Although valvular pathology was once thought to be a contraindication to left ventricular assist device (LVAD) placement,1 studies have shown that LVAD placement can be safely carried out in patients with aortic insufficiency or other valvular lesions requiring repair or replacement.2,3 With the approval of the Heartmate II (HMII; Thoratec Corp., Pleasanton, CA) continuous-flow LVAD (cf-LVAD) for bridge to transplant and destination therapy and its establishment as a safer, more efficacious treatment than pulsatile-flow devices, the number of patients receiving LVAD continues to be on the rise.4–6 That LVAD implantation is a well-established therapy for end-stage heart failure is indisputable.7–9 However, because cf-LVADs may result in less volume loading than pulsatile-flow LVADs, it is conceivable that persistent mitral regurgitation after cf-LVAD implantation may not allow pulmonary vascular resistance (PVR) to decrease. Accordingly, it is unclear whether patients with moderate or severe mitral regurgitation would benefit from mitral valve repair or replacement at the time of cf-LVAD implantation. This may explain why a significant number of patients continue to report New York Heart Association (NYHA) functional class II or III symptoms after implantation of cf-LVAD.10 In addition, decreasing the severity of mitral regurgitation may indirectly augment right ventricular (RV) function by decreasing RV afterload. Finally, persistent mitral regurgitation may limit the frequency of aortic valve opening due to differential flow, making it impossible to accomplish pulsatility. The goal of this study was to determine whether mitral valve repair or replacement (MVR) performed at the time of LVAD implantation confers additional advantage in terms of greater decrement in PVR, augmentation of RV function, or greater aortic valve opening, without compromising safety in a retrospective, multi-institutional study.
Materials and Methods
After approval from local institutional review boards, 57 contemporaneously matched patients undergoing HMII implantation were identified at four hospitals from 2009 to 2011. Of these 57 total patients, 21 (36.8%) underwent concomitant mitral valve repair or replacement. Patients were compared with a cohort of patients undergoing HMII implantation alone over this time period. The decision to perform an MVR was at the discretion of the operating surgeon and consisted of patients with moderate-to-severe mitral regurgitation with high PVR.
Data collected included patient demographics (age, race, and sex), medical history, preoperative ejection fraction and INTERMACS profile, preoperative PVR, and preoperative creatinine and bilirubin. Postoperative end-points were duration of mechanical ventilation or inotropic support, requirement of inhaled nitric oxide (INO), change in total bilirubin and creatinine, change in PVR, central venous pressure (CVP) over 15 mm Hg, end-diastolic diameter, and ratio of aortic valve openings per cardiac cycle. Hemodynamic data such as PVR, pulmonary artery pressures, and CVP were collected postoperatively at a median follow-up of 140 days. Creatinine and bilirubin were collected immediately before surgery and on the first postoperative day. Echo data were collected perioperatively.
All data analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). Continuous variables are presented as mean ± SD or median, and categorical variables are reported as percentages of the total number of data points available for that field. Analysis of variance, Student’s t-test, and Fisher’s exact test were used to analyze continuous and categorical variables. Kaplan-Meier analysis was used to estimate survival at 3 months and 1 year. A p value <0.05 was considered statistically significant.
Baseline Patient Characteristics
Baseline characteristics of the two groups are shown in Table 1. Cohort and control group were evenly matched with regard to age, sex, body mass index, ejection fraction, and proportion of INTERMACS profile 1 and 2 patients. The groups were also evenly matched with patients requiring other valvular surgery, medical history, and baseline PVR, creatinine, and total bilirubin. All patients receiving MVR + LVAD had moderate-to-severe mitral regurgitation, whereas 21 (58.3%) receiving HMII alone had moderate-to-severe mitral regurgitation (p = 0.001).
Of the patients undergoing MVR + LVAD, 15 (71.4%) underwent valve repair with a downsizing annuloplasty alone, 3 (14.3%) underwent complex mitral valve repair with leaflet repair or use of chordae, and 3 (14.3%) underwent valve replacement. Patients undergoing MVR + LVAD were evenly distributed across three of the four implant centers. Concomitant MVR was performed by four different surgeons. Cardiopulmonary bypass time was longer in the group that underwent concomitant MVR + LVAD (154.4 vs. 108.8 minutes, p = 0.01). The mitral valve operation was conducted with the heart beating in 18 (85.7%), fibrillatory arrest in 3 (14.3%), and an aortic cross-clamp in 13 (61.9%). Average pump speed used in the perioperative period in the MVR + LVAD group (8,600.0 ± 200.0 RPM) was not significantly different from that in the LVAD only group (8,733.3 ± 98.5 RPM, p = 0.11).
Postoperative outcomes are reviewed in Table 2. There was no significant difference in total hospital or intensive care unit length of stay. There was no significant difference in the duration of mechanical ventilation, time requiring inotropic support, or change in creatinine or total bilirubin. By postoperative day 140, magnitude of decrement in mean pulmonary artery pressure (54.0% vs. 32.1%, p = 0.04) and PVR (59.4% vs. 35.2%, p = 0.01) was significantly larger in the group undergoing MVR + LVAD. When comparing the MVR + LVAD group with LVAD only patients with moderate-to-severe mitral regurgitation, postimplant decrease in PVR was significantly greater in the MVR + LVAD group (59.4% vs. 17.2%, p = 0.02). Decrease in end-diastolic diameter was greater in the group undergoing MVR + LVAD but did not reach statistical significance (−18.2 vs. −13.5 mm, p = 0.33). Decrease in right atrial pressure and the ratio of aortic valve openings to cardiac cycle in the immediate perioperative period were not significantly different between the two groups.
Requirement for postoperative INO was not significantly different between the two groups (71.4% vs. 47.2%, p = 0.10). Amount of time spend with CVP >15 mm Hg and the presence of postoperative moderate-to-severe tricuspid regurgitation were not different between the two groups in the immediate perioperative period, suggesting that the salutary effects of MVR + LVAD are not apparent in the short-term.
There were five patients with preoperative PVR >5 Woods Units (WU) receiving MVR + LVAD. Of these, four patients (80%) went on to have postimplantation PVR <5 WU, rendering them eligible for cardiac transplantation. Two of these patients went on to have a successful heart transplant. The remaining two are still awaiting transplantation. There were three patients in the control group with PVR >5 WU. Two of these patients (67.7%) went on to have a postimplantation PVR <5 WU.
Kaplan-Meier survival curves for the two groups are shown in Figure 1. There was no statistically significant difference in survival between the MVR cohort and control groups at 3 months (89.7 vs. 83.3%) and 1 year (83.7 vs. 67.3%, p = 0.34). Predictors of mortality are shown in Table 3. Concomitant MVR + LVAD with implantation of HMII was not associated with mortality. Postoperative total bilirubin level was the only variable associated with mortality risk (hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.02–1.10, p = 0.01). Age, sex, body mass index, history of hypertension, diabetes, chronic obstructive pulmonary disease, or dialysis-dependent renal failure did not add risk of mortality. Preoperative PVR, postoperative PVR, preoperative total bilirubin, preoperative creatinine, and postoperative creatinine were not associated with mortality risk.
The continued success of mechanical circulatory support for end-stage heart failure has expanded the range of patients who are now able to derive benefit from cf-LVAD implantation.4,7–9 Clearly, the implantation of LVAD decreases PVR even in patients with end-stage heart failure who have medically refractive pulmonary hypertension.11–14 However, what is unknown is whether leaving patients with persistent mitral regurgitation when implanted with cf-LVAD—and therefore, an obligatory volume-loaded left ventricle—can result in less than optimal unloading of the pulmonary vasculature. Persistent mitral regurgitation in patients supported on cf-LVAD, particularly on exercise, could lead to worsening pulmonary congestion and adversely influence the patient’s reported outcomes of their own health status. This may explain why a significant proportion of patients receiving HMII continue to have NYHA class II or III symptoms.10 In addition, off-loading the pulmonary vasculature with the use of mitral valve repair or replacement may translate into a meaningful reduction in RV afterload, thereby ameliorating the incidence of RV dysfunction. Furthermore, repairing the mitral valve at the time of cf-LVAD implantation may allow blood to stream across the aortic valve due to altered resistance to flow and enhance pulsatility.
These hypotheses have led authors to recommend mitral valve repair or replacement at the time of device implantation.2 However, no studies to our knowledge have examined the safety and efficacy of MVR operation done at the time of cf-LVAD implantation. The goal of this study has been primarily to examine whether the addition of MVR to cf-LVAD implantation in patients with severe mitral regurgitation conferred additional advantage in the reduction of pulmonary artery pressures and PVR. Second, we investigated whether MVR + cf-LVAD translated into favorable RV performance in the immediate perioperative period and whether aortic valve opening would be enhanced by MVR + cf-LVAD.
In our analysis, patients undergoing concomitant MVR at the time of cf-LVAD implantation demonstrated a greater decrement in mean pulmonary artery pressures and PVR than those receiving cf-LVAD alone. This change persisted for a median follow-up of 140 days. Therefore, adopting a strategy of planned mitral valve operation at the time of LVAD implantation in a select group of patients with prohibitively high PVR, moderate, or severe mitral regurgitation and end-stage heart failure may augment the decrease in PVR seen with cf-LVAD implantation alone. It is therefore conceivable that a small group of patients who cannot be rendered eligible for cardiac transplantation due to very high PVR in the setting of mitral regurgitation may be rendered eligible by adding mitral valve operation to the LVAD implantation. In this study, four of five patients with PVR >5 WU, that were originally ineligible for transplantation, became transplant candidates after MVR + LVAD. Two of these patients went on to receive successful cardiac transplantation. Further studies are needed to determine the long-term effects of MVR + LVAD on PVR.
Left ventricular assist device implantation results in unloading of the failing heart and subsequent decrease in end-diastolic diameter.15,16 The repair of an incompetent mitral valve may improve off-loading of the heart by HMII. While patients receiving MVR in this study had greater decrease in end-diastolic diameter, this did not reach statistical significance (−18.2 vs. −13.5, p = 0.33). Given the limited follow-up, further studies are warranted to determine how end-diastolic diameter is affected in the long-term. In addition, MVR with concomitant HMII implantation may result in improvement of symptoms in patients with end-stage heart failure secondary to decreased pulmonary edema. Symptomatic improvement was not measured in this study, and further investigation as a potential benefit for patients receiving MVR with device implantation is merited.
Mitral valve repair or replacement + cf-LVAD may engender favorable RV performance by inducing a greater decrement in mean pulmonary artery pressure and PVR than cf-LVAD implantation alone. In this analysis, such a hypothesis does not hold true in the immediate perioperative period. In this very sick group of patients, an immediate reduction in PVR was not expected. In addition, the amount of time spent with a CVP >15 mm Hg and the presence of postoperative moderate-to-severe tricuspid regurgitation was not significantly different between the two groups in the immediate perioperative period. Similarly, enhancement of aortic valve opening could not be demonstrated in the immediate perioperative period. Whether this bears out in the long-term deserves further analysis. In this study, pump speed is routinely set using echocardiogram and if necessary, invasive hemodynamic monitoring to optimize cardiac output, interventricular septal positioning, and intracardiac filling pressures—specifically the wedge pressure (and thereby LVEDP and LVEDV).
The addition of MVR to cf-LVAD implantation is safe and does not result in worse survival as demonstrated by Kaplan-Meier analysis. The addition of MVR did not predict mortality in this study (HR: 0.58, 95% CI: 0.19–1.81, p = 0.35). The sole predictor of survival was postoperative total bilirubin (HR: 1.06, 95% CI 1.02–1.10, p = 0.01). This is consistent with previous studies that have shown liver dysfunction, and elevated total bilirubin predicts mortality in patients requiring LVAD.17,18
This contemporaneous cohort study demonstrates that MVR with concomitant HMII implantation is safe, and despite longer cardiopulmonary bypass times, it can be done without compromising morbidity or mortality. It does not result in increased length of stay, increased requirement of mechanical ventilation, or inotropic support. Change in kidney or liver function was not different between the two groups. The addition of MVR does not worsen survival. However, the addition of MVR to HMII could potentially confer some benefits to the end-stage heart failure patient without increasing the risk of morbidity or mortality. Further studies are needed to examine this topic and to determine the long-term effect of the addition of MVR to HMII on PVR.
This study had some limitations, including those related to retrospective review. All data were obtained from chart review, which introduces selection bias and some incomplete data collection. Patients receiving MVR had higher PVR at baseline in comparison with the control group, which may influence the more significant reduction following cf-LVAD placement. In addition, data on wedge pressure and v-waves were not available. Finally, the analysis had a small sample size for some end-points, thus limiting the power of the study.
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Keywords:Copyright © 2013 by the American Society for Artificial Internal Organs
left ventricular assist device; mechanical circulatory support; heart transplantation; heart failure