Myxomatous Disease Research Articles

Arrhythmic Mitral Valve Prolapse Syndrome and Ventricular Arrhythmias: A Comprehensive Review and the Role of Catheter Ablation.

Mitral valve prolapse (MVP) affects 2-3% of the general population, and despite its benign prognosis overall, it is associated with sudden death in a small subset of patients. The term "arrhythmic MVP syndrome" (AMVPS) refers to the presence of frequent or complex ventricular arrhythmias, commonly reported in female patients with a stereotypical phenotype including bileaflet myxomatous disease, ECG repolarisation abnormalities in inferior leads, mitral annular disjunction, and significant fibrosis in the inferolateral LV and papillary muscles. Modern imaging technologies have led to the identification of new risk factors that have been implemented in recent risk stratification guidelines; however, screening for patients with MVP who are at risk of sudden cardiac death (SCD) remains challenging. In addition, there is a limited amount of data on the outcomes of different treatment approaches in AMVP and no specific indication for targeted or disease-modifying therapies within current guidelines. Potential arrhythmic substrates in patients with AMVP syndrome have been the subject of interest in previous studies, with areas consisting of fibrosis at the papillary muscle level and the Purkinje system. Premature ventricular contractions (PVCs) originating from these areas have been shown to play an important role as triggers for ventricular fibrillation and SCD in patients with AMVP. Catheter ablation has emerged as a potential treatment modality in patients with MVP and ventricular arrhythmias (VAs), targeting arrhythmic substrates and triggering PVC foci. The aim of this review is to explore the role of catheter ablation in treating patients with AMVP.

Computed tomographic analysis of the morphometrics and dynamics of the tricuspid annulus in secondary functional tricuspid regurgitation

ObjectivesSecondary functional tricuspid regurgitation (FTR) management remains controversial mainly due to the lack of knowledge in its pathogenesis and the difficulties to measure the actual dimensions of tricuspid annulus (TA) with current imaging methods. Using a novel method based on multiphase cardiac computed tomography (CT) scan acquisition to accurately analyze the right atrioventricular junction size, we sought to explore modifications of TA morphometry and dynamics in secondary FTR. MethodsEchocardiographic and cardiac CT studies were obtained from 21 patients with severe mitral regurgitation (MR group) and 21 patients with dilated cardiomyopathy (DCMP group). Using an in-house software, a 3-dimensiontal (3D) semiautomated delineation of the TA perimeter was assessed. Modifications of diameters, 2-dimensional/3D areas and perimeters were analyzed through time. These 2 groups of patients were compared with 30 healthy subjects, considering the presence of a significant (≥2+) versus nonsignificant (<2+) FTR in each group. ResultsMaximum TA 3D areas were 7.0 ± 1.2 cm2/m2 in healthy subjects at mid-to-late diastole and were smaller than in the MR group (9.8 ± 2.1 cm2/m2, P < .001) and the DCMP group (9.2 ± 3.0 cm2/m2, P < .001). In the MR group, patients with FTR <2+ had also larger TA areas and diameters than healthy patients (P < .01 for all 3D/2-dimensional parameters). TA shape was more circular only in the DCMP group with FTR ≥2+ compared with other patients (P < .05 for eccentricity). In multivariate analysis, both RA area (P < .001) and RV volume (P = .002) were independently related to TA dilatation. ConclusionsBased on multiphase CT image analyses, TA dilatation was directly related to RV and RA enlargement. Patients with severe mitral myxomatous disease and nondysfunctional tricuspid valve had yet dilated TA, which questioned the current cut-off recommendation for concomitant tricuspid annuloplasty in this specific population.

Mitral Valve Operation After Tetralogy of Fallot Repair: Early and Late Outcomes

BackgroundThere is a paucity of data regarding reoperation for mitral valve (MV) disease after tetralogy of Fallot (TOF) repair. We aimed to characterize this population and to analyze outcomes. MethodsPatients with TOF who underwent mitral surgery between January 1971 and December 2020 at Mayo Clinic were reviewed retrospectively. Among 1278 patients who underwent reoperations after TOF repair, 23 (1.8%) had MV surgery and formed the final cohort. ResultsMedian age at MV operation was 52 years (interquartile range, 29.5 years), and time between TOF repair and MV operation was 25.2 years (interquartile range, 37 years). One patient (4.3%) was <18 years old. More than half of patients had ≥2 prior sternotomies. All had severe mitral regurgitation (MR); the most common cause was degenerative/prolapse (n = 17 [73.9%]). The pathologic process was anterior leaflet prolapse (n = 7 [30.4%]), bileaflet (n = 5 [21.7%]), posterior leaflet (n = 1 [4.3%]), or myxomatous change without prolapse (n = 3 [13%]). MV replacement was performed in 13 patients (56.5%) and MV repair in 10 (43.5%), typically using flexible partial annuloplasty bands. Concomitant procedures were performed in 19 patients (82.6%). Early death (within 30 days) occurred in 2 patients (8.7%). During median follow-up of 16.9 months, 6 patients (23.1%) underwent reoperation, 3 of which were MV replacement for recurrent MR. The 5- and 10-year survival was 64% and 56%, respectively. ConclusionsMR after TOF repair is uncommon and rarely occurs in isolation. The most common cause is myxomatous disease from anterior or bileaflet prolapse, and MV replacement is often required. Operative risk and need for reoperation are high and late survival is poor.

Echocardiographic description and outcomes in a heterogeneous cohort of patients undergoing mitral valve surgery with and without mitral annular disjunction: a health service evaluation

BackgroundMitral annular disjunction (MAD) is a structural abnormality characterized by the distinct separation of the mitral valve annulus/left atrium wall and myocardium. Little is known about the significance of MAD in patients requiring mitral valve surgery. This evaluation evaluates the echocardiographic characteristics and patient outcomes for patients with and without MAD who require mitral valve surgery.MethodsAll patients who underwent mitral valve surgery and who had a pre-surgical transthoracic echocardiogram between 2013 and 2020 were included. Patient demographics and clinical outcomes were collected on review of patient electronic records.ResultsA total of 185 patients were included in the analysis of which 32.4% had MAD (average MAD length 8.4 mm). MAD was seen most commonly in patients with mitral valve prolapse and myxomatous mitral valves disease (90% and 60% respectively). In the patients with MAD prior to mitral valve surgery, only 3.9% had MAD post mitral valve surgery. There were no significant difference in the severity of post-operative mitral regurgitation, arrhythmic events or major adverse cardiovascular events in patients with and without MAD.ConclusionsMAD is common in patients who undergo mitral valve surgery. Current surgical techniques are able to correct the MAD abnormality in the vast majority of patients. MAD is not associated with an increased risk of adverse clinical outcomes post mitral valve surgery.

Leaflet plication with neochordae implantation: A novel technique for mitral valve repair.

Leaflet plication with neochordae implantation: A novel technique for mitral valve repair.

Genetic background of mitral valve prolapse

Mitral valve prolapse (MVP) has a prevalence of 2-3% among the population. It involves a heterogeneous group of patients with different expressions and according to the phenotype can be further divided into fibroelastic deficiency, which is mainly considered as a degeneration due to aging, and myxomatous disease, frequently associated with familiar clusters. Thus, MVP can be present in syndromic, when part of a well-defined syndrome, and non-syndromic forms. The latter occurs more often. To the second belong both familiar and isolated or sporadic forms. On one hand, among familial forms, although X-linked transmission related to FLNA gene was initially identified, further studies reported also autosomal dominant mode involving MVPP genes, including DCHS1. On the other hand, genome-wide association studies (GWAS), among unrelated patients, allowed the identification of new MVP-associated genes, such as LMCD1, GLIS, and TNS1. Moreover, single nucleotide polymorphisms (SNPs) on metalloproteinase genes have been related to MVP. Interestingly some genes such as DCHS1 and DZIP1 have been reported to be involved in both familiar and isolated forms. The present review aims to illustrate the updated genetic background of MVP.

The Mitral Annulus disjunction in mitral valve prolapse: Presentation and outcome

Clinical knowledge regarding mitral annulus disjunction (MAD) of mitral-valve-prolapse (MVP) remains limited, controversial and its potential link with untoward outcomes unsubstantiated. To assess in MVP-patients, MAD prevalence, phenotypic characteristics and long-term outcome (clinical arrhythmic events and excess-mortality). A cohort of 595 (278 female, age 61 ± 16 years) consecutive patients with isolated MVP, with comprehensive clinical, rhythmic, Doppler-echocardiographic and consistent MAD assessment, was examined. MAD prevalence, associated MVP-phenotype and outcome (survival, clinical arrhythmic events) were analyzed in overall and matched cohort. MAD presence was common (186–31%) in MVP, generally in younger patients and independently associated with severe myxomatous disease ( P ≤ 0.0002). MAD presence was also independently associated with larger left ventricle ( P = 0.005). Age-matched-cohort survival after MVP diagnosis was not worse with MAD (10-year 93 ± 2% for no-MAD and 97 ± 1% for MAD, P = 0.4), even adjusted-comprehensively for MVP characteristics ( P = 0.8). During follow-up, 170 patients had clinical arrhythmic events [ventricular tachycardia-VT ( n = 159), arrhythmia ablation ( n = 14), Cardioverter-defibrillator implantation ( n = 14) and sudden cardiac death ( n = 3)]. MAD was independently associated with higher risk of arrhythmic events [adjusted-hazard-ratio 2.60(1.87–3.62), P < 0.0001]. MAD link to arrhythmic events was weaker post-mitral-surgery [adjusted-hazard-ratio 2.07 (1.24–3.43), P = 0.005] ( Fig. 1 ). MAD is frequent at MVP diagnosis and strongly linked to advanced-myxomatous-degeneration. MAD presence is independently associated with long-term excess-incidence of clinical arrhythmic events. However, within the first 10 years post-diagnosis MAD is not linked to excess-mortality and while reassurance should be provided from the survival point of view, careful monitoring for arrhythmias is in order with MAD.

438 Appearances are deceiving

Abstract Aims Mitral valve prolapse (MVP) is frequently found in the population (3% prevalence). MVP prognosis is generally benign; however, malignant arrhythmias and increased risk of arrhythmic sudden cardiac death (0.2% to 0.4% per year) was described in patients, usually female, mostly affected by bileaflet myxomatous disease, mid-systolic click, ripolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. The actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. Methods Z.T. is a 32 years old woman who was admitted to the Emergency Department (ED) with left arm and face paraesthesia. She also reported having suffered from migraine and hypertension a few days earlier. ECG: normal sinus rhythm, no ripolarization abnormalities. CT and MRI were executed to rule out cerebral ischaemic events and both resulted negative. No SCD was reported in the anamnesis and the patient denied syncopal and pre-syncopal episodes. Z.T. had undergone cardiologic examination for tachycardia 2 years before the present events, during her second pregnancy (she produced no documentation to this effect). No chronic therapy. Low blood pressure at home. Due to the patient’s cardiologic history, ECG monitoring was performed, evidencing frequent premature ventricular beats (PVBs), some couples, and triplets. Cardiologic evaluation was requested. On Echocardiogram: Normal bi-ventricular function. Bileaflet mitral valve prolapse with myxomatous degeneration. Minimal valve regurgitation. Mitral annulus disjunction. TE echocardiogram: no PFO. Nadolol 20 mg was prescribed and after 24 h of observation the patient was discharged, scheduling Holter ECG, cardiac MRI and arrhythmologic evaluation. Results One month later, the patient reported intolerance to nadolol due to hypotension and pre-syncopal episodes during postural changes. Holter ECG revealed: polymorphic PVBs (2009), couples (383), triplets (40). Cardiac MRI: mitral valve prolapse (11 mm), mitral annulus disjunction (8mm) systolic curling (3mm). No LGE. No oedema. Nadolol was discontinued and substituted with bisoprolol 2.5 mg. Physical activity was discouraged; Ergometric test and Holter ECG were ordered under treatment with bisoprolol. The Ergometric test revealed reduced extrasystolia during physical effort, isolated PVBs and some couples during recovery. Holter ECG revealed continuing isolated PVBs (980) and some couples (37). No complex arrhythmia. Conclusion Z.T. is affected by an arrhythmic MVP syndrome characterized by complex PVBs, mitral annular disjunction, and systolic curling, which have been described by pathological and cardiac magnetic resonance studies in sudden death victims. However, Z.T. is asymptomatic: no ECG ripolarization abnormalities at rest and good response to medical therapy with β-blockers. Our patient strategy was conservative and we decided to follow up with trimestral cardiologic evaluation and Holter ECG. Further research is needed to best identify high-risk patients and suggest treatments aimed to prevent sudden death.

Mitral Valve Surgery via Upper Ministernotomy: Single-Centre Experience in More than 400 Patients.

Background: Minimally invasive mitral valve (MV) surgery has emerged as an alternative to conventional sternotomy aiming to decrease surgical trauma. The aim of the study was to describe our experience with minimally invasive MV surgery through partial upper sternotomy (PUS) regarding short- and long-term outcomes. Methods: From January 2004 through March 2014, 419 patients with a median age of 58.9 years (interquartile range 18.7; 31.7% females) underwent isolated primary MV surgery using PUS. Myxomatous degenerative MV disease was the predominant pathology (77%). The patients’ mean EuroSCORE II risk profile was 3.9 ± 3.6%. Results: Mitral valve repair was performed in 384 patients (91.6%) and replacement in 35 patients (8.4%). Thirty-day mortality was 3.1%. In total, 29 (6.9%) deaths occurred during the follow-up. The overall estimated survival at 1, 5, and 10 years was 93.1 ± 1.3%, 87.1 ± 1.9%, and 81.1 ± 3.4%. Reoperation was necessary in 14 (3.3%) patients. The overall freedom from MV reoperation at 1, 5, and 10 years was 98.2 ± 0.7%, 96.1 ± 1.2%, and 86.7 ± 6.7% and the overall freedom from recurrent MV regurgitation > grade 2 in repaired valves at 1, 5, and 10 years was 98.8 ± 0.6%, 98.8 ± 0.6%, and 94.6 ± 3.3%. Conclusions: Minimally invasive MV surgery via PUS can be performed with particularly good early and late results. Thus, the PUS approach with the use of standard surgical instruments and cannulation techniques can be a valuable option for the MV surgery either in patients contraindicated or not suitable to minithoracotomy.

The Mitral Annular Disjunction of Mitral Valve Prolapse: Presentation and Outcome

ObjectivesThe aim of this study was to assess in patients with mitral valve prolapse (MVP) mitral annular disjunction (MAD) prevalence, phenotypic characteristics, and long-term outcomes (clinical arrhythmic events and excess mortality). BackgroundClinical knowledge regarding MAD of MVP remains limited and controversial, and its potential link with untoward outcomes is unsubstantiated. MethodsA cohort of 595 (278 women, mean age 61 ± 16 years) consecutive patients with isolated MVP, with comprehensive clinical, rhythmic, Doppler echocardiographic, and consistent MAD assessment, were examined. MAD prevalence, associated MVP phenotypes, and outcomes (survival, clinical arrhythmic events) starting at diagnostic echocardiography were analyzed. To balance important baseline differences, propensity scoring matching was conducted among patients with and those without MAD. ResultsThe presence of MAD was common (n = 186 [31%]) in patients with MVP, generally in younger patients, and was not random but was independently associated with severe myxomatous disease involving bileaflet MVP and marked leaflet redundancy (both P ≤ 0.0002). The presence of MAD was also independently associated with a larger left ventricle (P = 0.005). Age-matched cohort survival after MVP diagnosis was not worse with MAD (10-year survival 93% ± 2% for patients without MAD and 97% ± 1% for those with MAD; P = 0.40), even adjusted comprehensively for MVP characteristics (P = 0.80) and accounting for time-dependent mitral surgery (P = 0.60). During follow-up, 170 patients had clinical arrhythmic events (ventricular tachycardia, n = 159; arrhythmia ablation, n = 14; cardioverter-defibrillator implantation, n = 14; sudden cardiac death, n = 3). MAD was independently associated with higher risk for arrhythmic events (adjusted HR: 2.60; 95% CI: 1.87-3.62; P < 0.0001). The link between MAD and arrhythmic events persisted with time-dependent mitral surgery (adjusted HR: 2.54; 95% CI: 1.84-3.50; P < 0.0001), was strong under medical management (adjusted HR: 3.21; 95% CI: 2.03-5.06; P < 0.0001) but was weaker after mitral surgery (adjusted HR: 2.07; 95% CI: 1.24-3.43; P = 0.005). ConclusionsThis large cohort with MVP comprehensively characterized shows that MAD is frequent at MVP diagnosis and is strongly linked to advanced myxomatous degeneration. The presence of MAD was independently associated with long-term excess incidence of clinical arrhythmic events. However, within the first 10 years post-diagnosis, MAD was not linked to excess mortality, and although reassurance should be provided from the survival point of view, careful monitoring for arrhythmias is in order for MAD.

Role of the Epicardium in the Development of the Atrioventricular Valves and Its Relevance to the Pathogenesis of Myxomatous Valve Disease.

This paper is dedicated to the memory of Dr. Adriana “Adri” Gittenberger-de Groot and in appreciation of her work in the field of developmental cardiovascular biology and the legacy that she has left behind. During her impressive career, Dr. Gittenberger-de Groot studied many aspects of heart development, including aspects of cardiac valve formation and disease and the role of the epicardium in the formation of the heart. In this contribution, we review some of the work on the role of epicardially-derived cells (EPDCs) in the development of the atrioventricular valves and their potential involvement in the pathogenesis of myxomatous valve disease (MVD). We provide an overview of critical events in the development of the atrioventricular junction, discuss the role of the epicardium in these events, and illustrate how interfering with molecular mechanisms that are involved in the epicardial-dependent formation of the atrioventricular junction leads to a number of abnormalities. These abnormalities include defects of the AV valves that resemble those observed in humans that suffer from MVD. The studies demonstrate the importance of the epicardium for the proper formation and maturation of the AV valves and show that the possibility of epicardial-associated developmental defects should be taken into consideration when determining the genetic origin and pathogenesis of MVD.

The mitral annulus disjunction of mitral valve prolapse: Presentation and outcome

To assess in MVP-patients, MAD prevalence, phenotypic characteristics and long-term outcome. A cohort of 595 (278 female, age 61 ± 16 years) consecutive patients with isolated MVP, comprehensive clinical, rhythmic, Doppler-echocardiographic and consistent MAD assessment, was examined. MAD prevalence, associated MVP-phenotype and outcome [survival, ventricular arrhythmias (VA)] were analyzed. To balance important baseline differences, we also propensity score matched patients with and without MAD (no-MAD). MAD presence was common (186 – 31%) in MVP, generally in younger patients and was not random but independently associated with severe myxomatous disease and larger left ventricle ( P ≤ 0.005). Age-matched-cohort survival after MVP diagnosis was not worse with MAD (10-year 93 ± 2% for no-MAD and 97 ± 1% for MAD, P = 0.4), even adjusted-comprehensively for MVP characteristics ( P = 0.8) and accounting for time-dependent mitral-surgery ( P = 0.6). During follow-up, 218 patients were diagnosed with VA post-30 days from MVP diagnosis (159 with ventricular tachycardia-VT). MAD was independently associated with higher risk of VA (adjusted-hazard-ratio 2.39[1.79–3.22]) and VT (2.79[1.98–3.94], both P < 0.0001). MAD link to VA persisted with time-dependent mitral-surgery (adjusted-hazard-ratio 2.25[1.65–3.01], P < 0.0001), strongly under medical-management (adjusted-hazard-ratio 2.91[1.95–4.35], P < 0.0001) but weakly post-mitral-surgery (adjusted-hazard-ratio 1.77[1.12–2.79], P = 0.01). This large cohort with MVP comprehensively characterized, shows that MAD is frequent at MVP diagnosis and strongly linked to advanced-myxomatous-degeneration. MAD presence is independently associated with long-term excess-incidence of VA and VT. However, within the first 10 years post-diagnosis MAD is not linked to excess-mortality and while reassurance should be provided from the survival point of view careful monitoring for arrhythmias is in order with MAD.

P6490Paradoxycal restricted motion in diastole is a frequent finding in mitral valve prolapse/dystrophy patients

Abstract Background Filamin-A mitral valve prolapse/dystrophy (FLNA-MVP) phenotype associates MVP and a paradoxical restricted motion in diastole. Purpose We aim to assess the association of mitral valve prolapse to restricted motion in diastole in MVP patients (restricted MVP). Methods We prospectively enrolled 475 MVP probands (64±13 years) and controls relatives. Patients underwent a clinical examination and a comprehensive echocardiographic analysis of mitral valve apparatus. Results Among 475 consecutive probands, 48 (10.1%, 95% CI 7.7–13.3) had both a MVP and a doming aspect in diastole. Patients with restricted MVP exhibited shorted chordae tendinaes, and a shorter distance between papillary muscle tip and mitral annulus. Compared with controls, mitral valve leaflets were lenghtened, thickened and mitral valve annulus was enlarged. The prevalence of polyvalvular disease and bicuspid aortic valve was not increased in restricted MVP patients compared with conventional MVP. Familial form of restricted MVP was identified even in the absence of Filamin-A mutation. Conclusion Restricted MVP is a quite frequent finding in MVP patients and is associated with unique features of the MV apparatus. Restricted MVP can be regarded as a third type of MVP beside myxomatous Barlow disease and fibro-elastic deficiency MVP. Acknowledgement/Funding PHRC I Mitral, Fédération Française de Cardiologie, Fondation Coeur et recherche

Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death.

Despite a 2% to 3% prevalence of echocardiographically defined mitral valve prolapse (MVP) in the general population, the actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. The clinical profile is characterized by a patient, usually female, with mostly bileaflet myxomatous disease, mid-systolic click, repolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. Among the various pathophysiologic mechanisms of electrical instability, left ventricular fibrosis in the papillary muscles and inferobasal wall, mitral annulus disjunction, and systolic curling have been recently described by pathological and cardiac magnetic resonance studies in sudden death victims and patients with arrhythmic MVP. In addition, premature ventricular beats arising from the Purkinje tissue as ventricular fibrillation triggers have been documented by electrophysiologic studies in MVP patients with aborted sudden death. The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting premature ventricular beats because of a primary morphofunctional abnormality of the mitral valve annulus. The main clinical challenge is how to identify patients with arrhythmic MVP (which imaging technique and in which patient) and how to treat them to prevent sudden death. Thus, there is a necessity for prospective multicenter studies focusing on the prognostic role of cardiac magnetic resonance and electrophysiologic studies and on the therapeutic efficacy of targeted catheter ablation and mitral valve surgery in reducing the risk of life-threatening arrhythmias, as well as the role of implantable cardioverter defibrillators for primary prevention.

The "Paper Roll": A Simple but Useful Tool for Minimal Invasive Mitral Valve Repair Surgery.

During minimal invasive mitral valve repair, excessive valve tissue, as in myxomatous or Barlow disease, might be cumbersome to analyze and treat the subvalvular mitral valve apparatus. We developed a new, adaptive, flexible, and easy-to-use technique for better visualization of the subvalvular apparatus. After visualization of the mitral valve, a simple sterile paper ruler was curled up to a roll 1 cm in diameter and inserted through the mitral valve. By means of two endo forceps, the paper roll was uncurled to the desired diameter, thus pushing the valve leaflets away, allowing for a direct view onto the subvalvular apparatus. This technique was successfully used in 34 consecutive patients (mean ± SD age = 57.2 ± 11.5 years; 22 male). The calculated risk score for additive EuroScore, logistic EuroScore, and EuroScore II was 4 ± 2, 3.2 ± 2.1, and 2.5 ± 5.4, respectively. No patient died within the first 30 days. All patients presented mitral valve insufficiency grade 0 to 1 postoperatively. Artificial chords were implanted in all patients (3.6 ± 1.8 chords per patient). This simple, adaptive, and cheap technique facilitates the approach to the subvalvular apparatus, especially in patients with myxomatous or Barlow disease. The ease of use allows for prompt approach to the papillary muscles and quick removal.

Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves.

During postnatal heart valve development, glycosaminoglycan (GAG)-rich valve primordia transform into stratified valve leaflets composed of GAGs, fibrillar collagen, and elastin layers accompanied by decreased cell proliferation as well as thinning and elongation. The neonatal period is characterized by the transition from a uterine environment to atmospheric O2, but the role of changing O2 levels in valve extracellular matrix (ECM) composition or morphogenesis is not well characterized. Here, we show that tissue hypoxia decreases in mouse aortic valves in the days after birth, concomitant with ECM remodeling and cell cycle arrest of valve interstitial cells. The effects of hypoxia on late embryonic valve ECM composition, Sox9 expression, and cell proliferation were examined in chicken embryo aortic valve organ cultures. Maintenance of late embryonic chicken aortic valve organ cultures in a hypoxic environment promotes GAG expression, Sox9 nuclear localization, and indicators of hyaluronan remodeling but does not affect fibrillar collagen content or cell proliferation. Chronic hypoxia also promotes GAG accumulation in murine adult heart valves in vivo. Together, these results support a role for hypoxia in maintaining a primitive GAG-rich matrix in developing heart valves before birth and also in the induction of hyaluronan remodeling in adults.NEW & NOTEWORTHY Tissue hypoxia decreases in mouse aortic valves after birth, and exposure to hypoxia promotes glycosaminoglycan accumulation in cultured chicken embryo valves and adult murine heart valves. Thus, hypoxia maintains a primitive extracellular matrix during heart valve development and promotes extracellular matrix remodeling in adult mice, as occurs in myxomatous disease.

Non-functional tricuspid valve disease

Only 75% of severe tricuspid regurgitation is classified as functional, or related primarily to pulmonary hypertension, right ventricular dysfunction, or a combination of both. Non-functional tricuspid regurgitation occurs when there is damage to the tricuspid leaflets, chordae, papillary muscles, or annulus, independent of right ventricular dysfunction or pulmonary hypertension. The entities that cause non-functional tricuspid regurgitation include rheumatic and myxomatous disease, acquired and genetic connective tissue disorders, endocarditis, sarcoid, pacing, RV biopsy, blunt trauma, radiation, carcinoid, ergot alkaloids, dopamine agonists, fenfluramine, cardiac tumors, atrial fibrillation, and congenital malformations. Over time, severe tricuspid regurgitation that is initially non-functional, can blend into functional tricuspid regurgitation, related to progressive right ventricular dysfunction. Symptoms and signs, including a falling right ventricular ejection fraction, cardiac cirrhosis, ascites, esophageal varices, and anasarca, may occur insidiously and late, but are associated with substantial morbidity and mortality. Attempted valve repair or replacement at late stages carries a high mortality. Crucial to following patients with severe non-functional tricuspid regurgitation is attention to echo quantification of the tricuspid regurgitation and right ventricular function, patient symptoms, and the physical examination.

Operative Outcomes with Myxomatous Mitral Valve Repair: Experience with 586 Patients

American Heart Association (AHA) guidelines recommend mitral valve repair for myxomatous mitral regurgitation whenever possible to prevent LV dysfunction and early mortality. Here we review our early operative outcomes with mitral valve repair for myxomatous mitral regurgitation. We collected data from 586 consecutive patients that underwent mitral repair for myxomatous disease at the Prince Henry and Prince of Wales Hospitals Sydney between 1997 and 2012. All patients had pre- and postoperative transthoracic echocardiograms. In the first 30 days postoperatively there were five deaths (0.9%), four strokes (0.7%) and five transient ischaemic attacks (TIAs) (0.9%). Repair involved resection in 55.5%, neochordal reconstruction in 41.6%, and in 2.9% a combination of both. There was increasing use of neochordae since 2006. At discharge 99% had mitral regurgitation (MR) ≤ mild and ≤ trivial in 79.5%. For posterior leaflet disease neochordae had improved MR at discharge compared with resection (85% vs 78%, P<0.05). Preoperative triscupid regurgitation (TR) and pulmonary hypertension > mild were associated with a greater degree of MR at discharge (P<0.05) for reasons that are unclear. We have shown excellent early results for mitral repair with very low operative mortality and excellent freedom from significant MR. Successful mitral repairs with low morbidity have resulted in a pattern of early referral in keeping with the current guidelines.

Abstract 32: Mitral Valve Interstitial Cells With the Serotonin Transporter (SERT)-LL Polymorphism are More Efficiently Activated by Serotonin

Prolapse of the Mitral Valve (MV) leaflet is a hallmark of several cardiac disorders such as Myxomatous MV Disease (MMVD) or ischemic MV regurgitation (MR), and is only treated surgically. Elevated levels of serotonin (5HT) have been associated with valvulopathies. Ongoing studies in our laboratory suggest that 5HT signaling plays an important role in the progression of MMVD. In addition, a 44 base polymorphism in the promoter region of the 5HT transporter (SERT) gene, designated as short (S) or long (L) allele, has been reported with Mendelian distribution, with LL resulting in increased 5HT reuptake compared to SS. We hypothesized that patients with MMVD have enhanced 5HT signaling due to a high frequency of SERT-LL. DNA was extracted from 152 MMVD surgical patients, genomic fragment analysis performed to determine allelic frequencies, and a chi-square statistical test completed. We show that surgical patients with MMVD have a higher than expected frequency of SERT-LL (34% (52 of 152) vs. 25%). Notably, the frequency of SERT-LL is particularly enhanced (51% (21 of 41) vs. 25%) (p=0.009) in MMVD patients under 60 years old. Based on these findings, we tested whether MV interstitial cells (MVICs) expressing SERT-LL have increased susceptibility to 5HT-mediated activation. We demonstrate that SERT-LL MVICs respond to 5HT with a 4-fold increase in smooth muscle actin (SMA) mRNA expression, a marker of VIC activation, compared to a less than 1-fold increase in SERT-LS and SERT-SS cells. The SMA response is abrogated by specific pharmacological inhibitors of the 5HT receptors 5HTR2A and 5HTR2B, and SERT, as well as siRNA knockdown. Studies of 5HTR expression in cells of each genotype are in progress. Due to the enhanced frequency of the SERT-LL genotype among MMVD patients, particularly within the younger subset, and increased susceptibility of SERT-LL MVICs to 5HT, we postulate that the SERT-LL genotype may contribute to an increased risk of rapid disease progression by increasing the efficiency of 5HT signaling and uptake in MVICs resulting in extracellular matrix production leading to prolapse and impaired valve function. The SERT-genotype may constitute a novel means of identifying patients who may benefit from pharmacotherapy that alter 5HT-related mechanisms.

Mitral valve repair for ischemic mitral regurgitation.

Mitral valve repair for ischemic mitral valve regurgitation remains controversial. In moderate mitral regurgitation (MR), controversy exists whether revascularization alone will be adequate to restore native valve geometry or whether intervention on the valve (repair) should be performed concomitantly. When MR is severe, the need for valve intervention is not disputed. Rather, the controversy is whether repair versus replacement should be undertaken. In contrast to degenerative or myxomatous disease that directly affects leaflet integrity and morphology, ischemic FMR results from a distortion and dilation of native ventricular geometry that normally supports normal leaflet coaptation. To address this, the first and most crucial step in successful valve repair is placement of an undersized, complete remodeling annuloplasty ring to restore the annulus to its native geometry. The following article outlines the steps for repair of ischemic mitral regurgitation.