Abstract
Background
Percutaneous mitral valve repair (PMVR) is an interventional treatment option in patients with severe mitral regurgitation (MR) and at high risk for open‐heart surgery. Currently, limited information exists about predictors of procedural success after PMVR. Galectin‐3 (Gal‐3) and suppression of tumorigenicity 2 (ST2) induce fibrotic alterations in severe MR and heart failure. We sought to examine the predictive value of Gal‐3 and ST2 as specific indicators of therapeutic success in high‐risk patients undergoing PMVR.
Hypothesis
We hypothesize that extended cardiac fibrotic alterations might have impact on successful MR reduction after the MitraClip procedure.
Methods
A total of 210 consecutive patients undergoing PMVR using the MitraClip system were included in this study. Procedural success was defined as an immediate reduction of MR by ≥2 grades, assessed by echocardiography. Venous blood samples were collected prior to PMVR and at 6 months follow‐up for biomarker analysis.
Results
After PMVR there was a significant reduction in the severity of MR (MR grade: 3 ±0.3 vs 1.6 ±0.6, P <0.001). Low baseline Gal‐3 levels (PMVRsuccess: 22.0 ng/mL [IQR, 17.3‐30.9] vs PMVRfailure: 30.6 ng/mL [IQR, 24.8‐42.3], P <0.001) and ST2 levels (PMVRsuccess: 900.0 pg/mL [IQR, 619.5‐1114.5] vs PMVRfailure: 1728.0 pg/mL [IQR, 1051.March 1, 1930], P < 0.001) were associated with successful MR reduction after PMVR. Also, ROC analysis identified low baseline Gal‐3 and ST2 levels as predictors of therapeutic success after PMVR (AUCGal‐3:0.721 [IQR, 0.64‐0.803], P < 0.001; AUCST2: 0.807 [IQR, 0.741‐0.872], P < 0.001).
Conclusions
There was an association between low Gal‐3 and ST2 plasma levels and successful MR reduction in patients with severe MR undergoing PMVR using the MitraClip system.
Keywords: Biomarker, Cardiac Fibrosis, Heart Failure, MitraClip, Mitral Regurgitation, Percutaneous Mitral Valve Repair
1. INTRODUCTION
Percutaneous mitral valve repair (PMVR) is an interventional treatment option in patients with severe mitral regurgitation (MR) who are at high risk for open‐heart surgery.1, 2 In this approach, both mitral valve leaflets are attached with ≥1 clips (MitraClip; Abbott Vascular, Santa Clara, CA), resulting in a so‐called double‐orifice mitral valve.1, 2 PMVR is safe and feasible, and an improvement in MR and physical conditions was achieved in several randomized and nonrandomized multicenter trials.1, 2, 3, 4, 5, 6
In recent studies, therapeutic success was defined according to Mitral Valve Academic Research Consortium (MVARC) criteria: (1) absence of procedural mortality or stroke, (2) proper placement and positioning of the device, and (3) freedom from unplanned surgical or interventional procedures related to the device or access procedure. Moreover, Stolfo et al. described important morphological and anatomical aspects that have influenced procedural success or device failure.7 In this study, reduced left ventricular (LV) function, anatomical aspects (such as anteroposterior diameter of the mitral annulus), and LV end‐diastolic volume influenced the technical success of PMVR using the MitraClip System.7, 8 To date, however, there is no evidence of the impact of cardiac fibrotic burden on the success of MR reduction after PMVR using the MitraClip system, although the procedure is known to be technically successful.
MR‐associated volume and pressure overload burdens the LV, which initially leads to LV compensatory adaptation mechanisms.9, 10, 11, 12 These early compensatory changes are gradually replaced by a chronic remodeling process and extracellular matrix turnover.13, 14 Increased cardiac collagen synthesis and impaired degradation in response to pressure and volume overload in patients with MR lead to an imbalance in collagen metabolism and contribute to collagen accumulation and consequently cardiac structural remodeling processes, myocardial stiffness, and fibrosis.15, 16, 17 Galectin‐3 (Gal‐3), a member of the lectin family, and suppression of tumorigenicity 2 (ST2), a member of the interleukin‐1 family, are synthesized and secreted in response to increased cardiac volume and pressure overload and enhanced myocardial wall stress. Gal‐3 and ST2 induce fibrotic alterations and are upregulated in severe MR and LV dysfunction.18, 19, 20 Little is known, however, about the influence of these structural cardiac fibrotic alterations on successful MR reduction after PMVR using the MitraClip system. Therefore, the aim of the present study was to examine the diagnostic and prognostic value of Gal‐3 and ST2 as specific indicators of successful MR reduction in high‐risk patients undergoing PMVR using the MitraClip system.
2. METHODS
2.1. Patients and treatment
Between January 2014 and June 2016, a total of 210 consecutive patients with severe MR who underwent PMVR using the interventional MitraClip system at the Department of Cardiology, University of Giessen, Germany, and at the Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany, were included in this study. The indication for PMVR was assessed by the local heart team. Patients at high risk for open‐heart surgery who were symptomatic despite optimal medical treatment were included in this study. Clinical history, physical examination, and laboratory test results were assessed for all patients at admission. All patients included were on optimal medical treatment as recommend in the current heart failure (HF) guidelines from the European Society of Cardiology (ESC), which included diuretics, ß‐receptor blockers, angiotensin‐converting enzyme inhibitors, and aldosterone receptor antagonists at a maximally tolerated dose if there were no contraindications. The MR grade (1–4) was classified by standardized transesophageal echocardiography prior to the procedure. Procedural success was defined as an immediate reduction of MR by ≥2 grades as assessed by transthoracic echocardiography 48 hours postprocedurally. Primary clinical endpoints were defined as successful MR reduction after 48 hours and changes in biomarker levels (brain natriuretic peptide [BNP], ST2, Gal‐3) at the 6‐month follow‐up. Clinical data were assessed at the 6‐month follow‐up visit, including physiological parameters, New York Heart Association (NYHA) class, medication use, safety events, and all‐cause mortality, to complete the data. Patients with systemic infections, rheumatoid diseases, and malignancies were excluded.
All patients provided written informed consent for their participation in the study, and approval of the Institutional Review Board of the University of Giessen (99/13) was obtained. The investigation conforms to the principles outlined in the Declaration of Helsinki.
2.2. Laboratory assessment
Venous blood samples for determination of the specified biomarkers were collected at baseline prior to the procedure. Samples were processed immediately and frozen at −80°C until assay. ST2 levels were determined using a second‐generation, high‐sensitivity enzyme‐linked immunosorbent assay (ELISA; Critical Diagnostics, San Diego, CA) with a detection limit of 2 ng/mL. Gal‐3 levels were determined using an ELISA from BG Medicine (Waltham, MA). Interassay coefficients of variation were 7.6% for ST2 and 3.5% for Gal‐3. The analysis of the specified protein biomarkers in this study is experimental and not available in an ongoing clinical laboratory setting. Therefore, specially trained technicians performed the biomarker analysis at a core laboratory.
2.3. Statistical analysis
All data for continuous variables are expressed as mean ±SD or as median and interquartile range (IQR), as appropriate. Categorical variables are reported as number and percentage. After testing for normal distribution, values were compared by unpaired Student t test or Mann‐Whitney test, as appropriate. The Fisher exact test or a χ2 test was used for categorical variables with nominal scales. Receiver operating characteristic (ROC) curves were assessed for the determination of the performance of the specified biomarkers. Intergroup comparisons were made using the Mann‐Whitney test, analysis of variance (anova), or correlation and multiple linear regression models. All statistical tests were performed 2‐tailed, and P < 0.05 was considered to indicate statistical significance. For all statistical analyses, the software SPSS, version 20.0 (IBM Corp., Armonk, NY) for Windows was used.
3. RESULTS
A total of 210 consecutive patients (104 males [49.5%]; mean age, 77.4 ±8.1 years) were included in the present study. The MitraClip procedure was performed with a mean number of 1.7 ±0.6 MitraClip devices implanted per patient in a single‐stage procedure. Clinical and procedural characteristics of all patients enrolled in the study are shown in Table 1. Prior to the MitraClip procedure, patients had markedly limited physical activity (NYHA class III), moderately reduced LV ejection fraction (LVEF; 44.3% ±16.8%), and elevated BNP levels (370 ng/L; IQR, 207‐647 ng/L) and were at high risk for open‐heart surgery (EuroSCORE II score: 7.6 ±3.7). Forty‐eight hours after PMVR there was a significant reduction in the severity of MR (grade 3 vs grade 1‐2, P < 0.001; Table 1).
Table 1.
Preprocedural patient characteristics according to success of MR reduction by the MitraClip procedure
| All Patients, N = 210 | Success, n = 164 (78%) | Failure, n = 46 (22%) | P Value | |
|---|---|---|---|---|
| Clinical parameters | ||||
| Mean age, y | 77.4 ± 8.1 | 78.1 ± 4.6 | 76.1 ± 7.5 | 0.69 |
| EuroSCORE II | 7.6 ± 3.7 | 7.6 ± 3.2 | 6.7 ± 3.4 | 0.83 |
| Office BP | ||||
| SBP, mm Hg | 124.1 ± 19.2 | 120.5 ± 14.9 | 126.0 ± 21.6 | 0.75 |
| DBP, mm Hg | 72.3 ± 12.5 | 71.8 ± 12.4 | 71.8 ± 12.3 | 0.15 |
| NYHA class | 3.1 ± 0.7 | |||
| II | 39 (18.5) | 21 (12.8) | 7 (15.2) | 0.8 |
| III | 146 (69.5) | 121 (73.8) | 33 (71.7) | 0.9 |
| IV | 25 (11.9) | 22 (13.4) | 6 (13) | 0.9 |
| eGFR, mL/min/1.73 m2 | 53.5 ± 25 | 54 ± 25.1 | 62 ± 31.2 | 0.216 |
| Cr, mg/dL | 1.5 ± 0.8 | 1.5 ± 0.6 | 1.6 ± 0.9 | 0.165 |
| HF medication | ||||
| ß‐Blockers | 183 (87) | 141 (88.6) | 40.7 (86.6) | 0.47 |
| ACEIs/ARBs | 187 (89) | 141 (86) | 40 (86) | 0.75 |
| Diuretics | 199 (94) | 150 (92) | 42 (93) | 0.21 |
| Aldosterone receptor blockers | 136 (65) | 106 (65) | 28 (59) | 0.75 |
| Echocardiographic parameters at baseline | ||||
| MR grade | 3 | 3 | 3 | 1 |
| Vena contracta | 6.7 ± 2.4 | 6.7 ± 1.1 | 6.4 (± 1.2) | 0.9 |
| MR type | ||||
| Functional | 142 (67.6) | 95 (57.9) | 29 (63) | 0.64 |
| Degenerative | 40 (19.0) | 32 (19.5) | 8 (17.4) | 0.43 |
| Combined | 28 (11.9) | 19 (11.6) | 9 (19.6) | 0.09 |
| LVEF, % | 44.3 ± 16.8 | 46.1 ± 14.3 | 44.8 ± 9.6 | 0.29 |
| E/E′ | 21.2 ± 6.1 | 21.9 ± 11.1 | 20.7 ± 10.9 | 0.84 |
| sPAP, mm Hg | 42.4 ± 22.6 | 41.7 ± 19.3 | 43.8 ± 24.3 | 0.81 |
| LA, mm | 48 ± 15.5 | 49.7 ± 6.6 | 48.8 ± 7.8 | 0.56 |
| LVEDD, mm | 56.9 ± 16.5 | 55.5 ± 22.6 | 58.8 ± 20.5 | 0.38 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EuroSCORE, European System for Cardiac Operative Risk Evaluation; HF, heart failure; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; NYHA, New York Heart Association; SBP, systolic blood pressure; SD, SD; sPAP, systolic pulmonary artery pressure.
Data are presented as n (%) or mean ± SD.
Procedural success, defined as an immediate reduction of MR by ≥2 grades, was documented in 78% (n = 164/210) of the patients included (Table 1). There were no differences in the baseline characteristics between patients with successful MR reduction (n = 164) and patients with unsuccessful MR reduction (n = 46) after PMVR in terms of age (PMVRsuccess: 78.1 ±4.6 years vs PMVRfailure: 76.1 ±7.5 years, P = 0.69), LVEF (PMVRsuccess: 46.1% ±14.3% vs PMVRfailure: 44.8% ±9.6%, P = 0.29), or renal function (estimated glomerular filtration rate; PMVRsuccess: 54 ±25.1 mL/min/1.73 m2 vs PMVRfailure: 62 ±31.2 mL/min/1.73 m2, P = 0.216; Table 1).
Patients in whom PMVR resulted in successful reduction of the severity of MR had significantly lower baseline BNP serum levels than did patients with unsuccessful MR reduction immediately after PMVR (PMVRsuccess: 274.5 ng/L [IQR, 160.8‐578.7] vs PMVRfailure: 785 ng/L [IQR, 286.5‐1617.3], P = 0.002; Table 2, Figure 1). In addition, in patients with successful MR reduction, baseline serum levels of ST2 (PMVRsuccess: 894 ng/mL [IQR, 457‐1080] vs PMVRfailure: 1182 ng/mL [IQR, 1029‐1569], P = 0.001) and Gal‐3 (PMVRsuccess: 20.7 ng/mL [IQR, 16.4‐29.8] vs PMVRfailure: 31.3 ng/mL [IQR, 26.3‐43.9], P = 0.001) were also significantly lower than in patients with therapy failure (Table 2, Figure 1). ROC analysis was performed to assess the value of low baseline serum levels of BNP, ST2, and Gal‐3 as predictors of procedural success after PMVR using the MitraClip system. The areas under the curve (AUCs) for BNP, ST2, and Gal‐3 were 0.703 (IQR, 0.601‐0.804), 0.837 (IQR, 0.779‐0.894), and 0.743 (IQR, 0.667‐0.819), respectively; all P = 0.001 (Figure 2).
Table 2.
Biomarker values
| Biomarker Analysis | Success, n = 164 (78%) | Failure, n = 46 (22%) | P Value |
|---|---|---|---|
| BNP, ng/L | 274.5 (160.8–578.7) | 785 (286.5–1617.3) | 0.002 |
| ST2, pg/mL | 894 (457‐1080) | 1182 (1029‐1569) | 0.001 |
| Gal‐3, ng/mL | 20.7 (16.4–29.8) | 31.3 (26.3‐43.9) | 0.001 |
Abbreviations: BNP, brain natriuretic peptide; Gal‐3, galectin‐3; IQR, interquartile range; ST2, suppression of tumorigenicity 2.
Data are presented as median (IQR).
Figure 1.
Comparison of biomarker levels in patients with successful vs failed MR reduction. Median and IQR for (A) BNP, (B) ST2, and (C) Gal‐3 measured in serum at baseline for the group of patients with successful PMVR (n = 164) and the group with failed PMVR (n = 46). Abbreviations: BNP, brain natriuretic peptide; IQR, interquartile range; MR, mitral regurgitation; PVMR, percutaneous mitral valve repair; ST2, suppression of tumorigenicity 2
Figure 2.
ROC curves for biomarkers as predictors of successful MR reduction after PMVR. Curves and calculated AUC values for (A) BNP and (B) ST2 and Gal‐3. Abbreviations: AUC, area under the curve; BNP, brain natriuretic peptide; Gal‐3, galectin‐3; MR, mitral regurgitation; PVMR, percutaneous mitral valve repair; ROC, receiver operating characteristic; ST2, suppression of tumorigenicity 2
Six months after PMVR, the improvement in NYHA class (III vs I‐II; P = 0.001) and MR (baseline: 3.1 vs 1.6; P = 0.001) persisted and a tendency for improvement of the renal function (creatinine baseline: 1.5 ±0.7 mg/dL vs 6 months: 1.3 ±0.6 mg/dL, P = 0.006; and estimated glomerular filtration rate baseline: 50.3 ±19.8 mL/min/1.73 m2 vs 6 months: 55.3 ±217.6 mL/min/1.73 m2, P = 0.01) was observed (Table 3). At the 6‐month follow‐up, there were no significant changes in LVEF (baseline: 41.6% ±16.2% vs 6 months: 40.1% ±16.2%) or left ventricular end‐diastolic diameter (baseline: 53.9 ±10.5 mm vs 6 months: 54.4 ±8.2 mm) observed in the present study. The analysis of the levels of BNP (baseline: 497 ±83.6 ng/L vs 6 months: 420.6 ±78.7 ng/L, P = 0.21), ST2 (baseline: 900 ng/mL [IQR, 598‐1087] vs 6 months: 1005 ng/mL [IQR, 832‐1296], P = 0.08), and Gal‐3 (baseline: 24.2 ng/mL [IQR, 18.6‐32.2] vs 6 months: 23.8 ng/mL [IQR, 20.3‐31.6], P = 0.09) specifically indicating cardiac fibrotic alterations were not different at the 6‐month follow‐up compared with baseline values (Table 3).
Table 3.
Clinical parameters and biomarker values at baseline and 6‐month follow‐up
| Baseline | 6‐mo Follow‐up | P Value | |
|---|---|---|---|
| Clinical visit, n = 54 | |||
| NYHA class | 3.2 ±0.7 | 1.94 ±0.4 | 0.001 |
| BNP, ng/L, mean ±SEM | 497 ±83.6 | 420.6 ±78.7 | 0.21 |
| Cr, mg/dL | 1.5 ±0.7 | 1.3 ±0.6 | 0.006 |
| eGFR, mL/min/1.73 m2 | 50.3 ±19.8 | 55.3 ±217.6 | 0.01 |
| Echocardiographic parameters, n = 54 | |||
| LVEF, % | 41.6 ± 16.2 | 40.1 ±16.2 | 0.392 |
| LVEDD, mm | 53.9 ±10.5 | 54.4 ±8.2 | 0.691 |
| MR grade | 3.1 | 1.8 | 0.001 |
| MV mean gradient | — | 3.7 ± 1.6 | — |
| Biomarker analysis, n = 54 | |||
| BNP, ng/L, mean ± SEM | 497 ±83.6 | 420.6 ±78.7 | 0.21 |
| ST2, ng/mL | 900 (598–1087) | 1005 (832‐1296) | 0.08 |
| Gal‐3, ng/mL | 24.2 (18.6–32.2) | 23.8 (20.3–31.6) | 0.091 |
Abbreviations: BNP, brain natriuretic peptide; Cr, creatinine; eGFR, estimated glomerular filtration rate; Gal‐3, galectin‐3; IQR, interquartile range; LVEDD, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; MI, NYHA, New York Heart Association; SD, SD; SEM, SE of the mean; ST2, suppression of tumorigenicity 2.
Data are presented as mean ±SD or median (IQR) unless otherwise noted.
4. DISCUSSION
The present study identifies for the first time specific biomarkers of cardiac fibrotic alterations as predictors of successful MR reduction after PMVR using the MitraClip system. The biomarkers ST2 and Gal‐3 are key mediators in cardiac hypertrophy, myofibroblast proliferation, and fibrogenesis, processes that are pivotal to the maladaptive LV remodeling following the initial derangement that aggravates HF in severe MR.21, 22, 23, 24, 25, 26, 27 Importantly, Gal‐3 and ST2 levels represent the ongoing chronic pathophysiological process, and, therefore, the levels of these biomarkers are not affected by the current HF or volume status.28, 29
In some patients, PMVR results in insufficient MR reduction, even when the procedure was technically successful. In this respect, the capacity of the LV to change its shape after PMVR with subsequent improvement in functional MR is related to various factors, including the myocardial substrate and fibrosis.12, 20, 21 Accordingly, elevated plasma concentrations of Gal‐3 and ST2 were indicative of advanced myocardial fibrotic alterations that may influence the acute therapeutic success in high‐risk patients with severe MR undergoing PMVR using the MitraClip system.12, 20, 21 Moreover, the predictive values of ST2 and Gal‐3, reflecting cardiac fibrotic processes, were greater than the predictive value of BNP, the most investigated biomarker in HF. There are several reports on changes in BNP (or N‐terminal pro brain natriuretic peptide) values during or after medical treatment (such as angiotensin receptor blockers or ß‐blockers) and in association with the volume status in HF.10 Patients who were scheduled for the MitraClip procedure and who were included in the present study were on optimal medical treatment as recommend in the current HF guidelines from the ESC, which included diuretics, ß‐receptor blockers, angiotensin‐converting enzyme inhibitors, and aldosterone receptor antagonists at the maximally tolerated dose (if there were no contraindications).10 Thus, the patients' volume status was optimized before the procedure, which might have impacted the predictive value of baseline BNP levels. In particular, the stability of Gal‐3 and ST2 is consistent, also with respect to differences in loading conditions, and is less affected by volume status17, 23, 24, 29; the fact that the predictive value of the fibrotic biomarkers ST2 and Gal‐3 was also more pronounced than BNP under these conditions confirms the diagnostic sensitivity of the fibrotic biomarkers examined in this study. In a recent trial, the predictive value of Gal‐3 and ST2 for MR reduction after cardiac resynchronization therapy implantation in HF patients were analyzed.30 In the study of Beaudoin et al., elevated Gal‐3 levels, indicating adverse cardiac remodeling, were associated with a lack of response to cardiac resynchronization therapy‐related MR reduction, confirming the assumption that increased myocardial substrate and fibrosis at the cellular/molecular level may predict MR reduction after device therapy.30 However, further validation in randomized trials that build on the results of the present study might make the procedure more reliable, and specific biomarker assessment might help to identify those patients who will benefit the most from PMVR using the MitraClip system.
4.1. Study limitations
Several limitations should be mentioned. The present study was not randomized and did not have a control group, which can be considered a major limitation. The results of the study were based on a pretreatment biomarker analysis and are therefore exploratory in nature. The present study included patients with degenerative MR as well as functional MR and did not discriminate between different underlying pathophysiology and further anatomical characteristics; this should also be considered a limitation of the study.
5. CONCLUSION
This is the first study to investigate the use of specific biomarkers of cardiac fibrotic alterations for an immediate assessment of the success of MR reduction after the MitraClip procedure. There was an association between low Gal‐3 and ST2 plasma levels and successful MR reduction in patients with severe MR undergoing PMVR using the MitraClip system. Therefore, these specific biomarkers of cardiac fibrotic alterations may be useful.
Conflict of interest
The authors declare no potential conflicts of interest.
ACKNOWLEDGMENTS
The authors thank Elizabeth Martinson, PhD, for editorial assistance.
Dörr O, Walther C, Liebetrau C, et al. Galectin‐3 and ST2 as predictors of therapeutic success in high‐risk patients undergoing percutaneous mitral valve repair (MitraClip). Clin Cardiol. 2018;41:1164–1169. 10.1002/clc.22996
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