Characterization of Three-Dimensional Papillary Muscle Displacement in in vivo Ovine Models of Ischemic/Functional Mitral Regurgitation

Abstract

Objective:

Papillary muscle (PM) displacement contributes to ischemic/functional mitral regurgitation (IMR/FMR). The displaced PMs pull the mitral leaflets into the left ventricle (i.e. towards the apex) thus hampering leaflet coaptation. Intuitively apical leaflet tethering results from apical PM displacement. The three-dimensional directions of PM displacement are, however, incompletely characterized.

Methods:

Data from in-vivo ovine models of IMR (6 to 8 weeks of postero-lateral infarction, n=12) and FMR (9–21 days of rapid LV pacing, n=11) were analyzed. All sheep had radiopaque markers implanted on the anterior (APM) and posterior PPM) PM tips, around the mitral annulus, and on left ventricular apex. In order to explore three-dimensional PM displacement directions, differences in marker coordinates were calculated at end-systole before and during IMR/FMR using a right-handed coordinate system centered on the mitral annular “saddle horn” with the y-axis passing through the apical marker.

Results:

No apical PM displacement was observed during either IMR or FMR. The APM displaced laterally during FMR. Postero-lateral PPM displacement was observed during both, IMR and FMR.

Conclusions:

Experimental in-vivo ovine models suggest postero-lateral PPM displacement as predominant pathomechanism leading to apical leaflet tethering during IMR/FMR.

Graphical Abstract

Graphical Abstract: Data from studies using ovine models of ischemic/functional mitral regurgitation (IMR/FMR) and radiopaque marker tracking of anterior and posterior papillary muscle tips (APM and PPM, respectively) suggest postero-lateral PPM displacement as predominant pathomechanism leading to apical leaflet tethering during IMR/FMR. LV=left ventricle

Central Picture: Data from experimental ovine studies suggest that apical anterior mitral leaflet (AML) tethering is associated with postero-lateral papillary muscle (PPM) dislocation in ischemic/functional mitral regurgitation (IMR/FMR).

Central Message

Consistent postero-lateral, but not apical dislocation of the posterior papillary muscle was observed with experimental IMR/FMR.

Introduction

In patients with ischemic/functional mitral regurgitation (IMR/FMR) mitral valve replacement is increasingly advocated as surgical treatment standard¹ due to suboptimal results with reductive ring annuloplasty^2,3. Poor repair outcomes are thought to be related to ongoing LV remodeling and papillary muscle displacement leading to recurrent leaflet tethering⁴. Nevertheless, lasting mitral repair may be superior to valve replacement⁵, and surgical strategies that specifically aim to address subvalvular distortions of PM geometry have been introduced clinically to improve repair durability^6–13. However, due to incomplete understanding of the alterations of subvalvular geometry associated with IMR/FMR, no current consensus exists regarding optimal subvalvular repair. Mitral leaflet tethering has been shown to be associated with clinical and experimental IMR/FMR^14–15, and apical papillary muscle displacement has been intuitively assumed to be the putative mechanism. The precise PM displacement in patients with IMR/FMR is, however, difficult to determine as clinical imaging modalities are unable to accurately track distinct anatomic landmarks over time. Experimental studies using radiopaque markers or sonomicrometry crystals have failed to demonstrate apical PPM displacement^16–19 during IMR. To characterize 3-dimensional perturbations of papillary muscle geometry associated with IMR/FMR, we analyzed data from in vivo ovine studies using radiopaque marker tracking of the APM and PPM during experimental IMR and FMR.

Methods

Data from two experimental ovine studies performed by our research group were analyzed FMR to investigate 3-D vectors of APM and PPM displacement. These data have been partially published previously^20–22. All animal protocols were approved by the Stanford Medical Center Laboratory Research Animal Review committee and conducted according to Stanford University policy. All studies included radiopaque marker placement on APM and PPM tips and around the mitral annulus using cardiopulmonary bypass and cardioplegic arrest. In the study investigating the effects of IMR, baseline data from 12 sheep were acquired 6 to 8 days after surgical placement of radiopaque markers (Control). Experimental IMR data were acquired 6 to 8 weeks after induction of a postero-lateral infarct (snare occlusion of obtuse marginal branches, see Tibayan et al., Ref.²¹,for details). In the model of experimental FMR, baseline data from eleven sheep were acquired 5 to 8 days after surgical placement of radiopaque markers (Control). A rapid-pacing pulse generator (Prodigy S 8164, Medtronic Medical) was inserted into a subcutaneous pocket and connected to the previously externalized LV electrode, and the animal was recovered. Rapid pacing was initiated 24 hours later. FMR data were obtained 9 to 21 days after rapid left ventricular pacing (180 to 230beats per minute, see Timek et al., Ref.²², for details). All data acquisitions were performed using biplane videofluoroscopy (60Hz) in standardized fashion, and marker positions from both views were digitized, merged, and analyzed using customized computer software²³.

To assess the presence of apical PM displacement, the orthogonal distance from each papillary muscle marker to the least-squares mitral annular plane at end-systole was calculated before and during IMR or FMR.

In order to specify precise vectors of APM/PPM displacement, 3-D marker positions were determined at end-systole before and after induction of experimental IMR and FMR. A left-handed coordinate system was used with the lateral (y-) axis pointing towards the lateral mitral annular marker, the apical (x-) axis orthogonal to the y-axis in a plane with the LV apex marker. The z-axis was orthogonal to the x-y plane pointing posteriorly (Figure 1, small schematic). Displacement vectors were calculated as differences of x, y and z coordinates between baseline and respective experimental state. Data were compared using Student’s t-test for paired samples. The Bonferroni adjustment was applied to account for the different measurement conditions (three coordinate axes, distance to mitral annular plane) within the two different papillary muscles (overall significance level set to p <=0.05, Bonferroni corrected level of significance was set to p < 0.006). All results are presented with mean and standard deviation (SD). Statistical analysis was performed using SPSS 21 for Windows.

Figure 1:

Schematic illustrations depicting three-dimensional anterior and posterior papillary muscle (APM and PPM, respectively) displacement vectors in experimental ovine models of ischemic and functional mitral regurgitation (IMR and FMR, respectively). Arrows indicate vectors that reached statistical significance according to Table 2. Arrow lengths are proportionate to the average of the differences between Control and the respective IMR/FMR values. The small schematic illustrates the coordinate system used (see Methods). SH=saddle horn, api=apical, lat=lateral, post=posterior, #18=mid-lateral mitral annular marker.

Results

Both animal subgroups (experimental IMR and FMR) developed significant MR and signs of LV failure as indicated by an increase in left-ventricular end-diastolic volume (Table 1). Table 2 displays the distances of APM and PPM to the mitral annular plane before and during IMR and FMR. During both experimental conditions (IMR and FMR), none of the changes in distances of either APM or PPM to the mitral annular plane was statistically significant, but a trend towards a decrease of the PPM distance to the mitral annular plane during both, IMR and FMR was observed (3.82±0.53 vs. 3.16±0.41, p=.014 and 3.01±0.80 vs. 2.69±0.67, p=.026, respectively). Table 3 demonstrates the APM and PPM positions before and during IMR and FMR. The APM did not displace significantly during experimental IMR and laterally during FMR (lateral: 0.97±0.47 vs. 1.43±0.43, p<.001). The PPM displaced postero-laterally during both, IMR (posterior: 0.58±0.40 vs. 1.39±0.46, p<.001, lateral: 0.66±0.55 vs. 1.19±0.70, p=.001) and FMR (posterior: 0.10±0.46 vs. 0.22±0.48, p<.001, lateral: 0.74±0.48 vs.1.16±0.45, p<.001). Figure 1 illustrates APM and PPM displacement vectors that reached statistical significance.

Table 1:

Hemodynamics

	Control	IMR	p	Control	FMR	p
MR (0–4+)	0.6±0.5	2.5±0.6	<.001*	0.2±0.3	2.2±0.9	<.001*
LV dP/dtmax (mm Hg/s)	1979±785	1256±506	.002*	1350±219	1162±374	.290
EDV (ml/m2)	128±36	180±40	<.001*	160±57	201±67	.001*

Values are mean±1 SD, MR = mitral regurgitation; LV dP/dtmax, maximum of first derivative of pressure vs. time; EDV, end-diastolic volume,

^*= statistically significant after Holm-Bonferroni adjustment.

Table 2:

Distances of APM and PPM to the mitral annular (MA) plane before and during IMR and FMR

	Control	IMR	p	Control	FMR	p
Distance to MA plane (cm)
-APM	3.81±0.70	3.70±0.39	.627	2.50±0.85	2.52±0.79	.867
-PPM	3.82±0.53	3.16±0.41	.014	3.01±0.80	2.69±0.67	.026

Values are mean±1SD at end-systole, APM/PPM=anterior/posterior papillary muscle, IMR/FMR=ischemic/functional mitral regurgitation.

Table 3:

Anterior and posterior PM positions at end-systole before and during IMR and FMR

	Control	IMR	p	Control	FMR	p
APM position
-lateral	1.30±0.85	1.69±0.98	.498	0.97±0.47	1.43±0.43	<.001*
-posterior	−2.05±0.72	−2.18±0.54	.488	−2.15±0.28	−2.62±0.54	.009
-apical	5.06±1.02	4.79±0.86	.029	3.05±0.55	3.01±0.62	.743
PPM position
-lateral	0.66±0.55	1.19±0.70	.001*	0.74±0.48	1.16±0.45	<.001*
-posterior	0.58±0.40	1.39±0.46	<.001*	−0.10±0.46	0.22±0.48	<.001*
-apical	5.40±1.04	4.94±0.59	.282	4.11±0.67	4.46±1.01	.153

mean±1SD and describe papillary muscle (PM) positions at end-systole (see Methods for coordinate system used). Negative values represent a PM position in the opposite direction as indicated (i.e. septal, anterior and towards the LV base as opposed to lateral, posterior and apical, respectively).

^*= statistically significant after Holm-Bonferroni adjustment. APM/PPM=anterior/posterior papillary muscle, IMR/FMR=ischemic/functional mitral regurgitation.

Discussion

The main findings of this experimental work are displayed in the graphical abstract. During both, experimental IMR and FMR: 1) no apical PM displacement is observed; 2) the displacement vector of the PPM is directed postero-laterally. These findings suggest posterolateral PPM displacement as predominant pathomechanism leading to apical leaflet tethering during IMR/FMR.

Surgical mitral valve repair in patients with IMR/FMR using a ring annuloplasty alone is associated with high rates of residual/recurrent mitral regurgitation² as prosthetic ring implantation may enhance leaflet tethering while ongoing left ventricular dilatation leads to further PM displacement and recurrent MR²⁴. As a consequence, several authors have introduced adjunctive subvalvular techniques (in addition to annuloplasty) to counteract PM displacement^6–9,25.

In the clinical literature, papillary muscle displacements have frequently been associated with an apically directed vector^26–30. Based on increases in echocardiographically measured tethering lengths of both anterior and posterior PM in patient with FMR, Yiu and colleagues concluded that apical displacement of papillary muscles is a major determinant of valvular tenting²⁹. Numerous other clinical studies have used tethering lengths to characterize three dimensional changes of the subvalvular apparatus in patients with FMR/IMR^{24,29,31–35}. Tethering length, however, is a two-dimensional parameter and does not allow drawing conclusions about the 3-D vectors of PM displacement.

Several experimental studies exist that report three-dimensional alterations of the geometry of the PMs during IMR. Gorman and colleagues demonstrated a decrease in the distance between the PPM and the posterior commissure in an ovine model of IMR¹⁷ which suggests a lack of apical PPM displacement and is in accordance with our findings. Similar geometric perturbation of posterior papillary muscle geometry were reported by Lai during acute ovine IMR³⁶. Myocardial marker tagging of multi-headed papillary tips also failed to demonstrate apical displacement of any papillary muscle heads during acute ovine IMR¹⁹. The data from these acute studies demonstrate similar trends compared to our model of longer term IMR/FMR. Interestingly, in our IMR/FMR models the PPM distance to the mitral annular plane during both, IMR and FMR tended to decrease (3.82±0.53 vs. 3.16±0.41, p=.014 and 3.01±0.80 vs. 2.69±0.67, p=.026, respectively). This trend may have become significant with a bigger sample size and suggests that apical leaflet tethering may occur even if the papillary muscles move closer to the annular plane.

Our finding of postero-lateral, but not apical displacement of the PPM during IMR/FMR is also indirectly supported by other reports. Balloon repositioning of the displaced PPM in ovine IMR purely in the antero-septal direction decreased leaflet tethering and reduced mitral insufficiency^25,37. The Coapsys device which primarily repositions the PPM towards the LV septum has demonstrated a similar effect clinically³⁸. On the contrary, pulling the posterior PM towards the posterior commissure (which includes a vector mainly directed towards the LV base) during acute ovine IMR did not ameliorate mitral regurgitation³⁹ whereas PPM relocation towards the right fibrous trigone (which includes a septal and anterior vector) in addition to reductive annuloplasty decreased leaflet tethering in a porcine model of IMR/FMR⁴⁰.

A recent prospective, randomized trial in patients with severe IMR demonstrated improved long-term cardiac outcomes in patients undergoing restrictive mitral annuloplasty and a PM sling as compared to patients receiving a restrictive annuloplasty alone¹¹. In this novel subvalvular repair, PMs are approximated using a PTFE tube with the relocation vector of the PPM primarily directed anteriorly and towards the septum, but not towards the LV base.

Clinical Inference

For a meaningful discussion of clinical inferences the limitations of our data (see paragraph below) including potential differences to patients with long lasting IMR/FMR must be considered. An important goal of this work is therefore to stimulate further clinical research investigating three-dimensional papillary muscle displacement vectors during IMR/FMR. As mitral leaflets are often observed to be tethered apically in IMR/FMR, it is frequently assumed that apical leaflet tethering results from apical PPM displacement (Figure 2A). Our analysis of two different in vivo animal data sets from our laboratory, however, revealed that mitral leaflet tethering in experimental ovine in vivo models does not result from apical, but from postero-lateral PPM dislocation (Figure 1 B). In case these findings translate to patients with IMR/FMR these data suggest that subvalvular surgical or interventional approaches to IMR/FMR should focus on relocating the PPM anteriorly and towards the septum.

Figure 2:

Schematic illustrating the hypothesized predominant mechanism leading to leaflet tethering during IMR/FMR: Apical leaflet displacement is not – as frequently hypothesized – associated with apical (A), but with a postero-lateral displacement of the posteromedial papillary muscle (PPM) (B). AML=anterior mitral leaflet.

Study Limitations

The results of the presented data must be viewed in the context of several limitations. First, left ventricular alterations in these experimental models of IMR/FMR significantly differ from patients with long term IMR/FMR. Apical PM displacement could occur in IMR/FMR patients even secondary to postero-lateral PPM displacement. Clinical studies assessing 3-dimensional changes of the PM geometry in IMR/FMR patients over a longer time period are needed to resolve this issue. Second, our analyses focus solely on 3-D changes in the PM geometry and no additional hemodynamic data or data from alterations in LV or leaflet geometry were calculated. These data have, however, been published earlier and have been shown to be consistent with typical alterations observed during experimental IMR or FMR^20,22,41. Third, species differences in papillary muscle blood supply may limit the extrapolation of these results to patients⁴² and mitral valve anatomy may be heterogeneous between patients⁴³. Fourth, we investigated only one time point in the cardiac cycle (end-systole). Our analyses therefore do not provide insight into cases where FMR/IMR arises due to dynamic papillary muscle dysfunction⁴⁴. Lastly, recently published algorithms for the surgical treatment of IMR/FMR suggest the addition of subvalvular repair based on LV wall perfusion or motion abnormalities⁴⁵. In our study, no analysis of LV motion was performed, and it is possible that PM displacement vectors differ in individual patient. However, it is reasonable to assume that the observed alterations of PM geometry in our study apply to the majority of patients with IMR/FMR.

In conclusion, experimental in-vivo ovine models suggest postero-lateral PPM displacement as predominant pathomechanism leading to apical leaflet tethering during IMR/FMR.

Supplementary Material

1

Video: Presentation illustrating the key findings of this study.

Perspective Statement.

Papillary muscle (PM) displacement contributes to apical leaflet tethering during IMR/FMR. In these experimental ovine IMR/FMR studies consistent postero-lateral, but not apical displacement of the posterior PM was observed.

Glossary of Abbreviations

IMR/FMR

ischemic/functional mitral regurgitation

LV

left ventricle

PM

papillary muscle

APM/PPM

anterior/posterior papillary muscle

LCx

left circumflex artery