Cardiac resynchronization therapy is associated with a reduction in mitral regurgitation and this decrease in mitral regurgitation probably influences the favorable effects of CRT. The exact mechanism of this reduction by CRT has been only incompletely defined. Some studies suggest that contractile dyssynchrony between the anterior and posterior papillary muscles promotes mitral regurgitation, restoration of the left ventricular synchronous contraction pattern after CRT leads to a decrease of mitral regurgitation. Preliminary data suggested that CRT can acutely reduce mitral regurgitation in patients with dyssynchrony between the papillary muscles. Kanzaki et al. tested the hypothesis that an immediate reduction in mitral regurgitation after CRT resulted from improved coordinated timing of the papillary muscle insertion sites [9]. They studied 26 patients with at least mild mitral regurgitation undergoing CRT. Echocardiographic Doppler and strain imaging was performed immediately before and the day after CRT (see Fig. 16.3). Mitral regurgitation consistently decreased after CRT. At baseline the time delay between papillary muscle insertion sites was 106 ± 74 ms. This delay shortened after CRT to 39 ± 43 ms and was significantly correlated with reductions in mitral regurgitation fraction (R = 0.77, P < 0.001). Improved coordinated timing of the mechanical activation of the papillary muscle insertion sites appears to be a mechanistic contributor to immediate mitral regurgitation reduction by CRT. Karvounis et al. hypothesized that functional mitral regurgitation attenuation after cardiac resynchronization therapy is attributed to both an increased rate of left ventricular systolic pressure and to papillary muscle recoordinated contraction [17]. They studied 22 patients with moderate/severe mitral regurgitation at baseline and after CRT improvement. An increase in systolic deformation of the papillary muscles or the adjacent myocardial wall may in part account for the positive effect by preventing outward displacement during systole. CRT induced a significant reduction in mitral regurgitation as evaluated by the effective regurgitant orifice area (0.18 ± 0.11 mm² versus 0.35 ± 0.17 mm², P < 0.001). Also strain improved in both papillary muscles, although it was significant only in the anterolateral and posteromedial papillary muscle wall. Ypenburg et al. selected 25 patients that showed an acute reduction in mitral regurgitation severity – from 63 consecutive patients that had significant mitral regurgitation at baseline – treated with CRT [18]. This selected group underwent echocardiography including speckle tracking strain analysis to assess dyssynchrony between the anterior and posterior papillary muscle at baseline, after CRT initiation and during interruption of CRT at 6 months follow-up (see Figs. 16.4 and 16.5). Dyssynchrony between the papillary muscles decreased significantly after CRT initiation (169 ± 69 ms to 25 ± 26 ms P < 0.001) and were maintained at 6 months follow-up (25 ± 26 ms immediately after CRT versus 26 ± 28 ms at 6 months follow-up, P = NS). Importantly after interruption of CRT, acute loss of resynchronization was observed (dyssynchrony between the papillary muscles 134 ± 51 ms), with an acute recurrence of mitral regurgitation and worsening in mitral deformation indices. Besides the acute effect, reduction in mitral regurgitation has also been shown at long-term follow-up after CRT, and is most likely secondary to left ventricular reverse remodeling. In a subsequent study, Ypenburg et al. assumed that patients with late activation (dyssynchrony) of the myocardial segments adjacent to posterior papillary muscle will respond acutely in mitral regurgitation after CRT initiation (see Fig. 16.6) whereas patients with late activation (dyssynchrony) of the lateral left ventricular segments will show late improvement in mitral regurgitation due to left ventricular reverse remodeling (see Fig. 16.7) [19]. Lastly patients without dyssynchrony will show neither an acute or chronic improvement in mitral regurgitation nor reverse remodeling. The study population consisted of 68 patients with at least moderate mitral regurgitation that underwent echocardiography at baseline, 1 day after CRT initiation and at 6 months follow-up. Speckle tracking radial strain was used to assess left ventricular dyssynchrony at baseline. The majority of patients improved in mitral regurgitation after CRT, with 43 % improving immediately after CRT, and 20 % improving late (after 6 months) after CRT. Early and late responders had similar extent of left ventricular dyssynchrony (209 ± 115 ms versus 190 ± 118 ms, P = NS), however the site of latest activitation in early responders was mostly inferior or posterior (adjacent to the posterior papillary muscle) whereas the lateral wall was the latest activated segment in late responders. These data suggest that the presence of left ventricular dyssynchrony is related to improvement of mitral regurgitation after CRT. Left ventricular dyssynchrony involving the posterior papillary muscle may lead to an immediate reduction in mitral regurgitation, whereas left ventricular dyssynchrony in the lateral wall resulted in late response to CRT. Goland et al. evaluated 32 patients with at least grade 3 or more mitral regurgitation undergoing CRT [20]. The aim was to evaluate whether left ventricular dyssynchrony in mid left ventricular segments corresponding to papillary muscles insertion sites – evaluated by 2-dimensional radial strain – can predict early mitral regurgitation reduction post CRT. Fifteen (47 %) patients responded to CRT. Sixty-seven percent of responders had mild or no residual mitral regurgitation and 33 % had mild-to-moderate mitral regurgitation, while 70 % of non-responders had grade 3 or 4 mitral regurgitation (P = 0.0001) post CRT. Significant delay of time-to-peak radial strain in the mid posterior and inferior segments prior to CRT was found in responders compared with non-responders (580 ± 58 ms versus 486 ± 94 ms, P = 0.002 and 596 ± 79 ms versus 478 ± 127 ms, P = 0.005, respectively). Responders also had higher peak positive systolic 2-dimensional radial strain in the posterior and inferior segments compared to non-responders (22 ± 13 % versus 12 ± 7 %, P = 0.01 and 17 ± 9 % versus 9 ± 7 %, P = 0.02, respectively).

Both a decrease in left ventricular closing force and mitral valve tethering have been implicated as mechanisms for functional mitral regurgitation in dilated hearts. Normal mitral valve function results from a balance of both tethering and closing forces on the mitral valve. Tethering forces are transmitted via the chordae and keep the valve form prolapsing, closing forces depend on the pressure generated by the ventricle to close the mitral valve (see Fig. 16.1). A derangement in this relationship of tethering and closing forces results in functional mitral regurgitation. Breithardt et al. hypothesized that an increase in left ventricular closing forces achieved by CRT could act to reduce functional mitral regurgitation [11]. They studied the acute effects of cardiac resynchronization therapy on functional mitral regurgitation in 24 heart failure patients with a left bundle branch block. Acute changes in functional mitral regurgitation severity between intrinsic conduction and CRT were quantified according to the PISA method by measuring the effective regurgitant orifice area. Results were compared with the changes in estimated maximal rate of left ventricular pressure rise (LV + dP/dt(max)) and transmitral pressure gradients, both measured by Doppler echocardiography. CRT was associated with a significant reduction in mitral regurgitation severity. Effective regurgitant orifice area decreased from 25 ± 19 mm² to 13 ± 8 mm². The change in effective regurgitant orifice area was directly related to the increase in LV + dP/dt(max) (r = −0.83, P < 0.0001). Compared with intrinsic conduction, transmitral pressure gradients increased more rapidly during CRT, and a higher maximal transmitral pressure gradient was observed (intrinsic conduction 73 ± 24 mmHg versus CRT 85 ± 26 mmHg, P < 0.01). The authors concluded that functional mitral regurgitation is reduced by CRT and that the effect is directly related to the increased closing force LV + dP/dt(max). The results support the hypothesis that an increase in transmitral pressure gradients, mediated by a rise in LV + dP/dt(max) due to more coordinated left ventricular contraction, may facilitate effective mitral valve closure. Solis et al. hypothesized that CRT improves the comprehensive force balance acting on the valve, including favorable changes in both geometry and left ventricular contractile function [21]. They studied 34 heart failure patients before implantation and during follow up (209 ± 81 days). The authors used the strength of 3-dimensional echocardiography to quantify mitral valve geometry and analyzed transmitral flow velocities to provide insights into the dynamics of mitral valve closing forces, specifically including an integrated measure of left ventricular force generation based on transmitral Doppler velocities. After CRT, left ventricular end-diastolic volumes (253 ± 111 mL versus 221 ± 110 mL, P < 0.0001) decreased, as did left ventricular end-systolic volumes (206 ± 97 mL versus 167 ± 91 mL, P < 0.0001), whereas ejection fraction increased (19 ± 6 % versus 27 ± 9 %, P < 0.001). Mitral regurgitant volume decreased significantly from 35 ± 17 mL to 23 ± 14 mL (P < 0.001). There were favorable changes in mitral valve geometry after CRT with a decrease in mitral valve annular area, leaflet area during valve closure and tenting volume. The closing pressure ratio increased after CRT, consistent with more sustained closing forces on mitral valve during systole. Among the 34 patients, there were 62 % responders to CRT. The responders had significant beneficial changes in mitral valve geometry and improvement in closing forces after CRT compared with before CRT, whereas the nonresponder group did not have similar improvements in mitral valve geometry after CRT compared with before CRT. Comparison of mitral regurgitation reduction and mitral regurgitation no-reduction groups provided confirmatory support for the importance of improving the force-balance relationship in reducing mitral regurgitation. Despite similar reductions in left ventricular volumes and improvements in left ventricular ejection fraction, patients in the mitral regurgitation reduction group had significant decreases in mitral valve geometric patterns after CRT compared with before CRT, whereas patients without mitral regurgitation reduction did not have favorable changes in mitral valve geometry. The authors concluded that CRT is associated with a reduction in mitral regurgitation. The mechanism relates to optimization of the force-balance relationship, with favorable changes in both closing and tethering forces on mitral valve function. It does so by favorably affecting the force balance acting on the mitral valve in two ways: reducing tethering through reversal of left ventricular remodeling and increasing the systolic duration of high transmitral closing pressures.