Secondary Mitral Regurgitation

Definition

Secondary mitral regurgitation (SMR) is MR in which the MV apparatus is structurally normal but regurgitation results from alterations in LV or LA geometry, dyssynchrony, and imbalances between MV closing and tethering forces. Two distinct phenotypes are now formally recognised: ventricular SMR and atrial SMR.

Key Concepts

Ventricular SMR vs Atrial SMR

• Atrial SMR diagnostic criteria: LVEF ≥50%, no/mild LV dilatation (LV end-diastolic dimension <56 mm women / <63 mm men), MA AP diameter >35 mm, LAVI >34 mL/m²
• At advanced stages, overlap between phenotypes may occur — early characterisation is key sources/vhd-esc-2025 very high

Evaluation

• Assessment should be performed in euvolaemic, normotensive state after GDMT optimisation
• Severe ventricular SMR thresholds: EROA ≥30 mm² and/or RVol ≥45 mL (lower than PMR thresholds due to elliptical orifice and low-flow state)
• CMR confirms SMR severity and quantifies myocardial fibrosis (predictor of poor prognosis)
• Exercise echo helps identify severe dynamic SMR when resting values are inconclusive sources/vhd-esc-2025 very high

Management of Ventricular SMR

MATTERHORN Trial — TEER vs Mitral Valve Surgery (First Head-to-Head RCT)

• Design: n=210 (104 TEER, 104 surgery); Germany; investigator-initiated; noninferiority design (margin 17.5 pp); LVEF ≥20%; median EROA 0.22 cm²; mean LVEF 43.0% (relatively preserved); STS-PROM 2.0% — suitable for BOTH TEER and surgery per heart team sources/mvteer-matterhorn-nejm-2024 very high
• Primary efficacy (1 year composite): 16.7% TEER vs 22.5% surgery; diff −6 pp (95% CI −17 to 6); NI P<0.001; RRR 0.74 (0.41–1.34); not superior (log-rank P=0.30)
• Primary safety (30 days composite): 14.9% TEER vs 54.8% surgery; diff −40 pp (95% CI −51 to −27); P<0.001 — TEER overwhelmingly safer
  • Major bleeding (VARC): 3.1% vs 24.4% (diff −21 pp)
  • New-onset AF: 3.1% vs 27.8% (diff −25 pp)
  • Stroke/TIA: 0% vs 4.4%
  • Death at 30 days: 2.0% vs 4.3%
• MR recurrence ≥3+ at 1 year: 8.9% TEER vs 1.5% surgery — NI margin met (17.5 pp) but directionally worse; durability signal requiring longer follow-up
• MR ≤2+ at 1 year: 96.1% TEER vs 98.6% surgery (similar residual MR control)
• Functional outcomes: NYHA class, 6MWT improvement, and QoL similar between groups at 1 year
• Key implication: TEER and surgery are equivalent in 1-year hard outcomes in SMR patients eligible for either; TEER's markedly superior periprocedural safety profile favors it as the preferred first-line approach sources/mvteer-matterhorn-nejm-2024 very high

RESHAPE-HF2 Trial Evidence — MitraClip TEER in Moderate-to-Severe SMR

• Design: n=505 (250 device, 255 control); 30 sites, 9 countries; investigator-initiated; LVEF 20–50%; MR 3+/4+; median EROA 0.23 cm² (vs 0.40 in COAPT); median regurgitant volume 36 mL; HF hosp within 90 days or elevated NP sources/mvteer-reshapehf2-nejm-2024 very high
• Three co-primary endpoints (all met):
  • HF hosp or CV death: 37.0 vs 58.9/100 pt-yr; RR 0.64 (95% CI 0.48–0.85; P=0.002)
  • HF hosp alone: 26.9 vs 46.6/100 pt-yr; RR 0.59 (95% CI 0.42–0.82; P=0.002)
  • KCCQ-OS at 12 months: +21.6 vs +8.0 pts; mean difference +10.9 pts (95% CI 6.8–15.0; P<0.001)
• NNT = 5.1 to prevent one HF hospitalization per 100 patient-years
• All-cause mortality: HR 0.90 (95% CI 0.71–1.13) — not significant; consistent with less advanced HF than COAPT (control 2-year mortality 29.6% vs 46.1% in COAPT)
• Functional outcomes: NYHA I/II at 12 months 74.5% vs 58.5% (P<0.001); MR ≤2+ at 12 months 90.4% vs 36.1% (P<0.001)
• Device safety: 1.6% (4 patients); 2 hematomas, 1 pericardial effusion, 1 RA perforation requiring thoracotomy
• Key significance: First RCT to demonstrate TEER benefit below EROA 0.40 cm²; extends evidence to ~44% of real-world TEER candidates previously unrepresented in trials sources/mvteer-reshapehf2-nejm-2024 very high

COAPT 5-Year Trial Evidence — MitraClip TEER in Ventricular SMR

• Design: n=614 (302 device, 312 control); 78 US/Canadian sites; LVEF 20–50%; MR 3+/4+ despite maximal GDMT; open-label RCT sources/mvteer-coapt-nejm-2023 very high
• Primary endpoint (annualized HF hosp): 33.1%/yr vs 57.2%/yr; HR 0.53 (95% CI 0.41–0.68)
• All-cause mortality (5yr): 57.3% vs 67.2%; HR 0.72 (95% CI 0.58–0.89)
• Death or HF hospitalization (5yr): 73.6% vs 91.5%; HR 0.53 (95% CI 0.44–0.64)
• Days alive out of hospital: 1123.5 vs 894.8 days (device vs control)
• Device safety: 1.4% device-specific events — all within 30 days; no late device complications
• Severe MS post-TEER: 7.6% (MVO area <1.5 cm² core lab); no patient required surgery for MS
• Landmark analysis: HF hosp benefit diverged until year 3; mortality benefit until year 2; curve convergence thereafter largely due to 44.9% of eligible control patients crossing over to TEER after 2 years
• Crossover HR: Control patients who crossed over had subsequent death/HF hosp HR 0.53 — matching original device-arm outcomes
• Absolute burden persists: 73.6% of device patients died or were hospitalized by 5 years — MitraClip reduces MR volume/pressure overload but does not treat underlying LV cardiomyopathy sources/mvteer-coapt-nejm-2023 very high

Step 1: GDMT Optimisation (mandatory before any MV intervention)

• ACE-I/ARB/ARNI + beta-blocker + MRA + SGLT2i at maximum tolerated doses
• Up-titration must be rapid (within 6 weeks) with close follow-up
• ~40% of patients improve MR by ≥1 grade after 1–3 months of GDMT
• CRT (Class I per HF guidelines) should be implemented first if criteria met (LVEF ≤35%, wide QRS); reduces MR in 40–60% of patients

Ventricular SMR Without CAD — Intervention

• Class I A (upgraded 2025): TEER recommended to reduce HF hospitalisations and improve QoL in haemodynamically stable symptomatic patients (NYHA II–V) with LVEF <50% and persistent severe SMR despite GDMT + CRT, fulfilling all specific criteria (COAPT trial, RESHAPE-HF2, meta-analysis)
• Specific criteria for Class I TEER (Table 7):
  • NYHA ≥II; LVEF 20–50%; LVESD ≤70 mm
  • ≥1 HF hospitalisation in prior year or BNP ≥300 pg/mL or NT-proBNP ≥1000 pg/mL
  • SPAP ≤70 mmHg; no severe RV dysfunction; no Stage D/advanced HF
  • No CAD requiring revascularisation; no severe AV or TV disease; no HCM/RCM/amyloidosis
• Class IIb B: TEER for symptom improvement in patients not meeting the specific criteria above (after evaluating LVAD/HTx eligibility)
• Class IIb C: MV surgery in patients with severe ventricular SMR without advanced HF not suitable for TEER (MATTERHORN: TEER non-inferior to surgery with better safety; MR recurrence ≥3+ numerically higher with TEER at 1yr — durability question remains) sources/vhd-esc-2025 very high sources/mvteer-matterhorn-nejm-2024 very high

Ventricular SMR With Concomitant CAD

• MV surgery Class I B at time of CABG for severe ventricular SMR + CAD
• Isolated undersized annuloplasty: high recurrent MR rates; replacement required in large tenting area (>1.35 cm²/m² BSA)
• MV surgery Class IIb B in moderate SMR undergoing CABG
• PCI + re-evaluation of MR after revascularisation: Class IIb C (MR improves in ~1/3 after PCI)

Management of Atrial SMR (New 2025)

• Treat underlying causes: AF (rhythm control), HFpEF (SGLT2i, diuretics per guidelines)
• Rhythm control may reduce atrial SMR severity and reverse LA dilatation
• Class IIa B (new): MV surgery + surgical AF ablation + LAAO in symptomatic patients on optimal medical therapy
• Class IIb B (new): TEER if ineligible for surgery after optimising medical therapy including rhythm control — risk of gradient increase with planar coaptation must be assessed sources/vhd-esc-2025 very high

Follow-up After Intervention

• Ventricular SMR: clinical, laboratory, and echo every 3–6 months (high ongoing event rate even after TEER — 73.6% cumulative 5-year all-cause death/HF hospitalisation in COAPT device arm)
• Atrial SMR: yearly clinical + echo follow-up
• Asymptomatic moderate or dynamic SMR: at least twice-yearly follow-up

ACC/AHA 2020 — Secondary MR Management

• At time of ACC/AHA 2020 guideline, TEER for secondary MR was rated Class IIa B-NR (subsequently upgraded to Class I A by ESC 2025 based on RESHAPE-HF2)
• COAPT selection criteria (ACC/AHA 2020 standard): LVEF 20–50%; LVESD ≤70 mm; PASP ≤70 mmHg; persistent NYHA II–IV despite optimal GDMT; no CAD requiring revascularisation sources/VHD-AHA-2020 very high
• Class I B-NR (ACC/AHA 2020): Severe secondary MR + CAD undergoing CABG → concomitant MV surgery recommended
• Note: ACC/AHA 2020 does not formally distinguish atrial vs ventricular SMR (that distinction was formalised in ESC 2025) sources/VHD-AHA-2020 very high

Contradictions / Open Questions

• MATTERHORN MR recurrence durability gap: TEER had 8.9% vs 1.5% MR ≥3+ recurrence at 1 year — noninferiority margin (17.5 pp) barely met (diff +7 pp; 95% CI 0 to 14); over longer follow-up this gap may widen and compound on clinical outcomes; surgery may prove superior for durability in patients with long life expectancy sources/mvteer-matterhorn-nejm-2024 very high
• MATTERHORN vs COAPT/RESHAPE population mismatch: MATTERHORN mean LVEF 43% vs 31% in COAPT/RESHAPE — MATTERHORN is not a representative SMR trial for the typical guideline-eligible patient (HFrEF, LVEF <40%); results may not apply to the most common TEER candidate sources/mvteer-matterhorn-nejm-2024 very high vs sources/mvteer-coapt-nejm-2023 very high
• RESHAPE-HF2 vs COAPT: mortality discordance by disease severity: COAPT showed all-cause mortality benefit (HR 0.72 at 5yr) but RESHAPE-HF2 did not (HR 0.90; NS); patients in RESHAPE-HF2 were less sick (control 2yr mortality 29.6% vs 46.1%); this gradient of benefit raises the question of whether TEER confers mortality benefit only in severe/advanced SMR or if RESHAPE-HF2 was simply underpowered sources/mvteer-reshapehf2-nejm-2024 very high vs sources/mvteer-coapt-nejm-2023 very high
• KCCQ placebo effect risk in open-label trial: RESHAPE-HF2 KCCQ improvement was a co-primary endpoint but assessed by unblinded patients — a 10.9-point difference could partially reflect expectation bias; the concordant reduction in objective HF hospitalizations supports genuine benefit, but the QoL endpoint cannot be isolated from open-label bias sources/mvteer-reshapehf2-nejm-2024 very high
• Diminishing benefit after year 2–3: COAPT 5-year landmark analysis shows HF hosp benefit concentrated in years 1–3 and mortality benefit in years 1–2; thereafter event rates similar between groups — partly explained by 44.9% control crossover to TEER (protocol-permitted), but raises question of whether LV disease progression eventually equalises outcomes even with successful MR correction sources/mvteer-coapt-nejm-2023 very high
• SGLT2i era gap: Only 3 patients in COAPT received SGLT2i (all in final year); modern 4-pillar GDMT (including SGLT2i and ARNI) may shrink the pool of patients with refractory SMR requiring TEER, but benefit of MR correction is unlikely to be eliminated sources/mvteer-coapt-nejm-2023 very high
• First-generation device results: COAPT used first-generation MitraClip (MR ≤1+ achieved in 82.3% at discharge); third-generation devices improve leaflet approximation rates — modern TEER outcomes may exceed COAPT sources/mvteer-coapt-nejm-2023 very high
• COAPT vs MITRA-FR divergence: TEER reduced mortality in COAPT but not in MITRA-FR; likely due to MITRA-FR including more severely dilated LV (proportionate MR) and less rigid GDMT optimisation — the concept of "disproportionate SMR" (EROA:LV relationship) helps explain divergence but is not fully validated sources/VHD-AHA-2020 very high
• TEER class upgrade: ACC/AHA 2020 rated TEER for secondary MR as Class IIa; ESC 2025 upgraded to Class I A based on RESHAPE-HF2 — this represents one of the most significant recommendation evolutions between the two guidelines sources/VHD-AHA-2020 very high vs sources/vhd-esc-2025 very high
• Atrial SMR: No RCT comparing surgery vs TEER vs medical therapy; all recommendations are based on observational data; not formally recognised in ACC/AHA 2020
• Optimal timing of intervention: When to stop GDMT up-titration and proceed to TEER is not precisely defined
• MV surgery for ventricular SMR: Long-term benefit over TEER not proven; MATTERHORN showed non-inferiority of TEER for 1-year composite endpoint

Connections

• Related to concepts/Valvular-Heart-Disease
• Related to concepts/Primary-Mitral-Regurgitation
• Related to concepts/Tricuspid-Regurgitation
• Related to entities/Heart-Failure
• Related to entities/Atrial-Fibrillation

Sources

• sources/VHD-AHA-2020
• sources/vhd-esc-2025
• sources/mvteer-coapt-nejm-2023
• sources/mvteer-reshapehf2-nejm-2024
• sources/mvteer-matterhorn-nejm-2024