Percutaneous mitral repair as treatment in HFrEF (MitraClip/TEER) pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Pathophysiology

Mechanism of ventricular secondary mitral regurgitation

Ventricular secondary mitral regurgitation (vSMR) results when structurally normal mitral leaflets fail to coapt because of left ventricular (LV) remodeling. The central mechanical abnormality is an imbalance between tethering forces—apical and lateral papillary-muscle displacement, annular dilation and flattening, and increased leaflet stress—and closing forces, which are reduced by LV systolic dysfunction and interventricular dyssynchrony. Because these forces vary with loading conditions and throughout the cardiac cycle, vSMR is dynamic rather than fixed.[1][2]

Because these forces are load-dependent, vSMR may worsen substantially during exercise. Increased preload and afterload, greater LV sphericity, increased leaflet-coaptation distance, and systolic expansion of the mitral annulus can increase regurgitation without inducible ischemia and may precipitate acute pulmonary edema. An exercise-induced increase in effective regurgitant orifice area (EROA) of at least 13 mm² has been associated with symptoms and increased morbidity and mortality in secondary MR.[1][3]

Quantification during or immediately after exercise is technically limited by tachycardia and tachypnea. Pharmacologic stress has no established role in assessing MR severity.[3]


Symmetric tethering accompanies global LV remodeling and increased ventricular sphericity, generally producing a central regurgitant jet. Asymmetric tethering commonly follows localized posterior papillary-muscle remodeling, with tenting most marked near P3 and a posteriorly directed eccentric jet. Annular dilation is often a later contributor and may predominantly involve the posterior annulus. Nonischemic dilated cardiomyopathy more commonly produces global dilation, symmetric septal-lateral annular enlargement, and a central jet.[1]

Global LV ejection fraction (LVEF) does not fully describe the tethering substrate. Regional ischemic remodeling and papillary-muscle displacement can generate severe SMR despite preserved global LVEF.[1]

Leaflet, annular, and atrial remodeling

Chronic tethering stimulates adaptive mitral-leaflet growth through endothelial–mesenchymal transition mediated by transforming growth factor-β. Leaflet area was 35±20% greater in patients with LV dysfunction than in normal subjects, with preservation of the leaflet-area-to-annular-area ratio. Significant functional MR was instead associated with inadequate leaflet area relative to the area required for midsystolic closure: the total-leaflet-area-to-closure-area ratio was 1.29±0.15 in functional MR versus 1.78±0.39 in normal hearts (P=0.001).[4]

Leaflet adaptation is not uniformly protective. Growth may be quantitatively insufficient relative to annular dilation and closure-area requirements, or may become maladaptive through transforming growth factor-β-mediated fibrosis and leaflet stiffening despite adequate leaflet area.[5]

Three-dimensional assessment demonstrates that both the valve and annulus remodel in SMR. In one study, total leaflet area was 16.2±0.9 cm² in SMR versus 11.6±0.4 cm² in normal valves, while annular area was 12.7±0.7 versus 9.9±0.3 cm². The posterior-to-anterior leaflet-area ratio in SMR was 0.90±0.04, similar to normal valves, indicating relatively balanced remodeling of both leaflets.[6]

Failure of leaflet growth to keep pace with annular dilation reduces coaptation reserve and contributes to residual MR after mitral transcatheter edge-to-edge repair (M-TEER). Patients with significant residual MR after M-TEER have been observed to have larger annular areas despite similar total leaflet areas, producing a lower total-leaflet-area-to-annular-area ratio.[7]

Left atrial enlargement and atrial fibrillation may add an annular component to vSMR but should be distinguished from primary atrial secondary MR. In atrial SMR, total leaflet area initially increases with annular area but plateaus with profound annular dilation; the total-leaflet-area-to-closure-area ratio may fall below approximately 1.5 as regurgitation worsens.[8][9]

In the proposed atriogenic tethering mechanism, progressive atrial enlargement displaces the posterior annulus superiorly, reduces effective posterior-leaflet height, widens the posterior-leaflet angle, and may eventually produce anterior-leaflet pseudoprolapse and an eccentric jet.[5]


MR–ventricular remodeling feedback cycle

SMR produces left atrial volume overload, raises left atrial and pulmonary pressures, and reduces forward stroke volume. Regurgitant volume returning to the LV during diastole increases ventricular preload and wall stress, promoting further LV dilation, papillary-muscle displacement, leaflet tethering, and worsening MR. This creates a self-reinforcing MR–remodeling cycle superimposed on the underlying myocardial disease.[10][1]

Sustained pulmonary hypertension increases right ventricular (RV) afterload and promotes RV dysfunction, secondary tricuspid regurgitation, systemic venous congestion, and ultimately right-sided heart failure. Once advanced right-heart injury is established, correction of MR may not reliably restore RV function.[10][11]

Mechanism of action and mechanical trade-offs of M-TEER

M-TEER approximates opposing segments of the anterior and posterior mitral leaflets. Leaflet approximation restores coaptation and creates a double-orifice valve, thereby reducing the regurgitant orifice.[12]

M-TEER acts on the valve rather than the myocardium. It does not directly correct papillary-muscle displacement, annular dilation, ventricular dyssynchrony, or intrinsic contractile dysfunction. Its benefit therefore depends on whether MR is an important modifiable contributor to the hemodynamic burden rather than predominantly a marker of advanced myocardial disease.[12][2]

Leaflet approximation necessarily reduces the diastolic mitral-valve area, creating a trade-off between residual MR and iatrogenic mitral stenosis. A baseline mitral-valve area of 3.0 cm² or less with a mean gradient of at least 4 mm Hg identifies limited diastolic reserve and a high risk that device deployment will be constrained by potential stenosis; stenosis is unlikely when the three-dimensional transesophageal mitral-valve area is at least 4.1 cm². The relationship is not purely additive because significant residual MR itself augments the diastolic gradient. Further leaflet approximation may therefore lower rather than raise the measured gradient when the associated reduction in regurgitant flow is sufficiently large.[13]

Available outcome evidence suggests that the trade-off is generally asymmetric in favor of minimizing residual MR, although an elevated gradient is not prognostically inert. In CLASP IID patients with a suboptimal discharge result, 1-year freedom from the composite clinical endpoint was 87.9% with residual MR of 1+ or less and a gradient greater than 5 mm Hg, compared with 72.5% with residual MR of at least 2+ and a gradient of 5 mm Hg or less.[14]

In the PASCAL REPAIR registry (n=2,172), residual MR of 1+ or less was independently associated with lower 1-year mortality (HR 0.54; 95% CI 0.37–0.74), whereas a dichotomized transmitral gradient was not independently associated with mortality (HR 0.73; 95% CI 0.51–1.04). However, gradient analyzed continuously was associated with mortality (HR 1.10 per mm Hg; 95% CI 1.00–1.21; P=0.048), with attenuation after adjustment for residual MR.[15]

The association of elevated gradient with adverse outcomes remains inconsistent across cohorts. In the GIOTTO registry of 864 patients with functional MR, a residual gradient of at least 4 mm Hg independently predicted 2-year death or HF hospitalization (HR 1.54; 95% CI 1.14–2.08), as did residual MR of at least 2+ (HR 1.36; 95% CI 1.01–1.83).[16] A separate analysis similarly found gradient as a continuous variable independently associated with the 2-year endpoint (HR 1.10 per 1 mm Hg; P=0.008), while moderate residual MR was not independently associated.[17]

These data support prioritizing effective MR reduction while recognizing that a persistently high gradient may independently limit hemodynamic benefit. The relative prognostic weight of residual MR and gradient varies according to population, threshold definition, and statistical model.

Transseptal access creates an iatrogenic atrial septal defect (iASD). Persistent iASD was present in approximately 62% of patients at 6 months in one cohort.[18] A meta-analysis associated persistence with right-heart volume overload and increased HF rehospitalization (OR 2.71; P=0.003); reported predictors included preprocedural atrial fibrillation, residual MR greater than 2+, and residual tricuspid regurgitation greater than mild.[19]

Approximately 1% of patients require transcatheter iASD closure, usually early after M-TEER, for hypoxemia caused by right-to-left shunting or right-sided failure caused by a clinically important left-to-right shunt.[20] In the randomized MITHRAS trial, closure of a hemodynamically relevant persistent iASD did not improve event-free survival. Persistent iASD may therefore function mainly as a marker of advanced atrial and right-heart disease rather than a routinely correctable independent cause of adverse outcomes.[21]

Hemodynamic response and reverse remodeling

Reduction of the low-impedance regurgitant pathway shifts stroke volume forward and unloads the left atrium and pulmonary circulation. A meta-analysis of 42 studies involving 3,987 patients found reductions in LV end-diastolic and end-systolic volumes, LV diameters, and pulmonary artery systolic pressure after M-TEER for SMR. A small mean increase in LVEF (mean difference 1.51%; 95% CI 0.47–2.55) and TAPSE (mean difference 1.29 mm; 95% CI 0.60–1.97) was observed, but global longitudinal strain and left atrial end-systolic volume did not improve significantly.[22]

Evidence regarding the left atrial response is discordant. In contrast to the pooled finding, a dual-center registry of 851 patients demonstrated a reduction in median left atrial volume from 123 mL (IQR 92–169) to 104 mL (IQR 78–142) after M-TEER.[11]

These findings support interpreting post-M-TEER remodeling primarily as volume unloading and improved forward flow, rather than assuming recovery of intrinsic myocardial contractility. In nonischemic dilated cardiomyopathy, forward stroke-volume index increased from 20±7 to 26±8 mL/m² and LV volumes decreased after repair, while LVEF and LV-volume-corrected global longitudinal strain remained unchanged.[23]

RV recovery is less consistent than left-sided unloading. In the 851-patient registry, TAPSE did not change significantly (median 17 to 18 mm; P=0.603), nor did deep-learning-derived RV ejection fraction (43.1% to 43.2%; P=0.475) at 3 months, despite reductions in left atrial volume and pulmonary artery pressure.[11] Observational evidence suggests that improvement in RV function and reduction in tricuspid regurgitation occur mainly in patients with baseline RV dysfunction, whereas a high post-procedural transmitral gradient is associated with absent RV reverse remodeling. This links the mitral-stenosis trade-off to subsequent right-sided hemodynamics.[24]


Mechanisms of non-response, residual MR, and recurrence

  • Substrate-dominant disease: In a markedly dilated ventricle, MR that is proportionate to ventricular volume may predominantly reflect advanced myocardial disease. Valve-level correction may therefore produce limited clinical benefit despite technical MR reduction. The proportionate/disproportionate framework remains a mechanistic hypothesis and is not a validated stand-alone selection tool.[2][12]
  • Leaflet-to-annulus mismatch or maladaptation: Annular dilation that exceeds adaptive leaflet growth reduces coaptation reserve and increases the risk of residual MR. Fibrotic leaflet stiffening may further impair coaptation even when leaflet area has increased.[7][5]
  • Incomplete reduction limited by transmitral gradient: Further leaflet approximation may be constrained by limited diastolic valve area and a rising gradient; however, the gradient may fall when additional approximation markedly reduces regurgitant flow.[13]
  • Continued adverse remodeling: M-TEER does not correct the ventricular substrate. Progressive LV dilation or papillary-muscle displacement may recreate leaflet tethering and cause recurrent MR despite an initially satisfactory result. The durability of mitral repair in cardiomyopathy therefore depends substantially on regression versus progression of ventricular dilation.[25][26]
  • Advanced right-heart injury: Fixed pulmonary vascular disease, RV dysfunction, and secondary tricuspid regurgitation may sustain symptoms and congestion even after left-sided MR reduction.[11][10]

In COAPT, repeat mitral intervention occurred in 3.9% (10 of 293 patients) over 4 years. Patients requiring reintervention had larger mitral-annular diameters, fewer implanted clips, and were more likely to have MR of at least 3+ at discharge, linking recurrence to leaflet-to-annulus mismatch and incomplete acute MR reduction.[27]

Effect of HFrEF therapy on the regurgitant lesion

Guideline-directed medical therapy (GDMT) can modify the valve lesion by improving the balance between leaflet closing and tethering forces. In the double-blind PRIME trial (n=118), the reduction in EROA at 12 months was greater with sacubitril/valsartan than with valsartan (−0.058±0.095 versus −0.018±0.105 cm²; P=0.032), with a between-group regurgitant-volume difference of −7.3 mL (95% CI −12.6 to −1.9; P=0.009). LV volumes and incomplete mitral-leaflet closure area did not differ significantly between groups, except for LV end-diastolic volume index (P=0.044); the MR reduction therefore could not be attributed clearly to reverse remodeling alone.[28]

In an observational study, combined uptitration of a beta-blocker, renin–angiotensin-system inhibitor, and mineralocorticoid-receptor antagonist reduced SMR in 40% of patients.[2]

Sodium–glucose cotransporter-2 inhibition also modifies the lesion. In the double-blind randomized EFFORT trial (n=128; NYHA class II–III), the decrease in EROA at 12 months was greater with ertugliflozin than with placebo (−0.05±0.06 versus +0.03±0.12 cm²). Ertugliflozin also produced a between-group reduction in regurgitant volume of 11.2 mL (95% CI −16.1 to −6.3; P=0.009), reduced left atrial volume index by 6.0 mL/m² (P=0.005), and improved LV global longitudinal strain by 1.44% (P=0.004). There were no significant between-group differences in LV volume indices, LVEF, or NT-proBNP. As in PRIME, these findings demonstrate MR reduction without conventional LV reverse remodeling and suggest atrial unloading and improved myocardial deformation as candidate mechanisms.[29]

Cardiac resynchronization therapy acts through two mechanisms: reverse LV remodeling with restoration of papillary-muscle geometry and an acute increase in the rate of rise of the transmitral pressure gradient, which augments leaflet closing force. The response is inconsistent; severe SMR improves in no more than approximately half of treated patients. In a series of 85 patients with 3+/4+ secondary MR, MR grade decreased at 6 months in 42 patients (49%), and 2-year survival was 92% in responders versus 67% in nonresponders.[1]

An acute effect may precede structural remodeling. In a separate series of 63 patients with HF and moderate or severe MR, 43% improved by at least one MR grade immediately after CRT, with a further 20% improving by 6 months. An EROA of at least 0.20 cm² was associated with poor CRT response, increased mortality, and HF rehospitalization. Whether CRT improves the prognosis of SMR independently of its effect on LV dysfunction, or whether MR responders constitute an inherently more favorable cohort, remains unresolved.[1]

When otherwise indicated, CRT is reasonable front-line therapy alongside GDMT and should be performed before mitral surgery or transcatheter intervention. Both ACC/AHA and ESC/EACTS guidelines restrict mitral surgery or intervention for secondary MR to patients who remain symptomatic despite GDMT, including CRT when indicated; the corresponding recommendations are Class I-C in the American guideline and Class I-B in the European guideline.[1][30]

In atrial secondary MR, restoration and maintenance of sinus rhythm can reduce left atrial size, mitral-annular dimensions, and MR severity, providing a mechanism-directed treatment distinct from ventricular remodeling therapy.[12] Reduction in left atrial volume has also been observed after M-TEER in atrial functional MR, paralleling the atrial reverse remodeling observed after successful cardioversion or ablation and supporting a shared atrial-unloading mechanism.[31]

These mechanisms explain why the severity and persistence of SMR should be reassessed after optimization of HFrEF therapy rather than treating the initial regurgitant severity as a fixed valve abnormality.[10][25]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Asgar AW, Mack MJ, Stone GW (2015). "Secondary Mitral Regurgitation in Heart Failure: Pathophysiology, Prognosis, and Therapeutic Considerations". Journal of the American College of Cardiology. 65 (12): 1231–1248. doi:10.1016/j.jacc.2015.02.009.
  2. ↑ 2.0 2.1 2.2 2.3 Praz F, Beyersdorf F, Haugaa K, Prendergast B (2024). "Valvular Heart Disease: From Mechanisms to Management". Lancet. 403 (10436): 1576–1589. doi:10.1016/S0140-6736(23)02755-1.
  3. ↑ 3.0 3.1 Zoghbi WA, Adams D, Bonow RO; et al. (2017). "Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation: A Report From the American Society of Echocardiography Developed in Collaboration With the Society for Cardiovascular Magnetic Resonance". Journal of the American Society of Echocardiography. 30 (4): 303–371. doi:10.1016/j.echo.2017.01.007.
  4. ↑ Chaput M, Handschumacher MD, Tournoux F; et al. (2008). "Mitral Leaflet Adaptation to Ventricular Remodeling: Occurrence and Adequacy in Patients With Functional Mitral Regurgitation". Circulation. 118 (8): 845–852. doi:10.1161/CIRCULATIONAHA.107.749440.
  5. ↑ 5.0 5.1 5.2 Farhan S, Silbiger JJ, Halperin JL; et al. (2022). "Pathophysiology, Echocardiographic Diagnosis, and Treatment of Atrial Functional Mitral Regurgitation: JACC State-of-the-Art Review". Journal of the American College of Cardiology. 80 (24): 2314–2330. doi:10.1016/j.jacc.2022.09.046.
  6. ↑ El-Tallawi KC, Zhang P, Azencott R; et al. (2021). "Mitral Valve Remodeling and Strain in Secondary Mitral Regurgitation: Comparison With Primary Regurgitation and Normal Valves". JACC: Cardiovascular Imaging. 14 (4): 782–793. doi:10.1016/j.jcmg.2021.02.004.
  7. ↑ 7.0 7.1 Hirasawa K, Namazi F, Milhorini Pio S; et al. (2021). "Insufficient Mitral Leaflet Remodeling in Relation to Annular Dilation and Risk of Residual Mitral Regurgitation After MitraClip Implantation". JACC: Cardiovascular Imaging. 14 (4): 756–765. doi:10.1016/j.jcmg.2020.08.019.
  8. ↑ Deferm S, Bertrand PB, Verbrugge FH; et al. (2019). "Atrial Functional Mitral Regurgitation: JACC Review Topic of the Week". Journal of the American College of Cardiology. 73 (19): 2465–2476. doi:10.1016/j.jacc.2019.02.061.
  9. ↑ Kim DH, Heo R, Handschumacher MD; et al. (2019). "Mitral Valve Adaptation to Isolated Annular Dilation: Insights Into the Mechanism of Atrial Functional Mitral Regurgitation". JACC: Cardiovascular Imaging. 12 (4): 665–677. doi:10.1016/j.jcmg.2017.09.013.
  10. ↑ 10.0 10.1 10.2 10.3 Coats AJS, Anker SD, Baumbach A; et al. (2021). "The Management of Secondary Mitral Regurgitation in Patients With Heart Failure: A Joint Position Statement From the HFA, EACVI, EHRA, and EAPCI of the ESC". European Heart Journal. 42 (13): 1254–1269. doi:10.1093/eurheartj/ehab086.
  11. ↑ 11.0 11.1 11.2 11.3 Fortmeier V, Hesse A, Trenkwalder T; et al. (2025). "Employment of Artificial Intelligence for an Unbiased Evaluation Regarding the Recovery of Right Ventricular Function After Mitral Valve Transcatheter Edge-to-Edge Repair". European Journal of Heart Failure. doi:10.1002/ejhf.3705. PMID 40488515 Check |pmid= value (help).
  12. ↑ 12.0 12.1 12.2 12.3 O'Gara PT, Mack MJ (2020). "Secondary Mitral Regurgitation". The New England Journal of Medicine. 383 (15): 1458–1467. doi:10.1056/NEJMcp1903331.
  13. ↑ 13.0 13.1 Zoghbi WA, Asch FM, Bruce C; et al. (2019). "Guidelines for the Evaluation of Valvular Regurgitation After Percutaneous Valve Repair or Replacement: A Report From the American Society of Echocardiography". Journal of the American Society of Echocardiography. 32 (4): 431–475. doi:10.1016/j.echo.2019.01.003.
  14. ↑ Narang A, Hausleiter J, Lim DS; et al. (2026). "Impact of Residual Mitral Regurgitation and Gradient After M-TEER: 1-Year Outcomes From the CLASP IID Trial". JACC: Cardiovascular Imaging. 19 (7): 795–806. doi:10.1016/j.jcmg.2026.04.005. PMID 42233921 Check |pmid= value (help).
  15. ↑ Mustafa D, von Stein J, Stolz L; et al. (2025). "Relation of Residual Mitral Regurgitation and Gradient Following Mitral Valve Transcatheter Edge-to-Edge Repair". Circulation: Cardiovascular Interventions: e015845. doi:10.1161/CIRCINTERVENTIONS.125.015845. PMID 41150378 Check |pmid= value (help).
  16. ↑ De Felice F, Paolucci L, Musto C; et al. (2022). "Outcomes in Patients With High Transmitral Gradient After Mitral Valve Transcatheter Edge-to-Edge Repair for Mitral Regurgitation". The American Journal of Cardiology. 182: 46–54. doi:10.1016/j.amjcard.2022.07.036. PMID 36075753 Check |pmid= value (help).
  17. ↑ Tsunamoto H, Yamamoto M, Kagase A; et al. (2025). "Using Transmitral Pressure Gradients and Residual Mitral Regurgitation to Optimize Outcome After Transcatheter Edge-to-Edge Repair". Journal of the American College of Cardiology. 86 (19): 1684–1700. doi:10.1016/j.jacc.2025.07.041.
  18. ↑ Alachkar MN, Alnaimi A, Reith S; et al. (2021). "Incidence and Clinical Relevance of Persistent Iatrogenic Atrial Septal Defect After Percutaneous Mitral Valve Repair". Scientific Reports. 11 (1): 12700. doi:10.1038/s41598-021-92255-3.
  19. ↑ Lei D, Zhou C, Zhou J, Luo C, Zheng B (2025). "Iatrogenic Atrial Septal Defect Following Transcatheter Edge-to-Edge Mitral Valve Repair: A Systematic Review and Meta-Analysis". Medicine. 104 (52): e46486. doi:10.1097/MD.0000000000046486.
  20. ↑ Takaya Y, Akagi T, Hara H; et al. (2022). "Iatrogenic Atrial Septal Defect Requiring Transcatheter Closure Following Transcatheter Mitral Valve Repair". Circulation Journal. 86 (11): 1740–1744. doi:10.1253/circj.CJ-22-0048.
  21. ↑ Lurz P, Unterhuber M, Rommel KP; et al. (2021). "Iatrogenic Atrial Septal Defects Following Transcatheter Mitral Valve Repair and Implications of Interventional Closure". JACC: Cardiovascular Interventions. 14 (24): 2685–2694. doi:10.1016/j.jcin.2021.09.023.
  22. ↑ Lombardi M, Basile M, Jurado-Román A; et al. (2026). "Echocardiographic Indices of Cardiac Remodeling Following Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation: A Systematic Review and Meta-Analysis". Journal of the American Heart Association. 15 (4): e045616. doi:10.1161/JAHA.125.045616.
  23. ↑ Kamperidis V, van Wijngaarden SE, van Rosendael PJ; et al. (2018). "Mitral Valve Repair for Secondary Mitral Regurgitation in Non-Ischaemic Dilated Cardiomyopathy Is Associated With Left Ventricular Reverse Remodelling and Increase of Forward Flow". European Heart Journal – Cardiovascular Imaging. 19 (2): 208–215. doi:10.1093/ehjci/jex011.
  24. ↑ Italia L, Adamo M, Lupi L; et al. (2021). "Percutaneous Edge-to-Edge Mitral Valve Repair: Beyond the Left Heart". Journal of the American Society of Echocardiography. 34 (10): 1038–1045. doi:10.1016/j.echo.2021.05.013. PMID 34052316 Check |pmid= value (help).
  25. ↑ 25.0 25.1 Otto CM, Nishimura RA, Bonow RO; et al. (2021). "2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease". Journal of the American College of Cardiology. 77 (4): e25–e197. doi:10.1016/j.jacc.2020.11.018.
  26. ↑ Mariani A, Stolz L, von Bardeleben RS; et al. (2026). "Durability of Mitral Valve Transcatheter Edge-to-Edge Repair: An Expert Overview". JACC: Cardiovascular Interventions. 19 (9): 1057–1070. doi:10.1016/j.jcin.2026.02.019.
  27. ↑ Shahim B, Cohen DJ, Asch FM; et al. (2024). "Repeat Mitral Valve Interventions After Transcatheter Edge-to-Edge Repair: The COAPT Trial". The American Journal of Cardiology. 223: 7–14. doi:10.1016/j.amjcard.2024.05.025.
  28. ↑ Kang DH, Park SJ, Shin SH; et al. (2019). "Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation". Circulation. 139 (11): 1354–1365. doi:10.1161/CIRCULATIONAHA.118.037077. PMID 30586756.
  29. ↑ Kang DH, Park SJ, Shin SH; et al. (2024). "Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial". Circulation. 149 (24): 1865–1874. doi:10.1161/CIRCULATIONAHA.124.069144. PMID 38690659 Check |pmid= value (help).
  30. ↑ Coisne A, Lancellotti P, Habib G; et al. (2023). "ACC/AHA and ESC/EACTS Guidelines for the Management of Valvular Heart Diseases: JACC Guideline Comparison". Journal of the American College of Cardiology. 82 (8): 721–734. doi:10.1016/j.jacc.2023.05.061.
  31. ↑ Yoon SH, Makar M, Kar S; et al. (2022). "Outcomes After Transcatheter Edge-to-Edge Mitral Valve Repair According to Mitral Regurgitation Etiology and Cardiac Remodeling". JACC: Cardiovascular Interventions. 15 (17): 1711–1722. doi:10.1016/j.jcin.2022.07.004.
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