Is the mitral valve passive flap theory overstated? An active valve is hypothesized

The concept that the mitral valve of the heart is a passive flap that opens and closes like a barn door has been emphasized for decades by medical and biology professors to their students. But experimental findings, which are outlined in this report, support the theory of an active valve. We hypothesize that the two leaflets of the mitral valve are actively contractile; that physical forces generated in the valve itself may stabilize and add precision to the sum of forces that regulate valve movement. This precision could be of critical significance both in the moments preceding, and during, valve opening and closing. Evidence supporting our active valve hypothesis includes the profuse innervation of motor and sensory nerves that are present in the mitral valves of all animals studied. In addition, multiple contractile cell types have been found in the mitral valve, including cardiac muscle cells, smooth muscle cells, and cardiac valvular interstitial cells. In vitro work in our laboratories using the rat mitral valve shows that not only are the valves capable of contraction and relaxation, but that the contractions and relaxations are nerve-mediated. We theorize that the rich innervation and contractile cells in the mitral valve work together to modulate fine-tuning of valve movements and tone, thereby ensuring the integrity of the valve seal. Other investigators have reported that the mitral valve demonstrates contractile activity and that denervation localized to the mitral valve affects valve competence. The evidence for an active mitral valve presented by these and other experimental studies warrant a reexamination of the validity of the passive valve concept. An accurate and full understanding of the precise movements of the valve leaflets and the mechanisms that regulate these movements is likely to provide the information needed to understand and develop treatments for many different cardiac valve problems, including mitral valve diseases such as prolapse and myxomatous degeneration. In view of the available experimental evidence, the concept that the mitral valve functions only as a passive structure is challenged by numerous anomalies. A reinterpretation of the concept of valve function that incorporates active as well as passive roles for the valve leaflets and other components of the valve apparatus would have significant implications both for the directions taken in research involving the cardiac valves and for the approaches to treatment.     

Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation

Gaucher's disease is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase, which leads to glucocerebroside accumulation in the reticuloendothelial system. Homozygosity for the D409H mutation has been associated with cardiovascular valvular disease. We present a case of a 17-year-old Palestinian patient who presented with severe aortic and mitral valvular calcification, as well as calcification of the ascending aorta, the aortic arch and the ostia of his coronary arteries. The patient was confirmed to be homozygous for the D409H mutation in the glucocerebrosidase gene. The patient's enzyme assay for glucocerebrosidase activity was 5 nm/h/mg protein (normal 13-22 nm/h/mg). The patient presented with symptoms of dyspnea and chest pain. He had a 6-year history of documented aortic valve calcification by echocardiogram after two of his older brothers died of congestive heart failure and severe valvular calcification. Cardiac catheterization showed a severely calcified aorta with almost no motion of the aortic valve leaflets and severe calcification of the mitral valve and the mitral valvular apparatus. The patient underwent extensive cardiac surgery with aortic and mitral valve replacements and intraoperative findings confirmed calcification of the entire aortic root. Electron microscopy of the valves confirmed the presence of Gaucher's cells. Enzyme therapy with imiglucerase was initiated. The patient is in stable condition, 20 months post-operatively.     

In vivo validation of a fluid dynamics model of mitral valve M-mode echocardiogram

A fluid dynamics model of mitral valve motion during diastolic filling of the left heart is described. Given a pulsed Doppler velocity pattern in the mitral annulus, the radius of circular mitral orifice, the length of leaflets and the end-systolic left ventricular volume, the numerical model predicts the time course of the mitral leaflets during diastole: the mitral valve M-mode echocardiogram. Results obtained by computer simulation have been validated with in vivo data. It is shown that mitral valve flow is essentially a fluid dynamics process of floating mitral valve leaflets with blood flow due to the atrioventricular pressure gradient. In addition, a partial opening of the mitral valve as the initial boundary condition is required to simulate the overshooting of the leaflets during early peak filling. Some back flow is a condition for perfect closing of the native mitral valve. The higher the unsteady character of mitral flow, the less efficient is the opening and closing processes of the mitral valve.     

A Novel Left Heart Simulator for the Multi-modality Characterization of Native Mitral Valve Geometry and Fluid Mechanics

Numerical models of the mitral valve have been used to elucidate mitral valve function and mechanics. These models have evolved from simple two-dimensional approximations to complex three-dimensional fully coupled fluid structure interaction models. However, to date these models lack direct one-to-one experimental validation. As computational solvers vary considerably, experimental benchmark data are critically important to ensure model accuracy. In this study, a novel left heart simulator was designed specifically for the validation of numerical mitral valve models. Several distinct experimental techniques were collectively performed to resolve mitral valve geometry and hemodynamics. In particular, micro-computed tomography was used to obtain accurate and high-resolution (39 μm voxel) native valvular anatomy, which included the mitral leaflets, chordae tendinae, and papillary muscles. Three-dimensional echocardiography was used to obtain systolic leaflet geometry. Stereoscopic digital particle image velocimetry provided all three components of fluid velocity through the mitral valve, resolved every 25 ms in the cardiac cycle. A strong central filling jet (V ~ 0.6 m/s) was observed during peak systole with minimal out-of-plane velocities. In addition, physiologic hemodynamic boundary conditions were defined and all data were synchronously acquired through a central trigger. Finally, the simulator is a precisely controlled environment, in which flow conditions and geometry can be systematically prescribed and resultant valvular function and hemodynamics assessed. Thus, this work represents the first comprehensive database of high fidelity experimental data, critical for extensive validation of mitral valve fluid structure interaction simulations.     

The clinical anatomy of the mitral valve

As a result of the numerous clinical and surgical data accumulated so far, the classical image of the mitral valve-a bicuspid valve, with two leaflets and two papillary muscles-undergoes significant modifications. The valve, included into the larger concept of the mitral valvular complex unveils numerous important valences and characteristics, among which, some represent newer concepts, of clinical and surgical significance: the valvular complex is a subtle and finely-tuned system of elements acting in a coordinated manner; the mitral valve is an active valve and not a mere passive flap bordering the atrioventricular junction. Not least, the mitral valve contributes to the make up and function of the left ventricular outflow tract. The anatomical and functional interdependence between the mitral valve and the left ventricular myocardium is evident not only following their particularities of vascularization but also it is reflected in morbid states such as ischemic cardiac disease and dilated cardiomyopathy. All the new concepts and ideas, ask for a more profound study of the clinical anatomy of the mitral valve, underscoring the importance of a pertinent dialogue between specialists and by using a more appropriate and unitary terminology.     

应用于零维左心血液循环的二尖瓣模型的研究

提出一个可以准确合理地模拟二尖瓣动力学特性的瓣叶运动流阻模型。考虑影响二尖瓣瓣叶运动的跨瓣压差和血流推力,建立二尖瓣运动的控制方程,提出依赖于瓣叶打开角度θ的瓣叶运动流阻模型,把该模型应用于零维左心血液循环系统,得到血液动力学特性。在保持心输出量和反流分数一致的条件下,比较该模型、瞬态关闭的阶梯流阻模型和经验指定的时变流阻模型。结果发现,瓣叶运动流阻模型能反映瓣膜关闭过程中的血液动力学,如压差和流量的滞后性以及关闭流量,同时该模型可以通过调整单位转动惯量跨瓣压差影响系数K_p和血流影响系数K_b的大小,改变瓣膜打开过程和关闭过程所需时间,瓣膜打开和关闭时间分别为50.0和40.2 ms。该模型可弥补阶梯流阻模型中忽略瓣膜运动过程的瞬态关闭的缺点,同时也能避免时变流阻模型中关闭起始时间的不合理性。此模型较为合理准确地模拟二尖瓣关闭过程的动力学特性,且简单易控制。     

The genetics of mitral valve prolapse

Mitral valve prolapse (MVP) is a very common clinical condition that refers to a systolic billowing of one or both mitral valve leaflets into the left atrium. Improvements of echocardiographic techniques and new insights in mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. MVP can be sporadic or familial, demonstrating autosomal dominant and X-linked inheritance. Three different loci on chromosomes 16, 11 and 13 have been found to be linked to MVP, but no specific gene has been described. Another locus on chromosome X was found to cosegregate with a rare form of MVP called 'X-linked myxomatous valvular dystrophy'. MVP is more frequent in patients with connective tissue disorders including Marfan syndrome, Ehlers-Danlos and osteogenesis imperfecta. The purpose of this review is to describe previous studies on the genetics and prevalence of MVP. The report warrants the need for further genetically based studies on this common, albeit not fully understood, clinical entity.     

Optical methods for the nondestructive evaluation of collagen morphology in bioprosthetic heart valves

The aim of the present study was to assess the suitability of nondestructive optical methods as a means of evaluating collagen morphology in bioprosthetic heart valve leaflets. The results of this study demonstrate that transmitted polarized light and incident polarized light optics facilitate the imaging of the inherent birefringence of valvular collagen fibers. Polarized light optics readily document the different patterns of collagen orientation and configuration in porcine aortic valvular (PAV) and bovine pericardial valvular (BPV) bioprostheses. Incident polarized light optics also provide information on leaflet surface morphology. Verification that the birefringence observed by polarized ligh optics represents leaflet collagen was provided by conventional histologic and transmission electron microscopic methods. Quantitative determinations of the spacing of collagen bundle waves gave similar values in intact and in sectioned BPV leaflets. Potential applications of polarized light optics in the assessment of bioprosthetic valve collagen are as follows: the selection of the desired orientation of collagen bundles within pericardium intended to be configured into bioprosthetic leaflets; evaluation of the effects of mechanical stresses and leaflet motion on collagen morphology in bioprosthetic valve leaflets; and initial screening of leaflet specimens and selection of the desired collagen orientation for embedding and sectioning of samples for conventional morphologic studies.     

二尖瓣运动的流固耦合仿真

目的 建立包含左心和血液的二尖瓣理想模型,用流固耦合仿真研究二尖瓣在血流中的运动特性。方法 基于解剖学参数建立二尖瓣、左心和血液模型,流固耦合仿真采用有限元结合浸没边界法,使用有限元软件LS-DYNA模拟二尖瓣运动,获取形态学、力学和血液动力学参数,并与结构仿真结果进行对比。结果 两种仿真下二尖瓣形态学结果差异较大,流固耦合结果与超声影像吻合。流固耦合仿真和结构仿真的瓣叶应力分布结果一致,最大第1主应力分别为1.48、1.53 MPa,相对误差为3.27%。左心流场有较为复杂的涡旋结构,舒张期二尖瓣最大流速为1.02 m/s,与健康人体生理数据(0.89±0.15) m/s相吻合。结论 二尖瓣流固耦合仿真可以获取更贴近于生理的形态学结果;流固耦合仿真可以提供临床诊断不可或缺的流场参数信息;单研究瓣叶应力分布问题时,结构仿真更高效。     

An unusual complication associated with the Carpentier-Edwards porcine bioprosthesis

Primary tissue failure of bioprosthetic heart valves refers primarily to calcification of the leaflets of the bioprosthesis. A 75 year old patient underwent reoperation 15 years after mitral valve replacement with a Carpentier-Edwards porcine bioprosthesis. The extracted bioprosthetic valve was found to have one prolapsed leaflet and a small amount of calcification on all three leaflets without tear or perforation. The two commissures suspending the prolapsed leaflet were detached, causing mitral valve regurgitation.     

Myxoid heart disease: an assessment of extravalvular cardiac pathology in severe mitral valve prolapse.

Because of the microscopic features of the affected leaflets in mitral valve prolapse (MVP), myxoid degeneration of the valve is a common pathologic designation applied to this condition. We undertook this study as a means of gaining an insight into the occurrence and prevalence of extravalvular cardiac alterations in hearts with severe MVP. Tissues of 24 hearts with severe myxomatous transformation of the mitral valve as the sole cardiac abnormality were examined. Eighteen of the 24 subjects with severe MVP died suddenly. Only two of these had pathologic evidence of severe mitral insufficiency. Twenty-four normal hearts served as controls. The two groups of hearts came from victims of homicide, suicide, accident, or natural death. Sections of the mitral valve, working myocardium, conduction system, and cardiac nerves and ganglia were studied by routine and special connective tissue and proteoglycan stains. Similar to the findings in severely affected mitral valves, prominent deposits of proteoglycans in neural and conduction tissue readily distinguished hearts with myxomatous valve changes from the control hearts. We conclude that the commonly recognized local derangement of valvular tissue in MVP is but one specific reflection of a more general myxomatous alteration in cardiac connective tissue.     

Three-Dimensional Fluid-Structure Interaction Simulation of Bileaflet Mechanical Heart Valve Flow Dynamics

The wall shear stress induced by the leaflet motion during the valve-closing phase has been implicated with thrombus initiation with prosthetic valves. Detailed flow dynamic analysis in the vicinity of the leaflets and the housing during the valve-closure phase is of interest in understanding this relationship. A three-dimensional unsteady flow analysis past bileaflet valve prosthesis in the mitral position is presented incorporating a fluid-structure interaction algorithm for leaflet motion during the valve-closing phase. Arbitrary Lagrangian-Eulerian method is employed for incorporating the leaflet motion. The forces exerted by the fluid on the leaflets are computed and applied to the leaflet equation of motion to predict the leaflet position. Relatively large velocities are computed in the valve clearance region between the valve housing and the leaflet edge with the resulting relatively large wall shear stresses at the leaflet edge during the impact-rebound duration. Negative pressure transients are computed on the surface of the leaflets on the atrial side of the valve, with larger magnitudes at the leaflet edge during the closing and rebound as well. Vortical flow development is observed on the inflow (atrial) side during the valve impact-rebound phase in a location central to the leaflet and away from the clearance region where cavitation bubbles have been visualized in previously reported experimental studies.     

Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells

Cells respond to changes in mechanical strains by varying their production of extracellular matrix macromolecules. Because differences in strain patterns between mitral valve leaflets and chordae tendineae have been linked to different quantities and types of glycosaminoglycans (GAGs), we investigated the effects of various strain conditions on GAG synthesis by valvular interstitial cells (VICs) using an in vitro 3-dimensional tissue-engineering model. VICs from leaflets or chordae were seeded within collagen gels and subjected to uniaxial or biaxial static tension for 1 week. GAGs synthesized within the collagen gels and secreted into the surrounding medium were analyzed using fluorophore-assisted carbohydrate electrophoresis. In constrained conditions, more 4-sulfated GAGs were retained within the collagen gel, whereas more hyaluronan was secreted into the surrounding medium. Selected GAG classes were found in significantly different proportions in collagen gels seeded with leaflet cells versus chordal cells. The only significant difference between uniaxial and biaxial regions was found for 6-sulfated GAGs in the gels seeded with chordal cells (p<0.05). This study suggests how mechanical loading may influence GAG production and localization in the remodeling of the mitral valve and has design implications for engineered tissues.     

Overexpression of transforming growth factor-beta 1 in the valvular fibrosis of chronic rheumatic heart disease

For the purpose of determining the pathogenic role of transforming growth factor-beta1 (TGF-beta 1) in the mechanism of chronic rheumatic heart disease, we evaluated the expression of TGF-beta 1, proliferation of myofibroblasts, and changes in extracellular matrix components including collagen and proteoglycan in 30 rheumatic mitral valves and in 15 control valves. High TGF-beta 1 expression was identified in 21 cases (70%) of rheumatic mitral valves, whereas only 3 cases (20%) of the control group showed high TGF-beta 1 expression (p<0.001). Additionally, increased proliferation of myofibroblasts was observed in the rheumatic valves. High TGF-beta1 expression positively correlated with the proliferation of myofibroblasts (p=0.004), valvular fibrosis (p<0.001), inflammatory cell infiltration (p=0.004), neovascularization (p=0.007), and calcification (p<0.001) in the valvular leaflets. The ratio of proteoglycan to collagen deposition inversely correlated with TGF-beta 1 expression in mitral valves (p=0.040). In conclusion, an ongoing inflammatory process, the expression of TGF-beta 1, and proliferation of myofibroblasts within the valves have a potential role in the valvular fibrosis, calcification, and changes in the extracellular matrix that lead to the scarring sequelae of rheumatic heart disease.     

Is mitral valve prolapse a manifestation of adolescent growth spurt?

The exact aetiology of mitral valve prolapse (MVP) is unknown, although this is the most common cardiac valvular abnormality currently detected. MVP has high incidence in young individuals, particularly during the second and third decades. These individuals are usually of a slender body habitus indicating higher rates of linear growth, reflective of the adolescent growth spurt. MVP might represent the imbalance in the growth dynamics of the mitral valve apparatus especially between the leaflets, chordae tendineae and the rest of the heart. Several reports suggest the transient nature of MVP and even complete disappearance. MVP with systolic click, but without a systolic murmur signifying regurgitation may be considered as a manifestation of adolescent growth spurt and a normal variant transiently occurring during particular periods of lives of otherwise normal individuals. Strategies of identification of subsets of individuals likely to harbor the more sinister and progressive form of MVP are important and need to be developed.     

Normal distribution of melanocytes in the mouse heart

We report the consistent distribution of a population of pigmented trp-1-positive cells in several important septal and valvular structures of the normal mouse (C57BL/6) heart. The pigmented cell population was first apparent by E16.5 p.c. in the right atrial wall and extended into the atrium along the interatrial septum. By E17.5, these cells were found along the apical membranous interventricular septum near or below the surface of the endocardium. The most striking distribution of dark pigmented cells was found in the tricuspid and mitral valvular leaflets and chordae tendineae. The normal distribution of pigmented cells in the valvuloseptal apparatus of C57BL/6 adult heart suggests that a premelanocytic lineage may participate in the earlier morphogenesis of the valve leaflets and chordae tendineae. The origin of the premelanocyte lineage is currently unknown. The most likely candidate populations include the neural crest and the epicardially derived cells. The only cell type in the heart previously shown to form melanocytes is the neural crest. The presence of neural crest cells, but not melanocytes, in some of the regions we describe has been reported by others. However, previous reports have not shown a contribution of melanocytes or neural crest derivatives to the atrioventricular valve leaflets or chordae tendineae in mouse hearts. If these cells are of neural crest origin, it would suggest a possibly greater contribution and persistence of neural crest cells to the valvuloseptal apparatus than has been previously understood.     

On modelling and analysis of healthy and pathological human mitral valves: Two case studies

Biomechanical data and related constitutive modelling of the mitral apparatus served as a basis for finite element analyses to better understand the physiology of mitral valves in health and disease. Human anterior and posterior leaflets and chordae tendinae from an elderly heart showing no disease and a hypertrophic obstructive cardiomyopathic heart (HOCM) were mechanically tested by means of uniaxial cyclic extension tests under quasi-static conditions. Experimental data for the leaflets and the chordae tendinae showed highly nonlinear mechanical behaviours and the leaflets were anisotropic. The mitral valve from the HOCM heart exhibited a significantly softer behaviour than the valve from the healthy one. A comparison with porcine data was included because many previous mitral modelling studies have been based on porcine data. Some differences in mechanical response were observed. Material parameters for hyperelastic, transversely isotropic constitutive laws were determined. The experimental data and the related model parameters were used in two finite element studies to investigate the effects of the material properties on the mitral valve response during systole. The analyses showed that during systole the mitral valve from the HOCM heart bulged into the left atrium by taking on the shape of a balloon, whereas the anterior leaflet of the healthy valve remained in the left ventricle.     

A case of Carpentier–Edwards pericardial bioprosthesis in mitral position explanted 22 years after implantation

A case of Carpentier–Edwards PERIMOUNT (CEP) mitral pericardial bioprosthesis explanted 22 years after the valve replacement is reported. This patient underwent the previous replacement at the age of 50. The extracted bioprosthesis showed three rigid leaflets, one of which had a tear causing severe mitral regurgitation. The X-ray demonstrated calcification of varied extent among these leaflets, ranging from none to severe. When leaflet calcification is suppressed, perhaps the lifespan of a CEP valve can be prolonged more than previously expected. When a literature search was conducted, this case was found to represent the longest reported interval from the implantation of a CEP valve in the mitral position to the explantation as a result of severe mitral regurgitation caused by structural valve deterioration (SVD).     

Analysis of ATS leaflet behavior by in vitro experiment

It has been reported that the normally functional bileaflet valve ATS with open-pivot design does not exhibit a full opening motion either in the mitral or in the aortic position in patients. An in vitro experiment was conducted to investigate the mechanism of the ATS leaflet movement. ATS 29 mm for the mitral position was chosen in our experiment and SJM 29 mm was chosen as a control. Two pulsatile simulators were employed to investigate the factors affecting leaflet movement. Two different conduits to be incorporated downstream (in simulator I) and three different inlet coverings to alter the local flow field around the open pivot (in simulator II) were used. A high-speed video camera was employed to observe leaflet movment. The ATS valve could exhibit a fully open movement in straight conduit but could not fully open when an enlarging shape was incorporated downstream of the ATS valve. The covering of the ATS open pivot could make the leaflets fully open or increase the opening angle with the existene of the enlarging downstream shape. The enlargement downstream of the ATS valve, which induces a divergent transvalvular flow, is the main reason that the leaflets do not fully open. The local flow field around the open pivot, which induces an additional moment M_a, plays an important role in the movement of the ATS leaflets.