Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Predicting Survival in Repaired Tetralogy of Fallot: A Lesion-Specific and Personalized Approach.

OBJECTIVES: This study sought to identify patients with repaired tetralogy of Fallot (rTOF) at high risk of death and malignant ventricular arrhythmia (VA). BACKGROUND: To date there is no robust risk stratification scheme to predict outcomes in adults with rTOF. METHODS: Consecutive patients were prospectively recruited for late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) to define right and left ventricular (RV, LV) fibrosis in addition to proven risk markers. RESULTS: The primary endpoint was all-cause mortality. Of the 550 patients (median age 32 years, 56% male), 27 died (mean follow-up 6.4 ± 5.8; total 3,512 years). Mortality was independently predicted by RVLGE extent, presence of LVLGE, RV ejection fraction ≤47%, LV ejection fraction ≤55%, B-type natriuretic peptide ≥127 ng/L, peak exercise oxygen uptake (V02) ≤17 mL/kg/min, prior sustained atrial arrhythmia, and age ≥50 years. The weighted scores for each of the preceding independent predictors differentiated a high-risk subgroup of patients with a 4.4%, annual risk of mortality (area under the curve [AUC]: 0.87; P < 0.001). The secondary endpoint (VA), a composite of life-threatening sustained ventricular tachycardia/resuscitated ventricular fibrillation/sudden cardiac death occurred in 29. Weighted scores that included several predictors of mortality and RV outflow tract akinetic length ≥55 mm and RV systolic pressure ≥47 mm Hg identified high-risk patients with a 3.7% annual risk of VA (AUC: 0.79; P < 0.001) RVLGE was heavily weighted in both risk scores caused by its strong relative prognostic value. CONCLUSIONS: We present a score integrating multiple appropriately weighted risk factors to identify the subgroup of patients with rTOF who are at high annual risk of death who may benefit from targeted therapy.

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.

The Predicament of Surgical Correction of Tetralogy of Fallot.

Surgery for tetralogy of Fallot has a long history, which may be described as both a success story and a failure story. It is a success story because prognosis without surgery is very poor, but surgery makes it possible for affected babies to reach adulthood and lead productive lives. It is a failure story, however, since we still cannot cure this condition; we can only palliate it as illustrated in the sobering long-term outcome of affected patients. In this review article, we aim to explore the reason for this failure. This may be summed up in terms of the nature of the obstruction to the right ventricular outflow tract, which characterizes this malformation and must be relieved. This obstruction has several possible components, but none may be eliminated without harming the ventricle. There seems to be no 'extra' muscle band in tetralogy of Fallot that may be dispensed with without undermining ventricular function; every muscle band that is there should be there, just like in the normal heart, except that these are thicker than normal and somewhat displaced in tetralogy of Fallot, thus narrowing the right ventricular outflow tract. Consequently, ventricular function deteriorates with every muscle band that is cut, just like in the normal heart. We have to harm the heart in order to repair it. Every repaired Fallot is inevitably a damaged heart. Consequently, repair of this condition cannot be curative at present; it is palliative surgery.

Myxomatous Mitral Valve Disease with Mitral Valve Prolapse and Mitral Annular Disjunction: Clinical and Functional Significance of the Coincidence.

The morphological changes that occur in myxomatous mitral valve disease (MMVD) involve various components, ultimately leading to the impairment of mitral valve (MV) function. In this context, intrinsic mitral annular abnormalities are increasingly recognized, such as a mitral annular disjunction (MAD), a specific anatomical abnormality whereby there is a distinct separation between the mitral annulus and the left atrial wall and the basal portion of the posterolateral left ventricular myocardium. In recent years, several studies have suggested that MAD contributes to myxomatous degeneration of the mitral leaflets, and there is growing evidence that MAD is associated with ventricular arrhythmias and sudden cardiac death. In this review, the morphological characteristics of MAD and imaging tools for diagnosis will be described, and the clinical and functional aspects of the coincidence of MAD and myxomatous MVP will be discussed.

Uncertainties and challenges in surgical and transcatheter tricuspid valve therapy: a state-of-the-art expert review.

Tricuspid regurgitation (TR) is a frequent and complex problem, commonly combined with left-sided heart disease, such as mitral regurgitation. Significant TR is associated with increased mortality if left untreated or recurrent after therapy. Tricuspid regurgitation was historically often disregarded and remained undertreated. Surgery is currently the only Class I Guideline recommended therapy for TR, in the form of annuloplasty, leaflet repair, or valve replacement. As growing experience of transcatheter therapy in structural heart disease, many dedicated transcatheter tricuspid repair or replacement devices, which mimic well-established surgical techniques, are currently under development. Nevertheless, many aspects of TR are little understood, including the disease process, surgical or interventional risk stratification, and predictors of successful therapy. The optimal treatment timing and the choice of proper surgical or interventional technique for significant TR remain to be elucidated. In this context, we aim to highlight the current evidence, underline major controversial issues in this field and present a future roadmap for TR therapy.

Inadvertent transseptal puncture into the aortic root: the narrow edge between luck and catastrophe in interventional cardiology.

AIMS: Inadvertent puncture of the aortic root (AR) is a well-known complication of transseptal puncture (TSP). Strategies for handling of this potentially lethal complication have not been identified yet. In this study, we present typical anatomical locations and clinical management of aortic root puncture (ARP) due to TSP. METHODS AND RESULTS: All patients with ARP were retrospectively collected from seven hospitals. Aortic root puncture was identified and classified regarding angiographical and intraoperative findings in cardiac surgery: (i) TSP from the right atrium (RA) to the non-coronary sinus (NCS), (ii) TSP from RA to the non-coronary sinutubular junction (STJ), and (iii) TSP from RA to the ascending aorta (AA). A total of 24 patients with inadvertent ARP were identified. In 19 patients, penetration of the aorta was accomplished by the inner dilator, in 5 patients by the complete sheath. Previous cardiac surgery had been performed in six patients. There were 13 RA-to-NCS punctures, 2 RA-to-STJ punctures, and 9 RA-to-AA punctures. No cardiac tamponade (CT) occurred in patients with RA-to-NCS and RA-to-STJ punctures. In 8 of 9 patients with RA-to-AA puncture, CT occurred immediately requiring urgent pericardiocentesis and surgical repair. Two patients died after surgical repair. In the 16 patients without surgical therapy, no shunt from the AR to the RA was observed 3 months after the procedure. CONCLUSION: Aortic root puncture due to mislead TSP via NCS or STJ is usually not associated with a severe clinical course while ARP into the AA via the epicardial space generally leads to CT requiring surgical repair.

Rheumatic Mitral Valve Stenosis: Diagnosis and Treatment Options.

PURPOSE OF REVIEW: This review provides an update on rheumatic mitral stenosis. Acute rheumatic fever (RF), the sequela of group A ß-hemolytic streptococcal infection, is the major etiology for mitral stenosis (MS). RECENT FINDINGS: While the incidence of acute RF in the Western world had substantially declined over the past five decades, this trend is reversing due to immigration from non-industrialized countries where rheumatic heart disease (RHD) is higher. Pre-procedural evaluation for treatment of MS using a multimodality approach with 2D and 3D transthoracic and transesophageal echo, stress echo, cardiac CT scanning, and cardiac MRI as well as hemodynamic assessment by cardiac catheterization is discussed. The current methods of percutaneous mitral balloon commissurotomy (PMBC) and surgery are also discussed. New data on long-term follow-up after PMBC is also presented. For severe rheumatic MS, medical therapy is ineffective and definitive therapy entails PMBC in patients with suitable morphological mitral valve (MV) characteristics, or surgery. As procedural outcomes depend heavily on appropriate case selection, definitive imaging and interpretation are crucial. It is also important to understand the indications as well as morphological MV characteristics to identify the appropriate treatment with PMBC or surgery.

The morphologically right and left ventricles cannot be distinguished by their coronary arterial pattern.

OBJECTIVES: The morphologically right and left ventricles are distinguished from each other based on their internal anatomical features, because their external (epicardial) surfaces do not appear to have any distinguishing mark for such ventricular identification. Nevertheless, ventricular identification based on epicardial characteristics, if these were possible, would be interesting to surgeons, because this would enable them to identify each ventricle rapidly upon opening the chest. This made us curious as to whether or not the two ventricles may be distinguished based on their epicardial coronary arterial patterns, because this is the most obvious epicardial ventricular feature. METHODS: This idea led us to formulate the following 2 hypotheses: (i) The morphologically left ventricle is always the one that receives the higher number of the marginal arteries as compared to the morphologically right ventricle. (ii) Only the morphologically left ventricle receives the diagonal arteries from the anterior and posterior interventricular arteries. These hypotheses were tested in this anatomical observational study by examination of 98 normal and 398 congenitally malformed formaldehyde-preserved hearts encompassing most malformations, including rare ones and hearts in which 1 ventricle is hypoplastic. RESULTS: These examinations show that both hypotheses are false. CONCLUSIONS: The two ventricles cannot be distinguished from each other based on the number of marginal arteries that they receive or which one receives diagonal arteries; both ventricles may receive diagonal arteries from either or both interventricular arteries.

Morphological variability of the arterial valve in common arterial trunk and the concept of normality.

OBJECTIVE: Until now, no study established a morphometric evaluation of the truncal valve dysplasia and a description of its different presentation patterns. Thus, authors conducted an anatomopathological study describing the gross features and histological findings of the truncal valve. METHODS: 50 common arterial trunk (CAT) specimens were examined. The number of valvar leaflets was determined and valvar dysplasia was classified as absent, mild, moderate or severe. Selected leaflets were sectioned and submitted to histological analysis and linear measurements (thickness, length and area), besides quantification of collagen area fraction. RESULTS: 28 (56%) valves presented three, 15 (30%) four and 7 (14%) two leaflets. Valvar dysplasia was absent in 13 (26%) cases, mild in 19 (38%), moderate in 6 (12%) and severe in 12 (24%). A significant association was found between the presence of four leaflets and valvar dysplasia (p<0.001). Single coronary ostium was more common in two-leaflet cases than in three-leaflet cases (p=0.037). Leaflets medial thirds were thicker in the more dysplastic valves (p=0.006) and in those presenting anarchic collagen distribution (p=0.002). CONCLUSIONS: CAT semilunar valves present two main patterns. The first characterised by three leaflets and absent or mild dysplasia and the second by four leaflets and severe dysplasia. Still, great variability regarding thickness, microscopic organisation of the extracellular matrix and proportions of leaflets' dimensions exists, which may impact on the surgical outcomes.

Histological evidence of inflammatory reaction associated with fibrosis in the atrial and ventricular walls in a case-control study of patients with history of atrial fibrillation.

AIMS: Chronic inflammation in the atrial myocardium was shown to play an important role in the development of atrial fibrosis in patients with atrial fibrillation (AF). However, it is not clear to what extent atrial inflammatory reaction associated with AF extends on the ventricular myocardium. Our aim was to assess the extent of fibrosis and lymphomononuclear infiltration in human ventricular myocardium and explore its association with AF. METHODS AND RESULTS: Medical records from consecutive autopsies were checked for presence of AF. Heart specimens from 30 patients died from cardiovascular causes (64 ± 12 years, 17 men) were collected in three equal groups: no AF, paroxysmal AF, and permanent AF. Tissue samples were taken from the Bachmann's bundle, crista terminalis, posterior left atrium, left ventricle and right ventricle free walls and stained with Masson's trichrome for analysis of fibrosis extent. Immunohistochemistry was performed using antibodies against CD3- and CD45-antigens and quantified as number of antigen-positive cells per 1 mm2. Fibrosis extent, CD3+ and CD45+ cell counts were elevated in AF patients at all sites (P < 0.001 for all). Fibrosis extent demonstrated correlation with both CD3+ and CD45+ cell counts in the right (r = 0.781, P < 0.001 for CD45+ and r = 0.720, P < 0.001 for CD3+) and the left (r = 0.515, P = 0.004 for CD45+ and r = 0.573, P = 0.001 for CD3+) ventricles. Neither fibrosis nor inflammatory cell count showed association with either age or comorbidities. CONCLUSION: Histological signs of chronic inflammation affecting ventricular myocardium are strongly associated with AF and demonstrate significant correlation with fibrosis extent that cannot be explained by cardiovascular comorbidities otherwise.

Extracardiac Pulmonary-Systemic Connection via Persistent Levoatriocardinal Vein in Adults.

The levoatriocardinal vein is a very rare but clinically important intrathoracic venous anomaly that connects the systemic (cardinal) and pulmonary venous channels. We report 4 adults with pulmonary-systemic venous communications that can explain the morphology of the extracardiac interatrial shunting through the persistent levoatriocardinal vein. We discuss the imaging features of the 2 types of such communications: direct connection of the levoatriocardinal vein (1) with the left atrium and (2) with the left superior pulmonary vein in the absence of obstructive left heart disease. Accurate characterization of these diagnostically challenging cases is important because in addition to hemodynamic imbalance they are at risk of paradoxical embolism. Computed tomography and magnetic resonance imaging are noninvasive imaging techniques that should play increasingly important roles in the evaluation of these anomalies.

Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology--a position statement of the development, anatomy, and pathology ESC Working Group.

Congenital coronary artery anomalies are of major significance in clinical cardiology and cardiac surgery due to their association with myocardial ischaemia and sudden death. Such anomalies are detectable by imaging modalities and, according to various definitions, their prevalence ranges from 0.21 to 5.79%. This consensus document from the Development, Anatomy and Pathology Working Group of the European Society of Cardiology aims to provide: (i) a definition of normality that refers to essential anatomical and embryological features of coronary vessels, based on the integrated analysis of studies of normal and abnormal coronary embryogenesis and pathophysiology; (ii) an animal model-based systematic survey of the molecular and cellular mechanisms that regulate coronary blood vessel development; (iii) an organization of the wide spectrum of coronary artery anomalies, according to a comprehensive anatomical and embryological classification scheme; (iv) current knowledge of the pathophysiological mechanisms underlying symptoms and signs of coronary artery anomalies, with diagnostic and therapeutic implications. This document identifies the mosaic-like embryonic development of the coronary vascular system, as coronary cell types differentiate from multiple cell sources through an intricate network of molecular signals and haemodynamic cues, as the necessary framework for understanding the complex spectrum of coronary artery anomalies observed in human patients.

Juxtaposition of the atrial appendages: A nidus for thrombus in atriopulmonary Fontan?

Juxtaposition of atrial appendages is a rare cardiac congenital anomaly, usually associated with other cardiac malformations. Until now, it has not been linked to any significant clinical implications. We report cardiovascular magnetic resonance (CMR) findings of two adult patients who underwent atriopulmonary Fontan operation in the setting of left juxtaposition of the atrial appendages. The patients were in sinus rhythm at the time of the CMR study. Both patients had episodes of sustained atrial tachyarrhythmia requiring electrical cardioversion and were anticoagulated with warfarin with target INR 2-3. CMR images showed a thrombus located in the enlarged and juxtaposed right appendage in both patients. Blood flow frequently appears slow or sluggish in the dilated right atrium following atriopulmonary Fontan surgery. In addition, cine CMR suggested that blood flow reaches very low velocities in the massively dilated juxtaposed right atrial appendage cul-de-sac, thus potentially creating a substrate for clot formation. These findings propose that juxtaposed atrial appendages in atriopulmonary Fontan is an additional risk factor for clot formation, specifically in the dilated right atrial appendage on the left side juxtaposed with the left atrial appendage and that prophylactic anticoagulation is highly justified in these patients.

Systemic right ventricular fibrosis detected by cardiovascular magnetic resonance is associated with clinical outcome, mainly new-onset atrial arrhythmia, in patients after atrial redirection surgery for transposition of the great arteries.

BACKGROUND: We hypothesized that fibrosis detected by late gadolinium enhancement (LGE) cardiovascular magnetic resonance predicts outcomes in patients with transposition of the great arteries post atrial redirection surgery. These patients have a systemic right ventricle (RV) and are at risk of arrhythmia, premature RV failure, and sudden death. METHODS AND RESULTS: Fifty-five patients (aged 27±7 years) underwent LGE cardiovascular magnetic resonance and were followed for a median 7.8 (interquartile range, 3.8-9.6) years in a prospective single-center cohort study. RV LGE was present in 31 (56%) patients. The prespecified composite clinical end point comprised new-onset sustained tachyarrhythmia (atrial/ventricular) or decompensated heart failure admission/transplantation/death. Univariate predictors of the composite end point (n=22 patients; 19 atrial/2 ventricular tachyarrhythmia, 1 death) included RV LGE presence and extent, RV volumes/mass/ejection fraction, right atrial area, peak Vo(2), and age at repair. In bivariate analysis, RV LGE presence was independently associated with the composite end point (hazard ratio, 4.95 [95% confidence interval, 1.60-15.28]; P=0.005), and only percent predicted peak Vo(2) remained significantly associated with cardiac events after controlling for RV LGE (hazard ratio, 0.80 [95% confidence interval, 0.68-0.95]; P=0.009/5%). In 8 of 9 patients with >1 event, atrial tachyarrhythmia, itself a known risk factor for mortality, occurred first. There was agreement between location and extent of RV LGE at in vivo cardiovascular magnetic resonance and histologically documented focal RV fibrosis in an explanted heart. There was RV LGE progression in a different case restudied for clinical indications. CONCLUSIONS: Systemic RV LGE is strongly associated with adverse clinical outcome especially arrhythmia in transposition of the great arteries, thus LGE cardiovascular magnetic resonance should be incorporated in risk stratification of these patients.

"Isolated Atrial Inversion" Without Transposition Physiology: Yet Another "Twisted Heart".

Atrial inversion (or mirror-imaged atrial arrangement) occurring in isolation, that is, without corresponding mirror imagery of the viscera, has been previously shown with discordant atrioventricular connections resulting in transposition physiology. We hereby report a case of "isolated atrial inversion" wherein atrioventricular connections were concordant owing to the presence of criss-crossing of the ventricular inflows.

Substrates of atrial arrhythmias: histological insights from patients with congenital heart disease.

BACKGROUND: The impact of overload duration and age on remodelling process in human atria remains controversial. We analysed histological markers of right atrial (RA) remodelling in CHD patients in order to provide some insights into impacts of age and overload duration on substrates of atrial arrhythmias. METHODS: Sixty-five CHD patients who underwent initial cardiac surgery were enrolled (median age 18 years). Patients with dominant left atrial overload were excluded. RA tissues resected from CHD patients during surgery were examined by means of histology and immunohistochemistry and compared with RA tissues from age-matched control hearts from post-mortem (n=22, median age 22 years). Patient histories of preoperative SVTs and echocardiography were also examined. RESULTS: The greatest extent of fibrosis, the largest myocyte diameter and the longest capillary distance and the most CD45-positive cell infiltration was observed in CHD samples with SVT, followed by CHD without SVT and then control samples. All histological changes were correlated with age in CHD samples (r=0.462, 0.718, 0.529 and 0.447, respectively) with relatively steep and continuous manner, whereas only myocyte diameter was correlated with age in control samples (r=0.576). RA dimensions and area obtained from echocardiography also correlated with histological markers in CHD patients. CONCLUSIONS: Dominant and chronic RA overload due to CHD resulted in time-course related RA structural remodelling, which could provide the background for atrial arrhythmia. The overload duration, rather than age, seems to be a key factor for atrial histological degeneration in the cohort of CHD.

Histopathology of the great vessels in patients with pulmonary arterial hypertension in association with congenital heart disease: large pulmonary arteries matter too.

BACKGROUND: Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome. METHODS: We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities. RESULTS: Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (p<0.0001) and correlated positively with larger PT diameters (ρ=0.812, p<0.0001) and the degree of medial wall hypertrophy (ρ=0.749, p<0.0001). CONCLUSIONS: Chronic PAH in association with CHD results in marked macroscopic and histological abnormalities in the large pulmonary arteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort.

Magnetic navigation in adults with atrial isomerism (heterotaxy syndrome) and supraventricular arrhythmias.

AIMS: We analysed the type and mechanism of supraventricular arrhythmias encountered in a series of symptomatic adults with atrial isomerism undergoing catheter ablation procedures. METHODS AND RESULTS: The study population included consecutive adults with atrial isomerism who had previously undergone surgical repair or palliation of the associated anomalies. Patients underwent electrophysiological study for symptomatic arrhythmia in our institution between 2010 and 2012 using magnetic navigation in conjunction with CARTO RMT and three-dimensional (3D) image integration. Eight patients (five females) with a median age of 33 years [interquartile range (IQR) 24-39] were studied. Access to the cardiac chambers of interest was obtained retrogradely via the aorta using remotely navigated magnetic catheters in six patients. Radiofrequency ablation successfully targeted twin atrioventricular (AV) nodal reentrant tachycardia in two patients, atrial fibrillation (AF) in three, focal atrial tachycardia (AT) mainly originating in the left-sided atrium in four patients, and macro-reentrant AT dependent on a right-sided inferior isthmus in three patients. The median fluoroscopy time was 3.0 min (IQR 2-11). After a median follow-up of 10 months (IQR 6-21), five of the ablated patients are free from arrhythmia; two patients experienced episodes of self-terminated AF and AT, respectively, within one month post-ablation; the remaining patient had only non-sustained AT during the electrophysiological study and was managed medically. CONCLUSION: Various supraventricular tachycardia mechanisms are possible in adults with heterotaxy syndrome, all potentially amenable to radiofrequency ablation. The use of remote magnetic navigation along with 3D mapping facilitated the procedures and resulted in a short radiation time.

The prevalence and impact of deep clefts in the mitral leaflets in mitral valve prolapse.

AIMS: Deep clefts are a cause of early failure of mitral valve repair, but it is not known whether clefts represent normal morphology, or whether they occur more frequently in mitral valve prolapse (MVP). METHODS AND RESULTS: Deep clefts were defined as indentations extending ≥ 50% of the depth of the mitral valve leaflet. Using trans-oesophageal echo (TOE), 3D zoom images were acquired of the mitral valve in 176 patients: 76 patients with MVP, 43 patients with alternative causes of mitral regurgitation (MR), and 57 controls. Three-dimensional TOE results were corroborated with findings made at surgery for a subset of patients who subsequently underwent mitral valve surgery. An assessment of the proportion of the valve that was prolapsing was documented, and correlated to the number of clefts. The relationship of clefts to the region of prolapse or flail was recorded. Three-dimensional TOE was 93% sensitive and 92% specific for detecting clefts. Clefts were documented in 84% of patients with MVP, but significantly less frequently in patients with alternative MR (16%; P < 0.001) and controls (12%, P < 0.001). Clefts always appear in prolapsing regions or framing them, and the number of clefts increased in patients with more extensive prolapse. CONCLUSION: Clefts are frequently seen in MVP, but are uncommon in patients without this diagnosis. They occur in greater numbers as a larger proportion of the valve prolapses. They may play an important role in the development of MVP.