A prospective registry that commenced in 2013 and uses a standardized case report form has included all consecutive patients with MR undergoing echocardiography at our hospital. Case report forms, including patient demographics, clinical presentations, and echocardiographic data, were stored in an electronic database. From January 2013 to December 2022, 1,375 patients were diagnosed with HFmrEF (LVEF, 41% to 49%) or HFpEF (LVEF ≥50%) accompanied by moderate-to-severe FMR, persisting for more than 6 months despite standard medical therapy for HF. Among the 1,375 patients, those with significant aortic valve disease ( n = 837) or hypertrophic or restrictive cardiomyopathy ( n = 131) were excluded. The primary cohort comprised 407 patients with HFmrEF or HFpEF and moderate-to-severe FMR ( Figure 1 ). This study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board. The requirement for written informed consent was waived in accordance with the approved study protocol.

Flowchart of patient selection. FMR = functional mitral regurgitation; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; LVEF = left ventricular ejection fraction; MR = mitral regurgitation.

All patients underwent comprehensive two-dimensional and Doppler echocardiography performed by experienced echocardiographers using commercially available ultrasound systems. The sizes and functions of cardiac chambers’, as well as valvular disease were assessed and interpreted in accordance with the American Society of Echocardiography guidelines. ^, FMR was further classified into either ventricular functional mitral regurgitation (VFMR) or atrial functional mitral regurgitation (AFMR). VFMR was defined as restricted leaflet motion with the coaptation point displaced from the annular plane due to adverse remodeling of the LV, where tethering occurs either symmetrically in cases of global LV systolic dysfunction ( Figure 2 ) or asymmetrically in the posterior direction in cases of regional LV remodeling ( Figure 2 ). MR was classified as AFMR when the following features were observed: coaptation failure of normal leaflets caused by mitral annular enlargement associated with left atrial dilatation, with the leaflet coaptation point positioned at the annular level ( Figure 2 ). The severity of MR was graded using a multiparametric approach recommended by the current guideline including the effective regurgitant orifice area (EROA) using the proximal isovelocity surface area method. Left atrial end-systolic volume and LVEF were evaluated using the biplane Simpson method, with LVEF ≥50% defined as HFpEF and LVEF 41% to 49% as HFmrEF based on current guidelines. ^, LV global longitudinal strain (LVGLS) was measured semiautomatically using speckle-tracking technology (TomTec Imaging Systems). Three standard apical views were used for analysis, and the values were averaged. The right ventricular systolic pressure was estimated using the peak velocity of the tricuspid regurgitation jet and the estimated right atrial pressure.

Mechanisms of functional mitral regurgitation. In VFMR, MR occurs as a consequence of symmetrical tethering of the mitral valve in an enlarged left ventricle with global systolic dysfunction ( A ) or due to asymmetrical tethering of the mitral valve following regional left ventricular remodeling ( B ). In AFMR, unlike VFMR, the coaptation point of the mitral valve leaflets is positioned at the annulus level as a result of left atrial enlargement and annulus dilatation ( C ). AFMR = atrial functional mitral regurgitation; VFMR = ventricular functional mitral regurgitation; other abbreviations as in Figure 1 .

The primary endpoint was the composite occurrence of cardiovascular mortality or hospitalization due to HF during the follow-up period. The secondary endpoint included significant progression of FMR and mitral valve intervention. Cardiovascular mortality included deaths that resulted from sudden cardiac death, acute myocardial infarction, HF, ischemic and/or hemorrhagic stroke, and other cardiovascular causes. HF hospitalization was defined as the presence of worsening symptoms and signs, along with laboratory findings that support the diagnosis of worsening HF requiring hospitalization of at least 24 hours. Significant progression of MR was defined as an increase in EROA >0.1 cm ² on follow-up echocardiography. The primary and secondary endpoints were compared between patients with HFmrEF and HFpEF. Long-term outcome data were obtained through a review of medical records, and telephone surveys with patients or, if deceased, their family members. Follow-up data regarding clinical outcomes were complete for all study patients.

Continuous variables were expressed as mean with standard deviation if normally distributed, or as median with interquartile ranges (IQR) if not. Groups were compared using either Student’s t-test or the Mann-Whitney U test, as appropriate. Categorical variables were presented as frequencies and percentage. Comparisons were made using the chi-square test or Fisher’s exact test. Kaplan-Meier analysis was used to evaluate the cumulative probability of clinical events during follow-up, and differences in cumulative incidences between the two groups were assessed using the log-rank test. Cox proportional hazards analysis was performed to identify the risk factors for clinical events, yielding hazard ratios (HRs) with 95% confidence intervals (CIs). Variables for analysis were selected based on their clinical relevance and insights from previous studies. All variables included in the univariable analyses were included in the multivariable Cox models. Multicollinearity among the variables in the model was evaluated using correlation coefficients and variance inflation factor calculations. All tests were two-sided, and statistical significance was defined as p <0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, NY, USA).

Among a total of 407 patients, the median age was 71 years (IQR: 63 to 78 years) and 181 patients (44.5%) were men. HFmrEF was diagnosed in 156 patients (38.3%), while 251 patients (61.7%) had diagnosis of HFpEF. The baseline characteristics of the HFmrEF and HFpEF groups are shown in Table 1 . The HFpEF group was older and had a higher frequency of women than the HFmrEF group. Patients with HFmrEF had higher body surface area and higher incidence of ischemic heart disease and diabetes mellitus than those with HFpEF. The prevalence of atrial fibrillation (AF) was significantly higher in the HFpEF group compared to the HFmrEF group (82.5% vs 42.3%; p <0.001). Laboratory data showed that patients in the HFmrEF group had a higher B-type natriuretic peptide level and lower estimated glomerular filtration rate. Regarding medication use, proportion of patients receiving angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor-neprilysin inhibitor (ARNI) was higher in the HFmrEF group while diuretics were more commonly used in the HFpEF group.

In terms of echocardiographic characteristics, the median LVEF of patients with HFmrEF was 44% (IQR: 42% to 46%) and 58% (IQR: 55% to 63%) in those with HFpEF. LVGLS was also significantly lower in those with HFmrEF. Patients in the HFmrEF group exhibited larger LV end-diastolic dimension (59 vs 52 mm; p <0.001), LV end-systolic dimension (44 vs 37 mm; p <0.001), LV end-diastolic volume (134 vs 104 mL; p <0.001) and LV end-systolic volume (76 vs 43 mL; p <0.001) compared to those in the HFpEF group. Both left ventricular mass index (130 vs 118 g/m ²; p = 0.001) and E/e’ ratio (16 vs 13; p <0.001), the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity at the septal annulus, were also higher in the HFmrEF group . There were no significant differences between the two groups in terms of the EROA of FMR. The mechanism of FMR was more frequently AFMR in the HFpEF group (83.3%) and VFMR in HFmrEF group (87.8%) (p <0.001). In the HFpEF group, the left atrial (LA) volume index was significantly higher (83 vs 64 mL/m ²; p <0.001), and moderate-to-severe functional tricuspid regurgitation was observed more frequently.