
==== Front
Cardiol J
Cardiol J
Cardiology Journal
1897-5593
1898-018X
Via Medica

38742666
10.5603/cj.95415
cardj-31-4-538
Clinical Cardiology: Original Article
Reverse remodeling of mitral leaflets after medical treatment in recent-onset dilated cardiomyopathy
Kang Yu 1*
Wang Nan 1
Liu Keyi 1*
Yang Zixuan 1
Qu Nan 1
Zhong Xueke 2
Chen Xiaojing 1
Wang Mian 1
Zhang Qing 1
1 Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
2 Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
Address for correspondence: Qing Zhang, MD, PhD, Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China, tel.: 86-18980601267, e-mail: qzhang2000cn@163.com. Mian Wang, MM, Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China, tel.: 86-18980606044, e-mail: yangmian197@163.com
* These authors contributed equally to this work.

2024
29 8 2024
31 4 538545
04 5 2024
10 4 2024
Copyright © 2024 Via Medica
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.
Background

The growth of mitral leaflets (MLs) adaptive to left ventricluar (LV) remodeling has been observed. However, the elasticity of MLs upon mechanical stimuli would be supposed if it shrinks with LV reverse remodeling (LVRR).

Methods

Patients with idiopathic recent-onset dilated cardiomyopathy (RODCM) (n = 82) and 50 matched normal controls (NC) were prospectively enrolled. Echocardiography was performed at baseline and 6 months of follow-up for the anterior and posterior mitral leaflet (AML and PML) length, mitral annular dimension (MAD), and tenting height (TH). LVRR was measured as a ≥ 15% reduction in LV end-diastolic volume (LVEDV).

Results

After 6 months, LVRR was achieved in 69.5% of patients. The AML (28 ± 3 vs. 26 ± 3 mm, p = 0.004) and PML (19 ± 4 vs. 17 ± 3 mm, p < 0.001) decreased in length, as well as the MAD (31 ± 5 vs. 28 ± 5 mm, p = 0.001) and TH (10 ± 3 vs. 8 ± 2 mm, p < 0.001). Compared with the NC group, the AML and PML of the RODCM group were 16.7% and 35.7% longer at baseline and remained 8.3% and 21.2% longer at follow-up, respectively. The change in AML or PML correlated moderately with that in LVEDV (r = 0.487, p < 0.001; r = 0.516, p < 0.001, respectively). The AML and PML length decreased in the LVRR (+) subgroup (AML, 28 ± 3 vs. 26 ± 3 mm, p = 0.001; PML, 20 ± 4 vs. 16 ± 3 mm, p < 0.001), but remained the same in the LVRR (–) subgroup (27 ± 4 vs. 28 ± 4 mm, p = 0.318; 17 ± 3 vs. 17 ± 3 mm, p = 0.790).

Conclusions

Enlarged MLs could reverse accompanied by LV reverse remodeling. This study provided the other facet of ML plasticity adaptive to mechanical stretching.

recent-onset dilated cardiomyopathy
reverse remodeling
mitral leaflets
left ventricular
Chengdu Science and Technology Bureau2022-YF05-01572-SN National Science Foundation of Sichuan province, China2022NSFC1487 Science Technology Support Plan Projects of Sichuan Province2020YFS0241
==== Body
pmcIntroduction

The growth of mitral leaflets (MLs) adaptive to mechanical stretch caused by a dilated left ventricle (LV) and mitral annulus has gained increasing attention in recent years. Several clinical and experimental studies in non-ischaemic [1] and ischaemic cardiomyopathy [2–8], aortic regurgitation, and lone atrial fibrillation [9, 10] have demonstrated adequate ML enlargement proportionate to the LV, and mitral annular remodelling could prevent significant secondary mitral regurgitation (SMR). In contrast, inadequate ML growth has been proposed to contribute to the complex mechanisms of SMR. This extensibility of the MLs is not fully understood, including their histology, pathophysiology, positive or negative stimuli, and changes that occur after stimulus withdrawal. Therefore, the current study was the first to investigate the change of MLs in patients with idiopathic recent-onset dilated cardiomyopathy (RODCM) who received guideline-directed medical therapy (GDMT) as well as its relationship with LV reverse remodelling (LVRR — left ventricular reverse remod) and SMR improvement.

Methods

This prospective cohort study was approved by the institutional review board and ethics committee of West China Hospital. Informed consent was obtained from all patients.

Patient enrolment

The study population (n = 90) was enrolled from the cohort of the patients with idiopathic RODCM (ChiCTR2000038869). The inclusion criteria were: (1) aged ≥ 18 years; (2) met the criteria of DCM defined by the World Health Organization/International Society and Federation of Cardiology [11] and in the absence of volume overload or ischemic causes, including severe and uncontrolled hypertension, valvular heart disease, congenital heart disease, and coronary artery disease. Other identifiable non-genetic causes such as drugs, toxic endocrinology, infection or auto-immune diseases were also excluded [12]; (3) and < 6 months since the occurrence of heart failure (HF) symptoms. The exclusion criteria were: (1) reluctance to participate; (2) expected life span of < 1 year due to non-cardiac causes; and (3) follow-up duration of < 6 months. A group of subjects who had no cardiovascular diseases and a normal heart on echocardiography were enrolled as the normal control (NC) group (n = 50).

Clinical assessment and follow-up

Demographics and clinical data were collected at baseline following the protocol. The initiation and titration of GDMT were performed in all patients. Comprehensive echocardiography was performed at baseline and 6-month follow-up in the RODCM group.

Transthoracic echocardiography

Standard transthoracic echocardiography was performed using a Philips iE33 scanner and a 5-MHz transducer (Philips Medical Systems, Andover, MA). Images were acquired for the LV and mitral apparatus assessment as previously reported [1]. Off-line analyses were performed by two independent observers who were blinded to the results. The mitral regurgitation (MR) jet area and left atrial (LA) area were measured in the apical four-chamber view where the MR severity was reflected by the ([MR jet area/LA area] × 100%) ratio. Mild, moderate, and severe MR was indicated by a ratio of < 20%, 20–39%, and ≥ 40%, respectively. No MR was indicated by undetectable or untraceable trivial MR [13]. At the parasternal long-axis view, the anterior mitral leaflet (AML) or posterior mitral leaflet (PML) length was measured from the leaflet tip to its insertion point at a frame when it was fully stretched into a straight-line during diastole; the mitral annular dimension (MAD) or tenting height (TH) was measured at mid-systole. Interobserver and intraobserver variabilities for the AML, PML, TH, and MAD were obtained in 20 randomly selected images by two independent observers who performed the offline analysis twice on two different days. Good correlations were demonstrated for both intraobserver and interobserver reliabilities with intraclass correlation coefficients ranging from 0.750 to 0.926. The ratio of (AML + PML)/(MAD + TH) was calculated to reflect the ML length relative to mitral tenting size. LVRR was defined as a ≥ 15% reduction in LVEDV at 6-month follow-up.

Statistics

Continuous variables were checked for normality using the Shapiro-Wilk test and expressed as mean ± SD if normally distributed or median and interquartile range (IQR) otherwise. Categorical variables were reported as number and frequency (%). A paired t-test or signed Wilcoxon rank-sum test was used when appropriate to compare the parameters at baseline and 6-month follow-up. All tests were two-sided. The analyses were performed using SPSS software version 25.0. Statistical significance was set at p < 0.05.

Results

Baseline characteristics and clinical follow-up

A total of 90 patients with RODCM underwent the baseline assessment. None died, but eight did not undergo transthoracic echocardiography at the 6-month follow-up. Therefore, 82 patients with RODCM were included in the final analysis. In addition, 50 age, sex and body surface area matched NC were included. The RODCM group had a lower blood pressure and higher heart rate than the control group (p < 0.05).

Before enrolment, 50 out of 82 patients (61%) had initiated GDMT with a median duration of 1.3 ± 1.1 months. This proportion increased to 100% at the baseline visit. Baseline characteristics of the RODCM patients are listed in Table 1. At the end of 6 months, the New York Heart Association (NYHA) functional class was improved for at least one class in 21 (25.6%) patients. The N-terminal pro-brain natriuretic peptide level decreased to 159 (IQR, 62–389) pg/mL (p < 0.001). Fifty-one (62.2%) patients received the “four pillar” drugs. The median dose of angiotensin receptor-neprilysin inhibitor was 250 (IQR, 150–300) mg, while that of beta-blocker was 47.5 (IQR, 47.5–71.25) mg equivalent to metoprolol. Five patients underwent cardiac resynchronization therapy-defibrillator implantation, while another five underwent implantable cardioverter defibrillator implantation.

LV reverse remodelling and SMR reduction

At 6-month follow-up, LV size was reduced with an increase in systolic function, while LV wall thickness was unchanged. LVRR was achieved in 57 (69.5%) patients as defined. Those with LVRR (+) also had a greater improvement in left ventricular ejection fraction (LVEF) than those with LVRR (–) (14 ± 11% vs. 6 ± 8%, p < 0.001). LA size and function also improved significantly. The DCM group showed larger LV and LA size, but a lower LVEF compared to the NC group, both at baseline and 6-month follow-up. (Table 2).

As shown in Table 2, SMR severity decreased significantly at 6-month follow-up. The proportion of patients with SMR decreased from 61% to 39%. SMR reduction of ≥ 1 grade was observed in 22 (26.9%) patients. Among the 16 (19.5%) patients with moderate or severe SMR at baseline, one patient had SMR relief from severe to moderate, one from severe to mild, and six from moderate to mild or none, while moderate SMR persisted in the other eight patients. Those with LVRR (+) had a higher percentage of SMR improvement of ≥ 1 grade than those with LVRR (–) (35.1% vs. 8.0%, p = 0.014).

Changes in the MLs

The AML and PML of the RODCM group decreased at 6-month follow-up (Fig. 1). The AML tended to exhibit a lesser reduction than PML (–5% ± 14% vs. −10% ± 19%, p = 0.076); thus, the AML/PML ratio increased. Compared with the control group, the AML and PML of the DCM group were 16.7% and 35.7% longer at baseline, respectively, which remained 8.3% and 21.2% longer at follow-up. However, the AML/PML ratio was smaller at baseline and at 6 months (Table 3).

At both time points, MAD and TH were larger in the RODCM group than in the control group. MAD and TH were reduced in the RODCM group at 6-month follow-up. Since the extent of decrease in the (AML+PML) tended to be less than that in the (MAD+TH) (−8% ± 13% vs. −12% ± 15%, p = 0.059), the ratio of (AML+PML)/(MAD + TH) was increased (1.14 ± 0.12 vs. 1.20 ± 0.16, p = 0.001) (Table 3).

Shortening of elongated leaflets and LV reverse remodelling

The change in AML (ΔAML) and PML (ΔPML) correlated moderately with the change in LVEDV (ΔLVEDV) (r = 0.487, p < 0.001; r = 0.516, p < 0.001, respectively). The correlation was weaker with the change in LVEF (ΔLVEF) (r = −0.279, p = 0.011 and r =–0.321, p = 0.003, respectively) (Fig. 2). In addition, ΔAML and ΔPML were related to ΔMAD (r = 0.488, p < 0.001; r = 0.415, p < 0.001, respectively) and ΔTH (r = 0.528, p < 0.001; r = 0.529, p < 0.001, respectively).

Furthermore, the AML and PML decreased in those with LVRR (+) (AML, 28 ± 3 vs. 26 ± 3 mm, p = 0.001; PML, 20 ± 4 vs. 16 ± 3 mm, p < 0.001) but remained the same in those with LVRR (–) (AML, 27 ± 4 vs. 28 ± 4 mm, p = 0.318; PML, 17 ± 3 vs. 17 ± 3 mm, p = 0.790). The differences in ΔAML and ΔPML between the LVRR subgroups are shown in Figure 3.

Discussion

In this study, it was observed that the length of MLs in RODCM was elongated at baseline and, for the first time, was shortened (although not normalised) along with LV reverse remodelling after 6 months of GDMT. The PML demonstrated a greater stretching as well as a more contracting after treatment than the AML.

Histopathological basis of adaptive growth in the MLs

Mechanical stress induced specific cellular and molecular changes of the MLs contribute to morphological remodelling in SMR. In the transplant recipient heart of DCM and ischemic cardiomyopathy, the MLs showed increased cell proliferation and expanded extracellular matrix that contained more collagens and glycosaminoglycans compared to that of a normal heart, longer AML and PML were also observed by echocardiography before transplantation [14]. In an in vitro study, an additional fibrous layer was observed atop the original leaflet by exposure of cultured MLs to different haemodynamic conditions. The underlying mechanisms involve activation of the transforming growth factor-beta and bone morphogenetic protein signalling pathways as well as migration of valvular interstitial cells and macrophages through breakage of the endothelial cell lining [15]. In vivo studies that used volume overload [16], papillary muscle retraction [17, 18] and rapid pacing [19] models, LV remodelling was accompanied by ML growth over time by echocardiography. A larger ML was also demonstrated by gross pathology at sacrifice [17]. Histopathological changes in the stretched MLs included increased spongiosa layer thickness, decreased collagen alignment, and decreased α-smooth muscle actin+staining in the atrial endothelium, with nests of α-smooth muscle actin +cells penetrating the interstitium [17].

Reverse remodelling of MLs with LV reverse remodelling

If the changes in MLs after stretch force withdrawal was reversed, the proposed concept of mechanical stretch that induced ML growth could be more comprehensive. In the current study, it was confirmed that AML and PML shortening upon decreased tethering force and an increased closing force in terms of LVRR. It appeared to correlate more with Δ left ventricular end-diastolic dimension (LVEDD) than ΔLVEF, which supported the core role of mechanical stretching. Nishino et al. [20] also demonstrated a significantly reduced ML surface area with LA reverse remodelling after successful catheter ablation for atrial fibrillation. It was recently observed that chronic atrial fibrillation and diastolic heart failure induced LA enlargement was another stretch stimulus leading to adaptive ML growth [21].

However, mechanical stretch might not be the only stimulus for the enlargement of MLs in DCM. In previous studies, there were patients with significant SMR who exhibited insufficient ML growth relative to atrioventricular orifice dilation. In this study, the extent of decrease in MLs was less than that in the (MAD+TH) even in the patients undergoing LVRR. Apart from a short duration of treatment, which might be attributed to non-stretching stimuli associated with pathophysiologies of DCM itself, particularly fibrosis, that hinder adequate elongation and return to a normal state in response to stretch on and off, respectively. For instance, an experimental model of apical acute myocardial infarction, where the imposed tethering force on MLs did not increase, it was demonstrated that ischemia alone could lead to excessive interstitial collagen deposition in the MLs [6]. Inhibiting these non-stretch-induced changes would perhaps promote proportional ML growth in response to stretch, thus offering a potential approach to treat or prevent SMR [22].

Different behaviours of AML and PML in SMR

In line with a previous publication that compared AML and PML in unselected DCM patients [1], the PML demonstrated greater elongation than the AML in this group of patients with RODCM; furthermore, at 6-month follow-up, the PML demonstrated a greater shortening than the AML. This finding was supported by previous studies of excised porcine mitral valves [24, 25] which found greater extensibility in the circumferential and radial directions of the PML as well as lower stiffness in the posterior aspect of the mitral annulus. More recently, a study that assessed ML strain by three-dimensional transoesophageal echocardiography in patients with SMR and primary MR found higher strain in the PML [26]. It is likely that the AML and PML could be treated differently when exploring the relationship between deformative changes in MLs and SMR.

Study limitations

This was a single-centre obervational study with a relatively modest size and short period of time, that could be reasonable as a hypothesis-generating pilot study. Measurements of the MLs relied on a single plane by two-dimensional transthoracic echocardiography, but standardised image acquisition and off-line analysis yielded good reproducibility and acceptance in several studies [1, 27]. Although the association between ML changes and SMR was not the focus of this study, the low prevalence of moderate or severe SMR in the RODCM cohort made it inappropriate for further analysis.

Conclusions

The current study demonstrated that enlarged MLs could reverse along with LVRR after standardised therapy in patients RODCM. In this process, the PML showed a greater degree of changes than the AML. These findings support the hypothesis of ML plasticity adaptive to mechanical stress, though further studies are warranted.

Acknowledgments

None.

Figure 1 An example of a patient with RODCM who showed reverse remodelling in MLs and left ventricle. Compared with baseline (A and C), the length of AML and PML measured at the parasternal long axis view decreased (B), and the left ventricular dilation and systolic dysfunction measured by M-mode echocardiography improvement (D) at 6-month follow-up. LVEDD — left ventricular end-diastolic dimension; LVESV — left ventricular end-systolic dimension; LVRR — left ventricular reverse remodeling; PML — posterior mitral leaflet

Figure 2 Correlations between changes in ML length and LVEDV (A) and LVEF (B). LVEDV — left ventricular enddiastolic volume; LVEF — left ventricular ejection fraction. The rest of the abbreviations are as shown in Figure 1

Figure 3 Changes in ML length by LVRR subgroup. The remaining abbreviations are as shown in Figure 1

Table 1 Patient baseline characteristics

	RODCM (n = 82)	
Age, years	49 ± 12	
Male sex, n [%]	59 (72)	
Systolic blood pressure [mmHg]	107 ± 17	
Diastolic blood pressure [mmHg]	73 ± 12	
Heart rate [bpm]	78 ± 14	
Hypertension, n [%]	16 (19.5)	
Diabetes, n [%]	7 (8.5)	
Atrial fibrillation, n [%]	11 (13.4)	
NYHA class, n [%]	
I/II	78 (95.1)	
III/IV	4 (4.9)	
NT-proBNP [pg/mL]	549 (228–943)	
ARNI/ACEI/ARB/, n [%]	81 (98.8)	
Beta-blocker, n [%]	68 (82.9)	
SGLT2i, n [%]	45 (54.9)	
MRA, n [%]	65 (79.3)	
Diuretic, n [%]	69 (84.1)	
ACEI — angiotensin-converting enzyme inhibitors; ARB — angio-tensin receptor blockers; ARNI — angiotensin receptor-neprilysin inhibitor; MRA — mineralocorticoid receptor antagonists; NT-proBNP — N-terminal pro-brain natriuretic peptide; NYHA — New York Heart Association; RODCM — recent-onset dilated car-diomyopathy; SGLT2i — sodium glucose cotransporter 2 inhibiton.

Table 2 Post-treatment changes in the left heart

	RODCM (n = 82)	NC (n = 50)	
	
Baseline	6-month follow-up	P-value	
LV	
 LVD [mm]	64 ± 7*	58 ± 8*	< 0.001	47 ± 3	
 IVS [mm]	9 ± 2	10 ± 2	0.320	9 ± 2	
 LVPW [mm]	8 ± 2	8 ± 2*	0.644	8 ± 2	
 LVEDV [mL]	171 ± 61*	131 ± 50*	< 0.001	86 ± 16	
 LVESV [mL]	123 ± 56*	79 ± 41*	< 0.001	34 ± 9	
 LVEF	30 ± 9*	42 ± 9*	< 0.001	60 ± 5	
 LVSI	1.5 ± 0.2*	1.6 ± 0.2*	< 0.001	2.0 ± 0.2	
LA	
 LAEDV [mL]	71 ± 30*	56 ± 26*	0.007	36 ± 12	
 LAESV [mL]	41 ± 27*	25 ± 21*	0.001	12 ± 6	
 LAEF	46 ± 16*	59 ± 15*	< 0.001	67 ± 7	
IVS — interventricular septum; LAEDV — left atrial end-diastolic volume; LAEF — left atrial ejection fraction; LAESV — left atrial end-systolic volume; LVD — left ventricular dimension; LVEDV — left ventricular end-diastolic volume; LVEF — left ventricular ejection fraction; LVESV — left ventricular end-systolic volume; LVPW — left ventricular post-wall; LVSI — left ventricular sphericity index; RODCM — recent-onset dilated cardiomyopathy.

* p < 0.05 compared to the NC group

Table 3 Changes in the mitral apparatus

	RODCM (n = 82)	NC (n = 50)	
	
	Baseline	6-month follow-up	P value	
AML [mm]	28 ± 3*	26 ± 3*	0.004	24 ± 3	
PML [mm]	19 ± 4*	17 ± 3*	< 0.001	14 ± 3	
MAD [mm]	31 ± 5*	28 ± 5*	0.001	26 ± 4	
TH [mm]	10 ± 3*	8 ± 2*	< 0.001	7 ± 2	
AML+PML [mm]	47 ± 6*	43 ± 6*	< 0.001	38 ± 4	
MAD+TH [mm]	42 ± 6*	36 ± 6*	< 0.001	33 ± 5	
(AML+PML)/(MAD+TH)	1.1 ± 0.1	1.2 ± 0.2	< 0.001	1.2 ± 0.2	
AML/PML	1.5 ± 0.2*	1.6 ± 0.3*	< 0.001	1.9 ± 0.5	
SMR, n [%]			< 0.001		
Absence	33 (40.2)	50 (61.0)		47 (94.0)	
Mild	33 (40.2)	22 (26.8)		3 (6.0)	
Moderate	14 (17.1)	10 (12.2)		0	
Severe	2 (2.5)	0		0	
AML — anterior mitral leaflet; MAD — mitral annular dimension; NC — normal controls; PML — posterior mitral leaflet; TH — tenting height. The remaining abbreviations are as shown in Table 1.

* p < 0.05 compared to the NC group

Funding: The study was supported by the Chengdu Science and Technology Bureau (grant number 2022-YF05-01572-SN), National Science Foundation of Sichuan province, China (project number: 2022NSFC1487), and the Science Technology Support Plan Projects of Sichuan Province (project number: 2020YFS0241).

Conflict of interest: None declared.
==== Refs
References

1 Kang Yu Chen C Chen X Pattern of Mitral Leaflet Elongation and Its Association With Functional Mitral Regurgitation in Nonischemic Dilated Cardiomyopathy Am J Cardiol 2016 118 7 1069 1073 10.1016/j.amjcard.2016.06.058 27553098
2 Chaput M Handschumacher MD Tournoux F Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation Circulation 2008 118 8 845 852 10.1161/CIRCULATIONAHA.107.749440 18678770
3 Beaudoin J Dal-Bianco JP Aikawa E Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling Circ Cardiovasc Imaging 2017 10 11 10.1161/CIRCIMAGING.117.006512 29042413
4 Yoshida S Fukushima S Miyagawa S The Adaptive Remodeling of the Anterior Mitral Leaflet and Chordae Tendineae Is Associated with Mitral Valve Function in Advanced Ischemic and Nonischemic Dilated Cardiomyopathy International Heart Journal 2018 59 5 959 967 10.1536/ihj.17-465 30101845
5 Dal-Bianco JP Levine RA Hung J Mitral Regurgitation Postinfarction: The Mitral Valve Adapts to the Times Circ Cardiovasc Imaging 2020 13 12 e012130 10.1161/CIRCIMAGING.120.012130 33317331
6 Marsit O Clavel MA Côté-Laroche C Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction J Am Coll Cardiol 2020 75 4 395 405 10.1016/j.jacc.2019.11.039 32000951
7 Hirasawa K Namazi F Milhorini Pio S Insufficient Mitral Leaflet Remodeling in Relation to Annular Dilation and Risk of Residual Mitral Regurgitation After MitraClip Implantation JACC Cardiovasc Imaging 2021 14 4 756 765 10.1016/j.jcmg.2020.08.019 33129743
8 Nishino S Watanabe N Gi T Longitudinal Evaluation of Mitral Valve Leaflet Remodeling After Acute Myocardial Infarction: Serial Quantitation of Valve Geometry Using Real-Time 3-Dimensional Echocardiography Circ Cardiovasc Imaging 2020 13 12 e011396 10.1161/CIRCIMAGING.120.011396 33317332
9 Beaudoin J Handschumacher MD Zeng X Mitral valve enlargement in chronic aortic regurgitation as a compensatory mechanism to prevent functional mitral regurgitation in the dilated left ventricle J Am Coll Cardiol 2013 61 17 1809 1816 10.1016/j.jacc.2013.01.064 23500248
10 Takada H Tanaka H Yokota S Association of Relatively Short Posterior Mitral Leaflet With Mitral Regurgitation in Patients With Atrial Fibrillation Circ J 2019 83 11 2312 2319 10.1253/circj.CJ-19-0529 31527338
11 Richardson P McKenna W Bristow M Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies Circulation 1996 93 5 841 842 10.1161/01.cir.93.5.841 8598070
12 Pinto YM Elliott PM Arbustini E Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases Eur Heart J 2016 37 23 1850 1858 10.1093/eurheartj/ehv727 26792875
13 Dudzinski DM Hung J Echocardiographic assessment of ischemic mitral regurgitation Cardiovasc Ultrasound 2014 12 46 10.1186/1476-7120-12-46 25416497
14 Grande-Allen KJ Borowski AG Troughton RW Apparently normal mitral valves in patients with heart failure demonstrate biochemical and structural derangements: an extracellular matrix and echocardiographic study J Am Coll Cardiol 2005 45 1 54 61 10.1016/j.jacc.2004.06.079 15629373
15 Kruithof BPT Paardekooper L Hiemstra YL Stress-induced remodelling of the mitral valve: a model for leaflet thickening and superimposed tissue formation in mitral valve disease Cardiovasc Res 2020 116 5 931 943 10.1093/cvr/cvz204 31497851
16 Stephens EH Nguyen TC Itoh A The effects of mitral regurgitation alone are sufficient for leaflet remodeling Circulation 2008 118 14 Suppl S243 S249 10.1161/CIRCULATIONAHA.107.757526 18824762
17 Dal-Bianco JP Aikawa E Bischoff J Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation Circulation 2009 120 4 334 342 10.1161/CIRCULATIONAHA.108.846782 19597052
18 Dal-Bianco JP Aikawa E Bischoff J Leducq Transatlantic Mitral Network Myocardial Infarction Alters Adaptation of the Tethered Mitral Valve J Am Coll Cardiol 2016 67 3 275 287 10.1016/j.jacc.2015.10.092 26796392
19 Timek TA Lai DT Dagum P Mitral leaflet remodeling in dilated cardiomyopathy Circulation 2006 114 1 Suppl I518 I523 10.1161/CIRCULATIONAHA.105.000554 16820630
20 Nishino S Watanabe N Ashikaga K Reverse Remodeling of the Mitral Valve Complex After Radiofrequency Catheter Ablation for Atrial Fibrillation: A Serial 3-Dimensional Echocardiographic Study Circ Cardiovasc Imaging 2019 12 10 e009317 10.1161/CIRCIMAGING.119.009317 31594407
21 Deferm S Bertrand PB Verbrugge FH Atrial Functional Mitral Regurgitation: JACC Review Topic of the Week J Am Coll Cardiol 2019 73 19 2465 2476 10.1016/j.jacc.2019.02.061 31097168
22 Johnson TM Lowe L Brown MD Histology and physiology of tissue expansion J Dermatol Surg Oncol 1993 19 12 1074 1078 10.1111/j.1524-4725.1993.tb01002.x 8282904
23 Agrawal K Agrawal S Tissue regeneration during tissue expansion and choosing an expander Indian J Plast Surg 2012 45 1 7 15 10.4103/0970-0358.96566 22754146
24 May-Newman K Yin FC Biaxial mechanical behavior of excised porcine mitral valve leaflets Am J Physiol 1995 269 4 Pt 2 H1319 H1327 10.1152/ajpheart.1995.269.4.H1319 7485564
25 Gunning GM Murphy BP Determination of the tensile mechanical properties of the segmented mitral valve annulus J Biomech 2014 47 2 334 340 10.1016/j.jbiomech.2013.11.035 24326099
26 El-Tallawi KC Zhang P Azencott R Mitral Valve Remodeling and Strain in Secondary Mitral Regurgitation: Comparison With Primary Regurgitation and Normal Valves JACC Cardiovasc Imaging 2021 14 4 782 793 10.1016/j.jcmg.2021.02.004 33832661
27 Layoun H Mentias A Kanaan C Differences in patterns of progression of secondary mitral regurgitation Eur Heart J Cardiovasc Imaging 2023 24 2 223 231 10.1093/ehjci/jeac200 36256596
