Mitral Leaflet Changes Following Myocardial Infarction: Evidence for Maladaptive Remodeling Favoring Ischemic Mitral Regurgitation

Beaudoin, Jonathan; Dal‐Bianco, Jacob P.; Aïkawa, Elena; Bischoff, Joyce; Guerrero, Luis; Sullivan, Suzanne; Wylie-Sears, Jill; Aaron, Jacob; Levine, Robert A.

doi:10.1016/s0735-1097(12)62137-8

Cited by 25 publications

(44 citation statements)

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“…Insufficient leaflet growth in the setting of heart failure is however frequent and secondary MR remains common. Preliminary data recently showed that excessive leaflet thickening can occur after myocardial infarction and is associated with subsequent MR [101], which is in accordance with previous work suggesting the presence of adverse fibrotic leaflet changes in secondary MR. These changes include abnormal matrix composition, increased collagen concentration and turnover and activation of valvular interstitial cells leading to stiffer valves, potentially impairing coaptation and contributing to MR [96, 97, 102].…”

Section: Secondary Mitral Regurgitationsupporting

confidence: 89%

Basic Mechanisms of Mitral Regurgitation

Dal‐Bianco

Beaudoin

Handschumacher

et al. 2014

Canadian Journal of Cardiology

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Any structural or functional impairment of the mitral valve (MV) apparatus that exhausts MV tissue redundancy available for leaflet coaptation will result in mitral regurgitation (MR). The mechanism responsible for MV malcoaptation and MR can be dysfunction or structural change of the left ventricle, the papillary muscles, the chordae tendineae, the mitral annulus and the MV leaflets. The rationale for MV treatment depends on the MR mechanism and therefore it is essential to identify and understand normal and abnormal MV and MV apparatus function.

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Section: Secondary Mitral Regurgitationsupporting

confidence: 89%

Basic Mechanisms of Mitral Regurgitation

Dal‐Bianco

Beaudoin

Handschumacher

et al. 2014

Canadian Journal of Cardiology

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“…Although this study presented a detailed multiscale view into the mechanism of MV remodeling in IMR, For instance, a constant level of SMA could either be because IMR did not affect VIC/VEC SMA expression or an increase in VEC SMA expression, as observed previously 29,31,56 , is balanced by a decrease in VIC SMA expression. Therefore, the results were only attributed to specific cell types if the gene of interest has a very restricted cell type distribution (e.g., CLEC10A for CD1c+ dendritic cells 62 ).…”

Section: Limitations Of the Present Studymentioning

confidence: 73%

“…In fact, patients tolerating maximal ACEI/ARB therapy exhibit reduced leaflet thickening post-MI. 56 Regulator of calcineurin 1 (RCAN1) is elevated at 4 weeks post-MI ( 1 = 2.09, adjusted p-value = 0.063), but decreased in the subset of sheep with MR at 4 weeks post-MI ( 2 = -3.07, adjusted p-value = 0.0003).…”

Section: Changes In Gene Expression Reveal Both Mvic and Immune Cell mentioning

confidence: 99%

Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling

Howsmon

Rego

Castillero

et al. 2019

Preprint

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Aims: Ischemic mitral regurgitation is frequently observed following myocardial infarction and is associated with higher mortality and poor clinical prognosis if left untreated. Accumulating evidence suggests that mitral valve leaflets actively remodel post-myocardial infarction, yet the cellular mechanisms underlying these responses and how this affects tissue function remain largely unknown.We sought to elucidate mitral valve remodeling post myocardial infarction at the tissue, cellular, and transcriptomic levels. Methods and Results:The mechanical behavior of ovine mitral valve leaflets pre-and 8 weeks postmyocardial infarction reveal a significant decrease in radial direction extensibility, which essentially eliminated the mechanical anisotropy typically observed in healthy mitral valves. Quantitative histology and ultrastructural assessment by transmission electron microscopy revealed altered leaflet composition and architecture at 8 weeks post-myocardial infarction. Assessment of the mitral valve interstitial cell nuclear aspect ratio, a metric of cellular deformation, revealed that they were on average rounder following myocardial infarction. RNA sequencing indicated that YAP-induced genes were elevated at 4 weeks post-myocardial infarction and genes related to extracellular matrix organization were some of the most downregulated in sheep with IMR compared to sheep without ischemic mitral regurgitation at 4 weeks post-myocardial infarction. Additionally, RNA sequencing revealed the possible recruitment of immune cells in this remodeling process due to the drastic elevation of CXCL9 and CLEC10A. Conclusions:Our multiscale assessment revealed significant mechanical and microstructural changes due to myocardial infarction. RNA sequencing provided a baseline for global gene expression changes in response to myocardial infarction with and without ischemic mitral regurgitation and suggests YAPinduced mechanotransduction, altered expression of extracellular matrix-related genes, and recruitment of immune cells as mechanisms contributing to altered mitral valve biomechanics post-myocardial infarction.3 Keywords mitral valve | ischemic mitral regurgitation | tissue remodeling | valve interstitial cell | RNA sequencing

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“…There is substantial evidence that mitral leaflet stress causes leaflet remodeling. Mitral leaflet thickening occurs with volume loading associated with pregnancy [28] and with leaflet tethering insufficient to cause MR [29] and also in sheep [30] and humans with FMR associated with increased LV sphericity, mitral tenting and annular size [31]. Along these lines, it is interesting that the EVEREST investigators found a difference between FMR and DMR in healing response when the MitraClip was explanted > 30 days after implantation.…”

Section: Mitraclip Durabilitymentioning

confidence: 99%

Mechanical effects of MitraClip on leaflet stress and myocardial strain in functional mitral regurgitation – A finite element modeling study

Zhang

Wang

Morgan

et al. 2019

Preprint

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Purpose: MitraClip is the sole percutaneous device approved for functional mitral regurgitation (MR; FMR) but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD). Methods:Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV_VOLUME) and MitraClip was simulated with contracting beam elements (virtual sutures) placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedurerelated radial strain (Err) in the sub-valvular myocardium were calculated.Results: MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased Err in the sub-valvular lateral LV myocardium at ED by 0.09±0.04 (p<0.0001)). Furthermore, MitraClip in ↑LV_VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p=0.0268) and in PL by 22.5±23.7 kPa (p=0.0101). Conclusions:MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement. Abstract Word Count:249 AL P2 Ao MClip A. B. C.

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Mitral Leaflet Changes Following Myocardial Infarction: Evidence for Maladaptive Remodeling Favoring Ischemic Mitral Regurgitation

Cited by 25 publications

References 0 publications

Basic Mechanisms of Mitral Regurgitation

Basic Mechanisms of Mitral Regurgitation

Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling

Mechanical effects of MitraClip on leaflet stress and myocardial strain in functional mitral regurgitation – A finite element modeling study

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