In patients with aortic stenosis (AS) undergoing surgical or transcatheter aortic valve replacement (TAVR), the prevalence of moderate to severe mitral regurgitation (MR) ranges from 8% to 33%. The current recommendation for low-surgical risk patients with severe AS and significant MR is bivalvular surgery. However, the optimal treatment strategy remains a matter of debate for patients with high surgical risk [1].

Catheter-based therapies for valvular heart disease are rapidly advancing globally. TAVR for severe AS and transcatheter mitral valve edge-to-edge repair (m-TEER) for severe MR have emerged as alternatives to surgical intervention. These procedures have consistently shown improvements in quality of life, shorter hospital stays, and reduced risk of postoperative complications [2]. The interventional approach allows for staged procedures, facilitating evaluation of the effect of transcatheter aortic intervention on MR severity, with the option to perform mitral valve (MV) repair if necessary.

The optimal treatment approach for patients presenting with severe AS and significant MR remains a subject of ongoing debate, with a lack of guideline-based recommendations [3]. Conventional surgery involving both aortic valve (AV) and MV interventions carries substantial surgical risks, with reported hospital mortality rates ranging from 5%-12.5% for combined interventions compared to 1%-3% for isolated AV intervention [4]. Moreover, isolated AV intervention may prove ineffective in cases where hemodynamically significant MR persists or progresses, potentially leading to unfavourable outcomes despite successful correction of the AV condition. The persistence of moderate or severe MR following TAVR is also linked with increased mortality, with observed hazard ratios (HR) ranging from 1.49 (95% confidence interval (CI): 1.04-2.11; p=0.027), and is reported in 17%-35% of patients post-AV intervention [5].

Contemporary interventional technologies present a viable alternative to conventional surgery, reshaping the landscape of clinical decision-making toward an interventional paradigm. However, this shift raises new inquiries for future exploration, including the optimal staging, sequence, and timing of procedures within a stepwise approach. Particular research interest lies in evaluating the likelihood of MR regression after correcting AS, and understanding how uncorrected MR impacts clinical outcomes post-TAVR, and determining the necessity of treating persistent severe symptomatic MR. Additionally, the timing and sequence of procedures in bivalvular interventions are crucial, along with addressing the many unresolved questions that demand a detailed understanding of the mechanisms behind MR development.

This clinical case illustrates the selection of a treatment strategy for a patient with severe AS and concurrent severe MR, along with an analysis of the chosen approach.

An 83-year-old patient was admitted to the hospital with the following diagnosis: severe AS, severe MR, severe tricuspid regurgitation (TR), and high pulmonary hypertension. Additionally, the patient had atherosclerosis of the coronary arteries, coronary heart disease, stable exertional angina, II functional class. She had undergone aortocoronary bypass surgery in 2015. Upon admission, the patient reported experiencing dyspnea during moderate physical activity, palpitations, and elevated blood pressure (130/80 mm Hg on antihypertensive therapy). Table 1 outlines the chronology of events leading up to hospitalization.

Clinical outcomes in patients with severe MR after TAVR

The primary concern is the impact of MR on the early postoperative period after AV intervention. Whether postponing MV correction is viable considering its potential regression amidst LV reverse remodeling remains uncertain. Consequently, the question of prioritizing transcatheter intervention on the AV and MV is contentious.

The presence of moderate or severe MR in patients undergoing TAVR correlates with increased mortality and poorer clinical outcomes [6]. The PARTNER study indicates that moderate MR post-TAVR significantly elevates 30-day and long-term mortality rates in patients without concurrent MV intervention [7]. Moreover, the poorer outcomes in the absence of MV intervention for severe MR are highlighted in the meta-analysis by Nombela-Franco et al. (2015), revealing higher mortality rates at 30 days, 1 year, and 2 years following isolated TAVR [8].

According to data from the Swedish national registry, "The SWEDEHEART," patients experiencing progression or persistence of MR severity in a post-TAVR period face a twofold and 1.7-fold increase in mortality at the 5-year follow-up, respectively [9].

An 8-study meta-analysis involving 8,015 patients demonstrated elevated overall 30-day and 1-year mortality rates in patients with severe MR after TAVR compared to those without MR (OR 1.49, 95% CI 1.16 to 1.92; HR 1.32, 95% CI 1.12 to 1.55, respectively) [8]. Another meta-analysis encompassing 16 studies and 13,672 patients revealed a similar increase in both early all-cause mortality (а pooled analysis of 8 studies) and overall all-cause mortality (а pooled analysis of 14 studies), with respective 2.17-fold and 1.81-fold increments in patients with apparent relative to unapparent MR [10]. In a multicenter study by Cortes et al. involving 1,110 patients, a threefold increase in mortality was observed in patients with significant MR before TAVR at six months compared to those without significant MR (35.0% vs. 10.2%) [11]. The presented data suggest the influence of MR on the postoperative period, both immediately after TAVR and within a five-year timeframe. Ben-Assa et al. argues that the severity of post-procedural MR is associated with the lack of cardiac chamber remodeling, an increased incidence of adverse cardiac events, and fatal outcomes [12].

It is essential to evaluate the possibility of performing isolated TAVR with the aim of affecting both the aortic and mitral valves. Therefore, the next step is to assess the probability and potential for MR regression after AV correction. It is enough for the decrease in LV pressure post-TAVR to contribute to the reduction of MR, which is substantially dependent on afterload?

Natural Course of Mitral Regurgitation After TAVR

The coexistence of severe AS and clinically significant functional MR is relatively common. According to the PARTNER study, this combination occurs in approximately 20% of patients deemed at high surgical risk [7]. Relief of the obstruction in the AV area leads to a decrease in LV pressure, thereby reducing the overload on the MV and potentially contributing to a reduction in the severity of MR, particularly of functional aetiology.

Multiple processes can simultaneously influence the reduction of functional MR following TAVR. Immediately after AV intervention, hemodynamic changes play a predominant role over geometric changes in MR regression [13]. Subsequent MR changes are influenced by LV geometric remodeling, particularly the reverse remodeling often observed after TAVR [14]. However, persistence or even progression of MR severity has been observed in a subset of patients [15,16,17].

Predictors of persistent or worsening MR following transcatheter AV replacement include alterations in MV complex geometry resulting in significant leaflet malcoaptation [18], concurrent coronary artery disease, and sustained elevated LV pressure due to suboptimal aortic prosthesis positioning [19]. Massive calcification, particularly of the posterior annulus, severe tenting, or a combination of both, also contribute to the persistence of MR severity following TAVR [16]. Patients with baseline MR of grade 3 or higher, particularly of organic aetiology, also exhibit minimal MR regression or no response to aortic valve AV intervention. These patients have the lowest survival rates and the least symptom regression [5].

Other factors contributing to the progression of MR severity include deep valve implantation resulting in anterior mitral leaflet restriction [15], and paraprosthetic leak of severe or greater degree (odds ratio (OR) 8.104; 95% CI 1.78-36.87; p = 0.007) [18]. Paraprosthetic leaks are more commonly observed following the implantation of self-expanding prostheses [20], possibly due to incomplete apposition of the prosthesis and the shape of the LV outflow tract [21].

Additionally, several conditions associated with the progression of MR after TAVR include an initially low AV gradient, pulmonary hypertension, atrial fibrillation, a mitral annulus diameter exceeding 35.5 mm, calcification of the MV leaflets or annulus, organic MR, and a small LV volume [19]. These factors, beyond their individual significance, may act as cofactors in the development of MR, thereby amplifying their effects. Consequently, the prevalent yet underexplored coexistence of AS and MR exemplifies this clinical conundrum, the complexity of which is greater than the sum of its components [13].

I solated or bivalvular treatment strategy

According to the 2021 ESC/EACTS guidelines, in high-risk or inoperable patients with severe AS and severe MR, simultaneous (or more often staged) TAVR and m-TEER may be considered, but there is insufficient experience to provide reliable recommendations. In patients with severe functional MR, a thorough clinical and echocardiographic reassessment should be conducted after TAVR to determine the necessity for further MV intervention [1].

The success of a combined approach involving transcatheter MV repair during TAVR has been documented in several studies [22, 23]. The initial case series presenting the performance of TAVR and m-TEER was introduced by Rudolph and colleagues (2013). Transcatheter treatment of high surgical risk patients with concurrent severe AS and severe MR was found to be technically feasible, thus marking a significant expansion of the therapeutic options available [22].

Kische et al. observed persistent severe MR after TAVR compared to baseline values. Subsequently, 12 patients underwent m-TEER with favorable long-term outcomes. The study concluded that in selected high-risk patients unsuitable for conventional surgery, symptomatic severe AS and concomitant MR can be managed using a transcatheter approach with a high safety profile [23].

In a study conducted by Elbadawi et al (2021), various approaches ranging from single-stage to separate interventions were examined, with m-TEER performed either before or after TAVR in different cases [24]. Compared to isolated TAVR, the performance of TAVR and m-TEER was associated with higher in-hospital mortality (10.8% vs. 1.9%). The observed increased mortality was correlated with a heightened risk of hemodynamic disturbances, bleeding events, and acute kidney injury. The authors propose that the elevated risk of in-hospital mortality is likely multifactorial and linked to the cumulative risk of the two procedures in elderly patients with a high comorbidity burden and a higher frequency of pre-existing hospitalizations.

Zahid et al. (2023) reported extensive experience in treating this patient population, with a preference for m-TEER after TAVR in the majority of cases [25]. The authors observed no differences in in-hospital mortality rates based on the chosen treatment strategy; however, complication rates and prolonged hospital stays were notably higher in patients undergoing both procedures during a single hospitalization. Table 2 outlines the interventional treatment strategies–simultaneous or staged approaches–discussed in the aforementioned studies.

The optimal approach in cardiac surgery, whether correction of the leading AV malformation or bivalvular surgery, is still under investigation. Despite the numerous advantages of conventional surgery, m-TEER remains a viable option for patients at high risk of complications with preserved reconstructive potential of the MV. Moreover, the clinic's expertise allows for the expansion of the technology's application beyond its initial criteria, enabling interventional interventions across a broad spectrum of MV pathologies.

The advantages of the chosen transcatheter approach are evident in risk reduction compared to conventional surgery, utilization of interventional valve treatment technologies with established efficacy (TAVR, m-TEER), ability to reassess MR severity post-TAVR to decide on the need for further intervention, establishment of individualized timing between stages, and achievement of optimal hemodynamic outcomes post-procedure.

In high-risk patients with persistent severe symptomatic MR after TAVR, the m-TEER procedure is the preferred method. Although the timing and sequence of these procedures have not been clearly defined, determining the staging of interventions requires comparison of factors influencing effective reverse LV remodeling and the potential for MR reduction, along with an analysis of the dominant mechanism of MR progression/persistence and the prospects for its interruption.

Acknowledgement Statement: The authors would like to thank the reviewers for providing comments in helping this manuscript to completion.

Conflicts of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT Author contribution statements: All authors contributed equally to the manuscript and read and approved the final version of the manuscript.

Funding: The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.

Data Availability Statement: Data is available at request. Please contact the corresponding author for any additional information on data access or usage.

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