Continuous flow left ventricular assist devices (LVADs) and cardiac resynchronization therapy (CRT) are common therapies in patients with advanced heart failure. The concomitant use of the two therapies has become more common in patients with end-stage heart failure. In The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) study, approximately 35% of the cohort had CRT or CRT-D device implanted at the time of LVAD implantation.1
Left ventricular assist device therapy improves long-term outcomes, both by reducing mortality and improved functional status as compared with optimal medical therapy in stage D heart failure.2 , 3 The main purpose of LVAD implantation is to unload the left ventricle (LV) and improve the cardiac output (CO) and promote reverse remodeling.4 However, LVAD therapy creates a unique continuous flow physiology that eliminates the isovolumetric contraction and relaxation periods that are a typical feature of the cardiac cycle..5 This challenges our understating of standard resynchronization therapy, and more specifically, the cardiac electrophysiology in those with LVADs present.
Ventricular arrhythmias (VA) are common post-LVAD implantation specifically in patients with history of VA; however, our group has shown that the utility of implantable cardioverter defibrillators (ICDs) in preventing sudden cardiac death in LVAD patients is limited.6 Further, in the early postoperative phase, we have shown that ICD shocks for VA may be related to postoperative right ventricle (RV) failure.7 With mixed results regarding the utility of ICD therapy on improving mortality in patients implanted with LVAD,8–10 the long-term utility of other pacing technology as CRT-D come into question.
Cardiac resynchronization therapy reduces mortality and improves functional status, benefits that are related to the ability of CRT to promote reverse remodeling.11–13 Similar to the effects of LVAD, these benefits with CRT-D are thought to be related to cardiac reverse remodeling.14 However, for many patients implanted with LVAD, often biventricular pacing is continued with minimal data to support this practice. In the absence of an isovolumic contraction and relaxation period, it is unclear if CRT continues to provide synchronization between the right and LV. Furthermore, there may be a proarrhythmic effect of the LV lead in CRT pacing.15 Therefore, the benefit of active biventricular pacing in LVAD patients is unknown. In this study, we evaluate the hemodynamic and echocardiographic effects of concomitant CRT pacing in LVAD patients.
Materials and Methods
Subjects with either a HVAD (Medtronix International, Framingham, MA) or a HeartMate II (Abbott, Pleasanton, CA) LVAD who underwent a standardized invasive hemodynamic and echocardiographic ramp test between April 2014 to May 2016 were prospectively enrolled in this study. Ramp testing was performed for speed optimization as part of our routine clinical care protocol. Subjects with a suspected LVAD thrombus or other device malfunction were excluded from the study.
Evaluation of Cardiac Resynchronization Therapy Pacing
Subjects included in the study were evaluated regarding the presence of a pacemaker without ICD capability, ICD, CRT capable device, or no device. For those subjects with CRT capable devices, the most recent interrogation before the ramp testing was evaluated. Subjects were categorized in the CRT pacing group if they had an interrogation within 6 months before ramp testing showing biventricular pacing >95% in both leads with Electrocardiogram confirmation. All other subjects were categorized into the non-CRT pacing group.
Ramp Test Protocol
In the catheterization laboratory, subjects underwent an invasive hemodynamic ramp study with simultaneous echocardiography using methods previously reported16 , 17 with a simultaneous right heart catheterization for hemodynamic assessment. Hemodynamic and echocardiographic data were obtained at baseline and each interval speed increase during ramp testing via a standardized ramp protocol as described previously.17–19 Echocardiographic variables collected included left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD), mitral regurgitation severity, and degree amount of aortic valve opening during a 10 beat period. Hemodynamic data collected included central venous pressure (CVP); systolic, diastolic, and mean pulmonary artery pressures (PAP); pulmonary capillary wedge pressure (PCWP); and mean arterial blood pressure (MAP). Pulmonary artery saturation (PA sat), CO/cardiac index (CI) via the indirect Fick method, and pulmonary artery pulsatility index (PAPI) [(systolic PAP − diastolic PAP)/CVP] were calculated.
Subjects were stratified by CRT pacing. Demographics, clinical characteristics, hemodynamics, and echocardiographic characteristics were reported as mean ± standard deviation or as count with percentages. Categorical variables were compared between CRT and non-CRT pacing using χ2 analyses. Continuous demographic, hemodynamic, and echocardiographic variables were compared using the Student’s t-test. Hemodynamic and echocardiographic characteristics were compared between groups at baseline and set-speed LVAD speeds. Normal hemodynamics were defined as CVP <12 and PCWP <18 mm Hg.
Additionally, each subject’s LVEDD, CVP, PCWP, PA saturation, and CO as obtained during ramp testing were plotted against device speed. The slopes for these lines were generated by fitting a linear function to each of the respective characteristics. The mean off-loading slopes for each respective parameter were compared between groups using the Wilcoxon rank sum tests given a non-normalized distribution. Statistical analysis was performed using Microsoft Excel 2013 (Microsoft Corporation, Redmond, WA) and SAS 9.3 software (SAS Institute, Cary, NC) with results being considered as significant at p < 0.05 and trend toward significance at p < 0.10. The study was approved by the hospital’s institutional review board and individual patient consent was waived.
A total of 62 subjects were included in the study with 25 identified as having active CRT pacing. All those with CRT in place had devices placed before LVAD implantation. Average time from LVAD implantation to interrogation was 479 ± 609 days. Subjects were predominately male (60.0%) with a mean age of 59.6 ± 11.4 years. HeartMate II LVADs were present in 42 (67.7%) subjects and the majority of patients were implanted for destination therapy (77.4%; Table 1). As compared with those without active CRT pacing, subjects with active CRT pacing were older (63.9 ± 8.1 vs. 56.8 ± 12.3 years; p = 0.01). However, no other significant difference was found between the two groups in baseline demographics including a history of atrial fibrillation or VAs.
Baseline and Set-Speed Echocardiographic and Hemodynamics
Average time from LVAD implantation to ramp testing was 478 ± 516 days with no significant difference between active versus nonactive CRT pacing group (493 ± 553 vs. 468 ± 490 days; p = 0.85). Among all patients at the time of ramp testing (baseline speed), the LVEDD was 6.1 ± 1.3 cm and LVESD was 5.7 ± 1.3 cm (Table 2). On average, patients were hemodynamically optimized (CVP of 9.1 ± 5.3 mm Hg, PCWP of 13.1 ± 6.2 mm Hg, and CI of 2.7 ± 0.7 L/min) at the time of baseline ramp. No significant difference in PAPI was appreciated between groups. Baseline LVEDD was not significantly different between the two groups (6.2 ± 1.5 vs. 6.0 ± 1.1; p = 0.49). Similarly, no intergroup difference was seen with valvular regurgitation.
Among all patients at the end of ramp testing (set-speed) when comparing active CRT group to non-CRT pacing group, hemodynamics characteristics were similar and there was no difference in the percent of patients within the normalized hemodynamics zone between those with active CRT versus non-CRT pacing (72.0% vs. 67.6%; p = 0.78). Right-sided pressures and PAPI were not significantly different between groups. Echocardiographic measurements were also identical between the groups (Table 3).
Unloading Echocardiographic and Hemodynamics
The relationship between RPM steps and each of the echocardiographic and hemodynamics characteristics are summarized in Table 4. There was a decrease in the LVEDD, CVP, and PCWP with increasing LVAD speed. PA saturation and CO increased with increasing LVAD speed. No differences were seen between the two groups in unloading characteristics, measured by the slopes of LVEDD, CVP, PCWP, Fick CO (Table 4). Hemodynamic response to ramp testing was similar between those with and without active CRT pacing. Figure 1 shows the off-loading CO and CI slopes for those with non-CRT pacing versus CRT pacing who have HM2 LVAD.
To our knowledge, this study is the first to investigate the effects of active CRT pacing on hemodynamic and echocardiographic characteristics of unloading in patients supported with LVADs. Our main findings are as follows: 1) baseline or set-speed echocardiographic/hemodynamic characteristics are not significantly different between patients with and without active CRT pacing and 2) no significant difference in unloading characteristics was observed between patients with and without active CRT pacing.
Implantable cardioverter defibrillator therapy is indicated in heart failure with reduced ejection fraction for both primary and secondary prevention.20 An additional 25–40% of these patients will additionally qualify for CRT as demonstrated by improved mortality and morbidity in both ischemic and nonischemic cardiomyopathies.11 , 21 As a result, at least 35% of advanced heart failure patients will have CRT-D at the time of LVAD implantation.1
Synchronization of the RV, paced at a rate of 60–100 bpm, with the LV, supported by continuous flow support at speeds of 2,300–3,200 rpm (HVAD pump) to 8,000–12,000 rpm (HeartMate II) is impossible. In addition, the potential reverse remodeling induced by CRT may not be clinically significant in comparison to the remodeling benefit of LVAD implantation. Although individual case reports have promoted CRT implantation as a strategy to allow LVAD explanation,22 , 23 these reports involved short periods of LVAD support. Whether CRT is beneficial or harmful during long-term LVAD support is unknown. In one retrospective study, Gopinathannair et al.6 showed that there was no significant improvement in mortality or readmissions (both HF or all-cause) in patients with CRT-D as compared with an ICD alone.
Importantly, our current study suggests that there may be a lack of effect of CRT on acute hemodynamic and echocardiographic unloading of the LV during ramp testing. It is possible that a small benefit provided by CRT on unloading characteristics was overshadowed by the much more significant impact of LVAD unloading. More likely, the lack of benefit related to CRT is because of the fact that advanced heart failure patients who require LVAD therapy are, for the most part, CRT nonresponders, or have regressed after and initial response. Therefore, it is not surprising that there would be no additional benefit with biventricular pacing in the setting of LVAD therapy.6 Additionally, our study shows that there was no significant difference in RV failure between groups.
It is possible that there may be some additional risk of VAs in those with active CRT pacing at least in the early post-LVAD implantation. Choi et al.15 followed 35 LVAD patients in the early postoperative period and found that those with biventricular pacing had increased rates of VAs (64% vs. 4.3%; p =0.04) as compared with ICD alone. The physiology behind these findings is not completely clear. As we have previously suggested, similar to those with hypertrophic cardiomyopathy,24 the septal dyssynchrony away from the LVAD inflow cannula may prevent dynamic obstruction of flow and thereby decrease the likelihood for VAs.25 However, a more longitudinal study that evaluated patients post-LVAD implantation for VAs, ICD shocks, and hospitalizations found that there was no significant difference in those within biventricular pacing group as compared with those with an ICD.6
This study and ones to follow may suggest a benefit to deactivating the LV lead in LVAD patients with the goal of preserving battery life, limiting pulse generator replacements, and avoiding any potential proarrhythmic effects. Our practice is to turn off the LV lead if ventricular burden is high or if functional status is less than expected, and instead is replaced by RV only pacing or back up pacing. Although there has been conflicting evidence regarding the survival benefit among LVAD patients implanted with ICDs,8–10 , 26 the risk of continued ICD therapy after programming to include long detection delay and several rounds of antitachycardial pacing before shocks would be a compromise with little risks particularly in those with a high burden of VAs before LVAD implantation (Figure 2).
Our study has several important limitations. First, this is a small, nonrandomized, non–cross over, single-center study that does not evaluate the same patient with and without active biventricular pacing making it difficult to definitively state that no difference is present. However, we do note that no significant difference was present in baseline line echocardiographic or hemodynamic characteristics between groups. Second, we have limited information about CRT implantation and response before LVAD implantation because of the nature of our center as a tertiary referral center. We are unable to hypothesize on the effect of biventricular pacing chronicity on hemodynamics/echocardiographic characteristics. Third, although there was confirmation of high percentage of biventricular pacing, there was no standardized protocol for CRT programming and no interrogation that occurred on the day of the ramp.
In patients with advanced HF necessitating LVAD therapy, biventricular pacing via a previously implanted CRT device did not confer any additional benefits based on echocardiographic or invasive hemodynamic parameters before or after ramp speed optimization. Furthermore, LV unloading hemodynamics as assessed by ramp testing was not different between CRT patients and those without active biventricular pacing. These findings support prior literature that the two therapies are not synergistic and discontinuation of left ventricular pacing after LVAD implantation to promote device longevity may be prudent.
1. Mehra MR, Naka Y, Uriel N, et al; MOMENTUM 3 Investigators: A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2017.376: 440–450.
2. Rose EA, Gelijns AC, Moskowitz AJ, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group: Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001.345: 1435–1443.
3. Rogers JG, Aaronson KD, Boyle AJ, et al; HeartMate II Investigators: Continuous flow left ventricular assist device improves functional capacity and quality of life of advanced heart failure patients. J Am Coll Cardiol 2010.55: 1826–1834.
4. Marinescu KK, Uriel N, Mann DL, Burkhoff D. Left ventricular assist device-induced reverse remodeling: It’s not just about myocardial recovery. Expert Rev Med Devices 2017.14: 15–26.
5. Burkhoff D, Sayer G, Doshi D, Uriel N. Hemodynamics
of mechanical circulatory support. J Am Coll Cardiol 2015.66: 2663–2674.
6. Gopinathannair R, Birks EJ, Trivedi JR, et al. Impact of cardiac resynchronization therapy on clinical outcomes in patients with continuous-flow left ventricular assist devices. J Card Fail 2015.21: 226–232.
7. Garan AR, Levin AP, Topkara V, et al. Early post-operative ventricular arrhythmias in patients with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2015.34: 1611–1616.
8. Cantillon DJ, Tarakji KG, Kumbhani DJ, Smedira NG, Starling RC, Wilkoff BL. Improved survival among ventricular assist device recipients with a concomitant implantable cardioverter-defibrillator. Heart Rhythm 2010.7: 466–471.
9. Refaat MM, Tanaka T, Kormos RL, et al. Survival benefit of implantable cardioverter-defibrillators in left ventricular assist device-supported heart failure patients. J Card Fail 2012.18: 140–145.
10. Garan AR, Yuzefpolskaya M, Colombo PC, et al. Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices: Need for primary prevention? J Am Coll Cardiol 2013.61: 2542–2550.
11. Cleland JG, Daubert JC, Erdmann E, et al; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005.352: 1539–1549.
12. Tang AS, Wells GA, Talajic M, et al; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators: Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010.363: 2385–2395.
13. Moss AJ, Hall WJ, Cannom DS, et al; MADIT-CRT
Trial Investigators: Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009.361: 1329–1338.
14. Solomon SD, Foster E, Bourgoun M, et al; MADIT-CRT
Investigators: Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: Cardiac resynchronization therapy. Circulation 2010.122: 985–992.
15. Choi AD, Fischer A, Anyanwu A, Pinney S, Adler E. Biventricular pacing in patients with left ventricular assist devices—is left ventricular pacing proarrhythmic? J Am Coll Cardiol 2010.55: A22.E208.
16. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography
ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: The Columbia ramp study. J Am Coll Cardiol 2012.60: 1764–1775.
17. Uriel N, Sayer G, Addetia K, et al. Hemodynamic ramp tests in patients with left ventricular assist devices. JACC Heart Fail 2016.4: 208–217.
18. Nahumi N, Jorde U, Uriel N. Slope calculation for the LVAD
ramp test. J Am Coll Cardiol 2013.62: 2149–2150.
19. Kormos RL, Teuteberg JJ, Pagani FD, et al; HeartMate II Clinical Investigators: Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: Incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010.139: 1316–1324.
20. Hohnloser SH, Israel CW. Current evidence base for use of the implantable cardioverter-defibrillator. Circulation 2013.128: 172–183.
21. Bristow MR, Saxon LA, Boehmer J, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators: Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004.350: 2140–2150.
22. Keilegavlen H, Nordrehaug JE, Faerestrand S, et al. Treatment of cardiogenic shock with left ventricular assist device combined with cardiac resynchronization therapy: A case report. J Cardiothorac Surg 2010.5: 54.
23. Muratsu J, Hara M, Mizote I, et al. The impact of cardiac resynchronization therapy in an end-stage heart failure patient with a left ventricular assist device as a bridge to recovery. A case report. Int Heart J 2011.52: 246–247.
24. Nishimura RA, Trusty JM, Hayes DL, et al. Dual-chamber pacing for hypertrophic cardiomyopathy: A randomized, double-blind, crossover trial. J Am Coll Cardiol 1997.29: 435–441.
26. Enriquez AD, Calenda B, Miller MA, Anyanwu AC, Pinney SP. The role of implantable cardioverter-defibrillators in patients with continuous flow left ventricular assist devices. Circ Arrhythm Electrophysiol 2013.6: 668–674.
Keywords:Copyright © 2019 by the American Society for Artificial Internal Organs
LVAD; CRT; echocardiography; hemodynamics