The prognostic value of the visually assessed time difference between mitral valve and tricuspid valve opening score for patients with heart failure with mildly reduced ejection fraction

Abstract Background The visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score was correlated with the increase of left ventricular filling pressure (LVFP). Hypothesis We suspected that the VMT score might be a valuable prognostic biomarker for heart failure with mildly reduced ejection fraction (HFmrEF) patients. This study was to evaluate the predictive value of VMT score for 1‐year all‐cause and cardiovascular disease (CVD)‐cause mortality in HFmrEF patients. Methods This cohort study enrolled 379 patients aged ≥18 years old with HFmrEF. Univariable and multivariable Cox regression analysis was employed to assess the association between VMT score and all‐cause or CVD‐cause mortality in HFmrEF patients. Hazards ratio (HR), and 95% confidence interval (CI) were effect sizes. Kaplan–Meier curves showed the survival probability of patients. The area under the curve (AUC) evaluated the prognostic value of the VMT score. Results The risk of all‐cause mortality was increased in HFmrEF patients in the VMT score of 2 (HR = 2.80, 95%CI: 1.04–7.52) and 3 (HR = 4.29, 95%CI: 1.58–11.66). The VMT score of 3 was associated with an increased risk of 1‐year CVD‐cause mortality in patients with HFmrEF (HR = 7.63, 95%CI: 1.70–34.33). The AUC of VMT score for predicting 1‐year all‐cause mortality of HFmrEF patients was 0.724, and for predicting 1‐year CVD‐cause mortality of HFmrEF patients was 0.748. The survival probability of patients with the VMT score < 2 was higher than those with the VMT score of 2 and 3. Conclusion The VMT score might be a reliable prognostic index for 1‐year all‐cause or CVD‐cause mortality of HFmrEF patients.


| INTRODUCTION
Heart failure (HF) is a global pandemic with increasing prevalence, and the prevalence of HF was 1.3% in China. 1,2HF is the leading cause of hospitalization among adults, and the 1-year mortality was reported to range from 10% to 35%. 3 Based on the left ventricular ejection fraction (LVEF), heart failure can be classified into HF with reduced ejection fraction (HFrEF) (LVEF < 40%) and HF with preserved ejection fraction (HFpEF) (LVEF ≥ 50%). 4The range between these two fractions is called HF with mildly reduced ejection fraction (HFmrEF), referring to an LVEF of 41%-49%. 5mrEF is an under-recognized type of HF, and the prevalence of was 10%-25% in all HF cases. 6HFmrEF has some intermediate features between HFrEF and HFpEF, but HFmrEF, HFrEF and HFpEF exhibited heterogeneity in presentation and pathophysiology, which played an essential part on the prognosis and treatment of the disease. 7,8Patients with HFmrEF have a lower risk of cardiovascular disease (CVD)-cause mortality than patients with HFrEF and have similar or greater risk of non-CVD-cause mortality than those with HFrEF. 6To clearly identify biomarkers associated with the prognosis of patients with HFmrEF was of great value.
Cardiac remodeling is one of the mechanism of HF, and cardiac volume and pressure overload was an important factor in promoting cardiac remodeling, which played an essential role in the occurrence and development of HF. 9,10 Although HFmrEF was reported to be a heterogeneous group, there may be no single pathophysiological mechanism.Echocardiography is the most valuable examination method for quantitative or qualitative detection of atrioventricularrelated parameters, which provides objective indicators for the evaluation and treatment of HF. 11 Recently, the visually assessed time difference between the mitral valve (MV) and tricuspid valve (TV) opening (VMT), combined with an indicator of right atrial pressure [inferior vena cava (IVC) dimension], formed the VMT score. 12The VMT score was reported to be correlated with the increase of left ventricular filling pressure (LVFP), 12 and served as a useful indicator for evaluating the prognosis of HFpEF. 13Thus, we suspected that the VMT score might be a valuable prognostic biomarker for HFmrEF patients.
This study aimed to explore the association between the VMT score and the outcome of HFmrEF patients and evaluate the predictive values of the VMT score for the 1-year all-cause and CVD-cause mortality in HFmrEF patients.

| Study design and population
This cohort study enrolled 418 patients aged ≥ 18 years old with HFmrEF in Beijing Chaoyang Hospital, Capital Medical University.
HFmrEF was diagnosed according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic HF. 14  All participants provided the patient informed consent.

| Main variable
As the main variable in this study, the VMT score comprises two components: (1) visual assessment of the time sequence of atrioventricular valve openings and (2) estimation of right atrium pressure based on findings from IVC, IVC dimension, and IVC respiratory change.The time sequence of MV and TV openings was visually evaluated according to slow playback from cine loops (6-9 beats) of the apical four-chamber view.The assessment was categorized into three grades: 0 (TV opening first), 1 (simultaneous opening), and 2 (MV opening first).In cases where markers indicating abnormal RA pressure were observed (IVC dimension >21 mm and IVC respiratory change <50%), an additional point was assigned to calculate the VMT score as a four-grade scale ranging from 0 to 3 12 (Figure 1).

| Echocardiographic examination
The echocardiographic examination was performed based on the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines, utilizing Philips CX 50 system (Philips Medical Systems).The examination used a two-dimensional B mode operating an S5 1-MHz phased-array pure-wave crystal transducer. 15The biplane method of disk was employed to measure LVEDV, and LAVI.LVMI was calculated using the Devereux formula.
SV was determined by calculating the velocity-time integral of the LV ejection flow and the cross-sectional area of the LV outflow tract.
Transmitral peak E and EDT were evaluated in the apical LV long-axis view.The E/e' was the ratio of E to e'.The e' of the two sites at the ventricular septum side and the left ventricular side wall were detected, respectively; early-diastolic mitral annular velocities at the septal annulus and left ventricular side wall (e') was evaluated from the apical four-chamber view to calculate the average e'.The IVC dimension and its respiratory change were assessed just proximal to the junction of the hepatic veins.

| Outcome variables
The outcomes were 1-year all-cause mortality and 1-year CVD-cause mortality of patients with HFmrEF.The follow-up was conducted by telephone at intervals of 1-, 3-, 6-, 9-, and 12-month.The median follow-up time was 12 (12, 12) months.72.73% vs. 28.57%)or TR (68.52% vs. 50.45%vs. 27.62%) in the VMT score of 3 group was higher than the VMT score of 2 group and the VMT score <2 group.The mean E/e' in the VMT score of 3 group was higher than the VMT score of 2 group and the VMT score <2 group (18.08% vs. 16.86% vs. 10.29%).More detailed information of patients was shown in Table 1.

| Statistical analysis
The screen process of the participants.CVD, cardiovascular disease; HFmrEF, heart failure with mildly reduced ejection fraction.2).As exhibited in Supporting Information S1: Figure 1, the survival probability of patients with a VMT score < 2 was higher than those with a VMT score of 2 and a VMT score of 3. The AUC of the VMT score for predicting 1-year all-cause mortality of HFmrEF patients was 0.724 (95%CI: 0.663-0.785)(Supporting Information S2: Figure 2).
After stepwise regression, the covariates associated with 1-year CVD-cause mortality in patients with HFmrEF were age, neutrophil, eosinophil, BUN, eGFR, CNTI, and LVEF.In the unadjusted model, the VMT score of 3 might be a risk factor for 1-year CVD-cause mortality in patients with HFmrEF (HR = 17.05, 95%CI: 5.05-57.49).The increased risk of 1-year CVD-cause mortality in patients with HFmrEF was found in patients with the VMT score of 3 after the adjustment of covariates (HR = 6.51, 95%CI: 1.50-28.22).We further adjusted AFIB based on model 2, and found that the VMT score of 3 were associated with an increased risk of 1-year CVD-cause mortality in patients with HFmrEF (HR = 7.63, 95%CI: 1.70-34.33)(Table 3).
The Kaplan-Meier curve depicted that the survival probability of patients in the VMT score of 3 group was lower than those in the VMT score of 2 and the VMT score <2 group (Supporting Information S3: Figure 3).The AUC of the VMT score for predicting 1-year CVDcause mortality of HFmrEF patients was 0.748 (95%CI: 0.676-0.819)(Supporting Information S4: Figure 4).

| DISCUSSION
In the current study, the associations between the VMT score and  those with a high risk of mortality, relevant interventions should be timely provided.
There was evidence revealing that signs of elevated LVFP, such as the presence of lung congestion, invasively measured pulmonary artery wedge pressure, and echocardiographic diastolic function assessed in a stable state, were prognostic markers for hospitalized HF patients irrespective of EF. 16,17 Previously, several echocardiographic parameters were recognized to be markers of LVFP, and echocardiography was an essential method for the evaluation of LVFP and management of patients with HF. 18 Nevertheless, the diagnosis of elevated LVFP in HF patients is still challenging. 19While the algorithm recommended by the current guidelines has been invasively validated in large multicenter studies both in HFrEF and HFpEF, 20 and whether this algorithm was suitable for HFmrEF patients was unknown. 21 normal circumstances, the early diastolic opening of the TV precedes that of the MV, but as a major factor for HF, once LVFP is elevated, MV opening happens early and precedes TV opening, resulting from an early crossover of LA and LV pressures. 22,23The increase of LVFP can also lead to secondary postcapillary pulmonary hypertension, resulting in increased right ventricular pressure, impaired right ventricular diastolic function, and prolonged right ventricular diastolic time. 24The time delay of RV inflow relative to the LV inflow, as evaluated by the dual-Doppler system, was found to be an index of LVFP in patients with HF. 22 The correlation between the change of MV-TV opening time interval obtained from ultrasound examination and LVFP was identified based on the hemodynamic information, suggesting the simple algorithm of VMT scoring could be used as a novel parameter of LVFP. 12When the VMT score was ≥2, MV opening happens earlier than TV opening, or MT and TV simultaneous opening, accompanied by abnormal RA pressure, which was consistent with hemodynamic changes caused by LVFP increase.
Moreover, the VMT score ≥2 was confirmed to be correlated with the prognosis of HFpEF population 13 These gave evidence to the results in our study, which revealed that the VMT score ≥2 was associated with elevated risk of 1-year all-cause and the VMT score of 3 was correlated with increased risk of CVD-cause mortality.
The VMT score has good predictive value for all-cause and CVD-cause mortality in HFmrEF patients.For HFmrEF patients with atrial fibrillation who cannot evaluate LVFP using conventional algorithms, the VMT score might help evaluate the LVFP status.
Compared with the application value of two-dimensional ultrasound indicators such as E/A, E/e', and isovolumic relaxation time in HF, 15,25 the VMT score is more closely related to the pathophysiological  | 11 atrioventricular valves.The results should be interpreted with caution and if necessary, higher resolution might be required.

| CONCLUSIONS
The current study evaluated the prognostic value of the VMT score for 1-year all-cause or CVD-cause mortality of HFmrEF patients.The results showed that HFmrEF patients with a VMT score <2 had a higher survival probability of patients than those with a VMT score ≥2.The VMT score presented good predictive value for 1-year all-cause or CVD-cause mortality of HFmrEF patients.
Participants with previous LVEF ≤ 40%, right cardiac decompensation-related diseases or primary pulmonary hypertension, primary valvular heart disease, or receiving atrioventricular valve replacement, congenital heart disease, constrictive pericardial disease, receiving mechanical circulation or ventilation support and hemodialysis, tumor, severe infection, and those with low quality of ultrasound image were excluded.Finally, 379 patients were included.This study got approval from the Ethics Committee of Chaoyang Hospital, Capital Medical University (No. 2021-科−713).

3 | RESULTS 3 . 1 |
Comparisons of characteristics in HFmrEF patients with and without all-cause mortality as well as CVD-cause mortality The data of 418 patients aged ≥ 18 years old with HFmrEF were collected.In total, six patients with right cardiac decompensationrelated diseases or primary pulmonary hypertension, 14 patients with valvular heart disease or receiving atrioventricular valve replacement, two patients with congenital heart disease, eight patients receiving mechanical circulation or ventilation support and hemodialysis, two patients complicated with tumor, six patients with severe infection, and one patient with poor quality of ultrasound image were excluded.Finally, 379 patients were included.The screening process of the participants is exhibited in Figure 2. The mean age in patients with the VMT score of 3 was older than patients with the VMT score of 2 group and the VMT score <2 group (74.13 years vs. 69.70 years vs. 66.11years).The percentages of patients in different NYHA classifications were statistically different among the VMT score of 3, the VMT score of 2 group, and the VMT score <2 group.The percentage of patients with MR (75.93% vs. T A B L E 1 Comparisons of characteristics in HFmrEF patients with and without all-cause mortality as well as CVD-cause mortality.Variables Total (n = 379) VMT < 2 (n = 105) VMT of 2 (n = 220) VMT of 3 (n = 54) Statistics p Demographic variables Age, years, mean (± SD) of 2 might be a risk factor for all-cause mortality in patients with HFmrEF (HR = 2.74, 95%CI: 1.15-6.54).The VMT score of 3 might increase the risk of all-cause mortality in patients with HFmrEF (HR = 12.29, 95%CI: 5.09-29.65).After adjusting for confounding factors, elevated risk of all-cause mortality in HFmrEF patients was identified in those with the VMT score of 2 (HR = 3.01, 95%CI: 1.13-7.99),and the VMT score of 3 (HR = 5.02, 95%CI: 1.89-13.32).In model 3, AFIB was further adjusted based on model 2, the risk of all-cause mortality was increased in HFmrEF patients in the VMT score of 2 group (HR = 2.80, 95%CI: 1.04-7.52)and the VMT score of 3 group (HR = 4.29, 95%CI: 1.58-11.66)(Table

1 -
year all-cause or CVD-cause mortality of HFmrEF patients were assessed.The predictive values of the VMT score for the 1-year all-cause and CVD-cause mortality in HFmrEF patients were also evaluated.The results showed that elevated risk of all-cause mortality in HFmrEF patients was identified in those with a VMT score ≥2, and increased CVD-cause mortality in HFmrEF patients was identified in those with a VMT score of 3. The survival probability of patients with a VMT score <2 was higher than those with a VMT score of 2 and a VMT score of 3. The AUC of the VMT score for predicting 1-year all-cause mortality of HFmrEF patients was 0.724, and for predicting 1-year CVD-cause mortality of HFmrEF patients was 0.748.The findings might provide a quick tool to evaluate the prognosis of patients with HFmrEF, and for T A B L E 2 The association between the VMT score and 1-year all-cause mortality in patients with HFmrEF.
mechanism and hemodynamic changes of HF, which can avoid the limitations of pseudo-normalization of conventional indicators in evaluating LVFP.Thus, the VMT score might provide another choice of diagnostic methods for patients with HFmEF.Due to the mildly reduced ejection fraction and the increase in residual volume after ventricular ejection in patients with HFmrEF, the left ventricular end-systolic volume (LVESV) increases, and ventricular filling is limited, while the increase of LVFP might further aggravate the increase of LVESV and accelerate the process of cardiac remodeling.Due to the heterogeneity of clinical manifestations in HFmrEF patients, the assessment of their prognosis is relatively difficult, and there is no effective method recommended by guidelines.In our study, the VMT score ≥2 was identified as a prognostic marker for the prognosis of HFmrEF, which was expected to add a diagnostic option for HFmrEF patients.The VMT score was easy to calculate according to echocardiography, and the AUC value of the VMT score for predicting 1-year all-cause mortality of HFmrEF patients was 0.724, and for predicting 1-year CVD-cause mortality of HFmrEF patients was 0.748.This study confirms that the application of the VMT score can help rapidly and accurately evaluate the LVFP elevation in HFmrEF patients, which is helpful for the early identification of high-risk patients with poor prognoses.The VMT score can provide clinical guidance for early intervention in HFmrEF patients with a high risk of poor prognosis, standardize the comprehensive management of HF, and help delay the process of ventricular remodeling in patients to improve poor prognosis.There were several limitations in this study.Firstly, this was a singlecenter retrospective study with a small sample size, which might cause selection bias.Secondly, the results of the VMT score depended on the resolution of the two-dimensional echocardiogram, and high spatial resolution images were required.Thirdly, the temporal resolution of images was required as the VMT score was based on timing of T A B L E 3 The association between the VMT score and 1-year CVD-cause mortality in patients with HFmrEF.