Effect of Mitral Valve Surgery in Patients With Dilated Cardiomyopathy and Severe Functional Mitral Regurgitation

Hyemoon Chung; Makoto Amaki; Seiji Takashio; Hiroyuki Takahama; Takahiro Ohara; Takuya Hasegawa; Yasuo Sugano; Tomoyuki Fujita; Junjiro Kobayashi; Masanori Asakura; Hideaki Kanzaki; Toshihisa Anzai; Masafumi Kitakaze

doi:10.1253/circj.CJ-17-0104

Abstract

Background: Surgical treatment of functional mitral regurgitation (FMR) improves ventricular remodeling in patients with dilated cardiomyopathy (DCM). However, it is unclear whether surgical treatment improves long-term outcomes. We investigated the effects of mitral valve (MV) surgery in patients with DCM and FMR.

Methods and Results: Of 525 patients with DCM hospitalized due to heart failure between January 1996 and September 2014, 70 who had severe FMR despite receiving optimal medical therapy were enrolled in the study. Of these patients, 16 underwent surgery for FMR (surgery group; repair=14, replacement=2); the remaining 54 who refused or decided not to undergo surgery were classified as the medication group. There were no differences in age, sex, medication, or echocardiographic parameters between the 2 groups (P>0.05). During the mean follow-up period of 53.6±43.6 months, the occurrence of clinical outcomes (i.e., all-cause death or left ventricular assist device implantation) was 54.3%; the occurrence of clinical outcomes was lower in the surgery group (P=0.008, log-rank test). Multivariate Cox regression analysis using clinical data revealed that MV surgery (hazard ratio [HR] 0.257, 95% confidence interval [CI] 0.103–0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243–6.876; P=0.014) were independent predictors of clinical outcomes after adjusting for age and sex.

Conclusions: Surgery for severe FMR provides better long-term outcomes in patients with DCM.

Congestive heart failure (CHF), a major cause of mortality and morbidity worldwide,¹ is the end-stage outcome in many cardiovascular diseases, including myocardial infarction. Dilated cardiomyopathy (DCM) is one of the most common leading cause of severe CHF,² and severe functional mitral regurgitation (FMR) is present in 49% of patients with heart failure (HF).³ FMR is caused by either annular dilatation (Carpentier Type I) or posterior leaflet restriction (Carpentier Type IIIB).⁴ The former pathology is found in DCM resulting from left ventricular (LV) remodeling and dysfunction.⁵^,⁶ FMR is closely linked to poor long-term clinical outcomes in patients with DCM⁷^,⁸ because FMR further causes LV volume overload and thus worsens the severity of CHF; this suggests that it is necessary to treat either LV remodeling or FMR to break this vicious circle. Optimal medical therapy using β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics seems to be effective in treating LV reverse remodeling, but this is not true not in all cases, particularly in drug-refractory patients. It has been reported that approximately 20–60% of patients with DCM do not respond to β-blocker therapy.⁹^,¹⁰ Surgical correction of severe FMR may improve ventricular remodeling and function, and thus clinical outcomes. FMR repair decreases LV volume and improves contractile function;¹¹^–¹³ however, in a previous study, surgical FMR correction for ischemic or non-ischemic patients with CHF did not improve clinical outcomes.¹⁴ That study enrolled patients with very severe mitral regurgitation (MR) and severe contractile dysfunction, with the results hinting that surgical FMR correction is effective for patients with severe FMR but less severe cardiac dysfunction who are usually treated in outpatient clinics.¹⁴

To test this idea, we established a medical database of patients with CHF who had been followed-up in the outpatient clinic of the National Cerebral and Cardiovascular Center regardless of whether they were hospitalized for diagnosis and/or treatment. In the present study, using this clinical database of patients with CHF, we retrospectively compared the effects of surgical correction with those of medical therapy on clinical outcomes in patients with DCM and severe FMR.

Methods

Study Population

The present study was a single-center retrospective observational study. Figure 1 shows the disposition of patients in the study. Based on the Heart Failure Registry of our institution, from January 1996 to September 2014, 5,243 consecutive patients were hospitalized for the treatment of HF and were consecutively enrolled in the National Cerebral and Cardiovascular Center’s database. Patients with hypertrophic cardiomyopathy (n=392), hypertensive cardiomyopathy (n=178), ischemic cardiomyopathy (n=1,118), pacing-induced cardiomyopathy (n=43), cardiac sarcoidosis (n=74), and organic valvular heart disease (n=2,031), as well as those with an unclear etiology (n=882), were excluded from the study. In total, 525 patients were classified as having primary DCM. Of these, 146 were excluded because of insufficient clinical data or follow-up period. After excluding patients with less-than-moderate FMR, 133 patients with idiopathic DCM having severe FMR were identified. All these patients received maximum doses of β-blockers and ACE inhibitors or ARBs, although the maximum doses differed depending on the patient’s hemodynamic condition (i.e., blood pressure and heart rate). Of these 133 patients, 63 had a transient severe MR that improved to less-than-moderate MR after medical therapy and/or cardiac resynchronization therapy (CRT). Thus, 70 patients remained who had persistent severe FMR despite receiving appropriate medical therapy; these patients were enrolled in the present study (Figure 1). The clinical characteristics of the cohort who responded to medical therapy and/or CRT (transient severe MR group) and those who did not (persistent severe MR group) are summarized in Table S1.

Figure 1.

Schematic presentation patient disposition in the study. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; IHD, ischemic heart disease; MR, mitral regurgitation; NCVC, National Cerebral and Cardiovascular Center.

The present study was approved by the National Cerebral and Cardiovascular Center Research Ethics Committee. The Committee decided that according to the Japanese Clinical Research Guidelines,¹⁵ it was not necessary to obtain informed consent from patients chosen for inclusion in the study because the study was a retrospective observational study. Instead, a public announcement was made in accordance with the Ethics Committee’s request and Japanese Clinical Research Guidelines.

Conventional Echocardiography

Echocardiographic images were analyzed retrospectively. A comprehensive echo-Doppler evaluation was performed according to current American Society of Echocardiography guidelines.¹⁶ LV ejection fraction (EF) was obtained using the modified Simpson’s method, and fractional shortening (FS) was calculated using the following formula:

FS=100×(LVEDD−LVESD)/LVEDD

where LVEDD is the LV end-diastolic dimension and LVESD is the LV end-systolic dimension. Left atrial dimensions (LADs) were measured at the time of end-systole. Right ventricular systolic pressure (RVSP) was calculated as follows:

RVSP=4×(TRPV)²+RAP

where TRPV is tricuspid regurgitation peak velocity and RAP is right atrial pressure. RAP was measured using the inferior vena cava diameter and its respiratory variation in the subcostal view.¹⁷ MR severity was determined using a multiparametric approach, namely measurement of the width of the vena contracta and jet area on color flow Doppler, and assessment of regurgitant volume by the proximal isovelocity surface area or volumetric method. In the present study, severe FMR was defined as a regurgitant volume ≥30 mL, vena contracta width >3 mm, or MR jet area/left atrial (LA) ratio ≥40 mm².¹⁸^,¹⁹

Decisions Regarding Surgical or Non-Surgical Treatment of CHF

All 70 patients were considered to undergo surgical FMR correction because either medical therapy or CRT provided insufficient improvement in CHF. However, after patients had been given detailed explanations of the benefits and risks of the surgery by independent medical staff, only 16 patients agreed to undergo surgery, and the remaining 54 declined. These 16 and 54 patients were classified as the surgery and medication groups, respectively. Operative risks were calculate using the Society of Thoracic Surgeons (STS) risk score and European System for Cardiac Operative Risk (EuroSCORE) II,²⁰^,²¹ and there were no differences in the STS risk score or EuroSCORE II between the 2 groups (Table 1). For all patients treated with or without surgery, continuous best medical therapy or CRT was provided; for patients treated with surgery, the best perioperative care was also provided.

Table 1. Baseline Characteristics of the Study Sample

	Surgery group (n=16)	Medication group (n=54)	P value
Age (years)	52±14	54±15	0.552
Male	12 (75.0)	44 (81.5)	0.723
Initial NYHA Class 3 or 4	8 (50.0)	29 (53.7)	>0.999
SBP (mmHg)	109±18	114±23	0.434
DBP (mmHg)	62±11	68±15	0.178
HR (beats/min)	74±10	80±19	0.194
Initial log BNP (pg/mL)	5.64±1.80	5.84±1.69	0.436
Hypertension	0 (0)	7 (13.0)	0.339
Diabetes	2 (12.5)	10 (18.5)	0.720
AF	11 (68.8)	27 (50.0)	0.256
β-blockers	14 (87.5)	53 (98.1)	0.129
ACEi or ARB	14 (87.5)	50 (92.6)	0.614
CRT implantation	3 (18.8)	26 (48.1)	0.045
EuroSCORE II	5.04±5.40	4.66±3.38	0.774
STS score	2.01±2.13	1.06±1.05	0.172
Clinical outcome
Death	5 (31.5)	18 (33.3)	>0.999
LVAD implantation	2 (12.5)	13 (24.1)	0.492
Readmission for HF	40 (74.1)	10 (62.5)	0.529

Data are given as the mean±SD or as n (%). ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; CRT, cardiac resynchronization therapy; DBP, diastolic blood pressure; EuroSCORE, European System for Cardiac Operative Risk Evaluation; HF, heart failure; HR, heart rate; LVAD, left ventricular assistant device; NYHA, New York Heart Association; SBP, systolic blood pressure; STS, Society of Thoracic Surgeons.

Clinical Follow-up and Outcomes

Clinical outcomes for each patient treated with or without surgery were reviewed retrospectively with a mean (±SD) follow-up period of 53.6±43.6 months. In the present study, clinical outcomes were defined as all-cause death or LV assist device (LVAD) implantation. All patients were followed-up in outpatient clinics with physical examinations, echocardiography, and electrocardiography (ECG). CHF symptoms experienced between follow-up visits were evaluated by clinical examination, ECG, and echocardiography in 70 patients.

Statistical Analysis

Continuous variables that were normally distributed are reported as the mean±SD with or without as mean values with 95% confidence intervals (CIs). Student’s t-test was used to compare the means of continuous variables that were approximately normally distributed between the 2 groups. If the assumption of normality was violated, mean values were compared using the Mann-Whitney U-test. Normality was determined using the Kolmogorov-Smirnov goodness-of-fit test. Categorical variables were reported as counts (percentages) and were compared using Fisher’s exact test. Independent predictors of clinical outcomes were first assessed using univariate Cox proportional hazards regression models and then multivariable models based on the results of the univariate models. Multivariate analyses were performed for variables with P<0.1 in the univariate analysis. Differences in the cumulative survival rate between patients treated with and without surgery were explored using the Kaplan-Meier method followed by the log-rank test. All statistical analyses were performed using the SPSS version 19.0 statistical package (IMB, Markham, Canada). Two-sided P<0.05 was considered statistically significant.

Results

Baseline Characteristics

The baseline characteristics of the patients are presented in Table 1. Of the patients enrolled in the study, 56 (80%) were males, and 7 (10%) and 12 (17%) had a history of hypertension and diabetes mellitus, respectively. There were no differences in age, sex, initial New York Heart Association (NYHA) class, the prevalence of hypertension, diabetes mellitus, and atrial fibrillation or the administration of β-blockers, ACE inhibitors, or ARBs between the 2 groups. CRT was more frequently performed in the medication group than in the surgery group (18.8% vs. 48.1%; P=0.045). Analysis of echocardiographic parameters revealed no significant differences in EDD, ESD, FS, EF, RVSP, and LAD or the prevalence of concomitant tricuspid regurgitation between the 2 groups (all P>0.05; Table 2).

Table 2. Echocardiographic Characteristics of the Study Sample

	Surgery group (n=16)	Medication group (n=54)	P value
EDD (mm)	76±11	76±11	0.526
ESD (mm)	65±15	65±11	0.837
FS (%)	15±7	12±5	0.057
EF (%)	34±13	25±9	0.066
RVSP (mmHg)	46±21	39±14	0.274
LAD (mm)	51±8	49±9	0.457
TR			0.262
Mild	8 (50.0)	39 (72.2)
Moderate	4 (25.0)	8 (14.8)
Severe	4 (25.0)	7 (13.0)

Data are given as the mean±SD or as n (%). EDD, end-diastolic dimension; EF, ejection fraction; ESD, end-systolic dimension; FS, fractional shortening; LAD, left atrial dimension; RVSP, right ventricular systolic pressure; TR, tricuspid regurgitation.

Surgery for FMR

The surgical characteristics and outcomes for each patient are given in Table 3. All 16 patients who underwent surgery had experienced repeated hospitalization due to CHF before the surgery, and 69% (11/16) of patients had been prescribed inotropic agents. All 16 patients in the surgery group underwent surgical FMR correction due to uncontrolled HF despite receiving the optimal medical therapy. Of these, 12 patients underwent mitral valve (MV) repair and 4 underwent MV replacement with chordal preservation. Of the 12 patients with MV repair, 11 underwent MV ring annuloplasty only, and 1 patient concomitantly underwent the key stitch medial and lateral commissure with ring annuloplasty. Five patients simultaneously underwent surgery for LV volume reduction. There were 2 cases of early MR recurrence: 1 with moderate MR on Day 28 after surgery and 1 with severe MR on Day 18 after surgery. One patient was diagnosed with infective endocarditis of the repaired MV with a moderate grade of MR recurrence 4 months after MV surgery. During the mean follow-up period of 1,532±1,452 days, the recurrence rate of severe MR among all patients who underwent MV repair was 25% (4/16). Of these patients, 1 underwent an additional operation with MV replacement; of the remaining 3 patients, 1 died due to HF aggravation, another 1 patient died because of non-cardiac reasons, and remained 1 patient was alive at the last follow-up.

Table 3. Surgical Treatments and Outcomes

Patient no.	Sex	Age (years)	Surgery		Before surgery				After surgery		Mortality or LVAD	MR recurrence (severity)	Days between surgery and MR recurrence
Patient no.	Sex	Age (years)	Method	MV ring or valve size (brand)	No. times admitted for HF	Inotropic use	NYHA	BNP (pg/mL)	NYHA	BNP (pg/mL)	Mortality or LVAD	MR recurrence (severity)	Days between surgery and MR recurrence
1	M	16	MV replacement+Batista	29 mm (SJM)	2	0	3	907	2	139	0	No
2	M	54	MV replacement+TAP+CABG	29 mm (Magna Ease)	4	1	3	345	2	ND	0	Yes (moderate)	28
3	M	51	MV repair	25 mm (Duran)	5	1	3	474	1	457	1	Yes (severe)	286
4	M	60	MV repair+Batista+VT ablation	Unknown	2	0	2	84	2	66	0	Yes (moderate)	3,560
5	M	60	MV repair+Batista	26 mm (Physioring)	2	0	3	610	2	231	0	Yes (moderate)	777
6	M	72	MV repair+Maze	30 mm (Physio II)	4	0	2	975	2	137	0	Yes (moderate)	995
7	M	48	MV replacement	Unknown	4	1	4	3,800	4	15,400	1	No
8	M	47	MV repair+key stitch medial and lateral commissure	27 mm (Cosgrove)	3	1	3	265	3	415	1	Yes (severe)	18
9	F	58	MV replacement	27 mm (SJM)	1	1	3	1,770	2	ND	0	No
10	M	44	MV repair	Unknown	4	1	2	1,000		ND	1	No
11	F	55	MV repair	25 mm (Duran)	4	1	3	301	2	20	0	Yes (severe)	266
12	M	59	MV repair+overlapping+interpapillary muscle plication+AV replacement	25 mm (Duran)	5	1	2	232	3, 4	1,592	1	No
13	F	66	MV repair+maze+LAA ligation	26 mm (Physio II)	4	1	3	166	2	100	0	No
14	M	59	MV repair+TAP+LAA ligation	26 mm (Physioring)	2	1	2	20	2	ND	1	Yes (moderate)	550
15	M	59	MV repair+TAP+interpapillary muscle plication	26 mm (Physioring)	3	1	4	3,104	2	397	1	Yes (moderate)	428
16	M	26	MV repair	25 mm (Duran)	1	0	3	405	2	318	0	Yes (moderate)	1,940

AV, aortic valve; CABG, coronary artery bypass grafting; F, female; LAA, left atrial appendage; LV, left ventricle; M, male; MV, mitral valve; MR, mitral regurgitation; ND, not determined; SJM, St. Jude Medical; TAP, tricuspid annuloplasty; VT, ventricular tachycardia. Other abbreviations as in Table 1.

Clinical Outcomes

In all patients, the incidence of all-cause death or LVAD implantation was 54.3% (38/70), with a mean follow-up period of 53.6±43.6 months. According to the Kaplan-Meier analysis, the all-cause death or LVAD-free rate was significantly higher in patients treated with than without surgery (P=0.008, log-rank test; Figure 2).

Figure 2.

Kaplan-Meier survival curves in the surgery and medication groups. The surgery group had a higher cumulative death- or left ventricular assistant device (LVAD) event-free rate compared with the medication group. The surgery group included all types of operations.

Further analyses were performed to test the determinants for clinical outcomes in 70 patients. Univariate Cox regression analysis revealed that MV surgery and diabetes mellitus were related to clinical outcomes. Neither EF nor RVSP was related to all-cause mortality or the incidence of LVAD implantation (all P>0.05). Multivariate Cox regression analysis revealed that MV surgery (hazard ratio [HR] 0.257, 95% CI 0.103–0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243–6.876; P=0.014) were independent predictors of all-cause death or the incidence of LVAD implantation after adjusting for age and sex (Table 4).

Table 4. Univariate and Multivariate Cox Regression Analysis for Predicting Mortality and LVAD Implantation

	Hazard ratio (95% CI)	P value
Univariate Cox regression analysis
Age (years)	0.993 (0.970–1.017)	0.993
Male	1.255 (0.488–3.226)	0.637
SBP (mmHg)	0.993 (0.976–1.009)	0.376
DBP (mmHg)	0.985 (0.956–1.014)	0.307
Hear rate (beats/min)	0.992 (0.971–1.013)	0.452
Hypertension	1.150 (0.350–3.771)	0.818
DM	2.015 (0.957–4.629)	0.064
CKD	0.978 (0.506–1.892)	0.948
AF	0.867 (0.452–1.663)	0.667
MV operation, as a time-dependent covariate	0.339 (0.147–0.784)	0.011
Initial log BNP (pg/mL)	1.046 (0.832–1.315)	0.702
β-blocker	0.744 (0.178–3.105)	0.685
ACEi or ARB	2.729 (0.374–19.916)	0.322
EF (%)	0.973 (0.937–1.010)	0.153
EDD (mm)	1.018 (0.989–1.048)	0.217
ESD (mm)	1.016 (0.993–1.041)	0.178
FS (%)	0.950 (0.890–1.014)	0.124
LA dimension (mm)	0.995 (0.962–1.030)	0.795
Severe TR	1.900 (0.865–4.174)	0.110
RVSP (mmHg)	1.000 (0.981–1.020)	0.963
Multivariate Cox regression analysis
Age (years)	0.984 (0.958–1.011)	0.240
Male	0.929 (0.331–2.605)	0.888
DM	2.924 (1.243–6.876)	0.014
MV operation, as a time-dependent covariate	0.257 (0.103–0.640)	0.004

CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus. Other abbreviations as in Tables 1–3.

Among the 70 patients in the present study, 23 patients died: 5 in the surgery group and 18 in the medication group (see Table 1). In the surgery group, 3 patients died because of HF, 1 died because of endocarditis, and 1 died due to non-cardiac causes. In the medication group, 9 patients died because of HF, 6 patients died due to unknown causes, 1 patient died due to sudden cardiac death, and 2 patients died due to non-cardiac causes.

Discussion

Although DCM is the most frequent indication for heart transplantation in Japan, its etiology has not been elucidated, suggesting that causal treatment of DCM is difficult and that the correction of secondary deleterious sequelae becomes more important to reduce fatal cardiovascular events. Cardiovascular remodeling is the most frequent sequela in patients with DCM that worsens CHF severity; FMR largely contributes to cardiovascular remodeling after intensive medical therapy targeting cardiac reverse remodeling. Given these conditions, the major finding of the present study is that surgical correction of severe FMR improves clinical outcomes in patients with DCM. To our knowledge, the present study is the first to show that FMR correction in patients with DCM-induced severe CHF and FMR resulted in improved long-term clinical outcomes compared with identical patients who did not undergo surgical FMR correction. However, before this conclusion can be reached definitively, several fundamental issues need to be considered.

The role of FMR needs to be considered in CHF pathophysiology. If FMR does not have an effect on clinical outcomes in patients with CHF and FMR, there would be no rationale for MV surgery in such patients; however, this is not the case. Previous studies have reported that FMR is associated with poor outcomes in HF.⁵^,²²^,²³ In addition, Agricola et al²⁴ reported the prognostic value of FMR in patients with DCM, and the observational study of Stolfo et al²⁵ demonstrated that an early improvement in FMR is a favorable prognostic factor in DCM. FMR also causes volume overload, reduces forward stroke volume, increases diastolic wall stress, and leads to LV remodeling through neurohumoral and cytokine activation.²⁶^–²⁸ Patients in the present study had undergone sufficient medical therapy to inhibit their sympathetic nerves and the renin-angiotensin-aldosterone system. In such patients, FMR correction can be considered; FMR correction would be the last strategy for treatment before LVAD implantation or heart transplantation.²³^,²⁹ Wada et al reported that 36% of patients with acute decompensated HF had moderate/severe FMR and that only half these patients showed improvements to a lower grade of FMR after undergoing optimal medical therapy.⁸ Stolfo et al reported that 38% of patients with DCM had moderate/severe FMR at the time of early follow-up and that only half of these patients continued to have a diagnosis of persistent moderate/severe FMR after undergoing optimal medical therapy.²⁵ Persistent moderate/severe FMR despite sufficient medical therapy was also associated with poor outcomes in these studies.⁸ For example, in the study of Wada et al,⁸ patients with persistent moderate/severe FMR had a larger LA, lower LV systolic function and higher plasma B-type natriuretic peptide (BNP) concentrations. In the present study, 53% (70/133) of patients who were diagnosed with severe MR continued to have persistent severe MR despite the optimal medical therapy and/or CRT, indicating that patients whose FMR would have been improved were excluded from the study. CRT implantation also has a crucial role in improving MR. Short-term effects of CRT on FMR are due to: (1) resynchronization of the papillary muscle, which leads to a reduction in the duration of MR and a delay in the onset time of MR; (2) increasing ventricular contractility, which leads to augmentation of the transmitral pressure gradient; and (3) modification of mitral-annulus contraction.³⁰^–³² Long-term effects of CRT-induced ventricular remodeling also improve MR.³⁰^,³³ In previous study, improvement in MR ≥1 grade occurred in 46% of patients with moderate-to-severe or severe FMR.³⁴ In the present study, the CRT implantation rate was 41.4% (29/70). An CRT was not implanted in the remaining 41 patients (58.6%) because they did not meet the indication criteria, such as non-LBBB and atrial fibrillation, which were not considered as a favorable indications for CRT implantation according to previous guidelines.³⁵^,³⁶ In our Heart Failure Registry, a similar rate (17/46; 37%) of MR improvement was observed after CRT implantation. Of the patients with transient MR, 20 underwent CRT implantation. Of these 20 patients, 17 had severe FMR, whereas the remaining 3 patients had already improved to mild-moderate MR at the time of CRT implantation. Of patients with persistent MR, 29 underwent CRT implantation. Therefore, 46 patients had severe FMR at the time of CRT implantation; 17 patients with severe FMR improved to mild or moderate MR after CRT implantation, whereas 29 patients did not improve despite receiving optimal medical therapy and CRT implantation. Along this line, we investigated whether MV surgery for FMR improves clinical outcomes because of benefits associated with a reduction in MR and cardiac stress at the expense of perioperative risks and possible postoperative detriments associated with surgery. The findings revealed that outcomes following MV surgery were superior to those seen with the simple continuation of medical therapy. Surgery is associated with potential perioperative mortality and morbidity in high-risk patients.³⁷^,³⁸ Nevertheless, the results of the present study support the concept that correcting FMR could be beneficial in DCM.

Despite the close relationship between FMR and cardiac remodeling, surgical FMR correction for patients with ischemic or non-ischemic CHF did not improve clinical outcomes in previous study.¹⁴ In that study, it was reported that the predictors of favorable clinical outcome were the administration of β-blocker therapy, ACE inhibitor therapy, the absence of coronary artery disease, higher serum sodium concentrations, and higher mean arterial pressure. MV annuloplasty did not predict clinical outcome in that study.¹⁴ Before the present study, that study was the only one thus far to compare the outcomes of medical and surgical interventions in such a cohort of patients. Wu et al¹⁴ enrolled patients with very severe MR as well as those with more severe contractile dysfunction; one of the inclusion criteria for that study was an EF <30%.¹⁴ In the present study, EF in the surgery and medication groups was 34% and 25%, respectively, suggesting that almost half the patients had an EF >30%. The findings of the previous study suggest that MV surgery is not indicated in patients with an EF <30% because of the belated treatment;¹⁴ the present study suggests that MV surgery is indicated in patients with an EF >30%.

Differences between FMR and degenerative MR (DMR) need to be taken into consideration. Surgical therapy needs to be considered for DMR with severe regurgitation, and asymptomatic CHF as the primary cause of MR is attributable to degeneration of the MV apparatus.³⁹ However, because the pathophysiology of FMR can be primarily attributed to myocardial disorders, FMR treatment may not improve primary myocardial damage.¹⁴^,⁴⁰^,⁴¹ DMR knowledge cannot be extended to the clinical outcomes of surgery of FMR in patients with CHF. Current guidelines recommend MV surgery for severely symptomatic patients with HF having chronic severe FMR and persistent symptoms despite receiving optimal medical therapy (Class IIb, level of evidence C).⁴²^,⁴³ The European Society of Cardiology limits the indication for MV surgery to patients with EF >30%.⁴³ However, the Japanese Cardiology Society guidelines strongly recommend MV surgery for FMR for a broader category of patients compared with other guidelines: symptomatic patients with severe FMR and EF >30% as a Class I indication, and symptomatic patients with severe FMR and EF <30% as a Class IIa indication for isolated MV surgery.⁴⁴

FMR occurs in ischemic and non-ischemic hearts; however, the causes of FMR are different in these conditions,⁴ suggesting that clinical outcomes of surgical FMR correction in ischemic and non-ischemic patients are different. In ischemic CHF, “regional” wall motion abnormalities are the main cause and may be able to be corrected by coronary revascularization, whereas in DCM “global” wall motion abnormalities are common and reverse remodeling is completely dependent on MR improvement. Although favorable surgical effects for severe FMR in ischemic CHF have been demonstrated in previous reports, they are limited to improvements in LV remodeling and in clinical outcomes in association with coronary bypass surgery.¹¹^,¹²^,⁴²^,⁴⁵ Recently, the Cardiothoracic Surgical Trials Network (CSTN) revealed that the addition of MV repair did not lead to reverse remodeling of LV and improvement of cardiovascular outcome at 2 years in patients with moderate ischemic MR undergoing coronary artery bypass grafting.⁴⁶ However, outcomes of MV surgery for severe FMR with idiopathic DCM have not been tested or established. Studies have reported favorable effects of MV surgery on long-term improvements in reverse remodeling of LV and lowering mortality in patients with DCM.¹³^,⁴¹ However, these studies did not compare the effects of MV surgery on long-term clinical outcomes with those of medical therapy and/or CRT, so they did not conclude that MV surgery in patients with DCM and FMR is superior to medical therapy, although an improvement in MR severity will reduce LV end-systolic volume and end-systolic wall stress and show improvement in EF.⁴¹^,⁴⁶^–⁴⁸ The 5-year recurrence rate of severe MR or repeat mitral surgery was 19% in the Acorn trial, which is similar to that observed in the present study,⁴¹ with a 25% (4/16) recurrence rate of severe MR.

Most of the patients in the present study had MV repair, not MV replacement. Previous studies have reported that MV repair is associated with lower perioperative mortality; therefore, MV repair was preferred over MV replacement in earlier days.⁴⁹^–⁵¹ In the present study, based on these previous studies of the favorable results of MV repair, most patients underwent MV repair. Of the 4 patients who underwent MV replacement, 1 patient was very young (16 years), therefore MV replacement may have been performed to prevent MR recurrence; another 2 patients underwent MV replacement because MR had recurred immediately after MV repair in the operating room and the remaining patient underwent re-do surgery with MV replacement due to recurrence of severe MR after MV repair, and this patient had been enrolled in the study from the time of MV replacement. However, the randomized CSTN study revealed that chordal-sparing MV replacement provided a more durable correction of MR than MV repair without significant differences in operative mortality, ventricular remodeling, and long-term survival.⁴⁷ The decision whether to repair or replace the MV is very important, and our current strategy is based on updated concern. Additional randomized controlled trials are needed to investigate the efficacy of chordal-sparing MV replacement as current concern in non-ischemic FMR.

The present study revealed that DM worsens clinical outcomes in patients with DCM and severe FMR. There is a close relationship between DM and CHF,⁵² and the present study demonstrated a specific role for DM in DCM with FMR. High glucose exposure triggers cellular damage by producing oxidative stress,⁵³^–⁵⁵ which may damage cardiomyocytes, leading to myocardial dysfunction and worsening cardiac function. Moreover, insulin resistance may induce myocardial dysfunction as a result of energy depletion in the myocardium. Previously, our group reported that correction of abnormal glucose tolerance using an α-glucosidase inhibitor improved the severity of HF with reductions in LV dimensions, NYHA functional classification, and plasma BNP concentrations in patients with DCM.⁵² Therefore, attention needs to be paid to controlling serum glucose concentrations in addition to treating HF itself with either medication or interventional therapy. Moreover, it has been reported that DM worsens MV function due primarily to mitral annulus calcification.⁵⁶ Thus, attention needs to be paid to DM when the pathophysiology DCM with FMR is considered, although it should be noted that MV surgery and DM are independent predictors of clinical outcomes for patients with DCM and severe FMR.

Study Limitations

Although the results of the present study support the favorable prognostic effects of MV surgery in patients with DCM and severe FMR, some study limitations need to be addressed. First, because the present study was not a prospectively designed study, it was difficult to determine MR severity using a consistent method, and some patients had missing clinical parameters. A randomized prospective clinical trial is warranted in the near future, although this is extremely difficult. Second, the surgical procedure varied among patients. Although previous studies often analyzed at once regardless of concomitant surgical ventricular reduction,⁴⁹^,⁵⁷ LV volume reduction could affect the clinical outcome in addition to MV surgery. We performed further analyses after excluding 5 patients with concomitant LV volume reduction surgery, and similar results were obtained (Table S2) as in the full analysis. Third, analysis of postoperative ventricular remodeling was limited due to insufficient echocardiographic data because we the data reviewed retrospectively. Fourth, because the present study was performed in a tertiary referral and high-volume hospital for DCM treatment and cardiac surgery, selection and referral bias may have affected the results. This result is not necessarily applicable but can be achieved all over Japan or worldwide. Fifth, the number of patients enrolled in the study was relatively small, so other factors affecting clinical outcomes may have been missed because of the low statistical power of the study.

Conclusions

Surgical FMR correction leads to better long-term clinical outcomes in patients with idiopathic DCM with severe FMR. It is important to prevent further LV remodeling via surgical intervention for severe FMR in addition to administering the optimal medical therapy to aid the failing heart.

Acknowledgments

The authors thank the medical staff of the Department of Clinical Medicine and Development, Department of Cardiovascular Medicine and Department of Cardiac Surgery, National Cerebral and Cardiovascular Center, for help with this research.

Funding

None.

Conflict of Interest

None declared.

Supplementary Files

Supplementary File 1

Table S1. Clinical characteristics of patients with transient or persistent severe MR

Table S2. Univariate and multivariate cox regression analysis for predicting mortality and LVAD implantation after excluding concomitant LV volume reduction surgery

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0104

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