2022, Number 1
Plasticity and pathological remodeling of the mitral valve in ischemic mitral regurgitation. After an infarction, insufficiency with ''normal valves''? Or structural damage to the mitral valve accompanying the remodeling of the ventricle?
Full text
10.35366/105943
Language: English
References: 15
Page: 29-34
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ABSTRACT
Ischemic mitral regurgitation (IMR) is a spectrum of mitral regurgitation with a complex mechanism; its presence increases the incidence of heart failure and mortality of patients. It is resulting from a displacement of the papillary muscles and tethering of the valve after a myocardial infarction. For many years it has been accepted that the mitral valve is essentially normal and in the context of an infarction, the left ventricle undergoes remodeling and displacement of the papillary muscles, which leads to the tethering of the valve and this conditions mitral regurgitation. There are many mechanisms associated with the poor mechanical coaptation of the valve that contribute to mitral regurgitation; but it is also true (considering multiple studies) that the valve undergoes a transformation of its structure and that therefore it is not structurally normal. In the late stages of IMR, the thickness and stiffness of the leaflets and the sub valvular apparatus contribute to the degree of mitral regurgitation, showing that the damage to the valve is clearly structural. The objective of this manuscript is to give an overview of the physio pathogenesis of IMR.INTRODUCTION
Ischemic mitral regurgitation (IMR) is a spectrum of mitral regurgitation (MR), where segmental alterations and remodeling of the left ventricle (LV) due to a myocardial infarction result in displacement of the papillary muscles and tethering of the valve. In the case of inferior infarction, remodeling is asymmetric and is produced by the apical, posterior, and lateral displacement of the posteromedial papillary muscle, pulling the valve (this is named tethering) and generating an increase in the tension area (tenting); the same scenario occurs in anterior infarction, where both papillary muscles pull on the mitral valve (MV) through a symmetrical mechanism. All this pathophysiological mechanism alters the geometry of the valve, reducing the coaptation area and causing MR (Figure 1).1
CELLULAR PLASTICITY OF THE VALVES
Currently it is known that MV is not an inert structure and has the ability to adapt to hemodynamic and traction stimuli, this versatility has been called "cellular plasticity" and in healthy valve tissue implies the ability to change its morphology, generally increasing the length and thickness of the leaflets to adapt to a new hemodynamic condition; the latter can occur during growth or pregnancy.2 After embryonic development and during adult life, human valves maintain cell plasticity and their dynamic structure. Healthy heart valves can adapt to stress, and repair injury through connective tissue remodeling mediated by the synthesis, repair, and remodeling of extracellular matrix (ECM) components; in addition, interstitial valvular cells (IVCs) continually repair damage to collagen and other components of the extracellular matrix.3
IVCs comprise a diverse and dynamic population of resident cells that can modulate a spectrum of phenotypes regulated by environmental conditions. Although most IVCs in the normal valve are quiescent (inactive), IVCs are highly plastic and can shift from one phenotypic state to another during valve homeostasis, in response to adaptation to injury. The five distinct IVCs phenotypes include embryonic progenitor endothelial/mesenchymal cells (eIVCs), quiescent IVCs (qIVCs), activated IVCs (aIVCs), post developmental/ adult progenitor IVCs (pIVCs), and osteoblastic IVCs (ob-IVCs). The importance of knowing all these cellular components lies in the fact that they are the main protagonists of changes in the structure of the valve both in physiological and pathological scenarios.4 Research suggest that IVCs in adult valves can be continually replenished through circulating endothelial or mesenchymal cell precursors derived from bone marrow. These precursors contribute to vascular healing and remodeling under physiological and pathological conditions.5
PATHOBIOLOGY OF VALVULAR HEART DISEASE
There are four types of pathological changes of valves: (1) disruption of the formation of the functional valve architecture, for example: congenital abnormalities; (2) damage or inadequate collagen leading to leaflets weakness, exemplified by degeneration of the myxomatous valve; (3) nodular calcification beginning in the IVCs, as in calcific aortic sclerosis/stenosis; and (4) fibrotic thickening with neovascularization.3 Depending on the type of pathological change, the expression and mechanism of valve injury is different.
Regarding ischemic myocardiopathy, the ischemic myocardium can stimulate the growth of the MV leaflet and production of collagen through the secreting of TGF-β, which is elevated both in infarcted and remote non-infarcted myocardium.5,6 Other research lines have showed that the turbulent MR jet may further signal the MV leaflets to change.7,8 In the study by Dal-Bianco et al9 using adult sheep in which a tethering of the MV was surgically generated, in order to simulate the effect of tethering in an infarction, the authors observed that mechanical stresses imposed at the valve increase the leaflet area and thickness, with cellular changes and they concluded that this suggest reactivated embryonic development pathways. On the other hand, in patients with chronically tethered leaflets evaluated by three-dimensional echocardiography, have been evident that MV leaflet surface area is greater by an average of 35% in compared with normal controls.10 It would be reasonable to assume that in this pathologic IMR scenario an increase in surface mitral leaflet area might compensate for ventricular remodeling and tethering after myocardial infarction, and at least, decrease the degree of valvular regurgitation. However, not all patients have this valve plasticity, that is, they do not increase in size or thickness their mitral valve, some factors have already been associated with plasticity such as smoking associated with a loss of valve adaptability and diabetes mellitus of long evolution was associated with greater plasticity of the valve, possibly as a consequence of the trophic effects of insulin.11 Ischemic and volume overload lesions, may have other local and paracrine effects on valve growth that may help explain the frequent failure of leaflet adaptation to prevent IMR.7
THE ECHOCARDIOGRAPHY AND EVALUATION OF MITRAL VALVE PLASTICITY
In a previous study of our research group, we defined plasticity in patients with inferior infarction as an increase in the length of the anterior and/or posterior mitral leaflets and first order posterior tendinous chords measuring these structures linearly on a parasternal long axis, with two-dimensional echocardiography.11 The value accepted as normal for valve lengths was derived from anatomopathological studies of normal human hearts, where the length of the leaflets (measured from the annulus to the free edge of each leaflet) is 22-23 and 12-13 mm, for the anterior and posterior leaflets, respectively; normal length of tendinous cords is 18-22 mm.12,13 In Figure 2 there is an example of plasticity measure and some of the most important measurements in the IMR by bidimensional echocardiography.
ISCHEMIC MITRAL REGURGITATION WITH PLASTICITY AND /
Ischemic mitral regurgitation had been considered as a "functional" valvular disease for many years, this meant that, there is no structural damage in the MV, and the leaflets are essentially reported as "normal", only with tethering due to ventricular remodeling; in others words, an abnormal left ventricular (LV) shape and function with a valvular manifestation.14 This concept has been changing and in recent years the research has shown us that the advancement of IMR actually involves structural damage to the valves, that has been identified histologically, and also by echocardiography.10,15
In the study by Beaudoin15 the investigators observed that the leaflets shown an increase in thickness in the cusps that is proportionally associated with the time of evolution of IMR. This thickening causes stiffness of the cusp of the leaflet, preventing normal coaptation and allowing regurgitation of Flow. In the experimental study in sheep, the post-myocardial infarction histopathology analysis showed expansion of the spongiosa central layer and focal subendothelial collagen deposition, mainly on the atrial leaflet surface, and expression of α-smooth muscle actin (α-SMA) point out endothelial mesenchymal transformation.15 This study conclude MV thickness increases after myocardial infarction and correlates with MR, suggesting an organic component to IMR, and the fibrotic remodeling of MV could be a focus of future treatments.
In Figure 3 are showed the analysis the echocardiographic analysis of a patient before surgery of mitral valve replacement by severe ischemic mitral regurgitation. In Figure 4 is showed the explanted mitral valve and its histological analysis of the same patient.
OPINION AND PERSPECTIVE
Analyzing the researchers' findings, it has led us to think that mitral valve remodeling has possibly several phases: the initial one is plasticity, that is, the increase in the length of the leaflets and with the passage of time it is possible that remodeling it becomes pathological and appears thickening of the valve and the insufficiency is greater.
Trying to find a logical order of the events that occur in the MV after a cardiac infarction, we can think that the remodeling in the LV causes the tethering of the valve; This pull of the valve activates the endothelial cells (VECs), which in turn, activate the interstitial cells (IVCs), this activation leads to the transformation of the extracellular matrix with endothelial-mesenchymal transformation, which also produces infiltration and transformation of the interstitial cells, mainly myofibroblasts.
Thus, changes begin in the cellular structure of the valves, mainly affecting the spongiosa layer, which begins to increase in size, but there is also a deposit of collagen fibers which give strength and support to the valve. At this point, and thanks to the transformation of the extracellular matrix, the valve increases its size and thickness, but it remains strong thanks to the joint deposition of collagen fibers, this has been recognized as cellular plasticity and is considered until now as a favorable compensatory or remodeling phenomenon.
At some point in the evolution of IMR and due to mechanisms not well understood, a disproportionate increase in the spongiosa layer begins as a consequence of a large number of fibroblasts and the generation of glycosaminoglycans and myxoid tissue, a deposition of fibrous tissue is produced, and the collagen fibers begin to decrease in quantity as do elastin fibers with the consequent loss of support and flexibility of the leaflets. This part appears to be the form of pathological remodeling and has been seen to occur late in IMR. Little is known about the triggers of this pathological evolution, possibly local or systemic factors are associated, but knowing more about pathophysiology opens up therapeutic possibilities to be able to stop the pathological course of IMR, if it exists; many more studies are needed to determine the events that occur in the physiology of this valve disease.
But at present, and analyzing the different investigations, we can affirm with certainty that in IMR the leaflets in late stages "are not normal" and have frank structural damage with thickening and fibrosis that contributes to the loss of adequate cooptation and forms a mechanism more associated with the degree of mitral regurgitation.
REFERENCES
Otsuji Y, Handschumacher MD, Liel-Cohen N, Tanabe H, Jiang L, Schwammenthal E, et al. Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol. 2001; 37 (2): 641-648.
AFFILIATIONS
1 Outpatient Care Department, Former Resident, National Institute of Cardiology Ignacio Chavez. Mexico City, Mexico.
2 Pathology Department, National Institute of Cardiology Ignacio Chavez. Mexico City, Mexico.
3 Autonomous University of Ciudad Juarez. Mexico.
4 Medica Sur Clinical Foundation. Mexico City, Mexico.
5 Department of Outpatient Care; National Institute of Cardiology Ignacio Chavez. Mexico City, Mexico.
Conflict of interest: There is no conflict of interest between the authors.
CORRESPONDENCE
Nydia Ávila-Vanzzini. E-mail: vazzny74@yahoo.comReceived: 22/01/2021. Accepted: 18/02/2021