Impact of disproportionality in severe secondary mitral regurgitation according to disease etiology

doi:10.21203/rs.3.rs-2450397/v1

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Impact of disproportionality in severe secondary mitral regurgitation according to disease etiology

https://doi.org/10.21203/rs.3.rs-2450397/v1

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Aims Disproportionality in secondary mitral regurgitation (MR) provides insight into MR quantification in transcatheter edge-to-edge repair (TEER) candidates. Although secondary MR has two major etiologies, ischemic cardiomyopathy (ICMP) and dilated cardiomyopathy (DCMP), distinguishing analysis between these two etiologies has been insufficient. We sought to determine the prognosis of disproportional MR in each disease etiology and analyze the baseline characteristics.

Methods and results From 2009 to 2019, in Samsung Medical Center, South Korea, 207 patients with severe secondary MR (median age 69 years old, median left ventricular ejection fraction [LVEF] 27.3%) were collected. The cut-off point for disproportional MR was the median value of regurgitant volume (RV)/left ventricular end-diastolic volume (LVEDV), which was 0.17. The primary endpoint was all-cause death. In this study, we analyzed 1) the prognosis of severe secondary MR based on proportional and disproportional MR and 2) the prognosis of disproportional MR based on etiology of dilated cardiomyopathy or ischemic cardiomyopathy. In survival analysis, the disproportional MR group had a worse prognosis in all-cause death (hazard ratio [HR] 2.013, 95% CI [1.254 - 3.230], log-rank p-value = 0.004). In subgroup analysis based on etiology, the disproportional MR group showed a significantly higher risk of all-cause death (HR 3.493, 95% CI [1.457 - 8.375], log-rank p-value = 0.005) in DCMP. On the other hand, there was no significant difference in all-cause death according to disproportionality in ICMP.

Conclusion In severe secondary MR, disproportional MR has a worse prognosis than proportional MR due to age and comorbidities, and this difference is more prominent in DCMP than ICMP.

Disproportional MR

Severe secondary MR

ICMP

DCMP

MR quantification

Secondary mitral regurgitation (MR) is a consequence of underlying myocardial disease. The pathophysiology differs from primary MR, and the prognosis of secondary MR is worse than that of primary MR due to underlying cardiomyopathy. Because of this, the benefits of mitral valve intervention remain controversial.^1,2 The results of the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) provided profound insight into mitral valve manipulation in secondary MR. The superior effects of device therapy compared with medical treatment observed in the COAPT trial can be explained by more patients with disproportionality, more trained operators, and maximal medical treatment efforts.^3-6 Disproportionality in secondary MR provides an intuitive explanation for the incompatible result of two randomized MitraClip trial,^3,4 which is MITRA-FR⁷ (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation) and COAPT trial.⁸

Since the new concept of MR arose, there have been several attempts to demonstrate the prognosis of significant secondary MR according to disproportionality.^9,10 However, previous studies did not distinguish disease etiology in analysis, even though secondary MR is a myocardial disease. Secondary MR has two significant kinds of etiology, dilated cardiomyopathy (DCMP) and ischemic cardiomyopathy (ICMP), which are substantially different in pathophysiology and risk factors. Also, previous studies did not thoroughly analyze baseline characteristics that contribute to MR disproportionality.

This study sought to determine the prognosis of significant secondary MR according to prognosis by disproportionality according to etiology.

Study subjects and data collection

From 2009 to 2019, in Samsung Medical Center, South Korea, 1,375 patients with moderate-to-severe or severe MR were collected. Secondary mitral regurgitation defined as mitral regurgitation developed as a consequence of left ventricular dilatation and dysfunction without mitral valve structural damage. Only patients with reduced ejection fraction heart failure due to ICMP or DCMP were enrolled. Patients with ICMP were defined as having a previous history of myocardial infarction (MI) or revascularization such as percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) and with significant stenosis in the coronary artery. DCMP was defined as idiopathic DCMP, one without significant stenosis in a coronary artery, significant valve stenosis, severe aortic regurgitation, rheumatic valve disease, or restrictive physiology. Patients with the following conditions were excluded: heart failure with preserved ejection fraction (left ventricular ejection fraction [LVEF] ≥ 50%), heart failure with mildly reduced ejection fraction (LVEF 40-49%), primary mitral valve disease (mitral valve destruction or deformation), rheumatic valve disease, previous mitral valve surgery history, over moderate degree valve stenosis (moderate aortic stenosis [AS], moderate mitral stenosis [MS]), valvular heart disease due to aortic regurgitation, another cardiomyopathy (restrictive cardiomyopathy, amyloidosis, chemo-induced cardiomyopathy, or stress-induced cardiomyopathy), and palliative chemotherapy.

Among 393 patients, an assessment of disproportionality was performed with 207 patients who had values for both regurgitant volume (RV) and left ventricular end-diastolic volume (LVEDV). The cut-off point for disproportional MR in this study was the median value of RV (ml) / EDV (ml) of the study population, which was 0.17. Among the final 207 patients, 99 patients (47.8%) had proportional MR, and 108 patients (52.2%) had disproportional MR (Figure 1). The quantification method of disproportional MR proposed by Grayburn et al.¹¹ showed excellent correlation with the RV/EDV criteria in this study (online supplementary Figure S1).

The medical records of the enrolled patients were carefully reviewed. Baseline data were collected at the time of echocardiography. The presence of comorbidities such as diabetes, hypertension, stroke history, chronic kidney disease (CKD), and chronic obstructive lung disease (COPD) was checked by disease code in medical records. The presence of atrial fibrillation (AF), right bundle branch block (RBBB), and left bundle branch block (LBBB) was obtained with electrocardiography (ECG) review, which was taken on the same day as the echocardiogram. Medical prescription information was obtained from the hospital chart review.

Baseline vital signs, demographic data, ECG, comorbidity, laboratory data, and echocardiographic data were compared between the proportional and disproportional MR groups. The primary endpoint was all-cause death. Mortality data was obtained from the national insurance system, and the censor date was 4^th August 2021. The median follow-up duration for all patients was 37.9 (range, 16.8 - 56.4) months.

The study protocol was approved, and the requirement for informed consent of the individual patients was waived by the Institutional Review Board (IRB) of Samsung Medical Center. This study was conducted according to the principles of the Declaration of Helsinki. (IRB No. 2021-10-137)

Echocardiographic evaluation

Two-dimensional echocardiography was performed at hemodynamically stable conditions using commercially available equipment (Vivid 7/Vivid E90/ Vivid E95, GE Medical Systems, Milwaukee, WI; SC2000, Siemens Medical Solution, Mountain View, CA; or Sonos 5500/ EPIQ CVX/ EPIQ 7C, Philips Medical System, Andover, MA). End-diastole was defined as the frame with the largest cavity area immediately before the onset of the QRS and end-systole as the frame with the smallest cavity area. Left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were calculated from two-dimensional recordings using the modified biplane Simpson's method. Early diastolic mitral inflow velocity (E) and late diastolic mitral inflow velocity by atrium contraction (A) were measured using the pulsed wave Doppler method by placing the sample volume at the level of the mitral valve leaflet tips. Tissue Doppler-derived early diastolic mitral annular velocity (e’) was measured from the septal corner of the mitral annulus in the apical four-chamber view. LAVI (left atrium volume index) was assessed using the modified biplane area-length method and indexed to body surface area. Right ventricular systolic pressure (RVSP) was estimated by maximal tricuspid regurgitation (TR) velocity. Evaluation of MR grading was based on a comprehensive analysis with quantitative and qualitative methods by 2017 recommendations from the American Society of Echocardiography.¹² Regurgitant fraction (RF) was defined as a measure of dividing RV by LV stroke volume. RV was calculated by the proximal isovelocity surface area (PISA) method, while RV obtained with the volumetric method was excluded.

Statistical analysis

Continuous variables are presented as mean ± standard deviation or median (interquartile range [IQR]) using a student t-test or Mann-Whitney U test. The Shapiro-Wilk test was used for the normality assumption of continuous variables. Categorical variables were compared between groups using the Chi-square test or Fisher’s exact test and are presented as numbers and relative frequencies (%).

The cumulative incidence of events was presented as a Kaplan-Meier (KM) estimate and compared using a log-rank test. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). Correlation analysis was performed using the Spearman method.

All p-values were two-sided, and p-values <0.05 were considered statistically significant. Statistical analyses were performed using R Statistical Software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria).

In this study, 135 patients (65.2%) were male, and 106 patients (51.2%) had ischemic cardiomyopathy. The median age was 69 (58 - 75) years, and the median LVEF was 27.3 [22.9 - 31.8] %. Median LVEDV and median RV were 228.0 [176.9 - 289.7] ml and 39.6 [31.0 - 49.8] ml, respectively. During a median follow-up duration of 37.9 [16.8 - 56.4] months, all-cause death occurred in 79 patients. When censoring at seven years after echocardiography, 77 patients (KM estimated survival rate 50.5%) had died.

Patients in the disproportional MR group were relatively older than those in the proportional MR group in baseline characteristics analysis. They had many comorbidities, including hypertension and CKD. The disproportional MR group showed higher systolic blood pressure and lower body mass index (BMI). There was no statistical difference between the two groups regarding sex, ischemic etiology, and baseline rhythm. LVEF was lower in the proportional group than in the disproportional group. Septal wall thickness, diastolic dysfunction parameters such as e’, E/e’, DT (deceleration time), and E/A ratio, and LAVI and RVSP were not significantly different between the two groups (Table 1). In survival analysis at seven years of all-cause death according to proportionality, the disproportional group showed a worse outcome with hazard ratio (HR) 2.013 (95% CI 1.254 - 3.230, log-rank p-value = 0.004) (Figure 2). When dividing the study population according to etiology, i.e., DCMP or ICMP, the only significant prognostic implication of disproportional MR was observed in DCMP (Figure 3). In DCMP, patients with disproportional MR had a poorer prognosis with HR 3.493 (95% CI 1.457 - 8.375, log rank p-value = 0.005). In contrast to DCMP, the disproportionality of MR in ICMP was not statistically related to all-cause death, with HR 1.304 (95% CI 0.740 - 2.301, log rank p-value = 0.359). The interaction p value between disease etiology and MR proportionality for mortality was 0.001. However, when age, hypertension and LVEF were adjusted, disproportionality did not significantly correlate with mortality in whole study population as HR 1.516 (95% CI 0.935 – 2.457, p value 0.091). Only Age and hypertension were major prognostic factors in multivariable cox regression as p value <0.001 and 0.034, respectively.

In the analysis of baseline characteristics between the proportional and disproportional MR groups of patients with DCMP, a similar trend was maintained as with the analysis for the entire study population. Patients in the disproportional group were statistically older than those in the proportional group (69.0 years old and 56.0 years old, respectively, p value 0.011) and had a higher incidence of comorbidity such as hypertension, diabetes, CKD, and COPD. LVEF was also lower in the proportional group in the DCMP population. Baseline blood pressure, BMI, baseline ECG, septal wall thickness, diastolic dysfunction parameters, and RVSP were not significantly different between the two groups (Table 2). When age and LVEF were adjusted, disproportionality did not significantly correlate with mortality in DCMP group as HR 2.129 (95% CI 0.831 - 5.455, p value 0.116) and age was the only significant prognostic factor as p value 0.002.

In correlation analysis between components of disproportionality and age in each disease etiology, EDV tended to decrease significantly with increasing age in both DCMP (R² = - 0.299, p-value = 0.002) and ICMP (R² = - 0.237, p-value = 0.014), whereas RV did not show a significant correlation with age. The RV/EDV ratio significantly increased with increasing age in DCMP (R² = 0.290, p-value = 0.003), but did not show a significant correlation in ICMP (R²= 0.052, p-value 0.594) (Figure 4).

In the univariable Cox proportional hazards model, only the continuous RV/EDV had satisfactory prognostic implication across the whole study population with HR 12.77 (95% CI 1.362 - 119.8, p-value = 0.026). Other MR quantification methods, such as RV, EROA, and RF, RVSP and RV dysfunction marker were not significantly related to prognosis in this study (Table 3).

This study tried to evaluate the prognostic implication of disproportional MR in two major secondary MR etiologies. We found that disproportionality of severe secondary MR is related to poor prognosis due to age and combined comorbidity. The difference was more prominent in DCMP compared with ICMP.

With the rise of the concept of disproportional MR due to the success of transcutaneous edge-to-edge repair (TEER) in secondary MR, the prognostic implication of disproportional MR has been studied.^9,10,13 In previous studies, the prognosis of patients with disproportionate MR was worse than that of patients with proportional MR.^9,10 But focused evaluation according to disease etiology was insufficient in previous studies. The mechanism of ischemic MR and non-ischemic MR is undoubtedly different. Regional wall distortion of ischemic MR could induce significant secondary MR even in preserved ejection fraction,¹⁴ and asymmetric regurgitant jet is a feature of ischemic MR.¹⁵ On the contrary, with non-ischemic MR, global LV dilatation with increased sphericity is a significant determinant of MR severity¹⁶ and typically shows a central regurgitant jet.¹⁷ One of the reasons for the divergence of severe secondary MR quantification between the American Heart Association (AHA) 2017¹⁸ and European Society of Cardiology (ESC) 2017 guidelines¹⁹ was the concern about underestimation of the eccentric MR jet,^20,21 which is a prominent feature of ischemic MR. Individual analysis according to MR etiology was practical in disproportional MR as in this present study.

A major determinant of disproportionality in this study was age. EDV showed a statistically significant decrease with increasing age in both diseases, but RV numerically increased with age in DCMP and decreased with age in ICMP. The correlation coefficient between LVEDV and age was numerically higher in DCMP compared with ICMP. For these reasons, there was a difference in the pattern of disproportionality in the two diseases according to age. LV length, LV dimension, and the LV sphericity index decrease with age in the general population^22,23. Age related decrease of LVEDV is also well explained at echocardiography guideline in normal population²⁴. But age-related pattern of LV dimension in DCMP and ICMP has remained unclear since now. At the cellular level, telomere activity has been linked to the loss of left ventricular size and diastolic function in normal persons with aging.²³ As the ventricle stiffens with aging process, it is thought that diastolic phase ventricle cavity size decrease. According to the results of the present study, the change in LV dimension according to age seems to be applied to ICMP and DCMP as well as to normal people.

Results that were consistent with the previous disproportionality study⁹ were that hypertension was more prevalent in the disproportional group, and LVEF was lower in the proportional group due to larger LVEDV characteristics. Lower body mass index was also correlated with disproportional MR in this present study. Hypertension is an independent risk factor of primary and secondary MR.²⁵ Hypertension and lower body mass index were identified as MR risk factors in a subgroup analysis of the Framingham study.²⁶

In this study, only disproportionality was associated with prognosis in severe secondary MR, and known MR quantification methods such as RV, EROA, and RF had no prognostic values in severe secondary MR. RF, which reflects the contractility of the myocardium, also had a p-value of 0.069, which unfortunately was not related to prognosis. In the current guideline, the severity of primary MR and secondary MR is applied by the same quantification method, like EROA or RV. Secondary MR, however, is not valve disease but a consequence of myocardium distortion and contractility abnormality. The current criteria for the severity of secondary MR have fewer implications for myocardium status. Disproportional MR that reflects the LV cavity size could be the replaceable concept of MR severity in secondary MR. Although disproportionality was greatly affected by age and comorbidity in this study, age is a representative degeneration factor. Since this study confirmed that disproportionality expresses degeneration, it was proved that disproportionality can affect prognosis with degeneration related process. Of course, further studies are needed to determine whether disproportional MR is an independent prognostic factor even excluding the effect of age.

Limitations

Despite our efforts, there are several limitations in this study. First, due to the single-center retrospective study characteristics, the possibility of selection bias exists, and the generalizability of our findings may be limited. Second, since end-diastolic volume was obtained by modified Simpson’s method in 2D echocardiography²⁷, which uses the geometrical assumption of disk summation, exact volume estimation in ischemic cardiomyopathy, which has a myocardial contraction that is unsymmetrical in nature, was difficult compared with dilated cardiomyopathy. For more accurate volume estimation, 3D echocardiography or heart MRI (magnetic resonance imaging)^28,29 could be helpful. Third, the prognosis analysis of this study was limited to moderate-to-severe or severe mitral regurgitation since this study was inspired by the disproportionality study of a TEER candidate.^4,9,10 A disproportionality study of mild or moderate degree MR may be clinically helpful. Forth, it has not been long since TEER was conducted in Korea due to insurance issues. Therefore, none of the study patients performed TEER, and it was difficult to see the effect of them. Fifth, as a limitation of the retrospective study, indicators such as coaptation depth, tenting area, and sphericity index related to the quantification of secondary MR^16,30 were not used in this study because they were not used as routine values in the echocardiographic lab. If the mentioned values are used in future studies, more in-depth findings could be obtained.

In severe secondary MR, patients with disproportional MR have a worse prognosis than patients with proportional MR due to age and comorbidities, and this difference is more prominent in DCMP than in ICMP. Among MR quantification methods, only RV/EDV has prognostic implications in severe secondary MR.

MR = mitral regurgitation

DCMP = dilated cardiomyopathy

ICMP = ischemic cardiomyopathy

TEER = transcutaneous edge-to-edge repair

LV = left ventricle

LVEDV = left ventricle end-diastolic volume

RV = regurgitant volume

EROA = effective regurgitant orifice area

RF = regurgitant fraction

Conflict of Interest Statement

None of the authors have any conflicts of interest to declare.

Acknowledgments and Funding Sources

None

Ethical Approval

This study was conducted according to the principles of the Declaration of Helsinki. (IRB No. 2021-10-137)

Author Contributions

All authors contributed to the conception and interpretation of data, drafting of the manuscript, revising it critically for important intellectual content, and final approval of the manuscript.

Funding

This paper did not receive any financial support.

Data Availability Statement

The original contributions presented in this study are included in the article, further inquiries can be directed to the corresponding author.

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Table 1 Baseline characteristics compare proportional and disproportional MR

	Proportional MR (n = 99)	Disproportional MR (n = 108)	p-value
Demographic information
Age	64.0 [55.0 - 74.0]	70.5 [62.0 - 75.0]	0.009
Sex (male)	70 (70.7%)	65 (60.2%)	0.149
Body mass index (kg/m²)	24.0 [21.9 - 25.7]	22.6 [20.8 - 24.9]	0.016
Comorbidity
Etiology (ICMP)	46 (46.5%)	60 (55.6%)	0.243
Hypertension	48 (48.5%)	68 (63.0%)	0.050
Diabetes mellitus	26 (26.3%)	40 (37.0%)	0.130
Chronic kidney disease	15 (15.2%)	31 (28.7%)	0.030
COPD	3 (3.0%)	7 (6.4%)	0.405
Vital sign and ECG
SBP (mmHg)	106.0 [97.5 - 117.5]	114.0 [99.0 - 130.0]	0.027
DBP (mmHg)	68.0 [60.5 - 77.5]	70.0 [60.0 - 83.0]	0.637
AF	25 (25.3%)	34 (31.5%)	0.402
RBBB	12 (12.1%)	10 (9.3%)	0.659
LBBB	7 (7.1%)	5 (4.6%)	0.651
Lab
WBC (x10³/uL)	7.0 [5.8 - 8.5]	6.9 [5.4 - 8.3]	0.403
Hemoglobin (g/dL)	12.7 ± 2.0	12.3 ± 2.3	0.171
Platelet count (x10³/uL)	196.0 [160.0 - 241.0]	181.5 [148.0 - 225.0]	0.166
BUN (ml/dL)	22.4 [17.0 - 33.8]	26.6 [18.2 - 40.7]	0.223
Creatinine (ml/dL)	1.2 [1.0 - 1.6]	1.3 [1.0 - 2.3]	0.332
Total bilirubin (ml/dL)	1.0 [0.7 - 1.7]	1.0 [0.7 - 1.4]	0.480
Echocardiography
LVEF (%)	24.8 [20.5 - 29.3]	29.7 [25.9 - 34.0]	<0.001
LVEDV (ml)	260.9 [209.7 - 314.1]	192.4 [156.2 - 244.3]	<0.001
LVESV (ml)	194.5 [152.4 - 240.6]	136.7 [103.0 - 177.2]	<0.001
Regurgitant volume (ml)	31.5 [26.3 - 39.4]	48.6 [38.5 - 59.9]	<0.001
IVS diameter (mm)	9.0 [7.8 - 10.0]	8.4 [7.8 - 9.7]	0.598
e’	0.051 [0.041 - 0.064]	0.053 [0.038 - 0.069]	0.458
E/e’	22.7 [18.4 - 29.9]	21.0 [15.6 - 29.4]	0.155
DT (msec)	148.0 [124.0 - 182.7]	153.0 [125.0 - 178.4]	0.801
E/A	2.3 [1.6 - 3.2]	2.0 [1.5 - 3.2]	0.670
LA volume index (ml/m2)	80.7 [64.8 - 99.0]	81.8 [63.1 - 102.3]	0.635
RVSP (mmHg)	49.2 [40.6 - 59.0]	50.7 [42.2 - 61.5]	0.325

A, late diastolic mitral atrium contraction velocity; AF, atrial fibrillation; BUN, blood urea nitrogen; COPD, chronic obstructive lung disease; CKD, chronic kidney disease; DBP, diastolic blood pressure; DT, deceleration time; E, early diastolic mitral inflow velocity; e’, early diastolic mitral annular tissue velocity; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; ICMP, ischemic cardiomyopathy; IVS, interventricular septum; LA, left atrium; LBBB, left bundle branch block; LV, left ventricular; MR, mitral regurgitation; RBBB, right bundle branch block; RVSP, right ventricular systolic pressure; SBP, systolic blood pressure; WBC, white blood cell count

The values in bold indicate statistical significance (p < 0.05).

Table 2. Baseline characteristics compare proportional and disproportional MR in DCMP patients

	Proportional MR (n = 53)	Disproportional MR (n = 48)	p-value
Clinical information
Age	56.0 [45.0 - 71.0]	69.0 [56.5 - 75.0]	0.011
Sex (male)	33 (62.3%)	27 (56.2%)	0.681
Body mass index (kg/m²)	24.0 [21.7 - 25.6]	22.9 [21.1 - 24.7]	0.173
Comorbidity
Hypertension	20 (37.7%)	22 (45.8%)	0.534
Diabetes mellitus	11 (20.8%)	13 (27.1%)	0.609
Chronic kidney disease	6 (11.3%)	8 (16.7%)	0.625
COPD	1 (1.9%)	3 (6.2%)	0.541
Vital sign and ECG
SBP (mmHg)	103.5 [94.0 - 114.0]	110.0 [101.0 - 118.0]	0.177
DBP (mmHg)	69.2 ± 13.9	68.5 ± 14.4	0.824
AF	11 (20.8%)	17 (35.4%)	0.155
RBBB	6 (11.3%)	3 (6.2%)	0.587
LBBB	4 (7.5%)	3 (6.2%)	1.000
Lab
WBC (x10³/uL)	6.9 [5.8 - 8.3]	6.9 [5.2 - 8.2]	0.523
Hemoglobin (g/dL)	13.3 ± 1.7	12.6 ± 2.2	0.085
Platelet (x10³/uL)	195.0 [158.0 - 234.0]	178.0 [153.5 - 209.0]	0.265
BUN (ml/dL)	20.4 [15.5 - 32.2]	22.2 [15.9 - 35.1]	0.621
Creatinine (ml/dL)	1.1 [0.9 - 1.3]	1.1 [0.9 - 1.7]	0.418
Total bilirubin (ml/dL)	1.1 [0.8 - 2.1]	1.1 [0.7 - 1.5]	0.587
Echocardiography
LVEF (%)	24.0 [19.0 - 27.6]	29.0 [25.4 - 31.4]	<0.001
LVEDV (ml)	294.3 [225.1 - 347.9]	213.8 [173.7 - 265.1]	<0.001
LVESV (ml)	214.2 [161.2 - 263.2]	149.5 [113.9 - 187.2]	<0.001
Regurgitant volume (ml)	34.9 [28.1 - 43.0]	49.2 [39.5 - 61.5]	<0.001
IVS diameter (mm)	8.5 ± 1.5	8.4 ± 1.4	0.833
e’	0.052 [0.043 - 0.067]	0.064 [0.045 - 0.079]	0.182
E/e’	22.5 [16.8 - 27.2]	18.3 [14.2 - 22.8]	0.129
DT (msec)	144.8 [105.9 - 185.6]	155.5 [120.3 - 177.2]	0.666
E/A	2.6 ± 1.3	2.4 ± 1.0	0.544
LA volume index (ml/m2)	87.7 [77.0 - 104.9]	84.4 [67.8 - 116.0]	0.885
RVSP (mmHg)	47.6 ± 15.5	51.2 ± 14.3	0.226

DCMP, dilated cardiomyopathy ; Other abbreviations are listed in Table 1.

The values in bold indicate statistical significance (p < 0.05).

Table 3. Cox proportional hazard model for all-cause mortality according to MR quantification method

	Severe Secondary MR (n = 207)			DCMP subgroup (n = 101)			ICMP subgroup(n=106)
	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
EROA (mm²)	0.985	0.967 - 1.003	0.104	0.990	0.963 - 1.017	0.445	0.983	0.955 - 1.011	0.223
RV (ml)	1.000	0.986 - 1.015	0.999	1.008	0.985 - 1.032	0.488	0.997	0.979 - 1.016	0.773
RF	1.971	0.948 - 4.101	0.069	1.920	.466 - 7.916	0.367	1.824	0.803 - 4.146	0.151
RV/EDV	12.77	1.362 - 119.8	0.026	39.94	0.975 - 1637	0.052	3.342	0.168 - 66.34	0.429
RVSP (mmHg)	1.004	0.988 - 1.019	0.657	1.011	0.983 - 1.040	0.451	0.993	0.975 - 1.013	0.499
TAPSE (mm)	0.919	0.838 - 1.008	0.075	0.905	0.778 - 1.051	0.191	0.947	0.838 - 1.069	0.376

CI, confidence interval; EROA, effect regurgitant orifice area ; DCMP, dilated cardiomyopathy ; HR, hazard ratio; ICMP, ischemic cardiomyopathy ; RF, regurgitant fraction ; RV, regurgitant volume ; Other abbreviations are listed in Table 1.

The values in bold indicate statistical significance (p < 0.05).

No competing interests reported.

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Impact of disproportionality in severe secondary mitral regurgitation according to disease etiology

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