Because of a lack of donor hearts and long waiting lists, management of advanced heart failure in transplant waitlists has increasingly become reliant on the use of continuous-flow left ventricular assist devices (LVADs). Although LVAD therapy has been well established, a growing proportion of patients develop concomitant right ventricular dysfunction either pre- or post-LVAD implantation and may require biventricular assist device (BiVAD) therapy. There is increasing interest and experience in the use of smaller pumps such as the HeartWare HVAD for continuous-flow BiVAD.1,2 While promising, there are many uncertainties surrounding the use of dual LVAD therapy for biventricular support, particularly on the effects of pump performance and hemodynamic alterations of long-term BiVAD support in the presence of concomitant valvular disorders such as aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR).
Current data regarding the hemodynamic effects of long-term LVAD and BiVAD support in the presence of valvular disorders remain unexplored with only few studies reporting on pulsatile BiVADs.3,4 Although assessment of hemodynamic characteristics can be performed in vivo, they can be difficult to achieve as many factors including patient heterogeneity and challenges associated with measuring accurate hemodynamic parameters can mask direct associations. Thus, the aim of this study was to assess the impact of pump speed and of differences in preload during isolated LVAD as well as with BiVAD support in a pulsatile in vitro mock circulatory loop (MCL) in the presence of valvular regurgitation including AR, MR, and TR.
The pneumatic pulsatile MCL using dual HeartWare HVAD pumps (HeartWare Inc Framingham, MA) in this study has been previously described.5 A diagram of the MCL is shown in Figure 1, and a description of the experimental model and experimental procedure and data acquisition are summarized in the Supplemental Digital Content (http://links.lww.com/ASAIO/A310).
Effect of Valvular Regurgitation on Baseline Left Ventricular Assist Device Pump Flow Waveforms
As seen in Figure 2A, biventricular support increases overall pump flow because of an increase in diastolic flow (because of increased LVAD preload) without significant change in systolic flow. In all regurgitant valve lesions (Figure 2B–D), there is a decrease in isolated LVAD pump flow pulsatility. With MR (Figure 2B), there is marked diminution of peak systolic flow because of the regurgitation, with maintained diastolic flow. Overall forward pump flow is decreased. There is little impact of biventricular support in this scenario. In the setting of AR (Figure 2C), LVAD pump flow is markedly increased, because of recirculation, and again unaffected by biventricular support. With TR (Figure 2D), overall flows are decreased, although there is some benefit of biventricular support in this setting. In Figure 3, it can be seen that the baseline, unsupported mechanical circulatory support flow is lower with each of the regurgitant lesions compared with control.
Effect of Pump Speed on Regurgitant Flow
Figure 3 summarizes the effect of changes in pump speed on flow and pressure during control and abnormal valvular conditions such as AR, MR, and TR. Introduction of isolated LVAD and then BiVAD support increased overall mock loop flow. This was most marked in the control (intact valves), MR, and TR settings. As expected, for the LVAD control with intact valves, increased LVAD pump speed resulted in increased mean arterial pressure (MAP) and right atrial (RA) pressures and reduced left atrial (LA) and mean pulmonary arterial pressure (MPAP). Flow values for flowmeter, LVAD, and RVAD also increased. With increases in pump speed, the MAP increased very significantly, related to the fixed compliance state of the mock loop and the lack of auto-regulatory feedback mechanisms in the current model. Despite the increased MAP, there was successful LV unloading manifested by the decrease in LA and MPAP. Similar results were found with BiVAD, at higher overall mock loop flows with increased MPAP compared with baseline.
For AR, the pressures and flow parameters were very different to the rest of the conditions tested and there was little impact on mock loop flow at any pump speed. In comparison to LVAD control, TR and MR, increased LVAD speed during AR had little effect on MAP and RA pressures because of the high rate of recirculation through the aortic valve. Mean pulmonary arterial pressure was higher during BiVAD support and was maintained despite LVAD speed changes. Finally, flows measured with the flowmeter and RVAD were much lower compared with controls, whereas LVAD flows measured much higher in the setting of AR. Low mock loop circulation and high rates of regurgitation into the LV are suggestive of a closed loop.
Although RA pressures were slightly higher with TR and isolated LVAD compared with control, BiVAD support effectively compensated for TR. RA pressures only started to increase at the higher mock loop flows. Mitral regurgitation yielded similar trends to those seen in LVAD control with the exception of significantly elevated MPAP at baseline and slightly reduced overall flows compared with control. Isolated LVAD support effectively controlled the elevated MPAP. Biventricular assist device support resulted in increased MPAP and RA with increasing LVAD pump speeds. At low pump speed, RA pressure was decreased with BiVAD support, but as the RVAD speed was not increased in parallel with the LVAD speed, the RV was not completely unloaded and RA increased.
No Ventricular Assist Device Versus Left Ventricular Assist Device Versus Biventricular Assist Device Support
Figure 3 also illustrates the various flow and pressure trends between the differing support configurations tested such as no VAD support, isolated LVAD support, and BiVAD support. Compared with unsupported experiments isolated LVAD increased MAP and flow parameters while reducing LA and MPAP in control and TR. For AR, MPAP was slightly increased MAP and only marginally increased with increasing pump speeds. Furthermore, AR resulted in reduced LA, RA, and MPAP pressures and circulatory flow despite increased pump speeds. With the exception of elevated RA pressures, isolated LVAD support during MR yielded similar trends as its respective LVAD control group. However, once the experiment commenced, LA pressures decreased rapidly, whereas circulatory flows remained low. Although the shift from no VAD to isolated LVAD effectively reduces LA pressure and increases circulatory flow under all conditions except AR, it also increased RA pressures, which increases with increased pump speed. Biventricular assist device support appears to effectively reduce RA pressures, increase LA, MPAP, and circulatory flow parameters. Left ventricular assist device pumps speeds of 2400 RPM to 2800 RPM appear to effectively compensate for MR and TR conditions.
A limitation of the mock loop circulation can be seen with RA pressures increasing above MPAP at high pump speed and flows during isolated LVAD support. This may be because of the fact that the unsupported RV in the mock loop is not able to accommodate the increased flow because of fixed RV compliance, and the mock loop PVR is minimized to maintain mock loop flow. With TR, the PVR is “wide open” resulting in low MPAP. Increased isolated LVAD speed decreases LA and MPAP further with complete LV unloading. Biventricular assist device support overcomes this methodological limitation.
Protocol 2: Impact of Varying Left Atrial Pressure
Figure 4 illustrates the effects of isolated LVAD versus BiVAD support for various control and abnormal valvular conditions such as AR, MR, and TR at varying LVAD preload (10–25 mm Hg). During MR, MPAP was higher than control and TR, but similar to AR (albeit at better overall flows). During AR, MAP and MPAP dropped significantly during isolated LVAD support, whereas RA increased. Right atrial pressures were higher, and overall flows for all conditions were higher for the BiVAD configuration compared with isolated LVAD support. Although BiVAD support demonstrated similar MAP, LA, and MPAP to that of baseline, RA pressures continued to decrease. For all experiments, increasing LA pressure from 10 to 25 mm Hg at increments of 5 mm Hg had only minor effect on MCL flow parameters.
Pressure and Flow Waveforms in the Setting of Biventricular Support
Figure 5 shows pressure and flow waveforms for all experimental conditions and configurations. The waveforms produced were equivalent to physiologic waveform magnitudes and morphologies for control and pathologic valvular disorders. The ejection period (280 ms) created by the SynCardia Companion 2 Driver has been represented as a square wave ejection pulse and placed during the second cycle. Based on LVAD control waveforms, it can be seen that aortic pressure and VAD flows rise in a linear fashion during pneumatic compression of the artificial ventricles. The LA and pulmonary artery (PA) pressures also increase during the ventricular ejection period and then rapidly decrease upon ventricular expansion and opening of the mitral valve. Biventricular support resulted in improved flow and pressure waveforms compared with isolated LVAD and no VAD configurations. Elevated RA pressures were evident for all isolated LVAD experiments compared with no VAD and BiVAD configurations. Typical “V waves” were observed in both the LA pressure of MR and the RA pressure of TR, as would be seen clinically. The most notable difference was AR, with its reduced RVAD and flowmeter flow values (even negative diastolic flow recorded across the flowmeter) and high LVAD flow values. Moreover, aortic, MAP, and RA were lower than controls and PA was much higher.
Valvular pathologies are a common phenomenon in patients suffering from advanced heart failure and are often present in patients considered for VAD support. This study assesses for the first time the impact of pump speed and LV filling pressures in the setting of biventricular support for three common pathologic valvular conditions (AR, MR, and TR). This study confirms a significant impact of MR and AR on LVAD pump flow and shows that biventricular support has only a minor impact, except in the setting of TR.
Although concomitant surgical intervention via valve replacement or repair is often considered to stabilize patient hemodynamic parameters, concomitant repair/replacement may be associated with an increased risk of mortality in LVAD cohorts. There remains controversy on whether correction of significant TR or MR is required at VAD implant,6,7 although it is acknowledged that correction of AR is mandatory.8 Whereas MR and TR tend to decrease post-VAD implant,9 AR may progress.10
Aortic regurgitation occurs frequently in patients supported with continuous-flow VADs, regardless of the presence of preexisting aortic valve abnormalities. Factors which may contribute to AR include high pump speeds, increased aortic root diameter or circumference and a lack of aortic valve opening as a consequence commissural fusion and the deterioration of leaflet tissue.10,11 In the presence of AR, recirculation results in ineffective forward systemic flow, increased LV diastolic pressure, and decreased efficacy of VAD performance. Evidence indicates that continuous-flow LVAD implantation leads to worsening clinical outcomes in patients with preexisting AR10 and for that reason valve replacement or repair is recommended in the setting of preexisting AR.
To compensate for the regurgitant flow, increasing pump speeds have been suggested.11 Using a 5-elemental MCL, Gregory et al.12 demonstrated improved systemic flow with increased LVAD speed during mild and moderate AR events. However, severe AR showed minimum improvement with increased pump speeds. Although our findings also demonstrated minimum improvements to systemic flow during severe AR, higher pump speeds gradually decreased LV filling pressures (Figure 3).
Although BiVAD support was unable to compensate for severe AR, it did produce higher flow with reduced flow pulsatility compared with isolated LVAD configurations and restored RA pressures to physiologic boundaries (Figures 2 and 3). As AR worsens over time, identifying early signs is essential. Not only can recirculation due to significant aortic regurgitation cause hemolysis, reduced forward flow as a consequence of untreated AR could result in multiple organ failure and death (13).13 Based on our findings, high LVAD flows and power consumption (data not shown), combined with simultaneous low RVAD flows and dampened aortic pressure with dicrotic notches on waveforms, are indicators of AR, which may be confirmed with echocardiography. Complimentary to LVAD studies,10 concomitant repair or replacement may be considered in patients undergoing BiVAD support with or at risk of developing severe AR.
Whereas AR is usually degenerative, the etiology of MR in LVAD patients may be because of papillary muscle dysfunction resulting from inferior myocardial infarction or coaptation defect because of annular dilatation.14 Mitral valve repair or replacement has been suggested to enhance LVAD flow6; however, the increased complexity with mitral valve surgery accompanying LVAD has been associated with poor long-term outcomes.15 Evidence suggests a significant reduction of moderate to severe MR with LVADs. Low pump speeds may not provide enough support to compensate for the regurgitant flow, especially during LV recovery where restored native ventricular function increases regurgitant force into the atrium and pulmonary veins. Our findings show that, in the setting of maintained RV flow, MR does not adversely affect LVAD pump performance in a mock loop setting and supports conservative management of severe MR with mechanical support. Increasing pump speeds resulted in predictable trends of increased flows (RVAD, LVAD, and flowmeter), as well as MAP, LA, and RA pressures. Unlike LVAD control, MPAP remained mostly steady, which can be attributed to the severity of the MR (Figure 3).
Isolated LVAD support with increasing LVAD pump speed may result in elevated RA pressures in control, MR, and TR settings. This can be explained by the ventricular design and pneumatic output parameters. As the right ventricle settings were designed to mimic severe right ventricular dysfunction with minimum right ventricular performance (40 mm Hg with the pneumatic driver), the RV output was fixed and was thus unable to compensate for the increased flow facilitated by the LVAD. Although this is more exaggerated than seen clinically, it highlights the importance of considering poor RV function when adjusting LVAD pump speed. The low output combined with the severity of MR and the fact that the entire circulation was being driven by the LVAD could also explain why MPAP values were lower than RA values during MR. The risk of right ventricular dysfunction is reduced with BiVAD support when compared with LVAD as BiVAD provided improved flows (RVAD, LVAD, and flowmeter) as well as reduced RA pressures (Figure 3). During MR, LVAD pump speeds greater than 2800 RPM also resulted in increased RA pressures despite the presence of BiVAD support BiVADs, suggesting incomplete RV unloading. Although this could have been addressed by increasing the RVAD pump speed, in our experiments, RVAD pump speeds remained constant (2400 RPM), whereas the LVAD speeds alone were increased. Aside from slightly lower flows and steady elevated MPAP, no other hemodynamic indicators can be used to suspect MR. Left ventricular assist device waveform suggests lower flow pulsatility during MR (Figure 2).
Tricuspid regurgitation is common in patients with advanced heart failure with an incidence rate of 30–64%.16 Although it may be a sign of structural abnormality, TR often occurs with annular dilatation because of right ventricular enlargement or long-standing pulmonary hypertension,7 or pacemaker/defibrillator leads transgressing the tricuspid valve.17 Although some studies have demonstrated improved outcomes in patients undergoing concomitant tricuspid surgery with LVADs,3,7 this finding has not been universal.18–20 There are currently no recommendations for the management of TR in patients supported with continuous-flow BiVAD therapy. Potapov et al.3 compared the short-term outcomes of concomitant LVAD support and tricuspid repair (n = 7) versus BiVAD and total artificial heart support (n = 18). The study concluded no differences in the short-term outcomes between the two groups.
Our findings demonstrate improved flow and pressure waveforms with BiVAD support when compared with isolated LVAD support in the setting of TR (Figure 3). Moreover, increased LVAD speeds resulted in decreased MPAP and LA with relatively maintained RA until LVAD pumps speeds of 3200 RPM. Left ventricular assist device pump speeds between 2600 and 3000 appear to sufficiently compensate for regurgitant flow, while maintaining low RA and MPAP pressures to prevent long-term pulmonary and right ventricular complications. Except for the typical “V waves” seen in RA waveforms and general dampening of MAP pressures (Figure 5), there does appear to be a slight decrease in flow pulsatility in the isolated LVAD flow waveform with TR compared with isolated LVAD with competent valves (Figure 2D). Although BiVAD appears to be an effective alternative to concomitant surgical intervention and isolated LVAD support, the increased risk of dual pumps need to be considered and further in vivo studies are required to assess the effects of BiVAD outside this “in vitro” hemodynamic setting.
Despite successful replication of control and abnormal valvular states similar to those seen clinically, it is important to recognize that all outcomes achieved are limited to hemodynamic analysis. These in vitro models act as a testing platform to identify limitations and allow for exploration of hemodynamic conditions. Systemic flow values were lower than LVAD/RVAD flows. Although 40% glycerol solution is analogous to human blood viscosity, it lacks electrical conductivity and may yield slightly lower flow values. The addition of saline or 1% corn starch has been recommended to increase the ultrasound scattering particle.21 Furthermore, the HeartWare HVAD controller used in this study overestimates the flow values22 which may further explain the discrepancy between VAD and systemic flows. In addition, as an entire leaflet of the On-X mechanical bileaflet valve was removed, only severe regurgitation conditions were simulated. A further limitation is the fixed ventricular size in the mock loop setting. Although the RV dimension may change in response to loading conditions, the current loop is unable to account for volume shifts and is only valid for pressure measurements. Similarly, as the two ventricles are separate in the mock loop model, ventricular interaction cannot be simulated. As this model does not incorporate automated feedback control of systemic and pulmonary vascular resistance, arterial pressure increases in response to increases in pump speed, and heart rate does not change. Finally, the use of mechanical valves creates variations in waveform morphology during mechanical valve closure. Despite these limitations, the MCL presented here has demonstrated to be a useful tool for in vitro assessment of mechanical assist devices and simulating physiologic and abnormal valvular waveform function. The off-label use of the HeartWare HVAD for biventricular support is not Food and Drug Administration approved and is currently only approved for isolated LVAD support.
Using a 4-elemental Windkessel model, numerous control and abnormal valvular conditions were replicated using various pump speeds (2200–4000) and VAD configurations (isolated LVAD versus BiVAD) using the HeartWare HVAD. All regurgitant lesions were associated with a variable decrease in LVAD flow pulsatility. Dual BiVAD support provided improved flows for LVAD, RVAD, flowmeter and reduced RA pressure for all conditions when compared with isolated LVAD control. In addition, BiVAD stabilized hemodynamics during MR and TR states but remained ineffective during AR. High LVAD flows and power combined with low flows and dampened aortic pressure and MAP are strong indicators of severe AR during isolated or biventricular support.
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