Mimicking natural mitral adaptation to ischaemic regurgitation: a proposed change in the surgical paradigm

Ischaemic mitral regurgitation (IMR) represents a unique situation in cardiac surgery. Available data clearly show that patient outcome is negatively affected by the disease, but there is no evidence that correction of the disease can improve patient outcome. IMR has been considered a ventricular problem, with no significant contribution from the mitral valve (MV) in the process. Statements such as ‘the valve leaflets and chordal structures in affected patients are innocent bystanders’ and ‘the leaflets themselves are normal’ are rooted in the surgical community and, for decades, this thinking has informed the surgical strategies for MV repair in IMR. Given the accepted concept that the MV was ‘normal’, there was no need to intervene on the mitral apparatus. The dilated annulus was the only surgical target, and overreduction of the annulus (in general, 2 sizes less than usual) was the preferred surgical strategy. Any other surgical proposal, such as augmentation of the anterior or posterior mitral leaflet, second-order chord cutting, edge-to-edge repair and papillary muscle (PM) approximation or relocation, remained subjects of isolated reports, without any major impact on surgical decision-making. Unfortunately, the reliance on restrictive mitral annuloplasty (RMA) has slowly, but definitively, brought the idea of surgical treatment of IMR to a deadlock. The failure rate of isolated RMA has been reported to be, in the midterm, high [1, 2]. As a consequence, in patients with moderate IMR the advice was not to add MV repair to coronary artery bypass grafting, as clinical and echocardiographic results were similar after 2 years, with or without MV repair [1]. In patients with severe IMR, MV replacement has been advocated as the safest procedure, as the recurrence of moderate or more IMR, after 2 years from repair, was close to 60% [2]. In contrast to these recommendations, it was evident that patients in whom MV repair was successful had better left ventricular remodelling when compared with patients with failed MV repair (moderate or severe IMR recurrence at follow-up) or with successful MV replacement [3]. The problem is therefore essentially technical, as RMA alone is probably insufficient to assure a durable MV repair and repair of IMR can be more complex than it appears. To search for evidence that can help us to find a solution, let us see what happens to the MV after the onset of mitral regurgitation (MR) and why it happens. Primary MR is caused by chordal elongation or rupture, inflammatory or infective diseases, etc. Secondary MR often starts because of PM displacement and chordal tethering. After the onset of MR, a set of adaptations termed ‘mitral plasticity’ is initiated within the MV that serve to reduce the amount of regurgitation. This goal is achieved by an increase of the length and of the area of the leaflets and of the length of the tendinous chords. This plastic response mechanism is induced by stretching resulting from mechanical stress, which in turn arises from turbulent regurgitant flow. The plasticity is said to be ‘balanced’ if the MV remains competent or with mild regurgitation despite left ventricular dilation, PM displacement, etc. and ‘unbalanced’ if, despite adaptation, significant MR develops. Stretching alone can be sufficient to reduce or abolish MR, as it typically occurs in patients with aortic regurgitation (AR). Beaudoin et al. [4] demonstrated that, in patients with AR and dilated left ventricle (LV), secondary MR is rare, as MV leaflet area increases by >30% to match the demands that the enlarged LV imposes in terms of mitral systolic closure area. The mechanism of MV adaptation to IMR can be balanced even in presence of dilated hearts. In patients with ischaemic and non-ischaemic dilated cardiomyopathy, Yoshida et al. [5] found increased length of the anterior leaflet (AL) (+36%) and of the tendinous chords (+71%) and no or mild secondary MR despite severely dilated hearts. The posterior leaflet was neither larger nor longer than normal, supporting the theory that the mechanical stretching produced by displaced PMs in the dilated heart is more potent in the AL than in the posterior leaflet. This finding, however, is not consistent in the literature [6]. These data show that, even if PM displacement, and consequently chordal tethering, triggers MR, the compensatory mechanism put in place by the MV can be balanced, resulting in mild or absent MR. The MV remodels, becoming thicker, stiffer and in general more fibrous, but the remodelling is modest and does not interfere with the adaptive mechanisms. Stretch induced mitral plasticity and the resulting MV remodelling is a mechanism present in MR of any aetiology [7, 8] (Fig. 1). Primary mitral regurgitation due to posterior leaflet (PL) prolapse. Transoesophageal echocardiography. (A) There is wide PL prolapse, with a short (22 mm) and tethered (red arrow) anterior leaflet (AL). (B and C) The tethered portion of the AL is in the A3 area (red arrow), seen from the atrial and ventricular side. (D) After surgery, the PL prolapse was corrected, positioning the PL in a vertical position and the AL was augmented with a pericardial patch. Its length increased to 32 mm, with a coaptation length of 10 mm and a mean gradient of 1.5 mmHg. Primary mitral regurgitation due to posterior leaflet (PL) prolapse. Transoesophageal echocardiography. (A) There is wide PL prolapse, with a short (22 mm) and tethered (red arrow) anterior leaflet (AL). (B and C) The tethered portion of the AL is in the A3 area (red arrow), seen from the atrial and ventricular side. (D) After surgery, the PL prolapse was corrected, positioning the PL in a vertical position and the AL was augmented with a pericardial patch. Its length increased to 32 mm, with a coaptation length of 10 mm and a mean gradient of 1.5 mmHg. However, MV adaptation to MR is often unbalanced, as increase of MV leaflet area and length is not sufficient to cover the wider annular area and the tendinous chords do not lengthen. This happens more frequently when MR is a consequence of myocardial infarction (MI). The MV increases its dimensions but histological remodelling is more pronounced than in a balanced response and the valve becomes fibrotic, stiff, less distensible and thick [9]. This maladaptive process restricts leaflet motion and interferes with adequate leaflet coaptation. In patients who had MI, and early revascularization in almost all cases, Beaudoin et al. [10] demonstrated increased thickness of the mitral leaflets 2 years after MI and a further increase thereafter. There was a progressive reduction of the AL excursion and patients who developed more than mild IMR had thicker mitral leaflets than patients who did not. In an animal model of AR (isolated, AR group, or after induction of a small apical MI, AR + MI group), Marsit et al. [11] showed that the increase of mitral area, present in both groups in comparison to the controls, was smaller in AR + MI group than in AR group. The thickness of the leaflets in AR + MI was 1.4-fold versus the AR group and 2.1-fold versus the control. Animals in AR + MI group had regurgitant fraction that was 5 times higher than those in AR group. Of note, the adaptive mitral response to IMR may be favourable initially, but eventually leads to MV dysfunction and fibrosis. We then conceptualize 2 patterns at the extreme: (i) no or mild IMR due to balanced MV adaptation (longer and wider leaflets, longer chords, mild leaflet fibrosis) and (ii) moderate or severe IMR consequent to unbalanced adaptation (leaflet area and length can be increased, but do not match the wider annular area; chords remain tethered; thick, stiff and fibrotic leaflets and chords, with reduced mobility). The first (balanced) pattern would be expected when mechanical stretching is the main stimulus, the second (unbalanced) pattern would be expected when an MI is added to a setting of mechanical stretch. In between there are many possibilities that yield a variety of anatomical and functional patterns. Mitral leaflets are covered by a layer of endothelial cells (ECs) which play a role in the MV adaptation to haemodynamic and humoral changes after the onset of MR. During embryogenesis, ECs migrate into the region between the endocardium and myocardium, and synthetize valve-specific extracellular matrix. This process is called endothelial-to-mesenchymal transition (EndMT) and is mediated by transforming growth factor β (TGF-β). A part of the adult mitral ECs maintains the same characteristics, allowing a subset of cells of the adult valvular endothelium to undergo EndMT to replenish the turnover of valvular interstitial cells, thus maintaining valve tissue homeostasis [12]. MV adapts to mechanical stress, induced by MR of any origin, through EndMT and matrix remodelling, which facilitates leaflet growth. TGF-β activation is mild and the MV enlarges to match the enlarged LV. As a consequence, MR is absent or mild. After an MI, TGF-β signalling is excessive and overstimulates EndMT, resulting in profibrotic changes in the leaflets, with increased thickness, cellular proliferation, presence of scar-forming cells and excessive matrix turnover with collagen deposition [9]. Even if leaflet growth occurs, the stiff and fibrotic leaflets further impair the mechanism of closure, as systolic expansion and the flexibility necessary to bend and to seal the mitral annular area are reduced. Similar changes at the level of the chords further restrict leaflet movements. A study in explanted MVs of patients with IMR showed α-smooth muscle actin (a marker of EndMT) expression in ECs and valvular interstitial cells, similar to that found in animal models [13]. TGF-β can also drive fibrosis by activating valve interstitial cells to become contractile myofibroblasts that compact and remodel the extracellular matrix, further augmenting IMR by limiting the increase in valve area. Some of these cells may undergo osteogenic transformation and activation resulting in various pathological patterns. TGF-β may originate from the valve itself or can be released by the ischaemic myocardium together with other proinflammatory cytokines [14]. Cytokine-induced endothelial activation can recruit circulating cells into the tissue, further stimulating cytokine production and fibrosis [15]. Of particular interest for MV remodelling is the activation of renin–angiotensin system after MI, as angiotensin II can trigger TGF-β expression [16], enhancing the profibrotic effects on the MV. It is worth noting that there is great interest in the possibility of pharmacological modulation of the TGF-β upregulation by losartan, a blocker of angiotensin II receptors, which has been demonstrated in vitro [17] and in animal experiments [14]. Importantly, losartan-modulated EndMT still allows a comparable increase in total leaflet surface area while inhibiting profibrotic leaflet changes and excessive collagen deposition [14]. It is possible that sacubitril/valsartan could have the same clinical effect [18]. EndMT can be promoted by factors other than TGF-β. Some of these, such as angiotensin II [16], induce EndMT by converging with TGF-β signalling. Other factors like flow characteristics may well be involved in EndMT activation. ECs exposed to disturbed flow, with low, oscillatory shear stress can undergo EndMT, while uniform, laminar high shear stress is protective [19, 20]. Moreover, MR can induce EndMT due to turbulent flow, thus EndMT is at the same time the effect and the cause: the effect as it is induced by MR of any aetiology, and the cause as it stimulates processes that cause further MR. The statement ‘MR begets MR’ has a very solid evidence base. EndMT induced by flow patterns can be involved in atherosclerosis and in vein graft remodelling, in which ∼50% of the neointimal cells are EndMT-derived [21]. Figure 2 summarizes the main aspects of EndMT. In normal valves, VICs possess a quiescent phenotype. EndMT in heart valves is initiated by TGF-β upregulation due to stretching induced by mechanical stress. Myocardial infarction magnifies TGF-β signalling. Flow patterns, such as disturbed flow with low, oscillatory shear stress, can also stimulate EndMT. The activated VCAM1-positive endothelium undergoes EndMT, which generates more interstitial cells. Some of these cells may undergo osteogenic transformation and activation resulting in different anatomic patterns. Circulating CD45+ myeloid cells migrate into sites of inflammation or tissue injury and, under the influence of cytokines and TGF-β, transform into myofibroblast-like cells. The increases in CD45+ cells correlate with mitral valve fibrosis, mitral regurgitation severity and infarct size. CD: cluster of differentiation; EndMT: endothelial-to-mesenchymal transition; TGF-β: transforming growth factor β; VCAM: vascular cell adhesion molecule; VICs: valve interstitial cells. From Kovacic et al. [12], with permission. In normal valves, VICs possess a quiescent phenotype. EndMT in heart valves is initiated by TGF-β upregulation due to stretching induced by mechanical stress. Myocardial infarction magnifies TGF-β signalling. Flow patterns, such as disturbed flow with low, oscillatory shear stress, can also stimulate EndMT. The activated VCAM1-positive endothelium undergoes EndMT, which generates more interstitial cells. Some of these cells may undergo osteogenic transformation and activation resulting in different anatomic patterns. Circulating CD45+ myeloid cells migrate into sites of inflammation or tissue injury and, under the influence of cytokines and TGF-β, transform into myofibroblast-like cells. The increases in CD45+ cells correlate with mitral valve fibrosis, mitral regurgitation severity and infarct size. CD: cluster of differentiation; EndMT: endothelial-to-mesenchymal transition; TGF-β: transforming growth factor β; VCAM: vascular cell adhesion molecule; VICs: valve interstitial cells. From Kovacic et al. [12], with permission. As discussed above, it would seem that IMR grade is related more to the ability of the MV to efficiently adapt to the circumstances rather than to the anatomical patterns underlying IMR. As the adaptation can be insufficient, we propose a change of paradigm in MV repair. The role of reparative surgery should be to ‘take up where the nature left’ and complete the process of adaption by intervening at different levels on the MV and mimicking the natural adaptive mechanism. We have termed this surgical approach ‘surgical mitral plasticity’. The rationale behind surgical mitral plasticity can be summarized as follows: MV adapts to mechanical stretching by increasing the area and length of the leaflets and chordal length with mild fibrotic changes to the leaflet. In presence of a more powerful stimulus, such as MI, MV does not properly and completely adapt and instead becomes fibrotic with increasing leaflet and chordal thickness and stiffness. The area increases as well, but the leaflets are not pliable and less extensible. Fibrotic secondary tethered chords reduce the effective leaflet length and render the increase of the leaflet area insufficient for coaptation at annular level, as the MV is pulled down inside the ventricle (Fig. 3A and B). PM displacement initiates IMR, but the adaptive process is independent from PM position. Severely enlarged hearts with similar PM displacement can present no or mild MR or moderate to severe according to the effectiveness of the adaptation [22] and moderate or severe IMR can be present in small hearts. When MV adaptation is incomplete, ‘surgical mitral plasticity’ serves the purpose of completing the process by addressing the MV. To complete what nature could not, the AL has to be augmented and lengthened (by an autologous glutaraldehyde-treated or heterologous pericardial patch or any biological patch) and the second-order chords have to be cut to increase the effective AL length and area. It is worth emphasizing the necessity of second-order chords transection, as the fibrotic process, once started, can be progressive [23]. Moreover, by eliminating apical tethering, the AL can recover its normal curvature by removal, or reduction, of the tenting area (Fig. 3C and D). RMA should then complete the repair. Transoesophageal echocardiography. Preoperative 3-dimensional reconstruction in patients with severe ischaemic mitral regurgitation and coaptation depth of 13 mm (A) and 12 mm (B). The mitral valve in both cases is displaced inside the left ventricle. Postoperative 3-dimensional reconstruction (C and D) shows a similar aspect in both cases. The anterior leaflet has no tenting and is long enough to cover the mitral orifice with a coaptation length of 10 and 8 mm, respectively. The posterior leaflet is in vertical position. Transoesophageal echocardiography. Preoperative 3-dimensional reconstruction in patients with severe ischaemic mitral regurgitation and coaptation depth of 13 mm (A) and 12 mm (B). The mitral valve in both cases is displaced inside the left ventricle. Postoperative 3-dimensional reconstruction (C and D) shows a similar aspect in both cases. The anterior leaflet has no tenting and is long enough to cover the mitral orifice with a coaptation length of 10 and 8 mm, respectively. The posterior leaflet is in vertical position. None of these procedures are new. AL augmentation was proposed by Kincaid et al. [24] and chordal cutting by Messas et al. [25], but their impact on the surgical practice was modest. The combination of both repair techniques has a strong rationale, already known in the literature, but under-recognized by cardiac surgeons. Other valvular or subvalvular procedures have been proposed, such as posterior leaflet augmentation, edge-to-edge, PM approximation or relocation. All of them have a rationale, but only mid- and long-term results will point us in the right direction. In our recent experience [26] we obtained stable and satisfactory results by covering the annular area with a long, large and mobile AL, demonstrating that surgical mitral plasticity was effective in correcting chronic IMR in the midterm. MV repair is still the gold standard in the surgical treatment of IMR. Isolated RMA very likely is not able to correct adequately IMR in most of the patients and lack of durable results are still the Achilles’ heel of this procedure. The causative issue at play in IMR are multiple and require careful evaluation on an individual basis. Mechanisms of failure are related to the shortness and thickness of the AL, with lost flexibility and curvature being distracted towards the apex by chordal tethering (Fig. 4). Nowadays we have many strategies in addition to RMA, which still need to be analysed in depth in terms of long-term outcome. However, there is one thing we know for certain: we cannot leave behind the idea of MV repair for IMR (or secondary MR in general), as results with successful repair are outstanding. We must continue to work to find effective and reproducible strategies for a disease which is more technically demanding than we expected. Failure after isolated restrictive mitral annuloplasty for ischaemic mitral regurgitation. (A) Transthoracic echocardiography. The anterior leaflet is short (21 mm) and tethered (red arrow) and is not able to coapt with the posterior leaflet. There is moderate mitral regurgitation. (B and C) Transoesophageal echocardiography. There is a significant tenting volume, which pushes the mitral valve inside the left ventricle. The anterior leaflet has reduced mobility and cannot coapt with the posterior leaflet due to chordal tethering. Failure after isolated restrictive mitral annuloplasty for ischaemic mitral regurgitation. (A) Transthoracic echocardiography. The anterior leaflet is short (21 mm) and tethered (red arrow) and is not able to coapt with the posterior leaflet. There is moderate mitral regurgitation. (B and C) Transoesophageal echocardiography. There is a significant tenting volume, which pushes the mitral valve inside the left ventricle. The anterior leaflet has reduced mobility and cannot coapt with the posterior leaflet due to chordal tethering.