**4. Pathophysiology of functional mitral regurgitation**

assessed using other traditional measures of mitral regurgitation such as proximal isovelocity surface area (PISA) and *vena contracta* width [14]. Also the limitations of the volumetric method in the assessment of regurgitant volume and fraction are well-known issues [14]. Furthermore, low inter- and intra-observer agreement between cardiologists reviewing the same dataset was documented [17]. It is now known that due to the limitations inherent to each available method, no single parameter is accurate enough to quantify the degree of MR. Therefore, current guidelines recommend an integrative approach including multiple qualitative and quantitative parameters, along with certain signs and measures of MR severity, such as left ventricular size and function, left atrial size, mitral valve leaflet morphology and motion, mitral filling pattern, pulmonary venous flow pattern and others [13, 16]. If during the first attempt MR is not unequivocally defined as mild or severe, the integrative

**Table 1.** Quantitative echocardiographic criteria for severe MR in primary and secondary disease of the mitral valve [16].

EROA ≥0.4 cm<sup>2</sup> ≥0.2 cm<sup>2</sup> Regurgitant volume ≥60 mL ≥30 mL Regurgitant fraction ≥50% ≥50% Vena contracta ≥0.7 cm — Jet area Central jet >40% LA or holosystolic eccentric jet —

60 Structural Insufficiency Anomalies in Cardiac Valves

**Primary (organic) MR Secondary (functional) MR**

approach should be used to exclude the severe character of mitral regurgitation.

MR. An exercise-induced increase in EROA by at least 13 mm<sup>2</sup>

Functional MR is an evidently dynamic phenomenon. A typical phasic variation in regurgitant volume and orifice, with the maximum values observed in early and late systole and minimum ones in mid-systole (at peak transmitral pressure gradient generated by LV), is documented [18]. This intra-beat variability (referred to as the "loitering pattern") hinders functional MR assessment, which is traditionally carried out in mid-systole. The severity of functional MR may also show a beat-to-beat variability depending on changes in loading conditions and hemodynamic parameters (e.g., during arrhythmia). The dynamic nature of functional MR has particular practical meanings in two situations: during physical exertion and intraoperative assessment. Induction of anesthesia and inotropic agents may significantly reduce MR and thus, may directly affect intraoperative decisions regarding its repair. Owing the dynamic nature of functional MR, in patients whose symptoms at rest are inadequate to assess the severity of mitral regurgitation, more accurate information may be obtained during exercise echocardiography. Exercises contribute to a greater cardiac load and thus, may also trigger dynamic geometric changes in the LV and mitral valve apparatus (even despite the lack of provoked ischemia), which may eventually result in acute "flash pulmonary edema" [19]. This may be a reason behind worse prognosis associated with even a mild functional

higher morbidity and mortality [20]. Exercise echocardiography may also unmask increasing pulmonary artery pressure and the lack of LV contractile reserve, both being important predictors of the outcome [19, 20]. Finally, exercises may reveal or trigger greater LV dyssynchrony with increased functional MR [21]. Despite some caveats of this approach, current guidelines recommend echocardiographic quantification of secondary MR during exercises, as this may

was shown to correlate with

The term "functional mitral regurgitation" refers to a dysfunction of the valve without its primary organic damage. Optimal function of the mitral valve provides nonrestrictive blood flow during diastole and leak tightness during systole. This diastolic and systolic competence is possible due to a synchronous coordination of all components of the mitral valve apparatus, acting under a balanced influence of closing and opening forces. Mitral valve apparatus is an integrated unit consisting of mitral valve itself (formed by two leaflets and mitral annulus) and subvalvular components (chordae tendineae, two papillary muscles, left ventricle and posterior left atrial wall). An effective function of the mitral valve is determined not only by the compatible cooperation between its components but also by their appropriate structural and spatial relations.

#### **4.1. Left ventricular remodeling and dysfunction as a mechanism of functional mitral regurgitation**

All changes in LV function and geometry affect functioning of mitral valve through opposing strength vectors: the tethering force (created by displacement of papillary muscles) and the LV-generated leaflet closing force (created by effective contraction causing transmitral pressure gradient) (**Figure 1**) [22]. Global LV dilation results in incomplete mitral leaflet closure and mitral regurgitation, which correlates with LV dysfunction. Local or global dilation of the LV is a prerequisite for incomplete mitral leaflet closure [22]. However, functional MR does not result from LV dilatation per se but from an increase in LV sphericity and resultant posterolateral displacement of the papillary muscles [23, 24]. If functional MR has an ischemic etiology, it does not necessarily need to be preceded by global systolic dysfunction [25]. Regional abnormalities in cardiac wall motion after inferior myocardial infarction may contribute to mitral valve tethering (with systolic tenting of the leaflets), which is strong enough to cause severe mitral regurgitation despite preserved LV ejection fraction (LVEF) [25].

Two main patterns of leaflet tethering can be distinguished in functional mitral regurgitation (**Figure 2**) [26, 27]. The symmetric pattern is characterized by global LV dilation with increased sphericity and predominant apical displacement of both leaflets with central regurgitant jet direction. Also the mitral valve annulus dilates symmetrically, primarily in the septal-lateral direction [26, 27]. This configuration is typical for non-ischemic functional MR (Carpentier type III B symmetric) [27, 28]. The asymmetric pattern is typically resulted from local remodeling of the posterior papillary muscle-bearing wall segment, with posterior tenting of both leaflets and a posteriorly directed asymmetric regurgitant jet (Carpentier type III B asymmetric) [25–28]. While the displacement of posterior papillary muscle is similar regardless of the leaflet tethering pattern, symmetric tethering is characterized by greater posterior and lateral displacement of

While geometric changes of LV are an essential component of functional MR pathomechanism, it is the tethering distance between the tip of posterior papillary muscle and the anterior pole of mitral annulus ("posterior papillary-fibrosa distance"), which constitutes the final common pathway determining the plane of leaflet coaptation [22, 29]. Mitral annular dilation typically occurs at late stage of ischemic MR [30, 31]. Isolated dilation and flattening of mitral valve annulus are occasionally the cause of severe mitral regurgitation, representing type I in Carpentier's classification [28, 30, 31]. Although atrial fibrillation constitutes a quite frequent cause of functional MR, it rarely results in severe valve dysfunction. Isolated enlargement of the left atrium, with concomitant atrial fibrillation or without, leads to dilatation of mitral annulus and reduced leaflet coaptation [32]. Diastolic MR results from a reversal of atrioventricular pressure gradient during diastole. This form of MR occurs in patients with atrioventricular block, cardiomyopathy and aortic regurgitation, as well as in individuals with long

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**4.2. Cardiac dyssynchrony as a pathophysiologic factor of functional mitral** 

Dyssynchrony, defined as an uncoordinated regional myocardial contraction [33, 34], may manifest as (1) "primary electrical dyssynchrony" (i.e., electrical conduction delay which causes non-uniform timing of myocyte depolarization), (2) abnormalities in excitation-contraction coupling (a surrogate for regional electromechanical coupling is the interval between the onset of QRS complex in ECG and the onset of systolic velocity in spectral pulsed-wave tissue Doppler imaging), or (3) "primary mechanical dyssynchrony" (i.e., a regional delay in onset shortening and in time to peak shortening of LV segments) [34]. Primary electrical dyssynchrony is typical for left bundle branch block (LBBB) and primary mechanical dyssynchrony—for regional ischemia or fibrosis [33, 34]. Currently, QRS duration remains the only clinically significant surrogate for the timing of myocardial contraction and the only criterion amenable for CRT [35, 36]. Clinical significance of "clear" primary mechanical dyssynchrony remains ambiguous [37, 38]. CRT does not provide any benefit (and may be even harmful) in heart failure patients with mechanical dyssynchrony without QRS widening (<130 ms) [38]. Various echocardiographic measures of dyssynchrony turned out not to be a superior selection criterion for CRT [39, 40]. Moreover, unacceptable variability, poor reproducibility and limited practical predictive value of the most echocardiographic parameters of dyssynchrony are documented [41]. Thus, although the predictive value of prolonged QRS also varies from study to study [42, 43], qualification to CRT is still based primarily on

Functional MR correlates strongly with QRS duration. Left bundle branch block and right ventricular pacing (which produce a conduction abnormality similar to LBBB), but not right bundle branch block or left anterior hemi-block, are strongly associated with functional MR [44]. The relationship between right ventricular pacing and mitral regurgitation indicates that the key determinant of functional MR is a conduction abnormality, rather than the underlying disease causing LBBB [44]. Those findings have important implications for biventricular pacing as a treatment option in heart failure patients with

filling periods in atrial tachyarrhythmia [31].

**regurgitation**

this parameter [35, 36].

functional MR.

**Figure 1.** Mechanism of functional mitral regurgitation. (A) Balance of closing and tethering forces acting on mitral leaflets during systole. (B) Disrupted balance of closing and tethering forces due to local LV remodeling (dark shading). LA: left atrium; LV: left ventricle; PM: papillary muscle; Ao: aorta; ME: mitral regurgitation.

**Figure 2.** Patterns of leaflet tenting in functional mitral regurgitation. (A) Normal coaptation of mitral leaflets. (B) Asymmetric pattern—predominant posterior displacement of both leaflets with prevent restriction of posterior leaflet and large eccentric regurgitant jet. (C) Symmetric pattern—predominant apical displacement of both leaflets with central regurgitant jet.

anterior papillary muscle and longer inter-papillary distance [27]. Both patterns of leaflet tethering can be observed in ischemic MR [25–27]. The occurrence of the symmetric pattern in ischemic MR is associated with more advanced systolic dysfunction, global remodeling and increased LV sphericity [23, 24, 27]. This pattern is typical for non-ischemic dilated cardiomyopathy [26].

While geometric changes of LV are an essential component of functional MR pathomechanism, it is the tethering distance between the tip of posterior papillary muscle and the anterior pole of mitral annulus ("posterior papillary-fibrosa distance"), which constitutes the final common pathway determining the plane of leaflet coaptation [22, 29]. Mitral annular dilation typically occurs at late stage of ischemic MR [30, 31]. Isolated dilation and flattening of mitral valve annulus are occasionally the cause of severe mitral regurgitation, representing type I in Carpentier's classification [28, 30, 31]. Although atrial fibrillation constitutes a quite frequent cause of functional MR, it rarely results in severe valve dysfunction. Isolated enlargement of the left atrium, with concomitant atrial fibrillation or without, leads to dilatation of mitral annulus and reduced leaflet coaptation [32]. Diastolic MR results from a reversal of atrioventricular pressure gradient during diastole. This form of MR occurs in patients with atrioventricular block, cardiomyopathy and aortic regurgitation, as well as in individuals with long filling periods in atrial tachyarrhythmia [31].

#### **4.2. Cardiac dyssynchrony as a pathophysiologic factor of functional mitral regurgitation**

Dyssynchrony, defined as an uncoordinated regional myocardial contraction [33, 34], may manifest as (1) "primary electrical dyssynchrony" (i.e., electrical conduction delay which causes non-uniform timing of myocyte depolarization), (2) abnormalities in excitation-contraction coupling (a surrogate for regional electromechanical coupling is the interval between the onset of QRS complex in ECG and the onset of systolic velocity in spectral pulsed-wave tissue Doppler imaging), or (3) "primary mechanical dyssynchrony" (i.e., a regional delay in onset shortening and in time to peak shortening of LV segments) [34]. Primary electrical dyssynchrony is typical for left bundle branch block (LBBB) and primary mechanical dyssynchrony—for regional ischemia or fibrosis [33, 34]. Currently, QRS duration remains the only clinically significant surrogate for the timing of myocardial contraction and the only criterion amenable for CRT [35, 36]. Clinical significance of "clear" primary mechanical dyssynchrony remains ambiguous [37, 38]. CRT does not provide any benefit (and may be even harmful) in heart failure patients with mechanical dyssynchrony without QRS widening (<130 ms) [38]. Various echocardiographic measures of dyssynchrony turned out not to be a superior selection criterion for CRT [39, 40]. Moreover, unacceptable variability, poor reproducibility and limited practical predictive value of the most echocardiographic parameters of dyssynchrony are documented [41]. Thus, although the predictive value of prolonged QRS also varies from study to study [42, 43], qualification to CRT is still based primarily on this parameter [35, 36].

Functional MR correlates strongly with QRS duration. Left bundle branch block and right ventricular pacing (which produce a conduction abnormality similar to LBBB), but not right bundle branch block or left anterior hemi-block, are strongly associated with functional MR [44]. The relationship between right ventricular pacing and mitral regurgitation indicates that the key determinant of functional MR is a conduction abnormality, rather than the underlying disease causing LBBB [44]. Those findings have important implications for biventricular pacing as a treatment option in heart failure patients with functional MR.

anterior papillary muscle and longer inter-papillary distance [27]. Both patterns of leaflet tethering can be observed in ischemic MR [25–27]. The occurrence of the symmetric pattern in ischemic MR is associated with more advanced systolic dysfunction, global remodeling and increased LV sphericity [23, 24, 27]. This pattern is typical for non-ischemic dilated cardiomyopathy [26].

**Figure 2.** Patterns of leaflet tenting in functional mitral regurgitation. (A) Normal coaptation of mitral leaflets. (B) Asymmetric pattern—predominant posterior displacement of both leaflets with prevent restriction of posterior leaflet and large eccentric regurgitant jet. (C) Symmetric pattern—predominant apical displacement of both leaflets with central

**Figure 1.** Mechanism of functional mitral regurgitation. (A) Balance of closing and tethering forces acting on mitral leaflets during systole. (B) Disrupted balance of closing and tethering forces due to local LV remodeling (dark shading).

LA: left atrium; LV: left ventricle; PM: papillary muscle; Ao: aorta; ME: mitral regurgitation.

62 Structural Insufficiency Anomalies in Cardiac Valves

regurgitant jet.

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

**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 pre-

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

**1.** Immediate, short-term functional MR reduction occurring directly after the implantation of a CRT device. The effect manifests as better-coordinated contraction of the papillary muscle-bearing segment (diminished tethering force) and improvement of LV ejection function (an increase in transmitral pressure gradient—LV dP/dt, which represents the mitral valve closing force) [52–54]. CRT contributes primarily to a decrease in early-systolic MR [59, 60]. **2.** Late, long-term functional MR reduction occurring weeks to months after the implantation of a CRT device. This phase manifests primarily as reverse remodeling of the LV. A decrease in LV volume and sphericity induces favorable geometric changes in mitral valve apparatus, with the reduction of tethering force. The improvement of LV systolic function is reflected by an increase in closing force [53, 55, 57]. Attenuation of both resting and exercise-induced functional MR usually can be observed in this phase, along with the

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

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.

sent); this effect is only partially specific for this therapeutic method [58].

**5.1. Biphasic response of functional mitral regurgitation to cardiac** 

improvement of cardiopulmonary performance [61].

increase in LV longitudinal function [56].

**resynchronization therapy**

two phases:
