**5. Effect of cardiac resynchronization therapy on functional mitral regurgitation**

Cardiac resynchronization therapy is an established treatment option for patients with advanced chronic heart failure and prolonged QRS duration [35, 36]. The benefits of CRT are attributed mainly to increased efficiency of LV filling and ejection, resulting from the improvement in atrioventricular coupling, intra- and interventricular synchronization [46–48]. CRT can attenuate heart failure symptoms and improve exercise capacity and survival in patients with heart failure and prolonged QRS duration [49–51]. In line with current ESC guidelines, cardiac resynchronization therapy is recommended (class I recommendation) in symptomatic (despite optimal medical therapy) patients with heart failure in sinus rhythm, with LBBB and QRS duration of at least 130 ms, with LVEF ≤ 35%, and in individuals with LV dysfunction (regardless of the NYHA class) who have an indication for ventricular pacing and high degree atrioventricular block [36]. The outcome of cardiac resynchronization therapy is determined by a number of clinical factors, and improvement of functional mitral regurgitation is currently considered as one of the mechanisms underlying the beneficial effect of the treatment.

Echocardiographic studies demonstrate that cardiac resynchronization therapy may correct the pathophysiologic determinants of functional MR. The following mechanisms are considered to mediate the clinical efficacy of CRT.


**5.** Optimization of atrioventricular delay with the restoration of proper timing for atrioventricular synchrony/atrioventricular relaxation contributes to generation of an adequate transmitral pressure gradient during the cardiac cycle and eliminates diastolic MR (if present); this effect is only partially specific for this therapeutic method [58].

#### **5.1. Biphasic response of functional mitral regurgitation to cardiac resynchronization therapy**

LV dyssynchrony is a less important determinant of functional MR than systolic valvular tenting, which is the strongest predictor of EROA [45]. However, the impact of systolic valvular tenting on functional MR in different subsets of patients with LV dysfunction varies. Mitral valve tenting and local LV remodeling (in the papillary muscle-bearing wall segments), but not regional dyssynchrony, are independent predictors of functional MR degree in ischemic LV dysfunction; these local changes result directly from ischemic lesions. In non-ischemic LV dysfunction, regional dyssynchrony exacerbates functional MR independently of LV geom-

**5. Effect of cardiac resynchronization therapy on functional mitral** 

Cardiac resynchronization therapy is an established treatment option for patients with advanced chronic heart failure and prolonged QRS duration [35, 36]. The benefits of CRT are attributed mainly to increased efficiency of LV filling and ejection, resulting from the improvement in atrioventricular coupling, intra- and interventricular synchronization [46–48]. CRT can attenuate heart failure symptoms and improve exercise capacity and survival in patients with heart failure and prolonged QRS duration [49–51]. In line with current ESC guidelines, cardiac resynchronization therapy is recommended (class I recommendation) in symptomatic (despite optimal medical therapy) patients with heart failure in sinus rhythm, with LBBB and QRS duration of at least 130 ms, with LVEF ≤ 35%, and in individuals with LV dysfunction (regardless of the NYHA class) who have an indication for ventricular pacing and high degree atrioventricular block [36]. The outcome of cardiac resynchronization therapy is determined by a number of clinical factors, and improvement of functional mitral regurgitation is currently considered as one of the mechanisms underlying the beneficial effect of the treatment. Echocardiographic studies demonstrate that cardiac resynchronization therapy may correct the pathophysiologic determinants of functional MR. The following mechanisms are consid-

**1.** Restoration of the LV and papillary muscle synchronous contraction improves spatial relations and function of the subvalvular apparatus and the mitral valve itself (a decrease in mitral valve tethering force); the effect is specific for this therapeutic method [52, 53]. **2.** Improved coordination of LV wall contraction and resultant improvement of LV ejection function contribute to an increase in transmitral pressure gradient (greater mitral valve

**3.** Remote reverse remodeling of the LV with the reduction of LV volume and sphericity induce favorable changes in the geometry of mitral valve apparatus (a decrease in tethering force) and contribute to further improvement in LV systolic function (an increase in mitral valve closing force); the effect is not specific for this therapeutic method and particularly

**4.** The effect of cardiac resynchronization therapy on mitral valve annular size and function (through the recoordination of contraction in LV basal segments and then through reverse

closing force); the effect is specific for this therapeutic method [54, 55].

pronounced at the later phase of CRT [53, 55–57].

remodeling of the LV) is uncertain [52, 53].

etry but as a factor of lesser importance [45].

64 Structural Insufficiency Anomalies in Cardiac Valves

ered to mediate the clinical efficacy of CRT.

**regurgitation**

The improvement of functional MR after the use of cardiac resynchronization therapy has two phases:


In fact, the two phases of functional MR improvement may be less distinct. LV reverse remodeling can occur relatively early [10]. Subacute improvement in systolic shape of the LV (lesser sphericity) and subvalvular traction after CRT implementation are also probably related to an increase in LV longitudinal function [56].

Effective CRT reduces the transmitral regurgitant volume in about 40% of patients immediately and in the next 20% of them at a later stage [53]. The sequence of functional MR improvement may depend on a pattern of baseline dyssynchrony. Early and late responders may show a similar extent of LV dyssynchrony; however, the site of latest activation in early responders is mostly inferior or posterior (adjacent to the posterior papillary muscle), whereas in late responders, the latest activation occurs primarily in the lateral wall [53]. Late responders may also show acute improvement in LV end-systolic volume, presumably as an effect of recoordinated and, hence, more effective LV contraction. Acting through the mechanisms described above, CRT can attenuate moderate-to-severe functional mitral regurgitation to a clinically nonsignificant MR in about one-third of heart failure patients. Published data about the association between baseline functional MR and response to CRT are ambiguous [8, 62–64]. The post-CRT improvement of functional MR may be relatively more frequent in patients with greater severity of mitral regurgitation at the baseline. Moreover, an acute or subacute attenuation of functional MR is a predictor of further improvement [8]. Lack of improvement in functional MR in response to CRT is associated with worse prognosis (unfavorable profile of clinical evolution, higher incidence of arrhythmic events and lesser occurrence of LV reverse remodeling [62, 65]). This raises a question about the predictors of functional MR response to CRT.

#### **5.2. Predictors of functional mitral regurgitation improvement in response to cardiac resynchronization therapy**

persons who do not show an improvement in total functional MR after 3 months of post-CRT follow-up [60]. Correlation between clinical and echocardiographic indices of post-CTR improvement is rather weak [10, 77]. However, the direction and magnitude of LV reverse remodeling correlate with survival, and a 1-year mortality after CRT implementation is pre-

Cardiac Dyssynchrony as a Pathophysiologic Factor of Functional Mitral Regurgitation: Role…

http://dx.doi.org/10.5772/intechopen.76605

67

Finally, volumetric limitation for functional MR improvement in response to cardiac resynchronization therapy needs to be emphasized. Not only irreversibly damaged ischemic myocytes respond less to CRT, the post-CRT improvement in functional MR is also less likely in patients who present with greater degree of LV dilatation at the baseline. Lesser baseline LV diameters (end-diastolic and end-systolic) and volumes are the independent predictors of functional MR improvement in response to CRT [10, 67, 79–81]. The cut-off value for LV end-diastolic dimension is close to 75 mm [10, 82] and for LV end-systolic dimension index 29 mm/m<sup>2</sup> [67]. Non-responders present a significantly higher baseline LV dilatation. CRT may be insufficient to overcome poor natural history of systolic heart failure but may slow down its progression. The effectiveness of all currently available therapeutic options is limited, and critical enlargement of the left ventricle may trigger the previously mentioned vicious circle of self-

dicted by echocardiographic parameters, rather than by clinical indices [77].

perpetuating LV dilatation and functional mitral regurgitation [10, 83, 84].

**mitral regurgitation after the use of CRT**

**6. Management of patients with persistent significant functional**

Therapeutic targets in patients with functional MR include attenuation of symptoms, lesser number of heart failure hospitalizations, better quality of life and, potentially, survival. At present, the most effective therapies of functional MR are aimed at the underlying LV dysfunction. Therefore, as the first step, optimal medical therapy according to the guidelines for the management of heart failure should be used [36]. As the second step, whenever appropriate, CRT should be implemented in line with the respective guidelines [35, 36]. In patients who remain symptomatic despite optimal medical therapy and CRT (if indicated), mitral valve intervention (surgical or transcatheter repair) should be considered; however, there is no evidence that a reduction of functional MR improves survival [13]. Moreover, the surgery has never clearly been demonstrated to alter the natural history of the primary disease (dilated cardiomyopathy) [85]. Limited empirical data contribute to a lower level of evidence for management recommendations, highlighting the importance of decisions made by the Heart Team. The multidisciplinary Heart Team consisting of imaging experts, heart failure and electrophysiology specialists, interventional cardiologists, and cardiac surgeons should try to reach a consensus on appropriate care. Not only the feasibility of the procedure but also comorbidities, the level of surgical risk, and surgeon experience should be considered [13]. In patients undergoing revascularization, the evaluation and decision to treat (or not to treat) ischemic MR should be made prior to surgery. There is an overall agreement that severe functional MR should be addressed at the time of coronary artery bypass grafting (CABG). The management of moderate functional MR in patients undergoing CABG still raises controversies [86]. The thresholds of functional MR severity are also a matter of debate (as stated earlier). Surgical options in patients with functional MR include mitral valve repair and replacement.

Despite appropriate selection of candidates for CRT, not all of them respond to the treatment. The mechanisms responsible for post-CRT improvement in functional MR are complex. Although QRS duration is the main determinant of primary electrical dyssynchrony and a primary criterion considered during selection of patients for CRT, it is not a good predictor of response to the treatment [42, 43]. Aside from dyssynchrony, the post-CRT improvement in functional MR may also depend on other factors, such as myocardial viability, presence of scar/fibrosis and the extent of LV remodeling at the baseline [10, 66, 67].

Many echocardiographic measures of dyssynchrony do not confirm their value as the predictors of CRT outcomes [39–41]. Inter-ventricular mechanical delay (IVMD, the time difference between right ventricular and left ventricular ejection, determined as the time elapsed since the onset of the QRS to the onset of left ventricular vs. right ventricular ejection, usually measured using pulsed Doppler flow) seems to be a simple and reproducible parameter of dyssynchrony, correlating well with the response to CRT, either LV reverse remodeling or functional MR improvement [10, 41, 68, 69]. Also, speckle-tracking radial strain imaging (time difference in peak septal to posterior wall strain) appears as a relatively simple measure of dyssynchrony, having established a predictive value with regard to CRT outcome [67]. There is no unambiguous evidence regarding the site of the latest activation as an independent predictor of the improvement in functional MR [10, 53]. Myocardial viability (in heart failure with ischemic etiology) and contractile reserve (in non-ischemic cardiomyopathy) are important determinants of CRT effectiveness in terms of functional MR improvement [10, 70–73]. The outcome of CRT may be also associated with the location of contractile reserve (particularly in relation to the papillary muscle-bearing segments and to the paced LV region), as well as with the size of the contractile reserve area [10, 66, 72, 73]. The importance of discordant LV lead position and myocardial scar, especially extensive scar burden, as the predictors of CRT outcomes, is documented [74, 75]. The potential role of myocardial fibrosis stimulates research on biochemical predictors of CRT responses (among them on galactin-3, a protein involved in fibrogenesis) [76].

#### **5.3. Functional mitral regurgitation improvement and left ventricular reverse remodeling in response to CRT**

The change in LV end-diastolic volume after the use of cardiac resynchronization therapy proved to be the most powerful independent predictor of death [77]. CRT effectively reversed LV remodeling, both in patients with moderate-to-severe heart failure (NYHA III/ IV class) and in individuals with mild heart failure (NYHA I/II class) [49, 50]. The response to CRT may be influenced by the presence of functional mitral regurgitation prior to the implantation of a CRT device and by its persistence despite the treatment. Patients, who do not respond to CRT, present with a significant functional MR more often than the responders [78]. On the other hand, an improvement in pre-existing functional MR contributes to LV reverse remodeling during follow-up after the implantation of a CRT device [60]. The incidence of reverse remodeling, defined as an improvement in LVEF and forward stroke volume, is the highest in patients who show a reduction of total functional MR, intermediate in individuals with mild functional MR or lack thereof at the baseline and the lowest in persons who do not show an improvement in total functional MR after 3 months of post-CRT follow-up [60]. Correlation between clinical and echocardiographic indices of post-CTR improvement is rather weak [10, 77]. However, the direction and magnitude of LV reverse remodeling correlate with survival, and a 1-year mortality after CRT implementation is predicted by echocardiographic parameters, rather than by clinical indices [77].

**5.2. Predictors of functional mitral regurgitation improvement in response to cardiac** 

scar/fibrosis and the extent of LV remodeling at the baseline [10, 66, 67].

Despite appropriate selection of candidates for CRT, not all of them respond to the treatment. The mechanisms responsible for post-CRT improvement in functional MR are complex. Although QRS duration is the main determinant of primary electrical dyssynchrony and a primary criterion considered during selection of patients for CRT, it is not a good predictor of response to the treatment [42, 43]. Aside from dyssynchrony, the post-CRT improvement in functional MR may also depend on other factors, such as myocardial viability, presence of

Many echocardiographic measures of dyssynchrony do not confirm their value as the predictors of CRT outcomes [39–41]. Inter-ventricular mechanical delay (IVMD, the time difference between right ventricular and left ventricular ejection, determined as the time elapsed since the onset of the QRS to the onset of left ventricular vs. right ventricular ejection, usually measured using pulsed Doppler flow) seems to be a simple and reproducible parameter of dyssynchrony, correlating well with the response to CRT, either LV reverse remodeling or functional MR improvement [10, 41, 68, 69]. Also, speckle-tracking radial strain imaging (time difference in peak septal to posterior wall strain) appears as a relatively simple measure of dyssynchrony, having established a predictive value with regard to CRT outcome [67]. There is no unambiguous evidence regarding the site of the latest activation as an independent predictor of the improvement in functional MR [10, 53]. Myocardial viability (in heart failure with ischemic etiology) and contractile reserve (in non-ischemic cardiomyopathy) are important determinants of CRT effectiveness in terms of functional MR improvement [10, 70–73]. The outcome of CRT may be also associated with the location of contractile reserve (particularly in relation to the papillary muscle-bearing segments and to the paced LV region), as well as with the size of the contractile reserve area [10, 66, 72, 73]. The importance of discordant LV lead position and myocardial scar, especially extensive scar burden, as the predictors of CRT outcomes, is documented [74, 75]. The potential role of myocardial fibrosis stimulates research on biochemical predictors

of CRT responses (among them on galactin-3, a protein involved in fibrogenesis) [76].

The change in LV end-diastolic volume after the use of cardiac resynchronization therapy proved to be the most powerful independent predictor of death [77]. CRT effectively reversed LV remodeling, both in patients with moderate-to-severe heart failure (NYHA III/ IV class) and in individuals with mild heart failure (NYHA I/II class) [49, 50]. The response to CRT may be influenced by the presence of functional mitral regurgitation prior to the implantation of a CRT device and by its persistence despite the treatment. Patients, who do not respond to CRT, present with a significant functional MR more often than the responders [78]. On the other hand, an improvement in pre-existing functional MR contributes to LV reverse remodeling during follow-up after the implantation of a CRT device [60]. The incidence of reverse remodeling, defined as an improvement in LVEF and forward stroke volume, is the highest in patients who show a reduction of total functional MR, intermediate in individuals with mild functional MR or lack thereof at the baseline and the lowest in

**5.3. Functional mitral regurgitation improvement and left ventricular reverse** 

**resynchronization therapy**

66 Structural Insufficiency Anomalies in Cardiac Valves

**remodeling in response to CRT**

Finally, volumetric limitation for functional MR improvement in response to cardiac resynchronization therapy needs to be emphasized. Not only irreversibly damaged ischemic myocytes respond less to CRT, the post-CRT improvement in functional MR is also less likely in patients who present with greater degree of LV dilatation at the baseline. Lesser baseline LV diameters (end-diastolic and end-systolic) and volumes are the independent predictors of functional MR improvement in response to CRT [10, 67, 79–81]. The cut-off value for LV end-diastolic dimension is close to 75 mm [10, 82] and for LV end-systolic dimension index 29 mm/m<sup>2</sup> [67]. Non-responders present a significantly higher baseline LV dilatation. CRT may be insufficient to overcome poor natural history of systolic heart failure but may slow down its progression. The effectiveness of all currently available therapeutic options is limited, and critical enlargement of the left ventricle may trigger the previously mentioned vicious circle of selfperpetuating LV dilatation and functional mitral regurgitation [10, 83, 84].
