Secondary mitral regurgitation (sMR) is a frequent complication in patients with coronary artery disease (CAD), and results in greater mortality and comorbidity [1]. Percutaneous coronary intervention (PCI) can reduce reflux of sMR in the subsequent follow-up [2, 3, 4]. However, up to 30% of patients with moderate or severe sMR still have residual significant sMR after PCI; as a result, further adverse prognosis likely ensues [5].

Numerous clinical studies have reported trajectory problems in the changes of sMR after PCI [6, 7] and have identified risk factors for the progression of sMR, including significant left ventricular dilation, systolic dysfunction, and myocardial scar burden [8, 9, 10]. Semiquantitative assessment of regional systolic function using wall motion score index (WMSI) might be an alternative to left ventricular ejection fraction (LVEF) for the assessment of left ventricular systolic function, and some studies have indicated that the predictive value of WMSI for prognosis is greater than that of LVEF [11, 12, 13]. Increased WMSI could be considered a predictor of moderate or severe sMR [14]. However, the clinical impact of the WMSI on residual significant sMR in baseline moderate or severe cases has not been sufficiently characterized.

Therefore, in the present study, we analyzed the relationship between WMSI and persistent moderate or severe sMR and the prognostic meaning of the extent of echocardiographically detected WMSI in a consecutive series of patients with moderate or severe baseline sMR who underwent PCI therapy.

In this cohort, we found persistent moderate or severe sMR in more than 1/3 of the post-PCI patients. Elevated WMSI was independently associated with persistent moderate or severe sMR, conferring a 1.5-fold increased risk among CAD patients with baseline moderate or severe sMR at follow-up. The extent of echocardiographically detected WMSI before discharge might be an important predictor of comorbidity and mortality among these patients.

Epidemiological data suggest that moderate or severe sMR is a frequent cause of hospital admission, including readmission for heart failure, HF-related hospitalization, and all-cause hospitalization, which poses a significant societal burden [23, 24, 25]. In the chronic phase after myocardial infarction (MI), the presence of baseline sMR is associated with increased mortality, and the risk of mortality is directly related to the severity of sMR. Notably, sMR progression is also an independent predictor of poor outcomes. sMR progression is significantly and independently associated with more advanced left ventricular (LV) dilation and more extensive MI. Moreover, sMR progression provides additional risk stratification for patients with significant sMR at baseline. Patients with severe sMR but no significant sMR progression over time demonstrated significantly improved survival compared to those with severe sMR and continued progressive sMR [26, 27]. Revascularization has shown reliable improvement in sMR [28]. Many studies indicated that PCI is known to improve overall outcomes, can reduce the area of myocardial ischemia and reflux of sMR in subsequent follow-ups [2, 3]. One study demonstrated that in patients with severe sMR and CAD, PCI alone improved sMR in approximately 1/3 of patients (36%), and in at least 3/4 of these patients, the improvement was sustained [5]. However, sMR is known to be dynamic in nature: a proportion of patients show worsened sMR after an ischemic event or deterioration of HF even after accepting PCI, which could be easily overlooked by clinicians and researchers.

Some echocardiographic indicators, like end-systolic volume, have been shown to be predictors of worse outcomes, and have recently emerged as tools for predicting the progression of sMR [26]. Some studies have identified risk factors for progression of sMR, including significant LV dilation, systolic dysfunction, and myocardial scar burden [8, 9, 10]. Now, semiquantitative assessment of regional systolic function using WMSI is an alternative to LVEF for the assessment of left ventricular systolic function, and some studies have indicated that the predictive power of WMSI for prognosis is greater than that of LVEF [11, 12, 13].

Some previous studies have suggested that WMSI is superior to LVEF in predicting the combined endpoint of death, nonfatal reinfarction, unstable angina, and rehospitalization for CHF [12, 13]. Furthermore, LVEF may be almost normal, despite extensive regional wall motion abnormalities due to compensatory regional hyperkinesis [11, 29, 30]. Indeed, the left ventricle that undergoes post-infarction remodeling is a complex mixture of scar tissue (with varying degrees of transmurality) and residual myocardium with varying contractility. Traditional volume-based indices, such as left ventricular end-diastolic volume or LVEF, are inadequate in predicting outcomes since they depend on global ventricular measurements. Therefore, a more comprehensive screening tool is needed that accounts for the variability in function across different regions of the ventricle. In this regard, the WMSI holds promise as a reliable indicator since it can accurately reflect this information and provide a more nuanced assessment of ventricular function [31, 32].

There are many controversial findings in the literature regarding the precise mechanisms of sMR. Classically, significant ventricular remodeling and resultant apical displacement of the papillary muscles are thought to be the main contributors to sMR [33, 34, 35]. Post-ischemic LV remodeling is a gradual and continuous process. This process results in LV enlargement, thinning of the LV walls, increased wall stress, and progressive LV dysfunction. The LV distortion caused by post-ischemic LV remodeling, in which the LV becomes spherical rather than elliptical, can contribute to the development of ischemic mitral regurgitation (MR). This is due to changes in the dynamics of the mitral valve, which can result from papillary muscle dysfunction, mitral annulus dilation, and incomplete leaflet coaptation. Thus, the development of ischemic MR is influenced by the pathophysiological and mechanistic impact of LV distortion. It is crucial to effectively manage post-ischemic LV remodeling to prevent the progression of LV dysfunction and reduce the risk of developing ischemic MR [36, 37]. Kalra et al. [38] proposed a new mechanism of ischemic MR. It is based on the fact that the loss of wall thickening in the myocardial middle segments of the inferolateral and inferior walls reduced the interpapillary muscle distance, which tethered mitral leaflet edges and thus impaired their systolic closure independently of LV dilatation.

For patients with moderate or severe sMR undergoing PCI, employing targeted analyses for risk factors facilitated early identification. In addition, intervention before irreversible deterioration of sMR is warranted. An examination of WMSI can facilitate the prediction of persistent moderate or severe sMR and the prognosis of poor outcomes, suggesting the need for aggressive therapeutic interventions when coronary intervention by itself is not enough. In recent decades, several strategies have been developed, such as transcatheter mitral valve interventions (i.e., the Mitra-Clip procedure), in order to improve the reflux degree of moderate to severe sMR and reduce the risk of poor outcomes. However, it has not been widely used in the clinic. Two randomized controlled clinical trials have investigated the effects of MitraClip on patients with HF: the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) trial, which examined the effects of percutaneous repair with the MitraClip device on severe functional/secondary mitral regurgitation, and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial, which assessed the cardiovascular outcomes of MitraClip percutaneous therapy in HF patients with functional mitral regurgitation. In both trials, patients were randomly assigned to receive either MitraClip plus guideline-directed medical therapy (GDMT) or GDMT alone. While MITRA-FR did not demonstrate any significant reduction in the primary endpoint of all-cause mortality or HF hospitalizations, the COAPT trial reported a significant decrease in HF hospitalizations (primary endpoint) as well as in mortality alone. Nonetheless, the effectiveness of transcatheter mitral valve interventions in certain adapted populations remains a contentious issue [39, 40, 41]. Further studies are needed to determine whether patients who are at higher risk of progressive sMR would benefit from mitral valve intervention.

There are several limitations to the present study. First, there are many etiologies for sMR. In our study, the main goal was post-PCI residual moderate or severe sMR, and it was necessary to study the related factors and prognosis in other residual significant sMR samples. Second, inherent in the observational nature of this study, there are likely significant residual unmeasured confounding factors for prognosis; our results should therefore be considered hypothesis-generating. Furthermore, echocardiography and WMSI, in comparison with contrast-enhanced magnetic resonance imaging (MRI), have the disadvantage of not being able to distinguish viable or hibernating myocardium from scar tissue among segments of non-contracting myocardium. Then, it is likely that the small number in some subgroups might have affected our capacity to uncover and characterize some of the associations, potentially leading to false negative results. Thus, the findings from the subgroup analysis require further validation. Finally, a small number of patients were not on standardized doses of medications; this further limits the generalizability of our results.

Persistent moderate or severe sMR is common (approximately 40%) in PCI patients. Elevated WMSI in CAD patients after PCI is a predictor of persistent moderate or severe sMR, adverse events in worsening HF, and long-term all-cause mortality. Given the adverse prognosis of persistent moderate or severe sMR, screening for WMSI in CAD patients with baseline moderate or severe sMR can yield important information that can be used to refine risk stratification for more intensive treatment based on established cardiovascular risk factors.

WMSI, wall motion score index; sMR, secondary mitral regurgitation; CAD, coronary artery disease; PCI, percutaneous coronary intervention; HF, heart failure; MACE, major adverse cardiovascular events; LVEF, left ventricular ejection fraction; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CKD, chronic kidney disease; OR, odds ratio; HR, hazard ratio; CI, confidence interval.

Data are available from the corresponding author on reasonable request.

Research idea and study design: JYC and YL; Data acquisition: LFQ, HZH, JLL, CZJ, YBH, SJY, HYL, ZYZ, TC, SQC, NT, JYC and JL; Data analysis/interpretation: LFQ and HZH; Statistical analysis: LFQ and JL, Supervision and mentorship: JL and JYC; Writing guidance: JYC and JL. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The Ethics Committee of the Guangdong Provincial People’s Hospital approved the study (Approval No.GDREC2019555H[R1]). It was conducted in accordance with the principles of the Declaration of Helsinki. All participants provided oral informed consent by telephone.

Not applicable.

This research was funded and supported by Guangdong Provincial science and technology project [grant number: 2020B1111170011; KJ022021049]; The National Science Foundation for Young Scientist of China [grant number: 82070360].

The authors declare no conflict of interest.