Annals of Biomedical Engineering (Ó 2017) DOI: 10.1007/s10439-017-1804-x
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply:Demand in Chronic Heart Failure KEVIN G. SOUCY,1,2 CARLO R. BARTOLI,3 DUSTIN PHILLIPS,2 GURUPRASAD A. GIRIDHARAN,2 MICHAEL A. SOBIESKI,1 WILLIAM B. WEAD,4 ROBERT D. DOWLING,5 ZHONGJUN J. WU,1 SUMANTH D. PRABHU,6 MARK S. SLAUGHTER,1,2 and STEVEN C. KOENIG1,2 1
Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY 40202, USA; 2Department of Bioengineering, University of Louisville, Louisville, KY 40202, USA; 3Division of Cardiovascular Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; 4 Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA; 5Dowling Consulting, PSC, Louisville, KY 40202, USA; and 6Division of Cardiovascular Disease and Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA (Received 20 September 2016; accepted 27 January 2017) Associate Editor Aleksander S. Popel oversaw the review of this article.
Abstract—Continuous-flow left ventricular assist devices (CF LVADs) are rotary blood pumps that improve mean blood flow, but with potential limitations of non-physiological ventricular volume unloading and diminished vascular pulsatility. In this study, we tested the hypothesis that left ventricular unloading with increasing CF LVAD flow increases myocardial flow normalized to left ventricular work. Healthy (n = 8) and chronic ischemic heart failure (IHF, n = 7) calves were implanted with CF LVADs. Acute hemodynamics and regional myocardial blood flow were measured during baseline (LVAD off, clamped), partial (2–4 L/min) and full (>4 L/min) LVAD support. IHF calves demonstrated greater reduction of cardiac energy demand with increasing LVAD support compared to healthy calves, as calculated by rate-pressure product. Coronary artery flows (p < 0.05) and myocardial blood flow (left ventricle (LV) epicardium and myocardium, p < 0.05) decreased with increasing LVAD support in normal calves. In the IHF model, blood flow to the septum, LV, LV epicardium, and LV myocardium increased significantly with increasing LVAD support when normalized to cardiac energy demand (p < 0.05). In conclusion, myocardial blood flow relative to cardiac demand significantly increased in IHF calves, thereby demonstrating that CF LVAD unloading effectively improves cardiac supply and demand ratio in the setting of ischemic heart failure. Keywords—Mechanical circulatory support device, Coronary circulation, Cardiac tissue perfusion, Regional blood flow, Rate-pressure product. Address correspondence to Steven C. Koenig, Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY 40202, USA. Electronic mail: [email protected] Kevin G. Soucy and Carlo R. Bartoli contributed equally to this work.
INTRODUCTION Continuous-flow left ventricular assist devices (CF LVADs) have many technological advantages over pulsatile flow LVADs for treating advanced heart failure.11,12,20,21,31 Unlike the normal physiological conditions of cyclic ventricular ejection and pulsatile blood flow of the native heart or pulsatile flow LVADs, CF LVADs continuously unload the heart with smaller variation in end-diastolic and end-systolic volume and deliver blood flow with diminished pulsatility. CF LVADs are routinely operated at high levels of support to maximize ventricular unloading and mean blood flow. As rotary blood pump technology has progressed toward the development of smaller devices and longer implant durations, there is growing interest in the potential for partial LVAD support as therapy for patients with earlier stage heart failure and/or as a platform to promote myocardial recovery. The long-term biologic responses, such as myocardial perfusion, end-organ function, and myocardial remodeling, as well as the mechanisms associated with clinically significant adverse events at various levels of CF LVAD support have not been fully characterized.25 Pre-clinical LVAD studies are most often conducted in healthy large animal models with normal cardiovascular function to evaluate safety, reliability, and biocompatibility of CF LVADs. Our group developed and validated a bovine model of chronic ischemic heart failure (IHF) as evidenced by clinically relevant hemodynamic, ventricular geometric remodeling, car-
Ó 2017 Biomedical Engineering Society
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diac tissue fibrosis, and myocyte hypertrophy and apoptosis measurements.4,15,19 The utility of the IHF model has been demonstrated in pre-clinical and translational studies of CF LVADs.3,9,10,23,24,26 The chronic, large-animal IHF model has many of the same features of the clinical heart failure condition that may be affected by CF LVAD support, such as compromised myocardial flows due to diminished coronary flow reserve and compromised cardiac supply:demand relationship.6,13,16,27,28 In this study, we tested the hypothesis that left ventricular unloading with increasing CF LVAD flow increases myocardial blood flow relative to ventricular workload.
ment therapy for progressive IHF up to 60 days prior to the acute CF LVAD implant and experiment.
Surgical Procedures and Instrumentation
The objective of this study was to determine if myocardial blood flow varies as a function of CF LVAD support. Healthy and IHF calves were implanted with CF LVADs that were acutely operated at baseline (pump off), partial support, and full support levels. Hemodynamics and cardiac tissue blood flow measurements and analyses were performed to quantify the impact of LVAD flow on cardiac supply:demand ratios.
Calves were implanted with a clinically-approved CF LVAD—HeartMate II (Thoratec Corporation, Pleasanton, CA) were implanted in 5 normal calves and 3 IHF calves, and HVAD (HeartWare, Miami Lakes, FL) were implanted in 3 normal calves and 4 IHF calves. Under general isoflurane anesthesia, fluid-filled lines were implanted in the left carotid artery and external jugular vein for intraoperative fluid or drug administration. A left thoracotomy was performed at the 5th intercostal space to expose the heart. The CF LVADs were implanted in a left ventricular apex to proximal descending thoracic aorta arrangement without the use of cardiopulmonary bypass. High-fidelity pressure catheters (Millar Instruments, Houston, TX) were used to record left ventricular (LVP) and aortic pressures (AoP). Coronary artery flow (CAF), pulmonary artery flow, and LVAD flow (LVADF) were measured with transit-time ultrasonic flow probes (Transonic Systems, Ithaca, NY). Hemodynamic data were recorded at 400 Hz for 30 s epochs and analyzed using the HEART program in the MATLAB software package (MathWorks, Natick, MA).18
Bovine Model
Experimental Procedures
Hemodynamics and myocardial blood flow were measured in healthy (n = 8) and IHF-induced (n = 7) male Jersey calves (125 ± 8.6 kg). All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Louisville. All animals used in the study were handled in accordance with the University of Louisville IACUC and the Guide for the Care and Use of Laboratory Animals.
Hemodynamic and myocardial blood flow measurements were recorded during baseline conditions and with partial and full LVAD support. Baseline conditions were recorded after LVAD implantation, with the device ‘off’ and the outflow graft clamped to prevent retrograde flow. Partial support was defined as 2–4 L/min of LVADF (HeartMate II, 7000–9000 rpm; HVAD, 2200–3000 rpm) with periodic opening of the aortic valve. Full support was defined as LVADF greater than 4 L/min (HeartMate II, 11,000– 15,000 rpm; HVAD, 3000–4000 rpm) and with the aortic valve closed during systole, which was identified by separation between AoP and LVP during systole and loss of the dicrotic notch (Fig. 1a).
MATERIALS AND METHODS Experimental Design
Bovine Chronic Ischemic Heart Failure (IHF) Model To create the chronic IHF model, calves underwent coronary microembolization, as previously described.4,15,19 In brief, under anesthesia and fluoroscopic guidance, a 6-French catheter was introduced through the carotid artery to selectively engage the left main, left anterior descending, and/or circumflex coronary arteries. A suspension of 90 lm polystyrene microspheres (Polysciences, Inc., Warrington, PA) was injected into the coronary arteries in 1–3 mL boluses until severe ischemic electrocardiographic changes accompanied hemodynamic changes. Animals were recovered and treated with optimal medical manage-
Data Reduction and Analysis The following hemodynamic parameters were calculated on a beat-to-beat basis for each test condition: mean aortic pressure (MAP), systolic blood pressure (AoPsys), diastolic blood pressure (AoPdia), aortic pulse pressure (DP), left ventricular end-diastolic pressure (LVEDP), left ventricular end-systolic pressure (LVESP), LVADF, cardiac output (CO), and heart
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply
FIGURE 1. (a) Sample aortic pressure (AoP), left ventricular pressure (LVP), and left ventricular assist device flow (LVADF) waveforms recorded in healthy (normal) and ischemic heart failure (IHF) calves during baseline, partial, and full LVAD support. (b) LVAD flow of 2–4 L/min (partial support) and >4 L/min (full support) were produced in healthy (normal) and chronic ischemic heart failure (IHF) calves to investigate hemodynamic and myocardial blood flow responses. Differences in LVADF between healthy and IHF calves were statistically indiscernible during partial and full support. (c) Left ventricular end-diastolic pressure (LVEDP) was significantly affected by LVAD support. The IHF model demonstrated increased LVEDP at baseline and greater reduction in LVEDP during LVAD support than in normal calves. Full LVAD support achieved similar LVEDP in the IHF and normal bovine models. (d) Baseline diastolic aortic pressure (AoPdia) was significantly lower in IHF calves compared to normal calves. CF LVAD support produced significant, proportional increases of AoPdia in the IHF bovine model but not in the normal bovine model. Normal, n 5 8; heart failure, n 5 7. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, unless otherwise indicated, by repeated measures two-way ANOVA with Bonferroni post-tests.
rate (HR). Using HR and LVESP, the rate-pressure product (RPP) was calculated as an index of left ventricular energy demand. Coronary artery flow data were also recorded, with mean CAF, peak systolic CAF, peak diastolic CAF, average systolic CAF, average diastolic CAF, mean positive CAF, and mean negative CAF calculated.
Cardiac Tissue Perfusion Myocardial blood flow was quantified by injection of fluorescently-labeled, 15 lm diameter microspheres (NuFlow Microspheres, Interactive Medical Technology, Irvine, CA), as previously described.4,5,24 A volume containing 5.25 9 106 microspheres was injected
HR heart rate, MAP mean arterial pressure, AoPsys systolic aortic pressure, AoPdia diastolic aortic pressure, DP aortic pulse pressure, CO cardiac output, LVEDP left ventricular enddiastolic pressure, LVESP left ventricular end-systolic pressure, LVADF left ventricular assist device flow. a Significance of animal model and LVAD support as sources of variation are presented by p values as determined by two-way ANOVA with repeated measures. ns not significant, p > 0.05. b * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, determined by repeated measures two-way ANOVA Bonferroni post-tests. c p < 0.05, à p < 0.01, àà p < 0.001 vs. ‘Partial support’ of respective animal group, determined by repeated measures two-way ANOVA Bonferroni post-tests. d§ p < 0.05 between Normal and Heart Failure ‘Baseline’, determined by two-way ANOVA Bonferroni post-tests.
à
7.86 ± 1.40 7.10 ± 1.37 8.13 ± 1.48 ns ns 25.6 ± 2.3 12.5 ± 3.0 *** 3.74 ± 1.5***, àà ns 0.05. b * p < 0.05, ** p < 0.01 vs. ‘Baseline’ of respective animal group, determined by repeated measures one-way ANOVA Bonferroni post-tests.
support was determined to significantly affect all measured CAF parameters in the healthy calves (Table 2), which is consistent with other pre-clinical data. Ootaki et al. reported diminished coronary blood flow with increased CF LVAD support in a healthy porcine model and with induced left anterior descending artery stenosis.17 Ando et al. demonstrated a reduction in CAF and myocardial oxygen consumption in healthy goats supported by CF LVAD (EVAHEART) during 50% (partial) and 100% (full) LVAD support conditions.1,2 They also performed a study using a goat model of acute ischemic heart failure developed using a coronary embolization technique similar to ours. In the acute IHF model, CAF increased +7% with partial CF LVAD support and +14% with full CF LVAD support compared to no support,30 which is consistent with our findings of mean CAF increases (+3 and +5%, respectively) in the chronic IHF bovine model. The different cardiac blood flow responses to LVAD support in healthy and heart failure models may also be influenced by corresponding changes in diastolic aortic pressure, the primary driving pressure for myocardial perfusion. The IHF calves in our study demonstrated drastic increases of diastolic aortic pressure with CF LVAD support (+10 mmHg during partial support and +19 mmHg during full support), while healthy calves demonstrated respective increases of +2 and +7 mmHg (Table 1; Fig. 1c). As a result, elevated diastolic aortic pressures during CF LVAD support in the IHF model may help maintain myocardial perfusion in spite of reduced cardiac energy demands. Similar to our findings, Tuzun et al. reported reduced CAF, myocardial blood flow, and myocardial oxygen consumption with increasing CF LVAD (Jarvik 2000) support in a healthy bovine model.29 They
also reported a similar endocardial:epicardial perfusion ratio (1.17 ± 0.45) that did not change as a function of LVAD support in healthy animals. The endocardial:epicardial perfusion ratio may be compromised in pathologic conditions, such as LV hypertrophy, and increase the risk of endocardial ischemia.6 In our study, the endocardial:epicardial perfusion ratio was significantly reduced in the IHF calves compared to the healthy calves. Increasing LVAD support in the IHF calves resulted in partial recovery of the endocardial:epicardial perfusion ratio (+28% during full support), but the increases were not statistically significant. Collectively, these findings suggests that LVAD support may provide a more favorable milieu for myocardial remodeling by restoring blood flow, especially in the ischemic region. The loss of correlation of CAF and myocardial blood flow with increasing LVAD support in the chronic IHF model suggests a possible imbalance between myocardial blood supply and cardiac demand. Systolic CAF was found to be significantly affected by LVAD support in IHF calves, showing reduced systolic CAF during partial and full support. A tendency for increased diastolic CAF during CF LVAD support could be inferred (Table 2) but not statistically corroborated. Although CF LVADs unload the diseased heart and reduce ventricular workload, as calculated by RPP, the coronary flows in IHF calves were not proportionally reduced as in healthy calves. This loss of proportional reduction implies that the supply is not sufficient for the demand in the IHF model, which is further supported by the significantly lower normalized myocardial blood flow in IHF calves compared to healthy calves without LVAD support. Although coronary flow reserve was not directly measured in this study, these findings may represent diminished coro-
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply
FIGURE 4. Regional blood flow of left ventricle (LV), LV epicardium, LV myocardium, LV endocardium, and septum were normalized to paired rate-pressure products (RPP) as an indicator of myocardial blood supply:demand ratio. In the ischemic heart failure (IHF) bovine model, LVAD support significantly affected the normalized blood flow in the septum (p < 0.01), LV (p < 0.05), epicardium (p < 0.01), and myocardium (p < 0.05), but not the endocardium (p 5 0.07), as assessed by repeated measures one-way ANOVA. LVAD support was not a significant factor of normalized blood flow for any of the myocardial tissue regions in the normal calves. Normal, n 5 8; heart failure, n 5 7. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, unless otherwise indicated, by repeated measures one-way ANOVA with Bonferroni post-tests.
nary flow reserve or myocardial hypoxia, as identified in human heart failure patients.13,16,28 When normalized to RPP, LVAD support in IHF animals had a significant impact on relative myocardial blood flow, which suggests an improvement in the myocardial supply:demand ratio. There are several limitations associated with acute, large-animal model, mechanical circulatory support testing. Acute studies of implantable cardiovascular devices face the challenge to yield data in an intraoperative time frame that is applicable to chronic, clinical therapy. To help minimize the impact of sur-
gical trauma on acute study data, we continuously monitor the calves and administer anesthetic/analgesic treatments to provide stable hemodynamic conditions. Of the 15 total calves, 3 calves (1 normal and 2 IHF) experienced cardiac arrhythmia that required cardiopulmonary resuscitation or electric shock defibrillation to recover. As with any animal disease model, there exist variability between subjects and disease severity. From our prior experiences with bovine models, cardiac outputs are typically 10–12 L/min in healthy calves and reduced to 6–8 L/min in IHF calves. Although it is unclear why the healthy calves of
SOUCY et al.
FIGURE 5. The ratio of blood flow between the endocardial and epicardial regions was significantly reduced in the ischemic heart failure (IHF) bovine model compared to normal calves at baseline. The endocardial:epicardial perfusion ratio was virtually unchanged by LVAD support in the normal calves, while full LVAD support in the IHF calves resulted in a 28% restoration toward normal levels (p 5 ns). Normal, n 5 7; heart failure, n 5 7. ** p < 0.01 by two-tailed unpaired Student’s t test
this study presented cardiac output lower than expected from our previous studies, it is possible that animal size, anatomy, depth of anesthesia, and/or length of surgery may have played a role. In reviewing the surgical records, we noted the time from device implant to the start of data collection was significantly longer in healthy calves (100 ± 13 min) than in IHF calves (43 ± 14 min). In addition, the ‘baseline’ condition in this study is recorded after CF LVAD implant, with the device off and outflow graft clamped. This post-implant condition may affect the ‘baseline’ hemodynamics, with a more drastic impact on the healthy calves. Despite this limitation in the healthy calves, the IHF calves of this study achieved the expected cardiac output for the IHF model and demonstrated other indicators of heart disease, including reduced arterial pressures (mean, systolic, and diastolic) and elevated LVEDP. When considering all the hemodynamic metrics and our experience with the chronic IHF bovine model, we are confident that the severity of IHF induction was sufficient for the current study. Even though accurate coronary artery flow was collected in 3 of the healthy calves and 5 of the IHF calves only, notable trends and statistical differences were still discernable, specifically in the healthy calf model. While this study returned findings that may be of value for CF LVAD operation in human heart failure patients, it should be realized that this study focused on acute systemic and coronary responses. Chronic CF LVAD therapy and operation at high pump speeds have inherent risks that must be considered in the clinical setting, including diminished arterial pulsatility, aortic valve insufficiency, LV suction, and right heart failure.25 Thus, CF LVAD speed
should be set conservatively by clinicians with patient safety being paramount, while also realizing that higher device support may improve the cardiac supply:demand ratio and the potential for myocardial recovery. In conclusion, the study data support the hypothesis that increasing CF LVAD support improves myocardial blood flow in relation to cardiac demand in the chronic IHF bovine model. These findings may have clinical implications for managing the cardiac supply:demand ratio with CF LVAD therapy, especially as a potential platform technology for myocardial remodeling.
ACKNOWLEDGMENTS The authors thank the following individuals for their support of this study: Karen Lott, Laura Lott, Cary Woolard, and Leslie Sherwood, DVM. This study was completed, in part, in support of the doctoral thesis and dissertation of C.R. Bartoli, MD, PhD entitled Partial vs. Full Support of the Heart with a Continuous-Flow Left Ventricular Assist Device: Implications for Myocardial Recovery. Funding for this project was provided, in part, by Roger M. Prizant Research Trust Fund, University of Louisville Clinical Translational Science Pilot Grant Program, and University of Louisville Cardiac Implant Science Endowment. Dr. Slaughter and Dr. Koenig have received funding unrelated to this study from industry sponsors for training and pre-clinical testing (HeartWare, Miami Lakes FL; St. Jude Medical, Minneapolis MN; Thoratec, Pleasanton CA). The authors have no other conflicts of interest to disclose. The left ventricular assist devices were provided by HeartWare (Miami Lakes, FL) and Thoratec (Pleasanton, CA) under material transfer agreements (MTA).
REFERENCES 1
Ando, M., Y. Takewa, T. Nishimura, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. A novel counterpulsation mode of rotary left ventricular assist devices can enhance myocardial perfusion. J. Artif. Organs. 14:185–191, 2011. 2 Ando, M., Y. Takewa, T. Nishimura, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. Coronary vascular resistance increases under full bypass support of centrifugal pumps–relation between myocardial perfusion and ventricular workload during pump support. Artif. Organs. 36:105–110, 2012. 3 Bartoli, C. R., G. A. Giridharan, K. N. Litwak, M. Sobieski, S. D. Prabhu, M. S. Slaughter, and S. C. Koenig.
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply Hemodynamic responses to continuous versus pulsatile mechanical unloading of the failing left ventricle. Asaio. J. 56:410–416, 2010. 4 Bartoli, C. R., L. C. Sherwood, G. A. Giridharan, M. S. Slaughter, W. B. Wead, S. D. Prabhu, and S. C. Koenig. Bovine model of chronic ischemic cardiomyopathy: implications for ventricular assist device research. Artif Organs 37:E202–E214, 2013. 5 Bartoli, C. R., W. B. Wead, G. A. Giridharan, S. D. Prabhu, S. C. Koenig, and R. D. Dowling. Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva. J. Thorac. Cardiovasc. Surg. 144:402–408, 2012. 6 Carabello, B. A. Understanding coronary blood flow: the wave of the future. Circulation 113:1721–1722, 2006. 7 Chareonthaitawee, P., P. A. Kaufmann, O. Rimoldi, and P. G. Camici. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc. Res. 50:151–161, 2001. 8 Czernin, J., P. Muller, S. Chan, R. C. Brunken, G. Porenta, J. Krivokapich, K. Chen, A. Chan, M. E. Phelps, and H. R. Schelbert. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation 88:62– 69, 1993. 9 Giridharan, G. A., S. C. Koenig, K. G. Soucy, Y. Choi, T. Pirbodaghi, C. R. Bartoli, G. Monreal, M. A. Sobieski, E. Schumer, A. Cheng, and M. S. Slaughter. Hemodynamic changes and retrograde flow in LVAD failure. ASAIO J 61:282–291, 2015. 10 Giridharan, G. A., S. C. Koenig, K. G. Soucy, Y. Choi, T. Pirbodaghi, C. R. Bartoli, G. Monreal, M. A. Sobieski, E. Schumer, A. Cheng, and M. S. Slaughter. Left ventricular volume unloading with axial and centrifugal rotary blood pumps. ASAIO J. 61:292–300, 2015. 11 John, R., F. Kamdar, K. Liao, M. Colvin-Adams, A. Boyle, and L. Joyce. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann. Thorac. Surg. 86:1227–1234; discussion 1234–1225, 2008. 12 Kirklin, J. K., D. C. Naftel, F. D. Pagani, R. L. Kormos, L. W. Stevenson, E. D. Blume, S. L. Myers, M. A. Miller, J. T. Baldwin, and J. B. Young. Seventh INTERMACS annual report: 15,000 patients and counting. J. Heart Lung Transpl. 34:1495–1504, 2015. 13 Lund, G. K., N. Watzinger, M. Saeed, G. P. Reddy, M. Yang, P. A. Araoz, D. Curatola, M. Bedigian, and C. B. Higgins. Chronic heart failure: global left ventricular perfusion and coronary flow reserve with velocity-encoded cine MR imaging: initial results. Radiology 227:209–215, 2003. 14 Martina, J. R., B. E. Westerhof, N. de Jonge, J. van Goudoever, P. Westers, S. Chamuleau, D. van Dijk, B. F. Rodermans, B. A. de Mol, and J. R. Lahpor. Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices. ASAIO J. 60:154– 161, 2014. 15 Monreal, G., L. C. Sherwood, M. A. Sobieski, G. A. Giridharan, M. S. Slaughter, and S. C. Koenig. Large animal models for left ventricular assist device research and development. ASAIO J. 60:2–8, 2014. 16 Neishi, Y., T. Akasaka, M. Tsukiji, T. Kume, N. Wada, N. Watanabe, T. Kawamoto, S. Kaji, and K. Yoshida. Reduced coronary flow reserve in patients with congestive
heart failure assessed by transthoracic Doppler echocardiography. J. Am. Soc. Echocardiogr. 18:15–19, 2005. 17 Ootaki, Y., K. Kamohara, M. Akiyama, F. Zahr, M. W. Kopcak, Jr, R. Dessoffy, and K. Fukamachi. Phasic coronary blood flow pattern during a continuous flow left ventricular assist support. Eur. J. Cardiothorac. Surg. 28:711–716, 2005. 18 Schroeder, M. J., B. Perreault, D. L. Ewert, and S. C. Koenig. HEART: an automated beat-to-beat cardiovascular analysis package using Matlab. Comput. Biol. Med. 34:371–388, 2004. 19 Sherwood, L. C., M. A. Sobieski, S. C. Koenig, G. A. Giridharan, and M. S. Slaughter. Benefits of aggressive medical management in a bovine model of chronic ischemic heart failure. ASAIO J. 59:221–229, 2013. 20 Slaughter, M. S. Long-term continuous flow left ventricular assist device support and end-organ function: prospects for destination therapy. J. Card. Surg. 25:490–494, 2010. 21 Slaughter, M. S., A. L. Meyer, and E. J. Birks. Destination therapy with left ventricular assist devices: patient selection and outcomes. Curr. Opin. Cardiol. 26:232–236, 2011. 22 Slaughter, M. S., F. D. Pagani, J. G. Rogers, L. W. Miller, B. Sun, S. D. Russell, R. C. Starling, L. Chen, A. J. Boyle, S. Chillcott, R. M. Adamson, M. S. Blood, M. T. Camacho, K. A. Idrissi, M. Petty, M. Sobieski, S. Wright, T. J. Myers, D. J. Farrar, and I. I. C. I. HeartMate. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J. Heart Lung Transpl. 29:S1–39, 2010. 23 Slaughter, M. S., K. G. Soucy, R. G. Matheny, B. C. Lewis, M. F. Hennick, Y. Choi, G. Monreal, M. A. Sobieski, G. A. Giridharan, and S. C. Koenig. Development of an extracellular matrix delivery system for effective intramyocardial injection in ischemic tissue. ASAIO J. 60:730–736, 2014. 24 Soucy, K. G., G. A. Giridharan, Y. Choi, M. A. Sobieski, G. Monreal, A. Cheng, E. Schumer, M. S. Slaughter, and S. C. Koenig. Rotary pump speed modulation for generating pulsatile flow and phasic left ventricular volume unloading in a bovine model of chronic ischemic heart failure. J. Heart Lung Transpl. 34:122–131, 2015. 25 Soucy, K. G., S. C. Koenig, G. A. Giridharan, M. A. Sobieski, and M. S. Slaughter. Rotary pumps and diminished pulsatility: do we need a pulse? ASAIO J. 59:355–366, 2013. 26 Soucy, K. G., E. F. Smith, G. Monreal, G. Rokosh, B. B. Keller, F. Yuan, R. G. Matheny, A. M. Fallon, B. C. Lewis, L. C. Sherwood, M. A. Sobieski, G. A. Giridharan, S. C. Koenig, and M. S. Slaughter. Feasibility study of particulate extracellular matrix (P-ECM) and left ventricular assist device (HVAD) therapy in chronic ischemic heart failure bovine model. ASAIO J. 16:161–169, 2015. 27 Tansley, P., M. Yacoub, O. Rimoldi, E. Birks, J. Hardy, M. Hipkin, C. Bowles, H. Kindler, D. Dutka, and P. G. Camici. Effect of left ventricular assist device combination therapy on myocardial blood flow in patients with endstage dilated cardiomyopathy. J. Heart Lung Transpl. 23:1283–1289, 2004. 28 Tsagalou, E. P., M. Anastasiou-Nana, E. Agapitos, A. Gika, S. G. Drakos, J. V. Terrovitis, A. Ntalianis, and J. N. Nanas. Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 52:1391–1398, 2008.
SOUCY et al. 29
Tuzun, E., K. Eya, H. K. Chee, J. L. Conger, N. K. Bruno, O. H. Frazier, and K. A. Kadipasaoglu. Myocardial hemodynamics, physiology, and perfusion with an axial flow left ventricular assist device in the calf. ASAIO J. 50:47–53, 2004. 30 Umeki, A., T. Nishimura, M. Ando, Y. Takewa, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. Change of coronary flow by continuous-flow left ventricular assist device with cardiac
beat synchronizing system (native heart load control system) in acute ischemic heart failure model. Circ. J. 77:995– 1000, 2013. 31 Ventura, P. A., R. Alharethi, D. Budge, B. B. Reid, B. D. Horne, N. O. Mason, S. Stoker, W. T. Caine, B. Rasmusson, J. Doty, S. E. Clayson, and A. G. Kfoury. Differential impact on post-transplant outcomes between pulsatile- and continuous-flow left ventricular assist devices. Clin. Transpl. 25:E390–395, 2011.
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply:Demand in Chronic Heart Failure KEVIN G. SOUCY,1,2 CARLO R. BARTOLI,3 DUSTIN PHILLIPS,2 GURUPRASAD A. GIRIDHARAN,2 MICHAEL A. SOBIESKI,1 WILLIAM B. WEAD,4 ROBERT D. DOWLING,5 ZHONGJUN J. WU,1 SUMANTH D. PRABHU,6 MARK S. SLAUGHTER,1,2 and STEVEN C. KOENIG1,2 1
Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY 40202, USA; 2Department of Bioengineering, University of Louisville, Louisville, KY 40202, USA; 3Division of Cardiovascular Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; 4 Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA; 5Dowling Consulting, PSC, Louisville, KY 40202, USA; and 6Division of Cardiovascular Disease and Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA (Received 20 September 2016; accepted 27 January 2017) Associate Editor Aleksander S. Popel oversaw the review of this article.
Abstract—Continuous-flow left ventricular assist devices (CF LVADs) are rotary blood pumps that improve mean blood flow, but with potential limitations of non-physiological ventricular volume unloading and diminished vascular pulsatility. In this study, we tested the hypothesis that left ventricular unloading with increasing CF LVAD flow increases myocardial flow normalized to left ventricular work. Healthy (n = 8) and chronic ischemic heart failure (IHF, n = 7) calves were implanted with CF LVADs. Acute hemodynamics and regional myocardial blood flow were measured during baseline (LVAD off, clamped), partial (2–4 L/min) and full (>4 L/min) LVAD support. IHF calves demonstrated greater reduction of cardiac energy demand with increasing LVAD support compared to healthy calves, as calculated by rate-pressure product. Coronary artery flows (p < 0.05) and myocardial blood flow (left ventricle (LV) epicardium and myocardium, p < 0.05) decreased with increasing LVAD support in normal calves. In the IHF model, blood flow to the septum, LV, LV epicardium, and LV myocardium increased significantly with increasing LVAD support when normalized to cardiac energy demand (p < 0.05). In conclusion, myocardial blood flow relative to cardiac demand significantly increased in IHF calves, thereby demonstrating that CF LVAD unloading effectively improves cardiac supply and demand ratio in the setting of ischemic heart failure. Keywords—Mechanical circulatory support device, Coronary circulation, Cardiac tissue perfusion, Regional blood flow, Rate-pressure product. Address correspondence to Steven C. Koenig, Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY 40202, USA. Electronic mail: [email protected] Kevin G. Soucy and Carlo R. Bartoli contributed equally to this work.
INTRODUCTION Continuous-flow left ventricular assist devices (CF LVADs) have many technological advantages over pulsatile flow LVADs for treating advanced heart failure.11,12,20,21,31 Unlike the normal physiological conditions of cyclic ventricular ejection and pulsatile blood flow of the native heart or pulsatile flow LVADs, CF LVADs continuously unload the heart with smaller variation in end-diastolic and end-systolic volume and deliver blood flow with diminished pulsatility. CF LVADs are routinely operated at high levels of support to maximize ventricular unloading and mean blood flow. As rotary blood pump technology has progressed toward the development of smaller devices and longer implant durations, there is growing interest in the potential for partial LVAD support as therapy for patients with earlier stage heart failure and/or as a platform to promote myocardial recovery. The long-term biologic responses, such as myocardial perfusion, end-organ function, and myocardial remodeling, as well as the mechanisms associated with clinically significant adverse events at various levels of CF LVAD support have not been fully characterized.25 Pre-clinical LVAD studies are most often conducted in healthy large animal models with normal cardiovascular function to evaluate safety, reliability, and biocompatibility of CF LVADs. Our group developed and validated a bovine model of chronic ischemic heart failure (IHF) as evidenced by clinically relevant hemodynamic, ventricular geometric remodeling, car-
Ó 2017 Biomedical Engineering Society
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diac tissue fibrosis, and myocyte hypertrophy and apoptosis measurements.4,15,19 The utility of the IHF model has been demonstrated in pre-clinical and translational studies of CF LVADs.3,9,10,23,24,26 The chronic, large-animal IHF model has many of the same features of the clinical heart failure condition that may be affected by CF LVAD support, such as compromised myocardial flows due to diminished coronary flow reserve and compromised cardiac supply:demand relationship.6,13,16,27,28 In this study, we tested the hypothesis that left ventricular unloading with increasing CF LVAD flow increases myocardial blood flow relative to ventricular workload.
ment therapy for progressive IHF up to 60 days prior to the acute CF LVAD implant and experiment.
Surgical Procedures and Instrumentation
The objective of this study was to determine if myocardial blood flow varies as a function of CF LVAD support. Healthy and IHF calves were implanted with CF LVADs that were acutely operated at baseline (pump off), partial support, and full support levels. Hemodynamics and cardiac tissue blood flow measurements and analyses were performed to quantify the impact of LVAD flow on cardiac supply:demand ratios.
Calves were implanted with a clinically-approved CF LVAD—HeartMate II (Thoratec Corporation, Pleasanton, CA) were implanted in 5 normal calves and 3 IHF calves, and HVAD (HeartWare, Miami Lakes, FL) were implanted in 3 normal calves and 4 IHF calves. Under general isoflurane anesthesia, fluid-filled lines were implanted in the left carotid artery and external jugular vein for intraoperative fluid or drug administration. A left thoracotomy was performed at the 5th intercostal space to expose the heart. The CF LVADs were implanted in a left ventricular apex to proximal descending thoracic aorta arrangement without the use of cardiopulmonary bypass. High-fidelity pressure catheters (Millar Instruments, Houston, TX) were used to record left ventricular (LVP) and aortic pressures (AoP). Coronary artery flow (CAF), pulmonary artery flow, and LVAD flow (LVADF) were measured with transit-time ultrasonic flow probes (Transonic Systems, Ithaca, NY). Hemodynamic data were recorded at 400 Hz for 30 s epochs and analyzed using the HEART program in the MATLAB software package (MathWorks, Natick, MA).18
Bovine Model
Experimental Procedures
Hemodynamics and myocardial blood flow were measured in healthy (n = 8) and IHF-induced (n = 7) male Jersey calves (125 ± 8.6 kg). All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Louisville. All animals used in the study were handled in accordance with the University of Louisville IACUC and the Guide for the Care and Use of Laboratory Animals.
Hemodynamic and myocardial blood flow measurements were recorded during baseline conditions and with partial and full LVAD support. Baseline conditions were recorded after LVAD implantation, with the device ‘off’ and the outflow graft clamped to prevent retrograde flow. Partial support was defined as 2–4 L/min of LVADF (HeartMate II, 7000–9000 rpm; HVAD, 2200–3000 rpm) with periodic opening of the aortic valve. Full support was defined as LVADF greater than 4 L/min (HeartMate II, 11,000– 15,000 rpm; HVAD, 3000–4000 rpm) and with the aortic valve closed during systole, which was identified by separation between AoP and LVP during systole and loss of the dicrotic notch (Fig. 1a).
MATERIALS AND METHODS Experimental Design
Bovine Chronic Ischemic Heart Failure (IHF) Model To create the chronic IHF model, calves underwent coronary microembolization, as previously described.4,15,19 In brief, under anesthesia and fluoroscopic guidance, a 6-French catheter was introduced through the carotid artery to selectively engage the left main, left anterior descending, and/or circumflex coronary arteries. A suspension of 90 lm polystyrene microspheres (Polysciences, Inc., Warrington, PA) was injected into the coronary arteries in 1–3 mL boluses until severe ischemic electrocardiographic changes accompanied hemodynamic changes. Animals were recovered and treated with optimal medical manage-
Data Reduction and Analysis The following hemodynamic parameters were calculated on a beat-to-beat basis for each test condition: mean aortic pressure (MAP), systolic blood pressure (AoPsys), diastolic blood pressure (AoPdia), aortic pulse pressure (DP), left ventricular end-diastolic pressure (LVEDP), left ventricular end-systolic pressure (LVESP), LVADF, cardiac output (CO), and heart
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply
FIGURE 1. (a) Sample aortic pressure (AoP), left ventricular pressure (LVP), and left ventricular assist device flow (LVADF) waveforms recorded in healthy (normal) and ischemic heart failure (IHF) calves during baseline, partial, and full LVAD support. (b) LVAD flow of 2–4 L/min (partial support) and >4 L/min (full support) were produced in healthy (normal) and chronic ischemic heart failure (IHF) calves to investigate hemodynamic and myocardial blood flow responses. Differences in LVADF between healthy and IHF calves were statistically indiscernible during partial and full support. (c) Left ventricular end-diastolic pressure (LVEDP) was significantly affected by LVAD support. The IHF model demonstrated increased LVEDP at baseline and greater reduction in LVEDP during LVAD support than in normal calves. Full LVAD support achieved similar LVEDP in the IHF and normal bovine models. (d) Baseline diastolic aortic pressure (AoPdia) was significantly lower in IHF calves compared to normal calves. CF LVAD support produced significant, proportional increases of AoPdia in the IHF bovine model but not in the normal bovine model. Normal, n 5 8; heart failure, n 5 7. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, unless otherwise indicated, by repeated measures two-way ANOVA with Bonferroni post-tests.
rate (HR). Using HR and LVESP, the rate-pressure product (RPP) was calculated as an index of left ventricular energy demand. Coronary artery flow data were also recorded, with mean CAF, peak systolic CAF, peak diastolic CAF, average systolic CAF, average diastolic CAF, mean positive CAF, and mean negative CAF calculated.
Cardiac Tissue Perfusion Myocardial blood flow was quantified by injection of fluorescently-labeled, 15 lm diameter microspheres (NuFlow Microspheres, Interactive Medical Technology, Irvine, CA), as previously described.4,5,24 A volume containing 5.25 9 106 microspheres was injected
HR heart rate, MAP mean arterial pressure, AoPsys systolic aortic pressure, AoPdia diastolic aortic pressure, DP aortic pulse pressure, CO cardiac output, LVEDP left ventricular enddiastolic pressure, LVESP left ventricular end-systolic pressure, LVADF left ventricular assist device flow. a Significance of animal model and LVAD support as sources of variation are presented by p values as determined by two-way ANOVA with repeated measures. ns not significant, p > 0.05. b * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, determined by repeated measures two-way ANOVA Bonferroni post-tests. c p < 0.05, à p < 0.01, àà p < 0.001 vs. ‘Partial support’ of respective animal group, determined by repeated measures two-way ANOVA Bonferroni post-tests. d§ p < 0.05 between Normal and Heart Failure ‘Baseline’, determined by two-way ANOVA Bonferroni post-tests.
à
7.86 ± 1.40 7.10 ± 1.37 8.13 ± 1.48 ns ns 25.6 ± 2.3 12.5 ± 3.0 *** 3.74 ± 1.5***, àà ns 0.05. b * p < 0.05, ** p < 0.01 vs. ‘Baseline’ of respective animal group, determined by repeated measures one-way ANOVA Bonferroni post-tests.
support was determined to significantly affect all measured CAF parameters in the healthy calves (Table 2), which is consistent with other pre-clinical data. Ootaki et al. reported diminished coronary blood flow with increased CF LVAD support in a healthy porcine model and with induced left anterior descending artery stenosis.17 Ando et al. demonstrated a reduction in CAF and myocardial oxygen consumption in healthy goats supported by CF LVAD (EVAHEART) during 50% (partial) and 100% (full) LVAD support conditions.1,2 They also performed a study using a goat model of acute ischemic heart failure developed using a coronary embolization technique similar to ours. In the acute IHF model, CAF increased +7% with partial CF LVAD support and +14% with full CF LVAD support compared to no support,30 which is consistent with our findings of mean CAF increases (+3 and +5%, respectively) in the chronic IHF bovine model. The different cardiac blood flow responses to LVAD support in healthy and heart failure models may also be influenced by corresponding changes in diastolic aortic pressure, the primary driving pressure for myocardial perfusion. The IHF calves in our study demonstrated drastic increases of diastolic aortic pressure with CF LVAD support (+10 mmHg during partial support and +19 mmHg during full support), while healthy calves demonstrated respective increases of +2 and +7 mmHg (Table 1; Fig. 1c). As a result, elevated diastolic aortic pressures during CF LVAD support in the IHF model may help maintain myocardial perfusion in spite of reduced cardiac energy demands. Similar to our findings, Tuzun et al. reported reduced CAF, myocardial blood flow, and myocardial oxygen consumption with increasing CF LVAD (Jarvik 2000) support in a healthy bovine model.29 They
also reported a similar endocardial:epicardial perfusion ratio (1.17 ± 0.45) that did not change as a function of LVAD support in healthy animals. The endocardial:epicardial perfusion ratio may be compromised in pathologic conditions, such as LV hypertrophy, and increase the risk of endocardial ischemia.6 In our study, the endocardial:epicardial perfusion ratio was significantly reduced in the IHF calves compared to the healthy calves. Increasing LVAD support in the IHF calves resulted in partial recovery of the endocardial:epicardial perfusion ratio (+28% during full support), but the increases were not statistically significant. Collectively, these findings suggests that LVAD support may provide a more favorable milieu for myocardial remodeling by restoring blood flow, especially in the ischemic region. The loss of correlation of CAF and myocardial blood flow with increasing LVAD support in the chronic IHF model suggests a possible imbalance between myocardial blood supply and cardiac demand. Systolic CAF was found to be significantly affected by LVAD support in IHF calves, showing reduced systolic CAF during partial and full support. A tendency for increased diastolic CAF during CF LVAD support could be inferred (Table 2) but not statistically corroborated. Although CF LVADs unload the diseased heart and reduce ventricular workload, as calculated by RPP, the coronary flows in IHF calves were not proportionally reduced as in healthy calves. This loss of proportional reduction implies that the supply is not sufficient for the demand in the IHF model, which is further supported by the significantly lower normalized myocardial blood flow in IHF calves compared to healthy calves without LVAD support. Although coronary flow reserve was not directly measured in this study, these findings may represent diminished coro-
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply
FIGURE 4. Regional blood flow of left ventricle (LV), LV epicardium, LV myocardium, LV endocardium, and septum were normalized to paired rate-pressure products (RPP) as an indicator of myocardial blood supply:demand ratio. In the ischemic heart failure (IHF) bovine model, LVAD support significantly affected the normalized blood flow in the septum (p < 0.01), LV (p < 0.05), epicardium (p < 0.01), and myocardium (p < 0.05), but not the endocardium (p 5 0.07), as assessed by repeated measures one-way ANOVA. LVAD support was not a significant factor of normalized blood flow for any of the myocardial tissue regions in the normal calves. Normal, n 5 8; heart failure, n 5 7. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. ‘Baseline’ of respective animal group, unless otherwise indicated, by repeated measures one-way ANOVA with Bonferroni post-tests.
nary flow reserve or myocardial hypoxia, as identified in human heart failure patients.13,16,28 When normalized to RPP, LVAD support in IHF animals had a significant impact on relative myocardial blood flow, which suggests an improvement in the myocardial supply:demand ratio. There are several limitations associated with acute, large-animal model, mechanical circulatory support testing. Acute studies of implantable cardiovascular devices face the challenge to yield data in an intraoperative time frame that is applicable to chronic, clinical therapy. To help minimize the impact of sur-
gical trauma on acute study data, we continuously monitor the calves and administer anesthetic/analgesic treatments to provide stable hemodynamic conditions. Of the 15 total calves, 3 calves (1 normal and 2 IHF) experienced cardiac arrhythmia that required cardiopulmonary resuscitation or electric shock defibrillation to recover. As with any animal disease model, there exist variability between subjects and disease severity. From our prior experiences with bovine models, cardiac outputs are typically 10–12 L/min in healthy calves and reduced to 6–8 L/min in IHF calves. Although it is unclear why the healthy calves of
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FIGURE 5. The ratio of blood flow between the endocardial and epicardial regions was significantly reduced in the ischemic heart failure (IHF) bovine model compared to normal calves at baseline. The endocardial:epicardial perfusion ratio was virtually unchanged by LVAD support in the normal calves, while full LVAD support in the IHF calves resulted in a 28% restoration toward normal levels (p 5 ns). Normal, n 5 7; heart failure, n 5 7. ** p < 0.01 by two-tailed unpaired Student’s t test
this study presented cardiac output lower than expected from our previous studies, it is possible that animal size, anatomy, depth of anesthesia, and/or length of surgery may have played a role. In reviewing the surgical records, we noted the time from device implant to the start of data collection was significantly longer in healthy calves (100 ± 13 min) than in IHF calves (43 ± 14 min). In addition, the ‘baseline’ condition in this study is recorded after CF LVAD implant, with the device off and outflow graft clamped. This post-implant condition may affect the ‘baseline’ hemodynamics, with a more drastic impact on the healthy calves. Despite this limitation in the healthy calves, the IHF calves of this study achieved the expected cardiac output for the IHF model and demonstrated other indicators of heart disease, including reduced arterial pressures (mean, systolic, and diastolic) and elevated LVEDP. When considering all the hemodynamic metrics and our experience with the chronic IHF bovine model, we are confident that the severity of IHF induction was sufficient for the current study. Even though accurate coronary artery flow was collected in 3 of the healthy calves and 5 of the IHF calves only, notable trends and statistical differences were still discernable, specifically in the healthy calf model. While this study returned findings that may be of value for CF LVAD operation in human heart failure patients, it should be realized that this study focused on acute systemic and coronary responses. Chronic CF LVAD therapy and operation at high pump speeds have inherent risks that must be considered in the clinical setting, including diminished arterial pulsatility, aortic valve insufficiency, LV suction, and right heart failure.25 Thus, CF LVAD speed
should be set conservatively by clinicians with patient safety being paramount, while also realizing that higher device support may improve the cardiac supply:demand ratio and the potential for myocardial recovery. In conclusion, the study data support the hypothesis that increasing CF LVAD support improves myocardial blood flow in relation to cardiac demand in the chronic IHF bovine model. These findings may have clinical implications for managing the cardiac supply:demand ratio with CF LVAD therapy, especially as a potential platform technology for myocardial remodeling.
ACKNOWLEDGMENTS The authors thank the following individuals for their support of this study: Karen Lott, Laura Lott, Cary Woolard, and Leslie Sherwood, DVM. This study was completed, in part, in support of the doctoral thesis and dissertation of C.R. Bartoli, MD, PhD entitled Partial vs. Full Support of the Heart with a Continuous-Flow Left Ventricular Assist Device: Implications for Myocardial Recovery. Funding for this project was provided, in part, by Roger M. Prizant Research Trust Fund, University of Louisville Clinical Translational Science Pilot Grant Program, and University of Louisville Cardiac Implant Science Endowment. Dr. Slaughter and Dr. Koenig have received funding unrelated to this study from industry sponsors for training and pre-clinical testing (HeartWare, Miami Lakes FL; St. Jude Medical, Minneapolis MN; Thoratec, Pleasanton CA). The authors have no other conflicts of interest to disclose. The left ventricular assist devices were provided by HeartWare (Miami Lakes, FL) and Thoratec (Pleasanton, CA) under material transfer agreements (MTA).
REFERENCES 1
Ando, M., Y. Takewa, T. Nishimura, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. A novel counterpulsation mode of rotary left ventricular assist devices can enhance myocardial perfusion. J. Artif. Organs. 14:185–191, 2011. 2 Ando, M., Y. Takewa, T. Nishimura, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. Coronary vascular resistance increases under full bypass support of centrifugal pumps–relation between myocardial perfusion and ventricular workload during pump support. Artif. Organs. 36:105–110, 2012. 3 Bartoli, C. R., G. A. Giridharan, K. N. Litwak, M. Sobieski, S. D. Prabhu, M. S. Slaughter, and S. C. Koenig.
Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply Hemodynamic responses to continuous versus pulsatile mechanical unloading of the failing left ventricle. Asaio. J. 56:410–416, 2010. 4 Bartoli, C. R., L. C. Sherwood, G. A. Giridharan, M. S. Slaughter, W. B. Wead, S. D. Prabhu, and S. C. Koenig. Bovine model of chronic ischemic cardiomyopathy: implications for ventricular assist device research. Artif Organs 37:E202–E214, 2013. 5 Bartoli, C. R., W. B. Wead, G. A. Giridharan, S. D. Prabhu, S. C. Koenig, and R. D. Dowling. Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva. J. Thorac. Cardiovasc. Surg. 144:402–408, 2012. 6 Carabello, B. A. Understanding coronary blood flow: the wave of the future. Circulation 113:1721–1722, 2006. 7 Chareonthaitawee, P., P. A. Kaufmann, O. Rimoldi, and P. G. Camici. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc. Res. 50:151–161, 2001. 8 Czernin, J., P. Muller, S. Chan, R. C. Brunken, G. Porenta, J. Krivokapich, K. Chen, A. Chan, M. E. Phelps, and H. R. Schelbert. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation 88:62– 69, 1993. 9 Giridharan, G. A., S. C. Koenig, K. G. Soucy, Y. Choi, T. Pirbodaghi, C. R. Bartoli, G. Monreal, M. A. Sobieski, E. Schumer, A. Cheng, and M. S. Slaughter. Hemodynamic changes and retrograde flow in LVAD failure. ASAIO J 61:282–291, 2015. 10 Giridharan, G. A., S. C. Koenig, K. G. Soucy, Y. Choi, T. Pirbodaghi, C. R. Bartoli, G. Monreal, M. A. Sobieski, E. Schumer, A. Cheng, and M. S. Slaughter. Left ventricular volume unloading with axial and centrifugal rotary blood pumps. ASAIO J. 61:292–300, 2015. 11 John, R., F. Kamdar, K. Liao, M. Colvin-Adams, A. Boyle, and L. Joyce. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann. Thorac. Surg. 86:1227–1234; discussion 1234–1225, 2008. 12 Kirklin, J. K., D. C. Naftel, F. D. Pagani, R. L. Kormos, L. W. Stevenson, E. D. Blume, S. L. Myers, M. A. Miller, J. T. Baldwin, and J. B. Young. Seventh INTERMACS annual report: 15,000 patients and counting. J. Heart Lung Transpl. 34:1495–1504, 2015. 13 Lund, G. K., N. Watzinger, M. Saeed, G. P. Reddy, M. Yang, P. A. Araoz, D. Curatola, M. Bedigian, and C. B. Higgins. Chronic heart failure: global left ventricular perfusion and coronary flow reserve with velocity-encoded cine MR imaging: initial results. Radiology 227:209–215, 2003. 14 Martina, J. R., B. E. Westerhof, N. de Jonge, J. van Goudoever, P. Westers, S. Chamuleau, D. van Dijk, B. F. Rodermans, B. A. de Mol, and J. R. Lahpor. Noninvasive arterial blood pressure waveforms in patients with continuous-flow left ventricular assist devices. ASAIO J. 60:154– 161, 2014. 15 Monreal, G., L. C. Sherwood, M. A. Sobieski, G. A. Giridharan, M. S. Slaughter, and S. C. Koenig. Large animal models for left ventricular assist device research and development. ASAIO J. 60:2–8, 2014. 16 Neishi, Y., T. Akasaka, M. Tsukiji, T. Kume, N. Wada, N. Watanabe, T. Kawamoto, S. Kaji, and K. Yoshida. Reduced coronary flow reserve in patients with congestive
heart failure assessed by transthoracic Doppler echocardiography. J. Am. Soc. Echocardiogr. 18:15–19, 2005. 17 Ootaki, Y., K. Kamohara, M. Akiyama, F. Zahr, M. W. Kopcak, Jr, R. Dessoffy, and K. Fukamachi. Phasic coronary blood flow pattern during a continuous flow left ventricular assist support. Eur. J. Cardiothorac. Surg. 28:711–716, 2005. 18 Schroeder, M. J., B. Perreault, D. L. Ewert, and S. C. Koenig. HEART: an automated beat-to-beat cardiovascular analysis package using Matlab. Comput. Biol. Med. 34:371–388, 2004. 19 Sherwood, L. C., M. A. Sobieski, S. C. Koenig, G. A. Giridharan, and M. S. Slaughter. Benefits of aggressive medical management in a bovine model of chronic ischemic heart failure. ASAIO J. 59:221–229, 2013. 20 Slaughter, M. S. Long-term continuous flow left ventricular assist device support and end-organ function: prospects for destination therapy. J. Card. Surg. 25:490–494, 2010. 21 Slaughter, M. S., A. L. Meyer, and E. J. Birks. Destination therapy with left ventricular assist devices: patient selection and outcomes. Curr. Opin. Cardiol. 26:232–236, 2011. 22 Slaughter, M. S., F. D. Pagani, J. G. Rogers, L. W. Miller, B. Sun, S. D. Russell, R. C. Starling, L. Chen, A. J. Boyle, S. Chillcott, R. M. Adamson, M. S. Blood, M. T. Camacho, K. A. Idrissi, M. Petty, M. Sobieski, S. Wright, T. J. Myers, D. J. Farrar, and I. I. C. I. HeartMate. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J. Heart Lung Transpl. 29:S1–39, 2010. 23 Slaughter, M. S., K. G. Soucy, R. G. Matheny, B. C. Lewis, M. F. Hennick, Y. Choi, G. Monreal, M. A. Sobieski, G. A. Giridharan, and S. C. Koenig. Development of an extracellular matrix delivery system for effective intramyocardial injection in ischemic tissue. ASAIO J. 60:730–736, 2014. 24 Soucy, K. G., G. A. Giridharan, Y. Choi, M. A. Sobieski, G. Monreal, A. Cheng, E. Schumer, M. S. Slaughter, and S. C. Koenig. Rotary pump speed modulation for generating pulsatile flow and phasic left ventricular volume unloading in a bovine model of chronic ischemic heart failure. J. Heart Lung Transpl. 34:122–131, 2015. 25 Soucy, K. G., S. C. Koenig, G. A. Giridharan, M. A. Sobieski, and M. S. Slaughter. Rotary pumps and diminished pulsatility: do we need a pulse? ASAIO J. 59:355–366, 2013. 26 Soucy, K. G., E. F. Smith, G. Monreal, G. Rokosh, B. B. Keller, F. Yuan, R. G. Matheny, A. M. Fallon, B. C. Lewis, L. C. Sherwood, M. A. Sobieski, G. A. Giridharan, S. C. Koenig, and M. S. Slaughter. Feasibility study of particulate extracellular matrix (P-ECM) and left ventricular assist device (HVAD) therapy in chronic ischemic heart failure bovine model. ASAIO J. 16:161–169, 2015. 27 Tansley, P., M. Yacoub, O. Rimoldi, E. Birks, J. Hardy, M. Hipkin, C. Bowles, H. Kindler, D. Dutka, and P. G. Camici. Effect of left ventricular assist device combination therapy on myocardial blood flow in patients with endstage dilated cardiomyopathy. J. Heart Lung Transpl. 23:1283–1289, 2004. 28 Tsagalou, E. P., M. Anastasiou-Nana, E. Agapitos, A. Gika, S. G. Drakos, J. V. Terrovitis, A. Ntalianis, and J. N. Nanas. Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 52:1391–1398, 2008.
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Tuzun, E., K. Eya, H. K. Chee, J. L. Conger, N. K. Bruno, O. H. Frazier, and K. A. Kadipasaoglu. Myocardial hemodynamics, physiology, and perfusion with an axial flow left ventricular assist device in the calf. ASAIO J. 50:47–53, 2004. 30 Umeki, A., T. Nishimura, M. Ando, Y. Takewa, K. Yamazaki, S. Kyo, M. Ono, T. Tsukiya, T. Mizuno, Y. Taenaka, and E. Tatsumi. Change of coronary flow by continuous-flow left ventricular assist device with cardiac
beat synchronizing system (native heart load control system) in acute ischemic heart failure model. Circ. J. 77:995– 1000, 2013. 31 Ventura, P. A., R. Alharethi, D. Budge, B. B. Reid, B. D. Horne, N. O. Mason, S. Stoker, W. T. Caine, B. Rasmusson, J. Doty, S. E. Clayson, and A. G. Kfoury. Differential impact on post-transplant outcomes between pulsatile- and continuous-flow left ventricular assist devices. Clin. Transpl. 25:E390–395, 2011.
