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Right ventricular function and residual mitral regurgitation after left ventricular assist device implantation determines the incidence of right heart failure

Open ArchivePublished:April 04, 2019DOI:https://doi.org/10.1016/j.jtcvs.2019.03.089

      Abstract

      Background

      The effect of significant mitral regurgitation (MR) on outcomes after continuous flow left ventricular assist device (cfLVAD) implantation remains unclear.

      Methods

      We performed a retrospective review of prospectively collected data from 159 patients with preoperative severe MR who underwent cfLVAD implantation (2003-2017). Two-step cluster analysis using the log-likelihood distance for post-cfLVAD implantation parameters, which included right ventricular (RV) dysfunction, MR severity, and tricuspid regurgitation (TR) severity. Post-cfLVAD implantation echocardiographic parameters were obtained within the first month.

      Results

      Cluster analysis resulted in 3 groups. Group 1 (n = 67) had mild or less MR with moderate-severe RV dysfunction (RVD). Group 2 (n = 43) had moderate-severe MR with moderate-severe RVD. Group 3 (n = 49) had moderate MR with mild RVD. Group 2 had the largest proportion with Interagency Registry for Mechanically Assisted Circulatory Support score of 1 (30.2%) and 2 (41.9%). They were more likely to undergo temporary mechanical circulatory support (18.6%) and tricuspid valve procedure (62.8%). Group 2 had the highest rate of stroke (30.2%; P = .02), hemolysis (39.5%; P = .01), device thrombosis (30%; P = .01), and worst survival (46.5%; P = .01). Survival at 5 years for groups 1, 2, and 3 were 56.0%, 17.6%, and 55.8%. Regression analysis of the entire population showed that greater MR severity after cfLVAD was associated with RV failure (P < .05; odds ratio, 1.6) and RV assist device use (P = .09; odds ratio, 1.6). After excluding tricuspid valve repairs, MR severity had a positive correlation with TR severity (R = 0.33; P < .01).

      Conclusions

      After cfLVAD implantation, moderate-severe MR and RVD predicted RV failure. Patients with preoperative moderate-severe MR and TR coupled with moderate-severe RVD might benefit the most from mitral and tricuspid valve intervention.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      cfLVAD (continuous flow left ventricular assist device), LV (left ventricle), LVAD (left ventricular assist device), MCS (mechanical circulatory support), MR (mitral regurgitation), MV (mitral valve), OR (odds ratio), RV (right ventricular), RVAD (right ventricular assist device), RVD (right ventricular dysfunction), RVF (right ventricular failure), TR (tricuspid regurgitation), TV (tricuspid valve)
      Figure thumbnail fx2
      Cluster groups of post-LVAD implantation echocardiographic findings determine right ventricular failure.
      After LVAD implantation, significant mitral regurgitation accompanied by poor RV function is associated with worse outcomes. Concurrent surgery to improve competency warrants further investigation.
      A proportion of patients with preoperative severe mitral regurgitation (MR) have significant residual MR after left ventricular assist device implantation. Patients with postoperative moderate-severe MR accompanied by poor underlying right heart function tend to have a higher incidence of right ventricular failure, stroke, hemolysis, and pump thrombosis as well as poorer survival.
      See Commentaries on pages 906 and 908.
      The effect of persistent mitral regurgitation (MR) on outcomes after continuous flow left ventricular assist device (cfLVAD) implantation remains unclear. It has been generally assumed that preoperative MR resolves with unloading of the left ventricle (LV) during left ventricular assist device (LVAD) support because of favorable LV remodeling.
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      Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation.
      Therefore, concomitant mitral valve (MV) procedures are often not performed despite the presence of significant preoperative MR.
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      • et al.
      Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation.
      Morgan and colleagues previously reported that LVAD implantation decreased MR severity from moderate-severe in 76% of patients preimplantation, to 8% at 6 months postoperatively, suggesting that a significant proportion, but not all significant MR resolves with unloading of the LV during LVAD support.
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      • et al.
      Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation.
      Previous studies have shown that persistent significant MR after LVAD implantation leads to higher pulmonary vascular resistance and contributes to poor postoperative right ventricular (RV) function, persistent pulmonary hypertension, increased readmissions, subsequent heart failure, and worse survival.
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      Mitral valve repair at the time of continuous-flow left ventricular assist device implantation confers meaningful decrement in pulmonary vascular resistance.
      Several studies have suggested that preoperative severe MR does not affect postoperative clinical outcomes or survival after LVAD implantation, but many of the studies lack specific examination of patients with persistent severe MR after LVAD implantation.
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      Mitral valve repair at the time of continuous-flow left ventricular assist device implantation confers meaningful decrement in pulmonary vascular resistance.
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      Uncorrected pre-operative mitral valve regurgitation is not associated with adverse outcomes after continuous-flow left ventricular assist device implantation.
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      • et al.
      Pre-operative echocardiographic features associated with persistent mitral regurgitation after left ventricular assist device implantation.
      At present, there is no consensus indication for repair of moderate-severe MR at the time of LVAD implantation because of the lack of consistent data showing an adverse effect of persistent severe MR on clinical outcomes.
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      • et al.
      The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: executive summary.
      In this study we identified patients with severe preoperative MR who underwent LVAD implantation and stratified their postoperative outcomes according to varying degrees of severity of postoperative, persistent MR. We hypothesized that persistent significant MR after cfLVAD implantation is associated with worse clinical outcomes and is associated with a higher incidence of RV failure (RVF) dependent on the pattern of residual valvular pathology and RV function. We used a cluster analysis in an exploratory manner to define patterns of valvular pathology after cfLVAD implantation in those with preoperative severe MR.

      Methods

      Patients

      This study was approved by the University of Michigan institutional review board (IRB; number HUM00135533). A waiver of informed consent was approved by the University of Michigan IRB. We conducted a retrospective review of prospectively collected data (Figure 1) from the 490 total patients who underwent cfLVAD implantation at the University of Michigan Circulatory Support Registry (IRB number HUM00020274) from January 1, 2003 to June 1, 2017. From this population, we identified 159 consecutive patients with preoperative severe MR confirmed via echocardiogram who underwent implantation of a durable cfLVAD with or without an RV assist device (RVAD). As indicated in the graphical abstract, groupings analyzed in this study are on the basis of the postoperative echocardiographic findings in this population with preoperative severe MR.
      Figure thumbnail gr1
      Figure 1Consort diagram of patient population and summary of pre- and post-cfLVAD implantation echocardiographic data. Groups were clustered according to severity of RVD, MR, and TR as shown in postoperative echocardiography. Group 1 (n = 67) had mild or less MR with moderate-severe RVD and mild or less TR. Group 2 (n = 43) had moderate-severe MR with moderate-severe RVD and mild-moderate TR. Group 3 (n = 49) had moderate MR with mild RVD and mild TR. Group 2 has the worst post-cfLVAD implantation MR, TR, and RV function, which increases the risk of RVF. Risk of RVF is lower if MR severity is low (group 1) or RVD is mild or absent postoperatively (group 3). LVAD, Left ventricular assist device; MR, mitral regurgitation; cfLVAD, continuous flow left ventricular assist device; RVD, right ventricular dysfunction; TR, tricuspid regurgitation.
      The primary end point of interest in the study was the proportion of patients with RVF defined as a central venous pressure >18 mm Hg with a cardiac index <2.0 L/min/m2 in the absence of tamponade, ventricular arrhythmias, or pneumothorax requiring RVAD or inhaled pulmonary vasodilator (eg, nitric oxide) or inotropic therapy for >1 week at any time after LVAD implantation.
      • Topilsky Y.
      • Oh J.K.
      • Shah D.K.
      • Boilson B.A.
      • Schirger J.A.
      • Kushwaha S.S.
      • et al.
      Echocardiographic predictors of adverse outcomes after continuous left ventricular assist device implantation.
      Only postoperative RVF occurring during the index hospitalization after cfLVAD implantation was considered in the primary end point. The decision for using an RVAD was determined by the need for high-dose inotropes and vasopressors for hemodynamic support and/or when maximal pharmacological circulatory support was reached without maintaining adequate hemodynamics for peripheral perfusion as a result of RVF.

      Follow-up

      Echocardiographic follow-up after cfLVAD implantation was obtained within the first month of cfLVAD implantation (mean of 11.7 ± 11.2 days). Right-sided heart pressures with a pulmonary artery catheter were obtained for all patients. Preoperative pulmonary artery pressures were obtained intraoperatively before sternotomy and postoperative pulmonary pressures were obtained after weaning off cardiopulmonary bypass. Survival data were available for all 159 patients in this study. These were obtained through detailed clinical follow-up. Censoring was performed at the time of heart transplantation, or device explant (without replacement) for myocardial recovery. The longest follow-up was 9.8 years with a total follow-up of 316.4 patient-years. Median follow-up was 1.27 (range, 0.42-2.96) years with a mean follow-up of 2.0 ± 2.0 years. RV dysfunction (RVD) was graded as follows: 0 = normal, 1 = mild, 2 = moderate, 3 = severe RVD. Tricuspid regurgitation (TR), MR, and aortic valve insufficiency was graded as: 0 = none, 1 = trace, 2 = mild, 3 = moderate, and 4 = severe. The primary end point was postoperative RVF. Secondary end points included operative mortality, readmissions, stroke, and survival to heart transplantation.

      Statistical Methods

      Categorical variables were analyzed with Pearson χ2 test or Fisher exact test. Independent Student t test was used to compare continuous variables. Analysis of variance with post hoc Tukey testing or Kruskal-Wallis method with post hoc Dunn-Bonferroni testing was performed for comparison of continuous variables across multiple groups. Logistic regression was performed to determine the relationship between RVF and RVAD use with TR, and MR severity as well as degree of RVD. Kaplan-Meier survival analysis using Mantel-Cox statistics was used to examine time to first stroke, first hemolysis event, first pump thrombosis, and patient survival. Survival was censored at the time of heart transplantation or device inactivation (device remaining in place) or explant (without replacement) for myocardial recovery.
      A 2-step cluster analysis was performed using the log-likelihood distance for post-cfLVAD implantation echocardiographic parameters of RV function, severity of MR, and severity of TR using the Balanced Iterative Reducing and Clustering Using Hierarchies algorithm.
      • Zhang T.
      • Ramakrishnan R.
      • Livny M.
      BIRCH: an efficient data clustering method for very large databases.
      Small subclusters were formulated from the cases by building a modified cluster feature tree to groups of similar cases together in nodes on the basis of threshold distance determined according to mean and variance. For each successive record, starting from the root node, it is recursively guided by the closest entry in the node to find the closest child node, and descends along the clustering feature tree. The second step was then further aggregated from the previously determined subclusters using Bayesian hierarchical clustering. Clusters are recursively merged by defining a starting cluster for each of the subclusters produced in the precluster step. Pairs of clusters with the smallest distance between are then combined. The final optimal number of clusters was then determined by comparing the minimum intercluster distance among the hierarchically defined cluster possibilities and accept the one with the widest separation.
      • Kent P.
      • Jensen R.K.
      • Kongsted A.
      A comparison of three clustering methods for finding subgroups in MRI, SMS or clinical data: SPSS TwoStep Cluster analysis, Latent Gold and SNOB.
      • Dunson D.B.
      • Chen Z.
      • Harry J.
      A Bayesian approach for joint modeling of cluster size and subunit-specific outcomes.

      Chiu T, Fang D, Chen J, Wang Y, Jeris C. A robust and scalable clustering algorithm for mixed type attributes in large database environment. Presented at: Seventh ACM SIGKDD International Conference on Knowledge Discovery and Data Mining; August 26-29, 2001; San Francisco, Calif.

      • Fraley C.
      • Raftery A.E.
      How many Clusters? Which clustering method? Answers via model-based cluster analysis.
      Time to readmission was modeled using the Anderson-Gill recurrent events analysis with a different baseline hazard for each admission. A Cox proportional hazards model was fit to estimate the pairwise hazard ratios. Death is treated as independent censoring. All statistics were performed using Statistical Package for the Social Sciences version 24 software (IBM Corp, Armonk, NY).

      Results

      Study Population Characteristics

      Most of the patients were male (72.3%) with a mean age of 53.31 ± 13.99 years. The HVAD (Medtronic Inc, Minneapolis, Minn) was used in 49 patients (30.8%), the HeartMate II (Abbott Laboratories, Chicago, Ill) in 100 (62.9%), the HeartMate 3 (Abbott Laboratories) in 6 (3.8%), DuraHeart I (Terumo Inc, Tokyo, Japan) in 3 (1.9%), and DeBakey (Reliant Inc, Houston, Tex) in 1 patient (0.6%). Post cfLVAD implantation, severe RVD was observed in 30.2%, severe MR in 10.7%, and severe TR in 1.3% of the study cohort.

      Statistical Categorization of Postoperative Echocardiographic Parameters Using Unsupervised Clustering

      Figure thumbnail fx3
      Video 1This video provides an overview of the postoperative echocardiographic categories determined using cluster analysis. It also examines the association with clinical outcomes and implications of the findings for LVAD management strategies. Video available at: https://www.jtcvs.org/article/S0022-5223(19)30774-3/fulltext.
      Table 1Postoperative cohorts after LVAD implantation segregated on the basis of echocardiography using an unsupervised cluster analyses
      Post LVAD cluster1 (n = 67)2 (n = 43)3 (n = 49)P value
      RV dysfunction
       None0 (0.0)0 (0.0)25 (51.0)<.01
       Mild3 (4.5)0 (0.0)24 (49.0)<.01
       Moderate36 (53.7)23 (53.5)0 (0.0)<.01
       Severe28 (41.8)20 (46.)0 (0.0)<.01
      MR grade
       None13 (19.4)0 (0.0)4 (8.2).01
       Trace29 (43.3)0 (0.0)14 (28.6)<.01
       Mild25 (37.3)3 (7)11 (22.4)<.01
       Moderate0 (0)26 (60.5)17 (34.7)<.01
       Severe0 (0)14 (32.6)3 (6.1)<.01
      TR grade
       None14 (20.9)10 (23.3)3 (6.1).05
       Trace23 (34.3)9 (20.9)22 (44.9).05
       Mild27 (40.3)13 (30.2)18 (36.7).57
       Moderate2 (3.0)10 (23.3)6 (12.2).01
       Severe1 (1.5)1 (2.3)0 (0.0).59
      All nominal data expressed as presented as n and percentage of total population and compared with Pearson χ2 or Fisher exact test. LVAD, Left ventricular assist device; RV, right ventricular; MR, mitral regurgitation; TR, tricuspid regurgitation.
      Table 2Preoperative echocardiography findings
      Pre LVAD echocardiography1 (n = 67)2 (n = 43)3 (n = 49)P value
      RV dysfunction
       None12 (17.9)8 (18.6)8 (16.3).96
       Mild13 (19.4)6 (14.0)15 (30.6).13
       Moderate32 (47.8)18 (41.9)20 (40.8).72
       Severe10 (14.9)11 (25.6)11 (25.6).20
      MR grade
       None0 (0.0)0 (0.0)0 (0.0)1.00
       Trace0 (0.0)0 (0.0)0 (0.0)1.00
       Mild0 (0.0)0 (0.0)0 (0.0)1.00
       Moderate0 (0.0)0 (0.0)0 (0.0)1.00
       Severe67 (100.0)43 (100.0)49 (100.0)1.00
      TR grade
       None6 (9.0)1 (2.3)3 (6.1).38
       Trace1 (1.5)0 (0.0)3 (6.1).14
       Mild24 (35.8)9 (20.9)14 (28.6).25
       Moderate20 (29.9)16 (37.2)17 (34.7).71
       Severe16 (23.9)17 (39.5)12 (24.5).16
      Data are presented as n (%) except where otherwise noted. LVAD, Left ventricular assist device; RV, right ventricular; MR, mitral regurgitation; TR, tricuspid regurgitation.
      Table 3Demographic characteristics, comorbidities and surgical indication of the study cohort
      Cluster1 (n = 67)2 (n = 43)3 (n = 49)P value
      Age, y54.09 ± 13.0448.63 ± 15.1056.35 ± 13.45.03
      Male sex47 (70.1%)28 (65.1%)40 (81.6%).18
      Height, cm173.31 ± 10.17172.69 ± 12.12174.96 ± 11.37.59
      Weight, kg80.57 ± 25.4781.70 ± 23.2988.27 ± 23.19.04
      Body mass index26.48 ± 6.0928.96 ± 12.8828.73 ± 6.87.24
      Hypertension31 (46.3%)10 (23.3%)20 (40.8%)<.05
      Diabetes18 (26.9%)9 (20.9%)17 (34.7%).33
      Stroke or transient ischemic attack3 (4.5%)3 (7.0%)8 (16.3%).08
      Carotid disease3 (4.5%)3 (7.0%)4 (8.2%).71
      Hyperlipidemia34 (50.7%)13 (30.2%)34 (69.4%)<.01
      Atrial fibrillation9 (13.4%)8 (18.6%)8 (16.3%).76
      Dialysis0 (0.0%)0 (0.0%)0 (0.0%)1.00
      Implantable cardioverter defibrillator56 (83.6%)40 (93.0%)40 (81.6%).25
      Cardiac resynchronization therapy33 (51.6%)25 (61.0%)23 (59.0%).59
      INTERMACS scale
       110 (14.9%)13 (30.2%)3 (6.1%).01
       222 (32.8%)18 (41.9%)14 (28.6%).39
       329 (43.3%)11 (25.6%)25 (51.0%).04
       46 (9.0%)1 (2.3%)7 (14.3%).13
      Bridge to transplantation47 (70.1%)30 (69.8%)34 (69.4%)1.00
      Destination20 (29.9%)13 (30.2%)15 (30.6%)1.00
      All nominal data expressed as presented as n and percentage of total population and compared with Pearson χ2 or Fisher exact test. Continuous data expressed as mean ± standard deviation with comparisons calculated with one-way analysis of variance. INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support.

      Association of Cluster Grouping and Pre-cfLVAD Acuity

      Group 2 had the greatest acuity of illness (Table 3) with the largest percentage of patients presenting with Interagency Registry for Mechanically Assisted Circulatory Support score 1 (30.2%) and 2 (41.9%). Group 2 (Table 4) was also more likely to require preoperative temporary mechanical circulatory support (MCS; 18.6%) and undergo a tricuspid valve (TV) procedure concomitant with LVAD implantation (62.8%). Group 1 had the lowest proportion of patients with persistent MR after cfLVAD implantation and had the highest incidence of preoperative intra-aortic balloon pump (55.2%) use, but a low utilization of other forms of temporary MCS (3%). Group 1 had the lowest cardiac index (P = .02) preoperatively with the highest systemic vascular resistance (P < .01; Table 5). In contrast, group 2 had hemodynamic indicators consistent with the worst preoperative RV function including the highest central venous pressure (P = .01), central venous pressure/pulmonary capillary wedge pressure ratio (P = .01), total bilirubin (P < .01), and lowest RV stroke work index (P < .01; Table 5).
      Table 4Preoperative mechanical support, and operative parameters of the study cohort
      Cluster1 (n = 67)2 (n = 43)3 (n = 49)P value
      Temporary MCS2 (3.0%)8 (18.6%)1 (2.0%)<.01
      Mean temporary MCS duration, d5.50 ± 4.955.13 ± 2.705.00.96
      Intra-aortic balloon pump37 (55.2%)21 (48.8%)22 (44.9%)<.01
      Mean intra-aortic balloon pump duration, d2.41 ± 2.602.38 ± 2.841.86 ± 2.03.36
      Delayed sternal closure23 (34.3%)23 (53.5%)23 (46.9%).12
      Mean chest open days1.48 ± 0.791.22 ± 0.601.48 ± 0.79.30
      Redo sternotomy13 (19.4%)6 (14.0%)11 (22.4%).58
      Centrifugal pump31 (46.3%)17 (39.5%)10 (20.4%).02
      Axial pump36 (53.7%)26 (60.5%)39 (79.6%).02
      Cardiopulmonary bypass, minutes80.40 ± 29.3796.93 ± 36.5184.59 ± 32.89.03
      Concomitant surgery
       Valve procedure35 (52.2%)28 (65.1%)21 (42.9%).10
       Aortic valve procedure3 (4.5%)2 (4.7%)4 (8.2%).66
       TV procedure33 (49.3%)27 (62.8%)18 (36.7%)<.05
       MV procedure0 (0.0%)1 (2.3%)0 (0.0%).26
      All nominal data are presented as n and percentage of total population and compared with Pearson χ2 or Fisher exact test. Continuous data are expressed as mean ± standard deviation with comparisons calculated with 1-way analysis of variance. Kruskal-Wallis testing was used to analyze temporary MCS duration and intra-aortic balloon pump duration only for patients who underwent the corresponding support. MCS, Mechanical circulatory support; TV, tricuspid valve; MV, mitral valve.
      Table 5Preoperative hemodynamics of the study cohort
      Cluster1 (n = 67)2 (n = 43)3 (n = 49)P value
      Cardiac output, L/min4.01 ± 1.134.51 ± 1.224.71 ± 1.19.01
      Cardiac index, L/min/m22.07 ± 0.472.27 ± 0.542.35 ± 0.60.02
      PCWP, mm Hg20.30 ± 7.5121.12 ± 4.7920.46 ± 6.93.82
      Pulmonary vascular resistance, wood units3.18 ± 1.712.91 ± 1.472.74 ± 1.50.32
      Transpulmonary gradient, mm Hg11.73 ± 4.9512.16 ± 5.2112.00 ± 4.93.33
      Systemic vascular resistance, dynes/s/cm51430.56 ± 398.451217.32 ± 483.131179.68 ± 391.18<.01
      CVP, mm Hg8.30 ± 4.1711.21 ± 4.618.63 ± 5.36.01
      RVSWI, g/m/m2/beat547.72 ± 216.61524.69 ± 286.91686.44 ± 279.42<.01
      CVP/PCWP ratio0.44 ± 0.220.55 ± 0.240.42 ± 0.22.01
      Mixed venous oxygen saturation, %54.83 ± 8.5354.08 ± 10.4556.57 ± 9.49.45
      White blood count × 103/μL8.79 ± 3.019.37 ± 3.758.92 ± 3.28.74
      Sodium, mEq/L134.18 ± 4.34131.19 ± 4.37133.38 ± 4.45.03
      Bicarbonate, mEq/L27.73 ± 4.1728.30 ± 3.6726.93 ± 4.07.26
      Blood urea nitrogen, mg/dL29.46 ± 12.1230.05 ± 16.0231.43 ± 17.49.96
      Creatinine, mg/dL1.29 ± 0.411.28 ± 0.531.39 ± 0.43.36
      Alkaline phosphatase, IU/L96.27 ± 42.54106.47 ± 48.0298.18 ± 45.54.34
      Total bilirubin, mg/dL1.18 ± 0.571.80 ± 1.121.07 ± 0.72<.01
      Brain natriuretic peptide, pg/mL1014.59 ± 958.211235.48 ± 1192.25943.27 ± 914.13.50
      Continuous data expressed as mean ± standard deviation with comparisons calculated with 1-way analysis of variance. Brain natriuretic peptide comparisons were performed with the Kruskal-Wallis test. PCWP, Pulmonary capillary wedge pressure; CVP, central venous pressure; RVSWI, right ventricular stroke work index.

      Operative Parameters

      Group 2 had the greatest proportion of patients who underwent a TV procedure (62.8%; P = .05) with no significant difference in the performance of other valve surgeries (P > .05; Table 4). One patient in group 2 had a MV repair with an edge-to-edge Alfieri stitch placed through the LV apex. However, this patient remained with moderate MR postoperatively. The higher incidence of TV surgery in group 2 is consistent with the greater burden of TR (P = .03; Table 2). There was no difference in the number of redo sternotomy surgeries (P = .58) or delayed closure of the sternum (P = .12; Table 4). Group 1 had the highest incidence of centrifugal pump utilization whereas group 3 had the highest incidence of axial pump use (P = .04; Table 4). There was no difference in the distribution of the different types of LVAD devices between the 3 clusters. Mean pulmonary artery pressure significantly decreased after cfLVAD implantation in all groups (group 1, 29.08 ± 6.60 mm Hg, 20.83 ± 6.39 mm Hg [P < .01]; group 2 30.53 ± 9.34 mm Hg, 21.16 ± 7.50 mm Hg [P < .01], and group 3, 31.20 ± 8.38 mm Hg, 21.65 ± 5.14 mm Hg [P < .01]).

      Postoperative Outcomes

      Group 2 had the longest median length of hospital stay (P = .03) and median length of stay in the intensive care unit (P = .10; Table E1). The overall incidence of stroke was highest in group 2 (30.2%; P = .02; Figure E1) and consisted of hemorrhagic strokes in 16.2% (P = .07) and embolic strokes in 14.0% (P = .23). Group 2 also had the highest incidence of hemolysis (39.5%; P = .01; Figure E2), device thrombosis (30%; P = .01; Figure E3), and death while supported by an LVAD (46.5%; P = .01). However, there was no difference in 30-day operative mortality (P = .85) or survival to heart transplantation (P = .26). The combined LVAD survival and survival to heart transplantation was worse for group 2 (P = .03; Figure 2). Survival at 5 years for group 1, 2, and 3 was 56.0%, 17.6%, and 55.8%, respectively. When separating the entire cohort (n = 159) simply into those with post-cfLVAD implantation MR that was moderate-severe versus mild or less, a similar conclusion is reached with moderate-severe MR being associated with poorer survival (P = .05), as well as a higher incidence of stroke (P < .05), hemolysis (P < .01), and pump thrombosis (P < .01). Although the median number and duration of readmissions analyzed using the median test did not show a significant difference between the 3 clusters (Table E1), time to readmissions modeling with Anderson-Gill recurrent events analysis did show that cluster 2 had a greater rate of readmissions than cluster 1 (P < .01) and cluster 3 (P = .02). Cluster 1 and 3 had a similar rates of readmission episodes (P = .11).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier survival plot for cluster categories. Five-year left ventricular assist device implantation survival and survival to heart transplantation was poorest for group 2 (17.6%; P = .03) compared with the other 2 groups. Survival at 5 years for groups 1 and 3 were 56.0% and 55.8%, respectively.

      RVF and RVAD Utilization

      Binary logistic regression analysis showed that a greater severity of MR after cfLVAD implantation was associated with a higher incidence of RVF (P < .05; odds ratio [OR], 1.6) and RVAD use (P = .10; OR, 1.6). There was a robust correlation of preoperative TR severity with RVF (P < .01; OR, 4.0) and RVAD use (P = .01; OR, 3.74). The proportion of the entire study cohort with preoperative severe RVD (17.0%) was lower than postoperatively (30.2%; P = .01). However, when TV interventions were excluded, there was no difference in pre- and postoperative severe RVD (P = .23). When examining only patients who had TV interventions, incidence of severe RVD was higher postoperatively (38.5%) than preoperatively (19.2%; P = .01). This suggests the apparent worsening of RVD postoperatively is at least partially explained by re-establishment of TV competency.
      However, after excluding patients who received TV repair, the severity of post cfLVAD implantation MR had a strong positive correlation with TR severity (R = 0.33; P < .01). Group 2 had the highest proportion of patients with moderate-severe TR preoperatively (P < .05), and experienced the least improvement in MR severity (P < .01), and had the highest proportion of patients with significant residual TR (P = .01) after cfLVAD implantation. There was a positive correlation between severity of TR and MR post-cfLVAD implantation with an R value of 0.36 (P = .01). Indeed, group 2 had the highest incidence of RVF (20.9%; P = .01), and RVAD use (18.6%; P = .01), but no difference in incidence (P = .95) or duration (P = .08) of nitric oxide use (Table E1). Notably, of the patients with mild or no residual RVD (n = 52), only 3 patients (5.8%) had associated residual severe MR.

      Discussion

      In this study, we showed the role of residual MR in influencing clinical outcomes after cfLVAD implantation. Because of the complex interplay of multiple factors determining eventual RV function, we used cluster analyses to guide our interpretation of the various interactions between myocardial function and valvular pathologies. This statistical approach allows simultaneous consideration of multiple factors to formulate a phenotypical map of the echocardiographic categories that result after cfLVAD implantation. Our study identified that the degree of improvement of severe MR can vary greatly after cfLVAD implantation. MR severity improved the least in group 2 in which there was worse preoperative TR (P < .05), and the highest proportion of patients with RVF (20.9%; P = .01) and RVAD use (18.6%; P = .01). TR severity was the greatest in this group, pre- and postoperatively, despite TV intervention. Persistent TR after cfLVAD implantation in group 2 was likely not only due to the underlying TR and RVD but might have also reflected contributions from higher pulmonary artery pressures from persistent significant MR, upstream in a series circuit. This is reflected in the higher rate of RVF and RVAD use in group 2. Indeed, we showed that increasing postoperative MR severity independently correlated with the incidence of RVF (OR, 1.6) and RVAD use (OR, 1.6). We showed that TV repair to improve valve competence was associated with worsened RV function assessed using echocardiography. After excluding patients who received TV surgery, we showed a strong positive correlation between the degree of post cfLVAD implantation MR severity and severity of TR, which suggests that significant residual MR exerts significant afterload on the right heart. In group 2, incompletely resolved MR after cfLVAD implantation was associated with greater postoperative TR despite TV intervention to restore competency. Preoperative TR remains a robust predictor of postoperative RVF (P < .01) and RVAD use (P = .01) in our population with severe preoperative MR.
      In this select study population with severe preoperative MR, the severity of MR was severe in 10.7% and moderate in 27.0% after cfLVAD implantation. Morgan and colleagues reported that after cfLVAD implantation, MR severity decreased from moderate-severe in 76% preoperatively to 8% at 6 months postoperatively.
      • Morgan J.A.
      • Brewer R.J.
      • Nemeh H.W.
      • Murthy R.
      • Williams C.T.
      • Lanfear D.E.
      • et al.
      Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation.
      A sizable number of patients remain with moderate to severe MR after cfLVAD implantation, particularly in those with severe MR preoperatively and at least in the first month after cfLVAD implantation. Despite recent publications lending insight into the role of persistent MR in determining outcomes after cfLVAD implantation, reaching a consensus on surgical indications for moderate-severe MR remains elusive.
      • Feldman D.
      • Pamboukian S.V.
      • Teuteberg J.J.
      • Birks E.
      • Lietz K.
      • Moore S.A.
      • et al.
      The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: executive summary.
      Persistent MR postoperatively (group 2) was associated with a longer length of hospital and intensive care stay as well as a greater rate of readmissions. This group had the highest incidence of stroke (30.2%), hemolysis (39.5%), and RVF (20.9%) which likely contributed to a lower survival rate. In group 1, despite 95.5% of patients having moderate-severe RVD after cfLVAD implantation, the incidence of RVF and RVAD was relatively low at 9% and 7.5%, respectively. This is likely facilitated by the lack of moderate-severe residual MR in this group with trace to no residual MR in 62.7% of patients. For group 3 with exclusively mild or less RVD but a 40.8% incidence of moderate-severe residual MR, only 1 patient (2%) experienced RVF and no patient required an RVAD. Thus, significant residual moderate MR seems well tolerated by patients with relatively preserved RV function. Indeed, it is uncommon for patients with mild or no RVD to have associated severe residual MR (3/52; 5.8%).
      Although there was no significant difference in preoperative RV function among the 3 groups, our findings suggest that moderate residual MR is relatively well tolerated for those with RV function that is significantly improved by LVAD unloading of the left heart (group 3). Furthermore, even if the RVD remains predominantly moderate to severe after cfLVAD unloading, the lack of associated moderate-severe MR is still associated with a lower incidence of RVF and RVAD use (group 1). For patients who require preoperative temporary MCS and with preoperative severe TR, it is likely that after cfLVAD implantation, residual MR will still be moderate-severe, RV function will remain moderate-severely impaired, and residual TR will be mild-moderate despite surgical repair (group 2). The contribution of upstream moderate-severe MR to downstream impairment of RVD and TR remains unclear. However, group 2 is likely the population that might benefit the most from restoring MV competency with MV repair or replacement because this is the population most likely to have significant residual MR coupled with moderate-severe RVD. Indeed, the finding that there was a positive correlative relationship between MR and TR post cfLVAD implantation implicates a contribution of MR to significant TR downstream.

      Study Limitations

      This study is limited by the retrospective single institutional design with associated biases. Echocardiographic assessment of RV function can be subjective because of a lack of quantitative echocardiographic assessment of RV contractility. Objective echocardiographic data describing RV function (eg, tricuspid annular plane systolic excursion, RV dimension, RV ejection fraction) were not available. Visual assessment of ventricular contractility is pre- and after load-dependent, and might vary on a temporal basis. However, we have corroborated these qualitative findings on RV function with direct quantitative measurements using the RV stroke work index. Serial echocardiographic data were also not available. Only hospital outcomes were considered and we do not have outpatient data on patients who return with mild RVF symptoms. This might have underestimated the burden of late RVF. Because of the limited number of patients in our study, we were not able to include the cfLVAD device type in our analyses. Our results describe post-cfLVAD echocardiographic findings that affect postoperative RVF but other potentially important factors such as myocardial biology are very likely to contribute to clinical outcomes.

      Conclusions

      Our study highlights the correlation of significant residual MR with higher grades of TR post cfLVAD implantation. This configuration also predicted RVF and increased likelihood of RVAD use in our patient population. These data suggest that RVF occurs most often in patients with significant MR and significant RVD after LVAD implantation. Furthermore, significant MR is better tolerated by the right ventricle if underlying function is preserved. Conversely, there is a decreased risk of RVF despite significant RVD if MR burden is relatively low.

      Conflict of Interest Statement

      Keith D. Aaronson is an independent physician quality panel member and has received institutional funding for the A Prospective, Randomized, Controlled, Un-blinded, Multi-Center Clinical Trial to Evaluate the HeartWare Ventricular Assist System (VAS) for Destination Therapy of Advanced Heart Failure (ENDURANCE) trial from Medtronic , Inc. He also received institutional funding from Abbott , Inc, for the HeartMate 3 trials. Dr Aaronson is also a scientific advisory board member for Procyrion Inc, and a consultant for NuPulseCV, Inc. All other authors have nothing to disclose with regard to commercial support.

      Appendix

      Figure thumbnail fx4
      Figure E1Freedom from stroke was the worst for group 2 (30.2%; P = .01) compared with the other 2 groups. Incidence of stroke in groups 1 and 3 were 17.9% and 8.2%. respectively.
      Figure thumbnail fx5
      Figure E2Freedom from hemolysis was the worst for group 2 (39.5%; P < .01) compared with the other 2 groups. Incidence of stroke in groups 1 and 3 were 16.4% and 16.3%, respectively.
      Figure thumbnail fx6
      Figure E3Freedom from pump thrombosis was the worst for group 2 (30.2%; P < .01) compared with the other 2 groups. Incidence of stroke in groups 1 and 3 were 9.0% and 14.3%, respectively.
      Table E1Postoperative outcomes of the study cohort
      Cluster1 (n = 67)2 (n = 43)3 (n = 49)P value
      Median total intensive care unit stay (range), d6.00 (5.00-9.00)9.00 (6.00-17.00)7.00 (5.00-11.50).08
      Median total length of stay (range), d19.00 (16.00-26.00)27.00 (19.00-43.00)21.00 (16.50-26.50).03
      Median total days of readmission (range)11.00 (0.00-41.00)25.00 (0.00-74.00)15.00 (1.50-33.00).84
      Median number of readmissions (range)2.00 (0.00-4.00)4.00 (1.00-7.00)2.00 (0.00-4.00).15
      RV failure6 (9.0%)9 (20.9%)1 (2.0%).01
      RVAD5 (7.5%)8 (18.6%)0 (0.0%).01
      Median RVAD duration (range)19.00 (6.50-143.00)37.50 (2.25-69.50)0.38
      Nitric oxide use66 (98.5%)42 (97.7%)48 (98.0%).95
      Median nitric oxide duration (range)2.00 (1.00-3.00)2.00 (1.00-3.00)2.00 (2.00-2.00).08
      Device infection16 (23.9%)17 (39.5%)12 (24.5%).16
      Device exchange infection6 (9.0%)5 (11.6%)2 (4.1%).40
      Late aortic valve intervention0 (0.0%)0 (0.0%)1 (2.0%).32
      All stroke12 (17.9%)13 (30.2%)4 (8.2%).02
      Hemorrhagic stroke4 (6.0%)7 (16.3%)2 (4.1%).07
      Embolic stroke8 (11.9%)6 (14.0%)2 (4.1%).23
      Hemolysis11 (16.4%)17 (39.5%)8 (16.3%).01
      Pump thrombosis6 (9.0%)13 (30.2%)7 (14.3%).01
      Postoperative dialysis3 (4.5%)2 (4.7%)3 (6.1%).92
      Postoperative permanent dialysis2 (3.0%)1 (2.3%)2 (4.1%).89
      Operative mortality (30-day or in-hospital)3 (4.5%)3 (7.0%)2 (4.1%).79
      LVAD death, cumulative14 (20.9%)20 (46.5%)13 (26.5%).01
      Heart transplantation26 (38.8%)14 (32.6%)24 (49.0%).26
      All nominal data expressed as presented as n and percentage of total population and compared with Pearson χ2 or Fisher exact test. Continuous data expressed as median and interquartile range. Median test was used to analyze total days of readmission, RVAD duration, nitric oxide duration, and days of open chest. RV, Right ventricle; RVAD. right ventricular assist device; LVAD, left ventricular assist device.

      Supplementary Data

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