Elongation of chordae tendineae as an adaptive process to reduce mitral regurgitation in functional mitral regurgitation

Obase, Kikuko; Weinert, Lynn; Hollatz, Andrew; Farooqui, Farhan; Roberts, J. Devin; Minhaj, Mohammed; Tung, Avery; Chaney, Mark A.; Ota, Takeyoshi; Jeevanandam, Valluvan; Yoshida, Kiyoshi; Mor‐Avi, Victor; Lang, Roberto M.

doi:10.1093/ehjci/jev314

Cited by 25 publications

(33 citation statements)

References 24 publications

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“…Papillary muscle (PM) displacement due to left ventricular (LV) remodeling results in leaflet tethering that restricts valve closure. Ischemic MR also reflects a mismatch between valve and ventricular size as the damaged heart enlarges but the MV fails to keep pace (2–9). Stiffening and fibrosis further limit valve closure (10–12).…”

Section: Introductionmentioning

confidence: 99%

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction

Bartko

Dal‐Bianco

Guerrero

et al. 2017

Journal of the American College of Cardiology

104

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Background After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-β overexpression. In vitro, losartan-mediated TGF-β inhibition reduces EMT of MV endothelial cells. Objectives The authors tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-β inhibition. Methods We studied 17 sheep, including 6 sham-operated controls and 11 with apical MI and papillary muscle retraction short of producing MR: 6 treated with daily losartan, and 5 untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by 3-dimensional echocardiography at baseline and at 60 ± 6 days, and excised leaflets were analyzed by histopathology and flow cytometry.’ Results Post-MI LV dilation and tethering were comparable in losartan-treated and untreated LV-constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced arterial pressure changes. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm shams), TGF-β and downstream phosphorylated extracellular-signal–regulated kinase and EMT (27.2% ± 12.0% vs. 51.6% ± 11.7% α-smooth-muscle-actin-positive endothelial cells, p < 0.05; 7.2% ± 3.5% shams), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD)45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and Losartan-treated sheep. Conclusions Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR.

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Section: Introductionmentioning

confidence: 99%

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction

Bartko

Dal‐Bianco

Guerrero

et al. 2017

Journal of the American College of Cardiology

104

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“…In contrast, patients with dilated cardiomyopathy and moderate or severe MR showed unbalanced remodeling, such as short leaflets and short chordae tendinae. A correlation between chordal length and IMR development has also been suggested by others 18,19 . In general, it was demonstrated that the leaflet area increases in patients with chronic IMR, but leaflet adaptation does not seem to be adequate in patients with significant IMR 20,21 .…”

Section: Discussionmentioning

confidence: 57%

“…Activation of TGF‐β can be favorable, but, if enhanced by angiotensin II receptor activation, it can induce fibrotic changes in the MV, as described by Grande‐Allen et al, 13 eliminating the possibility of augmenting the valvular area. The second‐order chords are subjected to the same mechanisms 19 . If MV adaptation is balanced, IMR grade can be absent of mild even in the presence of a large heart.…”

Section: Discussionmentioning

confidence: 99%

Surgical mitral plasticity for chronic ischemic mitral regurgitation

et al. 2020

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Background and Aim of the Study The outcome of mitral valve (MV) repair for chronic ischemic mitral regurgitation (IMR) is suboptimal, due to the high recurrence rate of moderate or severe mitral regurgitation (MR) during follow‐up. The MV adapts to new MR increasing its area to cover the enlarged annular area (mitral plasticity). As this process is often incomplete, we aimed to evaluate if augmenting the anterior leaflet (AL) and cutting the second‐order chords (CC) together with restrictive mitral annuloplasty, a strategy we call “surgical mitral plasticity,” could improve the midterm results of MV repair for IMR. Materials and Methods From November 2017 to October 2019, 22 patients with chronic IMR underwent surgical mitral plasticity. Mean age was 73 ± 7 years and six were female. Mean ejection fraction was 32% ± 11%, IMR grade was moderate in 10 and severe in 12. Mean clinical and echocardiographic follow‐up was 12 ± 6 months. Results There was no early death, and one patient died 6 months after surgery. Ejection fraction improved from 32% ± 15% to 40% ± 6% (P = .031). IMR was absent or mild in all patients, and none showed recurrent moderate or more IMR. Tenting area decreased significantly from 2.5 ± 0.5 to 0.5 ± 0.3 cm² and coaptation length increased from 1.9 ± 0.7 to 7.8 ± 1.6 mm. All patients were in New York Heart Association class I or II. Conclusions Mitral plasticity, if uncomplete, is ineffective in preventing IMR to become significant. Surgical mitral plasticity, by completing incomplete process of MV adaptation, has a strong rationale, which however needs to be validated with longer follow‐up.

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“…Such chordal cutting reduces both MR and its associated LV remodelling 13 and has been successfully applied by several surgical groups. 14 -16 The pathological changes observed in chordae post-infarction 7 and the recent reported relation between secondary MR and chordal shortening, imposing additional restriction on the tethered leaflets, lend further support to the potential benefits of chordal cutting to relieve such MR. 17 The current paper reports a proof of concept for using pulsed cavitational focused ultrasound (histotripsy) to cut chordae non-invasively guided by real-time 3D echocardiography. 3 The authors show that secondary anterior chordae can be selectively cut in vitro and in vivo in the beating sheep heart with a high-energy Figure 1 (A) Functional/ischaemic MR: the PM is displaced posteriorly, laterally, and apically because of local LV dilatation and remodelling (arrows) caused by MI (shaded area).…”

mentioning

confidence: 99%

“…Three-dimensional transoesophageal echocardiography may offer improved guidance. 17 (iv) Application of cavitational focused ultrasound will need to be achieved without thoracotomy. Optimally, a transoesophageal or gastric window may prove to be sufficient.…”

mentioning

confidence: 99%

The power of ultrasound: treating secondary MR with sound waves

Dal‐Bianco¹,

Bartko²,

Levine³

2016

Eur Heart J Cardiovasc Imaging

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Innovations in physics and its applications often enable medical advances. Collaboration between physicists who developed a high-frame-rate ultrasound system and cardiovascular investigators has allowed non-invasive measurement of vascular and myocardial stiffness. 1,2 In this current issue of the European Heart JournalCardiovascular Imaging, members of these groups, using a related technology, have employed ultrasound to treat as well as to image the heart 3 in mitral regurgitation (MR) secondary to myocardial infarction (MI) that causes mitral valve (MV) leaflet tethering mediated by chordae to the displaced papillary muscles (PMs). 4 This is a condition for which a strong need is perceived for improved approaches. 5 Although there is evidence for adaptive MV growth in secondary MR,6,7 this extra leaflet tissue is often insufficient to compensate adequately for mitral annular (MA) enlargement and chordal tethering. 8 The MV leaflets thus become increasingly taut, being pulled by the annulus towards the base, and by chordae towards the left ventricular (LV) apex. The normally convex MV closing configuration towards left atrium becomes concave, and the anterior MV leaflet appears like a 'hockey stick' on Echo. 9 Once the necessary leaflet tissue redundancy for MV coaptation is exhausted, MR will develop, which will over time further advance annular remodelling and tethering by the collagen-based chordae 6,7,10 and therefore MR ( Figure 1A).Current medical and surgical and transcatheter repair therapies for secondary MR thus aim to reduce overall leaflet tethering to restore leaflet coaptation by addressing the impaired LV (optimal medical heart failure therapy, revascularization, resynchronization, potential myocardial regeneration) and the mitral annulus (restoration of normal sinus rhythm, annuloplasty). Not as clinically established, but shown to be safe and effective is to directly target the chordal apparatus by cutting secondary chordae attaching to the leaflet bodies to relieve their tethering and to restore a greater surface for leaflet coaptation 11,12 ( Figure 1B). Such chordal cutting reduces both MR and its associated LV remodelling 13 and has been successfully applied by several surgical groups. 14 -16 The pathological changes observed in chordae post-infarction 7 and the recent reported relation between secondary MR and chordal shortening, imposing additional restriction on the tethered leaflets, lend further support to the potential benefits of chordal cutting to relieve such MR. 17 The current paper reports a proof of concept for using pulsed cavitational focused ultrasound (histotripsy) to cut chordae non-invasively guided by real-time 3D echocardiography. 3 The authors show that secondary anterior chordae can be selectively cut in vitro and in vivo in the beating sheep heart with a high-energy Figure 1 (A) Functional/ischaemic MR: the PM is displaced posteriorly, laterally, and apically because of local LV dilatation and remodelling (arrows) caused by MI (shaded area). This LV wall-PM displace...

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Elongation of chordae tendineae as an adaptive process to reduce mitral regurgitation in functional mitral regurgitation

Cited by 25 publications

References 24 publications

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction

Surgical mitral plasticity for chronic ischemic mitral regurgitation

The power of ultrasound: treating secondary MR with sound waves

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