Myxomatous Mitral Valve Prolapse Research Articles

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.

Clinical genetic testing in arrhythmogenic mitral valve prolapse syndrome highlights a potential overlap with familial dilated cardiomyopathy

Abstract Background/Introduction Arrhythmogenic mitral valve prolapse syndrome (AMVPS) is a female-predominant sudden cardiac death (SCD)-predisposing disorder characterized clinically by myxomatous mitral valve prolapse (MVP), inferolateral T-wave inversions and complex ventricular ectopy. However, insights into the pathogenesis and potential genetic basis of AMVPS are currently lacking. Purpose Considering recent case reports that suggest a potential role for genetic cardiomyopathies in the pathogenesis of AMVPS, we sought to determine the yield of pathogenic/likely pathogenic (P/LP) genetic variants in strong evidence cardiomyopathy-susceptibility genes amongst AMVPS patients who underwent clinical genetic testing. Methods In this retrospective study, the medical records of 4,907 patients referred to our cardiovascular genetics clinic was used to identify those patients with a clinical phenotype consistent with AMVPS. After exclusion of individuals with severe mitral valve regurgitation, pertinent clinical, electrocardiographic, imaging and genetic testing data was extracted from the electronic record. For those AMVPS that underwent a form of genetic testing that encompassed 23 Clinical Genome Resource-defined strong/definitive evidence cardiomyopathy-susceptibility genes, ultra-rare (minor allele frequency ≤ 0.00005 in the Genome Aggregation Database [n=141,456 individuals]) non-synonymous variants identified within these genes were adjudicated independently as P, LP or variant of uncertain significance with the assistance of Varsome. The frequency of P/LP variants was then compared to a previously published cohort of 973 ostensibly healthy control exomes. Results Overall, 56 unrelated patients with suspected AMVPS were identified (82% female; average age at presentation of 31 ± 13 years; 32% with a family history of MVP and/or SCD). Of these, 24/56 (43%) underwent a form of clinical genetic testing that encompassed the pre-defined panel of cardiomyopathy-susceptibility genes. In comparison to control exomes (n=973), P/LP variants in strong/definitive evidence cardiomyopathy-susceptibility genes were over-represented in AMVPS patients [4/24 (16.7%) vs 20/973 (2.1%); p=0.002]. Interestingly, this enrichment was driven in large part by an excess number of A-band-localizing P/LP truncating variants in TTN-encoded titin in AMVPS cases [3/24 (12.5%) versus 4/973 (0.4%); p=0.0004]. Conclusion This study provides further evidence that a subset of AMVPS may arise secondary to a "two-hit" model whereby an underlying cardiomyopathic genetic substrate is exacerbated by the mechanical force generated by genetically unrelated myxomatous MVP resulting in maladaptive and ventricular arrhythmia-predisposing fibrosis within the inferobasal left ventricle and posteromedial papillary muscles. Larger studies are needed to better understand the potential role of genetic testing in the diagnosis, risk-stratification and management of patients with suspected AMVPS.

Biology of mitral valve prolapse: from general mechanisms to advanced molecular patterns-a narrative review.

Mitral valve prolapse (MVP) represents the most frequent cause of primary mitral regurgitation. For several years, biological mechanisms underlying this condition attracted the attention of investigators, trying to identify the pathways responsible for such a peculiar condition. In the last ten years, cardiovascular research has moved from general biological mechanisms to altered molecular pathways activation. Overexpression of TGF-β signaling, for instance, was shown to play a key role in MVP, while angiotensin-II receptor blockade was found to limit MVP progression by acting on the same signaling pathway. Concerning extracellular matrix organization, the increased valvular interstitial cells density and dysregulated production of catalytic enzymes (matrix metalloproteinases above all) altering the homeostasis between collagen, elastin and proteoglycan components, have been shown to possibly provide a mechanistic basis contributing to the myxomatous MVP phenotype. Moreover, it has been observed that high levels of osteoprotegerin may contribute to the pathogenesis of MVP by increasing collagen deposition in degenerated mitral leaflets. Although MVP is believed to represent the result of multiple genetic pathways alterations, it is important to distinguish between syndromic and non-syndromic conditions. In the first case, such as in Marfan syndrome, the role of specific genes has been clearly identified, while in the latter a progressively increasing number of genetic loci have been thoroughly investigated. Moreover, genomics is gaining more interest as potential disease-causing genes and loci possibly associated with MVP progression and severity have been identified. Animal models could be of help in better understanding the molecular basis of MVP, possibly providing sufficient information to tackle specific mechanisms aimed at slowing down MVP progression, therefore developing non-surgical therapies impacting on the natural history of this condition. Although continuous progress has been made in this field, further translational studies are advocated to improve our knowledge of biological mechanisms underlying MVP development and progression.

SCN5A variants as genetic arrhythmias triggers for familial bileaflet mitral valve prolapse

Mitral valve prolapse (MVP) is a common valvulopathy with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. The association of MVP with ventricular arrhythmias as a substrate of SCD has been documented in patients with MVP. Genetic variations in DCHS1, DZIP1, FLNA and PLD1 genes have been associated with MVP. The index case, a 42-year-old woman, was diagnosed with a bileaflet myxomatous MVP after a resuscitated SCD at the age of 27 years. MVP was the only abnormality found to explain the occurrence of life-threatening ventricular arrhythmia. Structural cardiac diseases and Brugada syndrome were excluded. Family screening revealed one symptomatic daughter with a history of two syncopes at 11 years old during physical effort. Her echocardiography showed a bileaflet MVP and a mildly dilated left ventricle. The MVP is complicated by moderate mitral regurgitation (MR). The oldest sister, 23 years old is currently asymptomatic. Her echocardiography revealed a prodromal MVP with a mild holosystolic MR. The father had normal echocardiography. The aim of this study was to identify the likely causative genetic etiology of the familial MVP and particularly the arrhythmias substrate linked to this phenotype. Whole exome sequencing (WES) was performed for the family. WES data were analyzed with a primary focus on genes related to MVP but also on genes implicated in valvular and aortic defects. Using family-based exome sequencing, no variants were found in known MVP genes. However, we identified two missense variants in the SCN5A gene. A rare variant SCN5A: p.Ala572Asp and the functional modifying SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as a potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.

Genetics and pathophysiology of mitral valve prolapse.

Mitral valve prolapse (MVP) is a common condition affecting 2-3% of the general population, and the most complex form of valve pathology, with a complication rate up to 10-15% per year in advanced stages. Complications include mitral regurgitation which can lead to heart failure and atrial fibrillation, but also life-threatening ventricular arrhythmia and cardiovascular death. Sudden death has been recently brought to the forefront of MVP disease, increasing the complexity of management and suggesting that MVP condition is not properly understood. MVP can occur as part of syndromic conditions such as Marfan syndrome, but the most common form is non-syndromic, isolated or familial. Although a specific X-linked form of MVP was initially identified, autosomal dominant inheritance appears to be the primary mode of transmission. MVP can be stratified into myxomatous degeneration (Barlow), fibroelastic deficiency, and Filamin A-related MVP. While FED is still considered a degenerative disease associated with aging, myxomatous MVP and FlnA-MVP are recognized as familial pathologies. Deciphering genetic defects associated to MVP is still a work in progress; although FLNA, DCHS1, and DZIP1 have been identified as causative genes in myxomatous forms of MVP thanks to familial approaches, they explain only a small proportion of MVP. In addition, genome-wide association studies have revealed the important role of common variants in the development of MVP, in agreement with the high prevalence of this condition in the population. Furthermore, a potential genetic link between MVP and ventricular arrhythmia or a specific type of cardiomyopathy is considered. Animal models that allow to advance in the genetic and pathophysiological knowledge of MVP, and in particular those that can be easily manipulated to express a genetic defect identified in humans are detailed. Corroborated by genetic data and animal models, the main pathophysiological pathways of MVP are briefly addressed. Finally, genetic counseling is considered in the context of MVP.

1125 AN UNDER-RECOGNIZED CAUSE OF VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH: A CASE REPORT

Abstract Mitral annular disjunction (MAD) is a structural abnormality which is commonly seen in patients with myxomatous mitral valve disease and mitral valve prolapse. MAD is a marker of severe disease including a higher need for mitral valve intervention and more arrhythmic events, which can be a cause of sudden cardiac death (SCD). A 72-years-old man with several cardiovascular risk factors (hypertension, diabetes mellitus, obesity, previous smoking, family history of cardiovascular diseases, chronic kidney disease) experienced two pre-syncopal episodes. Therefore, he was referred to a 24-hour Holter EKG that showed a non-sustained ventricular tachycardia (VT). A transthoracic 2D echocardiogram evidenced a mitral valve prolapse with mild regurgitation, normal left and right heart dimensions and function. Elective coronary angiography was performed to rule out an ischemic aetiology of ventricular arrhythmias (multiple cardiovascular risk factors and strong familiarity for coronary artery disease). The coronary angiography revealed a stenosis of 30% of left anterior descending artery and an intermediate stenosis of right coronary artery. A myocardial perfusion scintigraphy was performed to evaluate the intermediate coronary stenosis. The scintigraphy showed numerous focal perfusion abnormalities non indicative for coronary disease but rather for a degenerative or inflammatory disease. Indeed, we decided to perform a cardiac magnetic resonance (CMR). The CMR revealed a MAD with detachment of the root of the mitral annulus from the postero-lateral ventricular myocardium during systole, without areas of myocardial fibrosis evidenced by late gadolinium enhancement (LGE). Factors for high risk of SCD, such as fibrosis affecting the infero-basal left ventricle free wall or the papillary muscles, family history of SCD, personal history of complex ventricular arrhythmias, were not represented in our case. Therefore, we opted for a medical therapy with beta-blockers and a careful follow-up. MAD is an under-recognized cause of ventricular arrhythmias and SCD, generally associated to mitral valve prolapse. Echocardiography and CMR can identify and quantify MAD. A comprehensive evaluation, including multimodality imaging and clinical history, is mandatory for risk stratification of SCD and for optimal treatment.

Valvular Heart Disease Epidemiology.

Valvular heart disease is a rapidly growing cause of global cardiovascular morbidity and mortality with diverse and evolving geographic distribution. The prevalence of rheumatic heart disease, the most common valvular heart disease (affecting approximately 41 million people), has been rising in developing nations, likely due to the expansion of the young adult population and the decrease in premature mortality that has resulted from improved access to antibiotics, microbiological testing, and echocardiography. Rheumatic heart disease has also been rising among the impoverished and, often, indigenous populations of developed nations, spurring public health initiatives that are aimed at alleviating healthcare disparities. Aortic valve stenotic disease is the most commonly occurring valvular pathology in developed nations (afflicting 9 million people worldwide) and its prevalence has been increasing with population aging and the increased prevalence of atherosclerosis. Aortic regurgitation is associated with diastolic, but not systolic, hypertension and it has likewise seen a rise in the developed world. Mitral regurgitation affects 24 million people worldwide, with great variability between and among nations. Primary mitral regurgitation arises as a consequence of myxomatous degeneration and mitral valve prolapse, which is largely due to genetic predispositions, while secondary mitral regurgitation accounts for 65% of cases and arises secondary to dilation and heart failure. Tricuspid regurgitation has become more prevalent in developed nations due to the increased usage of intracardiac pacemakers. Infective endocarditis prevalence has also grown in developed nations, likely due to population aging and the increased utilization of transcatheter valve replacement and prosthetic valves as interventions against the previously discussed valvular pathologies.

A Rare Case of Ischaemic Stroke in A Young Man with Mitral Valve Prolapse

Mitral valve prolapse is a common valvular abnormality. It affects 2-3% of the general population. It often runs a benign course and the majority of patients are asymptomatic. Cardiac sources of thrombi account for about 20% of ischaemic strokes. There is lingering uncertainty regarding the causal link between mitral valve prolapse and ischaemic stroke. It has been suggested that changes on the surface of the valvular leaflets trigger platelet adherence and aggregation, leading to formation of platelet-fibrin thrombus which can embolize to the cerebral arteries, causing an ischaemic stroke. We herein report a case of a 25 year old young man who presented with sudden onset of left-sided weakness. Cardiac auscultation was notable for a late systolic murmur preceded by a midsystolic click at the apex. Transthoracic echocardiography showed an elongated and thickened anterior mitral valve leaflet which prolapsed into the left atrium during systole. Computed tomography scan of the brain revealed infarcts in the right frontal lobe and the right insular cortex. A diagnosis of myxomatous mitral valve prolapse complicated by ischaemic stroke was made and the patient was accordingly started on anticoagulant therapy with warfarin.

Mitral Annular Disjunction: Pathophysiology, Pro-Arrhythmic Profile and Repair Pearls

Mitral annular disjunction (MAD) is a structural abnormality defined by a distinct separation of the mitral valve annulus—left atrial wall continuum and the basal aspect of the posterolateral left ventricle. This anomaly is often observed in patients with myxomatous mitral valve prolapse. Importantly, MAD has been strongly associated with serious ventricular arrhythmias and predisposes to sudden cardiac death. Therefore, we have to emphasize the need to diagnose this morphologic and functional abnormality in routine practice in order to facilitate optimal mitral valve repair and minimize patient risks. Nevertheless, clinical knowledge regarding MAD still remains limited. In the present review, we aim to shed light on several aspects of MAD, including distinct anatomical and pathophysiological characteristics, imaging modalities, association with ventricular arrhythmias, and current methods of treatment.

Echocardiographic characteristics of non‐resectional ring‐only valve repair in mitral valve prolapse

AbstractBackgroundSimple mitral valve repair (MVR) using a ring‐only approach (ROA) was recently proposed for some complex forms of bileaflet myxomatous mitral valve prolapse (MVP). Nevertheless, few data are available concerning the characteristics of MVP patients that may benefit from this simple repair technique.MethodsBased on 39 consecutive patients (28 men; mean age 57 ± 15) with severe primary Mitral regurgitation (MR) caused by bileaflet MVP referred for MVR, we sought to identify the preoperative echocardiographic parameters associated with successful ROA repair.ResultsTwenty‐three patients (59%) underwent standard resectional MVR (SMVR) while 16 (41%) underwent ROA. Cardiopulmonary bypass and cross clamp times were lower in ROA than in SMVR (74 ± 27 min vs 99 ± 42 min and 49 ± 19 min vs 70 ± 25 min, respectively, p = 0.03 and p = 0.005). ROA patients were more frequently women (50% vs 13%, p = 0.027). Echocardiographic characteristics of successful ROA were mid‐late systolic MR, a paradoxical systolic papillary muscle displacement, and paradoxical systolic annulus expansion (PAE). A prolapsing depth <10 mm, the absence of flail leaflet and ruptured chordae, the presence of multiple jets, more often in the central part of the valve were also associated with ROA. Non hemodynamic systolic anterior motion and residual trivial MR tended to be more frequent in ROA than in SMVR.ConclusionSimple and fast MVR using a ROA is feasible in 4/10 patients with complex forms of bileaflet MVP. Successful ROA patients were more frequently women, with mid‐late systolic central multiple jet, low prolapse depth, absence of chordal rupture or flail leaflet and PAE.

Influence of prolapse volume in myxomatous mitral valve prolapse

Myxomatous mitral valve prolapse (MMVP) is characterized by excessive leaflet tissue leading to a wide spectrum of mitral regurgitation (MR) ranging from trivial to complex severe incompetence. The prolapse volume (PV) below the prolapsing leaflets in end-systole was suspected to impact both chamber remodeling and MR grading in MMVP. Based on 157 consecutive patients (45 women; mean age 62 ± 15) referred for CMR assessment of MR, either from MMVP ( n = 91; 58%) or fibroelastic disease (FED) ( n = 66; 42%), we sought to study: – the interaction between PV and cardiac chamber geometry; – to study the impact of PV on MR quantification in MMVP. Despite similar left ventricular (LV) size, PV was larger in MMVP (11 ± 9 mL) than in FED (2 ± 2 mL). PV progressively increased with the severity of MR in MMVP but not in FED. Despite a low regurgitant volume (32 ± 18 mL), some MMVP patients with less than moderate MR exhibit significant cardiac chambers remodeling compared to 52 age and sex-matched controls. PV correlated significantly ( r = 0.52) with the LV dilatation in severe MR but also in less than moderate MR. In MMVP, PV > 14 mL was associated with a significant underestimation (Bias = −26 ± 32 mL) of regurgitant volume by PISA compared to CMR. In conclusion, in MMVP, PV may play a role in left cardiac chambers remodeling, even in patients without severe MR, and in discordant grading of MR between echocardiography and CMR.

Mitral valve repair in myxomatous bileaflet mitral valve prolapse: Resectional versus non-resectional ring-only approaches

Simple mitral valve repair (MVR) using a ring-only approach (ROA) was recently proposed for some complex forms of myxomatous bileaflet mitral valve prolapse (MMVP). Nevertheless, few data are available concerning the characteristics of MMVP patients that may benefit from this simple repair technique. Based on 39 consecutive patients (28 men; mean age 57 ± 15) with severe primary Mitral regurgitation (MR) caused by bileaflet MMVP referred for MVR, we sought to (i) identify the clinical and echocardiographic predictors of a ROA (ii) to assess the postoperative clinical outcomes and valve function. 23 patients (59%) underwent standard resectional MVR (SMVR) while 16 (41%) underwent ROA. Cardiopulmonary bypass and cross clamp times were lower in ROA than in SMVR (74 ± 27 min vs. 99 ± 42 min and 70 ± 25 min vs. 49 ± 19 min, respectively, P = 0.03 and P = 0.005). None of the patients died in the postoperative period. Occurrence of stroke and postoperative atrial fibrillation was similar between groups. ROA patients were more frequently women (50% vs. 13%, P = 0.027). Echocardiographic predictors of successful ROA were prolapsing depth < 10 mm, absence of flail leaflet and ruptured chordae, presence of multiple jets, more often in the central part of the valve (A2P2). Mid-late systolic MR and paradoxical systolic annulus expansion (PAE) were also associated with ROA. The repaired valves showed mild pressure gradient of 3 ± 1 mmHg. Non hemodynamic systolic anterior motion and residual trivial MR tended to be more frequent in ROA than in SMVR (12% vs. 4%, P = 0.37 and 31% vs 18%; P = 0.35, respectively). ROA was more frequently associated with preservation of postoperative posterior leaflet mobility (75% vs. 18%, P = 0.0001). Simple and fast MVR using a ROA is feasible in 4/10 patients with complex forms of bileaflet MMVP, with good immediate results. Predictors of ROA were female gender, mid-late systolic central multiple jet, low prolapse depth, absence of chordal rupture or flail leaflet and PAE.

Assessment of Valvular Oxidative Stress in a Young Patient with Primary Severe Mitral Regurgitation

Mitral valve regurgitation (MR) is the most common valvular heart disease. Diagnosing and managing mitral regurgitation is often challenging and requires a structured approach, integrating findings on history, physical examination and imaging. A common cardiac anomaly is myxomatous mitral valve prolapse. Excess myxomatous leaflet tissue, bileaflet prolapse or billowing, chordae elongation and annular dilatation are all features of Barlow’s disease. Currently, there is no successful pharmacological treatment available to prevent or slow its progression. Here, we report the case of a 30-year-old male patient, with no previous significant medical background and no medication at home, who was diagnosed with severe mitral regurgitation at a regular check-up and was admitted to our clinic with mild exertion dyspnea and fatigue. Transthoracic echocardiography showed intensely thickened mitral leaflets with a myxomatous appearance, prolapse of the middle scallop of the posterior leaflet (P2), apparently with ruptured chordae, and severe mitral regurgitation with a holosystolic eccentric jet. While oxidative stress is a central pathomechanism of cardiovascular disease, information regarding valvular oxidative stress in the literature is rather scarce. In this respect, we assessed oxidative stress through confocal microscopy in a sample of a mitral valve harvested during valvular surgery. We found an increased production of reactive oxygen species in the mitral valve sample that was alleviated after incubation with the angiotensin 2 receptor type I (AT1) antagonist irbesartan. This case is worth mentioning as a starting point for a prospective study aimed at assessing the role of valvular oxidative stress and mitochondrial dysfunction in patients with various degrees of primary and secondary mitral regurgitation.

Abstract 12406: Mitral Valve Prolapse: Immune Response as a New Player

Introduction: Mitral Valve Prolapse (MVP) is observed in 3% of the population. The pathophysiological mechanisms leading to MVP remain elusive and the only therapeutic option is to perform valve surgery. We previously identified FLNA as the first gene causing MVP and generated a unique knock-in (KI) rat model for the FLNA-P637Q mutation. Hypothesis: We assessed the hypothesis that MVP pathophysiology is multifactorial. Methods: 5 WT and 10 KI rats were morphologically, functionally and histologically evaluated at 3, 6 and 13 weeks based on 2D echocardiography, 3D micro computed tomography (μCT) and histology. Mitral valve (MV) RNA-sequencing was performed and metaclusters (MC) have been identified. Immunofluorescence and cytometry experiments on MV were used. Results: Echocardiographic and μCT imaging confirmed the presence of MV prolapse, elongated anterior leaflet (+12 to +14% for all time points p&lt;0.01) and increased MV volume (+20 to +58% for all time points p&lt;0.05) in KI rats vs WT. Histological analyses revealed a myxomatous remodelling in KI MV. 6 MC were identified by RNA-seq: chemotaxis, epithelial and immune cell migration, extracellular matrix, stress molecular pathways, endothelial to mesenchymal transition and oxidative stress (all GO-terms p&lt;1x10-5). A higher proportion of CD45 + leukocytes (20% vs 14%, p=0.002), as well as a trend for CD206 + “resident macrophages” (28% vs 16%, p=0.09), and CD34 + stem cell progenitors (8% vs 15%, p=0.10) were observed in KI compared to WT rats. CD45 + and CD206 + cells were located in the medial third and atrial border of the MV leaflet in WT rats, and more diffusely observed in KI. Conclusions: Our results establish the KI FLNA-P637Q rat as a model of myxomatous MVP, a complex and multifactorial disease. Among others, we have characterized an increase of distinct immune cells in MVP. The course of cell recruitment, the cell-specific activity, and causality with the other MC need to be further studied.

Characterization of the electrophysiological substrate in patients with Barlow's disease.

Myxomatous mitral valve prolapse (MVP) and mitral-annular disjunction (Barlow disease) are at-risk for ventricular arrhythmias (VA). Fibrosis involving the papillary muscles and/or the infero-basal left ventricular (LV) wall was reported at autopsy in sudden cardiac death (SCD) patients with MVP. We investigated the electrophysiological substrate subtending VA in MVP patients with Barlow disease phenotype. Twenty-three patients with VA were enrolled, including five with syncope and four with a history of SCD. Unipolar (Uni < 8.3 mV) and bipolar (Bi < 1.5 mV) low-voltage areas were analyzed with electro-anatomical mapping (EAM), and VA inducibility was evaluated with programmed ventricular stimulation (PES). Electrophysiological parameters were correlated with VA patterns, electrocardiogram (ECG) inferior negative T wave (nTW), and late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance. Premature ventricular complex (PVC) burden was 12 061.9 ± 12 994.6/24 h with a papillary-muscle type (PM-PVC) in 18 patients (68%). Twelve-lead ECG showed nTW in 12 patients (43.5%). A large Uni less than 8.3 mV area (62.4 ± 45.5 cm2 ) was detected in the basal infero-lateral LV region in 12 (73%) patients, and in the papillary muscles (2.2 ± 2.9 cm2 ) in 5 (30%) of 15 patients undergoing EAM. A concomitant Bi less than 1.5 mV area (5.0 ± 1.0 cm2 ) was identified in two patients. A history of SCD, and the presence of nTW, and LGE were associated with a greater Uni less than 8.3 mV extension: (32.8 ± 3.1 cm2 vs. 9.2 ± 8.7 cm2 ), nTW (20.1 ± 11.0 vs. 4.1 ± 3.8 cm2 ), and LGE (19.2 ± 11.7 cm2 vs. 1.0 ± 2.0 cm2 , p = .013), respectively. All patients with PM-PVC had a Uni less than 8.3 mV area. Sustained VA (ventricular tachycardia 2 and VF 2) were induced by PES only in four patients (one with resuscitated SCD). Low unipolar low voltage areas can be identified with EAM in the basal inferolateral LV region and in the papillary muscles as a potential electrophysiological substrate for VA and SCD in patients with MVP and Barlow disease phenotype.

Morphology of Mitral Annular Disjunction in Mitral Valve Prolapse

Mitral annular disjunction (MAD) is an abnormal insertion of the hinge line of the posterior mitral leaflet on the atrial wall: the mitral annulus shows a separation or "disjunction" between the leaflet-atrial wall junction and the crest of the left ventricle myocardium. This anomaly is often observed in patients with myxomatous mitral valve prolapse. The anatomical substrate of MAD remains unclear for the following reasons: (1) most studies are focused on the association between MAD and arrhythmias, rather than on pathomorphological aspects of MAD; and (2) the complex anatomic architecture of the posterior mitral annulus is often simply described as the posterior segment of a fibrous ring. The aims of this paper are to review the pertinent normal anatomy of the mitral valve and to propose new hypotheses on the morphological nature of MAD.

Influence of Prolapse Volume in Myxomatous Mitral Valve Prolapse

Myxomatous mitral valve prolapse (MMVP) is characterized by excessive leaflet tissue leading to a wide spectrum of mitral regurgitation (MR) ranging from trivial to complex severe incompetence. The prolapse volume (PV) below the prolapsing leaflets in end-systole was recently suspected to impact both chamber remodeling and MR grading in Barlow's disease. The aims of the current study using Cardiac magnetic resonance (CMR) was (i) to assess the interaction between PV and cardiac chambers size and function (ii) to study the impact of PV on MR grading in Barlow's disease. Over a 60-months period, 157 patients (45 women; mean age 62 ± 15) consecutively referred at the Monaco Heart center, Monaco for CMR assessment of primary MR secondary to MVP either from MMVP ( n = 91; 58%) or fibroelastic disease (FED) ( n = 66; 42%)were eligible for inclusion into the study. Over the same period, we enrolled 52 age and sex-matched controls. Patients were imaged with a 3-Tesla Siemens Skyra scanner. Prolapse volume (PV) was calculated on the end systolic frame in each of the 4-, 3- and 2-chamber views. Despite similar left ventricular (LV) size, PV was larger in MMVP (11 ± 9 ml) than in FED (2 ± 2 ml). PV progressively increased with the severity of MR in MMVP but not in FED. PV correlated significantly ( r = 0.52) with the LV dilatation in severe MR but also in less than moderate MR. Despite a low RegV by CMR (32 ± 18 ml), some MMVP patients with less than moderate MR exhibit significant cardiac chambers remodeling compared to the 52 controls. In MMVP, PV > 14 ml was associated with a significant underestimation (Bias = −26 ± 32 ml) of RegV by PISA compared to CMR ( Fig. 1 ). In conclusion, in MMVP, PV may play a role in left cardiac chambers remodeling, even in patients without severe MR, and in discordant grading of MR between echocardiography and CMR.

Mitral Annular Disjunction: A Serendipitous Discovery by Intraoperative Transesophageal Echocardiography

MITRAL REGURGITATION (MR) presents as a consequence of a primary pathology of the mitral valve apparatus or secondary to ventricular dysfunction and remodeling. Most common etiology for primary MR is degenerative, with a prevalence of 1%-to-2%. 1 Freed LA Levy D Levine RA et al. Prevalence and clinical outcome of mitral valve prolapse. N Engl J Med. 1999; 341: 1-7 Crossref PubMed Scopus (717) Google Scholar Degenerative mitral valve disease is a progressive, noninflammatory, structural distortion of the valve apparatus, culminating in leaflet prolapse and regurgitation. Some of these patients present acutely due to rupture of the abnormal chordae, whereas most others present with chronic progressive MR. The spectrum of this disease is wide, ranging from fibroelastic degeneration, through forme-fruste, to Barlow's. Pathogenesis of mitral valve prolapse (MVP) has been shifting from a degenerative process involving the leaflets to an intrinsic annular abnormality. The subset in which this abnormal annular anatomy and kinetics have been demonstrated is now categorized as mitral annular disjunction (MAD). Although, primarily, MVP is characterized by leaflet and chordal involvement with secondary changes in the annulus, MAD is found to have a primary annular involvement with secondary changes in leaflets and myocardium. Typically, MAD presents as a discontinuation of the annuloatrial junction from the ventricular myocardium. It is more commonly associated with myxomatous MVP than the fibroelastic variant. 2 Essayagh B Iacuzio L Civaia F et al. Mitral annular disjunction in mitral valve prolapse: A cardiac magnetic resonance study. Arch Cardiovasc Dis Suppl. 2019; 11: 62-63 Google Scholar Similar to MVP, it has a female preponderance. 3 Putnam AJ Kebed K Mor-Avi V et al. Prevalence of mitral annular disjunction in patients with mitral valve prolapse and severe regurgitation. Int J Cardiovasc Imaging. 2020; 36: 1363-1370 Crossref PubMed Scopus (13) Google Scholar It still is unclear whether it is MAD or MVP that is the initiating trigger for MR.

1047 Increased interstitial fibrosis in patients with mitral valve prolapse and mitro-annular dysjunction

Abstract Background in patients with myxomatous mitral valve prolapse (MVP), mitral annular disjunction (MAD) has been associated with the presence of late gadolinium enhancement (LGE) at papillary muscle level and the risk of sudden cardiac death. However, patients with MAD but no detectable LGE still may have arrhythmia. We investigated the relation between MAD and the presence of interstitial fibrosis in the basal inferior left ventricular myocardium. Methods 28 patient with MVP and associated MAD underwent Cardiovascular Magnetic Resonance imaging (CMR) at 1.5 T scanner (Aera, Siemens Medical Solutions, Erlangen, Germany). Exclusion criteria were ischemic heart disease, infiltrative cardiomyopathy and contraindication to CMR. 12 patients with mitral valve regurgitation but no MAD and 10 patients without mitral disease served as the control group. MAD severity was measured from LA wall-posterior MV leaflet junction to the top of the LV infero-basal wall during end systole. Insterstitial fibrosis was assessed by calculating the extracellular volume (ECV) from T1 mapping of the left ventricular basal slice acquired before and after Gadolinium injection. Results Mean age was 47,5+\-23,3 years and 60% were male. ECV was higher in patients with MVP compared with controls (basal septum: 0.27 ± 0.04 vs 0.23 ± 0.03 p = 0.006; basal inferoposterior wall 0.28 ± 0.03 vs 0.23 ± 0.02 p = 0.003) and there was a significant correlation between MAD severity and ECV of the basal inferior wall (spearman rho 0.68, p &amp;lt; 0.0001) (Figure 1). Among MVP patients, ECV of the basal inferoposterior wall was higher in patients positive for LGE in the papillary muscles (ECV 0.31 ± 0.03 vs 0.27 ± 0.03 p 0,004). Conclusion In MVP patients, MAD severity was associated with a higher amount of interstitial fibrosis even in the absence of detectable macroscopic fibrosis in the papillary muscle region. Abstract 1047 Figure 1

Mitral annular disjunction: A systematic review of the literature.

Mitral annular disjunction (MAD) is a structural abnormality where there is a separation between the mitral valve annulus and the left atrial wall which is not well understood. We conducted a systematic review to evaluate the prevalence of MAD, factors associated with MAD and clinical outcomes among patients with MAD. A total of 19 studies were included in this review, and the number of noncase report studies had between 23 and 1439 patients. The pooled rate of MAD in studies of myxomatous mitral valve patients was 66/130 (50.8%, 3 studies), and among patients with mitral valve prolapse was 95/291 (32.6%, 3 studies). One study suggests that 78% of patients with MAD had mitral valve prolapse, and another suggested it was strongly associated with myxomatous mitral valve disease (HR 5.04 95% CI 1.66-15.31). In terms of clinical significance, it has been reported that MAD with disjunction>8.5mm was associated with nonsustained ventricular tachycardia (OR 10 95% CI 1.28-78.1). There is also evidence that gadolinium enhancement in papillary muscle (OR 4.09 95% CI 1.28-13.05) and longitudinal MAD distance in posterolateral wall (OR 1.16 95% CI 1.02-1.33) was predictive of ventricular arrhythmia and late gadolinium enhancement in anterolateral papillary muscle was strongly associated with serious arrhythmic event (OR 7.35 95% CI 1.15-47.02). Mitral annular disjunction appears to be common in myxomatous mitral valve disease and mitral valve prolapse which can be detected on cardiac imaging and may be important because of its association with ventricular arrhythmias and sudden cardiac death.