Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation

Myxomatous mitral valve prolapse (MVP) is the most common cardiac valvular abnormality in industrialized countries and a leading cause of mitral valve surgery for isolated mitral regurgitation. The key role of valvular interstitial cells (VICs) during mitral valve development and homeostasis has been recently suggested, however little is known about the molecular pathways leading to MVP. We aim to characterize bone morphogenetic protein 4 (BMP4) as a cellular regulator of mitral VIC activation towards a pathologic synthetic phenotype and to analyze the cellular phenotypic changes and extracellular matrix (ECM) reorganization associated with the development of myxomatous MVP. Microarray analysis showed significant up regulation of BMP4-mediated signaling molecules in myxomatous MVP when compared to controls. Histological analysis and cellular characterization suggest that during myxomatous MVP development, healthy quiescent mitral VICs undergo a phenotypic activation via up regulation of BMP4-mediated pathway. In vitro hBMP4 treatment of isolated human mitral VICs mimics the cellular activation and ECM remodeling as seen in MVP tissues. The present study characterizes the cell biology of mitral VICs in physiological and pathological conditions and provides insights into the molecular and cellular mechanisms mediated by BMP4 during MVP. The ability to test and control the plasticity of VICs using different molecules may help in developing new diagnostic and therapeutic strategies for myxomatous MVP.     

Unravelling the proteome of degenerative human mitral valves

Degenerative mitral valve disease (DMVD), which includes the syndromes of mitral valve prolapse (MVP) and flail leaflet, is a common valvular condition which can be complicated by mitral regurgitation and adverse cardiovascular outcomes. Although several genetic and other studies of MVP in dog models have provided some information regarding the underlying disease mechanisms, the proteins and molecular events mediating human MVP pathogenesis have not been unraveled. In this study, we report the first large‐scale proteome profiling of mitral valve tissue resected from patients with MVP. A total of 1134 proteins were identified, some of which were validated using SWATH‐MS and western blotting. GO annotation of these proteins confirmed the validity of this proteome database in various cardiovascular processes. Among the list of proteins, we found several structural and extracellular matrix proteins, such as asporin, biglycan, decorin, lumican, mimecan, prolargin, versican, and vinculin, that have putative roles in the pathophysiology of MVP. These proteins could also be involved in the cardiac remodeling associated with mitral regurgitation. All MS data have been deposited in the ProteomeXchange with identifier PXD000774 ( http://proteomecentral.proteomexchange.org/dataset/PXD000774 ).     

A Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 11p15.4

Mitral valve prolapse (MVP) is a common cardiovascular abnormality in the United States, occurring in approximately 2.4% of the general population. Clinically, patients with MVP exhibit fibromyxomatous changes in one or both of the mitral leaflets that result in superior displacement of the leaflets into the left atrium. Although often clinically benign, MVP can be associated with important accompanying sequelae, including mitral regurgitation, bacterial endocarditis, congestive heart failure, atrial fibrillation, and even sudden death. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependent penetrance. In this report, we describe the results of a genome scan and show that a locus for MVP maps to chromosome 11p15.4. Multipoint parametric analysis performed by use of GENEHUNTER gave a maximum LOD score of 3.12 for the chromosomal region immediately surrounding the four-marker haplotype D11S4124-D11S2349-D11S1338-D11S1323, and multipoint nonparametric analysis (NPL) confirms this finding (NPL=38.59; P=.000397). Haplotype analysis across this region defines a 4.3-cM region between the markers D11S1923 and D11S1331 as the location of a new MVP locus, MMVP2, and confirms the genetic heterogeneity of this disorder. The discovery of genes involved in the pathogenesis of this common disease is crucial to understanding the marked variability in disease expression and mortality seen in MVP.     

二尖瓣成形术与二尖瓣生物瓣置换术治疗风湿性二尖瓣重度关闭不全的效果比较

目的:探讨二尖瓣成形术(Mitral valve plasty,MVP)与二尖瓣生物瓣置换术(Mitral valve replacement,MVR)治疗风湿性二尖瓣重度关闭的临床疗效和安全性。方法:选择我院2014年1月至2019年1月收治的因风湿性二尖瓣重度关闭而行二尖瓣成形术或二尖瓣生物瓣置换术的患者60例,其中二尖瓣成形术组(MVP组)27例,二尖瓣生物瓣置换术组(MVR组)33例。比较两组患者的围手术期各项指标,治疗前后的心功能指标(左心室射血分数,左心房内径、左心室收缩末期内径、左心室舒张末期内径)及二尖瓣反流情况以及术后并发症的发生情况。结果:(1)MVP组患者的手术时间、体外循环时间均明显长于MVR组(P0.05);而术中出血量、呼吸机使用时间、住院时间MVP组均显著低于MVR组(P0.05);(2)术后,MVP组的LVEF和LVEDD水平高于MVR组,而LAD和LVESD水平则低于MVR组(P 0.05);(3)出院前及末次随访时,MVP组二尖瓣反流发生率与MVR组相比差异均无统计学意义(P0.05)。(4)MVP组患者的术后并发症发生率低于MVR组(P 0.05)。结论:二尖瓣成形术治疗风湿性二尖瓣重度关闭的临床疗效和安全性优于二尖瓣生物瓣置换术,但术者需严格掌控MVP的手术适应症。     

Molecular and developmental mechanisms of congenital heart valve disease

Congenital heart disease occurs in approximately 1% of all live births and includes structural abnormalities of the heart valves. However, this statistic underestimates congenital valve lesions, such as bicuspic aortic valve (BAV) and mitral valve prolapse (MVP), that typically become apparent later in life as progressive valve dysfunction and disease. At present, the standard treatment for valve disease is replacement, and approximately 95,000 surgical procedures are performed each year in the United States. The most common forms of congenital valve disease include abnormal valve cusp morphogenesis, as in the case of BAV, or defects in extracellular matrix (ECM) organization and homeostasis, as occurs in MVP. The etiology of these common valve diseases is largely unknown. However, the study of murine and avian model systems, along with human genetic linkage studies, have led to the identification of genes and regulatory processes that contribute to valve structural malformations and disease. This review focuses on the current understanding and therapeutic implications of molecular regulatory pathways that control valve development and contribute to valve disease.     

Increased prevalence of mitral valve prolapse in patients with migraine.

Patients with classic migraine (69 women and 31 men) selected randomly from a practice list of over 1000 were matched for age, sex and neighbourhood with 100 people who did not have headache problems, and both groups underwent M-mode and two-dimensional echocardiography and clinical examination by cardiologists blinded to the subjects'' clinical status. The mean ages were 34.9 +/- 11.3 years for the migraine group and 33.1 +/- 9.9 years for the control group. Definite and possible mitral valve prolapse (MVP), diagnosed according to predefined echocardiographic criteria, were found about twice as often in the migraine group as in the control group (in 15 v. 7 and 16 v. 8 patients respectively); the echocardiograms were definitely normal in 69 migraine patients and 85 controls (chi 2 = 8.39, p less than 0.025). Altogether 25% of the migraine group and 11% of the control group had evidence of MVP from a combination of the echocardiographic and auscultatory findings (chi 2 = 5.72, p less than 0.025). The odds ratio was 2.7, with 95% confidence limits of 1.17 and 6.29. The association between migraine and MVP has implications for the understanding of platelet abnormalities and episodes of cerebral ischemia occurring in both these conditions.     

Orthostatic hypotension,catecholamines, and alpha-adrenergic receptors in mitral valve prolapse.

The reported association of mitral valve prolapse with autonomic dysfunction and neuroendocrine abnormalities is derived from studies of patients selected because of symptoms or specifically referred for investigation. To determine whether such associations occur in nonreferred and unselected women with mitral valve prolapse, we measured blood pressure, heart rate, and norepinephrine response to standing in 13 volunteers with mitral valve prolapse and in 11 control subjects. Platelet alpha-adrenergic receptor quantity and affinity on standing also were determined in all persons. No significant differences were found between the groups in any of these measurements. Although small subsets of women with mitral valve prolapse may indeed have associated neuroendocrine epiphenomena and autonomic dysfunction, it is probably incorrect to generalize these findings to the vast spectrum of those with mitral valve prolapse.     

MITRAL VALVE PROLAPSE AND CONGENITAL PYLORIC STENOSIS IN IDENTICAL TWINS

Both congenital pyloric stenosis and the mitral valve prolapse syndrome are reported to have a familial incidence. Although mitral valve prolapse has been documented in twins, only one case has received echocardiographic confirmation. The present account describes typical symptomatic mitral valve prolapse in identical twins, both of whom had undergone surgery during infancy to correct congenital pyloric stenosis.     

Mitral valve prolapse detected during hemodynamic studies

To estimate frequency of the posterior mitral valve leaflet prolapse in routinely performed left ventriculography, 1000 consecutive ventriculograms of the right anterior oblique projection were analyzed. A group of patients consisted of 511 women and 489 men at mean age 46,5 years. Clinical diagnosis of heart lesions, myocardial disease, pulmonary hypertension or arrhythmias were indications for hemodynamic studies. In the investigated group of patients, there were no patients with clinical diagnosis of the coronary artery disease. Prolapse of the posterior mitral valve leaflet was diagnosed in 59 patients. Idiopathic mitral valve prolapse was diagnosed in 10 patients. Prolapse of the posterior mitral valve leaflet was most frequent in atrial septal defect (16.6%), myocardial lesion (12.5%), and after mitral commissurotomy (8.9%). Posterior mitral valve leaflet prolapse is not a frequent anomaly in routinely performed left ventriculography. Relatively often occurrence of the mitral valve prolapse in atrial septal defect and only occasional in the aortic lesions and dilated cardiomyopathy seems to point out at a role of the left ventricle size in pathogenesis of this syndrome.     

Coexistence of von Willebrand's disease with mitral valve prolapse]

The authors present the case of mitral valve prolapse. In a young woman with three-year history of systematically treated epilepsia mitral valve prolapse with a spurious string within left ventricle has been diagnosed echocardiographically in coincidence with the symptoms of haemorrhagic diathesis of von Willebrand type in form of haemoptysis and or/massive haemorrhages in mouth occasionally being preceded by heart rhythm disturbances. No local changes have been observed in otorhinolaryngologic examination, bronchoscopy and gastroscopy. Possible mutual dependence of 3 above stated abnormalities is being discussed. It is not excluded, that mitral prolapse may constitute the primary entity and epilepsia is of secondary character as a result of cerebral ischaemic incidents or of cerebral embolism. It is also a matter of discussion to what extent abrupt haemodynamic disturbances connected with critical fall of systemic blood pressure due to mitral prolapse may influence the haemorrhagic episodes.     

Arrhythmia in patients with mitral valve prolapse syndrome and the status of the sympathetic nervous system]

The study aimed at evaluating a possible relationship between the adrenergic system tone determined with the excretion of catecholamines with the urine and an incidence of the ventricular arrhythmias in patients with the mitral valve prolapse. The study included 20 patients (13 women and 7 men aged between 20 and 50 years; mean = 31.6 years) with the mitral valve prolapse syndrome diagnosed with the aid of the patients' history, physical examinations and echocardiography. Echocardiograms have shown anterior mitral leaflet prolapse in 7 patients, posterior mitral leaflet prolapse in 8 patients, and both mitral leaflets prolapse in the remaining 5 patients. Daily excretion of adrenaline and noradrenaline was measured with Van Euler and Lishajko's fluorimetric technique. Cardiac arrhythmias were determined with a 24-hour ECG monitoring and classified according to Lown. Premature ventricular contractions of class I were seen in 1 patient, of class II in 5, class III in 1, class IV in 2, and class V in 3 patients. Holter monitoring technique did not show the arrhythmias in 8 patients. Daily adrenaline and noradrenaline excretion with the urine was within the normal values (3.2-30.8 ug and 0.2-16.2 ug, respectively) in all examined patients. Daily urine noradrenaline was higher in patients with serious ventricular arrhythmias (Lown's class V) than mean values in the whole examined group.     

Programmed atrial and ventricular stimulation in patients with mitral valve prolapse--a personal experience]

Electrophysiological tests were performed in 60 patients aged between 18 and 63 years (mean age 38 years), and divided into two groups: with mitral valve leaves prolapse syndrome, and without this abnormality, in whom no other heart disease was diagnosed. Refraction of the right atrium, atrio-ventricular node, and right ventricle was evaluated together with cardiac response to different types of electrostimulation. A supraventricular dysrhythmia (most frequently atrial fibrillation) has been produced in 17 patients (42.5%) with mitral valve leaves prolapse syndrome whereas in the control group the same was produced in 2 patients (10%). Programmed stimulation of the ventricles did not produce ventricular tachycardia in none patient of both groups. Multiple ventricular beats have been produced in 3 patients with mitral valve prolapse syndrome and pairs of ventricular beats in other 3 patients of this group. Results suggest that "arrhythmogenic tendency", especially supraventricular dysrhythmia is more frequent in patients with mitral valve prolapse syndrome than in the general population.     

肥厚梗阻性心肌病的外科治疗

目的:总结肥厚室间隔切除术治疗肥厚梗阻性心肌病的手术效果,探讨外科治疗策略。方法:2002年3月至2010年10月,外科手术治疗33例肥厚梗阻性心肌病病人。其中男16例,女17例;年龄13～59岁,平均(42.7±13.6)岁;左室流出道压差(LVOTGP)70～120 mmHg(1 mmHg=0.133Kpa),平均(95.0±22.6)mmHg。其中合并二尖瓣关闭不全24例,主动脉瓣关闭不全7例,升主动脉增宽3例,冠心病2例。手术在全麻低温体外循环下完成,按常规经主动脉切口行室间隔心肌切除术,同期完成二尖瓣置换术(MVR)7例,二尖瓣成形术(MVP)7例,二尖瓣、主动脉瓣成形术(MVP+AVP)5例,二尖瓣、升主动脉成形术3例,二尖瓣、主动脉瓣成形、冠状动脉旁路移植术(MVP+AVP+CABG)2例。分析比较病人术前超声心动图(UCG),术中经食管心脏超声(TEE),以及术后1周、3月、6月、1年超声心动图结果。结果:手术死亡1例(3.0%,1/33例),主要死因为严重低心排综合症以及多脏器功能衰竭。二次开胸止血1例(3.0%,1/33例)。术中经食管心脏超声示所有病人二尖瓣前叶收缩期前向运动现象(SAM征)消失。存活病人手术效果良好,解剖狭窄解除,峰值压差降低,SAM现象基本消失。远期随访生存病人症状消失,生活质量明显改善,心功能I～II级,无远期死亡、并发症或再次手术。结论:外科治疗肥厚梗阻型心肌病具有良好的手术效果。了解病生理过程、术中仔细探察、手术切除彻底是手术成功的关键。     

肥厚梗阻性心肌病的外科治疗

目的：总结肥厚室间隔切除术治疗肥厚梗阻性心肌病的手术效果,探讨外科治疗策略。方法：2002年3月至2010年10月,外科手术治疗33例肥厚梗阻性心肌病病人。其中男16例,女17例;年龄13～59岁,平均（42.7±13.6）岁;左室流出道压差（LVOTGP）70～120 mmHg（1 mmHg=0.133Kpa）,平均（95.0±22.6）mmHg。其中合并二尖瓣关闭不全24例,主动脉瓣关闭不全7例,升主动脉增宽3例,冠心病2例。手术在全麻低温体外循环下完成,按常规经主动脉切口行室间隔心肌切除术,同期完成二尖瓣置换术（MVR）7例,二尖瓣成形术（MVP）7例,二尖瓣、主动脉瓣成形术（MVP＋AVP）5例,二尖瓣、升主动脉成形术3例,二尖瓣、主动脉瓣成形、冠状动脉旁路移植术（MVP＋AVP＋CABG）2例。分析比较病人术前超声心动图（UCG）,术中经食管心脏超声（TEE）,以及术后1周、3月、6月、1年超声心动图结果。结果：手术死亡1例（3.0%,1/33例）,主要死因为严重低心排综合症以及多脏器功能衰竭。二次开胸止血1例（3.0%,1/33例）。术中经食管心脏超声示所有病人二尖瓣前叶收缩期前向运动现象（SAM征）消失。存活病人手术效果良好,解剖狭窄解除,峰值压差降低,SAM现象基本消失。远期随访生存病人症状消失,生活质量明显改善,心功能I～II级,无远期死亡、并发症或再次手术。结论：外科治疗肥厚梗阻型心肌病具有良好的手术效果。了解病生理过程、术中仔细探察、手术切除彻底是手术成功的关键。     

Abnormal Gs function in mitral valve prolapse dysautonomia is not associated with abnormal alpha S cDNA sequence.

We have previously shown that a subset of patients with mitral valve prolapse and hyperadrenergic symptoms has enhanced isoprenaline-stimulated beta-adrenergic receptor high-affinity state formation (supercoupling) and increased adenylyl cyclase activity due to abnormal signal transduction by the stimulatory guanine nucleotide regulatory protein (Gs). In this study we looked for an alteration of the nucleotide coding sequence of the gene for alpha s, the subunit of Gs that is directly responsible for formation of the high affinity state and adenylyl cyclase activation, by cloning and sequencing the alpha s cDNA from neutrophils of 4 symptomatic patients and 1 control. No difference was observed between patients and control in the alpha s cDNA sequence. The splice variant concentrations in the fully expressed protein were also grossly unchanged in five patients and four controls. These data show that a primary alteration of the alpha s gene coding sequence is not responsible for defective Gs-associated signal transduction in dysautonomic MVP patients, and suggest that the molecular lesion could be an abnormal posttranslational modification of alpha s, a defect in the beta or gamma subunits of Gs, or an unusual interaction between the subunits in the Gs of these patients.     

Surgery Issue: Solving the Puzzle of Chronic Ischemic Mitral Regurgitation

Chronic ischemic mitral regurgitation is a prevalent problem among patients following a myocardial infarction. Until recently, the pathophysiology was poorly understood, resulting in surgical strategies with suboptimal results and limited durability. The surgical approach has evolved from revascularization alone to an additional mitral valve procedure, replacement, or repair. When the valve was repaired, isolated annuloplasty was performed. The dilemma that surgeons had when repairing a mitral valve was which type of ring to use and what size. In all series with annuloplasty alone, the results were poor with very high recurrence rates. The primary feature of ischemic mitral regurgitation is a prolapse of the anterior leaflet at A3 ± A2. This prolapse can be caused by fibrotic elongation of the papillary muscle supporting A3 ± A2 or tethering of P3 by a ballooning posterior left ventricular wall. Using a technique that corrects this prolapse with Gore-Tex neochords, we have achieved excellent results with effective and durable correction of the ischemic mitral regurgitation.     

Arrhythmia in patients with mitral valve prolapse]

An incidence of cardiac arrhythmias was evaluated in 119 patients with mitral valve prolapse. The disease was made basing on the results of clinical symptoms, echo-, angio- and phonocardiography. Electrocardiograms were recorded from the standard 12 lead and Holter technique for 24 hours in each patient to assess present arrhythmias. It was found that the most frequent cardiac arrhythmias accompanying mitral valve prolapse are ventricular extrasystolic contractions of Lown's class 1a and 1b. Only examination of strictly selected groups of patients (age groups with or without co-existing mitral valve insufficiency for adequate period of time) will facilitate precise evaluation of an incidence of different cardiac arrhythmias accompanying the underlying disease.     

Visual complications of mitral leaflet prolapse.

Four young women and six older men with mitral leaflet prolapse presented with visual disturbances consistent with embolism in the ophthalmic or posterior cerebral circulation. Cardiac arrhythmias were common, but these are rarely associated with focal ischaemia. The evidence that mitral leaflet prolapse caused the embolism in these patients is suggestive but not conclusive. Further studies are needed. All patients with acute cerebral or ocular ischaemia should undergo through cardiovascular assessment, which should include routine echocardiography.     

Robotic artificial chordal replacement for repair of mitral valve prolapse

Artificial chordal replacement (ACR) has emerged as a superior method of mitral valve repair with excellent early and late efficacy. It is also ideal to combine with robotic techniques for correction of mitral prolapse, and this article presents a current method of robotic Gore-Tex ACR. Patients with isolated posterior leaflet prolapse are approached with the fourth-generation DaVinci robotic system and endoaortic balloon occlusion. A pledgetted anchor stitch is placed in a papillary muscle, and a 2-o Gore-Tex suture is passed through the anchor pledget. After full annuloplasty ring placement, the Gore-Tex suture is woven into the prolapsing segment and positioned temporarily with robotic forceps. Chordal length is then "adjusted" by lengthening or shortening the temporary knot over 1-cm increments as the valve is tested by injection of cold saline into the ventricle. After achieving good leaflet position and valve competence, the chord is tied permanently. The "adjustable" ACR procedure preserves leaflet surface area and produces a competent valve in the majority of patients. Postoperative transesophageal echo shows a large surface area of coaptation. Patient recovery is facilitated by the minimally invasive approach, while long-term stability of similar open ACR techniques have been excellent with a 2% to 3% failure rate over 10 years of follow-up. Robotic Gore-Tex ACR without leaflet resection is a reproducible procedure that simplifies mitral repair for prolapse. The outcomes observed in early robotic applications have been excellent. It is suggested that most patients with simple prolapse might validly be approached in this manner.     

A genetic study of panic disorder pedigrees.

Pedigree analysis is done on 19 kindreds of panic disorder, and the results suggest that this disorder is transmitted as an autosomal dominant trait. Seven of these 19 kindreds were ascertained through a panic disorder proband with mitral valve prolapse. When the analysis is done omitting these seven kindreds, the results also suggest that panic disorder without prolapse is transmitted as an autosomal dominant trait.