Mitral Annulus Size Links Ventricular Dilatation to Functional Mitral Regurgitation

Mitral Annulus Size Links Ventricular Dilatation to Functional Mitral Regurgitation Zoran B. Popovic´, MD, PhD, Maureen Martin, Kiyotaka Fukamachi, MD, PhD, Masahiro Inoue, MD, Jun Kwan, MD, Kazuyoshi Doi, MD, Jian Xin Qin, MD, Takahiro Shiota, MD, PhD, Mario J. Garcia, MD, Patrick M. McCarthy, MD, and James D. Thomas, MD, Cleveland, Ohio

We compared the impact of annulus size and valve deformation (tethering) on mitral regurgitation in the animal dilated cardiomyopathy model, and assessed if acute left ventricular volume changes affect mitral annulus dimensions. We performed 3-dimensional echocardiography in 30 open-chest dogs with pacing-induced cardiomyopathy. Mitral annulus area was calculated from its two orthogonal diameters, whereas valve tethering was quantified by valve tenting area measurement. Mitral valve regurgitant volume showed the highest correlation with annulus area (r ⴝ 0.64, P < .001), left atrial volume (r ⴝ

Occurrence

of functional mitral regurgitation (MR) in the presence of systolic left ventricular (LV) dysfunction is associated with poor prognosis. Regurgitant volume (RV) and regurgitant orifice in this setting are usually smaller than the one detected in significant organic MR,1 and may fluctuate.2 Despite this, functional MR may have dire hemodynamic consequences.3 Although it has been shown that functional MR may be associated with mitral leaflet deformation, outward papillary muscle (PM) displacement, and mitral annulus dilation,4 impact of disease origin5 or its duration may modify the actual pathomorphologic substrate responsible for the presence of MR. For this reason, animal models of nonischemic heart failure have been used to elucidate the relationship between particular mitral valve apparatus characteristics and development of functional MR with, however, somewhat conflicting results.6,7 Resolution of this issue may be important for further development of MR correction procedures, and for echocardiographic prediction of patients in whom significant MR is liable to develop.

From the Departments of Cardiovascular Medicine, Biomedical Engineering (K.F., M.I., K.D.), and Thoracic and Cardiovascular Medicine (P.M.C.), The Cleveland Clinic Foundation. Reprint requests: James D. Thomas, MD, Department of Cardiovascular Medicine, Desk F-15, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2005 by the American Society of Echocardiography. doi:10.1016/j.echo.2005.01.011

0.40, P < .01), and left ventricular end-diastolic volume (r ⴝ 0.37, P < .01). Regurgitant volume showed poorer correlation with valve tethering in both septolateral and intercommissural planes (r ⴝ 0.35 and r ⴝ 0.31, P < .05 for both). Annulus dimensions correlated with acute changes of left ventricular end-diastolic volume (r ⴝ 0.68, P ⴝ .002). Mitral annulus dilation is the strongest predictor of functional mitral regurgitation in this animal dilated cardiomyopathy model. (J Am Soc Echocardiogr 2005;18:959-963.)

The aim of the study was to determine the variables that correlate with the quantitative measures of MR severity in the animal model of dilated cardiomyopathy. We sought to differentiate between importance of the presence of mitral annulus dilation, mitral leaflet deformation, and PM displacement as possible predictors of MR severity in this model of experimental heart failure. Then, the impact of acute LV volume change on mitral annulus size was assessed in a subgroup of animals.

METHODS We analyzed the data of the consecutive canines with tachycardia-induced cardiomyopathy that were included in various experimental heart failure treatment protocols from January 2001 to July 2002.8-11 All data were collected in a prospective manner. All animals received humane care in compliance with the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press (revised 1996).12 A total of 30 awake, healthy, mongrel dogs (weight 25-32 kg) underwent comprehensive closed-chest echocardiographic study with either 5-MHz or 3.5-MHz transducer and echocardiographic machine (Sequoia, Siemens, Erlangen, Germany) to ascertain normal LV function and absence of MR. At 1 day to 3 weeks after this initial echocardiography study, baseline, closedchest, hemodynamic evaluation was performed. We induced anesthesia with thiopental (15 mg/kg) and

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maintained it with isoflurane (0.5%-2.5%). The animals were instrumented by placing a thermistor-tipped balloon catheter into the pulmonary artery (Baxter-Edwards, Minneapolis, Minn) and a pressure-microtransducer catheter (SPC-562, Millar Instruments Inc, Houston, Tex) into the LV to obtain cardiac output (thermodilution method), peak systolic and end-diastolic pressures, and peak positive and negative pressure derivatives. We completed the procedure by right ventricular pacemaker implantation. The dogs were then paced at 230/min for an average of 29 ⫾ 3 days to induce dilated cardiomyopathy. At the end of induction, dogs underwent an open-chest hemodynamic evaluation.9 On the date of study, the pacemaker was reduced to demand mode at 30/min so that the animal would resume normal sinus rhythm. After anesthesia induction (as described) and the opening of the chest and pericardium, hemodynamic studies were repeated, and epicardial 2- and 3-dimensional (3D) echocardiography was performed. Epicardial 2-dimensional echocardiography was performed with the same equipment as above. Apical 2- and 4-chamber views were collected for calculation of LV volumes.6 Pulsed wave Doppler of the LV outflow tract and of the mitral annulus, and continuous wave Doppler of the mitral valve, were obtained from apical 4-chamber view. Real-time 3D echocardiography was performed using a 2.5-MHz transducer and echocardiographic machine (Volumetric Medical Imaging Inc, Durham, NC). Both apical and parasternal-equivalent epicardial images were acquired. In 6 of 30 dogs, 3 days after a first open-chest study, pacing was resumed at 190/min for an additional 4 weeks to maintain cardiomyopathy.9 After that period a second open-chest study was performed using the same instrumentation as described. During this second study hemodynamic data were obtained immediately after thoracotomy (6 dogs); after instrumentation for coronary sinus flow measurement that, because of duration of instrumentation, led to spontaneous preload decrease (6 dogs); after volume challenge with 600 mL of saline (6 dogs); and during infusion of 10 ␮g/min/kg of dobutamine (5 dogs). In these 6 dogs, 23 additional hemodynamic studies were successfully obtained. As a result we obtained and analyzed 53 open-chest studies. During induction and maintenance of cardiomyopathy dogs were treated with diuretics only. Chamber Volume Measurements Data were stored in digital format for further analysis. All echocardiographic measurements were performed in triplicate. LV end-diastolic and end-systolic volumes were measured by Simpson’s biplane method.6 Left atrial midsystolic volume was calculated from 3D echocardiographic data using 3D computer software (TomTec, Denver, Colo) by a disk summation method, with the disk distance of less than 7 mm.13

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Aortic

Mitral

SL tenting

960 Popovic´ et al

IC tenting

Figure 1 Schematic representation of mitral valvular complex in relation to intercommissural (IC), septolateral (SL), and papillary muscle (PM) planes. Broken arrows, PMmitral annulus distance. Three-dimensional Mitral Valve–related Measurements We used computer software (TomTec) to define measurement planes.5 For the determination of mitral annulus area, both apical and parasternal-equivalent views were used. In apical view, after a plane of the mitral valve that clearly visualizes both mitral commissures was obtained, it was used to define the intercommissural plane, a plane that passes through both commissures and the LV apex. Finally, septolateral (SL) plane perpendicular to the intercommissural plane that passed through the mitral-aortic fibrosa6 was defined for measuring the mitral annulus diameter and mitral valve tenting area (area demarcated by the mitral valve leaflets and mitral annulus plane) was measured. In parasternal-equivalent view, procedure was repeated; however, measurements were taken in SL plane only. Data from these two measurements were then averaged and used to calculate the mitral annulus area in midsystole and middiastole.6 To determine PM-mitral annulus distance, parasternal-equivalent view was used. The SL plane was rotated around the line defined by the intersection of SL plane and mitral valve plane first toward anterolateral, then toward posteromedial PMs.6 The distance between anterior aorto-mitral fibrous trigone and the PM tips, visualized using both SL plane and corresponding orthogonal cross-sectional plane, was measured and two distances were summed up to obtain total PM-mitral annulus distance (Figure 1).6 Inter-PM distance was measured from the cross-sectional PM plane of parasternal-equivalent view.6 Quantitative Doppler Echocarl diographic Determination of RV We applied the approach of Yiu et al.4 Total stroke volume was calculated first as a difference between end-diastolic

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Table 1 Hemodynamic and echocardiographic data before and after induction of dilated cardiomyopathy by rapid ventricular pacing Baseline

HR, beats/min 120 ⫾ 8 CO, L/min 2.5 ⫾ 0.6 LV PSP, mm Hg 114 ⫾ 21 LV EDP, mm Hg 7⫾2 ⫹dP/dt, mm Hg/s 1713 ⫾ 486 ⫺dP/dt, mmHg/s ⫺2,596 ⫾ 735 6.1 ⫾ 0.5 LVLd, cm LVLs, cm 5.2 ⫾ 0.5 LV EDV, mL 66.9 ⫾ 13.0 LV ESV, mL 25.1 ⫾ 6.5 EF .62 ⫾ .07 MA diameter 4-chamber, cm 2.54 ⫾ 0.36 MA diameter 2-chamber, cm 2.35 ⫾ 0.35

Dilated cardiomyopathy

95 1.8 93 18 731 ⫺752 6.2 6.0 89.3 69.3 .22 2.81 2.84

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

16* 0.3* 17* 8* 253* 242* 0.5 0.5* 17.7* 15.0* .08* 0.31* 0.35*

Table 2 Correlation coefficients of univariate regurgitant volume predictors calculated by quantitative Doppler echocardiography RV

MA area LA volume LV EDV LV ESV SL tenting area IC tenting area MA-PM distance PM separation

0.64* 0.40† 0.37† 0.28‡ 0.35† 0.31‡ 0.24 0.16

IC, Intercommisural plane; LA, left atrial; LV EDV, left ventricular enddiastolic volume; LV ESV, left ventricular end-systolic volume; MA, mitral annulus; PM, papillary muscle; RV, regurgitant volume; SL, septo-lateral plane. *P ⬍ .0001; †P ⱕ .01; ‡P ⱕ .05.

CO, Cardiac output; dP/dt, peak pressure derivative; EF, ejection fraction; HR, heart rate; LV EDP, left ventricular (LV), end-diastolic pressure; LV EDV, LV end-diastolic volume; LV ESV, LV end-sysstolic volume; LV PSP, LV peak systolic pressure; LVLd, LV length, diastolic; LVs, LV length, systole; MA, mitral annulus. *P ⬍ .001 for the comparison with baseline values.

and end-systolic volumes, and then as the mitral annulus velocity time integral-mitral annulus area (calculated from 3D echocardiographic measurements), and the results were averaged. Forward stroke volume was calculated as the product of LV outflow tract velocity-time integral and its 3D-determined area. RV was calculated as difference between total and forward stroke volume. Statistical Methods Data are presented as mean ⫾ SD. The change of echocardiographic variables induced by rapid right ventricular pacing was assessed by a paired t test. Simple and multiple linear regressions were used to evaluate relevant echocardiographic variables as possible RV predictors, whereas forward stepwise multiple regressions were attempted for the variables that showed significant correlation with RV on initial simple regression. The impact of LV volume change on mitral annulus dimensions was performed by repeated measures linear regression, as described.14 P value ⬍ .05 was considered significant.

RESULTS Table 1 shows hemodynamic and echocardiographic parameters associated with dilated cardiomyopathy induction. Although echocardiography data at baseline and after cardiomyopathy induction were acquired with the animal in conscious and anesthetized state, respectively, the dramatic change of parameters can still be appreciated. Interestingly, the only parameter that was not changed was LV long-axis length in diastole. MR was detected by color Dopp-

Figure 2 Linear regression between mitral annulus determined by 3-dimensional echocardiography, and mitral regurgitant volume determined by quantitative Doppler echocardiography method.

ler mapping in 42/53 studies. If MR was present, almost invariably two commissural jets were observed with one clearly dominant compared with the other. The additional regurgitation could occasionally be seen along the coaptation length. After dilated cardiomyopathy induction, average RV by quantitative Doppler echocardiography was 3.8 ⫾ 5.5 mL. To assess the sensitivity (precision) of RV determined by quantitative echocardiography we measured RV by this technique in animals in which no MR could be detected by color flow mapping of the LA. The RV by quantitative Doppler echocardiography was 1.5 ⫾ 3.6 mL. The mitral annulus area showed highest univariate correlation with RV (r ⫽ 0.64, P ⬍ .0001) (Table 2 and Figure 2), and was also its only multivariate predictor. However, mitral annulus area correlated with LV end-diastolic and end-systolic volumes (r ⫽ 0.67 and r ⫽ 0.58, respectively, P ⬍ .0001 for both), LA volume (r ⫽ 0.57, P ⬍ .0001), SL and intercommissural tenting area (r ⫽ 0.50 and r ⫽ 0.47, P ⬍ .001 for both), mitral annulus-PM distance (r ⫽ 0.43,

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Figure 3 Repeated measures linear regression of left ventricular end-diastolic volume and mitral annulus area in 6 dogs in which echocardiographic studies were repeated several times. Fair correlation was observed (r ⫽ 0.68, P ⫽ .002).

P ⫽ .001), and with PM separation (r ⫽ 0.38, P ⫽ .005). It is not known whether mitral annulus dilation in the setting of dilated cardiomyopathy is reversible and, if it is, what time span is necessary for mitral annulus to decrease. To assess the sensitivity of mitral annulus dimensions on acute changes of LV size, we performed repeated measures linear regression in 6 animals in which LV volumes and mitral annulus area were measured under different loading and inotropic conditions. We obtained a correlation of r ⫽ 0.68 (P ⫽ .002) between LV end-diastolic volume and mitral annulus area, implying the sensitivity of mitral annulus area to acute decrease or increase of LV volume (Figure 3). A correlation of r ⫽ 0.55 (P ⫽ .018) was detected between endsystolic volume and mitral annulus area.

DISCUSSION In this study, we have shown that the amount of functional MR observed in the presence of global LV dilation is coupled to mitral annular dilation. Interestingly, MR showed no consistent association with mitral leaflet deformation or PM tethering. However, mitral annular dilation showed correlation with these previously described features of functional MR, which may indicate that they all relate to the same underlying process, with mitral annulus area a most easily quantified feature. Finally, we have shown that mitral annulus dilation promptly follows LV size change. Previous Studies Although initial echocardiographic studies linked functional MR to mitral annulus dilation,15 a current consensus is that mitral leaflet deformation is also

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necessary for functional MR to occur.4,16 However, most of the clinical studies are marred by different disease origin, and by different duration of disease, which may affect mitral valve apparatus geometry.5 For this reason, several authors used animal heart failure models to assess functional MR in a controlled setting. In a small experimental study of acute LV dysfunction in which Otsuji et al6 assessed MR volume determinants by 3D echocardiography, the single multivariate predictor was PM displacement, with mitral annular dilation and mitral valve deformation being univariate predictors only. In contrast to this, Timek et al,7 in a study of 5 animals, have shown that MR after dilated cardiomyopathy induction is associated with mitral annulus dilation. Interestingly, in their study, although dilated cardiomyopathy induction increased PM to mitral annulus distance, leaflet deformation decreased. However, several studies, both experimental and human, have clearly shown that annular dilation per se cannot induce MR.17,18 Thus, it seems that interaction of mitral annulus dilation, ventricular enlargement, and PM displacement is necessary to produce nonischemic functional MR.7,17,19 Clinical Implications The implications of this study are 2-fold. First, precise quantification of functional MR is difficult as it frequently occurs in more than one jet,7 may be small,1 and its amount may fluctuate with loading conditions.20 Thus, it may be useful to use some echocardiographic predictor as a surrogate for its potential severity. Second, although several studies have indicated that functional MR may decrease with treatment, the mechanisms of this disappearance are not known.2,21,22 Our study indicates that LV volume reduction through its decrease of mitral annulus size may be a major determinant. This is an important finding, because recent studies reported that mitral annulus dilation involves fibrous portion of the annulus, implying that annular dilation is at least partly irreversible.23,24 On the other hand, our data are supported by the findings of Timek et al25 that showed mitral annulus dimension decreases during dobutamine infusion. Finally, our study implies that mitral annulus reduction must be within the armamentarium of novel devices that aim to decrease MR in a setting of dilated cardiomyopathy, suggesting that both LV remodeling and LV annular size reduction are necessary. Limitations First, our pacing protocol was short, and 4 weeks of heart failure cannot be equaled with 5 to 10 years of dilated cardiomyopathy history. However, LV morphologic and neurohormonal changes of these entities are similar.9 Second, there are limitations of

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resolution of echocardiographic equipment used. We tried to overcome this issue by assessing a large number of animals. In addition, strong signal intensities at the hinge points of the annulus enable tracking and measurement of its dimensions with ease.26 Finally, an open-chest model was used, which may influence mitral annulus and LV architecture, making our data more applicable for cardiac operation than for standard closed-chest setting. In conclusion, functional MR seen in animal dilated cardiomyopathy model without localized wallmotion abnormality is associated with mitral annulus dilation measured by 3D echocardiography, but less so with increased valve tethering. Furthermore, as mitral annulus area closely follows changes in LV size, mitral annulus dilation is potentially reversible and, thus, may in turn decrease associated MR. REFERENCES 1. McCully RB, Enriquez-Sarano M, Tajik AJ, Seward JB. Overestimation of severity of ischemic/functional mitral regurgitation by color Doppler jet area. Am J Cardiol 1994;74:790-3. 2. Rosario LB, Stevenson LW, Solomon SD, Lee RT, Reimold SC. The mechanism of decrease in dynamic mitral regurgitation during heart failure treatment: importance of reduction in the regurgitant orifice size. J Am Coll Cardiol 1998;32:1819-24. 3. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29:153-9. 4. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;102:1400-6. 5. Kwan J, Shiota T, Agler DA, Popovic ZB, Qin JX, Gillinov MA, et al. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study. Circulation 2003;107:1135-40. 6. Otsuji Y, Handschumacher MD, Schwammenthal E, Jiang L, Song JK, Guerrero JL, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96:1999-2008. 7. Timek TA, Dagum P, Lai DT, Liang D, Daughters GT, Ingels NB Jr, et al. Pathogenesis of mitral regurgitation in tachycardia-induced cardiomyopathy. Circulation 2001;104:I47-53. 8. McCarthy PM, Takagaki M, Ochiai Y, Young JB, Tabata T, Shiota T, et al. Device-based change in left ventricular shape: a new concept for the treatment of dilated cardiomyopathy. J Thorac Cardiovasc Surg 2001;122:482-90. 9. Takagaki M, McCarthy PM, Tabata T, Dessoffy R, Cardon LA, Connor J, et al. Induction and maintenance of an experimental model of severe cardiomyopathy with a novel protocol of rapid ventricular pacing. J Thorac Cardiovasc Surg 2002; 123:544-9. 10. Inoue M, McCarthy PM, Popovic ZB, Doi K, Schenk S, Nemeh H, et al. The Coapsys device to treat functional mitral regurgitation: in vivo long-term canine study. J Thorac Cardiovasc Surg 2004;127:1068-77. 11. Popovic ZB, Saracino G, Deserranno D, Yang H, Greenberg NL, Takagaki M, et al. Echocardiographic assessment of re-

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