Severe secondary mitral regurgitation (sMR) is a prevalent condition that negatively impacts the prognosis of patients with heart failure, with a mortality rate of 20% within the first year of diagnosis. The high burden of comorbidities, advanced age, and impaired ventricular function render these patients suboptimal for conventional surgical management. Fortunately, advancements in heart failure management and the development of percutaneous techniques offer new therapeutic avenues. Consequently, the authors of this article summarize the available evidence and propose an algorithm based on it to guide clinical decision-making. 

Secondary mitral regurgitation is defined as MR caused by alterations in supporting structures—namely, the left ventricle, left atrium, or mitral annulus—in contrast to primary MR, where the defect lies in the valve itself. Thus, addressing the underlying cause is crucial in sMR management, which involves: 

1. Quadruple therapy for heart failure (HF). 
2. Rhythm control strategies in atrial fibrillation (AF). 
3. Cardiac resynchronization therapy (CRT), when indicated. 
4. Direct intervention on the mitral valve, either percutaneously or surgically. 

Breaking down the authors’ review, sMR has seen significant advances over the past decade. The first major step in HF treatment was the introduction of sacubitril/valsartan (ARNI), which, since the PARADIGM-HF trial, has shown a significant reduction in ventricular volumes and improved ejection fraction, indirectly suggesting enhanced ventricular hemodynamics and reduced sMR, as later studies like PROVE-HF indicate, except in severely deteriorated ventricles. Additional milestones include the use of sodium-glucose cotransporter-2 inhibitors (iSGLT-2) and vericiguat, although their evidence is less robust in this context. STRONG-HF emphasizes the importance of rapid titration to optimal doses of HF medication, despite methodological discrepancies like the omission of iSGLT-2s from the therapy or the inclusion of few patients with de novo HF, underscoring improved prognosis with optimal medical therapy. 

Rhythm control holds significant prognostic value in HF, especially through AF ablation, now a class IB recommendation in the 2023 guidelines for AF management. Studies by Gertz et al. demonstrated reduced MR with rhythm control, implicating mechanisms like improved atrioventricular synchrony and beat regularization. CRT also improves MR in patients with intraventricular conduction delay (wide QRS, particularly with left bundle branch block), as evidenced in studies such as MIRACLE and secondary analyses from SCD-HEFT, highlighting ventricular synchrony as essential for optimal mitral subvalvular function. Although outcomes with left bundle or His-bundle pacing remain unexplored, physiopathological knowledge suggests they may enhance ventricular synchronization over conventional right ventricular apex pacing. 

Through these measures, approximately 40-50% of severe sMR cases can regress. Although significant, a substantial group of patients may still require additional therapy. A notable advancement here is MitraClip®, a device replicating the Alfieri technique percutaneously, presenting another dilemma reflected in MITRA-FR and COAPT: who benefits? Despite both studies assessing efficacy, significant discrepancies existed. MITRA-FR included patients with greater ventricular dysfunction, while COAPT selected patients with less impaired ventricles (e.g., DTDVI <70mm, operability criteria for the technique, absence of right ventricular dysfunction, etc.). This analysis introduces the concept of proportional or disproportionate sMR, suggesting that severe MR in a moderately dilated or impaired ventricle is more likely to benefit from this technique than the opposite. Grayburn et al. illustrated this concept by mapping the patient selection in both studies, with recent studies delving deeper into this phenomenon, as noted in the work of Soltz et al., where sMR staging based on ventricular and atrial involvement correlates with prognosis, advocating early referral to ensure favorable outcomes. 

Despite current knowledge, much remains unexplored. Further evidence is needed for other devices like PASCAL® and for other percutaneous systems such as Carrillon® and Cardioband® (both annuloplasty-based) or valve replacement devices like Tendyne®. 

The authors conclude with the following recommendations: 

1. Rapid titration of HF medical therapy to optimal doses within the first three months (based on STRONG-HF findings). 
2. Consider rhythm control in AF or CRT where indicated, alongside therapeutic optimization. 
3. If symptoms persist (NYHA ≥ II) and MR remains moderate to severe despite previous measures, a multidisciplinary Heart Team should assess eligibility for percutaneous intervention (preferable in most patients) or surgery, especially for those undergoing concurrent surgery or being considered for advanced therapies. 

COMMENTARY: 

Based on current evidence, the authors propose a straightforward therapeutic algorithm to assist clinical cardiologists in navigating available treatment options, prioritizing them based on evidence. The algorithm underscores the essential role of optimal HF medical therapy in managing and reversing sMR, often a clinical Achilles’ heel due to therapeutic inertia or follow-up challenges, leaving many patients without optimized therapy and with adverse prognostic implications. Nonetheless, intervention holds promise, and the scope of endovascular treatment for sMR will likely expand to include currently suboptimal or inoperable patients. 

While generally appropriate and widely accepted, this algorithm could, in my opinion, benefit from a particular focus on the frailest patients, who represent an increasing portion of daily practice. Rapid titration therapies may lead to hypotension and adverse effects not seen in younger groups. Additionally, incorporating frailty scales can help guide more or less invasive approaches in selected patients. It is important to mention when to consider palliative care if therapeutic measures pose significant risk or limited benefit given the patient’s condition. 

REFERENCE: 

Barnes C, Sharma H, Gamble J, Dawkins S. Management of secondary mitral regurgitation: from drugs to devices. Heart. 2024 Aug 14;110(17):1099-1106. doi: 10.1136/heartjnl-2022-322001.