Original Article Effect of lesional differences in prolapsed leaflets on

Introduction Mitral valve prolapse (MVP) is a valvular abnor-mality and a common cause of mitral regurgita-tion (MR) [1, 2]. Natural history of MVP is het-erogeneous and can vary from benign with a normal life expectancy to adverse with signifi-cant morbidity or mortality [3, 4]. Although the rate of serious complications is not high, some known risk factors are defined by both clinical and echocardiographic findings [1, 3-5]. A poor prognosis is associated with MVP complicated by atrial or ventricular arrhythmias, congestive heart failure (CHF), moderate to severe MR, chordal rupture, and infective endocarditis. To date, mitral valve repair may provide long-term survival and a life expectancy for patients simi-lar to that of the general population [6-8]. The timing of such surgery is therefore crucial for

patient survival, indicating the need to predict the progression of MVP by close echocardiogra-phy follow-up studies. The predisposing factors for severe MR include aging, male sex, severity of MR, prolapsed pos-terior mitral leaflet (PML), thickened mitral leaf-let, and holo systolic murmur [9-14]. Site-related difference in prolapsed leaflets could also be a predictor for clinical outcome, with posterior leaflet prolapse often cited as a con-siderable risk for the incidence and progression of MR [12, 13, 15]. However, there is little data on the progression of mild to moderate MR, and its relationship to the site of prolapsed leaflets and prognosis of MVP patients in reference to the development of complications and cardiac events. Furthermore, the differences in the clini-cal outcome among distinct prolapsed seg-

Am J Cardiovasc Dis 2012;2(3):152-159 www.AJCD.us /ISSN:2160-200X/AJCD1203007

Original Article Effect of lesional differences in prolapsed leaflets on clinical outcomes in patients with mitral valve prolapse Keiko Suzuki1, Mitsushige Murata2, Risako Yasuda1, Hikaru Tsuruta1, Naoki Tomotsugu3, Takayuki Abe3, Shiro Iwanaga4, Makoto Akaishi5, Keiichi Fukuda1 1Department of Cardiology; 2Department of Laboratory Medicine; 3Center for Clinical Research, Keio University, School of Medicine, Tokyo, Japan; 4Department of Cardiology, Tokyo Medical Universtiy, Tokyo, Japan; 5Department of Cardiology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan Received March 31, 2012; accepted May 27, 2012; Epub July 25, 2012; Published August 15, 2012 Abstract: Background: Mitral valve prolapse (MVP) is usually benign, although serious complications may occur. It remains unclear whether the region of prolapsed mitral leaflets might affect prognosis. The aim of this study was to investigate lesional differences of clinical courses of MVP. Methods and Results: We retrospectively investigated 128 MVP patients who had been followed up for for a mean of 56.4 months. They were classified into prolapse of the anterior mitral leaflet (AML, n = 59), posterior mitral leaflet (PML, n = 47), or both leaflets (AML & PML, n = 22). Echo-cardiographic and clinical data were examined from medical records. Average time to clinical events; MV surgery, new onset of atrial fibrillation (AF), echocardiographic evidence of new chordal rupture, and worsening of mitral regurgita-tion severity were all significantly shorter in PML prolapse than in those with AML or AML & PML prolapses. Increases in the left ventricular dimensions and estimated pulmonary arterial systolic pressures were significantly larger in PML prolapse, compared with AML or AML & PML prolapses. A subanalysis of PML prolapse revealed that new chordal rupture tended to be more frequent in middle scallop prolapse (48%) compared with lateral and medial scallops (18%). In contrast, new onset of AF tended to occur in lateral and medial scallop prolapses (44%) compared with middle scallop prolapse (20%). Conclusions: PML prolapse patients had a poor outcome, compared with AML or AML & PML prolapse patietns. Precise regional evaluation of the prolapsed leaflets may predict cardiac complications in MVP. Keywords: Mitral valve prolapse, mitral regurgitation, prognosis

Lesional differences affect outcome of mitral valve prolapse

153 Am J Cardiovasc Dis 2012;2(3):152-159

ments including medial, lateral, and central (or middle) areas have not been fully elucidated. The purpose of this study was to investigate site-related differences in prolapsed leaflets with respect to clinical outcomes in patients with MVP. Materials and methods We reviewed 65092 echocardiographic records of the Keio University Hospital from 1999 to 2007 and identified the patients who had mitral valve prolapse. Of these records, 3793 had mi-tral valve prolapse with at least mild mitral re-gurgitation. Prolapse of the anterior mitral leaf-let (AML) was observed in 1733 cases, PML prolapse in 1378, and both AML and PML prolapse was observed in 682 cases. The num-ber of the cases were counted from echocardio-graphical records and it included more than one record of the same patients who had echocardi-ography exams several times during follow-up period. Records also showing rheumatic heart disease, congenital heart disease, myocardial infarction, cardiomyopathy (DCM and HCM), Marfan syndrome, more than moderate aortic regurgitation, or infectious endocarditis were excluded. In addition, patients with no, trivial, or severe mitral regurgitation were excluded. From the remaining records, we identified the pa-tients who were followed up for more than 1 year and examined echocardiography at least twice at interval of more than one year. We en-rolled all of the patients of mitral valve prolapse who met all these conditions and criteria which were mentioned above. For these enrolled pa-tients, we retrospectively examined the clinical data including sex, date of birth, medical his-tory, ECG, medication, history of hospitalization for CHF, and previous mitral valve surgery. The ethical committee of Keio University School of Medicine approved our study protocol. Echocardiographic studies Two-dimensional (2D) and color Doppler echo-cardiography was performed using commercially available ultrasound systems. Prolapsed leaflets on 2D echocardiography was defined as a supe-rior protrusion of the mitral leaflets into the left atrium, with an annular overshoot of leaflets > 2 mm in the long axis view [2]. Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left atrial diameter (LAD) measurements were done by M-

mode echocardiography guided by 2D echocar-diography [16]. Pulmonary artery systolic pres-sure (PASP) was estimated from the tricuspid regurgitant velocity and IVC diameter was meas-ured to estimate right atrium (RA) pressure [17]. Repeated echocardiographic examinations were performed based on clinical judgment. The severity of mitral regurgitation was esti-mated semiquantitatively by color Doppler echo-cardiography, with the degree of mitral regurgi-tation based on area. Mild MR was diagnosed by small, central jets occupying < 20% of the left atrium (LA) and moderate MR was diag-nosed by central jets occupying < 40% of the LA or no existence of wall-impinging jets swirling in LA [18, 19]. Vena contracta widths were meas-ured and severe MR was diagnosed if the width was > 7 mm [16]. Anatomical disruption to any part of the mitral apparatus results in an eccentric direction of the regurgitation jet with an orientation opposite in direction to the affected leaflet. In this study, the prolapsed mitral valve section was identified using a combination of 2D echocardiography for prolapse existence and color Doppler echocardi-ography for MR jet direction [20]. Carpentier’s widely recognized nomenclature describes three posterior leaflet scallops [the lateral (P1), mid-dle (P2), and medial (P3)] and three anterior segments [the lateral (A1), central (A2), and medial (A3)] [21, 22]. The cases were then sorted into three groups: anterior mitral valve prolapse (AML), posterior mitral valve prolapse (PML), and AML & PML prolapse. Complications and cardiac events Events such as CHF, mitral valve surgery, echo-cardiographic evidence of worsening MR, and newly developed chordal ruptures were noted. New onset of atrial fibrillation (AF) by ECG was also noted as a complication. We compared changes in echocardiographic measurements such as LVEDD, LVESD, LAD, and estimated PASP during follow up among the AML prolapse, PML prolapse, and AML & PML prolapse groups. Statistical analysis Descriptive statistics (mean ± SD or frequency (percentage)) for the demographic and baseline characteristics were summarized by three MVP groups (AML prolapse, AML & PML prolapse and



PML prolapse). Survival function for each clini-cal outcome was estimated by means of the Kaplan-Meier method and was compared be-tween the MVP groups with the Log-rank test. Average of continuous variables was compared between groups with ANOVA model (Turkey's adjustment). In the subgroup analysis, Fisher’s exact test was used to compare binary end-points between groups. Data was analyzed us-ing SPSS17. Results Table 1 details the baseline characteristics of the 128 patients who were followed up for more than 1 year. Of these, 59 had AML prolapse only, 47 had PML prolapse only, and 22 had

both AML & PML prolapse. The mean age was 47 ± 17 years for AML prolapse, 57 ± 20 years for PML prolapse, and 61 ± 14 years for AML & PML prolapse. There was no difference in follow-up length between these three groups. (p = 0.37). The baseline echocardiographic data including LVEDD, LVESD, LAD, PASP, MR grade, and the presence of chordal rupture are also shown in Table 1. Table 2 indicates the sites of MVP. The lateral-sided leaflets in both AML and PML were less frequently prolapsed, compared with medial or central leaflets. Figure 1 shows transition of MR grade by semiquantitative analysis of color Dop-pler echocardiography. Of PML prolapse pa-tients, 11 (56%) with mild MR at baseline wors-

Table 1. Clinical characteristics AML prolapsed (n = 59) AML & PML prolapsed (n = 22) PML prolapsed (n = 47) Age, y 47 ± 17 57 ± 20 61 ± 14 Female/male 24/35 6/16 17/30 Follow-up periods, month 59 ± 25.7 50 ± 26.2 56.1 ± 25.7 Baseline echo data LVEDD, cm 4.9 ± 0.6 5.1 ± 0.5 5.0 ± 0.5 LVESD, cm 3.1 ± 0.5 3.1 ± 0.4 3.0 ± 0.4 EF, % 76 ± 6 77 ± 5 77 ± 5 LAD, cm 3.7 ± 0.7 3.9 ± 1 3.8 ± 0.5 PASP, mmHg 21 ± 7 25 ± 7 23 ± 7 MR grade Mild 31 9 16 Moderate 28 13 31 Chordal rupture 1 0 5 Hypertension 6 6 8 Medication ACE-I/ARB 12 5 13 diuretics 9 2 5 Atrial fibrillation 6 4 6 Data are presented as mean ± SD, with categorical data as occurrences. AML anterior mitral leaflet, PML posterior mitral leaflet, LVEDD left ventricular end-diastolic dimension, LVESD left ventricular end-systolic dimension, EF ejection fraction, LAD left atrial diameter, PASP pulmonary artery systolic pressure, MR mitral regurgitation, ACE-I/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Table 2. Identification of the prolapsed segment of mitral valve AML n (%) AML & PML n (%) PML n (%) A1 2 (3) A1P1 1 (5) P1 5 (11) A2 21 (36) A2P2 5 (23) P2 30 (64) A3 17 (29) A3P3 4 (1) P3 11 (23) A2A3 18 (31) P2P3 1 (2) Other 1 (2) Other 12 (55) Data are presented as occurrences (percentage). AML anterior mitral leaflet, A1: lateral portion, A2: central portion, A3: medial portion, PML posterior mitral leaflet, P1: lateral scallop, P2: middle scallop, P3: medial scallop.



ened in MR grade during follow up, compared to 4 (13%) AML prolapse patients with mild MR, and 1 (11%) AML & PML prolapse patients. Table 3 and Figure 2 showed that average time to mitral valve surgery differed significantly among AML prolapse, PML prolapse, and AML & PML prolpase patients (AML 104.5 months, PML 88.8 months, AML & PML 83.9 months, P

= 0.04). average time to new occurrence of atrial fibrillation (AML 97 months, PML 73.4 months, AML & PML 88.8 months, P = 0.02), echocardiographic evidence of new chordal rup-ture (P < 0.001), and worsening of MR (AML 90.7 months, PML 73.9 months, AML & PML 88.9 months, P = 0.01) also differed signifi-cantly among these three groups. Average time to admission due to CHF did not differed among these three groups.

Figure 1. Transition of MR grade by semiquantitative analysis of color Doppler echocardiography during follow-up.

Table 3. Event occurrence and mean survival time free from the event AML prolapse AML & PML prolapse PML prolapse n Survival,

mo 95%CI, mo n Survival,

mo 95%CI, mo n Survival,

mo 95%CI, mo

p

CHF admission 4 99.9 94.3-105.5 2 85.9 76.5-95.3 8 86.5 79-94 n.s MV surgery 1 104.5 101.5-107.4 3 83.9 74.4-93.4 6 88.8 81.3-96.2 0.04 New AF 5 97 89.7-104.3 1 88.8 80.8-96.7 14 73.4 71.3-87.4 0.04 Chordal rupture 1 0 17 0.001 Worsening of MR 11 90.7 83.6-97.8 1 88.9 81.2-96.6 19 73.9 65.4-82.4 0.01 Data are presented as occurrence and survival time as mean (mo, month) and 95% CI (confidence interval). In the analysis of new onset of atrial fibrillation, patients who had atrial fibrillation at baseline were excluded. In the analysis of new onset of chordal rupture, patients who had chordal rupture at baseline were excluded. AML anterior mitral leaflet, PML posterior mitral leaflet, CHF congestive heart failure, MV mitral valve, AF atrial fibrillation, MR mitral regurgitation.

Figure 2. Event-free survival curves for AML prolapse, AML & PML prolapse and PML prolapse. AML, anterior mitral leaflet; PML, posterior mitral leaflet; CHF, congestive heart failure; MV, mitral valve; AF, atrial fibrillation; MR, mitral regurgitation.



During the follow-up period, the increases in LVEDD, LVESD, and estimated PASP were sig-nificantly greater in patients with PML prolapse than in those with AML or AML & PML. (ΔLVEDD (cm); AML: + 0.07, PML: + 0.23, AML & PML: +

0.04, PML vs. AML P = 0.02, PML vs. PML & AML P = 0.01, ΔLVESD (cm); AML: + 0.06, PML: + 0.22, AML & PML: + 0.05, AML vs. PML P = 0.02, ΔLAD (cm); AML: 0.36, PML: 0.4, AML & PML: 0.05, AML vs. AML & PML P = 0.02, PML vs. AML & PML P = 0.01, ΔPASP (mmHg); AML: + 5, PML: + 9.4, AML & PML: + 5, PML vs. AML & PML P = 0.01; Table 4 and Figure 3). Table 5 shows results of the subanalysis within PML prolapse. Compared with P1 (lateral scallop) and P3 (medial scallop), which are commissure lesions, chordal rupture tended to occur more frequently in P2 (middle scal-lop) prolapse. New onset of atrial fibrillation tended to oc-cur in P1 or P3 prolapse com-pared with P2 prolapse.

Discussion This study focused on a subset of MVP patients with mild to moderate MR, since severe MR

Table 4. Comparison of mean alternation of echocardiographic measurements during follow up AML AML&PML PML p prolapse prolapse prolpase AML vs.

AML&PML PML vs.

AML PML vs.

AML&PML ΔLVEDD, cm 0.07 ± 0.04 0.04 ± 0.06 0.23 ± 0.04 n.s 0.02 0.01 ΔLVESD, cm 0.06 ± 0.04 0.05 ± 0.06 0.22 ± 0.04 n.s 0.02 n.s ΔLAD, cm 0.36 ± 0.05 0.05 ± 0.09 0.4 ± 0.07 0.02 n.s 0.01 ΔPASP, mmHg 5 5 9.4 n.s 0.01 n.s Data are presented as mean ± SE. AML anterior mitral leaflet, PML posterior mitral leaflet, LVEDD left ventricular end-diastolic dimension, LVESD left ventricular end-systolic dimension, EF ejection fraction, LAD left atrial diameter, PASP pulmonary artery systolic pressure.

Table 5. Subanalysis of PML prolapse P2 (n = 30) P1 or P3 (n = 16) P

n (%) n (%) CHF admission 4 (13) 4 (25) 0.32 MV surgery 4 (13) 2 (13) 0.93 New AF 6 (20) 7 (44) 0.09 Chordal rupture 13 (43) 3 (18) 0.09 Worsening of MR 12 (40) 6 (38) 0.89 Data are presented as occurrences (percentage). PML posterior mitral leaflet, P1: lateral scallop, P2: middle scallop, P3: medial scallop. CHF congestive heart failure, MV mitral valve, AF atrial fibrillation, MR mitral regurgitation.

Figure 3. Comparison of mean alternation-of-echocardiographic measure-ments during follow up. *P < 0.05 vs. AML; †P < 0.05 vs. AML; ‡P < 0.05 vs. AML & PML; AML, anterior mitral leaflet; PML, posterior mitral leaflet; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; EF, ejection fraction; LAD, left atrial diameter; PASP, pul-monary artery systolic pressure.



itself would be a predisposing factor for poor prognosis of MVP patients [5, 9, 14]. Occur-rence of complications such as AF, CHF, chordal rupture, and cardiac events including mitral valve surgery, infective endocarditis, cerebral infarction, and cardiac death were investigated, and site-related differences in the clinical out-comes including progression of MR, occurrence of complications, and cardiac events were eluci-dated. Our data demonstrated that the compli-cations such as CHF, mitral valve surgery, new onsets of AF and chordal rupture occurred more frequently in patients with PML prolapse com-pared with AML or AML & PML prolapses. Echo-cardiographic evidence of worsening of MR was also significantly more frequent in patients with PML prolapse. In addition, LV size, LA size, and estimated PASP were more highly increased in PML prolapses. These data indicated that the PML prolapse has a higher risk for cardiac com-plications and MR progression, compared with AML or AML & PML prolapses. Kamei et al. [15] associated PML prolapse with increased risk of cardiovascular complication, although compared to our study, their study population was much younger (mean age was 28 ± 15 years in AML prolapse and 41 ± 18 years in PML prolapse). Kim et al. [13] reported in 1996 that moderate to severe MR was more frequent in patients with PML prolapse and the occurrence of complications (such as AF or CHF) was significantly greater in the prolapsed poste-rior leaflet than AML prolapse by univariate lo-gistic regression analysis. In addition Fukuda et al. [12] reported in 1995 that PML prolapse was a predisposing factor for severe MR. According to the literature more broadly, the most fre-quent site of mitral valve prolapse is the poste-rior middle scallop, [1, 23, 24] and chordal rup-ture is most frequently associated with the mid-dle scallop of the posterior leaflet in surgically excised valves [25, 26]. Our results were consis-tent with these reports and supported that PML prolapse confers a higher risk of poor outcome. Mitral valve repair for MR due to MVP is associ-ated with excellent long-term survival [6-8]. Ac-cording to the AHA/ACC guidelines in 2006, patients with chronic severe MR with symptoms, mild to moderate LV dysfunction, and an end-systolic diameter greater than 40 mm are class I indications for MV repair [2]. Class IIa indica-tions are asymptomatic patients with preserved LV function and new-onset of AF or pulmonary hypertension [2]. One prospective study re-

vealed that asymptomatic patients with severe MR could be safely followed up until either symptoms occur or currently recommended cut-off values for LV size, LV function, or pulmonary hypertension are reached [27]. However, during the follow up of patients with MV prolapse, it is important to judge the best timing of surgery and not to miss the correct window. The present study indicated that MVP patients with PML prolapse should be more carefully followed up, including cases with mild MR. Several risks are associated with serious com-plications. Patients with depressed left ventricu-lar systolic function and moderate to severe MR at baseline have a higher overall mortality rate than those with normal ejection fraction and mild to moderate MR [1, 3, 5, 10]. Mild to mod-erate MR at baseline, AF, age older than 50 years, flail leaflet, and LA enlargement are known risk factors for cardiovascular morbidity [5]. One of the most important complication of MVP is MR, which may result from either progressive myxomatous degeneration or chordal rupture [1]. Subanalysis of PML prolapse cases in the present study revealed that new onset of chor-dal rupture tended to occur more frequently in P2 prolapse (43%) compared with prolapse at P1 or P3 (18%), as indicated in Table 5. In con-trast, new onset of AF and admission for CHF occurred more frequently in P1 or P3 scallop prolapse, compared with P2, while there were no differences in mitral valve surgery or worsen-ing of MR severity among locations of PML, as indicated in Table 5. Since a prolapse of P1 or P3 scallop regions would produce eccentric MR jets toward pulmonary veins, blood return from pulmonary veins to LA might be locally per-turbed and direct physical stimulation of pulmo-nary veins by MR jets might induce pulmonary extrasystole, a common cause of atrial fibrilla-tion, resulting in increased pressure on pulmo-nary veins and new onset of AF. Even though our current data did not show significant differ-ences in occurrence of the cardiac events by P1, P2, or P3, it is possible that the direction of MR jet caused by prolapsed mitral valve leaflets could have more specific effects such as chor-dal rupture and AF. Both chordal rupture and AF are important indicators of clinical conse-quences in MVP patients, and further studies focused on site-related differences in clinical events are currently underway to predict the prognosis of MVP patients during follow up.



Our results also showed that during the follow up, changes in LV enlargement, LA diameter, and PASP were significantly greater in the PML prolapse cases, compared with AML or AML & PML prolapses. These results are compatible with those of previous studies indicating that PML prolapse confers a poor prognosis. There-fore, precise diagnosis of the prolapsed seg-ments in mitral leaflets might help to predict the occurrence of cardiac complications and events. This study had some limitations. First, a retro-spective study may not be suitable for risk strati-fication of MVP by the location of prolapsed mi-tral valve. Accordingly, a prospective study is underway to confirm the present data. Second, quantitative analysis by the proximal isovelocity surface area (PISA) method or pulsed Doppler quantitative flow method were not performed, because acceleration flow of regurgitant flow could not generally be detected in mild MR cases. In conclusion, patients with PML prolapse showed worse clinical outcomes compared with AML prolapse and AML & PML prolapse pa-tients. Precise regional evaluation of prolapsed leaflets may predict the future occurrence of cardiac complications and events. Acknowlegments We would like to thank Ms. Makiko Dan, Kumiko Tomiyama, Yasuko Hatori, Akemi Oka-moto, Makiko Kondo, and Junko Shinohara for their technical assistance in echocardiographic examinations. Address correspondence to: Dr. Mitsushige Murata, Department of Laboratory Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Tel: +81-3-5843-6702; Fax: +81-3-5363-3875; E-mail: [email protected] References [1] Hayek E, Gring CN and Griffin BP. Mitral valve

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Original Article Effect of lesional differences in prolapsed leaflets on