The genetics of mitral valve prolapse

Mitral valve prolapse (MVP) is a very common clinical condition that refers to a systolic billowing of one or both mitral valve leaflets into the left atrium. Improvements of echocardiographic techniques and new insights in mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. MVP can be sporadic or familial, demonstrating autosomal dominant and X-linked inheritance. Three different loci on chromosomes 16, 11 and 13 have been found to be linked to MVP, but no specific gene has been described. Another locus on chromosome X was found to cosegregate with a rare form of MVP called 'X-linked myxomatous valvular dystrophy'. MVP is more frequent in patients with connective tissue disorders including Marfan syndrome, Ehlers-Danlos and osteogenesis imperfecta. The purpose of this review is to describe previous studies on the genetics and prevalence of MVP. The report warrants the need for further genetically based studies on this common, albeit not fully understood, clinical entity.     

The prevalence of mitral valve prolapse in healthy men and women in Sweden. An echocardiographic study

An asymptomatic population of 100 women and 101 men was studied with M-mode echocardiogram to determine the prevalence of mitral valve prolapse (MVP). One of the two patterns characteristic for MVP was found in 8% of the females and 7% of the males. The diastolic mitral valve excursion was significantly higher in the MVP group (p less than or equal to 0.001). A typical M-mode pattern in combination with a high mitral valve excursion probably enhances the diagnostic specificity.     

Panic attacks in families of patients with mitral valve prolapse

One explanation for the association between mitral valve prolapse (MVP) and panic attacks in clinic populations is that panic attacks represent a set of symptoms caused by mitral prolapse. Since mitral prolapse is often familial, this hypothesis predicts a higher incidence of panic attacks in relatives of persons with prolapse than the general population and the incidence of panic attacks in the relatives should be independent of panic attacks in the proband. We interviewed 50 probands with mitral prolapse and obtained family history data on panic attacks in their first degree relatives. The incidence of panic attacks in these relatives was 4.5 +/- 1.4% which is consistent with control rates which we have reported in previous studies. Twelve MVP probands also had panic attacks. The incidence of panic attacks in their relatives (15.7 +/- 5.1%) was significantly higher than the rate found among relatives of 38 probands without panic attacks (1.2 +/- 0.8%). These findings are consistent with the hypothesis that mitral prolapse and panic attacks are segregating independently in these families.     

Dermatoglyphs in children with mitral valve prolapse.

The dermatoglyphs of 50 Singapore school children with mitral valve prolapse (MVP) were studied, with special reference to the frequency of digital arches. The MVP was diagnosed clinically and substantiated by two dimensional echocardiography. In the study there were 35 Chinese and 15 Malay children, with ages ranging from 6 to 19 years. Four Chinese children had one or more arches on the digits but none of the Malay children was found to have arches. It was shown that the frequency of arches on the digits was not significantly higher than that among 50 controls (who were shown not to have MVP on two dimensional echocardiography) or when compared with the frequency of arches among the Chinese and Malay population in Singapore (2.0% and 2.9% respectively). No other dermatoglyphic abnormalities (including atd angle) were found.     

Evaluation of surgically excised mitral valves: Revised recommendations based on changing operative procedures in the 1990s

In 1990, 95 mitral valves from 54 women and 41 men (mean age, 61 years; age range, 8 to 85 years) were replaced (76%) or repaired (24%) at the Mayo Clinic. Functionally, 58% of the valves were purely regurgitant (MR), 25% were stenotic and regurgitant (MS-MR), and 17% were purely stenotic (MS). Postinflammatory (presumably rheumatic) disease accounted for 100% of MS cases, 92% of MS-MR cases, and 16% of MR cases. Other causes of pure MR included floppy valves (49%), ischemic heart disease (13%), infective endocarditis (9%), miscellaneous (9%), and indeterminate (4%). Thus, postinflammatory disease represented the major cause of both mitral stenosis (MS and MS-MR) and overall mitral valve disease in our surgical population. In contrast, floppy valves were the most commonly observed cause of pure MR. Among postinflammatory valves, 55% were completely excised and 45% had only the anterior leaflet removed; all were replaced. In contrast, floppy valves were incompletely excised in 96%; 67% were repaired and only 33% were replaced. Because mitral valves frequently are incompletely excised, rendering an accurate etiologic diagnosis requires not only a morphologic assessment of resected tissues but also a knowledge of the clinical history, operative details, and functional state of the valve.     

Comparison of outcome among double, bifoil and Inoue balloon techniques for percutaneous mitral valvuloplasty in mitral stenosis.

The efficacy and complications of three different methods of percutaneous mitral valvuloplasty (PMV) were evaluated in 245 patients with mitral stenosis (MS). Eight six patients (35%) had severe MS defined in the mitral valve area (MVA) less than 1.0 cm2 (0.8 +/- 0.2) and Echoscore greater than or equal to 8(8.9 +/- 1.1). The results including post MCA greater than or equal to 1.5cm2 and complications, i.e, increment of mitral regurgitation (MR) greater than or equal to +1 and atrial septal defect (ASD) with Qp/Qs greater than or equal to 1.5 were compared in overall and in severe MS groups. There was no statistically significant difference in size of MVA before and after PMV between overall patients group and severe mitral stenosis group (0.8 +/- 0.1 vs 1.7 +/- 0.4cm2 in the double technique, 0.8 +/- 0.2 vs 1.5 +/- 0.3cm2 in the Bifoil technique and 0.7 +/- 0.2 vs 1.8 +/- 0.3cm2 in the Inoue technique. p: NS). However, a significantly larger number of patients in the severe MS group had better MVA with the double than the Bifoil technique [MVA greater than or equal to 1.5cm2; 42 (72%) vs 6 (46%), p less than 0.005] whereas higher complications were observed with the Bifoil than the Inoue technique (MR greater than or equal to +1; 9 (69%) vs 4 (27%), ASD (Qp/Qs greater than or equal to 1.5' 6 (46%) vs 2 (13%) p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Valve replacement for chronic mitral insufficiency; long-term follow up using technetium pertechnetate scintigraphy

Technetium Pertechnetate Scintigraphy was performed in 12 patients (9 men and 3 women, average age 48 +/- 13 years) on an average 19.8 +/- 11 months after valve replacement for chronic mitral insufficiency. Preoperative conventional ventriculography had revealed increased enddiastolic and endsystolic volumes (230.9 +/- 66 resp. 73.5 +/- 26 ml). 59.4 +/- 9% of the stroke volume (157.5 +/- 47 ml) regurgitated into the left atrium. Ejection-fraction (67.7 +/- 6%) was normal in all cases. Postoperative first pass technique was employed using a fast multicrystal camera (Baird Atomic, system 77). Volumes were assessed measuring normalized total count rate (count integral of the left ventricle divided by the maximum count density). 19.8 +/- 11 months after valve replacement enddiastolic and endsystolic volumes revealed normal at rest (121.8 +/- 38 resp. 52.8 +/- 35 ml) and after maximum exercise (122.0 +/- 29 resp. 37.6 +/- 22 ml). Ejection fraction responded physiologically to exercise by rising from 57.7 +/- 12 to 69.7 +/- 10%.     

Prevalence of mitral valve prolapse in hypertension

Mitral valve prolapse was found in one of 133 patients with hypertension (0.75 percent) studied by two-dimensional echocardiography. This rarity may be related to the presence of hypertrophied papillary muscles that probably pull the chordae tendinae and mitral valve leaflets away from the left atrium in systole, thus preventing their eversion and prolapse.     

Epidemiology of symptomatic mitral valve prolapse in black patients.

This study analyzed the charts of 743 black patients who visited the emergency rom of a Nashville Hospital with symptoms of chest pain, palpitation, or fatigue. One hundred sixty-five met the criteria for the diagnosis of mitral valve prolapse (MVP). Epidemiologic factors of symptomatic MVP in blacks (ie, symptoms reported based on age and sex) were examined to determine whether there are significant differences in the prevalence of symptomatic MVP with relation to black males and females. Similarities were found in the patterns of the ages of both males and females and the symptoms that were reported. No significant differences were found between black males and females, which does not support previous findings.     

二尖瓣双病变和联合瓣膜病变二尖瓣口面积的测定

目的∶探讨二尖瓣双病变和联合瓣膜病变二尖瓣口面积（ＭＶＡ）的准确测定方法。材料与方法∶分别用二维超声（２ＤＥ）、压差减半时间（ＰＨＴ）、彩色多普勒二尖瓣口血流截面积（ＣＤＦ）和椭圆形面积法（ＣＤＪ）测定４３ 例风湿性心脏病二尖瓣狭窄（ＭＳ）拟行人工瓣置换术患者的ＭＶＡ,其中合并主动脉瓣反流（ＭＳ＋ ＡＲ） １０ 例,合并二尖瓣反流（ＭＳ＋ ＭＲ） １２ 例,（ＭＳ＋ ＭＲ＋ ＡＲ） ２１ 例,并与手术标本的实测面积（ＯＰ）相比较。结果∶ＣＤＦ法三组均为高度相关;２ＤＥ法ＭＳ＋ ＡＲ组为良好相关,其余两组亦为高度相关;ＰＨＴ法三组虽为高度相关,但在ＭＳ＋ ＭＲ和ＭＳ＋ ＭＲ＋ ＡＲ组显著低估了ＯＰ;ＣＤＪ法三组均显著低估了ＯＰ。结论∶二尖瓣狭窄合并二尖瓣反流或同时并主动脉瓣反流但以二尖瓣反流显著时,ＰＨＴ法明显低估了二尖瓣口面积,而此时应用ＣＤＦＩ测量二尖瓣口血流截面积却不失为一种新的简便而较为准确的定量二尖瓣狭窄的方法,临床上值得推广。     

Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers–Danlos syndrome and related disorders

Ehlers–Danlos syndromes (EDSs) are a group of inherited connective tissue disorders, and among them, classical EDS (cEDS) and hypermobile EDS (hEDS) are the most common. Mitral valve prolapse (MVP) and aortic root dilation (ARD) have previously been reported to occur at an increased frequency within cEDS and hEDS. More recently, a study performed in the pediatric population did not show increased prevalence (Ritter et al., American Journal of Medical Genetics Part A, 173(6), 1467–1472, 2017). The purpose of this study was to review a large population of individuals with cEDS, hEDS, and hypermobility spectrum disorders to determine the frequency of MVP and ARD. A retrospective chart review of 209 individuals with echocardiograms was performed. Overall, 6.4% (13/209) had MVP and 1.6% (3/189) were found to have ARD. Although the presence of MVP is higher than what has been reported in the general population, no patients had severe MVP or required surgical intervention. No patients in this cohort had an aortic root diameter requiring surgical repair. Based on the results of this study and previous studies, routine echocardiograms to assess for valvular diseases and ARD may not be necessary unless warranted by presence of symptoms or family history.     

Reduction of mitral regurgitation using the Coapsys device: a novel ex vivo method using excised recipients' hearts

The purpose of this study was to evaluate the ex vivo effects of the Coapsys device upon functional mitral regurgitation (MR) in human hearts. We used seven excised hearts from patients who underwent cardiac transplantation. All patients had functional MR of grade 2 or greater associated with dilated (n = 3) or ischemic (n = 4) cardiomyopathy. After the aortic valve was removed, the left ventricle was pressurized from the aorta with saline at a constant pressure. The degree of MR was then subjectively graded from the opened left atrium (from 0 to 4). The last three studies included volumetric measurements of MR. By tightening the device, the mean MR grade was reduced from 3.3 +/- 0.8 to 1.1 +/- 0.4 (p = 0.0002). In the quantitative analysis, mean regurgitation volume was reduced from 1,108 +/- 1,134 ml/min to 236 +/- 89 ml/min (p = not significant). The mitral annular septal-lateral dimension decreased from 2.0 +/- 0.3 cm to 1.6 +/- 0.5 (p = 0.043). The Coapsys device reduced functional MR in the ex vivo study using excised dilated hearts.     

Prevalence of mitral valve prolapse in panic disorder: effect of echocardiographic criteria

Although several investigators have found a higher incidence of mitral valve prolapse (MVP) in patients with panic disorder (PD) and agoraphobia with panic attacks (AgP), there are now several conflicting reports. Discrepancy in the rate of echocardiographic diagnosis of MVP in PD/AgP may be due to different criteria used in evaluating the echocardiogram. In this study, 15 echocardiograms performed on patients with PD/AgP were evaluated by two separate expert echocardiographers. Each used his own standard criteria for diagnosing MVP. The first reader diagnosed MVP in 9 of 15 patients with PD/AgP while the second did not diagnose MVP in any of the 15 patients. This substantiates the belief that criteria variance strongly influences estimates of the prevalence of MVP among patients with PD/AgP.     

Airway function disturbances reversibility after mitral valve replacement

Dyspnea, cough, recurrent airway infection, hemoptysis are the most common pulmonary symptoms of mitral valve disease and heart failure. Pathophysiological mechanism of those disturbances is complex and airway status is one of the most important. The aim of the study was to assess airway function disturbances reversibility after mitral valve replacement. The study group consisted of 30 patients qualified to mitral valve surgery. Patients were assessed by clinical cardiac noninvasive investigation and airway function study. Post-operative study was performed minimum 6 months after mitral valve replacement (mean after 8 months) and again after minimum 3 years (mean after 40 months). In most of assessed--22 patients (74%) airway obstruction was noticed, in 8 patients without obstruction nonspecific histamine provocation test was performed. Increased airway reactivity was found in 4 patients only, in another 4 patients (13%) there was no airway function disturbances. After mitral valve replacement significant improvement in all cardiac parameters including NYHA functional class was observed. No airway function improvement occurred. Only small tendency to improve airway function was noticed as far as it concerns VC, FEV1, MEF50, MEF75 iTGV with exclusion of Raw. Analysis after dividing study group into 3 subgroups with increasing airway function disturbances (from predicted to hyperreactivity and obstruction) was also performed. The improvement in airways function was noticed only in 6 patient (20% studied). In patients with mitral valve disease airway function disturbances as obstruction and bronchial hyperreactivity persist in long term follow-up after mitral valve replacement.     

Biopsy of the heart valves. 872 cases

In this study, 872 heart valves surgically excised from 810 patients during a period of 5 years (1994 through 1998) were examined pathologically. There was a predominance of aortic (506 patients) versus mitral valves (246 pts.). While aortic valves came more often from men (364) than from women (142), in mitral valves the M:F ratio is 82/164. Isolated calcific aortic stenosis appeared as the most frequent valvular disease (418 pts.), with predominance of its sclerotic-senile type (238 pts.). Mitral stenosis (185 pts.) remains the classical post-rheumatic disease. The relative frequency of a subvalvular stenosing mitral lesion is stressed. The "pure" incompetence of both aortic (70 pts.) and mitral (56 pts.) valve was usually based on valvular myxoid degeneration. An aorto-mitral disease requiring replacement of both valves (51 pts.) presented typically as a post-rheumatic lesion, however, a combination of a post-rheumatic mitral with a degenerative-sclerotic aortic valve disease may be possible. In 30 patients, the valvular replacement was performed for infective endocarditis or a post-IE lesion, mostly of the aortic valve. With the almost non-existence of acute rheumatic fever and with the increasing average age of population in this country, we may expect a long-term decline in mitral valve disease and an increase in aortic valve disease, particularly in the sclerotic type of aortic stenosis.     

四维经食管超声心动图在二尖瓣成形术中的应用

目的 探讨四维经食管超声心动图(4D-TEE)技术在二尖瓣成形术(MVP)中的应用价值。方法 回顾性分析2019年2-7月安徽医科大学第一附属医院行MVP的25例二尖瓣反流患者的临床资料,其中男15例、女10例,年龄(55.56±14.40)岁。患者MVP术前均行4D-TEE检查,精准评估二尖瓣反流的病因及病变分型、病变位置和反流程度,测量左-右纤维三角间距离、收缩期瓣环前外侧至后内侧直径(DAlPm)、瓣环前后径(DAP)、瓣叶各个分区(将二尖瓣前叶和后叶的外、中、内部分别命名为A1~A3和P1~P3)的高度等参数,依据检测结果制定手术方案。术中探查对术前超声检测结果进行验证,并选择合适的成形环尺寸,完成MVP操作后,利用亚甲蓝染色直视下测量瓣叶对合高度。心脏复跳后再次行TEE检查,测量瓣叶对合高度,即刻评估手术效果。21例MVP患者术后3个月行经胸超声心动图(TTE)检查,再次评估二尖瓣反流程度。(1)观察术前通过4D-TEE诊断的二尖瓣反流的病因和病变分型、病变位置、反流程度,以及与术中探查结果的一致性;(2)比较术前4D-TEE所得的二尖瓣各参数与手术最终使用的成形环尺寸的相关性;(3)比较心脏复跳后利用TEE测得的对合高度与术中术者在直视下利用亚甲蓝染色测量的对合高度的相关性等;(4)分析术后3个月反流程度的影响因素。结果 术前4D-TEE的检查结果与术中探查的结果对比,25例患者病因和病变分型诊断的准确率为96.0%(24/25)。对病变部位发生在瓣叶的单一区域或某两个区域诊断的准确率为14/14,对交界区病变及多个区域联合病变诊断的准确率分别为2/3、4/5。术前4D-TEE评估二尖瓣反流程度2级6例、3级2例、4级17例,与术中探查结果一致。通过术前4D-TEE测得的各指标对术中成形环尺寸的逐步多元线性回归分析显示,DAP(X₁)、左右纤维三角距离(X₂)两个参数进入回归模型,建立多元线性方程:成形环尺寸^Y=10.506+0.230X₁+0.395X₂,模型有统计学意义(P＜0.01),R²为0.613,提示模型拟合的效果良好。DAP的标准化偏回归系数为0.486,左-右纤维三角间距离的标准化偏回归系数0.450,提示二者对成形环尺寸的预测均有较大意义。以心脏复跳循环稳定即刻TEE测量的A1-P1、A2-P2、A3-P3的对合高度及三个对合缘的平均对合高度与术中亚甲蓝染色直视下测量的对合高度进行Pearson相关性分析,四组相关系数分别为0.838、0.916、0.951、0.953,均呈正相关(P值均＜0.01)。分析术后3个月反流程度的影响因素,进行逐步logistic回归分析结果显示,平均对合高度≤7 mm为术后反流的危险因素,比值比为30.0(P＜0.05),提示平均对合高度≤7 mm的患者术后更容易出现反流再次加重。结论 4D-TEE不仅可以在MVP术前精准地判定二尖瓣反流的病因和病变分型、病变位置及反流程度,并根据测量的定量参数预测术中实际使用的成形环尺寸,协助外科医生手术方案的决策,而且可以在术中实时评估手术疗效,提高手术的成功率;另外,它提供的参数对术后早期的成形效果也起到了一定的预测价值,具有相当重要的临床应用前景。     

Value of a modified continuity equation method to quantify mitral valve area in patients with mitral stenosis and sinus rhythm

Summary To quantify valve area in mitral stenosis, a modified continuity equation method using continuous wave Doppler and thermodilution measurements was applied. In 14 patients with mitral stenosis and sinus rhythm (age: 49±11 years), transmitral flow velocity was recorded by continuous wave Doppler during right and left heart catheterization. Mitral valve area was calculated by three different methods: 1. According to the continuity equation, stroke volume (thermodilution technique) was divided by the registered time velocity integral of the mitral stenotic jet (continuous wave Doppler). 2. Mitral valve area was calculated by the pressure half-time method. 3. Simultaneous pulmonary capillary wedge and left ventricular pressure measurements were used for determination of mitral valve area according to the Gorlin formula. The mitral valve area determined by application of the continuity equation (y) showed a close correlation to the valve area calculated by the Gorlin equation (x):y=0.73x+0.12, SEE=0.11 cm²,r=0.88,P<0.001. In contrast, the correlation between mitral valve area determined by pressure half-time (y) and the Gorlin formula (x) was not as good:y=0.77x+0.11, SEE=0.26 cm²,r=0.65,P<0.05. Thus, the continuity equation method using combined continuous wave Doppler and thermodilution technique allows a valid determination of mitral valve area. In patients with mitral stenosis and sinus rhythm, this technique is superior to the noninvasive determination of mitral valve area by the conventional pressure half-time method.Abbreviations bpm beats per minute - CO cardiac output - DFT diastolic filling time - HR heart rate - LV left ventricular - MMVG mean mitral valve gradient - MVA_CE mitral valve area determined according to the continuity equation method - MVA_G mitral valve area calculated according to the Gorlin formula - MVA_T1/2 mitral valve area determined according to the pressure half-time method - PCW pulmonary capillary wedge - SV stroke volume     

Filamin-A as a Balance between Erk/Smad Activities During Cardiac Valve Development

Mitral valve prolapse (MVP) affects 2.4% of the population and has poorly understood etiology. Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin-A) gene were identified as disease causing. Our in vivo and in vitro studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R-Ras. Herein, we report that Filamin-A is required for R-Ras expression and activation of the Ras–Mek–Erk pathway. Loss of the Ras/Erk pathway correlated with hyperactivation of pSmad2/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin-A was required for β1-integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin-A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin-A deficient valve interstitial cells to effectively remodel the increased ECM production through a β1-integrin mechanism. As a consequence, loss of Filamin-A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117–124, 2019. © 2018 Wiley Periodicals, Inc.     

两种人工瓣环置入修复单纯二尖瓣环扩张引起的二尖瓣关闭不全的比较

背景：退行性二尖瓣关闭不全的病例有逐渐增加的趋势,而单纯二尖瓣环扩张引起的二尖瓣关闭不全是退行性二尖瓣关闭不全的一种类型,国内尚无关于此类二尖瓣关闭不全的外科治疗的临床研究报告。 目的：观察单纯瓣环置入修复单纯二尖瓣环扩张引起的二尖瓣关闭不全早中期生物相容性的反应。 方法：单纯二尖瓣瓣环扩张致二尖瓣关闭不全患者48例,均行二尖瓣人工瓣环置入修复,其中使用Carpentier-Edwards生理环23例、SJMTM刚性鞍形成形环25例。出院后随访,采用超声心动图观察心功能和二尖瓣反流程度等变化,并比较两种瓣环与宿主生物相容性有无差别。 结果与结论：围术期无死亡,均治愈出院。48例均获随访,随访率100%,随访时间3个月至4年,无死亡病例。NYHA心功能分级Ⅰ级32例,Ⅱ级16例。与术前比较,随访期超声心动图显示左心房内径、左心室舒张末期内径、左心室收缩末期内径、肺动脉收缩压和反流速面积/左房面积均明显减少(P < 0.01),左室射血分数明显增加(P < 0.01)。跨瓣压差均< 3 mm Hg。二尖瓣无明显返流36例,微量返流10例,轻度反流2例。未出现成形环断裂、成形环撕脱及溶血现象。Carpentier-Edwards生理环组和SJMTM刚性鞍形成形环组比较,上述各指标差异无显著性意义(P > 0.05)。结果提示对于因单纯二尖瓣环扩张引起的退行性二尖瓣关闭不全,通过正确的置入技巧、选择合适的人工瓣环,应用人工瓣环置入有与宿主生物较好的生物相容性反应,置入后的瓣膜替代功能良好。中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程全文链接：