Mitral Valve Abnormalities Research Articles

Floppy Mitral Valve/Mitral Valve Prolapse and Manifestations Not Related to Mitral Regurgitation: Time to Search the Dark Side of the Moon.

Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a complex entity in which several clinical manifestations are not directly related to the severity of mitral regurgitation (MR). Patients with FMV/MVP and trivial to mild MR may have exercise intolerance, orthostatic phenomena, syncope/presyncope, chest pain, and ventricular arrhythmias, among others. Several anatomical and pathophysiologic consequences related to the abnormal mitral valve apparatus and to prolapse of the mitral leaflets into the left atrium provide some explanation for these symptoms. Further, it should be emphasized that MVP is a non-specific finding, while FMV (redundant mitral leaflets, elongated/rupture chordae tendineae, annular dilatation) is the central issue in the MVP story. The purpose of this review was to highlight the clinical manifestations of FMV/MVP not directly related to the severity of MR and to discuss the pathophysiologic mechanisms contributing to these manifestations.

Pathogenesis and Surgical Treatment of Dextro-Transposition of the Great Arteries (D-TGA): Part II.

Dextro-transposition of the great arteries (D-TGA) is the second most common cyanotic heart disease, accounting for 5-7% of all congenital heart defects (CHDs). It is characterized by ventriculoarterial (VA) connection discordance, atrioventricular (AV) concordance, and a parallel relationship with D-TGA. As a result, the pulmonary and systemic circulations are separated [the morphological right ventricle (RV) is connected to the aorta and the morphological left ventricle (LV) is connected to the pulmonary artery]. This anomaly is included in the group of developmental disorders of embryonic heart conotruncal irregularities, and their pathogenesis is multifactorial. The anomaly's development is influenced by genetic, epigenetic, and environmental factors. It can occur either as an isolated anomaly, or in association with other cardiac defects. The typical concomitant cardiac anomalies that may occur in patients with D-TGA include ventriculoseptal defects, patent ductus arteriosus, left ventricular outflow tract obstruction (LVOTO), mitral and tricuspid valve abnormalities, and coronary artery variations. Correction of the defect during infancy is the preferred treatment for D-TGA. Balloon atrial septostomy (BAS) is necessary prior to the operation. The recommended surgical correction methods include arterial switch operation (ASO) and atrial switch operation (AtrSR), as well as the Rastelli and Nikaidoh procedures. The most common postoperative complications include coronary artery stenosis, neoaortic root dilation, neoaortic insufficiency and neopulmonic stenosis, right ventricular (RV) outflow tract obstruction (RVOTO), left ventricular (LV) dysfunction, arrhythmias, and heart failure. Early diagnosis and treatment of D-TGA is paramount to the prognosis of the patient. Improved surgical techniques have made it possible for patients with D-TGA to survive into adulthood.

Mutation in PDGFRbeta: a potential new pathogenic variant for acquired mitral valve prolapse

Abstract Funding Acknowledgements None. Background Mitral valve prolapse (MVP) due to myxomatous degeneration is characterized by familial clustering, but few pathogenic genes have been identified. In a genetic screening program for MVP patients, we identified a platelet-derived growth factor receptor β (PDGFRβ)-E162K missense variant in a family with a bi-leaflet MVP phenotype in four affected family members. PDGFRβ is a receptor tyrosine kinase, which plays an important role in vascular development. Purpose In this study, we investigated whether the E162K substitution in PDGFRβ could lead to mitral valve abnormalities. Methods To assess the functional effects of the missense variant, proliferation and migration assays were performed using HeLa cells overexpressing wild-type (WT) or mutant PDGFRβ. Immunostainings were performed to determine PDGFRβ expression in the diseased valves from a family member undergoing surgical operation and from additional patients operated for MVP. Mouse models were created with the mouse equivalent of the human PDGFRβ-E162K variant (PDGFRβ-E161K) using CRISPR/CAS9. The variant was not lethal and transthoracic echocardiography was performed on adult homozygous PDGFRβE161K/E161K mice, heterozygous PDGFRβE161K/- mice, and WT mice . In addition, histology was performed in adult and neonatal mice to detect potential valvular defects. Results HeLa cells expressing PDGFRβ-E162K and stimulated with PDGFD showed reduced proliferation and migration, suggesting a loss of function of the mutant receptor. PDGFRβ was expressed in human diseased mitral valves. Echocardiographic evaluation revealed a significant larger mitral valve annulus diameter in both PDGFRβE161K/- and PDGFRβE161K/E161K compared to WT (WT: 1.97 mm; PDGFRβE161K/-:2.13, p=0.031; PDGFRβE161K/E161K:2.42 mm, p<0.0001). Histological data in PDGFRβE161K/E161K mice showed significant leaflet thickening in the free edge (FE) of the posterior mitral valve leaflet (PMVL) compared to WT (WT: 72.34 ɥm; PDGFRβE161K/E161K: 109.6 ɥm, p=0.040) and a larger leaflet area of the PMVL compared to WT (WT: 25280 ɥm²; PDGFRβE161K/E161K: 44494 ɥm², p=0.020). Moreover, an altered organization of the extracellular matrix reminiscent of the myxomatous degeneration in MVP was observed. These alterations were not observed in mutant neonatal hearts. Conclusions The PDGFRβ-E162K variant is associated with familial MVP and alters the function of PDGFRβ. Mice harboring this mutation display acquired mitral valve defects.

Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Mouse Congenital Myxomatous Valve Disease.

Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome includes valve leaflet thickening and progressive valve degeneration. However, the underlying mechanisms by which the disease progresses remain undefined. Mice with Fibrillin 1 gene variant Fbn1C1039G/+ recapitulate histopathologic features of Marfan syndrome, and Wnt (Wingless-related integration site) signaling activity was detected in TCF/Lef-lacZ (T-cell factor/lymphoid enhancer factor-β-galactosidase) reporter mice. Single-cell RNA sequencing was performed from mitral valves of wild-type and Fbn1C1039G/+ mice at 1 month of age. Inhibition of Wnt signaling was achieved by conditional induction of the secreted Wnt inhibitor Dkk1 (Dickkopf-1) expression in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1C1039G/+ mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for ECM (extracellular matrix) and immune cells were performed. Wnt signaling is activated early in mitral valve disease progression, before immune cell infiltration in Fbn1C1039G/+ mice. Single-cell transcriptomics revealed similar mitral valve cell heterogeneity between wild-type and Fbn1C1039G/+ mice at 1 month of age. Wnt pathway genes were predominantly expressed in valve interstitial cells and valve endothelial cells of Fbn1C1039G/+ mice. Inhibition of Wnt signaling in Fbn1C1039G/+ mice at 1 month of age prevented the initiation of MVD as indicated by improved ECM remodeling and reduced valve leaflet thickness with decreased infiltrating macrophages. However, later, Wnt inhibition starting at 2 months did not prevent the progression of MVD. Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation but is not responsible for later-stage valve disease progression once it has been initiated. Thus, Wnt signaling contributes to MVD progression in a time-dependent manner and provides a promising therapeutic target for the early treatment of congenital MVD in Marfan syndrome.

Mitral annular disjunction in idiopathic ventricular fibrillation patients: just a bystander or a potential cause?

Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. This retrospective multi-centre study included 185 IVF patients [median age 39 (27, 52) years, 40% female]. Cardiac magnetic resonance images were analyzed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD (42 vs. 2%, P < 0.001). Pro-arrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67 vs. 23%, P < 0.001 and 63 vs. 41%, P = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13 vs. 18%, P = 0.579). A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay.

Rheumatic heart disease presenting with paracentral acute middle maculopathy (PAMM): A case report from rural India

A 38-year-old gentleman presented to us with disturbance in his superior field of view for 3 days. His visual acuity in both eyes was 6/6, N6. The macula of the left eye had a hypopigmented band. OCT demonstrated hyperreflectivity of the inner plexiform, inner nuclear, and outer plexiform layers of the retina, and perimetry showed a corresponding visual field defect. The patient revealed a history of heart surgery 26 years ago, and an echocardiogram revealed mitral valve abnormalities. The history and findings led to a diagnosis of paracentral acute middle maculopathy (PAMM) secondary to rheumatic heart disease. The patient was referred to a cardiologist and started on anti-platelet medications. Thus, we report an unusual case of PAMM due to chronic rheumatic heart disease in a young male from remote rural India. In our case, we made sure to start the patient on anti-platelet medications to prevent future adverse events.

Mitral Valve Abnormalities Associated with Single-Ventricle Palliation, Cardiac Death or Transplant in Fetuses with Postnatally Confirmed Coarctation of the Aorta.

Predicting if a fetus with borderline left heart structures and coarctation of the aorta (CoA) will require single ventricle palliation (SVP) is challenging, partly due to the limitations of fetal echocardiography in defining valvar abnormalities. Fetal echocardiographic findings predictive of SVP, particularly in relation to the mitral valve (MV), are not well defined. We performed a retrospective review of fetuses with postnatally confirmed CoA from 2010 to 2020. Fetuses with complex congenital heart disease or unequivocal hypoplastic left heart syndrome were excluded. Data were compared between those who underwent biventricular repair (BVR) versus SVP, cardiac death or orthotopic heart transplant (OHT) to determine differences in fetal echocardiograms. Of 67 fetuses with 131 total echocardiograms, 62 (93%) underwent BVR and 5 (7%) experienced SVP, cardiac death or OHT. Fetuses with confirmed CoA who experienced SVP, cardiac death, or OHT, had fetal MV z-scores that were 2.03 lower, on average, than those who underwent BVR (z-score = - 3.98 vs. - 1.94, 95% CI - 2.93, - 1.13). The incidences of MV anomalies and left to right flow across the foramen ovale were higher in the SVP, cardiac death and OHT group. SVP, cardiac death or OHT in fetuses with confirmed CoA were associated with severe fetal MV hypoplasia, MV anomalies and left to right flow across the foramen ovale. These findings may help guide prenatal counseling about the likelihood of SVP, cardiac death or OHT in fetuses with CoA and borderline left heart structures.

Mutation in PDGFRbeta: a potential new pathogenic variant for mitral valve prolapse

Abstract Background Mitral valve prolapse (MVP) due to myxomatous degeneration is characterized by familial clustering, but few pathogenic genes have been identified. In a genetic screening program for MVP patients, we identified a platelet-derived growth factor receptor β (PDGFRβ)-E162K missense variant in a family with a bi-leaflet MVP phenotype in four affected family members. PDGFRβ is a receptor tyrosine kinase, which plays an important role in vascular development. Purpose In this study, we investigated whether the E162K substitution in PDGFRβ could lead to mitral valve abnormalities. Methods To assess the functional effects of the missense variant, proliferation and migration assays were performed using HeLa cells overexpressing wild-type (WT) or mutant PDGFRβ. Immunostainings were performed to determine PDGFRβ expression in the diseased valves from a family member undergoing surgical operation and from additional patients operated for MVP. Mouse models were created with the mouse equivalent of the human PDGFRβ-E162K variant (PDGFRβ-E161K) using CRISPR/CAS9. The variant was not lethal and a total of 12 homozygous PDGFRβ-E161K-/- mice, 11 heterozygous PDGFRβ-E161K+/- mice, and 7 WT mice were subjected to transthoracic echocardiography. In addition, histology was performed in all 30 mice to detect potential valvular defects. Results Stimulated HeLa cells expressing PDGFRβ-E162K showed reduced proliferation and migration, suggesting a loss of function of the mutant receptor. PDGFRβ was expressed in human diseased mitral valves. Echocardiographic evaluation revealed a significant larger mitral valve annulus diameter in both PDGFRβ-E161K+/- and PDGFRβ-E161K-/- compared to WT (WT: 1.97 mm; PDGFRβ-E161K+/-:2.13, p=0.031; PDGFRβ-E161K-/-: 2.42 mm, p&amp;lt;0.0001). Histological data in PDGFRβ-E161K-/- mice showed significant leaflet thickening in the free edge (FE) of the posterior mitral valve leaflet (PMVL) compared to WT (WT: 72.34 ɥm; PDGFRβ-E161K-/-: 109.6 ɥm, p=0.040) and a larger leaflet area of the PMVL compared to WT (WT: 25280 ɥm²; PDGFRβ-E161K-/-: 44494 ɥm², p=0.020). Moreover, an altered organization of the extracellular matrix reminiscent of the myxomatous degeneration in MVP was observed. Conclusions The PDGFRβ-E162K variant is associated with familial MVP and alters the function of PDGFRβ. Mice harboring this mutation display mitral valve defects and can be used as a model for mitral valve disease.

Abstract 17646: Maternal and Neonatal Outcomes in Pregnant Women With Congenital Heart Disease: The Magee Obstetric Maternal and Infant (MOMI) ACHD Substudy

Introduction: Adult patients with congenital heart disease (ACHD) have a life-long burden of cardiovascular morbidity that contributes to increased maternal and neonatal risk during pregnancy and the peripartum period. Hypothesis: Women with ACHD and their neonates have a higher risk of adverse pregnancy and peripartum outcomes as compared to women without ACHD. Methods: We matched 565 deliveries from women with ACHD and 1130 deliveries from women without cardiac disease (1:2 matching), for a delivery year, race and maternal age as a substudy of the Magee Obstetric Maternal and Infant (MOMI) study, of women who received perinatal care at the Magee-Womens Hospital at the University of Pittsburgh Medical Center between 1995-2020. We evaluated for in-hospital maternal and neonatal outcomes. Results: Of the 565 women with ACHD, 24.0% had aortic outflow and mitral valve abnormalities, 19.5% had pulmonary outflow and tricuspid valve abnormalities, 28.1% had isolated atrial or ventricular septal defects, 0.3% had single ventricle physiology, and 1.4% had outflow vessel abnormalities. Maternal and neonatal outcomes are summarized in Table 1. Women with ACHD had a higher rate of pregnancy loss (32.4% vs 26.2% p&lt;0.001), induction of labor, and cesarean section. Neonates from ACHD women were delivered at an earlier gestational age, with a lower birth weight, and had a higher incidence of respiratory distress syndrome. ACHD women had a higher incidence of cardiovascular events (predominantly arrhythmias and pulmonary edema) and required intensive care more frequently (10.5% vs 1.2%, p&lt;0.001) and for longer periods (2.1±1.8 vs. 1.1±0.3 days; P=0.027) after delivery. Conclusion: Women with ACHD are at higher risk for adverse clinical outcomes during pregnancy and delivery. Neonates of ACHD women are delivered slightly earlier by induction of labor and have consequent sequelae after birth.

Abstract 15521: Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Congenital Myxomatous Valve Disease

Introduction: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to cardiac dysfunction and heart failure. MVD in a mouse model of Marfan syndrome (MFS) includes valve leaflet thickening and increased immune cell infiltration. However, the underlying mechanisms by which immune cells are recruited in MFS valves remain undefined. Hypothesis: Inhibition of Wnt signaling prevents MVD progression in MFS valves. Methods: Mice with the Fibrillin 1 variant Fbn1 C1039G/+ recapitulate histopathological features of MFS and Wnt signaling activity was detected in TCF/Lef-lacZ reporter mice. Single-cell RNA sequencing was performed from mitral valves of WT and Fbn1 C1039G/+ mice at 1 month-of-age. Inhibition of Wnt signaling was achieved by conditional induction of Wnt inhibitor Dkk1 in valve interstitial cells of Fbn1 C1039G/+ ; Periostin-Cre; tetO-Dkk1; R26-rtTA mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for immune cells were performed. Results: Wnt signaling pathway gene expression is activated early in mitral valve disease progression, prior to immune cell infiltration in Fbn1 C1039G/+ mice. Single cell transcriptomics revealed similar mitral valve cell heterogeneity between WT and Fbn1 C1039G/+ mice at 1 month-of-age. Wnt ligands and responsive genes were predominantly increased in valve interstitial cells and valve endothelial cells of Fbn1 C1039G/+ mice. Inhibition of Wnt signaling by Dkk1 induction at 1 month-of-age prevented the initiation of MVD as indicated by reduced valve leaflet thickness with decreased CD45+ leukocytes and CCR2+ immune cells in Fbn1 C1039G/+ mice. However, later Wnt inhibition starting at 2 months when inflammation and myxomatous changes are occurring did not prevent the progression of MVD. Conclusions: Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation, but is not responsible for valve disease progression once it has been initiated. Thus, Wnt signaling inhibition prevents initiation of congenital MVD, which provides a promising therapeutic target for the early treatment of congenital MVD.

Mitral valve repair using leaflet expansion and subpartial annuloplasty in children

ObjectiveMitral valve reconstruction in the pediatric population is a challenge due to the frequent combination of annular dilatation and leaflet restriction and the need for growth. We present a novel strategy using leaflet expansion and subpartial annuloplasty with polytetrafluoroethylene reinforcement. MethodsFrom January 2014 through May 2021, 11 children aged 5 months to 14 years (median, 24 months) underwent elective mitral valve repair due to severe mitral valve regurgitation. The mitral valve abnormalities included congenital malformations (n = 7), postoperative leakage following commissurotomy (n = 1), and functional mitral valve regurgitation due to dilated cardiomyopathy (n = 3). Surgery consisted of leaflet expansions with autologous, untreated pericardium and subpartial annuloplasty with polytetrafluoroethylene reinforcement. ResultsAll children survived their surgeries with uneventful postoperative courses, except for 1 patient who needed an early reoperation to resolve a functional stenosis due to a spinnaker phenomenon. At discharge, mean gradient was 3.5 ± 3.9 mm Hg, with trivial mitral regurgitation in 9 patients (82%). All patients were alive and asymptomatic during the median follow-up of 3 years (range, 1-7 years). Their echocardiographic data showed a mean transmitral gradient of 4.4 ± 1.7 mm Hg and remained unchanged. Residual mitral valve regurgitation was trivial or mild in 9 patients (82%) and moderate in 2 patients (18%). ConclusionsLeaflet expansion with autologous pericardium and subpartial annuloplasty with polytetrafluoroethylene reinforcement for mitral regurgitation in the pediatric population gives stable and satisfactory results both early and at intermediate follow-up, permitting growth of the mitral valve.

Left posterior fascicular block and its relation to mitral valve abnormalities: a forgotten finding

Left posterior fascicular block and its relation to mitral valve abnormalities: a forgotten finding

Obstructive hypertrophic cardiomyopathy: a review of new therapies.

Hypertrophic cardiomyopathy (HCM) is a phenotypically heterogeneous disease with a genetic basis and variable penetrance. The hallmarks of HCM include dynamic left ventricular outflow tract obstruction, typically caused by asymmetric septal hypertrophy. However, abnormal papillary muscle placement, abnormal mitral valve and subvalvular apparatusand apical hypertrophic forms have also been described. Typical medical treatment has been stagnant for decades, although there have been significant advances in surgical treatment of patients with obstructive HCM. Herein, we describe a new class of drugs targeting the specific pathophysiology of HCM.

Prenatal diagnosis of hypoplastic left heart syndrome: current knowledge.

Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left-sided heart structures. The prenatal diagnosis of this congenital heart disease is crucial because a newborn with undiagnosed HLHS often presents with clinical signs of low cardiac output once the ductus arteriosus begins to close. With that in mind, the aim of this article was to perform a non-systematic review focusing on the key ultrasound features that can be used in the prenatal diagnosis of HLHS. Severe forms of HLHS are characterized by a markedly abnormal four-chamber view of the fetal heart (small left atrium, hypoplastic left ventricle, or abnormal mitral valve). The left ventricular outflow tract view allows the degree of hypoplasia in the tract to be evaluated and the diameter of the ascending aorta to be measured. The Z-scores are intended to aid in the diagnosis and follow-up of HLHS. In mild forms of HLHS, a right ventricle/left ventricle length ratio > 1.28 was the strongest predictor of a univentricular outcome.

Three-dimensional Echocardiography during Percutaneous Mitral Balloon Valvuloplasty

Percutaneous mitral balloon valvuloplasty (PMBV) has been frequently used as an alternative to open or closed surgical mitral commissurotomy for the treatment of selected patients with symptomatic rheumatic mitral stenosis. PMBV has been proven a safe and effective method, often performed under fluoroscopic guidance. With the advent of three-dimensional echocardiography (3DE), interventional cardiologists have been able to successfully perform complex procedures such as paravalvular leak closure, transcatheter edge-to-edge repair of the mitral valve (MV) using MitraClip, etc. With the expertise derived from these procedures, 3DE has received considerable interests in many other procedures, including PMBV. Pre-, intra-, and postprocedural assessments of the mitral valve (MV) area; commissural splitting; the presence, degree, and location of mitral regurgitation; and other procedure-related complications can be more accurately and readily made using 3DE. In addition, real-time 3D transesophageal echocardiography has been proven to be more accurate than two-dimensional (2D) techniques in identifying specific MV abnormalities associated with complex diseases. Moreover, real-time 3DE offers the advantage of shorter fluoroscopy and radiation times throughout PMBV. This article reviews the use of 3DE during PMBV in light of the most recent literature and based on expertise and discusses the pros and cons of 3DE, with emphasis on its superiority to conventional 2D echocardiography.

Mitral Valve in Obstructive Hypertrophic Cardiomyopathy: Abnormalities, Management and Controversies.

Obstructive hypertrophic cardiomyopathy (obstructive HCM) is a hereditary disease characterized by septal hypertrophy and dynamic left ventricular outflow tract (LVOT) obstruction. Other than septal hypertrophy, mitral valve abnormalities are also quite common in patients with obstructive HCM, which may contribute to systolic anterior motion (SAM) of the mitral valve and LVOT obstruction. Surgical myectomy is the standard treatment to achieve anatomic correction of obstructive HCM, but controversies remain on whether and how the mitral valve procedures should be performed at the same time. In this review, we first described the mitral valve abnormalities in patients with obstructive HCM and their surgical corrections, we then explained the controversies based on current clinical studies, and we finally made a brief introduction on our surgical strategy and results.

Abstract P1012: Wnt Signaling Is Required For Myxomatous Valve Disease In A Mouse Model Of Marfan Syndrome

Introduction: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome (MFS) includes valve leaflet thickening and increased immune cell infiltration. However, the underlying mechanisms by which immune cells are recruited in MFS valves remain undefined. Hypothesis: Inhibition of Wnt signaling prevents immune cell recruitment and MVD progression in MFS valves. Methods: Mice with the mutation of Fibrillin 1 ( Fbn1 C1039G/+ ) recapitulate histopathological features of MFS and Wnt signaling activity was detected in TCF/Lef-lacZ reporter mice. The expression level of C-C motif chemokine ligand 2 (CCL2) was detected in Fbn1 C1039G/+ mice by qPCR and RNAscope. Inhibition of Wnt signaling was achieved by conditional induction of the soluble Wnt inhibitor Dkk1 in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1 C1039G/+ mice. Dietary doxycycline was administered for one month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for immune cells were performed. Results: Wnt signaling as detected by TCF/Lef-lacZ reporters and CCL2 expression were upregulated early in mitral valve disease progression, prior to immune cell infiltration in Fbn1 C1039G/+ mice. Inhibition of Wnt signaling by Dkk1 induction at 1-month of age prevented the induction of myxomatous mitral valve disease, indicated by reduced valve leaflet thickness with decreased CD45+ leukocytes and CCR2+ immune cells in Fbn1 C1039G/+ mice. However, later Wnt inhibition starting at 2 months when inflammation and myxomatous changes are occurring did not prevent the progression of myxomatous mitral valve disease. Conclusions: Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation, but is not responsible for valve disease progression once it has been initiated.

The incidence and interrelationship of hemivertebra and concomitant cardiac abnormalities in congenital scoliosis

BackgroundCongenital scoliosis(CS) is associated with multiple organs defect, and cardiac abnormalities have been reported commonly associated with CS. Hemivertebra is caused by the failure of vertebral formation, which is a major constitute of CS. Till now, few studies focus on the incidence and interrelationship of hemivertebra and concomitant cardiac abnormalities in congenital scoliosis. We aimed to analyze the cardiac defect in CS patients with or without hemivertebra, and further explore the incidence of cardiac defect between different types of hemivertebra.MethodsThe ultrasonic cardiography (UCG) results of surgically treated congenital scoliosis (CS) patients between 2015 and 2018 were retrospectively analyzed. Patients were divided into hemivertebra group and non-hemivertebra group according to preoperative CT. Patients with hemivertebra was further divided into sub-group by single/multiple or fully/partially/mixed segmented hemivertebra. Demographic information, radiographic data and cardiac abnormalities were statistically compared between groups.ResultsA total of 329 patients were analyzed, including 216 patients with hemivertebra and 113 patients without hemivertebra. UCG results were abnormal in 89 cases (27.1%), including 41 males(12.5%) and 48 females(14.6%). Hemivertebra group had comparable incidence of cardiac abnormalities with non-hemivertebra group (p = 0.517). No significant difference in the incidence of UCG abnormalities between single and multiple hemivertebra group (P = 0.246). Binary logistic regression analysis showed that female sex with multiple hemivertebra was a risk factor for abnormal UCG (P = 0.009, OR = 3.449). Cardiac abnormalities was comparable among fully, partially and mixed segmented hemivertebra group(P = 0.264). In abnormal UCG, 33 patients with hemivertebra had non-valvular abnormalities, and 48.5% (16/33) were septal defects. 28 patients had valvular abnormalities, most of them were mitral valve abnormalities, especially mitral valve redundancy, prolapse and insufficiency(82.1%, 23/28). No significant difference between the incidence of non-valvular and valvular abnormalities in patients with hemivertebra (P = 0.581).ConclusionsThe incidence of abnormal UCG results was approximately 28.2% in CS patients with hemivertebra. Female patients with multiple hemivertebra had a higher risk of UCG abnormalities. Mitral valve abnormalities were the most common abnormality of UCG found in CS patients with hemivertebra.Trial registrationretrospectively registered.

Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction

BackgroundMitral annular disjunction (MAD) is an under-recognised phenotype associated with severe ventricular arrhythmias. Limited knowledge has been gained on its molecular genesis.MethodsA total of 150 unrelated deceased Chinese were collected...

Is There a Role for Alcohol Septal Ablation in Young Patients with Medically Refractory Hypertrophic Obstructive Cardiomyopathy?

Surgical myectomy is recommended for symptomatic hypertrophic obstructive cardiomyopathy (HOCM) after optimal pharmacological therapy. Percutaneous transluminal septal myocardial ablation (PTSMA) is reserved for high-risk adults. Symptomatic patients below 25years underwent either surgery or PTSMA after heart-team discussion and informed consent. Echocardiography assessed gradients in surgical group. PTSMA group underwent invasive transseptal hemodynamic assessment, selective coronary angiography and super-selective cannulation of septal perforators using microcatheters. Contrast echocardiography through the microcatheter identified the myocardial target for PTSMA. Hemodynamic and electrocardiographic monitoring guided alcohol injection. Both groups were continued on beta-blockers. Symptoms, echocardiographic gradients and Brain natriuretic peptide (NTproBNP) measurements were assessed on follow-up. Twelve patients aged 5-23years (11-98kg) formed the study group. Indications for PTSMA in 8 patients included abnormal mitral valve anatomy warranting replacement (n = 3), Jehovah's witness (n = 2), severe neurodevelopmental and growth retardation (n = 1) and refusal of surgery (n = 2). PTSMA targeted first perforator (n = 5), second perforator (n = 2) and anomalous septal artery from left main trunk (n = 1). Outflow gradient reduced from 92.5 ± 19.7 to 33.1 ± 13.5mmHg. At a median follow-up of 38months (range 3-120weeks), the peak instantaneous echocardiographic gradient was 32 ± 16.5mmHg. Gradient reduced in four surgical patients from 86.5 ± 16.3mmHg to 42 ± 14.7mm Hg. All patients were in NYHA class I/II on follow-up. The mean NTproBNP in PTSMA group reduced from 6084 ± 3628pg/ml to 3081 ± 2019pg/ml; it was 1396 and 1795pg/ml in surgery. PTSMA may be considered in medically refractory high-risk young patients. It relieves symptoms and reduces gradient. Though surgery is preferred in young patients, PTSMA may have a role in selected patients.