Left ventricular function in mitral valve prolapse

Malev Edward G.; Reeva Svetlana V.; Pshepiy Asiet R.; Timofeev Evgeniy V.; Zemtsovsky Edward V.

УДК 616.126.42

функция левого желудочка при пролапсе митрального клапана

1 ГБОУ ВПО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России. 194100, Санкт-Петербург, ул. Литовская, д. 2.

2 ФГБУ «СЗФМИЦ им. В.А. Алмазова» Минздрава России. 197341, Санкт-Петербург, ул. Аккуратова, д. 2г

Контактная информация: Эдуард Геннадиевич Малев — доктор медицинских наук, профессор. Кафедра пропедевтики внутренних болезней с курсом ухода за терапевтическим больным ГБОУ ВПО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России. Санкт-Петербург, ул. Литовская, д. 2. E-mail: edwardmalev@hotmail.com

РЕЗЮМЕ: С целью оценить функцию левого желудочка (ЛЖ) при пролапсе митрального клапана (ПМК) в исследование было включено 80 пациентов с пролапсом митрального клапана (ПМК) (средний возраст 19,7±1,6 лет; 72% юноши) из исследования РЕПЛИКА (РаспространЕнность Пролапса митрального Клапана среди лиц молодого возрастА). Контрольную группу составили 80 здоровых лиц сопоставимого возраста и пола. ПМК диагностировался при максимальном систолическом смещении створок митрального клапана за линию кольца митрального клапана более чем на 2 мм в парастернальном продольном сечении. Продольная деформация и скорость деформации миокарда оценивались в трех верхушечных отведениях с помощью методики spackle tracking (Vivid 7 Dim, EchoPAC'06, GE), при частоте кадров 50-55/сек. Результаты: При проведении кластерного анализа были выделены два кластера пациентов с ПМК. В первом кластере (17 человек, 28% от всей группы ПМК) наблюдалось значимое снижение глобальной продольной деформации миокарда (-14,1±3,1%) по сравнению со вторым кластером (61 человек, 72%) (-20,6±3,8%, р=0,00001) и контрольной группой (-19,6±3,4%, р = 0,00001). У пациентов второго кластера наблюдалось снижение деформации только в септальных сегментах. Заключение: ухудшение деформации миокарда может быть первым признаком ослабления систолической функции, обусловленной фиброзом миокарда ЛЖ.

КЛЮЧЕВЫЕ СЛОВА: пролапс митрального клапана; систолическая функция левого желудочка; деформация миокарда.

LEFT VENTRICuLAR FuNCTION IN MITRAL VALVE PROLAPSE

1 Saint-Petersburg State Pediatric Medical University. Litovskaya str., 2. Saint-Petersburg, Russia, 194100

2 Federal North-West Medical Resear ch Centre. 2 Akkuratova str., Saint-Petersburg, Russia, 197341

Contact Information: Eduard G. Malev — MD, PhD, Dr Med Sci, professor. Department of Propaedeutics internal medicine with a course of therapeutic care for patients St. Petersburg State Pediatric Medical University Ministry of Health of the Russian Federation. 2 Litovskaya Str., St.Petersburg, 194100, Russian Federation. E-mail: edwardmalev@hotmail.com

ABSTRACT. In some inherited connective tissue diseases with involving of the cardiovascular system, e. g. Marfan syndrome, has been reported early impairment of left ventricular systolic function, which have been described as Marfan-related cardiomyopathy. To reveal the evidence of the left ventricular (LV) function in mitral valve prolapse (MVP) we evaluate the 78 young adults with MVP from REPLICA study (pREvalence of mitral valve ProLapse In young Adults) in comparison with 80 sex- and age-matched healthy subjects. MVP was diagnosed by billowing of 1 or both mitral leaflets >2 mm above the mitral annulus in the long-axis parasternal view. Longitudinal strain and strain rate (SR) were determined from three standard apical views, using spackle tracking (Vivid 7 Dimension GE, EchoPAC'08) with grey-scale frame rate 50-55/sec. Results: During the k-means clustering we have identified two clusters of subjects with MVP. In 1st cluster (17 subjects) observed a significant reduction of global strain (-15.5±2.9%) compared with

the control group (-19.6±3.4%; p<0.0001) and the 2nd cluster (61 subjects) (-20.6±3.8%; p<0.0001). Global strain in the second cluster did not differ from the control group, but there were decrease of systolic strain in interventricular septum. Conclusions: Changes of deformation may be the feature of the LV dysfunction in MVP, which may be caused by increased myocardial fibrosis.

KEY WORDS: mitral valve prolapse; left ventricular systolic function; myocardial deformation.

In inherited connective tissue disorders that involve the cardiovascular system, e. g. Marfan and Ehlers-Danlos syndromes, osteogenesis imperfecta, and pseudoxanthoma elasticum, impairment of the left ventricular (LV) systolic and diastolic function has been reported, which does not appear to depend on secondary valvular regurgitation [14, 22, 24, 26]. Well known that the organization and function of the myocardium is highly dependent on the cardiac extracellular matrix, which is comprised of fibril-lar proteins, as well as signaling molecules (such as TGF-P) and enzymes [27].

Mitral valve prolapse (MVP) is also a hereditary connective tissue disease with sporadic or familial autosomal dominant and recessive inheritance (DCHS1, LTBP3) and X-linked inheritance (FLNA) [9, 10, 16]. MVP refers to a systolic billowing of 1 or both mitral leaflets into the left atrium with or without MR. Utilizing current echocardiographic criteria for diagnosing MVP of > 2 mm above the mitral annulus in the long-axis parasternal view, the prevalence of this entity according to The Framingham Heart Study is 2.4% of the population [1, 13]. In young patients the Barlow's disease is dominant form of MVP in which myxoid infiltration of the valve results in a remarkable for excess thickened leaflet tissue with destroyed 3-layer leaflet architecture [5]. LV contraction abnormalities in symptomatic MVP patients without severe mitral regurgitation (MR), but with ventricular arrhythmias have been described in some studies using cardiac tomography, radionuclide angiography and single photon emission computed tomography [7, 8, 19]. Also, a marked decrease of myocardial deformation indices has been demonstrated in patients with degenerative severe MR [17, 20]. Two-dimensional speckle-tracking echocardiography (STE) is a relatively new technique used for the evaluation of myocardial function. Strain and strain rate (SR) analysis increase sensitivity in detecting subclinical cardiac involvement in some conditions including valvular heart diseases [3, 25]. However, there are currently no data regarding LV systolic function in asymptomatic young subjects with MVP.

Therefore, the goal of this study was to evaluate the LV function in young adults with MVP without significant mitral regurgitation, using two-dimensional speckle-tracking echocardiography.

METHODS

A total of 78 asymptomatic young subjects (28% female, 72% male) with MVP from REPLICA study (pREvalence of mitral valve ProLapse In young Adults) [4] were enrolled in our observational, prospective, single-center study. Mean age of the subjects was 19.7±1.6 years old. The control group consisted of 80 gender and

age-matched healthy subjects. All gave informed consent and the protocol was approved by the local ethics committee.

ECHOCARDIOGRAPHY

Standard echocardiography extended with speckle-tracking echocardiography (strain rate and strain imaging) was performed in all subjects. All echocardiographic measurements were performed by an experienced, certified echocardiographer using a Vivid 7 ultrasound system (by GE Healthcare), equipped with a harmonic 3.5 MHz phased-array transducer.

MVP was diagnosed by billowing one or both mitral leaflets >2 mm above the mitral annulus in the long-axis parasternal view. By maximal leaflets thickness > 5 mm MVP defined as classic, otherwise as nonclassic [1, 13]. Mitral regurgitation was assessed according the EAE recommendations, vena contracta imaging of the MR jet was obtained and proximal isovelocity surface area imaging was performed [18].

The end-diastolic and end-systolic LV diameters were measured using B-mode echocardiography. The LV end-diastolic and end-systolic volumes, LV ejection fraction were calculated using a modified Simpson's rule. The transmitral flow velocity was recorded from the apical four-chamber view. The mitral annular motion velocity was recorded at the septum and lateral wall using pulsed tissue Doppler imaging.

TWO-DIMENSIONAL SPECKLE-TRACKING ECHOCARDIOGRAPHY

Longitudinal strain and strain rate (SR) were determined from three standard apical views, using two-dimensional STE with a gray-scale frame rate of 50-85 fps.

At each plane, one cardiac cycle were acquired (while the subject held their breath) and stored. Image analysis was performed offline on an EchoPAC'08 workstation (GE Healthcare). The LV was divided into 18 segments. SR was determined as the maximal negative value during the ejection phase (Figure 1), and peak systolic strain as the magnitude of strain at the aortic valve closure [28].

STATISTICAL ANALYSIS

The variables are presented as mean ± SD. The categorical variables are presented as percentages. All echocardio-graphic data and myocardial deformation indices were normally distributed. Differences between groups were analyzed using the two-sided Student's t-test for continuous variables and the chi-square test for categorical variables. The relationship between pairs of continuous variables was expressed by the Pearson cor-

Fig. 1. Analysis of longitudinal strain rate in apical four-chamber view (S — peak systolic strain rate, E — early diastolic strain rate, A — late diastolic strain rate)

Table 1

Demographic and anthropometric characteristics of MVP and control groups

MVP (n=78) Control (n=80) P

Age (years) 19.7±1.6 19.9±1.5 0.42

Gender (male,%) 56 (72%) 48 (60%) 0.11

Height (m) 1.86±0.11 1.79±0.09 <0.0001

Weight (kg) 61.6±7.9 60.5±9.5 0.43

Body surface area (m2) 1.88±0.08 1.78±0.16 <0.0001

Heart rate (b. p.m.) 76.8±14.3 74.2±15.7 0.28

Systolic BP (mmHg) 115.6±8.5 117.8±9.4 0.13

Diastolic BP (mmHg) 69.8±7.4 71.3±8.9 0.25

BP — blood pressure

relation. Cluster analysis (k-means clustering with maximal variability between clusters) was performed to distinguish patients

Table 2

Echocardiography data in MVP and control groups

MVP (n=78) Control (n=80) P

EDD (mm) 46.9±5.7 45.6±4.5 0.11

ESD (mm) 29.5±4.9 28.4±3.9 0.12

EDV (ml) 92.6±22.9 89.3±19.2 0.32

ESV (ml) 34.5±11.6 33.9±8.9 0.72

LV EF (%) 62.7±6.6 62.0±5.4 0.47

E/A 1.66±0.41 1.74±0.42 0.23

E-DT (ms) 167±34 164±40 0.61

e' (cm/s) 15.2±1.2 15.4±1.4 0.34

E/e' 5.9±1.7 5.8±1.2 0.67

LV mass index (g/m2) 82.5±21.4 83.7±15.9 0.69

LAVI (ml/m2) 22.1±2.7 21.6±2.9 0.26

RVEDD (mm) 23.5±3.7 24.3±3.4 0.16

Aortic root (mm) 28.6±2.9 26.7±3.2 0.0001

Z-score (cm/m2) 1.52±0.12 1.50±0.17 0.39

Ascending aorta (mm) 26.0±4.4 24.7±3.9 0.05

Pulmonary artery (mm) 19.4±2.6 19.9±2.8 0.25

Anterior leaflet length (mm) 25.6±3.3 21.8±2.3 < 0.0001

Anterior leaflet thickness (mm) 3.4±1.1 2.6±0.6 < 0.0001

Posterior leaflet length (mm) 14.2±2.8 11.3±2.0 < 0.0001

Posterior leaflet thickness (mm) 3.5±1.2 2.8±0.6 < 0.0001

Mitral annular diameter (mm) 31.3±3.7 26.0±3.6 < 0.0001

Mitral regurgitation (none/mild,%) 16 (21%)/62 (79%) 26 (33%)/54 (67%) 0.11

Late-systolic mitral regurgitation (%) 46 (59%) 21 (26%) <0.0001

EDD — end-diastolic diameter, ESD — end-systolic diameter, EDV — end-diastolic volume, ESV — end-systolic volume, LV EF — left ventricular ejection fraction, E-DT — peak E deceleration time, e' — peak early diastolic mitral annular motion velocity, E/e' — ratio of transmitral and annular early diastolic velocities, LAVI — left atrial volume index, RVEDD — right ventricular end-diastolic diameter, Z-score — aortic root diameter, standardized to BSA

with varying degrees of LV function reduction. Myocardial deformation indices were tested as dependent variables using univariate linear regression analyses to explore the significance of possible influencing factors. Statistical significance was set at p<0.05. All statistical analyses were performed using Statistica 8 software (StatSoft, Inc.).

results

MVP and control groups do not differed in most demographic and clinical characteristics (Table 1), such as age, gender proportion, weight, heart rate and blood pressure. However, patients with MVP were taller and had a larger body surface area (BSA).

Standard echocardiographic parameters of the studied subjects are presented in Table 2. There were no significant differences in LV dimensions and volumes nor in global systolic function between the MVP group and control group. Other chamber dimensions and volumes (right ventricular EDD and left atrial volume index) also did not differ from group to group. Global diastolic LV function, evaluated by transmitral and tissue Doppler, did not vary between MVP and healthy subjects.

MVP subjects, when compared with the control group, had larger aortic root dimensions at the sinus level of the Valsalva and ascending aorta, but the Z-score was the same in both groups

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Fig. 2. Bull-eye — longitudinal systolic strain (left,%) and strain rate (right, 1/s) in MVP group. Segments of interventricular septum with reduction of deformation indices highlighted in gray

because of the higher BSA in MVP subjects. By contrast, the pulmonary artery diameter was similar in both groups. Subjects with MVP had significantly longer and thicker mitral valve leaflets and a larger mitral annulus diameter than did the healthy subjects. Mitral regurgitation was none-to-mild in both groups, mostly late-systolic in the MVP subjects (p=0.013).

29 subjects from the MVP group had classic MVP, 42 subjects had nonclassic. These two subgroups did not differed in anthro-

Table 3

Global and local longitudinal strain (%) in MVP clusters and control group

MVP 1st cluster (n=17) MVP 2nd cluster (n=61) Control (n=80) P

Anteroseptal -15.5±2.2 -17.1±3.2 -18.7±3.4 *0.07 T0.0003 i0.005

Anterior -16.5±2.4 -21.8±3.6 -19.9±3.3 *0.00001 T0.00001 t0.0014

Anterolateral -15.7±2.8 -20.3±4.4 -17.3±4.2 *0.0001 T0.12 t0.0001

Inferolateral -15.1±3.1 -20.7±3.8 -18.4±4.1 *0.0013 T0.00001 i0.0009

Inferior -15.9±3.3 -21.6±2.9 -19.9±3.5 *0.00001 T0.00001 i0.003

Inferoseptal -14.4±3.6 -19.5±3.6 -20.7±3.1 *0.00001 T0.00001 J0.06

Global -15.5±2.9 -20.6±3.8 -19.6±3.4 *0.00001 T0.00001 J0.10

* — significance of differences between clusters; t — significance of differences between the first cluster and the control group; $ — significance of differences between the second cluster and the control group

Table 4

Global and local longitudinal systolic SR (1/s) in MVP clusters and control group

MVP 1st cluster (n=17) MVP 2nd cluster (n=61) Control (n=80) P

Anteroseptal -0,89±0,22 -1,01±0,21 -1,13±0,2 *0.04 T0.00001 i0.0007

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Anterior -1,05±0,21 -1,37±0,18 -1,23±0,26 *0.00001 T0.00001 i0.0004

Anterolateral -1,08±0,26 -1,45±0,3 -1,24±0,31 *0.00001 T0.05 t0.0001

Inferolateral -1,11±0,29 -1,37±0,31 -1,28±0,3 *0.003 T0.04 i0.08

Inferior -1,1±0,21 -1,4±0,16 -1,22±0,2 *0.00001 T0.03 t0.00001

Inferoseptal -0,95±0,18 -1,11±0,2 -1,19±0,19 *0.00001 T0.003 J0.02

Global -1,03±0,2 -1,32±0,16 -1,22±0,18 *0.00001 T0.0002 i0.0008

* — significance of differences between clusters; t — significance of differences between the first cluster and the control group; $ — significance of differences between the second cluster and the control group.

pometric and echocardiography data, except for the thickness of their mitral valve leaflets — anterior leaflet: 4.7±1.3 mm (classic) vs. 2.3±0.6 mm (nonclassic); posterior leaflet: 5.0±1.1 mm (classic) vs. 3.1±0.8 mm (nonclassic).

MYOCARDIAL DEFORMATION INDICES

From 2844 segments, only 2019 (71%) were accepted for deformation analysis. There were no differences in the global longitudinal peak systolic strain (-18.9±2.9% vs. -19.0±2.9%, p=0.83) and SR (—1.21±0.16/s vs. -1.22±0.18/s, p=0.71) between the MVP and control groups. However, we found a significant decrease in septal longitudinal strain and SR in MVP subjects, when compared to the control group (Figure 2). In other segments, there were no significant differences in longitudinal deformation indices.

Global myocardial indices in the MVP group positively correlated with the aortic root diameter (longitudinal strain: r=0.46, p=0.001). The same correlation was found in the septal segment deformation indices (inferoseptal longitudinal strain: r=0.49, p=0.0009). None of the deformation indices correlated with the maximal depth of mitral leaflet prolapse.

To select patients with the greatest reduction in LV function, cluster analysis was performed. During the k-means clustering we have identified two clusters of subjects with MVP: the first cluster (17 subjects, 28% of the MVP group) and second cluster (61 subjects, 72%). Tables 3 and 4 show the global and local longitudinal strain and SR indices in both clusters.

In the 1st cluster, we observed a significant reduction of global longitudinal systolic strain — as compared with the control group (-15.5±2.9% vs. —19.6±3.4%; p=0.00001) and the 2nd cluster (-15.5±2.9% vs. -20.6±3.8%; p=0.00001). Similar differences were observed for all LV walls. Diastolic longitudinal global SR was also decreased — when compared with the control group (1.3±0.25/s vs. —1.62±0.25/s; p=0.0001) and the 2nd cluster (1.3±0.25/s vs. 1.62±0.25/s; p=0.00001). Global longitudinal strain in the second cluster did not differ significantly from the control group (p=0.1), but there was a significant decrease of local longitudinal systolic strain (-17.1±3.2% vs. -20.7±3.1%; p=0.001) and diastolic SR (1.38±0.25/s vs. 1.55±0.22/s; p=0.00001) in the interventricular septum.

discussion

This study revealed a subgroup of young asymptomatic subjects with MVP with significant decrease in LV systolic and dia-stolic function estimated by speckle-tracking echocardiography. Deterioration of LV function in young adults with MVP have not been reported previously.

The function of the myocardium depends on the cardiac extracellular matrix. The cardiac connective tissue is a framework for maintaining spatial registration of myocytes, for limiting the extension of myocytes during diastole, and for transmission of force and storage of energy during systole [27]. The increased presence of extracellular matrix proteins within the myocardium results in an alteration of ventricular properties that causes both systolic and diastolic dysfunction [15, 23].

The present study has also detected a decrease of longitudinal deformation in septal segments in majority of young adults with MVP. In genetic diseases such as Friedreich's ataxia, Fabry disease, or Duchenne cardiomyopathy, the first regional deformation changes occurs in the inferolateral segment: as fibrosis develops first in this area, the reduction of local strain rates becomes apparent [6]. We suggest that the local reduction of myocardial indexes — identified in asymptomatic MVP subjects — is associated with septal fibrosis, but further studies using MRI are needed. However, these changes of deformation may be the first signs of future deterioration of the LV systolic function by MVP progression [17, 20].

We have found typical myxomatous changes in mitral valve morphology and in aortic root dimensions in young subjects with MVP in our study. It is known that MVP associated with aortic root enlargement in patients with inherited connective tissue disorders and is an independent predictor of greater aortic size in a large population with otherwise normal echocardiographic parameters [21].

MVP also is associated with systemic features that may include thoracic cage deformity, pectus excavatum, mild joint laxity, and long limbs [2]. In this study, subjects with MVP were taller and had a larger BSA, which is common for young adults with this disease [11].

In summary, the connective tissue of the mitral valve leaflets is not isolated. It is a continuum with the connective tissue of the myocardium [12]. Our results indicate a link between MVP and myocardial dysfunction. This deterioration can be explained by damage of the intramyocardial extracellular matrix in myxomatous MVP.

conclusion

Septal myocardial deformation indices are decreased in most young subjects with MVP. In contrast, a minority of people with MVP have significantly reduced global myocardial strain. These changes of deformation may be the first signs of deterioration of the LV systolic function in asymptomatic young subjects with MVP. However, further studies using MRI are needed to assess the severity and extent of cardiac fibrosis in MVP.

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