Pulmonary hypertension (PH) is a commonly associated comorbidity in patients with advanced heart failure. Over time, pressure and volume overload can lead to pulmonary vascular remodeling and significant increase in resistance across the pulmonary circulation in patients with left heart failure.1–4 Elevated pulmonary vascular resistance (PVR) among heart transplant recipients is associated with an increased risk of death, right ventricular (RV) dysfunction, and allograft failure.5–8
Patients treated with the left ventricular assist device (LVAD) demonstrate improvement in cardiac and pulmonary filling pressures as the left ventricle is off-loaded, reducing PVR after LVAD placement.9–12 Patients believed to have fixed PH (did not improve despite aggressive medical interventions) demonstrated significant hemodynamic improvements after LVAD implantation significant enough to achieve transplant candidacy.10,13
Patients with severe concurrent RV dysfunction may require biventricular support or a total artificial heart (TAH).14 The TAH replaces both ventricles and restores circulation to a normal or even high flow state. Replacing the impaired left ventricle removes the passive source of pressure and congestion and notionally allows pulmonary pressures to eventually return to normal values.14,15 Implanting a competent synthetic RV, however, abruptly changes RV-pulmonary artery coupling interactions and increases flow, pulmonary pressure, and shear stress. Theoretically, this may attenuate “reverse” remodeling of the pulmonary arteries.16,17 The impact of PH before TAH implantation on posttransplant hemodynamics and survival is unknown. We, therefore, conducted this study to evaluate the impact of TAH implantation on posttransplant hemodynamics in patients stratified according to severity of pulmonary hypertension (HTN).
This is a single center retrospective review of consecutive patients who underwent TAH implantation from April 1, 2006 to June 1, 2011. The study was approved by the Virginia Commonwealth University Institutional Review Board. Patients were excluded if baseline hemodynamics were not obtained. The final cohort of patients was compiled into a database, including baseline demographics, clinical characteristics, and invasive hemodynamics.
Data were obtained from medical records. Hemodynamic time points included pre-TAH placement (within 1 month) and after heart transplantation (HT) at 1 and 12 months. Hemodynamic indices included right atrial pressure (RAP), RV systolic pressure (RVSP), RV diastolic pressure (RVDP), pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), Fick and thermodilution cardiac output (CO), and cardiac index (CI). From these indices, the transpulmonary gradient (TPG) and PVR were calculated. Transpulmonary gradient was measured by subtracting PCWP from MPA; PVR was calculated as TPG divided by Fick CO unless unavailable.
The baseline characteristics and hemodynamics for the entire sample were initially compared. The patients were then subdivided into two groups based on the severity of PVR: PVR greater than or equal to 3 Woods units (WU) and PVR less than 3 WU. The data between the two groups were compared to determine whether there were significant differences before and after HT. The comparison was made between baseline (pre-TAH placement) and two posttransplant time periods: early (1 month) and late (12 months) within each group.
Total Artificial Heart
All patients were bridged to transplantation with the CardioWest TAH (Syncardia; Tuscon, AZ). The TAH is a pulsatile biventricular support device; consisting of two pneumatically driven pumps with the ability to deliver up to 9 L/min of flow. There are two Medtronic-Hall mechanical tilting valves in each ventricle one in the inflow position (mitral or tricuspid) and one in the outflow position (aortic or pulmonary). The external console has the ability to modulate systolic function by adjusting both drive pressure (0–300 mmHg) and ejection time of each ventricle. Diastole is modulated with vacuum pressure suction (0–60 mmHg). The pump ejection rate is typically set around 120–130 bpm.
The SPSS Statistics, version 19 (Chicago, Illinois) software package was used for all analyses. Continuous data were expressed as mean and standard deviations and categorical variables are expressed as percentages. Chi-square analysis was used to compare discrete variables. A paired two-tailed Student’s t-test was used to compare the continuous variables. To measure the influence of baseline PVR on survival after heart transplant, Kaplan–Meier cumulative survival curve was constructed, and mortality at 1 year was compared between two groups. The p value less than 0.05 was considered statistically significant.
There were 46 patients who underwent TAH placement during the time period studied. Thirty-four patients were eligible for the final analysis of which 12 patients were in the high PVR group and 22 in the low PVR group (Figure 1). In high PVR group, PVR ranged from 3.6 to 5.5 WU with an average value of 4.3 WU. Out of 12 patients in high PVR group, five patients had PVR between 3 and 4 WU, five patients had PVR between 4 and 5 WU, and two patients had PVR greater than 5 WU.
Baseline patient demographics, clinical characteristics, and invasive hemodynamics are presented in Table 1 for both the high and low PVR groups. Baseline clinical and demographic characteristics were similar between the groups. The low PVR group had lower MPAP, but otherwise there were no significant differences in hemodynamics between groups (Table 1).
Figures 2 and 3 show early and late changes in cardiac hemodynamics after heart transplant. In the high PVR group, the baseline PVR was 4.31 ± 0.7 WU, and baseline TPG was 15.8 ± 3.3 mmHg. One month after HT, both PVR (1.69 ± 0.7 WU, p <0.001) and the TPG (11.57 ± 5.0 mmHg, p = 0.07) had improved. These changes were maintained at 12 months (PVR: 1.48 ± 0.9 WU, p < 0.001 and TPG: 8.50 ± 4.0 mmHg, p = 0.008). The low PVR group did not show significant changes in PVR (baseline: 1.68 ± 0.8; 1-month: 1.18 ± 0.5; 12-month: 1.33 ± 0.6, p = >0.05) or TPG (baseline: 7.5 ± 4.5; 1-month: 7.6 ± 2.9, p = >0.05; 12-month: 8.2 ± 3.2, p = >0.05; Figure 2, A and B). At 12 months, two groups did not show any significant difference in PVR (1.33 ± 0.6 vs. 1.48 ± 0.9, p = 0.71) and TPG (8.16 ± 3.2 vs. 8.50 ± 4.0, p = 0.83). Patients in high PVR group, with PVR greater than 4 WU had reduction in PVR (baseline: 4.77 ± 0.5; 1-month: 2.12 ± 0.9; 12-month: 1.7 ± 0.8) similar to patients with PVR between 3 and 4 WU (baseline: 3.67 ± 0.2; 1-month: 1.16 ± 0.2; 12-month: 0.98 ± 0.8), although it remained none significantly higher.
Figure 3 shows improvements in MPAP, PCWP, and RAP in both groups. Although MPAPs improved from baseline to 1 month and 12 months after heart transplant, the difference between low PVR and high PVR groups persisted (at 1 month, 22.8 ± 7.2 vs. 30.3 ± 8.2, p = 0.07; and at 12 months, 19.2 ± 5.5 vs. 28.0 ± 7.6, p = 0.01).
In the Kaplan–Meier survival curve analysis, baseline PVR before TAH implantation did not affect survival (p = 0.97; Figure 4). Of 10 patients in high PVR group who underwent successful transplant, 1 year survival was 80% (8/10) compared with 81% (17/21) for patients in low PVR group. One patient in high PVR group died within 1 week after heart transplant because of cardiogenic shock, whereas another patient died because of acute coronary syndrome (day 271) noted on autopsy study. Patients in low PVR group died from cardiogenic shock (1 week after heart transplant), graft rejection (day 135), sepsis (day 67), and pulmonary embolism (day 34).
This is the first study to report early and late changes in cardiac hemodynamics after HT in patients bridged with the TAH. Our study showed that patients supported with TAH who had a baseline PVR greater than or equal to 3 WU (high PVR group) achieved significant improvement in PVR and TPG after HT reaching similar values as with low PVR group. We also observed improvement in MPAP, PCWP, and RAP in patients with high PVR group, although these remained elevated when compared with the low PVR group at 12 months follow-up. There was no difference in survival between high and low PVR groups at 12 months follow-up, suggesting that the degree of PH did not affect heart transplant survival in patients bridged by the TAH.
Long standing heart failure frequently leads to PH from persistently elevated filling pressure, reactive vasoconstriction, and pulmonary arterial remodeling.3 Presence of fixed PH5,6 in heart transplant recipients is shown to be associated with early mortality and poorer survival mainly because of potential for RV failure and is, therefore, considered relative contraindication for cardiac transplantation.7,8 Thus evaluation of pulmonary hemodynamics to determine the presence of PH and assess PVR, in particular reversibility of PVR, is considered an important component to determine eligibility for HT.13–19
The TAH is a mechanical circulatory assist device that may be more beneficial for patients in whom left ventricular or biventricular assist device are contraindicated, including those with aortic regurgitation, cardiac arrhythmias, left ventricular thrombus, acquired ventricular septal defect, or irreversible biventricular failure.14,15 Copeland et al.14 demonstrated that survival to transplant was achieved in 79% patients with refractory heart failure with the use of TAH.
Although the data regarding pulmonary hemodynamics in patients undergoing TAH implantation as a bridge to transplant are sparse, recent studies involving patients with LVAD have shown that these devices when used as a bridge to transplant can reverse significant pulmonary HTN in patients with end-stage heart failure making them eligible for cardiac transplantation.12,13 Our study extends this finding to patients who are bridged to transplant with TAH. Pulmonary vascular resistance improved in patients enrolled in high PVR group after bridging with a TAH to cardiac transplantation. The pulmonary and intracardiac pressures continued to remain mildly elevated in the high PVR group, suggesting that there may be an irreversible component to pulmonary vascular remodeling after device unloading and transplantation. Additionally, other patient characteristics associated with increased PVR (i.e., duration of heart failure, liver disease, etc.) may contribute elevated filling pressures after transplantation.
Besides the inherent limitation of a retrospective study, and despite having a reasonable TAH study group, to assess differences in PH and outcomes, this study is relatively small. Twelve patients at 1 month and 11 patients at 12 months posttransplant did not undergo repeated right-sided pressure estimation, and thereby, restraining its analysis and report. Furthermore, the temporal effect of TAH implantation on pulmonary hemodynamics was not studied due to inability to perform invasive hemodynamics assessment in patients supported with TAH. TAH system provides pneumatic waveform that allows indirect estimation of PASP.20 We have not collected these data in this retrospective study. Perhaps, future study with implantable hemodynamic monitoring devices such as CardioMEMS21 may be useful to determine early changes in pulmonary artery pressures after TAH implantation.
In conclusion, our study demonstrates that patients with PH and elevated PVR who are bridged to transplant with TAH show improvement in posttransplant pulmonary pressures without any significant change in survival in comparison with low PVR group. The reduction in pulmonary pressures is sustained at 12 months of follow-up post transplant. TAH can be safely used as bridge to transplant (BTT) in patients with biventricular failure and pulmonary HTN.
1. Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult–a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2012;31:913–933
2. Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: part 1: epidemiology, pathophysiology, and definitions. Circ Heart Fail. 2013;6:344–354
3. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000;102:1718–1723
4. Kalogeropoulos AP, Georgiopoulou VV, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: part 2: prognosis, noninvasive evaluation, treatment, and future research. Circ Heart Fail. 2013;6:584–593
5. Kjaergaard J, Akkan D, Iversen KK, et al. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol. 2007;99:1146–1150
6. Alba AC, Rao V, Ross HJ, et al. Impact of fixed pulmonary hypertension on post-heart transplant outcomes in bridge-to-transplant patients. J Heart Lung Transplant. 2010;29:1253–1258
7. Bourge RC, Naftel DC, Costanzo-Nordin MR, et al.for the Transplant Cardiologists Research Database Group. Pretransplantation risk factors for death after heart transplantation: a multi-institutional study. J Heart Lung Transplant. 1993;12:549–562
8. Goland S, Czer LS, Kass RM, et al. Pre-existing pulmonary hypertension in patients with end-stage heart failure: impact on clinical outcome and hemodynamic follow-up after orthotopic heart transplantation. J Heart Lung Transplant. 2007;26:312–318
9. John R, Liao K, Kamdar F, Eckman P, Boyle A, Colvin-Adams M. Effects on pre- and posttransplant pulmonary hemodynamics in patients with continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2010;140:447–452
10. Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg. 2011;40:971–977
11. Torre-Amione G, Southard RE, Loebe MM, et al. Reversal of secondary pulmonary hypertension by axial and pulsatile mechanical circulatory support. J Heart Lung Transplant. 2010;29:195–200
12. Zimpfer D, Zrunek P, Roethy W, et al. Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates. J Thorac Cardiovasc Surg. 2007;133:689–695
13. Mikus E, Stepanenko A, Krabatsch T, et al. Left ventricular assist device or heart transplantation: impact of transpulmonary gradient and pulmonary vascular resistance on decision making. Eur J Cardiothorac Surg. 2011;39:310–316
14. Copeland JG, Smith RG, Arabia FA, et al.CardioWest Total Artificial Heart Investigators. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004;351:859–867
15. Kasirajan V, Tang DG, Katlaps GJ, Shah KB. The total artificial heart for biventricular heart failure and beyond. Curr Opin Cardiol. 2012;27:301–307
16. Toporoff B, Marini CP, Grubbs PE Jr, et al. Pulmonary complications of a roller pump right ventricular assist device. J Surg Res. 1988;45:21–27
17. Eda K. Optimal pulse pressure of pulmonary circulation under bi-ventricular assist after cardiogenic shock. Ann Thorac Cardiovasc Surg. 1999;5:365–369
18. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation. 1995;92:3593–3612
19. Klotz S, Wenzelburger F, Stypmann J, et al. Reversible pulmonary hypertension in heart transplant candidates: to transplant or not to transplant. Ann Thorac Surg. 2006;82:1770–1773
20. Shiose A, Nowak K, Horvath DJ, Massiello AL, Golding LA, Fukamachi K. Speed modulation of the continuous-flow total artificial heart to simulate a physiologic arterial pressure waveform. ASAIO J. 2010;56:403–409
21. Crozier I, Smith W. Modern device technologies. Heart Lung Circ. 2012;21:320–327