Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation.

BACKGROUND AND OBJECTIVES: MitraClip implantation is an established therapy for secondary mitral regurgitation (MR) in high-risk patients and has shown to improve several important outcome parameters such as functional capacity. Patient selection is both challenging and crucial for achieving therapeutic success. This study investigated baseline predictors of functional improvement as it was quantified by the six-minute walk distance (6MWD) after transcatheter mitral valve repair. METHODS AND
RESULTS: We retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation at an academic tertiary care center. Before and four weeks after the procedure, all patients underwent comprehensive clinical assessment, six-minute walk tests and echocardiography. 6MWD significantly improved after MitraClip therapy (295 m vs. 265 m, p < 0.001). A linear regression model including seven clinical baseline variables significantly predicted the change in 6MWD (p = 0.002, R2 = 0.387). Female gender, diabetes mellitus and arterial hypertension were found to be significant negative predictors of 6MWD improvement. At baseline, female patients had significant higher left ventricular ejection fraction (49% vs. 42%, p = 0.019) and lower 6MWD (240 m vs. 288 m, p = 0.034) than male patients.
CONCLUSION: MitraClip implantation in secondary MR significantly improves functional capacity in high-risk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favourable functional outcome. While further validation in a larger cohort is recommended, these parameters may improve patient selection for MitraClip therapy.

Introduction

Secondary mitral regurgitation (MR) is a very common valvular heart disease and associated with poor prognosis in patients with heart failure [1-3]. Surgical therapy consisting of valve repair or replacement did not show to improve prognosis and is often prohibited by an unacceptable high perioperative risk in patients with secondary MR [4-6]. As an alternative to otherwise conservative management, the MitraClip procedure is an established method for the percutaneous edge-to-edge repair of the mitral valve with a superior safety profile in high-risk patients [7,8]. As two randomized controlled studies recently delivered differing results, the procedure’s efficacy in reducing mortality in patients with secondary MR remains controversial [9,10]. Yet, several registry studies consistently demonstrated an improvement in symptoms and quality of life after treatment with the MitraClip procedure [7,8,11], which seems to be a preferential outcome measure in those elderly and multimorbid patients.

The underlying cardiac pathology and mechanism leading to the development of secondary MR are highly variable. They comprise ischemic heart disease, nonischemic cardiomyopathy, annular dilation and abnormal leaflet tethering [12]. Additionally, patients with secondary MR often exhibit significant cardiac and noncardiac comorbidities, which further contribute to the heterogeneity of this collective [4]. As a consequence, selecting patients who will benefit from MitraClip implantation is both important and challenging [13]. Various studies attempted to identify predictors of therapeutic success after MitraClip implantation, mainly focusing on mortality [14-18] and thereby neglecting functional improvement as an equivalent outcome parameter. Therefore, besides improving prognosis, a main therapeutic goal is the reduction of symptoms and improvement in functional capacity. To assess the latter, the six-minute walk test is a widely used tool in cardiovascular research which correlates with echocardiographic signs of MR reduction after transcatheter mitral valve repair [19,20]. In order to improve patient selection, the aim of this study was to identify clinical baseline predictors of the improvement in the six-minute walk distance (6MWD) after MitraClip implantation.

Methods

Study population

Patients who underwent transcatheter mitral valve repair by MitraClip implantation at the University Hospital Regensburg from 2011-2019 were analyzed retrospectively. Qualifying inclusion criterion was symptomatic moderate-to-severe or severe secondary MR with or without left ventricular (LV) systolic dysfunction. Indication for MitraClip therapy was given by an interdisciplinary Heart Team consisting of interventional cardiologists, cardiac surgeons and anesthesiologists. The procedure was performed as described elsewhere [21] under general anesthesia, guidance by fluoroscopy and three-dimensional transesophageal echocardiography. Exclusion criteria were intraprocedural failure to implant a clip, conversion to surgery or repeat MitraClip procedure. Also, patients who did not complete the follow-up and/or did not perform a six-minute walk test were excluded in the intent of a complete case analysis. The study was approved by the local ethics committee. As only pre-existing data was analyzed retrospectively and anonymously, consent was not required. The inclusion process is illustrated in Fig 1.

Fig 1

Flow chart depicting the inclusion process.

Only patients who completed 6MWD at baseline and at the four weeks follow-up were included in the intent of a complete case analysis. mon, month; MR, mitral regurgitation; 6MWD, six-minute walk test.

Clinical and echocardiographic assessment

As part of the routine care at our institution, all patients underwent a clinical and echocardiographic assessment at baseline and four weeks after MitraClip implantation. Evaluation incorporated past medical history, physical examination, laboratory measurements, transthoracic echocardiography, New York Heart Association (NYHA) functional class and measurement of 6MWD. Additionally, NYHA functional class was also evaluated at a short visit twelve months after the procedure. Echocardiography included measurement of left ventricular dimensions, left ventricular systolic function and quantification of MR in accordance to current guidelines [22]. MR grading was based on color and continuous wave Doppler evaluation including vena contracta width, effective regurgitant orifice area and regurgitation volume estimated by proximal isovelocity surface area method, and regurgitant jet area. MR grade was scored from 1 to 4 (1: mild, 2: mild-to-moderate, 3: moderate-to-severe, 4: severe). Device success was defined as residual MR grade ≤ 2 after MitraClip implantation.

Six-minute walk tests were conducted as described elsewhere [19]. Δ6MWD was calculated as 6MWD at four weeks after MitraClip procedure minus 6MWD at baseline.

Statistical analysis

Continuous variables with normal distribution were reported as mean ± standard deviation, continuous variables with skewed distribution as median [interquartile range]. Categorical variables were reported as numbers and percentages. Differences between continuous variables in paired data were tested with a paired t-test, continuous variables in unpaired data were compared with an unpaired t-test. Ordinal variables in paired samples and ordinal variables in unpaired samples were compared using Wilcoxon signed-rank tests and Mann-Whitney U tests, respectively. Comparisons of nominal variables were performed by Pearson's chi-squared tests, comparisons of binary variables by McNemar’s test. Correlation between variables was analyzed by calculating Spearman's rank correlation coefficient.

To identify independent predictors of improvement in 6MWD after MitraClip implantation, multiple linear regression was used. Selection of predictors was based on clinical considerations and exploratory statistical analysis. To avoid overfitting the regression model, clinical and echocardiographic predictors were investigated in two separate regression models. Each model included age, MR grade and baseline 6MWD as covariates. Outliers were identified by calculating studentized residuals and Cook’s distance. A two-sided p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics 25.0 (IBM, Armonk, NY USA).

Results

Patient characteristics

In total, 79 consecutive patients who underwent MitraClip implantation between November 2011 and January 2019 were included in the study. Baseline characteristics are shown in Table 1. Mean age was 76 ± 7 years, gender distribution was almost equal (46.8% female). Preserved left ventricular ejection fraction (LVEF >50%) was present in 40.5% of patients, while 35.4% had reduced LVEF (<40%) and the remaining 24.1% being classified as mid-range LVEF (40-50%). Concerning underlying heart disease, 59.5% of patients suffered from coronary artery disease and 15.2% presented with dilated cardiomyopathy. Atrial fibrillation, arterial hypertension and chronic kidney disease were very common comorbidities (64.6%, 65.8% and 64.6%, respectively). Mean logistic EUROScore and EUROScore II were 19.6 ± 12.3% and 7.6 ± 6.5%, reflecting high perioperative risk. One MitraClip was implanted in 63.3% of the patients, the remaining 36.7% received two MitraClips. Intake of heart failure medication and loop diuretics was highly prevalent at baseline and did not significantly change four weeks after the procedure (see Table 2).

Table 1

Baseline characteristics of the study population (n=79).

Age, y	76 ± 7
BMI, kg/m2	26.1 ± 4.4
Female gender	37 (46.8)
Heart failure entity
HFpEF	32 (40.5)
HFmrEF	19 (24.1)
HFrEF	28 (35.4)
Coronary artery disease	47 (59.5)
Dilated cardiomyopathy	12 (15.2)
Prior PCI	38 (48.1)
Prior CABG	19 (24.1)
Prior myocardial infarction	25 (31.6)
Atrial fibrillation	51 (64.6)
Arterial hypertension	52 (65.8)
Diabetes mellitus	25 (31.6)
Chronic kidney disease	51 (64.6)
COPD	9 (11.4)
CRT	9 (11.4)
ICD	22 (27.8)
Logistic EuroSCORE, %	19.5 ± 12.3
EuroSCORE II, %	7.6 ± 6.5
NTproBNP, pg/ml	3618 [1949–5983]
Serum creatinine, mg/dl	1.48 ± 0.63
GFR, ml/min	47 ± 19
MR etiology
secondary	73 (92.4)
mixed	6 (7.6)
No. of clips implanted
1	50 (63.3)
2	29 (36.7)

Continuous variables with normal distribution are expressed as mean ± SD, continuous variables with skewed distribution as median [IQR]. Categorical variables are expressed as n (%).

BMI, body mass index; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; GFR, glomerular filtration rate; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; MR, mitral regurgitation; PCI, percutaneous coronary intervention; SD, standard deviation.

Table 2

Echocardiographic data, functional capacity and medication at baseline and four weeks after MitraClip implantation (MCI).

	baseline	4 weeks after MCI	p
NYHA functional class
NYHA I	0	11 (13.9)	<0.001
NYHA II	2 (2.5)	38 (48.1)
NYHA III	61 (77.2)	15 (19.0)
NYHA IV	14 (17.7)	0
6MWD, m	265 ± 103	295 ± 104	<0.001
Δ6MWD, m		30 ± 68
MR Grade
1	0	56 (70.9)	<0.001
2	0	19 (24.1)
3	21 (26.6)	4 (5.1)
4	58 (73.4)	0
MR PISA EROA, cm2	0.33 ± 0.17	0.12 ± 0.08	<0.001
MR PISA RVol, ml	53 ± 27	18 ± 10	<0.001
MV mean pressure gradient, mmHg	2.4 ± 1.2	3.7 ± 1.8	<0.001
Device success		75 (94.9)
LVEF, %	45 ± 14	45 ± 13	0.719
LVEDD, mm	59 ± 9	57 ± 9	0.035
LVESD, mm	47 ± 11	46 ± 11	0.049
LAVI, ml/m2	71 ± 36	71 ± 33	0.914
sPAP, mmHg	38 ± 12	36 ± 11	0.186
Severe tricuspid regurgitation	15 (19.0)	19 (24.1)	0.317
ACE inhibitor	27 (50.9)	31 (50.0)	1.000
AT1 antagonist	13 (24.5)	14 (22.6)	1.000
ARNI	4 (7.5)	5 (8.1)	1.000
β-adrenergic antagonist	49 (92.5)	52 (83.9)	0.219
Aldosterone antagonist	27 (50.9)	39 (62.9)	0.289
Loop diuretic	49 (94.2)	59 (95.2)	1.000
Loop diuretic dose, mg furosemide equivalenta	20 [10–40]	20 [10-60]	0.103

Continuous variables are expressed as mean ± SD, continuous variables with skewed distribution as median [IQR]. Categorical variables are expressed as n (%). P-values represent results of the comparison of baseline and four weeks after MitraClip implantation using paired t-tests for continuous variables, Wilcoxon signed-rank tests for categorical variables and McNemar’s test for binary variables.

a10 mg torasemide was converted to 20 mg furosemide equivalent.

ACE, Angiotensin-converting-enzyme; ARNI, Angiotensin receptor neprilysin inhibitor; AT1, Angiotensin II receptor type 1; EROA, effective regurgitation orifice area; IQR, interquartile range; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; MCI, MitraClip implantation; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association; PISA, proximal isovelocity surface area; RVol, regurgitation volume; SD, standard deviation; sPAP, systolic pulmonary artery pressure; 6MWD, six-minute walk distance.

Echocardiographic and functional data at baseline and four weeks after MitraClip implantation

All patients showed moderate-to-severe or severe MR at baseline (grade 3 26.6%, grade 4 73.4%), which was significantly reduced four weeks after MitraClip implantation (grade 1 70.9%, grade 2 24.1%, grade 3 5.1%, p < 0.001). Thus, device success was achieved in 94.9% of patients. Mean LVEF was 45 ± 14% and remained unchanged in the short follow up after the procedure. Left ventricular end diastolic (LVEDD) and end systolic diameter (LVESD) decreased slightly yet significantly four weeks after MitraClip therapy (59 ± 9 mm vs. 57 ± 9 mm, p = 0.035 and 47 ± 11 mm vs. 46 ± 11 mm, p = 0.049). Data are reported in detail in Table 2.

At baseline, the study population was highly symptomatic, with 77.2% presenting with NYHA functional class III and 17.7% with class IV. Symptoms significantly improved four weeks after MitraClip procedure, when 62.0% of the patients were judged NYHA class I or II (p < 0.001). Improvement in NYHA class remained stable after twelve months (I: 20.0%, II: 52.7%, III: 27.3%, IV: 0%, p < 0.001 vs. baseline). Correspondingly, 6MWD was markedly reduced at baseline and significantly improved at the four weeks follow up (265 ± 103 m vs. 295 ± 104, p < 0.001). Furthermore, postprocedural 6MWD correlated with NYHA class both four weeks and twelve months after MitraClip therapy (r=-0.38 and r=-0.36, see Fig 2). Mean Δ6MWD was 30 ± 68 m and did not differ between patients with baseline MR grade 3 and grade 4 (17 ± 88 m vs. 34 ± 60 m, p = 0.312).

Fig 2

Correlation between 6MWD four weeks after the procedure with NYHA functional class.

Data is shown as a scatterplot with a line of best fit. (A) Correlation between 6MWD four weeks after MCI and NYHA class four weeks after MCI. (B) Correlation between 6MWD four weeks after MCI and NYHA class twelve months after MCI. Results are expressed as Spearman’s rank correlation coefficient r. MCI, MitraClip implantation; mon, months; NYHA, New York Heart Association; wk, weeks; 6MWD, six-minute walk distance.

Baseline predictors of improvement in 6MWD four weeks after MitraClip implantation

A multiple linear regression including eight clinical variables, adjusted for age, MR grade, baseline LVEDD and 6MWD, significantly predicted Δ6MWD from baseline to the four weeks follow up (p = 0.002, see Table 3). R2 of the overall model was 0.387, indicating a high goodness-of-fit. While no positive baseline predictors of Δ6MWD were found, several independent negative predictors were identified. The strongest negative predictor was diabetes mellitus (B = -46.9, p = 0.002), followed by arterial hypertension (B = -39.2, p = 0.010). Furthermore, 6MWD at baseline and female gender also negatively predicted Δ6MWD (B = -0.2, p = 0.044 and B = -32.3, p = 0.042). Coronary artery disease, dilated cardiomyopathy and atrial fibrillation did not independently predict Δ6MWD.

Table 3

Clinical predictors of Δ6MWD four weeks after MitraClip implantation in the multiple linear regression model.

	B	SE	β	t	p
6MWD at baseline	-0.2	0.1	-0.28	-2.06	0.044
Age	0.5	1.2	0.06	0.41	0.684
MR grade	10.0	16.1	0.07	0.62	0.534
LVEDD	0.4	1.0	0.07	0.45	0.658
Atrial fibrillation	-12.6	16.6	-0.10	-0.76	0.453
Coronary artery disease	-12.7	16.5	-0.10	-0.77	0.446
Dilated cardiomyopathy	20.8	22.4	0.13	0.93	0.356
Arterial hypertension	-39.2	14.6	-0.31	-2.67	0.010
Diabetes mellitus	-46.9	14.6	-0.37	-3.20	0.002
Female gender	-32.3	15.6	-0.27	-2.08	0.042
Preserved LVEF	14.2	16.0	0.12	0.88	0.381
NYHA functional class at baseline	-4.4	16.4	-0.03	-0.27	0.790
R	0.622
R2	0.387
Adjusted R2	0.260
F	(12, 58) = 3.048
p	0.002
n	77

Results on the predictors are reported as coefficient B, standard error SE, standardized coefficient β, t-statistic t and p-value. Overall model characteristics are reported as multiple correlation coefficient R, coefficient of determination R2 and F-ratio F.

LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; NYHA, New York Heart Association; SE, standard error; 6MWD, six-minute walk distance.

To assess echocardiographic predictors of functional improvement, an additional multiple regression model including four variables, adjusted for baseline 6MWD, age and MR grade, was calculated (see S1 Table). The model significantly predicted Δ6MWD from baseline to the four weeks follow up with moderate goodness-of-fit (p = 0.028, R2 = 0.226). Apart from baseline 6MWD (B = -0.3, p = 0.001), no independent predictor was identified. Neither LVEF, LVEDD, left atrial volume index or left ventricular mass index independently predicted Δ6MWD.

Gender-specific differences in baseline characteristics and outcomes

Considering the findings of the regression model, baseline characteristics and outcomes of the study population were analyzed for gender-specific differences. Results on baseline characteristics are shown in Table 4. Men and women were of similar age. Distribution of dilated cardiomyopathy and coronary artery disease did no differ significantly, yet there was a trend towards a higher percentage of men suffering from coronary artery disease (69.0% vs. 48.6%, p = 0.065). Rates of atrial fibrillation, diabetes mellitus and arterial hypertension were comparable between female and male patients. Also, perioperative risk as expressed by logistic EUROScore and EUROScore II was without significant gender-related differences.

Table 4

Gender-specific differences in baseline characteristics.

	male	female	p
Age, y	76 ± 6	76 ± 8	0.974
Heart failure entity
HFpEF	12 (28.6)	20 (54.1)	0.032
HFmrEF	10 (23.8)	9 (24.3)
HFrEF	20 (47.6)	8 (21.6)
Coronary artery disease	29 (69.0)	18 (48.6)	0.065
Dilated cardiomyopathy	8 (19.0)	4 (10.8)	0.309
Atrial fibrillation	30 (71.4)	21 (56.8)	0.174
Arterial hypertension	29 (69.0)	23 (62.2)	0.520
Diabetes mellitus	15 (35.7)	10 (27.0)	0.407
Chronic kidney disease	31 (73.8)	20 (25.3)	0.067
Logistic EuroSCORE, %	20.1 ± 11.6	18.9 ± 13.2	0.680
EuroSCORE II, %	8.6 ± 6.7	6.5 ± 6.1	0.156
NTproBNP, pg/ml	3244 [2168-5843]	3911 [1362-6228]	0.923
NYHA functional class
NYHA I	0	0	0.224
NYHA II	2 (4.9)	0
NYHA III	33 (80.5)	28 (77.8)
NYHA IV	6 (14.6)	8 (22.2)
6MWD, m	288 ± 89	240 ± 112	0.034
MR Grade
1	0	0	0.035
2	0	0
3	7 (16.7)	14 (37.8)
4	35 (83.3)	23 (62.2)
LVEF, %	42 ± 14	49 ± 12	0.019
LVEDD, mm	63 ± 9	54 ± 7	< 0.001
LVESD, mm	51 ± 11	42 ± 10	< 0.001
LAVI, ml/m2	77 ± 43	64 ± 25	0.152

Continuous variables with normal distribution are expressed as mean ± SD, continuous variables with skewed distribution as median [IQR]. Categorical variables are expressed as n (%). P-values represent results of unpaired t-tests for continuous variables, Pearson's chi-squared tests for nominal variables and Mann–Whitney U tests for ordinal variables.

HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IQR, interquartile range; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association; SD, standard deviation; 6MWD, six-minute walk distance.

Gender-specific differences in echocardiographic and functional outcome four weeks after MitraClip implantation are shown in Table 5. While NYHA functional class was without gender-specific disparities, 6MWD was notably lower in women both at baseline (240 ± 112 m vs. 288 ± 89 m, p = 0.034) and four weeks after MitraClip implantation (267 ± 109 m vs. 320 ± 94 m, p = 0.024). Baseline LVEF was markedly better in female than in male patients (49 ± 12% vs. 42 ± 14%, p = 0.019), mainly driven by a higher percentage of women with preserved LVEF (54.1% of female vs 28.6% of male patients, p=0.032). Concomitantly, baseline LVEDD and LVESD were significantly smaller in female patients (54 ± 7 mm vs. 63 ± 9 mm, p < 0.001 and 42 ± 10 mm vs. 51 ± 11 mm, p < 0.001). Additionally, baseline MR grade was less severe in women than in men (grade 3 37.8% vs. 16.7%, grade 4 62.2% vs. 83.3%, p = 0.035), while residual MR after MitraClip therapy did not differ. However, mitral valve mean pressure gradient after MitraClip procedure was significantly higher in women (4.2 ± 2.1 mmHg vs 3.2 ± 1.2 mmHg, p = 0.017). Considering this finding, additional regression analysis adjusted for age, baseline 6MWD and MR Grade was conducted and revealed a negative correlation between post-procedural mitral valve mean pressure and Δ6MWD in the overall collective (B = -9.2, p = 0.023, see S2 Table). Heart failure medication and diuretics intake four weeks after the intervention was without gender-specific difference.

Table 5

Gender-specific differences in echocardiographic parameters, functional outcome and medication four weeks after MitraClip implantation.

	male	female	p
NYHA functional class
NYHA I	6 (17.6)	5 (16.7)	0.391
NYHA II	22 (64.7)	16 (53.3)
NYHA III	6 (17.6)	9 (30.0)
NYHA IV	0	0
6MWD, m	320 ± 94	267 ± 109	0.024
MR Grade
1	32 (76.2)	24 (64.9)	0.181
2	10 (23.8)	9 (24.3)
3	0	4 (10.8)
4	0	0
MV mean pressure gradient, mmHg	3.2 ± 1.2	4.2 ± 2.1	0.017
LVEF, %	41 ± 14	49 ± 11	0.008
LVEDD, mm	62 ± 9	53 ± 7	< 0.001
LVESD, mm	51 ± 11	40 ± 9	< 0.001
LAVI, ml/m2	74 ± 39	67 ± 23	0.316
ACE inhibitor	17 (53.1)	13 (43.3)	0.459
AT1 antagonist	6 (18.8)	8 (26.7)	0.550
ARNI	4 (12.5)	1 (3.3)	0.355
β-adrenergic antagonist	29 (90.6)	24 (80.0)	0.294
Aldosterone antagonist	22 (68.8)	16 (53.3)	0.298
Loop diuretic	30 (93.8)	28 (96.6)	1.000
Loop diuretic dose, mg furosemide equivalenta	20 [10–40]	20 [10-60]	0.862

Continuous variables with normal distribution are expressed as mean ± SD, continuous variables with skewed distribution as median [IQR]. Categorical variables are expressed as n (%). P-values represent results of the comparison between male and female patients using unpaired t-tests for continuous variables, Mann–Whitney U tests for categorical variables and Fisher’s exact test for binary variables.

ACE, Angiotensin-converting-enzyme; ARNI, Angiotensin receptor neprilysin inhibitor; AT1, Angiotensin II receptor type 1; IQR, interquartile range; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association; SD, standard deviation; 6MWD, six-minute walk distance.

a10 mg torasemide was converted to 20 mg furosemide equivalent.

Discussion

To the best of our knowledge, this is the first study to investigate clinical predictors of improvement in 6MWD after MitraClip implantation. Our main findings were:

Patients showed a significant increase in 6MWD and a decrease in NYHA class four weeks after MitraClip implantation, reflecting relevant functional improvement early after intervention. Higher postprocedural 6MWD was associated with lower NYHA class twelve months after the intervention.

Diabetes mellitus and arterial hypertension were negative predictors of improvement in 6MWD after MitraClip implantation.

Female gender was a negative predictor of increase in 6MWD after MitraClip therapy, with women presenting more often with preserved LVEF, less LV dilatation and higher postprocedural mitral valve mean pressure gradient than male patients.

Identifying the patients who profit from transcatheter mitral valve therapy is crucial for both achieving therapeutic success and avoiding futile interventions [13]. As heart failure symptoms like exertional dyspnea are a pivotal criterion for patient selection in current guidelines [23], symptom relief is a main therapeutic goal of transcatheter mitral valve repair. Therefore, improvement in functional capacity as expressed by an increase in 6MWD is an important aspect of the outcome of MitraClip therapy. Our study identified several factors indicative of worse functional outcome which could aid to improve patient selection and generate new hypotheses on the determinants of therapeutic response to transcatheter mitral valve repair.

Gender-related differences in functional outcome of MitraClip therapy

Our analysis identified female gender to be a negative predictor of improvement in 6MWD after MitraClip implantation, expressing a less favourable functional outcome in women compared to men. Significant gender-specific differences have been reported in the outcome after mitral valve surgery, with female patients exhibiting both higher short- and long-term mortality [24-27]. Also, surgical mitral valve repair restored life expectancy to normal compared to matched controls in men, but not in women [25]. According to previous investigations, this does not apply to transcatheter mitral valve repair. In several registries, short- and long-term mortality was equal between men and women, with one study even reporting superior long-term survival in women [28-32]. However, congruous with our observations, gender-related differences were noted in the functional improvement after transcatheter mitral valve repair. In the TRAMI registry, female patients exhibited less improvement in functional NYHA class one year after MitraClip implantation than male patients [30]. In another retrospective study, Tigges et al reported an increase in 6MWD only in men, while it stagnated in women [29]. Notably, procedural efficacy in reducing MR did not differ between males and females. Furthermore, a subgroup analysis of the randomized COAPT-Trial also supports our observations. Patients’ gender nearly significantly interacted with the rate of hospitalization for heart failure, with a notable trend towards worse outcome in women [10].

The reasons for the observed gender-related differences in functional outcome are not clear and most likely multifactorial. In our study population, women and men showed comparable age, perioperative risk and non-cardiac comorbidities. However, female patients presented more commonly with preserved LVEF and less LV dilatation than male patients. Given similar findings in other registry studies [28-30], these gender-specific disparities in baseline characteristics appear to be inherent in the population treated with transcatheter mitral valve repair. Worse functional outcome in women might implicate that therapeutic response to MitraClip implantation is less effective in patients with preserved LVEF. Conversely, differences in LV geometry between male and female patients may constitute a major cause for female gender negatively predicting functional improvement. Furthermore, smaller and different mitral valve morphologies in women [26], which are mirrored by the lower number of clips implanted in female patients [29,30], possibly pose a higher challenge to transcatheter mitral valve repair. This might particularly lead to higher postprocedural mitral valve pressure gradients in women than in men, as it was observed in our study. Importantly in this context, postprocedural mitral valve pressure gradient negatively correlated with improvement in 6MWD in the overall study population. Elevated mitral valve pressure gradient might increase left atrial pressure, of which the latter is associated with less improvement in 6MWD after MitraClip implantation [33]. A recent trial on MitraClip therapy for secondary MR did not show a correlation between postprocedural mitral valve pressure gradient and 6MWD, but with worse NYHA class [34]. Therefore, elevated mitral valve pressure gradient in women might be an important factor in the observed gender-specific difference.

In our study population, women tended to have less severe MR at baseline, which could lead to the assumption that our observations are not genuinely gender-related. However, functional outcome was equal between patients with MR grade 3 and grade 4. Besides, given the lack of indexed cut-off parameters in MR grading [22], echocardiography might underestimate MR severity in female patients. This could also lead to a delay in diagnosis and treatment in a later stage of the disease.

While female gender was identified as a negative predictor for improvement in 6MWD, NYHA functional class was not significantly different between male and female patients. This is most likely due to the fact that NYHA functional class is a highly subjective and approximate measure of functional status, relying on the physician’s opinion derived from patient’s history [35]. Indeed, clinical research demonstrated that reproducibility of NYHA classification when assessed by two independent physicians is only 56% [36]. The 6MWD, however, is an objective measure of functional performance with good reproducibility in patients with heart failure [37,38]. Hence, in our study, NYHA classification might not have been sensitive enough to detect the gender-specific difference in functional outcome which was observed in the results of the 6MWD. Previous research reported an increase in 6MWD after repeated administration within one day or one week in the absence of any intervention, demonstrating a learning or training effect [39,40]. However, as our study population only performed 6MWD twice and four weeks apart and considering the immobilization during the hospital stay, a significant training effect seems unlikely. Still, it cannot be ruled out when interpreting the results.

Apart from reasons of physical nature, socioeconomic factors and health behavior might also contribute to the observed gender-specific differences. As our study population was treated at a center for transcatheter valve repair, evaluation for MitraClip therapy relied on the referral of symptomatic patients by general practitioners and external cardiologists. It is possible that women underexaggerate their disease or display atypical symptoms, leading to delayed treatment. Concomitantly, experience from mitral valve surgery shows that women are less likely to receive elective therapy, but present more frequently on an urgent basis and with advanced disease [27]. Thus, in the context of our findings, valve repair might be performed at a stage when MR already inflicted irreversible impairment of ventricular and atrial function. On the other hand, it is also thinkable that women are more sensitive in perceiving symptoms of MR such as dyspnea. In previous studies on the clinical care of heart failure, women experienced more symptoms than men [41,42]. This might result in a larger proportion of female patients with clinical less significant MR and worse functional improvement after MitraClip procedure, consecutively. Furthermore, patients’ gender might also influence perception and decision of medical personnel and family members when considering performing an invasive therapy in this elderly patient population.

Impact of diabetes mellitus und arterial hypertension on the outcome of MitraClip implantation

Diabetes mellitus and arterial hypertension are very frequent comorbidities in patients with secondary MR [4]. In this study, both diseases were identified as negative predictors of the functional improvement after MitraClip procedure. Consistent with our results, diabetes mellitus was found to be a determinant of NT-proBNP nonresponse after MitraClip implantation [43]. In a large MitraClip registry study, it was also an independent predictor of 1-year mortality [44]. Diabetes is known to cause diabetic cardiomyopathy, which is characterized by myocardial interstitial fibrosis and extracellular remodeling, leading to LV hypertrophy and reduced LV compliance [45]. Arterial hypertension also classically induces LV hypertrophy with myocardial fibrosis [46,47]. Thus, both diseases contribute to the development of LV diastolic dysfunction with increased myocardial stiffness and elevated LV filling pressures.

Our results might indicate that these hemodynamic changes respond less favorable to a reduction of secondary MR by transcatheter repair. Furthermore, differences in the pathophysiology of MR induced by diastolic dysfunction as opposed to MR caused by severe systolic dysfunction could affect the success of MitraClip therapy. Interestingly, these considerations fit to our observations concerning gender-related differences as described above, as female patients more often had preserved LVEF and less LV dilation. Apart from left atrial volume, whose validity in estimating LV filling pressure is limited in the presence of MR [48], our study did not investigate additional parameters of diastolic function. Thus, this interpretation remains hypothetical and should be investigated in future studies.

Previous randomized controlled studies on the efficacy of transcatheter mitral valve repair in secondary MR only included patients with severe LV systolic dysfunction [9,10]. In contrast, our study and other large registries report that in common practice a significant proportion of patients treated with MitraClip implantation for secondary MR has preserved LVEF [8,30]. This calls for further investigation of the efficacy of transcatheter mitral valve repair in patients with secondary MR and heart failure with preserved ejection fraction.

Limitations

Our study might have some limitations. It presents outcome data of an experienced academic institution and might therefore not be transferable to other MitraClip centers. Participants without four-weeks follow-up and/or a missing 6MWD at baseline were excluded from the analysis. This markedly reduced the study population, thus potentially limiting the statistical power of our analysis. As the reasons for not conducting 6MWD or the follow-up were not reported, attrition bias cannot be ruled out. Hence, our results need to be considered exploratory and should be validated in a greater cohort. Still, our sample size is comparable to other registry studies on the outcome of MitraClip therapy [49,50]. As data on 6MWD at later timepoints was not available, our findings might not be applicable to long-term functional outcome in full extent. However, NYHA class remained stable after twelve months and strongly correlated with short-term 6MWD. Due to the retrospective analysis and lack of a control group, clinical and echocardiographic assessment might have been influenced by observation bias. However, the six-minute walk test is considered to be robust against bias and is widely used in the assessment of patients with cardiopulmonary diseases because of its validity and reliability [19].

Although functional capacity is an important aspect in the treatment of patients suffering from heart failure, we acknowledge that the decision for MitraClip therapy should primarily be based on mortality and morbidity outcomes. Therefore, guidance for patient selection cannot be given solely on the basis of our results. Unlike several previous registry studies on predictors of outcome [16,18,49], we only included patients with MR of secondary origin, given its distinct pathophysiologic difference to primary MR. Nevertheless, the mechanisms causing secondary MR and the underlying heart disease are manifold [12]. Consequently, our study collective remains considerably heterogenous, reflecting the patient population treated with transcatheter mitral valve repair. Hence, the identified predictors might not be applicable to all subgroups of the collective. Further subgroup and sensitivity analysis, which could not be conducted in this study due to the sample size, would be useful to confirm our results. Last, we acknowledge that a complete evaluation of functional outcome after MitraClip therapy should also incorporate information on quality of life, which could not be collected in our study due to its retrospective design.

Conclusions

In this retrospective study, we confirmed that MitraClip therapy of secondary MR in a real-world and high-risk collective improved functional capacity even in the short-term. Female gender was found to be a negative predictor of functional improvement, with women exhibiting preserved LVEF more often, less LV dilatation and higher postprocedural mitral valve pressure gradient. Diabetes mellitus and arterial hypertension, both diseases associated with LV hypertrophy and diastolic dysfunction, were also found to be predictors of less favourable functional outcome. While further validation of the results in a larger cohort is recommended, these parameters may be used to improve patient selection for MitraClip therapy.

Echocardiographic predictors of Δ6MWD four weeks after MitraClip implantation.

(DOCX)

Click here for additional data file.

Correlation between post-procedural mitral valve mean pressure gradient and Δ6MWD.

(DOCX)

Click here for additional data file.

Complete raw data of the study.

(XLSX)

Click here for additional data file.

9 Dec 2019

PONE-D-19-24140

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation

PLOS ONE

Dear Dr. Paulus,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process and quoted below.

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #2: No

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5. Review Comments to the Author

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Reviewer #1: In the present paper from Paulus et al. the authors retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation. Before and four weeks after the procedure, the patients underwent 6MWD and echocardiography. In the general population 6MWD significantly improved. However, female gender, diabetes mellitus and arterial hypertension were found to be predictors of reduced 6MWD improvement. The authors concluded that MitraClip therapy improves functional capacity in high-risk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favorable functional outcome. At least in the reviewers opinition, the following comments have to be addressed:

Major points:

1. The main query relates to the clinical impact of the study and the conclusion of the authors. Selecting the endpoint “improvement in 6-MWT four weeks following PMVR” simply cannot serve as any guidance for patient selection. In the current age, the majority of patients who undergo PMVR do have hypertension, every second patient is female and about every fifth patient suffers from diabetes. Patient selection for PMVR should be performed on the basis of “hard endpoint” trials, thus the clinical benefit of the current trial appears somewhat limited.

2. Trial inclusion went on over a total of nine years. Please indicate the reason for the rather small number of participants. Is there a selection bias compared to the all-comers clip cohort in your center? Even more important, please indicate how outcome in terms of 6MWT 4 weeks following PMVR correspond to NYHA class or survival at later timepoints, which should be available in the majority of participants.

3. Data describing the interaction between post-procedural MVPG and improvement in 6MWT are missing. This could be of prime importance, because the authors stated that diastolic dysfunction (hypertension and diabetes) might be the reason for the observation that men seem to benefit more than women. Gradients created by PMVR will at further resistance to the already impaired diastolic filling. As a matter of fact, in the current trial women tended to have higher post-procedural MVPG than men (p=0.017). In theory, this may explain the less improvement in 6MWT in women. Previous data investigated the impact of post-procedural MVPG and LA pressure and found that a lower MVPG and reduction in LA pressure were predictors of improvement in 6MWT. Therefore, data comparing the post-procedureal MVPG in patients with and without improvement in 6MWT need to be addressed.

Minor points:

4. The authors describe that they “solely included patients with MR of secondary origin, given its distinct pathophysiologic difference to primary MR”. As a matter of fact, even secondary MR comprises of numerous entities (e.g. ischemic versus dilative, thethering of the leaflets, atrial functional MR), who at least in part show distinct survival and distinct response to PMVR by MitraClip. In other words, the small cohort referred to in the manuscript may not be as homogenous at it appears on first glance. This should be clarified.

5. The fact that 6MWT following 4 weeks after MitraClip is higher in men than in women albeit the heart failure symptoms according to NYHA class are identical needs further clarification. Could it be possible that man react different to repetitive 6MWT than women in terms of training effects? Relative increases in repetitive 6MWD in the range of 5% have been shown in the literature.

6. Another important fact is the change of medication, e.g. in diuretic therapy. In many cases, medication is changed after MitraClip implantation with higher doses of diuretics which might also influence functional capacity and 6MWT. Therefore, it would be helpful if the authors provided data on medication prior and after MitraClip implantation.

7. In results section and tables NT-proBNP is presented as median and standard deviation which should be median and percentiles.

8. The authors have to be congratulated for investigating functional outcome following PMVR. However, the manuscript in its current form applies 6MWT, only which is certainly one piece in the puzzle of quality of life only. It would be extremely helpful if the 6MWT data could be underscored by corroborating quality of life questionnaires.

Reviewer #2: General comments:

The authors aimed to elucidate predictors of symptomatic improvement by means of 6 minutes walk distance (6MWD) after MitraClip for the treatment of functional severe MR. Secondary MR is a very common valvular heart disease and associated with poor prognosis in patients with heart failure. While the two recent RCTs (Mitra-FR and COAPT) showed the competing effect of MitraClip on all-cause mortality and HF rehospitalization, however, one of the main goal of this therapy is also to improve functional capacity. The topic could be interesting and the findings are hypothesis generating. However, several aspects should be nonetheless addressed.

My comments are below:

・Statistical analysis) “a multiple linear regression model was calculated to identify independent predictors of improvement in 6MWD after MitraClip implantation. Selection of predictors was based on clinical considerations and exploratory statistical analysis.” Please consider also age and baseline echocardiographic parameters (e.g. LVEDD, severity of MR) as covariates, because these parameters are supposed to be associated with functional capacity.

・Results) The authors determined the history of hypertension, diabetes, and female sex are negative indicators of symptomatic improvement by means of 6MWD. Please consider to perform sensitivity analyses to confirm these results. For example, are the associations of these factors consistent in the subgroup (e.g., age ≤75 or >75, male or female sex etc)？

・Results) Female sex, hypertension, and diabetes mellitus might suggest that HEFPEF or diastolic function could be associated with poor improvement of symptomatic status after MitraClip. Please consider to conduct an additional model including echo parameters, such as LVEF, LAVI, and LVMI, which are indicating HEFPEF and diastolic function.

・Discussion) “Performing MitraClip implantation in secondary MR in a high-risk collective resulted in a high device success rate even in the short-term”. But the authors are not able to mention this, because the authors excluded patients who failed to implant MitraClip and those who did not complete follow-up examinations. Please modify or omit this sentence.

・Limitations) The study included 79 patients who underwent MitraClip and were available for data of 6MWD. The limited sample size and the study population render the results and conclusion dubious. Because the present study was based on the population only who were able to perform FU-6 MWD, so I’m not sure that the indicated clinical predictors are useful to improve patient selection, in our clinical practice. How many consecutive patients were treated with MitraClip in the study period？ And how many patients were excluded due to No technical success or No FU-assessment？

Minor comments:

・ Please define MR grade in the methods section.

・ English proofreading may be required.

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Reviewer #1: No

Reviewer #2: No

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15 Jan 2020

REVIEWER 1

We gratefully appreciate that Reviewer 1 acknowledges our investigation of the functional outcome after MitraClip implantation. We are also very thankful for the valuable comments which we would like to address as follows.

The Reviewer expresses that the trial’s clinical impact and its use for patient selection is limited because it did not investigate hard endpoints.

We clearly agree with the Reviewer’s opinion that patient selection for MitraClip implantation should primarily be based on hard endpoints like mortality. Nevertheless, in our clinical experience, patients who consider undergoing MitraClip expect symptom relief and improvement in their functional status, which is why clinical endpoints are increasingly acknowledged as relevant outcome parameters. Therefore, in our opinion, short-term improvement in functional capacity as expressed by an increase in 6MWT is still an important aspect of the outcome of MitraClip therapy. This is especially true for the collective of patients with secondary mitral regurgitation, whose prognosis is often significantly limited by the severe comorbidities. Yet, we acknowledge that while our study adds new hypothesis-generating aspects, guidance for patient selection cannot be given solely on the basis of our results. In our revised manuscript, this is clarified in the discussion section.

The Reviewer asks for details on the inclusion process and possible selection bias, as he perceives a discrepancy between the number of included patients and the length of the inclusion period.

To more clearly demonstrate the inclusion process of our study, we added a detailed flowchart to the methods section of our revised manuscript which explicitly states the total number of patients who underwent MitraClip therapy at our center during the inclusion period. The most frequent reason for exclusion was MR of primary origin. As in many other MitraClip centres, the quantity of procedures increased over the years, clearly reflecting the growing clinical acceptance of this therapeutic modality. Due to the retrospective nature of our study, we do not have information on the reasons for patients not completing the follow-up examinations. Consequently, attrition bias cannot be ruled out when interpreting our results. Therefore, in the revised manuscript, we added this fact as a limitation in the discussion section.

The Reviewer asks for data on NYHA class and mortality at later timepoints and their correlation with short-term increase in 6MWD.

We agree with the Reviewer that the correlation between improvement in 6MWD and long-term functional class is an important aspect and are thankful for this valuable comment. Therefore, in the revised manuscript, we included data on NYHA functional class twelve months after the procedure which is available for the majority of patients. Additionally, further statistical analysis revealed a moderate correlation between postprocedural 6MWD and NYHA functional class both four weeks and twelve months after the procedure.

Because our study design was dedicated to functional outcome after MitraClip therapy, we did not evaluate mortality endpoints.

The Reviewer requests an analysis of the interaction between post-procedural MVPG and improvement in 6MWD.

We are grateful for this excellent remark. In the revised manuscript, we conducted an additional analysis, revealing a negative correlation between post-procedural MVPG and increase in 6MWD. This indeed may play an important role in the observed gender-specific differences, which is outlined in the discussion section of the revised manuscript.

The Reviewer states that the trial’s cohort, although limited to patients with secondary MR, is heterogenous regarding the pathomechanism of MR.

The Reviewer is right that our study population comprises numerous entities of secondary MR and underlying structural heart disease, reflecting the patient collective treated with MitraClip implantation. In the revised manuscript, this is clarified in the discussion section.

The Reviewer requests further clarification of the aspect that while female gender predicted worse improvement in 6MWD, NYHA functional class is not different between male and female patients. Additionally, the Reviewer asks if assessment of 6MWD in our study might have been subject to a learning effect.

Indeed, while female gender was identified as an independent predictor of less improvement in 6MWD, NYHA class was not significantly different between male and female patients. This is likely explained by the limitations of the NYHA classification: It is subjective and exhibits a rather low reproducibility rate. In contrast, the 6MWT is an objective measure of functional performance with high reproducibility in patients with heart failure. Therefore, we consider the 6MWT to be superior in detecting differences in functional outcome. In the revised manuscript, this is clarified in the discussion section.

The Reviewer is right that 6MWT exhibits a training effect when conducted repeatedly during one day or one week. However, as our study population only performed 6MWT twice and four weeks apart and considering the immobilization during the hospital stay, we consider a significant training to be unlikely. Still, it cannot be completely ruled out when interpreting the results.

The Reviewer requests data on medication before and after MitraClip therapy, as this might also influence functional capacity.

We agree that a change in medication, particularly diuretics intake, might have an impact on functional capacity. Therefore, in the revised manuscript, we included data on medication at baseline and four weeks after the procedure, which did not change significantly. Also, medication four weeks after MitraClip therapy did not differ between men and women.

The reviewer suggests that the data on NTproBNP should be presented as median and percentiles.

We are thankful for this justified remark. In the revised manuscript, NTproBNP is presented as median and percentiles.

The reviewer asks for data of quality of life questionnaires.

We clearly agree with the reviewer that quality of life questionnaires are very important tools for further investigation of functional outcome. As our study was retrospective and quality of life questionnaires were not part of our routine clinical care, we cannot provide these additional data. In our revised manuscript, this aspect was added as a limitation in the discussion section.

REVIEWER 2

We are thankful that the Reviewer finds our manuscript interesting and its findings hypothesis-generating. We also appreciate the useful comments to which we would like to respond as follows:

The Reviewer suggests adding age and baseline echocardiographic parameters such as MR grade as covariates in the linear regression model.

We appreciate this valuable recommendation. In the revised manuscript, age and baseline MR grade were added as covariates in the linear regression model.

The Reviewer recommends performing sensitivity or subgroup analyses.

We acknowledge that conducting sensitivity analysis would be useful to further confirm the validity of the identified predictors. However, this possibility is restricted by the sample size. Performing the regression model on a subgroup (e.g. female patients) would reduce the sample size to such an extent that overfitting of the model occurs, leading to invalid results. We added this aspect in the limitations section of the revised manuscript.

The Reviewer asks for an additional regression model which includes echocardiographic parameters, particularly parameters of diastolic dysfunction.

We are grateful for this recommendation. In the revised manuscript, we conducted an additional regression model which includes several echocardiographic parameters. No independent echocardiographic predictor was identified. As a measure for diastolic dysfunction, left ventricular mass index and left atrial volume index were analyzed. As tissue doppler imaging was not part of our clinical routine follow up, we are not able to provide more specific parameters of diastolic function.

The Reviewer states that our discussion cannot draw conclusions on device success rate as patients who failed to implant MitraClip or did not complete follow-up were omitted from analysis.

We fully agree that our study is not able to draw conclusions on device success due to its study design. Therefore, we omitted this sentence in the revised manuscript.

The Reviewer expresses that the impact of the study is limited by the sample size and asks for further details on the number of excluded patients.

To elucidate the inclusion process, we included a study flow chart to the methods section of the revised manuscript, depicting the number of patients who underwent MitraClip implantation at our center during the inclusion period as well as the number of patients who were excluded from analysis. Exclusion because of failure to implant a clip was rare, occurring only in six patients. Patients without a 6MWT were excluded in the intent of a complete case analysis. As we do not have information on the reasons why patient did not perform 6MWT, we agree that attrition bias cannot be ruled out when interpreting our results. In the revised manuscript, this was added as a limitation in the discussion section.

As mentioned in the discussion section of our manuscript, we agree that the sample size could be seen as a limitation to our study. While its results need to be validated in a larger cohort, our trial may aid to improve patient selection and generate new hypotheses on the mechanisms determining therapeutic response to MitraClip implantation.

The Reviewer asks for definition of MR grade in the methods section.

Corresponding to this comment, we detailed MR grading in the methods section.

Submitted filename: rebuttal_letter.docx

Click here for additional data file.

25 Mar 2020

PONE-D-19-24140R1

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation

PLOS ONE

Dear Dr. Paulus,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please be sure to consider the additional points raised by reviewer#4 and try and add some of the aspects to the next Version of your mansucript.

We would appreciate receiving your revised manuscript by May 09 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

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Reviewer #4: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: The topic is highly relevant and of interest. In the revised manuscript the authors have fully addressed the reviewer's concerns. I have no further comments/ concerns.

Reviewer #4: In this manuscript, Paulus et al. present retrospective data on the improvement of 6MWD 4 weeks after MitraClip procedure in 79 patients with functional mitral regurgitation. They show that 6MWD improves significantly. Their main finding is, however, that female gender is negatively associated with 6MWD improvement. Although functional outcomes are important, we doubt that the difference in improvement of 6MWD is only attributable to female gender. This is due to the many differences between the male and the female group (e.g. LV-EF, LVEDD, LVESD, NYHA class, HFpEF/HFrEF and many more). We think that the main message of the paper could be strengthened by adding of at least some of these parameters to the multivariate regression model.

Gender-related differences in 6MWD improvement have been observed 4 weeks after MitraClip procedure. Do females improve later? Are there any data on 6MWD at later timepoints?

Authors switch between the terms “6MWT” and “6MWD”. Since this is the main outcome, it should be consistent

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #3: No

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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7 Apr 2020

REVIEWER 4

We thank Reviewer 4 for thoroughly reviewing our manuscript and appreciate the valuable comments which we would like to address as follows.

The Reviewer expresses that the observed gender-specific difference in functional outcome might in part be caused by differences in the baseline characteristics between male and female patients. For further clarification, the Reviewer recommends adding baseline parameters with observed gender-specific differences to the regression model.

We are grateful for this excellent remark. In the revised manuscript, we added baseline LVEDD, preserved LVEF and NYHA functional class as variables to the regression model. After correcting for these parameters, female gender remains a significant predictor of 6MWD improvement, confirming our findings. Yet, we fully agree with the Reviewer’s opinion that the reasons for the observed gender-related difference are multifactorial and may in part be explained by differences in baseline characteristics, especially in LV geometry and systolic function. However, given similar findings in the analysis of the GRASP and TRAMI registry, these gender-specific differences in baseline characteristics do not occur exclusively in our patient collective, but appear to be inherent in the population treated with TMVR. In the revised manuscript, these considerations were added to the discussion section.

The Reviewer asks for data on 6MWD improvement at later timepoints.

We agree with the Reviewer that, although short-term 6MWD strongly correlated with long-term NYHA class in our cohort, data on 6MWD at later timepoints could give further insight into determinants of functional outcome. However, as evaluation of long-term 6MWD was not part of our routine follow-up, we do not have sufficient data for valid statistical analysis. In the revised manuscript, this aspect was added as a limitation in the discussion section.

The Reviewer suggests a consistent use of either “6MWD” or “6MWT” as an abbreviation for the six-minute walk distance.

In the previous version of our manuscript, the abbreviation “6MWT” was used when referring to the walk test itself while “6MWD” referred to the result of the walk test. We clearly agree with the reviewer that this might confuse readers. Therefore, in the revised manuscript, we now consistently use the abbreviation “6MWD”.

Submitted filename: response_to_reviewers.docx

Click here for additional data file.

23 Apr 2020

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation

PONE-D-19-24140R2

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29 Apr 2020

PONE-D-19-24140R2

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation

Dear Dr. Paulus:

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