High prevalence of ‘mitral valve prolapse syndrome’ (MVPS) among older children andadolescents in a contained population

Sanjay G. Gokhale a,⁎, Sankalp Gokhale b,1

a Department of Pediatrics and Neonatology, Rajhans Hospital, Saphale 401102, Indiab Department of Neurology (Medicine), Duke University Hospital, Durham, NC 27710, USA

a r t i c l e i n f o

Article history:Received 10 April 2013Accepted 20 April 2013Available online 15 May 2013

Keywords:Contained populationConsanguinityGenetic driftPrevalenceMVPS

Mitral valve prolapse (MVP) is a disorder of closure of mitral valveand billowing out of the valve during cardiac systole [1]. Pathophysiol-ogy of MVP is thought to be a continuing process of repeated minorinjury and repair occurring during the cardiac cycle in a mitral valvewith minor congenital anatomical variations in the valve apparatus.This may explain the age dependent development and progression ofprolapse [1,2]. Two distinct types of ‘mitral valve prolapse’ (MVP) arerecognized. The primary or the classic type is also known asmitral valveprolapse syndrome (MVPS). It is associatedwith abnormalities ofmitralvalve leaflets as well as perivalvular supportive tissue such as chordaetendineae and annulus. In addition, MVPS is also associated with extracardiac manifestations such as skeletal, connective tissue and neurop-sychiatric features [1]. In the secondary or non-classic type, the defect isrestricted to mitral valve without perivalvular or systemic manifesta-tions [1].

The presentation of MVPS is more obvious in adults than in childrenwhich accords with the predictions of the response to injury hypothesisfor the pathogenesis of progressive changes. Almost half of the cases ofMVPS show ‘Benign Joint Hypermobility Syndrome (BJHS)’ [3]. Asignificant proportion of subjects with MVPS have tall, thin habitus aswell as thoracic cage deformity [4]. It is possible that the body habitusand thoracic cage deformity may change the cardiac position withrespect to body axes and predispose mitral valve to billow out duringcardiac systole [4,5]. Interestingly, there is some evidence to support anassociation between mitral valve prolapse and slender body habituseven in pediatric population [5]. Thus, body habitus and thoracic cagedeformity could be causative as well as genetically associated feature ofMVPS. In addition, subjects with MVPS are often noted to haveimbalance of autonomic nervous system (ANS) also known as‘dysautonomia’ [6]. This probably explains atypical chest pain, dyspnea,palpitations, vertigo, anxiety, and neuropsychiatric symptoms like panicattacks, fatigue, migraines and irritable bowel syndrome [7]. Embry-ologically, neural crest cells derived from ectoderm contribute tosympathetic ganglia, adrenal medulla as well as the semilunar valvesand the cardiac conduction system [8]. The common developmentalorigin of these structures explains the varied clinical manifestationsincluding cardiac as well as neuropsychiatric, specifically, autonomicfeatures in subjects with MVPS.

We report interesting observations from a community hospitalserving a contained rural population. This was a retrospectiveobservational study involving patient chart reviews. The study wasapproved by the institutional review board (IRB) and ethics committee.

A retrospective chart review was carried out of a total of 5678patients (from the age group of 5–18 years) who were seen in generalpediatric outpatient clinic at our center over 4 years (1/1/2001 to 12/31/2004). Patients with a diagnosis of mitral valve prolapse syndrome(MVPS) based on clinical and transthoracic echocardiographic criteriawere included in the analysis. Out of 5678 patients reviewed, 21 cases ofmitral valve prolapsed syndrome (MVPS) were diagnosed with aprevalence of 37.8/10,000. Associations of MVPS included Marfanoidfeatures as follows: pectus excavatum 38%; horizontal armspan N height 67%, arachnodactyly 48%, high arched palate 76% andhyper mobile joints 58%. A significant proportion of patients (67%) hadevidence of thin tall stature. A number of neuropsychiatric manifesta-tions were observed as follows: frequent mood changes 20%, anxietydisorder 14% and depression in one patient (she committed suicide atthe age of 16 years).

Our observations are unique and distinctly different from theavailable literature. The prevalence of isolated MVPS in children isreported as only 0.3 per 1000 (3 per 10, 000) [2]. A small percentageof these subjects has evidence of Marfanoid features (8% have pectusand 2% show arachnodactyly) andmany (50–60%) have asthenic thinbody habitus [2–4]. Few of them suffer from anxiety and otherneuropsychiatric manifestations. It is quite obvious that prevalenceof those with MVPS and skeletal abnormalities would be definitelyless than 3/10,000 and prevalence of thosewith additional features ofneurocirculatory asthenia would be a fraction of 3/10,000. Thesenumbers are in contrast to our observations. We report an MVPSprevalence of 37.8/10,000 in our study and postulate few explana-tions for this observation.

Our study population is a contained population with sub-groups ofcommunities. These subgroups demonstrate tendency towards isola-tion and marriages within themselves for social and cultural reasons. Insmall, reproductively isolated populations, special circumstances existthat can produce rapid changes in gene frequencies totally independentof mutation and natural selection. These changes are due solely tochance factors. The smaller the population, the more susceptible it is tosuch random changes. This phenomenon is known as genetic drift.Genetic drift accounts for the familial aggregations of autosomalrecessive and dominant conditions [9]. Another important smallpopulation effect is known as the founder principle or founder effect[10]. This occurs when a small number of subjects have manydescendants surviving after a number of generations. The result for apopulation is often higher frequencies of specific genetic traits inheritedfrom the few common ancestors. When a small part of a populationmoves to a new locale, orwhen the population is reduced to a small sizebecause of some environmental change, the genes of the “founders” ofthe new society are disproportionately frequent in the resultingpopulation [10].

Thus, high prevalence of MVPS in this population may be due tocontained population, tradition of second or third degree consangui-neous marriages and marriages within the sub-groups or communities.This is analytical inference and no genetic studies could be carried outdue to lack of resources. Additional studies are needed to define thebasis for this clustering.

⁎ Corresponding author. Tel.: +91 922 614 3027; fax: +1 919 251 8499.E-mail addresses: rajhanssanjay@gmail.com (S.G. Gokhale),

sankalpsgokhale@gmail.com (S. Gokhale).1 Tel.: +1 617 784 8529; fax: +1 919 251 8499.

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References

[1] Levine HJ, Isner JM, Salem DN. Primary versus secondary mitral valve prolapse:clinical features and implications. Clin Cardiol 1982;5:371–5.

[2] Perloff JK, Child JS. Clinical and epidemiologic issues in mitral valve prolapse:overview and perspective. Am Heart J 1987;113:1324–32.

[3] Hirschfeld SS, Rudner C, Nash Jr CL, Nussbaum E, Brower EM. Incidence of mitralvalve prolapse in adolescent scoliosis and thoracic hypokyphosis. Pediatrics1982;70:451–4.

[4] Arfken CL, Schulman P, McLaren MJ, Lachman AS. Mitral valve prolapse and bodyhabitus in children. Pediatr Cardiol 1993;14:33–6.

[5] Zema MJ, Chiaramida S, DeFilipp GJ, Goldman MA, Pizzarello RA. Somatotype andidiopathic mitral valve prolapse. Cathet Cardiovasc Diagn 1982;8:105–11.

[6] Boudoulas H,Wooley CF. Mitral valve prolapse syndrome. Evidence of hyperadrenergicstate. Postgrad Med 1988:152–62 Spec No.

[7] Alpert MA, Mukerji V, Sabeti M, Russell JL, Beitman BD. Mitral valve prolapse, panicdisorder, and chest pain. Med Clin North Am 1991;75:1119–33.

[8] Jain R, Engleka KA, Rentschler SL, et al. Cardiac neural crest orchestrates remodelingand functionalmaturation ofmouse semilunar valves. J Clin Invest 2011;121:422–30.

[9] Awdeh ZL, Alper CA. Mendelian inheritance of polygenic diseases: a hypotheticalbasis for increasing incidence. Med Hypotheses 2005;64:495–8.

[10] Jaworski MA, Severini A, Mansour G, et al. Genetic conditions among CanadianMennonites: evidence for a founder effect among the old colony (Chortitza)Mennonites. Clin Invest Med 1989;12:127–41.

0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.http://dx.doi.org/10.1016/j.ijcard.2013.04.187

Different coronary artery calcium scores with discrepant progression risks☆

Cheng-An Wang a, Wei-Ta Chen a, Jen-Hung Huang a, Ying-Chin Lin b, Ming-Hsiung Hsieh a, Yi-Jen Chen a,c,⁎a Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwanb Department of Health Examination, Wan Fang Hospital, Taipei Medical University, Taiwanc Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

a r t i c l e i n f o

Article history:Received 11 April 2013Accepted 20 April 2013Available online 20 May 2013

Keywords:Coronary calcium scoreCoronary artery diseaseRisk factors

Atherosclerosis is the main cause of coronary artery disease (CAD).Calcified lesions can be seen in the early stage of atherosclerosis, andcalcified atherosclerosis is more frequent with more-advanced lesions[1]. The coronary calcium score (CCS) was demonstrated to be a usefultool for CAD risk evaluation. The CCS is associated with the severity ofCAD, and it is a predictor of cardiovascular events, all-cause mortality,and malignancy [2,3]. An upward progression of CCS is also a usefulpredictor for cardiovascular events [4]. However, it is not clearwhy somepatients have a stable CCS, but others have rapid progression of the CCS.This study was designed to evaluate the factors related to upwardprogression and to a lack of upward progression of the CCS.

This study included all individuals who received repeated CCSanalyses with Agatston score during a physical checkup or CADevaluation in our hospital from January, 01, 2006 to December, 31,2011. Patients were classified as low- (CCS, 0–10), moderate- (CCS, 11–100), and high-risk patients (CCS, 101–400) according to the CCS fromthe first computed tomography (CT) [5]. Upward progression of the CCSwas identified as the CCS value changing from low to moderate or highrisk or changing from moderate to high risk during two separate CTevaluations. Individualswith an initial CCS of N400were excluded, since

these cases were already at high risk, which cannot have upwardprogression.We defined an “annual calcium score progression point” as[(Follow-up CCS− Baseline CCS) / Follow-up duration inmonths] × 12.

Continuous variables are expressed as mean ± SD and comparedusing Student's t test. Comparisons among the four groups wereanalyzed by one-way ANOVA analysis with a post hoc of Fisher Method.Kaplan–Meier curves were constructed and the outcomes of differentpatient groups were compared using the log rank test. A two tailedP b 0.05 was considered statistically significant.

In 65 cases with progression of CCS, most of them were notdiagnosed as CAD (82%). Percentages of low- (43.5% vs. 35.7%, p N 0.05),moderate- (30.4% vs. 38.1%, p N 0.05), and high-risk (26.1% vs. 26.2%,p N 0.05) CCS patients were similar between patients with (n= 23)and without (n=42) upward progression in CCS. The follow-updurationwas similar (1.7 ± 0.67 vs. 1.8 ± 0.83 years, p N 0.05) betweenthese two groups. Patients with upward progression in the CCS had ahigher fasting sugar and hs-C reactive protein (hs-CRP) (Table 1). Wecorrelated the baseline CCS and the annual CCS progression and found agood correlation in the group without upward progression and for allcases, but not in the group with upward progression (Fig. 1).

We evaluated differences between patients with and without CCSprogression in the low-, moderate-, and high-risk groups (Table 2). Inlow-risk group, those with upward progression only had a significantlyhigher creatine kinase (CK). Inmoderate-risk group, thosewith upwardprogression had significantly higher fasting sugar and low-densitylipoprotein (LDL). In high-risk group, patients with upward progressionhad significantly higher platelet numbers and hs-CRP.

The present study is the first study to evaluate people with possibleCAD according to different risks based on the CCS. We used the annualCCS progression to identify different CCS follow-up durations.We foundthat the annual CCS progression had a good correlationwith thebaselineCCS in individuals without upward progression of CCS, but it was notgood in the upward progression group. This reveals that there are otherfactors that affect the upward progression of the CCS.

In the low-risk group, we found no differences in traditional riskfactors or biomarkers between those with and without upwardprogression. This finding might have been caused by the fact thattheir atherosclerosis was mild. The traditional risk factors or othermarkersmight not have been sensitive enough to detect the differences.We found the CK level was higher in upwardly progressing patients.Previous study found that the prognosis is different in individuals with

☆ This author takes responsibility for all aspects of the reliability and freedom frombias of the data presented and their discussed interpretation.⁎ Corresponding author at: Division of Cardiovascular Medicine, Wan-Fang Hospital,

Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei 116, Taiwan. Fax: +886 229339378, +886 2 28735656.

E-mail address: a9900112@ms15.hinet.net (Y.-J. Chen).URL: http://tctspss.blogspot.com/2009/11/blog-post.html (Y.-J. Chen).

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