Orthotropic heart transplantation (OHT) is the gold standard treatment for end-stage heart failure (HF). The presence of pulmonary hypertension (PH) secondary to left heart disease, also known as World Health Organization (WHO) group 2 PH, may influence patient candidacy for OHT1–3 because of the risk of right ventricular (RV) primary graft failure.4–6 Currently, there is no real consensus on the level of PH above which there is increased risk of posttransplant morbidity and mortality7,8; however, recent results from United Network for Organ Sharing registry analysis suggested that increased pretransplant pulmonary vascular resistance (PVR) to ≥2.5 Wood units (WU) is associated with a modest increase in posttransplant mortality.9 Several studies have shown the impact of left ventricular assist devices (LVADs) on lowering pulmonary pressures by unloading the left ventricle, thus improving patient candidacy for OHT.10–14 Currently, continuous-flow devices (CF-LVADs) including axial flow and centrifugal flow pumps have replaced the old pulsatile flow (PF-LVAD) pumps and carry better durability with an excellent survival rate.
Studies comparing LV unloading with CF-LVADs versus with PF-LVADs revealed conflicting results. In two studies, CF-LVADs were superior to PF-LVAD in reducing LV end-diastolic pressure and volume.15,16 However, other studies showed better LV unloading with PF-LVAD than with CF-LVAD.17–19 Klotz et al.20 showed a greater LV volume unloading with PF-LVADs; however, LV pressure unloading and reduction in pulmonary pressures were equal in both types. Short-term improvement of PH was seen in heart transplant recipients bridged with PF-LVADs.14 However, it remains unclear whether CF-LVADs provide adequate and sustained effect on PH posttransplant and whether that impacts outcomes. The purpose of this study is to compare the ability of both LVAD modalities to improve pulmonary vascular hemodynamics in patients with advanced HF during the period of LVAD support and long term after heart transplant.
Our data source was the Utah Transplant Affiliated Hospital (UTAH) program, which is a consortium of the University of Utah Hospital, Intermountain Medical Center, Salt Lake City Veterans Affairs Medical Center and the Primary Children’s Hospital in Salt Lake City, Utah. We retrospectively reviewed data of patients with end-stage HF and functional New York Heart association (NYHA) class III–IV symptoms with WHO group 2 PH who underwent either PF-LVAD or CF-LVAD placement as a bridge to transplant from 2001 to 2011. The decision to accept a donor heart was made by the heart transplant cardiologist on call based on the available echocardiogram data. Invasive hemodynamic data were not available on all donors before transplant. We excluded patients younger than 16 years old, patients with combined heart–lung transplantation, and those with LVAD support time of <30 days. Patients with severe RV failure as demonstrated by echocardiogram were not eligible for LVAD implant. Objective data on all patients were obtained by means of conventional pulmonary artery catheterization. In addition, all patients were followed clinically, and their eligibility for transplantation was frequently re-evaluated. The number of clinic visits varied based on each patient’s postoperative course. The study was approved by the institutional review board at participating institutions. Individual consent for this study was waived.
We obtained invasive hemodynamics with pulmonary artery catheterization using a Swan-Ganz catheter inserted through the internal jugular or femoral vein. Measurements were obtained at pre-LVAD placement (baseline), pretransplantation, and then at 3 months, 1 year, and between 3 and 5 years posttransplantation. All measurements were obtained with patients in supine position. The recorded hemodynamics included right atrial (RA) pressure, systolic pulmonary artery pressure (PAPs), diastolic pulmonary artery pressure (PAPd), mean pulmonary arterial pressure (PAPm), pulmonary capillary wedge pressure (PCWP), PVR, resting cardiac output (CO) by Fick method, and resting cardiac index (CI). Transpulmonary gradient (TPG) was calculated using the formula (PAPm − PCWPm). We defined PH by PAPm ≥25 mm Hg.
Posttransplant biopsies obtained around the time of invasive hemodynamic measurements were studied to evaluate the influence of rejection on hemodynamics. Right ventricular endomyocardial biopsy results were scored based on the International Society of Heart and Lung Transplantation grading system. A grade of ≥2R was considered significant.
We computed means and standard deviations for each type of LVADs at each time point. We also compared the change in values by computing a t-test on the differences between two time points (e.g., each patients baseline value was subtracted from their pretransplant value, and the two sets of differences were used in an independent sample t-test).
A total of 38 patients met our inclusion criteria, of whom 19 patients received PF-LVADs (HeartMate XVE, Thoratec, Pleasanton, CA) and 19 patients received CF-LVADs (HeartMate II, Thoratec, Pleasanton, CA [n = 15]; Jarvik-Jarvik heart, New York, NY [n = 3]; or Levacor-World Heart, Salt Lake City, UT [n = 1]) as a bridge to transplant. The total duration of LVAD support was 3,645 patient-days for the PF-LVAD group and 4,482 patient-days for the CF-LVAD group. Baseline characteristics for both groups are summarized in Table 1.
Hemodynamic data at baseline before LVAD implant are summarized in Table 2.
Hemodynamic Response During the Left Ventricular Assist Device Support Period
Continuous-Flow Left Ventricular Assist Device.
During the LVAD support time, the PAPs and PAPm decreased significantly from a baseline of 53.7 ± 18.0 and 37.4 ± 11.6 mm Hg to 34.6 ± 11.8 and 22.4 ± 7.7 mm Hg, respectively. Additionally, PVR decreased significantly from a baseline of 3.73 ± 2.9 to 2.06 ± 1.1 WU. The mean TPG decreased significantly from a baseline of 12.5 ± 10.1 to 9.6 ± 4.5 mm Hg.
Pulsatile Flow Left Ventricular Assist Device.
During the LVAD support time, the PAPs and PAPm decreased significantly from a baseline of 62.7 ± 14.9 and 45.2 ± 10.6 mm Hg to 31.8 ± 5.9 and 19.8 ± 4.4 mm Hg, respectively. Additionally, PVR decreased significantly from a baseline of 4.82 ± 2.49 to 2.05 ± 0.88 WU. The mean TPG decreased significantly from baseline of 16.3 ± 7.9 to 10.4 ± 4.2 mm Hg.
Comparison of Hemodynamics During Left Ventricular Assist Device Support
Interestingly, the decrease in PAPm was more pronounced in PF-LVAD group than in CF-LVAD group (−25.32 ± 8.98 vs. −15 ± 12.35 mm Hg, p = 0.005). Similarly, PAPs decreased significantly in PF-LAVD group compared with PAPs in CF-LVAD group (−30.95 ± 13.02 vs. −19.11 ± 19.36 mm Hg, p = 0.03). There was no significant difference between the two groups with regards to the drop in PVR (−2.79 ± 2.05 vs. −1.73 ± 2.52 WU, p = 0.2) and TPG (−5.84 ± 6.83 vs. −2.95 ± 8.86 mm Hg, p = 0.3).
Hemodynamics After Heart Transplantation
Continuous-Flow Left Ventricular Assist Device.
The improvement of pulmonary hemodynamics during LVAD support time was also sustained after heart transplant at follow-up time points 3, 12, 24, and 36–60 months. Mean PAP kept its improvement after transplant throughout follow-up times (21.3 ± 8.0 mm Hg at 3 months, 22.1 ± 9.1 mm Hg at 12 months, 19.8 ± 5.6 mm Hg at 24 months, and 22.2 ± 8.4 mm Hg at 36–60 months, p = 0.375). Similarly, PAPs improvement was sustained after transplant (31.5 ± 11.8 mm Hg at 3 months, 32.6 ± 12.1 mm Hg at 12 months, 31.0 ± 9.1 mm Hg at 24 months, and 33.8 ± 9.6 mm Hg at 36–60 months, p = 0.615). Pulmonary vascular resistance also had similar values after transplant (1.71 ± 0.89 WU at 3 months, 1.90 ± 1.21 WU at 12 months, 1.93 ± 1.25 WU at 24 months, and 1.81 ± 1.94 WU at 36–60 months, p = 0.7483). Additionally, TPG stayed improved as well (10.11 ± 4.9 mm Hg at 3 months, 10.89 ± 5.0 mm Hg at 12 months, 9.72 ± 4.8 mm Hg at 24 months, and 9.20 ± 4.9 mm Hg at 36–60 months, p = 0.3075).
Pulsatile Flow Left Ventricular Assist Device.
The improvement of pulmonary hemodynamics during LVAD support was sustained after heart transplant at follow-up time points 3, 12, 24, and 36–60 months. Mean PAP remained improved after transplant and throughout follow-up times (22.9 ± 7.0 mm Hg at 3 months, 19.9 ± 6.6 mm Hg at 12 months, 20.1 ± 5.7 mm Hg at 24 months, and 22.6 ± 6.5 mm Hg at 36–60 months, p = 0.117). Similarly, the improvement in PAPs was sustained after transplantation (32.7 ± 11.5 mm Hg at 3 months, 31.8 ± 9.6 mm Hg at 12 months, 29.7 ± 6.8 mm Hg at 24 months, and 32.2 ± 9.2 mm Hg at 36–60 months, p = 0.749). Pulmonary vascular resistance also had similar values after transplant (1.79 ± 0.82 WU at 3 months, 1.48 ± 0.99 WU at 12 months, 1.69 ± 1.06 WU at 24 months, and 2.05 ± 1.16 Wu at 36–60 months, p = 0.2324). Additionally, TPG stayed improved as well (9.83 ± 5.10 mm Hg at 3 months, 8.11 ± 4.65 mm Hg at 12 months, 9.00 ± 4.07 mm Hg at 24 months, and 10.17 ± 5.24 mm Hg at 36–60 months, p = 0.501).
Comparison of Hemodynamics Posttransplant
After 3–5 years post heart transplant, the improvement in PAPm in both groups was sustained similarly with no significant rebound. There was no statistical difference in the change between two groups (22.2 ± 8.4 mm Hg in CF-LVAD vs. 22.6 ± 6.5 mm Hg in PF-LVAD, p = 0.09). Similarly, the improvement in PAPs was similar in both groups (33.8 ± 9.6 mm Hg in CF-LVAD vs. 32.2 ± 9.2 mm Hg in PF-LVAD, p = 0.8). Additionally, there was no significant difference between two groups in regards to PVR (1.81 ± 1.94 WU in CF-LVAD vs. 2.05 ± 1.16 WU in PF-LVAD, p = 0.5) or TPG (9.20 ± 4.9 mm Hg in CF-LVAD vs. 10.17 ± 5.24 mm Hg in PF-LVAD, p = 0.8).
Hemodynamics and the Rate of Rejection
There were 20 biopsies with a grade of ≥2R in the CF-LVAD group and 26 biopsies with a grade of ≥2R in the PF-LVAD group. Hemodynamics correlating to the time points of RV biopsy showed no significant effects of acute rejection on patients’ hemodynamics. The average of PAPm, PVR, PCWP, RA, and TPG in PF-LVAD groups was 22.2 ± 6.6 mm Hg, 2.0 ± 1.1 WU, 10.2 ± 4.5 mm Hg, 5.5 ± 3.6 mm Hg, and 11.4 ± 4.1 mm Hg, respectively. The average of PAPm, PVR, PCWP, RA, and TPG in CF-LVAD groups was 20.5 ± 8.6 mm Hg, 1.9 ± 1.1 WU, 10 ± 6.4 mm Hg, 5.5 ± 4.1 mm Hg, and 10.5 ± 4.7 mm Hg, respectively.
This study compares the impact of PF-LVADs versus CF-LVADs on improving filling pressures during long-term left ventricle unloading. Moreover, it describes the course of pulmonary vascular hemodynamics up to 5 years posttransplant.
Hemodynamics During Left Ventricular Assist Device Support
Our study lends support to the evidence previously reported by others that PH secondary to LV systolic dysfunction can be reversed by the placement of either CF-LVADs or PF-LVADs. Torre-Amione et al.21 reported reversal of PH (defined by a TPG > 15 mm Hg) in a series of nine HF patients who received mechanical circulatory support with either PF-LVADs or CF-LVADs. Salzberg et al.11 reported a series of six patients with end-stage HF with PH (mean PAPs, 47 mm Hg) and elevated PVR (398 dyn·s/cm5), and four patients were successfully transplanted. Martin et al.14 studied six patients bridged with a PF-LVAD. During LVAD support, PVR normalized and patients were subsequently transplanted.
PF-LVAD was superior to CF-LVAD in unloading LV when Thohan et al.17 compared echocardiographic parameters between patients supported by PF-LVAD or CF-LVAD. In their study, left ventricular end-diastolic dimension, end-diastolic volume, and left atrial volume were more pronounced in PF-LVAD group than in CF-LVAD group. In our study, PF-LVADs were associated with more reduction in PAP than CF-LVAD, but these findings could be explained by the fact that patients with PF-LVAD had higher pre-LVAD pulmonary pressures than those with CF-LVAD. Importantly, the decreases in PVR and TPG were not different between both groups. In our study, we did not intend to study echocardiography findings as we did not have a specific follow-up echocardiography protocol during the PF-LVAD support.
Long-term assessment of hemodynamics in heart transplant recipients has not been widely studied. Early work by von Scheidt et al.22 showed no significant change in hemodynamics in a small cohort of 57 patients followed heart transplantation over a time period of 2.2 years. To our knowledge, our study is the first to offer an assessment on pulmonary hemodynamics in patients up to 5 years posttransplant after bridging with either a PF-LVAD or a CF-LVAD. Data are limited on whether posttransplant pulmonary vascular hemodynamics behave similarly in patients whose PH improved by medical management versus mechanical circulatory support before transplant. In one study, Goland et al.6 showed posttransplant residual PH at the 1 year follow-up in 17% of patients who had pretransplant mild PH and in 20% with severe PH. The vast majority of these recipients were not bridged with LVADs. There was a decreased survival in recipients with residual PH compared with those with normal pulmonary pressures at 1 year posttransplant.
In another study, Gude et al.23 showed a significant difference in PAPm, TPG, and PVR at 1 year posttransplant in 34 patients who received extracorporeal membrane oxygenation or LVAD support compared with a group that did not need mechanical circulatory support. Elevated PAPm defined as >20 mm Hg at 1 year after heart transplant was found in 21.8% of patients.
Our study demonstrates the presence of posttransplant residual PH of 22% and 39% in the PF-LVAD group at the 1 and 3–5 year follow-up, respectively. Similarly, there was a posttransplant residual PH of 37% and 27% in the CF-LVAD group at the 1 and 3–5 year posttransplant follow-up, respectively. Interestingly, the survival rate was not different between the two groups. The difference in posttransplant residual between our study and the one by Gude et al.23 could be explained by the difference in the definition of PH.
Short-term, posttransplant pulmonary vascular hemodynamics evaluation was done in a cohort of 50 patients with end-stage HF who received HeartMate II as a bridge to transplant.24 There was a significant decrease in PAPs and PVR during LVAD support which remained within normal limits 1 month after transplant. This study lacked a comparison group of patients randomized to receiving a PF-LVAD. Additionally, the posttransplant follow-up period was only 3 months. In contrast, we demonstrated a direct comparison between CF-LVADs and PF-LVADs in their ability to favorably impact pulmonary hemodynamics. Interestingly, both groups behaved similarly with regards to normalizing hemodynamics during the 5 years post OHT.
Irreversible PH is considered a contraindication for heart transplantation because of significant morbidity and mortality following surgery.4–6 However, mean pulmonary pressure may not be the defining factor for a patient’s candidacy. Mikus et al.25 studied 120 HF patients with severe PH treated with inotropes before LVAD implantation. The study showed that TPG and PVR but not mPAP were predictive parameters for successful heart transplantation. In our study, a small number of patients with severe PH in both groups limited our ability to run a sub-group analysis.
The mechanism of improving PH during LVAD support is not well known. However, the reduction of PVR can be explained by an increase in CO, a decrease in TPG, or both. Furthermore, endothelin-1, a strong vasoconstrictor, was found to be increased in the plasma of patients with PH with improved levels during LVAD support.26 Additionally, it is not well known whether the augmentation of sympathetic innervations plays a role in the mechanism of improving hemodynamics during LVAD. Drakos et al.27 have shown that unloading with either a PF-LAVD or a CF-LVAD was associated with myocardial recovery of sympathetic innervations. Furthermore, Rundqvist et al.28 showed that the augmented total body and regional sympathetic outflow to the renal and skeletal muscle vascular beds was normalized after transplantation.
Our study is limited by its small sample size, retrospective nature, and by virtue of being a single center study. The sample size was restricted by our strict inclusion criteria that included pulmonary artery catheterization before LVAD support, before heart transplant, and at various points up to 5 years posttransplant, which is rarely performed as part of routine care. Additionally, our study is limited by the inability to provide the level of LVAD support because of lack of data on several patients.
In conclusion, both PF-LVAD and CF-LVAD effectively improved pulmonary vascular hemodynamics during long-term support, and both LVAD types had favorable hemodynamics at the time of heart transplant, which was sustained up to 3–5 years later.
Competency in Medical Knowledge
Long-term LVAD support improves pulmonary vascular hemodynamics, and the new generation of CF-LVAD is proven effective in this regard. Reversal of PH by mechanical support before heart transplant is sustained after transplant.
Future studies should prospectively investigate whether there should be a limitation to using newer generation LVADs based on specific profiles of pulmonary vascular hemodynamics. Specific protocols addressing the duration of support and the structure of follow-up are necessary to limit the development of unpredictable RV failure perioperatively after heart transplant.
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