[Mitral valve prolapse and mitral annulus disjunction: be aware of a potential arrhythmogenic substrate]. / Prolasso valvolare mitralico e disgiunzione mitro-anulare. La consapevolezza di un possibile substrato aritmico.

Mitral valve prolapse is a relatively common disease with a good overall prognosis. However, in specific clinical and instrumental contexts, patients at high risk of ventricular arrhythmias and sudden cardiac death can be identified. Female sex, history of palpitations or syncope, bi-leaflet myxomatous valve, ECG repolarization abnormalities in the inferior leads, complex ventricular arrhythmias, left ventricular fibrosis detected by cardiac magnetic resonance correlate with a higher risk clinical profile. Additionally, morpho-functional abnormalities of the mitral valve annulus, particularly mitral annulus disjunction, may cause a mechanical stretch at the inferior basal ventricular wall and posterior papillary muscles, predisposing to myocardial fibrosis and arrhythmias. A risk stratification strategy is needed to identify patients with mitral valve prolapse and/or mitral annulus disjunction at high risk of arrhythmias; however, few data are available. Further prospective multicenter studies are warranted, focusing on medical therapy, the role of implantable cardioverter-defibrillators for primary prevention, efficacy of targeted catheter ablation or mitral valve surgery.

Floppy mitral valve/mitral valve prolapse: A complex entity with multiple genotypes and phenotypes.

Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a common valvular abnormality affecting 2% to 3% of the general population. It occurs in a heterogeneous group of patients with varying and age dependent expressions. FMV/MVP can be familial or sporadic, isolated (called non-syndromic) or as a part of a well-defined syndrome of heritable connective tissue disorders or other diseases. A wide range of phenotypic expression exists ranging from asymptomatic to non-specific symptoms related to neuroendocrine or autonomic nervous system functional abnormalities, varying degrees of mitral regurgitation that may require interventional therapy, heart failure, infective endocarditis, cardiac arrhythmias and/or sudden cardiac death. FMV/MVP is predominantly considered a heritable disorder with clinical manifestations not present at birth, but appearing later in life. Though a variant gene may initiate the development of FMV/MVP, precise phenotypic expression may be related to multiple other molecular, genetic and epigenetic factors that modify the final expression of the disease. A better understanding of these mechanisms will help to better define the natural history of the disease, inhibit disease progression and even prevent the phenotypic expression of FMV/MVP.

Surviving cardiac arrest from mitral annular disjunction: A case report.

A 38-year-old man with no previous medical history presented to hospital after having an out-of-hospital cardiac arrest. He was found to have a ventricular fibrillation and was successfully resuscitated after receiving cardiopulmonary resuscitation and three shocks. Extensive investigations were performed which included an electrocardiogram that showed no significant abnormality, coronary angiogram which showed unobstructed arteries, and a flecainide challenge test which was negative for Brugada syndrome. A resting echocardiogram showed a myxomatous mitral valve with mild bi-leaflet bowing, trivial mitral regurgitation, normal left ventricular systolic function, and no other structural abnormalities. A cardiac magnetic resonance imaging showed no significant late gadolinium enhancement to suggest infarct or myocardial scarring. He was subsequently diagnosed with idiopathic ventricular fibrillation and treated with a subcutaneous internal cardioverter-defibrillator for secondary prevention. A follow-up echocardiogram was performed which revealed the presence of mitral annular disjunction which has been recently shown to be associated with significant life-threatening arrhythmias and sudden cardiac death. This case highlights the importance of improving awareness of mitral annular disjunction which is not often considered as a cause for adverse patient outcomes.

Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis.

Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.

Management and outcomes in mitral valve prolapse with ventricular arrhythmias undergoing ablation and/or implantation of ICDs.

BACKGROUND: While there is an association between isolated mitral valve prolapse (MVP) and sudden cardiac arrest (SCA), the baseline characteristics and outcomes of patients with isolated MVP who experience ventricular arrhythmias (VAs) and then subsequently undergo catheter ablation and/or implantable cardioverter defibrillator (ICD) implantation are unknown. METHODS: We performed a retrospective review of all patients at the Cleveland Clinic with isolated MVP between 1997 and 2016 who underwent VA catheter ablation or secondary prevention ICD implantation. RESULTS: Of 617 screened patients, we identified 43 patients with isolated MVP and significant VA who underwent ICD placement (n = 13, 30%) or catheter ablation (n = 30, 70%). Both leaflets were most commonly involved (n = 22, 52%) with posterior MVP being next most common (n = 15, 36%). The most common foci of VA origin was the left ventricular papillary muscle (n = 9, 27%). Ablation was successful in the majority of cases (n = 20, 65%). At a mean follow-up of 2.5 years, 11 patients (26%) had recurrent VT. CONCLUSIONS: Patients with isolated MVP and VA were more likely to have bileaflet prolapse and at least moderate mitral regurgitation. VA originated more commonly from left-sided foci. While ablation was acutely successful in the majority of cases, there was still a moderate rate of VA recurrence. There is still more study needed on factors that will predict malignant VAs and management of these VAs in the MVP population.

Mitral valve prolapse.

Introduction: Mitral valve prolapse (MVP) is a common valve pathology with a spectrum of disease from isolated prolapse to myxomatous, multi-scallop Barlow's disease. The main complications relate to progression of mitral regurgitation, endocarditis, sudden death, and stroke. The timing of intervention in patients with asymptomatic severe mitral regurgitation is controversial. Areas covered: This article reviews the pathophysiology, genetics, clinical features, diagnostic imaging, complications, long-term outcomes, and indications for intervention in MVP. Expert commentary: Several key dilemmas in the management of MVP remain. Factors which influence progression of mitral regurgitation are unclear and therefore, we have no therapeutic targets to prevent progression. Evidence-based methods to reduce the risk of sudden death, stroke, and endocarditis have not been identified. In symptomatic patients with severe mitral regurgitation valve surgery is recommended. In asymptomatic patients, careful risk stratification incorporating markers of left ventricular dysfunction, atrial fibrillation, pulmonary hypertension, and valve reparability is required to identify the optimal timing of intervention.

Arrhythmic Mitral Valve Prolapse: JACC Review Topic of the Week.

There is an increasing awareness of the association between mitral valve prolapse and sudden cardiac death. There are several clinical risk factors associated with an increased risk of mitral valve prolapse-related sudden cardiac death, most of which can be evaluated with noninvasive diagnostic modalities. For example, characteristic changes on the electrocardiogram (T-wave inversions in the inferior leads), complex ventricular ectopy, a spiked configuration of the lateral annular velocities by echocardiography, and evidence of myocardial fibrosis by cardiac magnetic resonance imaging have all been implicated as markers of risk. Herein, the authors review the reported incidence of sudden death to mitral valve prolapse, the clinical profile of at-risk patients, and the basic components necessary to initiate and perpetuate ventricular arrhythmias (substrate and trigger) as well as potential interventions to consider for those at highest risk.

Clinical Outcome of Degenerative Mitral Regurgitation: Critical Importance of Echocardiographic Quantitative Assessment in Routine Practice.

BACKGROUND: Echocardiographic quantitation of degenerative mitral regurgitation (DMR) is recommended whenever possible in clinical guidelines but is criticized and its scalability to routine clinical practice doubted. We hypothesized that echocardiographic DMR quantitation, performed in routine clinical practice by multiple practitioners, predicts independently long-term survival and thus is essential to DMR management. METHODS: We included patients diagnosed with isolated mitral valve prolapse from 2003 to 2011 and any degree of mitral regurgitation quantified by any physician/sonographer in routine clinical practice. Clinical/echocardiographic data acquired at diagnosis were retrieved electronically. The end point was mortality under medical treatment analyzed by Kaplan-Meier method and proportional hazard models. RESULTS: The cohort included 3914 patients (55% male) mean age (±standard deviation) 62±17 years with left ventricular ejection fraction 63±8% and median after routinely-measured effective regurgitant orifice area (EROA) [interquartile range], 19 [0-40] mm2. During follow-up (6.7±3.1 years), 696 patients died under medical management, and 1263 underwent mitral surgery. In multivariate analysis, routinely-measured EROA was associated with mortality (adjusted hazard ratio, 1.19; 95% confidence interval, 1.13-1.24; P<0.0001 per 10 mm2) independently of left ventricular ejection fraction and end-systolic diameter, symptoms, and age/comorbidities. The association between routinely-measured EROA and mortality persisted with competitive risk modeling (adjusted hazard ratio, 1.15; 95% confidence interval, 1.10-1.20; P<0.0001 per 10 mm2), or in patients without guideline-based class I/II surgical triggers (adjusted hazard ratio, 1.19; 95% confidence interval, 1.10-1.28; P<0.0001 per 10 mm2) and in all subgroups examined (all P<0.01). Spline curve analysis showed that, compared with general population mortality, excess mortality appears for moderate DMR (EROA ≥20 mm2), becomes notable at EROA ≥30 mm2, and steadily increases with higher EROA levels (eg, higher EROA levels beyond the 40 mm2 threshold). CONCLUSIONS: Echocardiographic DMR quantitation is scalable to routine practice and is independently associated with clinical outcome. Routinely-measured EROA is strongly associated with long-term survival under medical treatment. Excess mortality versus the general population appears in the moderate DMR range and steadily increases with higher EROA. Hence, individual EROA values should be integrated into therapeutic considerations, in addition to categorical DMR grading.

[Malignant bileaflet mitral valve prolapse syndrome in otherwise idiopathic ventricular fibrillation]. / Malignes Mitralklappenprolapssyndrom bei "idiopathischem" Kammerflimmern.

A 32-year-old, otherwise healthy woman was admitted after successful out-of-hospital resuscitation due to ventricular fibrillation. Established cardiac, pulmonary, metabolic, and toxicological causes were excluded. However, persisting (biphasic) negative T waves in the inferior ECG leads and premature ventricular contractions (PVC) were noted. PVC morphology indicated a focus alternating between the posterior papillary muscle/the left posterior fascicle and the left ventricular outflow tract region/anterior papillary muscle. Echocardiography revealed a bileaflet mitral prolapse with mild mitral valve regurgitation. This case is a typical presentation of the recently described malignant bileaflet mitral valve prolapse syndrome. The patient was discharged without overt neurological deficit after implantation of a cardioverter-defibrillator.

STRUCTURAL HEART ANOMALIES (REVIEW).

Structural heart anomalies (SHA) are congenital abnormalities of cardiovascular system, characterized by various anatomical departures of heart and great vessels from normal conditions. SHA are a part of connective tissue dysplasia syndrome (CTDS), one of the most common congenital autosomal-dominant diseases in people of young and middle age. The most common SHA are a mitral valve prolapse, abnormal chords of left ventricle and their combinations. The clinical significance of these anomalies depends on a degree of severity and impact on intracardial hemodynamics, as described in the article. The most prognostically dangerous are multiple abnormal chords of left ventricle, which can be a sign of serious hereditary disease - a left ventricular non-compaction.

Mitral Annular Dimensions and Geometry in Patients With Functional Mitral Regurgitation and Mitral Valve Prolapse: Implications for Transcatheter Mitral Valve Implantation.

OBJECTIVES: The aims of this study were to determine D-shaped mitral annulus (MA) dimensions in control subjects without significant cardiac disease and in patients with moderate to severe mitral regurgitation (MR) being considered for transcatheter mitral therapy and to determine predictors of annular size, using cardiac computed tomography. BACKGROUND: The recently introduced D-shaped method of MA segmentation represents a biomechanically appropriate approach for annular sizing prior to transcatheter mitral valve implantation. METHODS: Patients who had retrospectively gated cardiac computed tomography performed at our institution (2012 to 2014) and were free of significant cardiac disease were included as controls (n = 88; 56 ± 11 years of age; 47% female) and were compared with patients with moderate or severe MR due to functional mitral regurgitation (FMR) (n = 27) or mitral valve prolapse (MVP) (n = 32). MA dimensions (projected area, perimeter, intercommissural, and septal-to-lateral distance), maximal left atrial (LA) volumes, and phasic left ventricular volumes were measured. RESULTS: MA dimensions were larger in patients with FMR or MVP compared with controls (area index 4.7 ± 0.6 cm(2)/m(2), 6.0 ± 1.3 cm(2)/m(2), and 7.3 ± 1.7 cm(2)/m(2); perimeter index 59 ± 5 mm/m(2), 67 ± 9 mm/m(2), and 75 ± 10 mm/m(2); intercommissural distance index 20.2 ± 1.9 mm/m(2), 21.2 ± 3.1 mm/m(2), and 24.7 ± 3.2 mm/m(2); septal-to-lateral distance index 14.8 ± 1.6, 18.1 ± 3.3, and 19.5 ± 3.4 mm/m(2) in controls and patients with FMR and MVP, respectively; p < 0.05 between controls and MR subgroups). Absolute MA area was 18% larger in patients with MVP than patients with FMR (13.0 ± 2.9 cm(2) vs. 11.0 ± 2.3 cm(2); p = 0.006). Although LA and left ventricular volumes were both independently associated with MA area index in controls and patients with MVP, only LA volume was associated with annular size in patients with FMR. CONCLUSIONS: Moderate to severe MR was associated with increased MA dimensions, especially among patients with MVP compared with control subjects without cardiac disease. Moreover, unlike in controls and patients with MVP, annular enlargement in FMR was more closely associated with LA dilation.

Bileaflet Mitral Valve Prolapse and Risk of Ventricular Dysrhythmias and Death.

INTRODUCTION: Bileaflet mitral valve prolapse (BiMVP) is common among survivors of otherwise unexplained sudden cardiac death, but prognostic implications of BiMVP are unknown. This study evaluated whether patients with BiMVP are at higher risk for ventricular dysrhythmias, ICD placement, or death compared to controls with either single-leaflet mitral valve prolapse (SiMVP) or no mitral valve prolapse (MVP). METHODS AND RESULTS: This retrospective, matched cohort study included 18,786 patients who underwent echocardiography at Mayo Clinic between June 1990 and September 2014. The study included three cohorts: BiMVP, SiMVP, and controls without MVP. We assessed rates of ventricular dysrhythmias, ICD placement, and all-cause mortality between groups. BiMVP was associated with higher rates of ventricular tachycardia compared to SiMVP and controls (adjusted HR 1.48 [1.14-1.92], P = 0.003 and 1.40 [1.04-1.88], P = 0.026, respectively); however, there were no statistically significant differences in rates of ventricular fibrillation/cardiac arrest or ICD placement between groups. BiMVP was associated with a lower rate of all-cause mortality compared to SiMVP and controls (adjusted HR 0.86 [0.79-0.94], P = 0.0008, and 0.55 [0.50-0.60], P < 0.0001, respectively). CONCLUSION: Although BiMVP is associated with ventricular tachycardia, it is not associated with an increased risk of cardiac arrest/ventricular fibrillation or ICD implantation and is, paradoxically, associated with a better survival compared to SiMVP or matched controls. The findings suggest that, despite its association with ventricular tachycardia, BiMVP in the absence of other risk factors does not seem to portend a poor prognosis at the population level.

P210Long- term outcome of primary mitral valve prolapse: results from a population of 250 patients referred to a tertiary cardiovascular center.

BACKGROUND: Outcome of Mitral Valve Prolapse (MVP) was controversial for long time. Many studies reported great differences in the incidence of cardiovascular events due, above all, to heterogeneous and small studied populations. Most of theme were also published to late '80 of the last century till early '00. PURPOSE: To make a contemporary survey on the incidence of cardiovascular events in a selected population of patients affected by primary MVP referred to a tertiary cardiovascular center for the medical and surgical care of valvular heart disease. METHODS: We reviewed our MVP database; patients with at least 2 cardiologic evaluations inclusive of echocardiographic examination and at least 6 months follow up were enrolled. A total of 250 patients (126 F) were selected. Their mean age was 52.1 years (ranging from 13 to 88 yo). The average follow-up time was 100 months (8,33 yrs). RESULTS: At the first medical and echocardiographic examination 8 patients (3,2%) had no mitral regurgitation (MR), 104 (41.6%) have a trace/mild MR, 93 (37,2%) a moderate MR and 46 (18,4%) a severe MR. They were widely asymptomatic (NYHA I 205-82%, NYHA II 44-17.60%, NYHA III 1- 0.40%). Most of theme presented a bileaflet (140-55.8%) or a posterior MVP (94 - 37.6%); an isolated anterior MVP was rare (16 - 6,4%). Flail leaflet was present in 8 (3,2%) and 25 (10%) had a chordal rupture. Respectively 165 (65,6%) and 115 (46,1%) patients had thick and redundant leaflets. Mean antero-posterior mitral annulus diameter was 37 mm. During the follow up 7 patients died of non-cardiac cause and 5 (2%) of suspected cardiac cause (2 because of acute coronary syndrome and 3 died suddenly). MR progresses in 43 (17,2%) patients and finally we observed 81 (32,4%) moderate/severe and severe MR. 12 new chordal rupture occurred during the follow up in most cases concerning mitral chordae linked to posterior mitral leaflet (10 cases-83,3%). The worsening of MR provoked an evolution of the clinical condition of 48 patients (19.2%) which developed Dyspnea On Excertion (DOE) with 42 new NYHA II and 6 new NYHA III. At the end of the follow up the amount of patients symptomatic for DOE was 93 (37.2% vs 18% at the initial evaluation). A total of 45 patients (18%) underwent mitral valve surgery. 40 needed in-hospital treatment in most cases due to the development of atrial fibrillation (19 -7.6%) or heart failure ( 8- 3,2%). Endocarditis occurred in 4 patients (1.6%) and cerebrovascular accidents/cardioembolic event in 6 (2.4%). The overall cardiovascular event rate was 4,33/100 patients-year, significantly higher than reported in community based studies. CONCLUSIONS: The prognosis of a MVP population referred to a tertiary cardiovascular center is not benign. The most frequent complications are progression of MR and MV surgery. Sudden death is also more frequent than in general population. More studies are needed to identify what patients with MVP are at risk for it.