Mitral regurgitation post infarction: The mitral valve adapts to the times

The mitral valve is often perceived to be a static fibrous tissue flap - a fixed sized door that closes against a rigid frame. Nothing could be further from the evidence. Human and experimental findings without doubt support a dynamic cellular mitral valve (MV) tissue environment that actively adapts to superimposed stresses. Why is this important? Harnessing leaflet adaptation in a remodeling ventricle with leaflet-targeted therapies has the potential to restore optimal leaflet-to-mitral annular area ratio while maintaining leaflet flexibility to reduce post-infarction mitral regurgitation (MR). Nishino, Watanabe et al. in this issue of Circulation Cardiovascular Imaging provide further evidence and important insights into intrinsic MV changes associated with ischemic MR in patients with acute myocardial infarction (MI) treated with percutaneous revascularization (PCI) and followed over time.

Physiologic MV adaptation occurs during fetal to adult growth, with leaflets enlarging twenty-fold to match the growing left ventricle (LV) and mitral annulus (MA) [1]. This maintains an optimal leafletto-mitral annular area ratio of ~2:1 which maintains proper coaptation and prevents MR [2]. Leaflet growth is tightly regulated by developmental processes: Overshooting MV leaflet growth can result in prolapse or LV outflow obstruction due to MV systolic anterior motion; inadequate MV leaflet adaptation relative to LV size may result in MR due to insufficient leaflet surface area for proper coaptation [3].

Acute and chronic disease states that imbalance the spatial and temporal 3-dimensional (3D) interplay of the MV apparatus can prompt leaflet adaptation responses.

Experimental data have confirmed that MV adaptation occurs over time after MI [4] and in cardiomyopathy [5, 6]. Infarction and myopathy cause mitral leaflet tethering that adaptively increases MV area by reactivating the developmental process of endothelial-mesenchymal-transformation (EndMT, [7]), as shown in MV leaflets mechanically tethered without MI for 2 months [8]. Adding myocardial infarction to mechanical tethering compounds leaflet area growth but also induces exuberant EndMT as the substrate for counterproductive interstitial collagen deposition and limitation of valve area expansion [9]. Treatment with the angiotensin II receptor antagonist (ARB) Losartan that also inhibits pro-fibrotic transforming growth factor (TGF)-β modulates the excessive EndMT and collagen response while preserving adaptive leaflet area growth [10].

In humans, Chaput et al. [11] found MV leaflets were ~35% larger in patients with dilated ischemic and nonischemic cardiomyopathy (CMP) compared with normal subjects. Less MR corresponded to sufficient leaflet growth in relation to leaflet tethering and MA size [11]. Subsequent MV adaptation studies in similar patient populations by Saito et al. [12], and Debonnaire et al. [13] support these findings. Beaudoin evaluated patients with chronic aortic regurgitation (AR) and a dilated, nonischemic LV [14]. MV leaflet area was ~31% larger than normal. Despite significant LV dilatation and leaflet tethering there was very little MR, supporting effective MV adaptation [14]. Adaptive processes can therefore match MV area increase to LV dilation in the nonischemic setting; however, when MI was added to chronic AR in an animal model, MV leaflet adaptation was impaired, leading to increased MR [15].

In this issue of Circulation Cardiovascular Imaging, Nishino, Watanabe et al. studied first-onset acute anterior (n=30) and inferior (n=30) MI patients promptly revascularized and started on standard post-MI medications . All patients had a transthoracic echocardiogram including 3D-imaging prior to PCI, at 6 months, and again 12 months and later. MV apparatus 3D geometry including MV leaflet area and thickness were analyzed using dedicated software. The authors also examined the MV histopathology of 18 patients who had undergone MV surgery for ischemic MR (n=7 acute ischemic MR; n=11 chronic ischemic MR). The authors report significant MV leaflet area and thickness increases over time, with leaflet area changes greater in those with more LV enlargement and increases in annular area and tenting volume. Acute ischemic MR leaflets were thinner and less fibrotic than those from patients with chronic ischemic MR. Patients with greater ischemic MR had significantly larger MA area (especially anterior-posterior diameter), LA volume, mean tenting height and tenting volume, and a lower proportion of leaflet involved in coaptation.

These findings confirm that MV adaptation enables significant MV leaflet growth after MI. Nevertheless, MV adaptation is unable to prevent significant MR in ~30% of patients, despite a preserved LV ejection fraction and overall limited LV remodeling due to prompt MI intervention. Inferior versus anterior MI usually results in more MR due to more severe MV apparatus geometric distortion and tethering [16], but the authors unexpectedly could not detect differences in leaflet adaptation in this setting. It may be worth exploring the relation of overall infarct size on pro-fibrotic leaflet changes, as Bischoff et al. demonstrated a relationship between MI size and leaflet CD45+ cells that correlated with MV fibrosis and MR severity [17]. In terms of mechanism, the MV leaflets of patients who required MV surgery in this study [ref Nishino] were thickened with increased collagen and smooth muscle actin, a marker of EndMT and interstitial cell activation. This confirms prior studies [refs] and further supports the concept that the ischemic / MI milieu influences MV adaptation in a way that becomes potentially counterproductive, resulting in enlarged, but stiff and fibrotic MV leaflets with compromised coaptation (Figure 1) [15, 18-21]. This highlights an area for therapy to modulate MV leaflet adaptation. In vitro, a CD45 inhibitor blocks induction of EndMT and fibrosis [17]. In a retrospective analysis, Beaudoin et al. showed that early post-MI patients tolerating maximum renin-angiotensin blocking agents had less MV leaflet thickening over time, which correlated with less MR [21].

Figure 1. Ischemia alters mitral valve adaptation: Cellular and molecular events in the tethered mitral valve with MI compared with tethered valve alone, and impact on valve function.

Upper panel: Compared to tethered-alone leaflets, the endothelium of tethered + myocardial infarction (MI) mitral valves undergoes excessive endothelial-to-mesenchymal cell transition (EMT) and is vascular cell adhesion molecule-1 (VCAM-1)-positive, indicating endothelial activation; the interstitium shows abundant CD45-positive cells and microvessels that may act as additional ports of cellular entry. Extracellular matrix remodeling is markedly upregulated in tethered + MI leaflets (increased TGF-β, MMPs), along with a hyperproliferative increase in Ki67-positive cells. Lower panel: Leaflet area increase has the potential to adapt to post-MI left ventricular (LV) remodeling and tethering and prevent mitral regurgitation (MR); inadequate area increase, with potential retraction and thickening of the tethered leaflets and chordae by induced α-smooth muscle actin+ myofibroblasts, can augment MR following MI. MMP = matrix metalloproteinase; TGF-β = transforming growth factor-beta; VIC = valvular interstitial cell (adapted and permission from Dal-Bianco et al. [9])

The current study by Nishino, Watanabe et al. highlights the need to explore MV adaptation further on tissue, cellular and regulatory pathway levels. Mechanical stretch seems central in leaflet adaptation, but we need to understand its modulating factors and response in different cardiac diseases, especially ischemia, and inter-individual variations (Figure 1). Investigations into why MV adaptation is effective in physiologic cardiac growth and pathologic LV dilatation in chronic AR, but not in secondary, especially ischemic MR are needed. In an animal model with controlled leaflet tethering and MI short of producing MR, we demonstrated that the ARB Losartan modulates excessive EndMT leaflet fibrosis while preserving leaflet growth [10]. In the current study more than 75% of patients were on ACE-I or ARB, but no therapy effect could be demonstrated, which may be related to the respective drug dose [21] and to differences between ACE-I and ARB in modulating TGF-β signaling [add refs Holm and Habashi]. The findings of this study further motivate efforts to prevent ischemic MR by identifying medical therapies that modulate MV leaflet adaptation towards optimal tissue growth with minimal leaflet fibrosis,preserved flexibility and maximal coaptation. Such therapy can interrupt the vicious cycle of LV remodeling and MR-induced volume overload [Beeri JACC 2008], culminating in reduced heart failure.