FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration.

BACKGROUND: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the human transcription factor FOXC1 are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine Foxc1 and its closely related factor, Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix). METHODS: Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC-specific, compound Foxc1;Foxc2 mutations (ie, EC-Foxc-DKO and lymphatic EC-Foxc-DKO mice, respectively) were used to study the function of Foxc1 and Foxc2 in the maintenance of MVs. The EC and lymphatic EC mutations of Foxc1/c2 were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry/RNAscope, Movat pentachrome/Masson Trichrome staining, and Evans blue injection. RESULTS: EC deletions of Foxc1 and Foxc2 in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc-DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2 mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-Foxc1/c2 mutant MVs. Lymphatic EC deletion of Foxc1/c2 also resulted in similar structural/ECM abnormalities as seen in EC-Foxc1/c2 mutant MVs. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications.

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow's disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow's disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

Generation of an integration-free induced pluripotent stem cell (iPSC) line (SDHI001-A) from a 65-year old adult mitral valve prolapse (MVP) patient.

Human iPSC line, SDHi001-A, was generated from 65-year-old male patient with mitral valve prolapse, using non-integrative reprogramming method. This cell line shows pluripotency both in vitro and in vivo, and has a normal karyotype.

Defining the Role of the miR-145-KLF4-αSMA Axis in Mitral Valvular Interstitial Cell Activation in Myxomatous Mitral Valve Prolapse Using the Canine Model.

Mitral valve prolapse (MVP) is a common valvular disease, affecting 2-3% of the adult human population and is a degenerative condition. A total of 5-10% of the afflicted will develop severe mitral regurgitation, cardiac dysfunction, congestive heart failure, and sudden cardiac death. Naturally occurring myxomatous MVP in dogs closely resembles MVP in humans structurally, and functional consequences are similar. In both species, valvular interstitial cells (VICs) in affected valves exhibit phenotype consistent with activated myofibroblasts with increased alpha-smooth muscle actin (αSMA) expression. Using VICs collected from normal and MVP-affected valves of dogs, we analyzed the miRNA expression profile of the cells and their associated small extracellular vesicles (sEV) using RNA sequencing to understand the role of non-coding RNAs and sEV in MVP pathogenesis. miR-145 was shown to be upregulated in both the affected VICs and sEV, and overexpression of miR-145 by mimic transfection in quiescent VIC recapitulates the activated myofibroblastic phenotype. Concurrently, KLF4 expression was noted to be suppressed by miR-145, confirming the miR-145-KLF4-αSMA axis. Targeting this axis may serve as a potential therapy in controlling pathologic abnormalities found in MVP valves.

Insights into malignant mitral valve degenerative disease from a sudden cardiac death cohort highlighting significant measurement differences from normal.

AIMS: Mitral valve prolapse (MVP) is an accepted cause of sudden cardiac death (SCD) in most autopsy series. Diagnosis at autopsy relies upon subjective assessment with no established objective pathological criteria. This study set out to establish objective measurements to help pathologists dealing with SCD. METHODS: We diagnosed 120 (1.5%) cases of MVP in 8108 cases of SCD. We measured the mitral annulus, anterior and posterior leaflets, rough zone and mitral annular disjunction (MAD) in 27 MVP cases and compared them to 54 age- and sex-matched normal mitral valves. RESULTS: Age of death was 39 ± 16 years, with 59 females and 61 males. History of mild MV disease was present in 19 (16%). Eleven (9%) died associated with exertion. Left ventricular hypertrophy was present in nine (15%) females and 10 (16%) males. Both MV leaflets showed thickening and ballooning in all individuals. MVP showed highly significantly increased annular circumference, elongation and thickening of both leaflets as well as increased MAD (all P < 0.001). Left ventricular fibrosis was present in 108 (90%), with interstitial fibrosis in the posterolateral wall and papillary muscle in 88 (81%) and coexisting replacement fibrosis in 40 (37%). CONCLUSION: This is the largest MVP associated with SCD series highlighting a young cohort with equal representation of males and females. There is involvement of both leaflets with significant annular dilatation, elongation and thickening of both leaflets with MAD. Left ventricular fibrosis explains arrhythmia. Our quantitative measurements should serve as a reference for pathologists assessing post-mortem hearts for MVP.

Considerations & challenges of mitral valve repair in females: diagnosis, pathology, and intervention.

PURPOSE OF REVIEW: Disparities in mitral valve (MV) repair outcomes exist between men and women. This review highlights sex-specific differences in MV disease aetiology, diagnosis, as well as timing and type of intervention. RECENT FINDINGS: Females present with more complicated disease: anterior or bileaflet prolapse, leaflet dysplasia/thickening, mitral annular calcification, and mixed mitral lesions. The absence of indexed echocardiographic mitral regurgitation (MR) severity parameters contributes to delayed intervention in women, resulting in more severe symptom burden at time of surgery. The sequelae of chronic MR also necessitate concomitant procedures (e.g. tricuspid repair, arrhythmia surgery) at the time of mitral surgery. Complex MV pathology, greater patient acuity, and more complicated procedures collectively pose challenges to successful MV repair and postoperative recovery. As a consequence, women receive disproportionately more MV replacement than men. In-hospital mortality after MV repair is also greater in women than men. Long-term outcomes of MV repair are comparable after risk-adjustment for preoperative status; however, women experience a greater incidence of postoperative heart failure. SUMMARY: To address the inequity in MV repair outcomes between sexes, indexed diagnostic measurements, diligent surveillance of asymptomatic MR, increased recruitment of women in large clinical trials, and mandatory reporting of sex-based subgroup analyses are recommended.

Valvopatia na mulher - contracepção e gravidez / Valvar cardiopathy in women

A doença valvar na mulher tem mudado seu espectro, havendo redução gradativa dos casos reumáticos e aumento das alterações degenerativas. Apesar do avanço nas técnicas diagnósticas e terapêuticas, a doença valvar continua sendo um desafio permanente, sobretudo no ciclo gravídico-puerperal, fonte de descompensação de muitas delas. O planejamento familiar é hoje fundamental no aompanhamento dessas pacientes. A melhoria na educação em saúde representa igualmente uma evolução do papel social e economico da mulher e deve ser um dos pilares do tratamento da mulher cardiopata, particularmente da portadora de cardiopatia.

Prolapso da valva mitral e elasticidade cuspidiana / Mitral valve prolapse and cusp elasticity

PURPOSE--To verify if systolic bulging of floppy mitral cusps can to elastic behavior of their myxomatous collagen tissue. METHODS--Five hearts with floppy mitral valves obtained from autopsies were distended with air (20 to 250 mmHg) through a catheter connected to the left ventricle. It was observed if some area of the atrial surface of the coapted cusps showed variable bulging according to the variation of air injection pressures. Molding of those surfaces (gypsum) allowed the same kind of analysis by other four researches. It was analyzed the cut surfaces of these radially sectioned molds. Lately, isolated tendinae chords were submitted to repeated tractions and observed if they exhibited elastic behavior. Histological study defined the presence of collagen myxomatous degeneration and quantified the amount of elastic tissue. RESULTS--In no case it was detected elastic bulding of mitral cusps. Cut surfaces of the molds confirmed that no increment of the prominent areas occurred, even in those regions with extensive, histologically confirmed, myxomatous substitution of the native collagen tissue. CONCLUSION--Increment of the degree of mitral bulging occurring during ventricular systole can not be ascertained to cusp elasticity but probably to papilar muscle traction

Prolapso de la válvula mitral en pacientes con espondilitis anquilosante: estudio prospectivo

La espondilitis anquilosante (EA) es una enfermedad sistémica que puede cursar con manifestaciones en diversos órganos o sistemas. Se han identificado problemas cardiovasculares, principalmente lesiones valvulares, aortitis o pericarditis así como defectos de conducción. En este trabajo, se estudian las manifestaciones cardiovasculares en 15 pacientes adultos con diagnóstico de EA por medio de métodos precisos en cuanto a la función y estado anatómico cardiovascular y aórtico. Se encontró problema en 4 pacientes, 2 con prolapso de valva posterior de la válvula mitral, uno con insuficiencia aórtica y otro con dilatación de la aorta. A los dos pacientes con prolopso valvular no se les había detectado problema clínicamente ni por electrocardiografía. A un grupo de 13 pacientes tomados como control, con diagnóstico de artritis reumatoide con edad similar y el mismo protocolo basado en evaluación clínica por cardiólogo, radiografía P.A. de tórax, electrocardiograma convencional en todas las derivaciones y ecocardiograma no se le encontró ninguna lesión similar

Patogênese do prolapso da valva mitral em chagásicos crônicos: estudo da miocardite dos músculos papilares / Pathogenesis of mitral valve prolapse in chronic chagas' heart disease patients: study of papillary muscle myocarditis

Objetivo - Estudar a valva mitral na cardiopatia chagásica crônica buscando eventual relaçäo entre causa e efeito com o prolapso daquele aparelho. Métodos - Dezessete coraçöes de indivíduos com cardiopatia chagásica crônica, sendo 11 do sexo masculino, idade entre 31 e 84 (média = 54) anos, resultantes de necrópsias realizadas até há um ano. As peças, devidamente conservadas, foram analisadas macro e microscopicamente. Foram retirados fragmentos dos músculos papilares da valva mitral, das regiöes anterior, lateral e posterior do ventrículo esquerdo, septo interventricular, parede livre de ventrículo direito e paredes dos átrios. Resultados - Miocardite crónica foi encontrada nos 17 casos (leve em 6, moderada em 7 e grave em 4). Também em todos os casos os músculos papilares apresentaram miocardite, sendo que, em 15 o grau de intensidade foi igual ou maior do que o observado nas outras regiöes do coraçäo. Conclusäo - Os músculos papilares da valva mitral säo sede muito freqüente de miocardite na cardiopatia chagásica crônica, fato que deve ser lembrado ao se discutir a patogênese do prolapso da mesma

Purpose- Studring the mitral valva in chronic Chagas' heart disease, searching a possible cause effect relationship between this condition and valve prolapse. Methods Seventeen hearts were surveged from individuals exhibiting chronic chagasic cardiopathy, 11 males and 6 females, aged between 31-84 (average 54) years. The hearts came from necropsies carried out until a year before. Properly preserved samples were analyzed macro and microscopicaly. Fragments were excised from the mitral valve papillary muscles, anterior, lateral and posterior regions of the left ventricle, interventricular septum, free wall of right ventricle and atrium walls. Results - Chronic myocarditis was found ill all the samples (mild in 6 of them, moderate in 7 and severe in 4). Also, the papillary muscles exhibited miocarditis in all of the samples, and in 15 of them the degree of severety was equal to or superior than the observed in degree other regions of the heart. Conclusion The chronic chagasic cardiopathy, the papillary muscle constitute afrequent site of myocardites. This fact must be held in mind when one discusses the pathogenesis of the prolapse of the valve

Prolapso de valva mitral nas 8ª e 9ª décadas de vida: estudo anátomo-patológico em três casos / Mitral valve prolapse in the 8th and 9th decades of life: anatomo-pathological study in 3 cases

Säo apresentadas as características anátomo-clínicas de três casos de Prolapso da Valva Mitral (PVM) detectados em pacientes idosos e do sexo masculino, o que contrasta em termos da sua conhecida prevalência entre mulheres jovens. Do ponto de vista anátomo-patológico os três casos ilustram duas importantes características anatômicas que o PVM pode apresentar: dimensäo do óstio e estado da cordoalha. O 1§ caso exibe grande dilataçäo ostial, preferencial acometimento da cúspide anterior e acentuada ruptura de cordas, de que resultou grave quadro congestivo, o 2§ caso mostra grande dilataçäo ostial, sem lesäo significativa de cordoalha, sendo menor, o grau do defeito valvar; no 3§ caso, o processo degenerativo mixomatoso, tal como nos casos anteriores, acomete ambas as cúspides, mais acentuado na posteror, sendo normal o diâmetro do óstio e íntegras as cordas, embora nitidamente alongadas, observando-se adequada competência valvar. Conclui-se que a dilataçäo do anel fibroso valvar e a ruptura da cordoalha säo mais deletérios que o processo degenerativo isolado

Prolapso de válvula mitral / Mitral valve prolapse

El prolapso valvular mitral (PVM) es un desplazamiento sistólico excesivo de uno o ambos velos mitrálicos hacia la aurícula. La principal etiología es una degeneración mixomatosa de la cuerdas tendíneas, velos y anillo mitral. Puede ocurrir como una alteración aislada (primaria) o asociada a discolagenosis sistémicas. Un desplazamiento acentuado de velos mitrílicos normales puede ocurrir secundario a una disminución de tamaño del ventrículo izquierdo. La prevalencia del PVM primario varía entre 1% y 8%. La mayor parte de los pacientes son asintómaticos. De las muchas manifestaciones adscritas al PVM, aquellas que muestran la mejor asociación con ella son: bajo peso y presión arterial, alteraciones óseas torácicas, palpitaciones y tendencia a la hipotensión ortostática y al síncope. La expresión característica es la auscultación de uno o más ruidos de eyección meso o telessistólicos y un soplo telesistólico claros y reproducibles de mayor intensidad en la punta y movibles con intervenciones físicas. El mejor standar de referencia para apoyar el diagnóstico es la ecocardiografía siempre que se use con prudencia. Debido a la geometría del anillo mitrálico la visión apical de cuatro cámaras produce muchos falsos positivos y el diagnóstico no debe basarse sólo en esta visión. Mientras no se conozca la topografía de los velos mitrálicos y su rango normal muchas observaciones quedarán indefinidas y no deberán ser catalogadas como PVM. Las principales complicaciones del PVM son la insuficiencia mital aguda y la crónica. Otras complicaciones como endocarditis infecciosa, arritmias ventriculares, muerte súbita y tromboembolismo cerebral tienen un riesgo no superior al observado en la población general salvo en presencia de insuficiencia mitral y aún así su prevalencia es muy baja

Mitral valve prolapse

This very common cardiac valve abnormality affects some 5 percent of the USA population. The condition is often inherited as an autosomal dominant and is a disorder of connective tissue. Palpitation is the commonest of the many possible symptoms and diagnosis is made by auscultation and/or echocardiography. Thoracic skeletal abnormalities are a common accompanying feature. The commonest complication is infective endocarditis, requiring prophylactic antibiotics for such procedures as dental surgery. Symptomatic patients need only reassurance of the benign nature of the condition and avoidance of such stimulants as caffeine. Persistent or serious arrhythymias will need beta-blockers or more intensive investigations and therapy (AU)