MR (irrespective of MR severity at rest). Graph (A) displays the LAI in dependence of the MR severity at rest and during handgrip exercise; graph (B) shows the LAI according to the presence of dynamic MR (increase in EROA in the fourth quartile of the study cohort) during handgrip exercise and irrespective of MR severity.
Figure 3

Comparison of the LAI according to MR severity at rest and during exercise and in dependence of the presence of dynamic MR (irrespective of MR severity at rest). Graph (A) displays the LAI in dependence of the MR severity at rest and during handgrip exercise; graph (B) shows the LAI according to the presence of dynamic MR (increase in EROA in the fourth quartile of the study cohort) during handgrip exercise and irrespective of MR severity.

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Prognostic impact of dynamic severe MR

Follow-up was completed in 78 of the 80 patients (97.5%). The median follow-up duration was 12 months (IQR 4–17 months). During the follow-up period, 35 patients (44.9%) experienced adverse events (Table 4). The Kaplan–Meier survival analysis revealed the combined endpoint in patients with severe MR at rest and those with dynamic severe MR more frequently compared with patients with non-severe MR (log-rank test, P < 0.001; Figure 4). Furthermore, MV surgery/TEER during follow-up occurred more often in patients with severe MR at rest (58.8%) and in those with dynamic severe MR (58.3%), compared with those with non-severe MR (6.3%) (log-rank test, P < 0.001; Figure 4). The addition of handgrip exercise to echocardiography at rest improved the prediction of MV surgery/TEER compared with resting echocardiography (Figure 5).

Kaplan–Meier survival curves for the combination of all-cause mortality, HF hospitalizations, MV TEER, and surgery according to the severity of MR at rest and during handgrip exercise. (A) Kaplan–Meier survival curves for combined events; (B) Kaplan–Meier survival curves for the event of MV TEER or surgery.
Figure 4

Kaplan–Meier survival curves for the combination of all-cause mortality, HF hospitalizations, MV TEER, and surgery according to the severity of MR at rest and during handgrip exercise. (A) Kaplan–Meier survival curves for combined events; (B) Kaplan–Meier survival curves for the event of MV TEER or surgery.

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The addition of handgrip exercise to echocardiographic assessment at rest improved the global χ2 (an index of predictive power) and the Harrell’s c-index for the prediction of future MV surgery/interventions.
Figure 5

The addition of handgrip exercise to echocardiographic assessment at rest improved the global χ2 (an index of predictive power) and the Harrell’s c-index for the prediction of future MV surgery/interventions.

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Table 4
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Adverse events during follow-up according to severity of MR at rest and during handgrip exercise

EventNon-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)
Adverse events14 (28.6)8 (66.7)13 (76.5)
 All-cause mortality0 (0.0)0 (0.0)3 (17.7)
 HF hospitalization9 (18.4)1 (8.3)2 (11.8)
 MV intervention/surgery3 (6.1)7(58.3)10 (58.8)
 MV TEER2 (4.1)6 (50.0)7 (41.2)
 MV surgery1 (2.0)1 (8.3)3 (17.7)
EventNon-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)
Adverse events14 (28.6)8 (66.7)13 (76.5)
 All-cause mortality0 (0.0)0 (0.0)3 (17.7)
 HF hospitalization9 (18.4)1 (8.3)2 (11.8)
 MV intervention/surgery3 (6.1)7(58.3)10 (58.8)
 MV TEER2 (4.1)6 (50.0)7 (41.2)
 MV surgery1 (2.0)1 (8.3)3 (17.7)
Table 4
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Adverse events during follow-up according to severity of MR at rest and during handgrip exercise

EventNon-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)
Adverse events14 (28.6)8 (66.7)13 (76.5)
 All-cause mortality0 (0.0)0 (0.0)3 (17.7)
 HF hospitalization9 (18.4)1 (8.3)2 (11.8)
 MV intervention/surgery3 (6.1)7(58.3)10 (58.8)
 MV TEER2 (4.1)6 (50.0)7 (41.2)
 MV surgery1 (2.0)1 (8.3)3 (17.7)
EventNon-severe MR (n = 51)Dynamic severe MR (n = 12)Severe MR at rest (n = 17)
Adverse events14 (28.6)8 (66.7)13 (76.5)
 All-cause mortality0 (0.0)0 (0.0)3 (17.7)
 HF hospitalization9 (18.4)1 (8.3)2 (11.8)
 MV intervention/surgery3 (6.1)7(58.3)10 (58.8)
 MV TEER2 (4.1)6 (50.0)7 (41.2)
 MV surgery1 (2.0)1 (8.3)3 (17.7)

Mechanisms of dynamic MR

To determine the mechanisms of dynamic MR, patients were divided into two groups according to the EROA change from rest to exercise, irrespective of MR severity. Patients with marked exercise-induced increases in EROA (in the fourth quartile) were classified as having ‘dynamic MR’ and patients with lower changes in EROA (first to third quartile) were classified as ‘non-dynamic MR’. Supplementary data online, Table S1 summarizes the baseline characteristics of patients with and without dynamic MR. Supplementary data online, Table S2 shows the echocardiographic parameters of the two groups. There were no differences in baseline characteristics between both groups, except for body mass index, which was lower in patients with dynamic MR than in those with non-dynamic MR (see Supplementary data online, Table S2). Patients with dynamic MR exhibited shorter AML and PML; however, there was no difference in the systolic and diastolic annular dimensions (see Supplementary data online, Table S2). Thus, the LAI was reduced in patients with dynamic MR (1.04 ± 0.10 vs. 1.17 ± 0.17; P = 0.002; Figure 3). All other echocardiographic parameters at rest were similar in both groups (see Supplementary data online, Table S2).

Discussion

In the present study, we investigated the role of handgrip exercise echocardiography for the assessment of aFMR. In this patient cohort, we observed that: (i) handgrip exercise led to a reclassification of MR severity in every third aFMR patient and unmasked dynamic severe MR in every fifth patient with non-severe aFMR at rest; (ii) addition of handgrip exercise to echocardiography at rest increased the number of MV surgeries/TEER during follow-up; and (iii) increased annular dimensions were associated with severe aFMR at rest, whereas insufficient mitral leaflet remodelling in relation to annular dimensions provoked dynamic aFMR during exercise.

Prevalence of dynamic aFMR

The prevalence of aFMR reportedly ranges between 7 and 27%.1,17 Similarly, in our cohort, 17.9% of the patients had aFMR. This is the first study to assess the prevalence of ‘dynamic aFMR’. Approximately, 17.5% of patients with non-severe MR at rest developed dynamic severe MR during handgrip exercise. Furthermore, handgrip exercise led to a reclassification of MR severity in 28 patients (35.0%). Thus, the implementation of handgrip exercise may explain the discrepancy between symptoms and echocardiographic findings at rest. Furthermore, the implementation of handgrip exercise may identify additional patients with dynamic severe MR during exercise who might benefit from therapeutic interventions. The prevalence rate of dynamic MR is reportedly in the range of 20–50% during various exercise modalities (bicycle or treadmill exercise), depending on the definition of ‘dynamic MR’ and the included patient population.4–6 A comparison of hemodynamic responses and MR severity during bicycle versus handgrip exercise is given in Supplementary data online, Figure S2 and S3. In fact, a uniform definition of ‘dynamic MR’ has not been established yet.

Mechanisms and haemodynamic consequences of dynamic aFMR

Previous studies have demonstrated that changes in LV regional wall motion abnormality, LV dyssynchrony, LV sphericity, increased MV coaptation depth, tenting area, and mitral annular dilatation during exercise are responsible for the development of dynamic ventricular functional MR.18 In our cohort of patients with aFMR, those with dynamic MR exhibited shorter mitral leaflet lengths, while there was no difference in systolic and diastolic annular dimensions between the groups. Thus, the LAI was reduced in patients with dynamic MR compared with those without dynamic MR. The LAI is reportedly a pathophysiological mechanism for aFMR development in patients with atrial fibrillation.19,20 This corroborates our finding that only the LAI was a predictor of exercise-induced increases in aFMR severity. Furthermore, we investigated changes in mitral annulus dimensions at rest and during exercise but did not detect a significant increase in annular diameter that could be responsible for the increase in MR severity (see Supplementary data online, Table S3). Another possible explanation for the increase in aFMR severity during exercise might be a marked increase in LV pressure during isometric exercise because most patients presented with concomitant diastolic dysfunction. Future studies need to focus on invasive haemodynamics and 3D transoesophageal echocardiography to further characterize these findings.

In patients with dynamic MR, we observed a more pronounced increase in SPAP compared with patients without dynamic MR (see Supplementary data online, Table S3). These changes might be explained by the sudden increase in left atrial pressure during exercise caused by the worsening backward MR and led to a pressure load on the pulmonary circulation. Interestingly, there were only small changes in TR severity from rest to exercise (see Supplementary data online, Table S4). In this regard, TR might be more sensitive to changes in preload (bicycle exercise) than in afterload (handgrip exercise). Vice versa, concomitant TR is highly prevalent in patients with aFMR, and previous studies already demonstrated its role as an important prognosticator in these patients. Thus, further studies should focus on the prognostic value of dynamic aFMR using bicycle exercise testing.

Medical treatment including β-blocker medication was not stopped for the exercise test. Especially, β-blocker medication may have affected haemodynamic conditions and, thus, changes in MR severity from rest to exercise. However, we believe that continuing medication best matches with daily circumstances of the patients and therefore decided not to stop it prior exercise testing.

Impact of dynamic aFMR on clinical outcomes

The presence of moderate or severe aFMR is associated with unfavourable outcomes. Patients with aFMR reportedly have a poorer prognosis than patients with primary MR.21 In our cohort, patients with dynamic severe aFMR and those with severe aFMR at rest had similar clinical outcomes. Furthermore, the rates of MV surgery/TEER during follow-up were similar in both cohorts. Thus, the implementation of handgrip exercise during echocardiography identifies additional patients with non-severe MR at rest and exercise-induced dynamic severe MR, who might benefit from MV surgery/TEER. In this regard, exercise echocardiography improved the predictive power of future surgery/TEER compared with echocardiography at rest alone. Therefore, exercise testing may be recommended for selected symptomatic patients with non-severe aFMR to further guide therapeutic decision-making. However, further trials that randomize patients with mild/moderate aFMR at rest and dynamic severe aFMR to optimal medical therapy vs. early MV surgery/TEER groups are required to assess the prognostic benefit of these early diagnostic and therapeutic strategies.

Limitations

The main limitation of the current study was that patients were not randomized to exercise testing. Thus, there may be a selection bias for patients undergoing MV surgery or TEER during follow-up. Moreover, cardiologists and cardiac surgeons were not blinded to the results of the exercise tests; thus, the decision to perform surgery or TEER may have been partly influenced by these results. Furthermore, MV surgery/TEER during follow-up may have also affected the clinical outcomes of the patients. Another limitation is that the accuracy of the assessment of MR severity is reduced in patients with atrial fibrillation. To account for this, we analysed at least three to five cardiac cycles in each patient. Another limitation is that echocardiographic examinations and image analysis were performed using two different echo machines and different software.

Conclusion

In patients with aFMR, handgrip exercise during echocardiography unmasks dynamic severe MR in every fifth patient without severe MR at rest. Thus, exercise testing may be useful in symptomatic patients with non-severe aFMR at rest. Future studies are needed to determine whether patients with dynamic severe aFMR may benefit from an early surgical/interventional strategy before the use of handgrip exercise can be widely recommended.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Funding

This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf (No. 2021-03, to M.S.).

Data availability

The data underlying this article cannot be shared publicly for the reason of maintaining the privacy of individuals who participated in the study. The data will be shared on reasonable request to the corresponding author.

References

1

Deferm
 
S
,
Bertrand
 
PB
,
Verbrugge
 
FH
,
Verhaert
 
D
,
Rega
 
F
,
Thomas
 
JD
  et al.  
Atrial functional mitral regurgitation: JACC review topic of the week
.
J Am Coll Cardiol
 
2019
;
73
:
2465
–
76
.

Google Scholar

Crossref
Search ADS
PubMed

 
2

Zoghbi
 
WA
,
Levine
 
RA
,
Flachskampf
 
F
,
Grayburn
 
P
,
Gillam
 
L
,
Leipsic
 
J
  et al.  
Atrial functional mitral regurgitation: a JACC: cardiovascular imaging expert panel viewpoint
.
JACC Cardiovasc Imaging
 
2022
;
15
:
1870
–
82
.

Google Scholar

Crossref
Search ADS
PubMed

 
3

Kim
 
DH
,
Heo
 
R
,
Handschumacher
 
MD
,
Lee
 
S
,
Choi
 
YS
,
Kim
 
KR
  et al.  
Mitral valve adaptation to isolated annular dilation: insights into the mechanism of atrial functional mitral regurgitation
.
JACC Cardiovasc Imaging
 
2019
;
12
:
665
–
77
.

Google Scholar

Crossref
Search ADS
PubMed

 
4

Magne
 
J
,
Lancellotti
 
P
,
Piérard
 
LA
.
Exercise-induced changes in degenerative mitral regurgitation
.
J Am Coll Cardiol
 
2010
;
56
:
300
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
5

Lancellotti
 
P
,
Gérard
 
PL
,
Piérard
 
LA
.
Long-term outcome of patients with heart failure and dynamic functional mitral regurgitation
.
Eur Heart J
 
2005
;
26
:
1528
–
32
.

Google Scholar

Crossref
Search ADS
PubMed

 
6

Lancellotti
 
P
,
Lebrun
 
F
,
Piérard
 
LA
.
Determinants of exercise-induced changes in mitral regurgitation in patients with coronary artery disease and left ventricular dysfunction
.
J Am Coll Cardiol
 
2003
;
42
:
1921
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
7

Farhan
 
S
,
Silbiger
 
JJ
,
Halperin
 
JL
,
Zhang
 
L
,
Dukkipati
 
SR
,
Vogel
 
B
  et al.  
Pathophysiology, echocardiographic diagnosis, and treatment of atrial functional mitral regurgitation: JACC state-of-the-art review
.
J Am Coll Cardiol
 
2022
;
80
:
2314
–
30
.

Google Scholar

Crossref
Search ADS
PubMed

 
8

Otto
 
CM
,
Nishimura
 
RA
,
Bonow
 
RO
,
Carabello
 
BA
,
Erwin
 
JP
,
Gentile
 
F
  et al.  
2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines
.
J Am Coll Cardiol
 
2021
;
77
:
450
–
500
.

Google Scholar

Crossref
Search ADS
PubMed

 
9

Vahanian
 
A
,
Beyersdorf
 
F
,
Praz
 
F
,
Milojevic
 
M
,
Baldus
 
S
,
Bauersachs
 
J
  et al.  
2021 ESC/EACTS guidelines for the management of valvular heart disease developed by the task force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)
.
Eur Heart J
 
2022
;
43
:
561
–
632
.

Google Scholar

Crossref
Search ADS
PubMed

 
10

Alachkar
 
MN
,
Kirschfink
 
A
,
Grebe
 
J
,
Almalla
 
M
,
Frick
 
M
,
Milzi
 
A
  et al.  
Dynamic handgrip exercise for the evaluation of mitral valve regurgitation: an echocardiographic study to identify exertion induced severe mitral regurgitation
.
Int J Cardiovasc Imaging
 
2021
;
37
:
891
–
902
.

Google Scholar

Crossref
Search ADS
PubMed

 
11

Kagiyama
 
N
,
Toki
 
M
,
Yuri
 
T
,
Aritaka
 
S
,
Hayashida
 
A
,
Sengupta
 
PP
  et al.  
Physiological and prognostic differences between types of exercise stress echocardiography for functional mitral regurgitation
.
Open Heart
 
2021
;
8
:
1
–
8
.

Google Scholar

Crossref
Search ADS

 
12

Harada
 
Y
,
Utsunomiya
 
H
,
Susawa
 
H
,
Takahari
 
K
,
Takemoto
 
H
,
Ueda
 
Y
  et al.  
Determinants of exercise-induced mitral regurgitation using three-dimensional transesophageal echocardiography combined with isometric handgrip exercise
.
Am J Cardiol
 
2021
;
151
:
78
–
85
.

Google Scholar

Crossref
Search ADS
PubMed

 
13

Mesi
 
O
,
Gad
 
MM
,
Crane
 
AD
,
Ramchand
 
J
,
Puri
 
R
,
Layoun
 
H
  et al.  
Severe atrial functional mitral regurgitation: clinical and echocardiographic characteristics, management and outcomes
.
JACC Cardiovasc Imaging
 
2021
;
14
:
797
–
808
.

Google Scholar

Crossref
Search ADS
PubMed

 
14

Cramariuc
 
D
,
Alfraidi
 
H
,
Nagata
 
Y
,
Levine
 
RA
,
van Kampen
 
A
,
Andrews
 
C
  et al.  
Atrial dysfunction in significant atrial functional mitral regurgitation: phenotypes and prognostic implications
.
Circ Cardiovasc Imaging
 
2023
;
16
:
e015089
.

Google Scholar

Crossref
Search ADS
PubMed

 
15

Goliasch
 
G
,
Bartko
 
PE
,
Pavo
 
N
,
Neuhold
 
S
,
Wurm
 
R
,
Mascherbauer
 
J
  et al.  
Refining the prognostic impact of functional mitral regurgitation in chronic heart failure
.
Eur Heart J
 
2018
;
39
:
39
–
46
.

Google Scholar

Crossref
Search ADS
PubMed

 
16

Bartko
 
PE
,
Arfsten
 
H
,
Heitzinger
 
G
,
Pavo
 
N
,
Toma
 
A
,
Strunk
 
G
  et al.  
A unifying concept for the quantitative assessment of secondary mitral regurgitation
.
J Am Coll Cardiol
 
2019
;
73
:
2506
–
17
.

Google Scholar

Crossref
Search ADS
PubMed

 
17

Gertz
 
ZM
,
Raina
 
A
,
Saghy
 
L
,
Zado
 
ES
,
Callans
 
DJ
,
Marchlinski
 
FE
  et al.  
Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control
.
J Am Coll Cardiol
 
2011
;
58
:
1474
–
81
.

Google Scholar

Crossref
Search ADS
PubMed

 
18

Bertrand
 
PB
,
Schwammenthal
 
E
,
Levine
 
RA
,
Vandervoort
 
PM
.
Exercise dynamics in secondary mitral regurgitation
.
Circulation
 
2017
;
135
:
297
–
314
.

Google Scholar

Crossref
Search ADS
PubMed

 
19

Kagiyama
 
N
,
Hayashida
 
A
,
Toki
 
M
,
Fukuda
 
S
,
Ohara
 
M
,
Hirohata
 
A
  et al.  
Insufficient leaflet remodeling in patients with atrial fibrillation: association with the severity of mitral regurgitation
.
Circ Cardiovasc Imaging
 
2017
;
10
:
2
–
5
.

Google Scholar

Crossref
Search ADS

 
20

Kagiyama
 
N
,
Mondillo
 
S
,
Yoshida
 
K
,
Mandoli
 
GE
,
Cameli
 
M
.
Subtypes of atrial functional mitral regurgitation: imaging insights into their mechanisms and therapeutic implications
.
JACC Cardiovasc Imaging
 
2020
;
13
:
820
–
35
.

Google Scholar

Crossref
Search ADS
PubMed

 
21

Dziadzko
 
V
,
Dziadzko
 
M
,
Medina-Inojosa
 
JR
,
Benfari
 
G
,
Michelena
 
HI
,
Crestanello
 
JA
  et al.  
Causes and mechanisms of isolated mitral regurgitation in the community: clinical context and outcome
.
Eur Heart J
 
2019
;
40
:
2194
–
202
.

Google Scholar

Crossref
Search ADS
PubMed

 

Author notes

Conflict of interest: None declared.

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