FACTORS PREDICTING THE RISK OF VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH MITRAL VALVE PROLAPSE

Tudoran Cristina^1-3, Florica Voiță-Mekeres ^4,5*, Ioan Bogdan Voiță⁶, Paula Marian⁷, Alin Ovidiu Petriș⁵, Larisa Bianca Galea-Holhoș⁴, Adrian Osiceanu⁴, Mariana Tudoran³, Bianca Neli Burtă⁸, Radu Fodor⁸

ABSTRACT

Mitral valve prolapse (MVP) has an incidence ranging from 2 to 3%. It is usually a benign condition, but it can be associated with an increased risk of ventricular arrhythmias (VA) leading to sudden cardiac death (SDC). Our study aimed to evidence to victims of SDC, the incidental presence of MVP, and the associated histological alterations. In patients with MVP, we assessed the increased risk for VA, by studying the Heart Rate Variability (HRV) and Heart Rate Turbulence (HRT). Firstly, in 2021, we conducted a morpho-pathological study on 225 victims of SDC, and concomitantly, a clinical study was performed on 50 patients with MVP who underwent 24 hours Holter monitoring. In the first study, we evidenced in 8 subjects, alterations of the mitral valve (MV) suggestive of MVP, and associated with fibrotic lesions in the vicinity of MV. The patients included in the clinical study were divided into two groups based on age, clinical particularities, and 2D-echocardiographic aspect: group A: 23 subjects younger than 40 years with myxomatous degeneration of the MV and group B, 27 elderly patients with MVP and associated cardiovascular pathology. In patients with MVP, 24-hour Holter monitoring may evidence alterations of HRV and HRT, frequently related to the severity of mitral regurgitation (MR), which could explain the increased risk for VA.

Keywords: Mitral valve prolapse, Sudden cardiac death, Myxomatous degeneration, Ventricular arrhythmia, Heart rate variability, Heart rate turbulence

Introduction

Mitral valve prolapse (MVP) represents a fairly common valvular anomaly of the mitral valve (MV) with a prevalence ranging from 2 to 3% [1-3]. It is induced by fibro-myxomatous degeneration with thickening and lengthening of the anterior and/or posterior MV leaflets, with their displacement into the left atrium (LA) during systole, associated with poor coaptation [1]. MVP can be associated with connective tissue diseases (CTD) or other cardiovascular (CV) pathologies [4-7]. In 40-50% of cases, there is a familial aggregation, suggesting the involvement of genetic factors [1, 4, 5]. There are two main aetiological forms of MVP: primary "non-syndromic" (mixomatous degeneration without identifiable fibroelastic or CTD) and secondary "syndromic" (associated with CTD such as Marfan, Loeys-Dietz, and Ehlers-Danlos syndrome, etc.) [1, 8].

Two-dimensional (2D) echocardiography is the most commonly employed method for the screening of MVP, the diagnosis being certified by the nonsymmetrical displacement of one or both leaflets above the plane of the mitral annulus, in a buckling appearance [9].

Commonly MVP represents a benign condition, but in some patients, it can be associated with ventricular arrhythmias (VA) or even sudden cardiac death (SCD) or it can result in severe mitral regurgitation (MR) and heart failure [4, 10, 11]. The risk of developing VA can be estimated on the 24-hour Holter monitoring and by analyzing the heart rate variability (HRV) and heart rate turbulence (HRT), both characterizing the status of the autonomic nervous system (ANS) [4, 5, 12]. These methods are used in various studies to estimate the sympathovagal imbalance in patients with CV pathologies and to predict an increased CV risk and morbidity [12-14]. The sympathovagal imbalance favors the onset of VA and increases the risk of SCD [5, 14, 15].

This study aims to evidence the increased risk for VA through the study of HRV and HRT on the 24-hour Holter monitoring, in patients with MVP assessed echocardiographically [16-18]. Another purpose is to document, in victims of SCD, the morpho-pathological changes associated with MVP.

Materials and Methods

Morphopathological study: of all 225 victims of SCD examined during 2021 in the Forensic Department of our County, 29 subjects were under 40 years and 196 had ages between 40 and 75 years. In three cases of the first category and five of the second, the anatomopathological examination revealed alterations of MV leaflets, suggesting MVP. MV leaflets involvement, as well as the presence of endocardial fibrous plaques on the left ventricular (LV) postero-lateral, was studied on the collected hearts. Probes from leaflets, papillary muscles, and the affected adjacent endocardium, were collected and fixed in Formalin-solution. Sections 5 μm thick were stained with hematoxylin-eosin and examined by a skilled pathologist [17-20].

Study groups: based on age, clinical particularities, and 2D-echocardiographic assessment, fifty patients diagnosed with MVP were assigned to 2 groups: Group A: included 23 patients, 10 men and 13 women, aged between 18 and 39 years, diagnosed with MVP, of one or both leaflets, associated with MR of various severity. None of them was certainly diagnosed with Marfan syndrome. Group B: 27 patients, 14 men and 13 women, aged between 42 and 74 years, with MVP, mostly of the posterior leaflet, accompanied by MR were included in this group.

Cardiologic evaluation: after a rigorous physical examination, and 12-lead ECG, all patients were evaluated by 2-D echocardiography, all assessments being performed by the same skilled operator. MVP was certified by the evidence of an over 2 mm displacement of one or both leaflets of MV into LA during systole, taking on a buckling appearance, with a leaflet thickening ˃ 5 mm during diastole in longitudinal long axis and apical 4-chamber views [9]. We also determined LV mass index (LVMI), and LA maximum volume index (LAVI) ejection fraction (EF) in the Simpson method. Doppler echocardiography was used to quantify the severity of MR [9].

All patients had 24-hour Holter monitoring, performed with a Holter Labtech Cardiospy device. We analyzed the presence and severity of VA. To analyze the obtained data we used the Nevrokard Long-Term aHLV (L-aHRV V.5.0.0.) program. Regarding HRV, which describes the spontaneous fluctuations in heart rate (HR) and normal RR intervals, we assessed the standard deviation of all normal to normal (NN) intervals (SDNN) in the time domain. Patients with SDNN values below 50 ms were classified as unhealthy, 50–100 ms had compromised health, and above 100 ms were healthy [14]. To determine HRT we included in our study only patients with at least 6 PVC. For HRT, which analyzes the sinus rhythm cycle length variation after isolated premature ventricular contractions (PVC), we determined the turbulence onset (TO) - early sinus acceleration after a PVC and the turbulence slope (TS) - late sinus deceleration following a PVC. In most studies, TO˂0% and TS˃2.5 ms/R-R interval are considered normal, but according to risk stratification studies, HRT can be divided into 3 categories: Category 0 - TO and TS are normal, category 1 – TO or TS is abnormal, category 2 - TO and TS are abnormal [14, 15].

Statistical methods: Data analysis was performed using SPSS v.25 (Statistical Package for the Social Sciences, Chicago, IL, USA). Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), and categorical variables were presented as frequency and percentages. The results of the normality test (Shapiro-Wilk) showed a non-Gaussian distribution, the reason why we continued to use nonparametric tests. To compare continuous variables between groups we applied the Mann–Whitney U test. To evaluate the relation between MR and HRT we used Spearman`s correlation test. A p-value of less than 0.05 was considered to indicate a statistically significant difference.

The study was approved by the Ethics Committee of our hospital (Nr. 4052/19.06.2020) and all patients signed a written informed consent.

Results and Discussion

Morphopathological Study

225 victims of SCD were examined in the Forensic Department of our County in 2021. In 3 out of 29 subjects aged under 40 years and in 5 of the 196 with ages between 40 and 75 years, the macroscopic examination of collected hearts revealed alterations of the MV suggestive of MVP and patchy fibrosis in the adjacent areas. In younger SCD victims with MVP, on gross examination, there was evidence of posterior (66%) or bileaflet (33%) myxomatous degeneration. Valvular leaflets were thickened, with elongated chordae. In the older SDC subjects with MVP, there was evidence of bileaflet involvement in 40% and only of the posterior leaflet in 60%. Regional thickening of the leaflets, with elongated, fibrotic chordae and fibrous plaques of the adjacent posterolateral wall was observed in all cases.

Histological examinations of the MV, evidenced in younger patients, myxomatous infiltration with mucopolysaccharide accumulation, (Figure 1a) while in the older ones, fibroelastic alterations prevailed. Collagen disruption and elastin fragmentation were present in both types. Overall, in 6 cases (75%), there was evidence of endo-myocardium alterations with patchy fibrosis (Figure 1b) of the posterior leaflet, adjacent free wall, and the top of the papillary muscle where some hypertrophied cardiomyocytes with dysmorphic and dissymmetric nuclei were also detected.

Table 1. Results of clinical data, 2D echocardiography, and 24-hour Holter monitoring

Legend: BMI –body mass index; MVP –mitral valve prolapse; MR –mitral regurgitation; LAVI –left atrial volume index; LVMI – left ventricular mass index; EF –ejection fraction; HR –heart rate; PVC –premature ventricular contractions; VT –ventricular tachycardia; SDNN – standard deviation of normal-normal RR intervals; HRT – heart rate turbulence.

Clinical Study

Group A included 23 patients, 10 men, and 13 women, with a median age of 27 (21-34) years, diagnosed with MVP using 2D echocardiography, Figure 2. Their clinical and laboratory data are illustrated in Table 1. In most cases (52.17%) the prolapse of the posterior leaflet prevailed Figure 2a, followed by the bileaflet form, Figure 2b. The associated MR was mild in most cases (60.83%). In this group, 20 patients had SDNN over 100 ms with HRT category 0. They had mild MR and only 6 had moderate MR.