Mitral Chordal-Leaflet-Myocardial Interactions in Mitral Valve Prolapse Sherryn Rambihar, MD, FRCPC, Anthony J. Sanfilippo, MD, FRCPC, FASE, and Zion Sasson, MD, FRCPC, FASE, Toronto and Kingston, Ontario, Canada
Background: The submitral apparatus maintains annular-papillary continuity and myocardial geometry. In mitral valve prolapse (MVP), elongated chords and redundant leaflets can interact at the region of myocardial attachment, leading to apparent discordant motion of the basal inferolateral wall. The aim of this study was to test the hypothesis that basal inferolateral wall inward motion would occur later in MVP and that this delay is associated with MVP severity. Methods: Thirty consecutive patients with MVP and matched controls underwent stress echocardiography. Time to peak transverse displacement (TPD) of the inferolateral wall compared with the anteroseptal wall was measured using speckle-tracking echocardiography. The time difference was analyzed as raw data, normalized to the RR interval, and as a percentage of the time to maximal displacement of the anteroseptal segment(s). Results: Compared with controls, TPD was delayed in patients with MVP both at rest and at peak stress, when evaluating basal segments or basal-mid segments as a unit, both in real time and, more importantly, when correcting for anteroseptal TPD. In patients compared with controls, observed delay at rest and at peak stress was 50 6 90 versus 30 6 90 msec (P = .006) and 70 6 80 versus 30 6 60 msec (P < .0001), respectively; relative to TPD of the anteroseptal segment, the observed delay at rest and at peak stress was 117 6 24% versus 97 6 22% (P = .007) and 144 6 68% versus 95 6 21% (P = .003), respectively. Similar significant findings were observed in basal-mid segments. TPD results were not statistically significant when stratified by prolapse severity. Intraclass correlation coefficients were 0.88 and 0.93, and two-tailed t tests indicated good interobserver and intraobserver variability. Conclusions: Inferolateral wall TPD is delayed in MVP. TPD is a novel method to characterize chordal-leafletmyocardial interactions in patients with MVP. Prolapse severity does not predict TPD, likely because of the timing of prolapse and dynamic loading conditions. Implications of this observation include attribution of a perceived wall motion abnormality in MVP during stress echocardiography to a physiologic state and new mechanistic insights into mitral valve physiology. (J Am Soc Echocardiogr 2014;-:---.) Keywords: Mitral valve prolapse, Mechanics, Echocardiography, Speckle strain
The mitral chordal apparatus plays a key role in the maintenance of ventricular geometry and performance.1-12 Mitral valve prolapse (MVP) is a condition characterized, in part, by elongation of the chordal apparatus and delay in maximal stretch during systole.13,14 This delay may influence the timing of myocardial motion in the segment(s) to which the elongated chordae attach and therefore complicate the assessment of left ventricular (LV) systolic function, both at rest and with the enhanced inotropy associated with exercise. A better understanding of this phenomenon may
therefore benefit the echocardiographic interpretation of systolic function at rest and after exercise in patients with MVP. We therefore sought to characterize mitral chordal-leafletmyocardial (CLM) interactions in MVP using novel applications of speckle-tracking echocardiography. We hypothesized that the delay in mitral chordal-leaflet maximal stretch in patients with MVP will result in delayed maximal inward motion of the basal inferolateral wall compared with the opposing corresponding basal anteroseptal segment and that this delay is associated with MVP severity.
From the Division of Cardiology, University of Toronto, Toronto, Ontario, Canada (S.R., Z.S.); and Division of Cardiology, Queen’s University, Kingston, Ontario, Canada (A.J.S.).
METHODS
Reprint requests: Zion Sasson, MD, FRCPC, FASE, Mount Sinai Hospital, 1601600 University Avenue, Toronto, ON M5X 1B2, Canada (E-mail: zsasson@ mtsinai.on.ca). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.02.011
Study Population The study population consisted of 30 consecutive patients with MVP meeting the inclusion criteria, who underwent stress echocardiography. Prolapse was defined as maximal end-systolic displacement of the body of the posterior mitral leaflet >2 mm superior to the line connecting the annular hinge points in the parasternal long-axis view.15-18 All individuals had posterior mitral leaflet 1
2 Rambihar et al
involvement. Inclusion criteria were mitral regurgitation of LV = Left ventricular less than moderate severity, normal LV systolic function, MVP = Mitral valve prolapse and no LV regional wall TPD = Time to peak motion abnormalities. Thirty transverse displacement age-matched and sex-matched controls were selected from a population of contemporaneous patients referred for stress echocardiography at the same institution. Abbreviations
Exercise Stress Echocardiography All patients underwent maximal symptom-limited treadmill exercise echocardiography according to the Bruce protocol, as previously outlined by the American Society of Echocardiography.19 Doppler echocardiography with color flow was performed using a commercially available system (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway). Images were acquired from standard parasternal and apical views and stored digitally in cine loop format for three consecutive analyzable beats. Offline measurements were performed by a single observer using EchoPAC version 104.3.0 (GE Vingmed Ultrasound AS). Quantification of the extent of MVP was performed by two individuals.20 To assess intraobserver variability and avoidance of recall bias, the same observer reassessed the amount of prolapse 6 months after initial assessment in 10 randomly selected patients. To assess interobserver variability, a second observer, blinded to the results of the first, performed 10 independent measurements on the same patients for two different parameters on a different reading station. Speckle-Tracking Strain Analysis Standard grayscale two-dimensional images were obtained in parasternal and apical views. All images were recorded at frame rates of 70 to 100 Hz and digitally saved in cine loop format. Offline speckle-tracking analysis was performed using software for echocardiographic quantification (EchoPAC version 104.3.0). Endocardial borders of the left ventricle were manually traced within the endsystolic frame. The epicardial tracing was automatically generated
Journal of the American Society of Echocardiography - 2014
by the software algorithm and manually adjusted when necessary. Tracking was accepted only if both visual inspection and EchoPAC software analysis confirmed that it was adequate. Peak transverse displacement in the basal inferolateral, middle inferolateral, basal anteroseptal, and middle anteroseptal walls was assessed in apical long-axis views, and a time-displacement profile was exported to Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA) for quantitative analysis. Time to peak transverse displacement (TPD) was defined as the time to maximal inward motion of a given myocardial segment (Figure 1). Speckle-tracking consistently tracks pixels within myocardial segments, thus tracking the displacement of myocardial segments at rest and immediately after exercise. By measuring and comparing this parameter in basal and mid inferolateral and anteroseptal segments, the extent of dyssynchrony could be determined in patients with normal mitral valve and ventricular structure and in those with MVP (Figures 2–4, Videos 1–4; available at www. onlinejase.com). Because chordal attachments may be variable, we assessed both the relative differences between TPD in basal segments and the average of TPD in all anteroseptal versus inferolateral segments. Both groups were assessed at rest and immediately after exercise. All data were abstracted electronically, using customprogrammed software macros, and checked qualitatively to ensure that computer-derived results were not spurious. To assess intraobserver variability, measurements of TPD and extent of MVP were performed by the same observer in 10 randomly selected subjects (five patients and five controls) on the same cardiac cycle at baseline and repeated 6 months later. To assess interobserver variability, a second observer blinded to the results of the first performed independent measurements of the same variables in the same 10 subjects and the same cardiac cycle on a different reading station. Statistical Analysis Statistical analyses were performed using SPSS versions 11.0 and 20.0 (SAS Institute Inc, Cary, NC). Prespecified analyses were performed using paired and unpaired t tests for discrete variables and comparisons for continuous variables, within and between patients with MVP and controls, at rest and at peak stress. Results are expressed
Figure 1 Speckle strain analysis, with automatic tracking of the LV endocardial borders in the apical long axis. Demonstration of automated measurement of peak displacement, from which the primary end point, TPD, was derived.
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Figure 2 Apical long-axis images at rest (A) and post-stress (B) in a patient with MVP, illustrating the MVP-related wall motion abnormality in the basal inferolateral wall(s). (Additional content: Video 1, patient with MVP at rest; Video 2, patient with MVP poststress).
Figure 3 Speckle strain analysis, with automatic tracking of the LV endocardial borders in the apical long axis in a control subject (A) and in a patient with MVP (B). The basal inferolateral (yellow), mid inferolateral (cyan), basal anteroseptal (red), and mid anteroseptal (blue) segments are shown. (Additional content: Video 3, control; Video 4, patient with MVP).
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Figure 4 Transverse displacement (y axis, mm) versus time (x axis, sec) derived from speckle strain analysis in the apical long axis, in a control subject (A) and in a patient with MVP (B). The basal inferolateral (yellow), middle inferolateral (cyan), basal anteroseptal (red), and middle anteroseptal (blue) segments are shown.
Table 1 Baseline characteristics Variable
Patients with MVP (n = 30)
Controls (n = 30)
Women 87% (26) 87% (26) Age (y) 61.4 6 17.1 61.4 6 17.1 Height (cm)* 160.3 6 6.5 161.3 6 9.2 Weight (kg)* 64 6 8.6 65.5 6 11.9 Resting HR (beats/min) 81 6 13 82 6 16 Peak HR (beats/min) 147 6 15 149 6 20 Resting BP (mm Hg) 118 6 18/73 6 9 120 6 20/69 6 12 Peak BP (mm Hg) 168 6 27/72 6 17 170 6 24/66 6 11 Time on treadmill (min) 7.7 6 2.4 8.6 6 2.6 Mets achieved 8.7 6 2.8 9.63 6 3.6 0.3 6 0.3 0.5 6 0.4 Maximal ECG STsegment deviation at rest (mm) Maximal ECG ST1.0 6 0.7 1.1 6 0.9 segment deviation at peak stress (mm)
P
NS NS NS NS NS NS NS NS NS NS NS
between groups, with identical ages and sex and similar weights, heights, rest and peak heart rates, rest and peak blood pressures, and maximal ST-segment deviation at rest and during stress. Compared with controls, patients with MVP demonstrated significant delay in TPD of the segment(s) associated with the prolapsing leaflet at rest and at peak stress (P < .003 to P < .0001; Tables 2 and 3). Results were statistically significant for all prespecified analyses: raw data, normalized to the RR interval, and relative to the TPD for anteroseptal segment(s). For the assessment of subgroups, we divided patients into groups of those with less severe and more severe prolapse according to the modal value in the population, #4-mm or >4-mm deviation from the annular plane. Results are shown in Table 4. The delay in TPD was not significantly different when assessed by severity of prolapse; numerically, however, the values trended in the hypothesized direction, with the myocardial segment involved with the prolapsing leaflet demonstrating earlier TPD and ‘‘normalizing’’ the perceived delay.
NS
BP, Blood pressure; ECG, electrocardiographic; HR, heart rate. Data are expressed as percentage (number) or mean 6 SD. *Limited data on height and weight were available for patients in the case arm; data were abstracted from 9 subjects.
as means or percentages with 95% confidence intervals. Nonparametric comparisons between groups were based on Wilcoxon’s rank-sum test. Parametric comparisons between the two groups were based on a two-sample Student’s t test. P values < .05 were considered statistically significant. For the assessment of subgroups, the cut point for defining milder versus more severe prolapse was the modal value for prolapse, 4 mm. Unpaired t tests were used to determine differences between the two groups. Paired-samples two-tailed t tests with Pearson’s correlation coefficients were used to assess the intraobserver variability of the same measures taken at baseline and 6 months later, and intraclass coefficients were used to assess interobserver variability.
RESULTS Clinical, electrocardiographic, and echocardiographic characteristics of patients with MVP and age-matched and sex-matched controls are compared in Table 1. There were no significant differences
Reproducibility and Interobserver Variability Excellent interobserver and intraobserver variability was observed, using data from 10 randomly selected patients for the amount of MVP and TPD of the inferolateral and anteroseptal segments. Two-tailed t tests of values between one individual at baseline and after 6 months were not statistically significant, with a Pearson’s coefficient of 0.656 for amount of prolapse and P = .883 for TPD. The mean difference between observers varied from 0% to 14%. Intraclass coefficients demonstrated excellent agreement (r = 0.88 for amount of prolapse, r = 0.931 for TPD).
DISCUSSION In MVP, the inward motion of the inferolateral myocardial segments, papillary muscle, and adjacent structures is temporarily dissociated from the remaining LV wall segments. This appears to be due to the delayed application of tethering forces by the abnormal mitral leaflets and chordae on the inferolateral papillary muscle and adjacent structures. We believe this is the first comprehensive evaluation of CLM interactions in this population. We demonstrated a delay in TPD in MVP involving the segment(s) to which abnormal chords are attached. Although chordal insertion is variable, the delay was demonstrated in both proximal and averaged subtended segments. Prolapse severity does not predict TPD, possibly because of issues with timing and dynamic physiologic loading conditions.
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Table 2 TPD: delay of basal inferolateral wall relative to basal anteroseptal wall Patients with MVP (n = 30)
Variable
Rest Real time (msec) Relative to TPD of anteroseptal segment (%) (anteroseptal segment = 100%) Peak stress Real time (msec) Relative to TPD of anteroseptal segment (%) (anteroseptal segment = 100%)
Controls (n = 30)
P
50 6 90 117 6 24
30 6 90 97 6 22
.006 .007
70 6 80 144 6 68
30 6 60 95 6 21
4 mm beyond the annular line.
Much of our understanding of the physiologic interactions between the mitral valve and the left ventricle is derived from cardiac surgical literature assessing the role of chordal preservation in mitral valve surgery.1-12,21-24 The ‘‘papillary muscle–annular continuity’’ is crucial in mediating geometrically effective LV contraction during systole23 and moderating LV distension in diastole. The complex saddle shape of the mitral valve also deforms through the cardiac cycle, with leaflet-annular relationships crucial in reducing leaflet stress and enhancing systolic competence.25-27 Much of the literature to date characterizes the physiology and mechanics of the mitral apparatus by focusing on leaflet-annular relationships using three-dimensional geometric modeling, two-dimensional echocardiography with radiopaque markers, and, more recently, real-time three-dimensional, full-volume acquisition with transesophageal echocardiography.25-30 TPD by speckle-tracking echocardiography is a novel method to characterize CLM interactions in patients with MVP, which we believe
adds further insight to the understanding of mitral and LV dynamics in MVP. In MVP, increased leaflet redundancy, chordal elongation, and billowing of the prolapsing segment into the left atrium in systole applies a delayed and rapidly developing force to the papillary muscle.21 This is translated to the adjacent segment of the basal to mid inferolateral wall and visualized as a late and brisk deformation. Using speckle-tracking echocardiography, we were able to demonstrate this as a delay in TPD of the basal inferolateral segment relative to the corresponding opposite wall, a novel method for characterizing mitral CLM interactions in patients with MVP. A recent cardiac magnetic resonance imaging study demonstrated localized basal inferolateral hypertrophy in patients with MVP, corresponding to the delayed segment of interest in our study.31 The association between these two observations is intriguing but requires further study. A significant association between the severity of MVP and delay in TPD was not observed. This may be because severity, quantified as the absolute distance of leaflet prolapse, is not equivalent to timing, and factors governing timing may not affect severity per se. Additionally, as more severe MVP tends to occur earlier in systole, an earlier pull exerted on the papillary muscle results in a more rapid TPD, mimicking, in the extreme, normal synergy with onset of TPD in early systole. Superimposed on these scenarios are numerous physiologic factors that influence preload, afterload, and inotropy and may confound the timing of prolapse. As such, more complex models may be required to better characterize these relationships. The implications of our research extend beyond physiologic characterization to patient care. The association between MVP and symptoms such as chest pain could possibly be associated with the rapid development of tensile forces, which can be studied
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prospectively in the future. With stress echocardiography, the delayed displacement of the inferolateral wall due to physiologic mitral CLM interactions may be identified as hypokinesis or tardokinesis and falsely interpreted as ischemia. Attribution of a perceived wall motion abnormality in MVP during stress echocardiography to an MVPrelated wall motion abnormality may thus be helpful. Limitations This study was a post hoc observational analysis, which attempted to explore and characterize mechanistic aspects of mitral valve and LV motion in patients with MVP. The small number of patients in the MVP cohort may explain the wide confidence intervals, but robust statistical significance was achieved for all primary analyses. Control patients were referred for stress echocardiography for clinical indications and may not represent a random population sample. However, with normal results on rest and stress echocardiography, we believed that this subset represented an appropriate control group. Finally, the inability to delineate differences in TPD in milder versus more severe MVP likely relates to the role of timing in severity of prolapse and small sample size, or both.
CONCLUSIONS Using novel speckle-tracking echocardiographic techniques, we have demonstrated that in patients with MVP, there is a delay in maximal inward motion of the basal inferolateral wall compared with the opposite corresponding basal anteroseptal segment and that this delay varies with exercise inotropy. This builds on data from the surgical literature regarding the physiologic importance of chordal apparatus and provides new mechanistic insights that inform our understanding of the mitral chordal-leaflet-myocardial interactions.
SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.echo.2014.02.011. REFERENCES 1. Sarris GE, Fann JI, Niczyporuk MA, Derby GC, Handen CE, Miller DC. Global and regional left ventricular systolic performance in the in situ ejecting canine heart: importance of the mitral valve apparatus. Circulation 1989;80(suppl):24-42. 2. Gams E, Schad H, Heimisch W, Hagl S, Mendler N, Sebening F. Preservation versus severance of the subvalvular apparatus in mitral valve replacement: an experimental study. Eur J Cardiothorac Surg 1990;4: 250-6. 3. David TE, Uden DE, Strauss HD. The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation. Circulation 1983;68(suppl):II-76-82. 4. David TE, Burns RJ, Bacchus CM, Druck MN. Mitral valve replacement for mitral regurgitation with and without preservation of chordae tendineae. J Thorac Cardiovasc Surg 1984;88:718-25. 5. Bonchek LI, Olinger GN, Siegel R, Tresch DD, Keelan MH Jr. Left ventricular performance after mitral reconstruction for mitral regurgitation. J Thorac Cardiovasc Surg 1984;88:122-7. 6. David TE, Ho WC. The effect of preservation of chordae tendineae on mitral valve replacement for postinfarction mitral regurgitation. J Thorac Cardiovasc Surg 1986;74(suppl):I-116-20.
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7. Goldman ME, Mora F, Guarino T, Fuster V, Mindich BP. Mitral valvuloplasty is superior to valve replacement for preservation of left ventricular function: an intraoperative two-dimensional echocardiographic study. J Am Coll Cardiol 1987;10:568-75. 8. Angell WW, Oury JH, Shah P. A comparison of replacement and reconstruction in patients with mitral regurgitation. J Thorac Cardiovasc Surg 1987;93:665-74. 9. Miki S, Kusuhara K, Ueda Y, Komeda M, Ohkita Y, Tahata T. Mitral valve replacement with preservation of chordae tendineae and papillary muscles. Ann Thorac Surg 1988;45:28-34. 10. Pitarys CJ II, Forman MB, Panayiotou H, Hansen DE. Long-term effects of excision of the mitral apparatus on global and regional ventricular function in humans. J Am Coll Cardiol 1990;15:557-63. 11. Tischler MD, Cooper KA, Rowen M, LeWinter MM. Mitral valve replacement versus mitral valve repair. Circulation 1994;89:132-7. 12. Takayama Y, Holmes JW, LeGrice I, Covell JW. Enhanced regional deformation at the anterior papillary muscle insertion site after chordal transection. Circulation 1996;93:585-93. 13. Freed L, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, et al. Prevalence and clinical outcome of mitral valve prolapse. N Engl J Med 1999;341:1-7. 14. Adams D, Rosenhek R, Falk V. Degenerative mitral valve regurgitation: best practice revolution. Eur Heart J 2010;31:1958-67. 15. Nishimura RA, McGoon MD, Shub C, Miller FA Jr., Ilstrup DM, Tajik AJ. Echocardiographically documented mitral-valve prolapse: long-term follow-up of 237 patients. N Engl J Med 1985;313:1305-9. 16. Marks AR, Choong CY, Sanfilippo AJ, Ferre M, Weyman AE. Identification of high-risk and low-risk subgroups of patients with mitral-valve prolapse. N Engl J Med 1989;320:1031-6. 17. Levine RA, Stathogiannis E, Newell JB, Harrigan P, Weyman AE. Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol 1988;11:1010-9. 18. Shah PM. Echocardiographic diagnosis of mitral valve prolapse. J Am Soc Echocardiogr 1994;7:286-93. 19. Pellikka PA, Nagueh SF, Elhendy AA, Kuehl CA, Sawada SG. American Society of Echocardiography recommendations for performance, interpretation and application of stress echocardiography. J Am Soc Echocardiogr 2007;20:1021-41. 20. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802. 21. Sanfilippo AJ, Harrigan P, Popovic A, Weyman AE, Levine RA. Papillary muscle traction in mitral valve prolapse: quantitation by twodimensional echocardiography. J Am Coll Cardiol 1992;19:564-71. 22. Granier M, Jensen M, Honge J, Bel A, Menasche P, Nielsen SL, et al. Consequences of mitral valve prolapse on chordal tension: ex vivo and in vivo studies in large animal models. J Thorac Cardiovasc Surg 2010;142:1585-7. 23. David TE. Papillary muscle-annular continuity: is it important. J Card Surg 1994;9(suppl):252-4. 24. Athanasiou T, Chow A, Rao C, Aziz O, Siannis F, Ali A, et al. Preservation of the mitral valve apparatus: evidence synthesis and critical reappraisal of surgical techniques. Eur J Cardiothorac Surg 2008;33:391-401. 25. Levine RA, Handschumacher MD, Sanfilippo AJ, Hagege AA, Harrigan P, Marshall JE, et al. Three-dimensional echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse. Circulation 1989;80:589-98. 26. Levine RA, Triulzi MO, Harrigan P, Hagege AA, Harrigan P, Marshall JE, et al. The relationship of mitral annular shape to the diagnosis of mitral valve prolapse. Circulation 1987;75:756-67. 27. Salgo IS, Gorman JH, Gorman RC, Jackson BM, Bowen FW, Plappert T, et al. Effect of annular shape on leaflet curvature in reducing mitral leaflet stress. Circulation 2002;106:711-7. 28. Ormiston J, Shah P, Tei C, Wong M. Size and motion of the mitral valve annulus in man, II: abnormalities in mitral valve prolapse. Circulation 1982;65:713-9.
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29. Grewal J, Suri R, Mankad S, Tanaka A, Mahoney DW, Schaff HV, et al. Mitral annular dynamics in myxomatous valve disease: new insights with real-time 3-dimensional echocardiography. Circulation 2010;121: 1423-31. 30. Biaggi P, Jedrzkiewicz S, Gruner C, Meineri M, Karski J, Vegas A, et al. Quantification of mitral valve anatomy by three-dimensional transesopha-
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geal echocardiography in mitral valve prolapse predicts surgical anatomy and the complexity of mitral valve repair. J Am Soc Echocardiogr 2012;25: 758-65. 31. Zia M, Valenti V, Cherston C, Criscito M, Uretsky S, Wolff S. Relation of mitral valve prolapse to basal left ventricular hypertrophy as determined by cardiac magnetic resonance imaging. Am J Cardiol 2012;109:1321-5.
Background: The submitral apparatus maintains annular-papillary continuity and myocardial geometry. In mitral valve prolapse (MVP), elongated chords and redundant leaflets can interact at the region of myocardial attachment, leading to apparent discordant motion of the basal inferolateral wall. The aim of this study was to test the hypothesis that basal inferolateral wall inward motion would occur later in MVP and that this delay is associated with MVP severity. Methods: Thirty consecutive patients with MVP and matched controls underwent stress echocardiography. Time to peak transverse displacement (TPD) of the inferolateral wall compared with the anteroseptal wall was measured using speckle-tracking echocardiography. The time difference was analyzed as raw data, normalized to the RR interval, and as a percentage of the time to maximal displacement of the anteroseptal segment(s). Results: Compared with controls, TPD was delayed in patients with MVP both at rest and at peak stress, when evaluating basal segments or basal-mid segments as a unit, both in real time and, more importantly, when correcting for anteroseptal TPD. In patients compared with controls, observed delay at rest and at peak stress was 50 6 90 versus 30 6 90 msec (P = .006) and 70 6 80 versus 30 6 60 msec (P < .0001), respectively; relative to TPD of the anteroseptal segment, the observed delay at rest and at peak stress was 117 6 24% versus 97 6 22% (P = .007) and 144 6 68% versus 95 6 21% (P = .003), respectively. Similar significant findings were observed in basal-mid segments. TPD results were not statistically significant when stratified by prolapse severity. Intraclass correlation coefficients were 0.88 and 0.93, and two-tailed t tests indicated good interobserver and intraobserver variability. Conclusions: Inferolateral wall TPD is delayed in MVP. TPD is a novel method to characterize chordal-leafletmyocardial interactions in patients with MVP. Prolapse severity does not predict TPD, likely because of the timing of prolapse and dynamic loading conditions. Implications of this observation include attribution of a perceived wall motion abnormality in MVP during stress echocardiography to a physiologic state and new mechanistic insights into mitral valve physiology. (J Am Soc Echocardiogr 2014;-:---.) Keywords: Mitral valve prolapse, Mechanics, Echocardiography, Speckle strain
The mitral chordal apparatus plays a key role in the maintenance of ventricular geometry and performance.1-12 Mitral valve prolapse (MVP) is a condition characterized, in part, by elongation of the chordal apparatus and delay in maximal stretch during systole.13,14 This delay may influence the timing of myocardial motion in the segment(s) to which the elongated chordae attach and therefore complicate the assessment of left ventricular (LV) systolic function, both at rest and with the enhanced inotropy associated with exercise. A better understanding of this phenomenon may
therefore benefit the echocardiographic interpretation of systolic function at rest and after exercise in patients with MVP. We therefore sought to characterize mitral chordal-leafletmyocardial (CLM) interactions in MVP using novel applications of speckle-tracking echocardiography. We hypothesized that the delay in mitral chordal-leaflet maximal stretch in patients with MVP will result in delayed maximal inward motion of the basal inferolateral wall compared with the opposing corresponding basal anteroseptal segment and that this delay is associated with MVP severity.
From the Division of Cardiology, University of Toronto, Toronto, Ontario, Canada (S.R., Z.S.); and Division of Cardiology, Queen’s University, Kingston, Ontario, Canada (A.J.S.).
METHODS
Reprint requests: Zion Sasson, MD, FRCPC, FASE, Mount Sinai Hospital, 1601600 University Avenue, Toronto, ON M5X 1B2, Canada (E-mail: zsasson@ mtsinai.on.ca). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.02.011
Study Population The study population consisted of 30 consecutive patients with MVP meeting the inclusion criteria, who underwent stress echocardiography. Prolapse was defined as maximal end-systolic displacement of the body of the posterior mitral leaflet >2 mm superior to the line connecting the annular hinge points in the parasternal long-axis view.15-18 All individuals had posterior mitral leaflet 1
2 Rambihar et al
involvement. Inclusion criteria were mitral regurgitation of LV = Left ventricular less than moderate severity, normal LV systolic function, MVP = Mitral valve prolapse and no LV regional wall TPD = Time to peak motion abnormalities. Thirty transverse displacement age-matched and sex-matched controls were selected from a population of contemporaneous patients referred for stress echocardiography at the same institution. Abbreviations
Exercise Stress Echocardiography All patients underwent maximal symptom-limited treadmill exercise echocardiography according to the Bruce protocol, as previously outlined by the American Society of Echocardiography.19 Doppler echocardiography with color flow was performed using a commercially available system (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway). Images were acquired from standard parasternal and apical views and stored digitally in cine loop format for three consecutive analyzable beats. Offline measurements were performed by a single observer using EchoPAC version 104.3.0 (GE Vingmed Ultrasound AS). Quantification of the extent of MVP was performed by two individuals.20 To assess intraobserver variability and avoidance of recall bias, the same observer reassessed the amount of prolapse 6 months after initial assessment in 10 randomly selected patients. To assess interobserver variability, a second observer, blinded to the results of the first, performed 10 independent measurements on the same patients for two different parameters on a different reading station. Speckle-Tracking Strain Analysis Standard grayscale two-dimensional images were obtained in parasternal and apical views. All images were recorded at frame rates of 70 to 100 Hz and digitally saved in cine loop format. Offline speckle-tracking analysis was performed using software for echocardiographic quantification (EchoPAC version 104.3.0). Endocardial borders of the left ventricle were manually traced within the endsystolic frame. The epicardial tracing was automatically generated
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by the software algorithm and manually adjusted when necessary. Tracking was accepted only if both visual inspection and EchoPAC software analysis confirmed that it was adequate. Peak transverse displacement in the basal inferolateral, middle inferolateral, basal anteroseptal, and middle anteroseptal walls was assessed in apical long-axis views, and a time-displacement profile was exported to Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA) for quantitative analysis. Time to peak transverse displacement (TPD) was defined as the time to maximal inward motion of a given myocardial segment (Figure 1). Speckle-tracking consistently tracks pixels within myocardial segments, thus tracking the displacement of myocardial segments at rest and immediately after exercise. By measuring and comparing this parameter in basal and mid inferolateral and anteroseptal segments, the extent of dyssynchrony could be determined in patients with normal mitral valve and ventricular structure and in those with MVP (Figures 2–4, Videos 1–4; available at www. onlinejase.com). Because chordal attachments may be variable, we assessed both the relative differences between TPD in basal segments and the average of TPD in all anteroseptal versus inferolateral segments. Both groups were assessed at rest and immediately after exercise. All data were abstracted electronically, using customprogrammed software macros, and checked qualitatively to ensure that computer-derived results were not spurious. To assess intraobserver variability, measurements of TPD and extent of MVP were performed by the same observer in 10 randomly selected subjects (five patients and five controls) on the same cardiac cycle at baseline and repeated 6 months later. To assess interobserver variability, a second observer blinded to the results of the first performed independent measurements of the same variables in the same 10 subjects and the same cardiac cycle on a different reading station. Statistical Analysis Statistical analyses were performed using SPSS versions 11.0 and 20.0 (SAS Institute Inc, Cary, NC). Prespecified analyses were performed using paired and unpaired t tests for discrete variables and comparisons for continuous variables, within and between patients with MVP and controls, at rest and at peak stress. Results are expressed
Figure 1 Speckle strain analysis, with automatic tracking of the LV endocardial borders in the apical long axis. Demonstration of automated measurement of peak displacement, from which the primary end point, TPD, was derived.
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Figure 2 Apical long-axis images at rest (A) and post-stress (B) in a patient with MVP, illustrating the MVP-related wall motion abnormality in the basal inferolateral wall(s). (Additional content: Video 1, patient with MVP at rest; Video 2, patient with MVP poststress).
Figure 3 Speckle strain analysis, with automatic tracking of the LV endocardial borders in the apical long axis in a control subject (A) and in a patient with MVP (B). The basal inferolateral (yellow), mid inferolateral (cyan), basal anteroseptal (red), and mid anteroseptal (blue) segments are shown. (Additional content: Video 3, control; Video 4, patient with MVP).
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Figure 4 Transverse displacement (y axis, mm) versus time (x axis, sec) derived from speckle strain analysis in the apical long axis, in a control subject (A) and in a patient with MVP (B). The basal inferolateral (yellow), middle inferolateral (cyan), basal anteroseptal (red), and middle anteroseptal (blue) segments are shown.
Table 1 Baseline characteristics Variable
Patients with MVP (n = 30)
Controls (n = 30)
Women 87% (26) 87% (26) Age (y) 61.4 6 17.1 61.4 6 17.1 Height (cm)* 160.3 6 6.5 161.3 6 9.2 Weight (kg)* 64 6 8.6 65.5 6 11.9 Resting HR (beats/min) 81 6 13 82 6 16 Peak HR (beats/min) 147 6 15 149 6 20 Resting BP (mm Hg) 118 6 18/73 6 9 120 6 20/69 6 12 Peak BP (mm Hg) 168 6 27/72 6 17 170 6 24/66 6 11 Time on treadmill (min) 7.7 6 2.4 8.6 6 2.6 Mets achieved 8.7 6 2.8 9.63 6 3.6 0.3 6 0.3 0.5 6 0.4 Maximal ECG STsegment deviation at rest (mm) Maximal ECG ST1.0 6 0.7 1.1 6 0.9 segment deviation at peak stress (mm)
P
NS NS NS NS NS NS NS NS NS NS NS
between groups, with identical ages and sex and similar weights, heights, rest and peak heart rates, rest and peak blood pressures, and maximal ST-segment deviation at rest and during stress. Compared with controls, patients with MVP demonstrated significant delay in TPD of the segment(s) associated with the prolapsing leaflet at rest and at peak stress (P < .003 to P < .0001; Tables 2 and 3). Results were statistically significant for all prespecified analyses: raw data, normalized to the RR interval, and relative to the TPD for anteroseptal segment(s). For the assessment of subgroups, we divided patients into groups of those with less severe and more severe prolapse according to the modal value in the population, #4-mm or >4-mm deviation from the annular plane. Results are shown in Table 4. The delay in TPD was not significantly different when assessed by severity of prolapse; numerically, however, the values trended in the hypothesized direction, with the myocardial segment involved with the prolapsing leaflet demonstrating earlier TPD and ‘‘normalizing’’ the perceived delay.
NS
BP, Blood pressure; ECG, electrocardiographic; HR, heart rate. Data are expressed as percentage (number) or mean 6 SD. *Limited data on height and weight were available for patients in the case arm; data were abstracted from 9 subjects.
as means or percentages with 95% confidence intervals. Nonparametric comparisons between groups were based on Wilcoxon’s rank-sum test. Parametric comparisons between the two groups were based on a two-sample Student’s t test. P values < .05 were considered statistically significant. For the assessment of subgroups, the cut point for defining milder versus more severe prolapse was the modal value for prolapse, 4 mm. Unpaired t tests were used to determine differences between the two groups. Paired-samples two-tailed t tests with Pearson’s correlation coefficients were used to assess the intraobserver variability of the same measures taken at baseline and 6 months later, and intraclass coefficients were used to assess interobserver variability.
RESULTS Clinical, electrocardiographic, and echocardiographic characteristics of patients with MVP and age-matched and sex-matched controls are compared in Table 1. There were no significant differences
Reproducibility and Interobserver Variability Excellent interobserver and intraobserver variability was observed, using data from 10 randomly selected patients for the amount of MVP and TPD of the inferolateral and anteroseptal segments. Two-tailed t tests of values between one individual at baseline and after 6 months were not statistically significant, with a Pearson’s coefficient of 0.656 for amount of prolapse and P = .883 for TPD. The mean difference between observers varied from 0% to 14%. Intraclass coefficients demonstrated excellent agreement (r = 0.88 for amount of prolapse, r = 0.931 for TPD).
DISCUSSION In MVP, the inward motion of the inferolateral myocardial segments, papillary muscle, and adjacent structures is temporarily dissociated from the remaining LV wall segments. This appears to be due to the delayed application of tethering forces by the abnormal mitral leaflets and chordae on the inferolateral papillary muscle and adjacent structures. We believe this is the first comprehensive evaluation of CLM interactions in this population. We demonstrated a delay in TPD in MVP involving the segment(s) to which abnormal chords are attached. Although chordal insertion is variable, the delay was demonstrated in both proximal and averaged subtended segments. Prolapse severity does not predict TPD, possibly because of issues with timing and dynamic physiologic loading conditions.
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Table 2 TPD: delay of basal inferolateral wall relative to basal anteroseptal wall Patients with MVP (n = 30)
Variable
Rest Real time (msec) Relative to TPD of anteroseptal segment (%) (anteroseptal segment = 100%) Peak stress Real time (msec) Relative to TPD of anteroseptal segment (%) (anteroseptal segment = 100%)
Controls (n = 30)
P
50 6 90 117 6 24
30 6 90 97 6 22
.006 .007
70 6 80 144 6 68
30 6 60 95 6 21
4 mm beyond the annular line.
Much of our understanding of the physiologic interactions between the mitral valve and the left ventricle is derived from cardiac surgical literature assessing the role of chordal preservation in mitral valve surgery.1-12,21-24 The ‘‘papillary muscle–annular continuity’’ is crucial in mediating geometrically effective LV contraction during systole23 and moderating LV distension in diastole. The complex saddle shape of the mitral valve also deforms through the cardiac cycle, with leaflet-annular relationships crucial in reducing leaflet stress and enhancing systolic competence.25-27 Much of the literature to date characterizes the physiology and mechanics of the mitral apparatus by focusing on leaflet-annular relationships using three-dimensional geometric modeling, two-dimensional echocardiography with radiopaque markers, and, more recently, real-time three-dimensional, full-volume acquisition with transesophageal echocardiography.25-30 TPD by speckle-tracking echocardiography is a novel method to characterize CLM interactions in patients with MVP, which we believe
adds further insight to the understanding of mitral and LV dynamics in MVP. In MVP, increased leaflet redundancy, chordal elongation, and billowing of the prolapsing segment into the left atrium in systole applies a delayed and rapidly developing force to the papillary muscle.21 This is translated to the adjacent segment of the basal to mid inferolateral wall and visualized as a late and brisk deformation. Using speckle-tracking echocardiography, we were able to demonstrate this as a delay in TPD of the basal inferolateral segment relative to the corresponding opposite wall, a novel method for characterizing mitral CLM interactions in patients with MVP. A recent cardiac magnetic resonance imaging study demonstrated localized basal inferolateral hypertrophy in patients with MVP, corresponding to the delayed segment of interest in our study.31 The association between these two observations is intriguing but requires further study. A significant association between the severity of MVP and delay in TPD was not observed. This may be because severity, quantified as the absolute distance of leaflet prolapse, is not equivalent to timing, and factors governing timing may not affect severity per se. Additionally, as more severe MVP tends to occur earlier in systole, an earlier pull exerted on the papillary muscle results in a more rapid TPD, mimicking, in the extreme, normal synergy with onset of TPD in early systole. Superimposed on these scenarios are numerous physiologic factors that influence preload, afterload, and inotropy and may confound the timing of prolapse. As such, more complex models may be required to better characterize these relationships. The implications of our research extend beyond physiologic characterization to patient care. The association between MVP and symptoms such as chest pain could possibly be associated with the rapid development of tensile forces, which can be studied
6 Rambihar et al
prospectively in the future. With stress echocardiography, the delayed displacement of the inferolateral wall due to physiologic mitral CLM interactions may be identified as hypokinesis or tardokinesis and falsely interpreted as ischemia. Attribution of a perceived wall motion abnormality in MVP during stress echocardiography to an MVPrelated wall motion abnormality may thus be helpful. Limitations This study was a post hoc observational analysis, which attempted to explore and characterize mechanistic aspects of mitral valve and LV motion in patients with MVP. The small number of patients in the MVP cohort may explain the wide confidence intervals, but robust statistical significance was achieved for all primary analyses. Control patients were referred for stress echocardiography for clinical indications and may not represent a random population sample. However, with normal results on rest and stress echocardiography, we believed that this subset represented an appropriate control group. Finally, the inability to delineate differences in TPD in milder versus more severe MVP likely relates to the role of timing in severity of prolapse and small sample size, or both.
CONCLUSIONS Using novel speckle-tracking echocardiographic techniques, we have demonstrated that in patients with MVP, there is a delay in maximal inward motion of the basal inferolateral wall compared with the opposite corresponding basal anteroseptal segment and that this delay varies with exercise inotropy. This builds on data from the surgical literature regarding the physiologic importance of chordal apparatus and provides new mechanistic insights that inform our understanding of the mitral chordal-leaflet-myocardial interactions.
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