scholarly journals Mitral Plasticity: The Way to Prevent the Burden of Ischemic Mitral Regurgitation?

2022 ◽  
Vol 8 ◽  
Author(s):  
Mattia Vinciguerra ◽  
Silvia Romiti ◽  
Eleonora Wretschko ◽  
Mizar D'Abramo ◽  
David Rose ◽  
...  

The ischemic impairment of the left ventricular contractility, followed by an adverse remodeling leading to the displacement of the papillary muscles (PMs), increased tethering forces and loss of valve competence has been the long-term accepted definition of ischemic mitral regurgitation (IMR). Over the years, different approaches of management have attempted to address valve regurgitation, nevertheless failing to achieve satisfactory outcomes. Recent studies have observed some structural and molecular changes of the mitral valve (MV), challenging the concept of a bystander passive to the subvalvular involvement. Indeed, the solely mechanical stretch of the PMs, as in the dilated left ventricle because of the aortic valve regurgitation, is not enough in causing relevant MV regurgitation. This setting triggers a series of structural changes called “mitral plasticity,” leaflets increase in their size among others, ensuring an adequate systolic area closure. In contrast, the ischemic injury not only triggers the mechanical stretch on the subvalvular apparatus but is also a powerful promotor of profibrotic processes, with an upregulation of the transforming growth factor (TGF)-β signaling pathway, leading to a MV with exuberant leaflet thickness and impaired mobility. In this article, we revise the concept of IMR, particularly focusing on the new evidence that supports dynamic changes in the MV apparatus, discussing the consequent clinical insights of “mitral plasticity” and the potential therapeutic implications.

Author(s):  
Estibaliz Castillero ◽  
Daniel P. Howsmon ◽  
Bruno V. Rego ◽  
Samuel Keeney ◽  
Kathryn H. Driesbaugh ◽  
...  

Objective: Ischemic mitral regurgitation (IMR) often develops after an ischemic event, which results in distortion of the valvulo-ventricular complex and incomplete mitral valve (MV) leaflet coaptation. After left ventricular ischemic events, only some patients develop IMR. The susceptibility of the MV to remodel may influence whether IMR develops. We hypothesized that impaired signaling response in MV cells may contribute to IMR development by inducing maladaptive tissue remodeling. Approach and Results: Sheep (n=14) were subjected to ligation of the circumflex coronary artery to induce myocardial infarction. IMR was reported by echocardiography. MV leaflets and MV interstitial cells (MVICs) were collected at baseline (control, n=10), 4 and 8 weeks post-myocardial infarction. RNA sequencing highlighted differences in TGFβ (transforming growth factor beta) signaling between MV with/without IMR. SMAD6/7 and ID2 (inhibitor of DNA binding 2) were the highest increased TGFβ-signaling genes associated with IMR. MVICs from myocardial infarction sheep were less responsive to BMP (bone morphogenic protein) 4 pro-osteogenic stimulation (ID2, OPN [osteopontin], and OC [osteocalcin] mRNA) than control. MVICs from IMR sheep had a diminished COL (collagen) 1A1 mRNA response to TGFβ1 and enhanced prochondrogenic RUNX2 (runt-related transcription factor 2) and SOX9 mRNA response to BMP4 versus non-IMR MVICs. Baseline CD45 expression was detectable only in IMR MVICs. Upon TGFβ1 stimulation, CD45 expression was detected in all groups. Immunostaining confirmed increased presence of CD45+ cells in IMR MV interstitium. Conclusions: MVs from sheep with IMR had an altered TGFβ/BMP response, associated with increased CD45+ cell presence within the tissue interstitium. Pharmacological strategies aimed to modulate TGFβ/BMP signaling after myocardial infarction may protect from pathological MV remodeling leading to IMR.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Estibaliz Castillero ◽  
Daniel P Howsmon ◽  
Bruno V Rego ◽  
Yingfei Xue ◽  
Robert C Gorman ◽  
...  

Introduction: Ischemic mitral regurgitation (IMR) develops in a fraction of patients in response to left ventricular (LV) remodeling after ischemia. IMR independently predicts adverse events and doubles mortality. While largely driven by LV distortion, the susceptibility of the mitral valve (MV) to undergo remodeling may play a role in determining whether MR develops. We hypothesized that impaired cellular response in MV cells may contribute to MR development by inducing maladaptive tissue remodeling. Methods: Dorsett hybrid sheep (n=32) were subjected to ligation of the circumflex coronary artery to induce myocardial infarction (MI). Development of MR was reported by echocardiography. MV leaflets and isolated MV interstitial cells (MVIC) were collected at baseline (Control), 4-, and 8-weeks post MI. RNAseq (150 paired end reads, 20 million reads/sample) was performed on MV leaflets from all groups. MVICs were treated with for 24h with 10ng/ml TGFβ1 of 50ng/ml BMP4. Results: Gene set enrichment analysis using pre-defined gene sets from the Gene Ontology project, considering genes with significant changes (p<0.05) between MV with/without MR showed enrichment of cardiac contraction biological processes. TGFβ/BMP-dependent SMAD7 was the main hub in the protein-protein-interaction network of the top contributing genes to the enriched pathways in MR. In vitro, collagen matrix-contracting ability of MR MVICs was higher than non-MR MI MVICs. MVICs from MI sheep were less responsive to BMP4 pro-osteogenic stimulation (as reflected by blunted increased in ID2, osteopontin and osteocalcin mRNA) than control. MVICs from sheep with MR had a diminished COL1A1 mRNA response to TGFβ1 and enhanced pro-chondrogenic RUNX2 and SOX9 mRNA response to BMP4 vs. non-MR MVICs. Baseline CD45 expression was detectable only in MR MVICs. Upon TGFβ1 stimulation, CD45 expression was detected in all groups. Immunostaining confirmed increased presence of CD45+ cells in IMR MV interstitium. Conclusions: MVs from sheep developing MR had altered TGFβ/BMP response, which may be partially mediated by increased CD45+ fibrocyte presence. Pharmacological strategies aimed to modulate TGFβ/BMP signaling after MI may protect from pathological MV remodeling leading to IMR.


Author(s):  
Christiane Bretschneider ◽  
Hannah-Klara Heinrich ◽  
Achim Seeger ◽  
Christof Burgstahler ◽  
Stephan Miller ◽  
...  

Objective Ischemic mitral regurgitation is a predictor of heart failure resulting in increased mortality in patients with chronic myocardial infarction. It is uncertain whether the presence of papillary muscle (PM) infarction contributes to the development of mitral regurgitation in patients with chronic myocardial infarction (MI). The aim of the present study was to assess the correlation of PM infarction depicted by MRI with mitral regurgitation and left ventricular function. Methods and Materials 48 patients with chronic MI and recent MRI and echocardiography were retrospectively included. The location and extent of MI depicted by MRI were correlated with left ventricular function assessed by MRI and mitral regurgitation assessed by echocardiography. The presence, location and extent of PM infarction depicted by late gadolinium enhancement (LGE-) MRI were correlated with functional parameters and compared with patients with chronic MI but no PM involvement. Results PM infarction was found in 11 of 48 patients (23 %) using LGE-MRI. 8/11 patients (73 %) with PM infarction and 22/37 patients (59 %) without PM involvement in MI had ischemic mitral regurgitation. There was no significant difference between location, extent of MI and presence of mitral regurgitation between patients with and without PM involvement in myocardial infarction. In 4/4 patients with complete and in 4/7 patients with partial PM infarction, mitral regurgitation was present. The normalized mean left ventricular end-diastolic volume was increased in patients with ischemic mitral regurgitation. Conclusion The presence of PM infarction does not correlate with ischemic mitral regurgitation. In patients with complete PM infarction and consequent discontinuity of viable tissue in the PM-chorda-mitral valve complex, the probability of developing ischemic mitral regurgitation seems to be increased. However, the severity of mitral regurgitation is not increased compared to patients with partial or no PM infarction. Key points  Citation Format


2005 ◽  
Vol 289 (3) ◽  
pp. H1218-H1225 ◽  
Author(s):  
Hsi-Yu Yu ◽  
Mao-Yuan Su ◽  
Yih-Sharng Chen ◽  
Fang-Yue Lin ◽  
Wen-Yih Isaac Tseng

The present study tests the hypothesis that a mitral tetrahedron (MT) is a useful geometrical surrogate for assessment of chronic ischemic mitral regurgitation (CIMR). Fifty-eight subjects were divided into three groups on the basis of left ventricular ejection fraction (LVEF) and the presence or absence of CIMR: LVEF ≥0.5 and negative CIMR ( group 1, n = 28), LVEF <0.5 and negative CIMR ( group 2, n = 12), and LVEF <0.5 and positive CIMR ( group 3, n = 18). MT was defined by its four vertices at the anterior annulus, posterior annulus, and medial and lateral papillary muscle roots, determined by MRI at peak systole. The results showed no clear cutoff values of MT parameters between groups 2 and 1. In contrast, all MT indexes were significantly different between groups 3 and 2 ( P < 0.05), and significant cutoff values differentiated the two groups. A scoring system employing parameters of the whole MT confirmed the absence of CIMR with total edge length index <268 mm/BSA1/3, total surface area index <2,528 mm2/BSA2/3, and volume index <5,089 mm3/BSA (where BSA is body surface area). The sensitivity, specificity, and positive and negative predictive values were 1.00. This preliminary study demonstrates that MT might serve as a good geometrical surrogate for assessing CIMR. The derived geometrical criteria of MT may be useful in surgical correction of CIMR.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Carlo Fino ◽  
Isabelle Piazza ◽  
Bruno Vito Domenico ◽  
Philippe Pibarot ◽  
Attilio Iacovoni ◽  
...  

Background and Objective: Surgical treatment of severe secondary ischemic mitral regurgitation (IMR) may improve symptoms and functional capacity, however there are few data on its effect on long-on the evolution of heart failure. Time-course changes in brain natriuretic peptide (BNP) are a good marker of the heart failure status and outcomes. We investigated the association between the exercise stress echocardiographic (ESE) parameters and the changes in brain natriuretic peptide (BNP) following surgery for secondary IMR. Methods: We prospectively analyzed data on 50 patients (median age: 67, 61-64 y; EF: 35, 34-40%), undergoing mitral valve annuloplasty or replacement and coronary artery bypass graft (CABG). A valve annuloplasty with undersized ring was performed in 20 patients (40%) and a replacement in 30 (60%). A six minute walking test (6-MWT), BNP levels and ESE were performed at 1 year and at median follow-up (FU) of 6 years (4-7). Results: BNP level was: 388 (329-441) pg/ml before surgery, 175 (142-743) pg/ml at 1 y, and 123 (100-979) pg/ml at last FU (p=0.2). The relative changes of BNP from baseline to last FU significantly correlated with exercise tricuspid annulus plane systolic excursion (TAPSE) at last FU (r= -0.7, p<0.001), with preoperative and FU exercise LVEF, respectively ( r=-0.7 p= 0.01) (r=-0.93, p<0.001).On multivariable analysis, preoperative exercise EF was strongly and independently associated with independent BNP levels at last FU and with the changes in BNP from baseline to last FU. Conclusions: Despite surgical treatment of severe secondary IMR, BNP levels progressively increased over time in nearly 50% of the patients. Lower preoperative and 1-year FU exercise-stress EF was associated with increased levels of BNP during FU..


2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R Piatkowski ◽  
J Kochanowski ◽  
M Budnik ◽  
M Grabowski ◽  
P Scislo ◽  
...  

Abstract Late recovery of left ventricular function in patients with non-severe ischemic mitral regurgitation and multivessel disease qualified to cardiosurgery treatment. Purpose In patients (pts) after myocardial infarction (MI) with chronic left ventricle (LV) dysfunction, the presence and degree of ischemic mitral regurgitation (IMR) are predominantly related to LV remodelling and mitral valvular deformation. The aim of this study was to compare functional recovery (LVFR) as well as reverse remodelling of the left ventricle (LVRR) in pts with non-severe IMR qualified for cardiosurgical treatment - coronary artery bypass grafting alone (CABGa) or CABG with mitral repair (CABGmr in the 12-month follow-up. Materials and methods A total of 100 pts (mean age 64,4 ± 7,9 years) after MI, eligible for CABG, were included in a prospective study. Echo and clinical assessment were performed before and 12-months after surgery. Pts were referred for CABG a(gr.1; n = 74) or CABGmr (gr.2; n = 26) based on clinical assessment, 2D echo at rest and exercise and myocardial viability assessment (low dose dobutamine - dbx). Effective regurgitation orifice area (EROA) was used for quantitative IMR assessment. An increase in EF≥ 5% (ΔEF) from baseline value was considered as LVFR. A decrease in LV end-systolic volume &gt; 15% from baseline value was considered as LVRR. Multivariable logistic regression analysis was used to identify the strongest factors of lack of LVFR and LVRR. Results An LVFR was observed, at late control, in 35 (49%) of pts in the CABGa group and in 11 (48%) of pts in CABGmr group (p = 0,948). LVRR was observed in 41 (56%) of pts in the CABGa group and in 16 (70%) of pts in CABGmr group 12 months follow-up (p = 0,5). In pts with LVFR, there was a lower incidence of at least moderate IMR at follow-up (ΔEF dbx≥5% vs ΔEFdbx &lt; 5%:11% vs 30% pts; p = 0,05). Multivariable logistic regression analysis revealed that in both CABGa and CABGmr group only preoperative age and EF changes during stress echo remained the independent predictors of the lack of LVFR in 12 months follow-up (table 1). Conclusions 1. LVFR and LVRR were reported in most of the pts in both analyzed groups. 2. Preoperative assessment of changes EF during dbx (ΔEFdbx)can be used to identify pts with IMR at increased risk of lack of improvement in LV function and risk of residual IMRin 12-month f-up after surgery. Parameters Odds ratio (OR) Odds ratio (OR) p CABGa vs CABGmr 0,644 0,215 - 1,927 0,432 Age (increase by every 5 years) 1,11 1,039 - 1,879 0,003 ΔEF dbx (increase by every 5%) 0,21 0,096 - 0,46 &lt;0,001 Table 1. Prognostic factors lack improvement in left ventricle function.


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