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Mechanism of Diastolic Mitral Regurgitation in Candidates for Cardiac Resynchronization Therapy
Mechanism of Diastolic Mitral Regurgitation in Candidates for Cardiac Resynchronization Therapy Eyal Nof, MDa,c, Michael Glikson, MDa,c, David Bar-Lev, MDa,c, Osnat Gurevitz, MDa,c, David Luria, MDa,c, Michael Eldar, MDa,c, and Ehud Schwammenthal, MDa,b,c,* It was hypothesized that restricted diastolic leaflet motion is implicated not only in the mechanism of systolic mitral regurgitation (MR) but also in the mechanism of diastolic MR observed in patients with severe heart failure. Cardiac resynchronization therapy (CRT) can oppose increased mitral leaflet tethering by increasing transmitral pressure, thereby providing an opportunity to explore this hypothesis. A total of 26 consecutive candidates for CRT with diastolic MR were compared with 26 candidates without diastolic MR. Maximal diastolic mitral leaflet opening and inflow direction and measures of mitral valve apparatus (i.e., mitral annular diameters, calculated mitral annular area, and tethering distance) were assessed from the apical 4-chamber view before and during CRT. There were no significant differences in New York Heart Association functional class, ejection fraction, QRS duration, PR interval, systolic MR grade, or 2-dimensional geometry of the mitral valve apparatus between the groups. Patients with diastolic MR had more restricted maximal diastolic leaflet openings (54° ⴞ 17° vs 71° ⴞ 11°, p ⴝ 0.003) and substantially smaller inflow angles (66° ⴞ 7° vs 79° ⴞ 9°, p ⴝ 0.0003) compared with patients without diastolic MR. After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve apparatus. In conclusion, abnormal mitral valve tethering is a constitutive element of the mechanism of diastolic MR in patients with left ventricular dysfunction. Its acute resolution after CRT does not seem to be caused by changes in mitral valve geometry but rather by an increase in transmitral closing forces. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:1611–1614) Cardiac resynchronization therapy (CRT) with biventricular pacing, which has been increasingly used as adjunct therapy in patients with heart failure and ventricular conduction disturbances,1– 4 has been shown to diminish systolic mitral regurgitation (MR).5 Biventricular pacing can acutely increase the maximal rate of left ventricular (LV) systolic pressure elevation, and thus, transmitral pressure.5 Such an increase in transmitral pressure may facilitate more effective mitral valve closure by opposing the increased mitral leaflet tethering forces not only in systole but also in late diastole. Biventricular pacing therefore represents a unique opportunity to explore the hypothesis that increased mitral tethering is the underlying cause of diastolic MR. •••
The study included 52 candidates for CRT: 26 consecutive patients with diastolic MR who were compared with 26 patients without diastolic MR, examined during the same study period (2001 to 2003). All patients were candidates for CRT according to current guidelines and received biventricular pacing devices with right ventricular apical leads a Heart Institute and bCardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel Hashomer; and cSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received August 11, 2005; revised manuscript received and accepted December 8, 2005. * Corresponding author: Tel: 972-3-530-3068; fax: 972-3-530-5905. E-mail address: [email protected] (E. Schwammenthal).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.064
and LV pacing electrodes implanted through the coronary sinus and positioned in a LV epicardial vein. An atrial lead was implanted in the right atrial appendage in patients who were not in permanent atrial fibrillation. Transthoracic echocardiography was performed before and after the implantation of the CRT system during active biventricular pacing (immediately after implantation or during follow-up of up to 1 month). All patients underwent atrioventricular delay optimization using the Ritter method.6 Complete 2-dimensional and Doppler examinations with Doppler color flow mapping were performed in all patients before and after the implantation of the CRT system. The LV end-diastolic and end-systolic cavity areas were traced in the apical 4-chamber views, and LV volumes and ejection fractions were calculated using the modified biplane Simpson’s method.7 MR was graded by color Doppler flow mapping using an algorithm that integrated jet expansion within the left atrium,8,9 jet eccentricity,10 and the size of the proximal flow convergence area.11,12 The presence of diastolic MR was assessed by pulse-wave Doppler echocardiography, defined as an atrioventricular flow inversion at end-diastole, indicating a reversal of the atrioventricular pressure gradient before the onset of ventricular contraction13 (Figure 1). The systolic configuration of the mitral leaflet was also evaluated in the apical 4-chamber view.14 This evaluation included measurements of the area between the leaflets and www.AJConline.org
1612
The American Journal of Cardiology (www.AJConline.org)
Figure 1. Diastolic MR (dMR), defined as an atrioventricular flow inversion at end-diastole, indicating a reversal of the atrioventricular pressure gradient before the onset of ventricular contraction.
the mitral annular line at the time of mid-systole and the distances between the bases of the mitral leaflets and between the mitral annular line and the leaflets at the time of mid-systole (Figure 2). Tethering distance was measured between the papillary muscle tip and the base of the mitral leaflet (Figure 2). The area between the leaflets and the mitral annular line was traced in this view at the time of maximal systolic closure to integrate the apical displacement of the tethered mitral leaflets over the mitral annulus. Diastolic leaflet opening motion was measured in the same view used to evaluate its systolic configuration (Figure 2). Measurements were based on the predominant clinical observation of restricted anterior diastolic excursion of the anterior mitral leaflet. The angle at maximal leaflet opening (␣2) was measured between the base of the leaflet and the line connecting the annular hinge points (the annulus line) at maximal diastolic opening (Figure 2); ␣1 was the angle measured at endsystole, 1 frame before diastolic leaflet opening (Figure 2). The general direction of mitral inflow in the apical 4-chamber view was determined using Doppler color flow mapping at the time of maximal early diastolic rapid filling, as the line connecting the center of the filling flow signal at the mitral annulus and chordal levels between the leaflets. The angle between this line and the annulus was measured as the mitral inflow direction angle (⌽) (Figure 2). Comparison between groups was performed using the 2-tailed Student’s t test for normally distributed parameters. Data are expressed as mean ⫾ SD, and a p value of ⬍0.05 was considered significant. There were no significant differences between the 2 patient groups in the baseline characteristics and the 2-dimensional geometry of the mitral valve apparatus (Table 1). Patients with diastolic MR had more restricted
Figure 2. (A) The systolic configuration of the mitral leaflets (i.e., the area between the leaflets and the mitral annular line at the time of mid-systole). (B) ␣1: the angle measured at end-systole. (C) ␣2: the angle at maximal leaflet opening and tethering distance, measured between the papillary muscle tip and the base of the mitral leaflet. (D) The general direction of mitral inflow in the apical 4-chamber view was determined using Doppler color flow mapping at the time of maximal early diastolic rapid filling as the line connecting the center of the filling flow signal at the mitral annulus and chordal levels between the leaflets. The angle between this line and the annulus was measured as the mitral inflow direction angle (⌽). LA ⫽ left atrium; LV ⫽ left ventricle.
Table 1 Baseline characteristics and 2-dimensional geometry mitral valve apparatus parameters of both patient groups Variable
New York Heart Association class Ejection fraction (%) QRS duration (ms) Systolic mitral regurgitation grade PR interval (ms) Diameter (cm) Area (cm2) Tethering distance (cm)
Diastolic MR Yes (n ⫽ 26)
No (n ⫽ 26)
3 ⫾ 0.4 21 ⫾ 5 183 ⫾ 36 2.5 ⫾ 0.9 215 ⫾ 77 2.9 ⫾ 0.8 1.7 ⫾ 0.9 3.9 ⫾ 0.8
3 ⫾ 0.54 24 ⫾ 5 182 ⫾ 36 2.2 ⫾ 1.3 194 ⫾ 49 3 ⫾ 0.5 1.5 ⫾ 0.6 3.7 ⫾ 1.2
p Value
0.13 0.11 0.9 0.3 0.2 0.6 0.4 0.5
maximal diastolic leaflet openings (␣2 ⫽ 54° ⫾ 17° vs 71° ⫾ 11°, p ⫽ 0.003) compared with patients without diastolic MR (Figure 3). In the 2 patient groups, mitral inflow was directed posterolaterally, but patients with diastolic MR had reduced inflow direction angles compared with patients with LV dysfunction but without diastolic MR. In the latter, inflow, like the anterior leaflet, was only mildly redirected (66° ⫾
Heart Failure/Diastolic Mitral Regurgitation in Resynchronization Therapy
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Figure 3. (A) Patients with diastolic MR (dMR) had more restricted maximal diastolic leaflet openings compared with patients without diastolic MR. (B) Substantially, patients with diastolic MR had reduced inflow direction angles (⌽) compared with patients without diastolic MR. Table 2 Parameters of mitral valve annulus and the left ventricular ejection fraction and dimensions in patients with diastolic mitral regurgitation before and after cardiac resynchronization therapy Variable
Before CRT (n ⫽ 26)
After CRT (n ⫽ 26)
p Value
Diastolic leaflet opening angle (°) Diameter (cm) Area (cm2) Tethering distance (cm) LV ejection fraction (%) LV end-diastolic dimension (mm) LV end-systolic dimension (mm)
54 ⫾ 17 2.9 ⫾ 0.8 1.7 ⫾ 0.9 3.9 ⫾ 0.8 21 ⫾ 5 69 ⫾ 8 62 ⫾ 9
55 ⫾ 10 3.1 ⫾ 0.7 2⫾1 4.1 ⫾ 0.7 21 ⫾ 7 69 ⫾ 9 61 ⫾ 1
0.6 0.4 0.4 0.4 0.7 0.9 0.7
7° in patients with diastolic MR vs 79° ⫾ 9° in patients without diastolic MR, p ⫽ 0.0003). After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve annulus (Table 2). •••
In normal subjects, the volume shift induced by left atrial contraction increases LV diastolic pressure above left atrial pressure. This reversal of the small diastolic atrioventricular pressure gradient usually moves the mitral leaflets close to each other before the onset of ventricular contraction.15 In the presence of an abnormally tethered mitral valve, the diastolic reversal of the pressure gradient may not exert enough force to move the leaflets toward closure and may therefore directly result in diastolic MR (Figure 4). Comparing patients with similar degrees of LV dysfunction, we found that those with diastolic MR demonstrated increased mitral valve tethering not only in systole but also in diastole. The increased diastolic mitral tethering in patients with diastolic MR manifests itself in the significantly restricted diastolic anterior leaflet excursion (Figure 3), which results in the substantially smaller inflow angles observed in these patients (Figure 3). Abnormal diastolic mitral valve tethering appears therefore to be a constitutive
Figure 4. The effect of end-diastolic inversion of the atrioventricular pressure gradient on a normally and abnormally tethered mitral valve. Abbreviations as in Figure 1.
element of the mechanism of diastolic MR in patients with LV dilation and dysfunction. The results of this study agree with those of Otsuji et al,14 who showed that the characteristic diastolic configuration of the mitral valve is due to the increased tethering of abnormally tensed chordae and increased separation between the mitral leaflet attachments at the mitral annulus. The altered balance between tethering and closing forces may impede effective mitral valve closure, a process that starts in the latter half of diastole. Just as systolic MR depends on the altered balance between reduced closing forces and increased tethering forces, so does diastolic MR. If this balance is not only disturbed in systole but also in diastole, diastolic MR will ensue. Under the conditions of a tethered mitral valve, mitral regurgitant orifice area will be determined largely by the phasic changes in transmitral pressure.16 –18 The worsening of LV dysfunction with a decreased rate of LV (and thus transmitral) pressure increase will further increase diastolic MR severity due to the impaired closing force. After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve annulus, tethering distance, or even the diastolic leaflet opening angle. Breithardt et al5 demonstrated that CRT in selected patients with advanced heart failure and electrical conduction delay acutely reduced the severity of functional systolic MR by causing an accelerated increase in transmitral pressure and an increase in peak transmitral closing during isovolumic contraction. Thus, directly improving LV systolic function can effectively counteract the increased tethering forces that impair effective mitral valve closure. Our study represents a direct application of this concept. Because the resolution of diastolic MR after the institution of CRT in our patients was not caused by changes in tethering forces (mitral valve geometry was unchanged; Table 2), it must have been
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The American Journal of Cardiology (www.AJConline.org)
caused by changes in closing forces in conjunction with shortening of the atrioventricular delay. No measurements of left atrial and LV pressure were performed in this study because of a lack of clinical indication. We also did not examine the potential long-term effect of late reverse remodeling on mitral valve geometry and the degree of regurgitation, because we used only shortterm follow-up. It is conceivable that reverse remodeling after long-term CRT, a well-documented phenomenon, may result in decreased mitral tethering and thus in itself contribute to mitral valve competence in systole as well as diastole. Nevertheless, these limitations should not have affected the principal finding of this study. 1. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, et al, Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 880. 2. Gras D, Mabo P, Tang T, Luttikuis O, Chatoor R, Pedersen AK, Tscheliessnigg HH, Deharo JC, Puglisi A, Silvestre J, et al. Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol 1998;21:2249 –2255. 3. Linde C, Cazeau S, Kappenberger L, Sutton R, Bailleul C, Daubert JC. Long-term benefit of biventricular pacing in congestive heart failure. One year results from patients in atrial fibrillation in the MUSTIC (Multisite Stimulation in Cardiomyopathy) study. Eur Heart J 2001; 22:441. 4. Abraham W, Fisher W, Smith A, William T, Delurgio D, Leon A, Loh E, Kocovic D, Packer M, Clavell A, et al, for the MIRACLE Study Group. Cardiac resynchronization therapy in chronic heart failure. N Engl J Med 2002;346:1845–1853. 5. Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 2003;41:765–770. 6. Ritter P, Dib JC, Lelievre T. Quick determination of the optimal AV delay at rest in patients paced in DDD mode for complete AV block. Eur J CPE 1994;4:A163. 7. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommen-
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dations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, Gatewood RP. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation 1987;75:175–183. Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. Prevalence and clinical determinants of mitral, tricuspid and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 1999;83:897–902. Chen CG, Thomas JD, Anconina J, Harrigan P, Mueller L, Picard MH, Levine RA, Weyman AE. Impact of impinging wall jet on color Doppler quantification of mitral regurgitation. Circulation 1991;84: 712–720. Rossi A, Dujardin KS, Bailey KR, Seward JB, Enriquez-Sarano M. Rapid estimation of regurgitant volume by the proximal isovelocity surface area method in mitral regurgitation: can continuous wave Doppler echocardiography be omitted? J Am Soc Echocardiogr 1998; 11:138 –148. Bargiggia GS, Tronconi L, Sahn DJ, Recusani F, Raisaro A, De Servi S, Valdes-Cruz LM, Montemartini C. A new method for quantitation of mitral regurgitation based on color flow Doppler imaging of flow convergence proximal to regurgitant orifice. Circulation 1991;84:1481–1489. Sanada J, Kawahira M, Kubo H, Kuroiwa N, Nakamura K, Hashimoto S. Late diastolic mitral regurgitation studied by pulsed Doppler echocardiography. Am J Cardiol 1987;59:1366 –1370. Otsuji Y, Gilon D, Jiang L, Otsuji Y, He V, Leavitt M, Roy MJ, Birmingham MJ, Levine RA. Restricted diastolic opening of the mitral leaflets in patients with left ventricular dysfunction: evidence for increased valve tethering. J Am Coll Cardiol 1998;32:398 – 404. Panidis IP, Ross J, Munley B, Nestico P, Mintz GS. Diastolic mitral regurgitation in patients with atrioventricular conduction abnormalities: a common finding by Doppler echocardiography. J Am Coll Cardiol 1986;7:768 –774. Hung J, Otsuji Y, Handschumacher MD, Schwammenthal E, Levine RA. Mechanism of dynamic regurgitant orifice area variation in functional mitral regurgitation: physiologic insights from the proximal flow convergence technique. J Am Coll Cardiol 1999;33:538 –545. Schwammenthal E, Chen C, Benning F, Block M, Breithardt G, Levine RA. Dynamics of mitral regurgitant flow and orifice area: clinical data and experimental testing. Circulation 1994;90:307–322. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine R. A. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation 1997;96: 1826 –1834.
The study included 52 candidates for CRT: 26 consecutive patients with diastolic MR who were compared with 26 patients without diastolic MR, examined during the same study period (2001 to 2003). All patients were candidates for CRT according to current guidelines and received biventricular pacing devices with right ventricular apical leads a Heart Institute and bCardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel Hashomer; and cSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received August 11, 2005; revised manuscript received and accepted December 8, 2005. * Corresponding author: Tel: 972-3-530-3068; fax: 972-3-530-5905. E-mail address: [email protected] (E. Schwammenthal).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.064
and LV pacing electrodes implanted through the coronary sinus and positioned in a LV epicardial vein. An atrial lead was implanted in the right atrial appendage in patients who were not in permanent atrial fibrillation. Transthoracic echocardiography was performed before and after the implantation of the CRT system during active biventricular pacing (immediately after implantation or during follow-up of up to 1 month). All patients underwent atrioventricular delay optimization using the Ritter method.6 Complete 2-dimensional and Doppler examinations with Doppler color flow mapping were performed in all patients before and after the implantation of the CRT system. The LV end-diastolic and end-systolic cavity areas were traced in the apical 4-chamber views, and LV volumes and ejection fractions were calculated using the modified biplane Simpson’s method.7 MR was graded by color Doppler flow mapping using an algorithm that integrated jet expansion within the left atrium,8,9 jet eccentricity,10 and the size of the proximal flow convergence area.11,12 The presence of diastolic MR was assessed by pulse-wave Doppler echocardiography, defined as an atrioventricular flow inversion at end-diastole, indicating a reversal of the atrioventricular pressure gradient before the onset of ventricular contraction13 (Figure 1). The systolic configuration of the mitral leaflet was also evaluated in the apical 4-chamber view.14 This evaluation included measurements of the area between the leaflets and www.AJConline.org
1612
The American Journal of Cardiology (www.AJConline.org)
Figure 1. Diastolic MR (dMR), defined as an atrioventricular flow inversion at end-diastole, indicating a reversal of the atrioventricular pressure gradient before the onset of ventricular contraction.
the mitral annular line at the time of mid-systole and the distances between the bases of the mitral leaflets and between the mitral annular line and the leaflets at the time of mid-systole (Figure 2). Tethering distance was measured between the papillary muscle tip and the base of the mitral leaflet (Figure 2). The area between the leaflets and the mitral annular line was traced in this view at the time of maximal systolic closure to integrate the apical displacement of the tethered mitral leaflets over the mitral annulus. Diastolic leaflet opening motion was measured in the same view used to evaluate its systolic configuration (Figure 2). Measurements were based on the predominant clinical observation of restricted anterior diastolic excursion of the anterior mitral leaflet. The angle at maximal leaflet opening (␣2) was measured between the base of the leaflet and the line connecting the annular hinge points (the annulus line) at maximal diastolic opening (Figure 2); ␣1 was the angle measured at endsystole, 1 frame before diastolic leaflet opening (Figure 2). The general direction of mitral inflow in the apical 4-chamber view was determined using Doppler color flow mapping at the time of maximal early diastolic rapid filling, as the line connecting the center of the filling flow signal at the mitral annulus and chordal levels between the leaflets. The angle between this line and the annulus was measured as the mitral inflow direction angle (⌽) (Figure 2). Comparison between groups was performed using the 2-tailed Student’s t test for normally distributed parameters. Data are expressed as mean ⫾ SD, and a p value of ⬍0.05 was considered significant. There were no significant differences between the 2 patient groups in the baseline characteristics and the 2-dimensional geometry of the mitral valve apparatus (Table 1). Patients with diastolic MR had more restricted
Figure 2. (A) The systolic configuration of the mitral leaflets (i.e., the area between the leaflets and the mitral annular line at the time of mid-systole). (B) ␣1: the angle measured at end-systole. (C) ␣2: the angle at maximal leaflet opening and tethering distance, measured between the papillary muscle tip and the base of the mitral leaflet. (D) The general direction of mitral inflow in the apical 4-chamber view was determined using Doppler color flow mapping at the time of maximal early diastolic rapid filling as the line connecting the center of the filling flow signal at the mitral annulus and chordal levels between the leaflets. The angle between this line and the annulus was measured as the mitral inflow direction angle (⌽). LA ⫽ left atrium; LV ⫽ left ventricle.
Table 1 Baseline characteristics and 2-dimensional geometry mitral valve apparatus parameters of both patient groups Variable
New York Heart Association class Ejection fraction (%) QRS duration (ms) Systolic mitral regurgitation grade PR interval (ms) Diameter (cm) Area (cm2) Tethering distance (cm)
Diastolic MR Yes (n ⫽ 26)
No (n ⫽ 26)
3 ⫾ 0.4 21 ⫾ 5 183 ⫾ 36 2.5 ⫾ 0.9 215 ⫾ 77 2.9 ⫾ 0.8 1.7 ⫾ 0.9 3.9 ⫾ 0.8
3 ⫾ 0.54 24 ⫾ 5 182 ⫾ 36 2.2 ⫾ 1.3 194 ⫾ 49 3 ⫾ 0.5 1.5 ⫾ 0.6 3.7 ⫾ 1.2
p Value
0.13 0.11 0.9 0.3 0.2 0.6 0.4 0.5
maximal diastolic leaflet openings (␣2 ⫽ 54° ⫾ 17° vs 71° ⫾ 11°, p ⫽ 0.003) compared with patients without diastolic MR (Figure 3). In the 2 patient groups, mitral inflow was directed posterolaterally, but patients with diastolic MR had reduced inflow direction angles compared with patients with LV dysfunction but without diastolic MR. In the latter, inflow, like the anterior leaflet, was only mildly redirected (66° ⫾
Heart Failure/Diastolic Mitral Regurgitation in Resynchronization Therapy
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Figure 3. (A) Patients with diastolic MR (dMR) had more restricted maximal diastolic leaflet openings compared with patients without diastolic MR. (B) Substantially, patients with diastolic MR had reduced inflow direction angles (⌽) compared with patients without diastolic MR. Table 2 Parameters of mitral valve annulus and the left ventricular ejection fraction and dimensions in patients with diastolic mitral regurgitation before and after cardiac resynchronization therapy Variable
Before CRT (n ⫽ 26)
After CRT (n ⫽ 26)
p Value
Diastolic leaflet opening angle (°) Diameter (cm) Area (cm2) Tethering distance (cm) LV ejection fraction (%) LV end-diastolic dimension (mm) LV end-systolic dimension (mm)
54 ⫾ 17 2.9 ⫾ 0.8 1.7 ⫾ 0.9 3.9 ⫾ 0.8 21 ⫾ 5 69 ⫾ 8 62 ⫾ 9
55 ⫾ 10 3.1 ⫾ 0.7 2⫾1 4.1 ⫾ 0.7 21 ⫾ 7 69 ⫾ 9 61 ⫾ 1
0.6 0.4 0.4 0.4 0.7 0.9 0.7
7° in patients with diastolic MR vs 79° ⫾ 9° in patients without diastolic MR, p ⫽ 0.0003). After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve annulus (Table 2). •••
In normal subjects, the volume shift induced by left atrial contraction increases LV diastolic pressure above left atrial pressure. This reversal of the small diastolic atrioventricular pressure gradient usually moves the mitral leaflets close to each other before the onset of ventricular contraction.15 In the presence of an abnormally tethered mitral valve, the diastolic reversal of the pressure gradient may not exert enough force to move the leaflets toward closure and may therefore directly result in diastolic MR (Figure 4). Comparing patients with similar degrees of LV dysfunction, we found that those with diastolic MR demonstrated increased mitral valve tethering not only in systole but also in diastole. The increased diastolic mitral tethering in patients with diastolic MR manifests itself in the significantly restricted diastolic anterior leaflet excursion (Figure 3), which results in the substantially smaller inflow angles observed in these patients (Figure 3). Abnormal diastolic mitral valve tethering appears therefore to be a constitutive
Figure 4. The effect of end-diastolic inversion of the atrioventricular pressure gradient on a normally and abnormally tethered mitral valve. Abbreviations as in Figure 1.
element of the mechanism of diastolic MR in patients with LV dilation and dysfunction. The results of this study agree with those of Otsuji et al,14 who showed that the characteristic diastolic configuration of the mitral valve is due to the increased tethering of abnormally tensed chordae and increased separation between the mitral leaflet attachments at the mitral annulus. The altered balance between tethering and closing forces may impede effective mitral valve closure, a process that starts in the latter half of diastole. Just as systolic MR depends on the altered balance between reduced closing forces and increased tethering forces, so does diastolic MR. If this balance is not only disturbed in systole but also in diastole, diastolic MR will ensue. Under the conditions of a tethered mitral valve, mitral regurgitant orifice area will be determined largely by the phasic changes in transmitral pressure.16 –18 The worsening of LV dysfunction with a decreased rate of LV (and thus transmitral) pressure increase will further increase diastolic MR severity due to the impaired closing force. After the institution of CRT, diastolic MR was eliminated in all patients, although there were no significant changes in any of the parameters of mitral valve annulus, tethering distance, or even the diastolic leaflet opening angle. Breithardt et al5 demonstrated that CRT in selected patients with advanced heart failure and electrical conduction delay acutely reduced the severity of functional systolic MR by causing an accelerated increase in transmitral pressure and an increase in peak transmitral closing during isovolumic contraction. Thus, directly improving LV systolic function can effectively counteract the increased tethering forces that impair effective mitral valve closure. Our study represents a direct application of this concept. Because the resolution of diastolic MR after the institution of CRT in our patients was not caused by changes in tethering forces (mitral valve geometry was unchanged; Table 2), it must have been
1614
The American Journal of Cardiology (www.AJConline.org)
caused by changes in closing forces in conjunction with shortening of the atrioventricular delay. No measurements of left atrial and LV pressure were performed in this study because of a lack of clinical indication. We also did not examine the potential long-term effect of late reverse remodeling on mitral valve geometry and the degree of regurgitation, because we used only shortterm follow-up. It is conceivable that reverse remodeling after long-term CRT, a well-documented phenomenon, may result in decreased mitral tethering and thus in itself contribute to mitral valve competence in systole as well as diastole. Nevertheless, these limitations should not have affected the principal finding of this study. 1. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, et al, Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873– 880. 2. Gras D, Mabo P, Tang T, Luttikuis O, Chatoor R, Pedersen AK, Tscheliessnigg HH, Deharo JC, Puglisi A, Silvestre J, et al. Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol 1998;21:2249 –2255. 3. Linde C, Cazeau S, Kappenberger L, Sutton R, Bailleul C, Daubert JC. Long-term benefit of biventricular pacing in congestive heart failure. One year results from patients in atrial fibrillation in the MUSTIC (Multisite Stimulation in Cardiomyopathy) study. Eur Heart J 2001; 22:441. 4. Abraham W, Fisher W, Smith A, William T, Delurgio D, Leon A, Loh E, Kocovic D, Packer M, Clavell A, et al, for the MIRACLE Study Group. Cardiac resynchronization therapy in chronic heart failure. N Engl J Med 2002;346:1845–1853. 5. Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 2003;41:765–770. 6. Ritter P, Dib JC, Lelievre T. Quick determination of the optimal AV delay at rest in patients paced in DDD mode for complete AV block. Eur J CPE 1994;4:A163. 7. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommen-
8.
9.
10.
11.
12.
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14.
15.
16.
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