Abstract
Aims
Mechanisms of chronic ischaemic mitral regurgitation (IMR) are well-characterized by apically tethered leaflet caused by papillary muscles (PMs) displacement and adynamic mitral apparatus. We investigated the unique geometry and dynamics of the mitral apparatus in first acute myocardial infarction (MI) by using quantified 3D echocardiography.
Methods and results
We prospectively performed 3D echocardiography 2.3 ± 1.8 days after first MI, in 174 matched patients with (n = 87) and without IMR (n = 87). 3D echocardiography of left ventricular (LV) volumes and of mitral apparatus dynamics throughout cardiac cycle was quantified. Similar mitral quantification was obtained at chronic post-MI stage (n = 44). Mechanistically, acute IMR was associated with larger and flatter annulus (area 9.29 ± 1.74 cm2 vs. 8.57 ± 1.94 cm2, P = 0.002, saddle shape 12.7 ± 4.5% vs. 15.0 ± 4.6%, P = 0.001), and larger tenting (length 6.36 ± 1.78 mm vs. 5.60 ± 1.55 mm, P = 0.003) but vs. chronic MI, mitral apparatus displayed smaller alterations (all P < 0.01) and annular size, PM movement remained dynamic (all P < 0.01). Specific to acute IMR, without PM apical displacement (P > 0.70), greater separation (21.7 ± 4.9 mm vs. 20.0 ± 3.4 mm, P = 0.01), and widest angulation of PM (38.4 ± 6.2° for moderate vs. 33.5 ± 7.3° for mild vs. 31.4 ± 6.3° for no-IMR, P = 0.0009) wider vs. chronic MI (P < 0.01).
Conclusions
3D echocardiography of patients with first MI provides insights into unique 4D dynamics of the mitral apparatus in acute IMR. Mitral apparatus remained dynamic in acute MI and distinct IMR mechanism in acute MI is not PM displacement seen in chronic IMR but separation and excess angulation of PM deforming the mitral valve, probably because of sudden-onset regional wall motion abnormality without apparent global LV remodelling. This specific mechanism should be considered in novel therapeutic strategies for IMR complicating acute MI.
Keywords: mitral regurgitation, acute myocardial infarction, 3D echocardiography, left ventricle
Introduction
Ischaemic mitral regurgitation (IMR) affects up to 50% of patients with myocardial infarction (MI),1,2 mostly with structurally normal leaflets.3,4 While carrying worse prognosis,1,5,6 its pathophysiology remains poorly defined. With chronic remodelling post-MI, enlarged, flat, and adynamic7,8 mitral annulus, apical displacement of papillary muscles (PMs) with tethered leaflets yield incomplete coaptation producing IMR.9 However, whether these concepts apply to acute MI is unknown, since pathophysiologic mechanisms were only studied in chronic post-MI IMR.7–10 Although in acute MI11 IMR generally follows variations in left ventricular (LV) size/function, it occurs without severe ventricular dilatation and acute MI-linked LV alterations yielding IMR remain uncertain. These mechanistic gaps of knowledge, while acute IMR worsens prognosis at least as much as chronic IMR,5,11 hinder applicability of innovative surgical,12–14 and percutaneous15,16 repair techniques.
Technical issues impede mechanistic understanding of acute IMR. Animal models, which provided the only IMR-mechanistic information, suggested various mitral distortions,17–19 but could not delineate a unified mechanism. Defining clinical acute IMR mechanisms is challenging, requiring prospective enrolment early after first acute MI to avoid previous MI and pre-existing remodelling. Imaging is equally challenging, including bedside collection of high-quality 3D echocardiography with offline comprehensive characterization of mitral annular, valvular and sub-valvular alterations, and of LV remodelling vs. patients with acute MI but without IMR. With recent demonstration that dynamic annular alterations contribute to mitral regurgitation,20 complex 4D imaging and mitral computation is indispensable.
Applying new 4D imaging/software to quantify dynamically mitral/LV characteristics, we prospectively enrolled first MI in US and Japanese communities to define acute IMR pathophysiology vs. chronic stages post-MI. We hypothesized that mitral apparatus dynamic alterations differed between chronic and acute IMR.
Methods
Identification of incident MI
Mayo Clinic, Rochester, MN, USA
All troponin-T (TnT) results were prospectively obtained 2014–16. Patients with TnT ≥0.03 ng/mL or TnT-delta (maximum-minimum) ≥0.03 ng/mL were screened. We excluded prior MI, heart failure, cardiomyopathy/apical-ballooning, or coronary bypass surgery. After consent 4D echocardiography was performed.
Miyazaki Medical Association, Japan
Patients with acute MI21 July 2014–16 with prospective 4D echocardiography and troponin-I ≥0.036 ng/mL were enrolled with subsequent sequential measurement of creatine-kinase-MB.
In both centres, the mitral valve was carefully examined by 3D imaging and the presence of organic disease such as myxomatous degeneration or thickening due to rheumatic disease was vigilantly searched and excluded. Similarly, other causes of cardiac remodelling such as ≥mild aortic valve disease, were carefully excluded.
Studies were approved by Institutional Review Boards.
Data collection
Echocardiography
Echocardiography used standardized methods10 and equipment (iE33 and EPIQ, Philips Medical System, USA) with S3-probe (2D) and X5-1-probe (3D). Transthoracic 2D Doppler-echocardiography and 3D full-volumetric images were obtained from apical view after 2D verification of positioning and image quality. Volumetric frame-rate was 15–25 frames/s with imaging depth approximately 15 cm. Full-volume 3D datasets were digitally stored for offline analysis.
3D LV volumes, ejection fraction (EF), and stroke volume (SV) were measured using QLAB software (Philips-Medical-System, USA). Mitral annular, leaflets and PM characteristics were measured with custom 3D software (REAL VIEW, YD, Japan). Steps in mitral quantification were (i) defining, in cross-sectional planes, LV long axis through mitral annular centre, and mitral anterior-posterior and inter-commissural axes, (ii) automated 3D cropping in 18 radial planes spaced 10° apart, and (iii) automated placement of annular marks and leaflet tracings, manually adjusted, on each radial plane (Figure 1). All mitral measurements were performed four times over cardiac cycle, mid-diastole, and early-, mid-, and late-systole. Mitral measurements (Figure 2) involved annular size (area, circumference, anteroposterior, and inter-commissural diameters) and height to calculate annular saddle shape (height/inter-commissural ratio),20 valvular mean/maximum tenting height and volume, PM area (triangle between PM tips and mitral fibrosa), distance fibrosa-anterior/posterior PM tips (APM-AA and PPM-AA length), inter-PM width (triangle base), and inter-PM angle (acute angle of triangle summit at fibrosa). Measurement variability relied on repeat analysis of stored 3D datasets >1 month later. Deformation imaging was also performed offline using apical views and speckle-tracking technology.
Figure 1.
Method of quantification of mitral apparatus. Upper row: centre: 3D volumetric dataset is positioned appropriately and automatically cropped into 18 equally spaced radial planes. Lateral panels: mitral annulus and tips of PPM and APM are marked, and leaflets traced. Lower row: Processed 3D data with en-face view and measurement of mitral annulus (centre), rendering of mitral tenting and PM positioning (left panel), and rendering of annular height and saddle shape (right panel). Quantitative measurements were obtained by dedicated software (REAL VIEW, YD, Japan). A, anterior; L, lateral; LV, left ventricle; M, medial; P, posterior.
Figure 2.
Schematic mitral measurements by 3D echocardiography. Upper two panels: annulus measurements for annular height and saddle shape (left panel) and for diameters, area, and circumference (right panel). Lower left panel: mitral valvular tenting height and volume measurement. Lower right panel: PM spatial position measurements in regard to the central fibrosa as a triangle with a base (PM width), two sides (displacement of both PM), and an apex angle of PM separation. A, anterior; AL, anterolateral; AO, aortic valve; P, posterior; PM, posteromedial.
IMR was deemed secondary if no structural abnormality and its severity evaluated by integrative grading per American Society of Echocardiography.22,23 IMR regurgitant volume (RVol) was measured by 3D volumetric and aortic-Doppler SVs measurements and PISA if possible and was counted as null if no-IMR was detected. Each IMR (≥mild) case was matched 1:1 to MI no MR on age (±10 years), sex, centre, and cardiac biomarker quartile to compare groups with similar MI size with vs. without IMR.
Clinical characteristics
Clinical characteristics included cardiac risk factors, renal failure, Killip class, and chest pain. Body size, heart rate, blood pressure, and rhythm were ascertained during echocardiography. ST-segment elevation and MI location were ascertained from Minnesota-code of ECG.24
Comparison to patients with chronic MI
Comparison to patients with chronic MI and similarly structurally normal mitral leaflets used similar methods involving dynamic 4D echocardiography, at chronic stages post-MI (>1 year) with (n = 27) or without (n = 17) IMR.10 These patients were prospectively enrolled by our team at initiation of the study to assess the feasibility of transthoracic dynamic 4D quantitation post-MI as a prelude to enrolment of acute MIs using the same methodology. After prospective recruitment of acute MIs, we then compared dynamic 4D mitral characteristics between acute and chronic MI overall and stratified by IMR presence.
Statistical analysis
Results were expressed as mean ± standard deviation for continuous variables and percentage for categorical variables. Differences between groups were analysed with the two-sided Student’s t-tests, the χ2 or Fisher exact tests. Comparisons between MR degrees in three groups used ANOVA. Multivariable modelling used logistic or multiple linear models as appropriate. Dynamic changes of each mitral measurement were analysed with two-way repeated-measures ANOVA. The F-tests were used to evaluate group and cardiac cycle timing effect with and without interactions terms.
Results
MI cohort
Three hundred and seventy-four patients with MI were prospectively enrolled and underwent 4D echocardiography; 37 were excluded for technically inadequate echocardiography. Among the remainder, 87 had IMR and were matched 1:1 to patients with similar MI but with no-IMR, resulting in a sample of 174 (n = 78 from Mayo and n = 96 from Miyazaki) with first acute MI. There was no difference in risk factors or MI size between groups. The 3D echocardiography was performed at 1.8 ± 1.1 days vs. 2.1 ± 1.3 days (P = 0.33) post-MI in both groups respectively (Table 1).
Table 1.
Clinical characteristics overall and by MR status
| Overall (n = 174) | IMR (n = 87) | No MR (n = 87) | P-value | |
|---|---|---|---|---|
| Patient characteristics | ||||
| Age (years) | 66.7 ± 12.1 | 67.3 ± 12.8 | 66.1 ± 11.4 | 0.51 |
| Female gender (%) | 26.4 | 26.4 | 26.4 | 1.00 |
| Body mass index (kg/m2) | 27.1 ± 5.9 | 26.9 ± 5.8 | 27.2 ± 6.0 | 0.76 |
| Hypertension (%) | 71.8 | 73.6 | 70.1 | 0.61 |
| Hyperlipidaemia (%) | 63.2 | 60.9 | 65.5 | 0.53 |
| Diabetes mellitus (%) | 25.3 | 27.6 | 23.0 | 0.49 |
| Familial coronary disease (%) | 13.2 | 14.9 | 11.5 | 0.50 |
| Current smoker (%) | 32.2 | 32.2 | 32.2 | 1.00 |
| MI characteristics | ||||
| ST-elevation MI (%) | 50.0 | 47.1 | 52.9 | 0.45 |
| Q-wave MI (%) | 51.2 | 48.8 | 53.5 | 0.54 |
| Anterior MI (%) | 43.7 | 41.4 | 46.0 | 0.54 |
| Chest pain (%) | 90.8 | 87.4 | 94.3 | 0.12 |
| Killip classification (%) | 0.80 | |||
| Class I | 90.2 | 89.7 | 90.8 | |
| Class II/III/IV | 9.8 | 10.3 | 9.2 |
Aggregated phasic echocardiographic characteristics
3D echocardiography (2.3 ± 1.8 days post-MI) showed LV EF in the expected range for first MI (Table 2). Of note the similarity of EF between the two groups was corroborated by similar strain (−15.1 ± 3.6% with IMR vs. −15.2 ± 3.6% with no-MR, P = 0.96). IMR was mild in 72 patients and moderate in 15. IMR was associated with larger LV dimensions/volumes, higher E-velocity, shorter mitral deceleration time, larger left atrium (LA), and higher right ventricular (RV) systolic pressure. The RVol was 14 ± 12 mL, higher with moderate IMR (34 ± 15 mL vs. 11 ± 9 mL, P < 0.0001) and forward stroke volume index (SVI) was markedly reduced with IMR (23 ± 10 mL/m2 for moderate vs. 33 ± 8 mL/m2 for mild and 38 ± 8 mL/m2 for no-IMR, P < 0.0001) despite larger LV end-diastolic volume. Hence, while RVol was modest by standard criteria, notable volumetric, and haemodynamic alterations characterized IMR.
Table 2.
2D and 3D echo characteristics overall and by MR status
| Overall (n = 174) | IMR (n = 87) | No MR (n = 87) | P-value | |
|---|---|---|---|---|
| 2D echo | ||||
| LVSd (mm) | 10.8 ± 1.7 | 10.8 ± 1.6 | 10.9 ± 1.8 | 0.53 |
| LVPW (mm) | 10.1 ± 1.5 | 10.1 ± 1.4 | 10.2 ± 1.6 | 0.66 |
| LVDd (mm) | 48.5 ± 5.5 | 49.7 ± 5.4 | 47.3 ± 5.4 | 0.004 |
| LVDs (mm) | 33.5 ± 6.7 | 34.7 ± 6.7 | 32.3 ± 6.4 | 0.02 |
| WMSI | 1.40 ± 0.36 | 1.42 ± 0.37 | 1.38 ± 0.35 | 0.40 |
| E-wave velocity (m/s) | 0.72 ± 0.20 | 0.77 ± 0.20 | 0.67 ± 0.18 | 0.001 |
| A-wave velocity (m/s) | 0.77 ± 0.22 | 0.73 ± 0.22 | 0.80 ± 0.21 | 0.07 |
| E/A | 1.04 ± 0.52 | 1.17 ± 0.53 | 0.91 ± 0.49 | 0.002 |
| DcT (ms) | 191.0 ± 52.1 | 177.2 ± 44.9 | 205.1 ± 55.4 | 0.0004 |
| LAVI (mL/m2) | 37.9 ± 11.2 | 40.9 ± 11.0 | 34.6 ± 10.5 | 0.001 |
| RVSP (mmHg) | 32.7 ± 8.7 | 35.3 ± 9.7 | 29.4 ± 5.9 | <0.0001 |
| 3D LV | ||||
| EDV (mL) | 139.2 ± 37.3 | 146.7 ± 40.1 | 131.8 ± 32.9 | 0.01 |
| EDVI (mL/m2) | 76.6 ± 16.7 | 81.4 ± 17.7 | 71.8 ± 14.3 | 0.0001 |
| ESV (mL) | 68.0 ± 27.6 | 73.0 ± 31.1 | 63.1 ± 22.8 | 0.02 |
| ESVI (mL/m2) | 43.1 ± 11.5 | 46.2 ± 12.5 | 39.9 ± 9.5 | 0.0002 |
| EF (%) | 52.2 ± 9.5 | 51.4 ± 9.8 | 53.0 ± 9.3 | 0.29 |
| RVol (mL) | 5 ± 10 | 14 ± 12 | 0 | 0.0001 |
| Forward SVI (mL/m2) | 35 ± 9 | 31 ± 10 | 38 ± 9 | 0.0001 |
DcT, deceleration time; EDV-EDVI, end-diastolic volume-index; EF, ejection fraction; ESV-ESVI, end-systolic volume-index; IVSd, interventricular septal thickness in diastole; LAVI, left atrial volume index; LVDd, left ventricular diastolic dimension; LVDs, left ventricular systolic dimension; LVPW, left ventricular posterior wall thickness; RVol, regurgitant volume; RVSP, right ventricular systolic pressure; SVI, stroke volume index; WMSI, wall motion score index.
Systolic mitral measurements were aggregated to compare average systolic to diastolic values (Table 3). In diastole and systole, in IMR vs. no MR mitral annulus was larger (areas/circumferences/diameters) and flatter (reduced height and saddle shape). Leaflets showed larger systolic tenting (maximum/mean length and volume) with IMR vs. no-MR. For PM spatial positions, PMs were more separated with IMR vs. no MR in diastole and systole (inter-PM width and PM-spread angle and area). Conversely, no PM apical displacement was noted in IMR vs. no MR (APM-AA and PPM-AA length). Importantly, mitral changes were larger with more IMR severity: For example with moderate vs. mild vs. no-MR, systolic AP-diameter was larger (31.3 ± 2.8 mm vs. 30.0 ± 3.2 mm vs. 28.3 ± 3.6 mm, P < 0.0008), saddle shape flatter in diastole (9.1 ± 5.1% vs. 11.2 ± 4.3% vs. 13.6 ± 5.5%, P < 0.0005), and systole (10.3 ± 3.5% vs. 13.2 ± 4.5% vs. 15.0 ± 5.0%, P < 0.0005) and PM-angle wider in systole (38.4 ± 6.2° vs. 33.5 ± 7.3° vs. 31.4 ± 6.3°, P = 0.0009). Furthermore, in multivariable analysis adjusting for age, EF, and wall motion score index (WMSI), the only annular/valvular independent determinants of MR severity were systolic saddle shape and tenting volume (both P = 0.01). In turn, valvular/annular determinants of systolic tenting volume were systolic annular saddle shape and annular-area (both P < 0.00001). Finally, systolic PM angle was the only subvalvular independent determinant of MR severity (P = 0.001) and valvular tenting (P = 0.0004).
Table 3.
Diastolic and systolic 3D mitral apparatus characteristics
| Mid-diastole |
Average systole |
|||||
|---|---|---|---|---|---|---|
| IMR (n = 87) | No MR (n = 87) | P-value | IMR (n = 87) | No MR (n = 87) | P-value | |
| Annulus | ||||||
| Annular area (cm2) | 9.29 ± 1.74 | 8.57 ± 1.94 | 0.01 | 8.18 ± 1.59 | 7.40 ± 1.62 | 0.002 |
| Annular circumference (mm) | 109.5 ± 10.1 | 105.2 ± 11.6 | 0.01 | 102.7 ± 10.0 | 97.8 ± 10.6 | 0.002 |
| AP diameter (mm) | 31.8 ± 3.4 | 30.2 ± 4.2 | 0.01 | 30.2 ± 3.2 | 28.3 ± 3.6 | 0.001 |
| IC diameter (mm) | 36.3 ± 3.7 | 34.7 ± 3.8 | 0.01 | 33.4 ± 3.5 | 31.8 ± 3.4 | 0.003 |
| Annular height (mm) | 3.93 ± 1.64 | 4.72 ± 1.93 | 0.004 | 4.23 ± 1.52 | 4.74 ± 1.53 | 0.03 |
| Saddle shape (%) | 10.8 ± 4.5 | 13.6 ± 5.5 | 0.0003 | 12.7 ± 4.5 | 15.0 ± 4.6 | <0.01 |
| Leaflet tenting | ||||||
| Maximum tenting length (mm) | 6.36 ± 1.78 | 5.60 ± 1.55 | 0.003 | |||
| Mean tenting length (mm) | 2.78 ± 1.15 | 2.11 ± 0.95 | <0.0001 | |||
| Tenting volume (cm3) | 1.89 ± 0.88 | 1.38 ± 0.57 | <0.0001 | |||
| Papillary muscles | ||||||
| PM area (cm2) | 3.90 ± 1.07 | 3.53 ± 0.90 | 0.01 | 3.68 ± 1.02 | 3.40 ± 0.81 | 0.048 |
| PMP-AA length (mm) | 36.5 ± 4.7 | 37.5 ± 6.0 | 0.22 | 37.5 ± 4.4 | 37.7 ± 5.0 | 0.76 |
| ALP-AA length (mm) | 34.8 ± 5.3 | 34.7 ± 5.1 | 0.89 | 35.1 ± 4.7 | 35.1 ± 5.2 | 0.93 |
| PMP/ALP ratio | 1.06 ± 0.14 | 1.08 ± 0.13 | 0.24 | 1.08 ± 0.11 | 1.08 ± 0.10 | 0.81 |
| Inter-PM width (mm) | 23.5 ± 4.9 | 21.2 ± 4.3 | 0.001 | 21.7 ± 4.9 | 20.0 ± 3.4 | 0.01 |
| Inter-PM angle (°) | 38.1 ± 8.0 | 33.8 ± 8.4 | 0.001 | 34.3 ± 7.3 | 31.4 ± 6.3 | 0.01 |
AA, anterior annulus fibrosa; ALP, anterolateral papillary; AP, anteroposterior; IC, inter-commissural; PM, papillary muscle; PMP, posteromedial papillary.
Dynamic echocardiographic characteristics of first MI with and without IMR
‘Mitral annulus’ (top row, Figure 3) remained dynamic throughout the cardiac cycle (with greater enlargement) in acute IMR vs. no MR with similar phasic changes in AP-diameter or saddle shape (phasic P all <0.01) in both groups (all P for interaction >0.05). ‘Valvular dynamics’ (middle row, Figure 3) showed similar trend for systolic tenting decline in IMR vs. no MR (larger tenting with IMR). ‘PMs positions’ (bottom row, Figure 3) remained dynamic: systolic decrease of PMs-mitral annulus distance with IMR (P value phase, all P < 0.01) and similarly to no MR (P interaction, all P > 0.05) although with wider separation of PMs with IMR.
Figure 3.
Mitral apparatus dynamics in acute MI with and without IMR. Dynamic changes throughout the cardiac cycle in acute MI comparing IMR to no MR regarding: mitral annulus: (A) area; (B) AP (anteroposterior) diameter; and (C) saddle shape (instantaneous ratio of annular height to inter-commissural diameter), valvular tenting: (D) maximum tenting length; (E) mean tenting length; (F) tenting volume, and PM spatial position: (G) area of the PM-fibrosa triangle; (H) PM separation width; (I) papillary muscle angulation. Note that mitral annular, valvular, and sub-valvular dynamics are maintained throughout the cardiac cycle, with larger and flatter annulus, higher tenting, and more separated PM with IMR. ∗Statistical difference between the IMR and no MR groups at specific time points (P<0.05). #Statistical differences between all time-points values in each group based on interaction term. Error bars denote SEM. The phase of the cardiac cycle is indicated at the bottom of each graph.
Comparing acute and chronic MI with and without IMR
In chronic MI, 27 had IMR (Chronic MI IMR group) and 17 had no/trivial MR (Chronic MI no MR group). Lower systolic (115.2 ± 19.4 vs. 126.4 ± 21.9 mmHg, P = 0.02) and diastolic (66.8 ± 14.2 vs. 72.3 ± 11.9 mmHg, P = 0.049) blood pressure was observed with chronic IMR vs. acute IMR. Table 4 shows the expected lower EF, larger LV, WMSI, LA, and RV systolic pressure in chronic MI vs. acute MI. Despite lower EF, chronic MI is associated with larger RVol with IMR and larger forward SVI associated with larger LV remodelling.
Table 4.
Echocardiographic data in acute and chronic MI
| IMR |
No-MR |
|||||
|---|---|---|---|---|---|---|
| Acute MI (n = 87) | Chronic MI (n = 27) | P-value | Acute MI (n = 87) | Chronic MI (n = 17) | P-value | |
| LVDd (mm) | 49.7 ± 5.4 | 64.5 ± 7.6 | <0.0001 | 47.3 ± 5.5 | 57.4 ± 4.8 | <0.0001 |
| LVDs (mm) | 34.6 ± 6.6 | 54.6 ± 8.0 | <0.0001 | 32.2 ± 6.5 | 44.5 ± 7.2 | <0.0001 |
| 2D EF (%) | 52.6 ± 11.9 | 27.0 ± 10.4 | <0.0001 | 54.9 ± 10.3 | 39.5 ± 14.3 | <0.0001 |
| WMSI | 1.42 ± 0.37 | 2.42 ± 0.46 | <0.0001 | 1.38 ± 0.35 | 2.00 ± 0.48 | <0.0001 |
| E-wave velocity (m/s) | 0.78 ± 0.20 | 1.01 ± 0.29 | <0.0001 | 0.67 ± 0.18 | 0.80 ± 0.30 | 0.02 |
| DcT (ms) | 176.9 ± 45.0 | 153.6 ± 43.1 | 0.02 | 205.5 ± 56.1 | 189.4 ± 64.6 | 0.34 |
| LAVI (mL/m2) | 41.4 ± 10.9 | 56.4 ± 15.0 | <0.0001 | 35.3 ± 10.7 | 46.2 ± 12.1 | 0.001 |
| RVSP (mmHg) | 35.3 ± 9.7 | 53.9 ± 12.6 | <0.0001 | 29.4 ± 5.9 | 40.1 ± 14.0 | <0.0001 |
| Forward SVI (mL/m2) | 30.6 ± 9.8 | 36.6 ± 14.7 | 0.047 | 37.5 ± 7.9 | 45.5 ± 10 | 0.0004 |
| RVol (mL) | 14 ± 12 | 38 ± 14 | <0.0001 | |||
DcT, mitral deceleration time; EF, ejection fraction; LAVI, left atrial volume index; LVDd, left ventricular diastolic dimension; LVDs, left ventricular systolic dimension; RVol, regurgitant volume; RVSP, right ventricular systolic pressure; SVI, stroke volume index; WMSI, wall motion score index.
For mitral apparatus 3D measurements (Table 5), while annulus size was similar in diastole in acute vs. chronic MI regardless of IMR, in it was larger with IMR and in chronic MI irrespective of IMR. Hence, acute MI ‘with’ IMR had annular size similar to chronic MI ‘without’ IMR (all P > 0.30), showing that annular enlargement is modest in acute IMR, at levels insufficient to produce IMR chronically. Similarly, mitral annulus is flatter with IMR and in chronic MI irrespective of IMR. Hence, acute MI ‘with’ MR has systolic annular saddle shape similar to chronic MI ‘without’ IMR (P = 0.11), showing that annular flattening is modest in acute IMR, at level insufficient to produce IMR chronically. Larger tenting was observed with IMR and in chronic MI with or without IMR. Hence, tenting degree in acute IMR is modest.
Table 5.
3D mitral apparatus characteristics in acute and chronic MI
| Mid-diastole |
Average systole |
||||||
|---|---|---|---|---|---|---|---|
| Acute MI | Chronic MI | P-value | Acute MI | Chronic MI | P-value | ||
| Annulus | |||||||
| Area (cm2) | IMR | 9.29 ± 1.74 | 9.54 ± 2.00 | 0.53 | 8.18 ± 1.59 | 8.99 ± 1.65 | 0.02 |
| No-MR | 8.57 ± 1.94 | 8.71 ± 2.05 | 0.78 | 7.40 ± 1.63 | 8.31 ± 1.99 | 0.04 | |
| Circumference (mm) | IMR | 109.5 ± 10.1 | 111.3 ± 11.5 | 0.45 | 102.7 ± 10.0 | 108.0 ± 9.5 | 0.02 |
| No-MR | 105.2 ± 11.6 | 106.0 ± 12.3 | 0.81 | 97.8 ± 10.6 | 103.5 ± 11.9 | 0.05 | |
| AP diameter (mm) | IMR | 31.8 ± 3.4 | 33.0 ± 4.5 | 0.15 | 30.2 ± 3.2 | 31.4 ± 3.8 | 0.08 |
| No-MR | 30.2 ± 4.2 | 31.3 ± 4.0 | 0.37 | 28.3 ± 3.6 | 29.9 ± 4.1 | 0.10 | |
| IC diameter (mm) | IMR | 36.3 ± 3.7 | 35.9 ± 3.7 | 0.63 | 33.4 ± 3.5 | 35.5 ± 2.8 | 0.01 |
| No-MR | 34.7 ± 3.8 | 34.0 ± 3.5 | 0.48 | 31.8 ± 3.4 | 34.0 ± 3.7 | 0.02 | |
| Height (mm) | IMR | 3.93 ± 1.64 | 2.80 ± 1.86 | 0.004 | 4.23 ± 1.52 | 3.17 ± 1.41 | 0.002 |
| No-MR | 4.72 ± 1.93 | 3.16 ± 1.22 | 0.002 | 4.74 ± 1.53 | 3.59 ± 1.52 | 0.01 | |
| Saddle shape (%) | IMR | 10.8 ± 4.5 | 7.8 ± 5.1 | 0.01 | 12.7 ± 4.5 | 8.9 ± 3.9 | 0.0002 |
| No-MR | 13.6 ± 5.5 | 9.4 ± 3.8 | 0.004 | 15.0 ± 4.6 | 10.8 ± 4.8 | 0.001 | |
| Leaflet tenting | |||||||
| Maximum tenting length (mm) | IMR | 6.36 ± 1.78 | 11.28 ± 2.76 | <0.0001 | |||
| No-MR | 5.60 ± 1.55 | 8.56 ± 2.41 | <0.0001 | ||||
| Mean tenting length (mm) | IMR | 2.78 ± 1.15 | 4.75 ± 1.73 | <0.0001 | |||
| No-MR | 2.11 ± 0.95 | 3.52 ± 1.63 | <0.0001 | ||||
| Tenting volume (cm3) | IMR | 1.89 ± 0.88 | 3.89 ± 1.56 | <0.0001 | |||
| No-MR | 1.38 ± 0.57 | 2.57 ± 1.29 | <0.0001 | ||||
| Papillary muscles | |||||||
| PM area (cm2) | IMR | 3.90 ± 1.07 | 5.09 ± 1.63 | <0.0001 | 3.68 ± 1.02 | 5.50 ± 1.36 | <0.0001 |
| No-MR | 3.53 ± 0.90 | 4.63 ± 2.05 | 0.001 | 3.40 ± 0.81 | 4.68 ± 1.46 | <0.0001 | |
| PMP-AA length (mm) | IMR | 36.5 ± 4.7 | 49.0 ± 6.6 | <0.0001 | 37.5 ± 4.4 | 50.3 ± 6.0 | <0.0001 |
| No-MR | 37.5 ± 6.0 | 49.8 ± 6.9 | <0.0001 | 37.7 ± 5.0 | 47.8 ± 6.6 | <0.0001 | |
| ALP-AA length (mm) | IMR | 34.8 ± 5.3 | 44.5 ± 7.8 | <0.0001 | 35.1 ± 4.7 | 45.5 ± 5.8 | <0.0001 |
| No-MR | 34.7 ± 5.1 | 44.0 ± 6.7 | <0.0001 | 35.1 ± 5.2 | 43.7 ± 4.8 | <0.0001 | |
| PMP/ALP ratio | IMR | 1.06 ± 0.14 | 1.13 ± 0.19 | 0.03 | 1.08 ± 0.11 | 1.12 ± 0.16 | 0.14 |
| No-MR | 1.08 ± 0.13 | 1.10 ± 0.09 | 0.55 | 1.08 ± 0.10 | 1.09 ± 0.11 | 0.69 | |
| PM width (mm) | IMR | 23.5 ± 4.9 | 24.6 ± 6.2 | 0.36 | 21.7 ± 4.9 | 25.4 ± 5.0 | 0.001 |
| No-MR | 21.2 ± 4.3 | 22.1 ± 7.0 | 0.47 | 20.0 ± 3.4 | 22.3 ± 6.0 | 0.03 | |
| PM angle (°) | IMR | 38.1 ± 8.0 | 28.9 ± 9.3 | <0.0001 | 34.3 ± 7.3 | 28.8 ± 6.6 | 0.001 |
| No-MR | 33.8 ± 8.4 | 24.3 ± 7.9 | 0.0002 | 31.4 ± 6.3 | 24.1 ± 5.1 | <0.0001 | |
Data are expressed as mean ± SD.
AA, anterior annulus fibrosa; ALP, anterolateral papillary; AP, anteroposterior; IC, inter-commissural; PM, papillary muscle; PMP, posteromedial papillary.
For PM spatial positions, PMs symmetry (PMP/ALP ratio) is similar in acute and chronic MI, with or without IMR. Conversely, PM displacement is radically different in acute and chronic MI: More apical displacement (PMP-AA and ALP-AA lengths) in chronic MI (particularly IMR); Wider PMs angle with IMR and much wider in acute MI than chronic MI (Table 5, lower two rows). Because PMs are attached to leaflets by inextensible chordae, widened PMs angle deforming leaflets, affects coaptation and is specific of IMR in acute MI.
Dynamic changes in mitral annular and PMs over the cardiac cycle (Figure 4) show different dynamics of IMR with acute vs. chronic MI. Reduced dynamics in chronic MI (phasic P > 0.10) particularly with IMR (yellow dots) for annular area (left graph) and saddle shape (second left graph) contrast with acute MI (red and blue dots). The middle graph shows large tenting adynamic in chronic MI with IMR, vs. dynamic decrease in acute MI. PM area (second graph to right) is largest and adynamic in chronic MI with IMR (P value phase, P > 0.10) while it decreases dynamically in acute MI. PM-angle (right graph) shows dynamic change in acute MI but is constantly larger (particularly with IMR) than in chronic MI (P for interaction, all < 0.05). Hence dynamically, PM-angle widening specific to IMR of acute MI persists throughout the cardiac cycle.
Figure 4.
Mitral apparatus dynamics in acute vs. chronic MI with and without IMR. Dynamic changes in acute (red and blue symbols) vs. chronic (yellow and purple symbols) MI with IMR vs. without IMR: mitral annulus: (A) area; (B) saddle shape (instantaneous ratio of annular height to inter-commissural diameter), valvular tenting: (C) tenting volume papillary muscles, spatial position: (D) area of the papillary muscles-fibrosa triangle; (E) papillary muscle angulation. Mitral annular and valvular deformations are larger with chronic IMR (green symbols averaged) even without IMR. Sub-valvular deformation shows larger PM areas with chronic MI (apical displacement of PM) while PM angle is largest in acute MI particularly with IMR. Mitral dynamics are mostly lost with chronic MI and maintained throughout the cardiac cycle with acute MI. Statistical difference between acute and chronic MI. #Group with dynamic change throughout the cardiac cycle by MANOVA.
Interobserver and intraobserver variability for 3D measurements
Intraobserver agreement was good: EDV (mean-difference, 2.08 ± 7.79 mL, P = 0.56; r = 0.98); EF (mean-difference 0.72 ± 2.62%, P = 0.55; r = 0.88); mitral annular area (mean-difference 0.01 ± 0.44 cm2, P = 0.95; r = 0.96); annular height (mean-difference 0.48 ± 0.61 mm, P = 0.11; r = 0.74). Bland–Altman plots showed random scatter of points around 0 with no systematic bias or shift. Measurement variability (within-subject coefficient of variation and 95% confidence interval of Bland–Altman): EDV, 7.4%, ±7.79 mL; EF, 7.5%, ±2.62%; annular area, 7.9%, ±0.44 cm2; annular height, 17.0%, ±0.61 mm.
Interobserver agreement was good: EDV (mean-difference, 5.10 ± 10.38 mL, P = 0.30; r = 0.95); EF (mean-difference 0.20 ± 3.94%, P = 0.91; r = 0.84); mitral annular area (mean-difference 0.16 ± 0.75 cm2, P = 0.64; r = 0.78); annular height (mean-difference 0.48 ± 0.61 mm, P = 0.11; r = 0.74). Bland–Altman plots showed random scatter of points around 0 with no systematic bias or trend. Measurements variability were EDV, 10.1%, ±10.38 mL; EF, 10.9%, ±3.94%; annular area, 13.0%, ±0.75 cm2; and annular height, 16.8%, ±0.65 mm.
Discussion
We prospectively enrolled patients with acute MI, with and without IMR, balanced for age and MI size with early 4D echocardiography, dynamic analysis and comparison to chronic MI. We uncovered novel insights into IMR pathophysiology. First, despite similar MI size and low RVol, IMR is associated with marked haemodynamic alterations, larger LV volumes and markedly reduced forward stroke-volume, worse with increasing IMR severity. Second, contrasting with loss of dynamicity of annulus and PMs of IMR associated with chronic MI, in acute MI annulus and PMs remain dynamic. Third, traditional IMR mechanisms, flattening/enlargement of mitral annulus, and valvular tenting, while present in acute IMR are modest, less severe than in chronic MI, but are linked to MR severity. Finally, we uncovered the deformation specifically associated with IMR complicating acute MI, greater PM angulation resulting in excessive leaflets tension, and regurgitation. PM excess angulation, while dynamic, remains widest throughout the cardiac cycle in acute IMR. Hence, our findings reveal pathophysiology of IMR complicating acute MI and should guide novel therapies.
Dynamics of mitral apparatus in health and disease
The normal mitral annulus displays acute contraction of anteroposterior diameter20 that decreases annular area and approximates leaflets before LV pressure rises. Simultaneously, the annulus accentuates its saddle shape25 in early systole with deepening of commissures,20 also bringing leaflets together and reducing their tension. These two components are essential to prevent early systolic MR. Subvalvular apparatus is also dynamic with early PM contraction, pre-tensioning mitral leaflets followed by PM movement towards the annulus minimizing valvular tenting. Abnormal mitral dynamic is mostly known in myxomatous disease whereby annulus is poorly contracting in early-systole and enlarges in late-systole contributing to MR severity. Conversely, mitral dynamics in IMR is only known in mostly severe chronic cases, where adynamic annulus and subvalvular apparatus cause uncompensated tenting, yielding chronic IMR.10,20,26 This raises questions of mitral dynamics in acute MI to consider mitral annuloplasty as therapy.27 Contrary to expectations, acute IMR is not associated with reduced mitral dynamics despite marked haemodynamic and LV with adverse outcomes.1,5,28 Thus, persistent mitral dynamics in acute MI is a major difference with chronic IMR and raises the issue of specific IMR cause in acute MI.
Specific pathophysiologic mechanisms in acute MI
Common concepts regarding IMR link tethering forces caused by PM apical displacement29–32 to valvular tenting,33 leaflets uncoaptation34 annulus dilatation,26 and flattening.7 One could surmise that similar mechanisms operate acutely as acute IMR is not just function of coronary patency35 but follows LV response to MI.11 However, we show that IMR in acute MI is not linked to the same PM apical displacement and is associated with less LV remodelling.10,36,37 In chronic MI, extensive LV remodelling with apical PM displacement yields more leaflet tenting,10,38 and annulus is larger/flatter.10,20 In acute MI these changes are modest and difficult to consider responsible for IMR. We cannot rule out that these small changes pre-existed the MI, although it is unlikely, Conversely, one prominent change in IMR of acute MI is PM angulation, which imposes an acute lateral traction on leaflets, and is the widest observed in any group. Hence, the specific mitral deformation linked to IMR in acute MI is marked widening of angle separating PMs from the centre of mitral leaflets (fibrosa). Similar observations have been reported recently in animal models of acute IMR.19,39 this angular separation has been hypothesized as the basis for IMR surgical treatment40 or post-repair IMR recurrence41 but has never been directly documented in patients with acute MI. Our findings are consistent with interventions approximating PMs through ‘sling’ implantation that result in less recurrent IMR post-repair,42 better leaflet mobility,40 and improved reverse remodelling,42,43 and should guide development of new therapies.
Limitations, strengths, and clinical implications
While 3D datasets originate from two centres, all measurements were standardized with rigorous quality control. No difference was noted between Japanese and US patients. Without imaging before MI, MR presence before MI cannot be excluded but is unlikely given structurally normal leaflets. We did not match patients with and without IMR for all MI characteristics but rather for the most important such as age and MI size. However, the acute MI groups were quite similar in term of MI location (anterior in 41% with IMR vs. 46% with no-MR, P = 0.54) and of multivessel disease (65% with IMR vs. 47% with no-MR, P = 0.42) demonstrating the balanced nature of these groups apart from the IMR. Comparing acute and chronic MI, matching LV size is impossible but it is the nature of progression to chronic stage. Future studies using repeated 3D imaging should assess changes over time and their link to presence and progression of IMR in the chronic phase of MI. Percutaneous treatment of IMR in acute MI has been considered contra-indicated and rarely used.44 However, given ominous implications of IMR in acute MI, 28 various therapeutic options13,45 may be considered in the future based on our data.
Conclusions
Prospective quantitative 3D echocardiography reveals distinct changes associated with IMR in incident MI. Despite modest RVol, acute IMR is associated with serious haemodynamic and LV alterations. Mechanistically, unlike chronic IMR, in acute IMR mitral apparatus remains dynamic and valvular tenting is modest but linked to MR severity. Tenting and IMR are independently linked to angulation of PMs, a distinct alteration to be considered in novel treatment strategies.
Acknowledgements
The authors thank Ellen E. Koepsell, RN, and Deborah S. Strain for their study support.
Funding
This work was supported by a grant from the National Institutes of Health, National Heart, Lung and Blood Institute [grant number R01 HL120957]. The funding sources played no role in the design, conduct, or reporting of this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, National Heart, Lung and Blood Institute.
Conflict of interest: none declared.
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