Preclinical Proof-of-Concept of a Minimally Invasive Direct Cardiac Compression Device for Pediatric Heart Support.

PURPOSE: For pediatric patients, extracorporeal membrane oxygenation (ECMO) remains the predominant mechanical circulatory support (MCS) modality for heart failure (HF) although survival to discharge rates remain between 50 and 60% for these patients. The device-blood interface and disruption of physiologic hemodynamics are significant contributors to poor outcomes. METHODS: In this study, we evaluate the preclinical feasibility of a minimally invasive, non-blood-contacting pediatric DCC prototype for temporary MCS. Proof-of-concept is demonstrated in vivo in an animal model of HF. Hemodynamic pressures and flows were examined. RESULTS: Minimally invasive deployment on the beating heart was successful without cardiopulmonary bypass or anticoagulation. During HF, device operation resulted in an immediate 43% increase in cardiac output while maintaining pulsatile hemodynamics. Compared to the pre-HF baseline, the device recovered up to 95% of ventricular stroke volume. At the conclusion of the study, the device was easily removed from the beating heart. CONCLUSIONS: This preclinical proof-of-concept study demonstrated the feasibility of a DCC device on a pediatric scale that is minimally invasive and non-blood contacting, with promising hemodynamic support and durability for the initial intended duration of use. The ability of DCC to maintain pulsatile MCS without blood contact represents an opportunity to mitigate the mortality and morbidity observed in non-pulsatile, blood-contacting MCS.

Evaluation of the CorInnova Heart Assist Device in an Acute Heart Failure Model.

While the number of patients supported with temporary cardiac assist is growing, the existing devices are limited by a multitude of complications, mostly related to contact with the blood. The CorInnova epicardial compressive heart assist device was tested in six sheep using an acute heart failure model. High esmolol dose, targeting a 50% reduction in CO from healthy baseline, resulted in a failure state with mean CO 1.9 L/min. Heart assist with the device during failure state resulted in an average absolute increase in CO of 1.0 L/min, along with a decline in ventricular work to 67.5% of the total LV SW. Combined with repeated success of minimally invasive device implant, the resulting increases in cardiac hemodynamics achieved while still unloading the heart demonstrate the potential of the CorInnova device for temporary heart assist.

Preclinical Evaluation of the EVAHEART 2 Centrifugal Left Ventricular Assist Device in Bovines.

The EVAHEART 1 left ventricular assist device was miniaturized to the EVAHEART 2, with a new inflow cannula designed to mitigate the risks of malposition. To evaluate the safety of the new double-cuff tipless inflow cannula, in vivo studies were performed in healthy bovines. Eight consecutive studies were done: five short-term studies of hematological adaptation and three long-term studies of tissue adaptation. Each inflow cannula was purposefully implanted in the worst-case setting with marked malposition. Two studies terminated early: one because of an animal-specific ancillary component and one because of an accidental radial fracture. Six studies reached the study endpoint without major adverse events. One animal could not achieve proper anticoagulation because of warfarin resistance. Pump speed and power were maintained within stable, normal ranges. There were no major organ dysfunction or suction events. Necropsy results showed two cases of pannus formation around the inflow ostium because of warfarin resistance and hyperinflammation at the inflow cuff suture line. There was one case of trivial pannus; four cases were pannus-free, with no evidence of ventricular wall suction. No wedge thrombus formation occurred. The EVAHEART 2 tipless inflow cannula may reduce adverse events attributable to the inflow cannula, such as stroke.

Introduction of sacrificial bonds to hydrogels to increase defect tolerance during suturing of multilayer vascular grafts.

Small-caliber vascular grafts used in coronary artery bypass procedures typically fail due to the development of intimal hyperplasia or thrombosis. Our laboratory has developed a multilayered vascular graft with an electrospun polyurethane outer layer with improved compliance matching and a hydrogel inner layer that is both thromboresistant and promotes endothelialization. Initial in vivo studies showed that hydrogel particulates were dislodged from the hydrogel layer of the grafts during suturing. To address this problem, we developed and characterized a new hydrogel formulation that resists damage during suturing. Introduction of sacrificial, hydrogen bonds to poly(ethylene glycol)-based hydrogels via co-polymerization with n-vinyl pyrrolidone (NVP) increased the fracture energy as determined by single edge notch testing. This enhanced defect tolerance resulted in a hydrogel layer that was resistant to suture-induced damage with no dislodged particles observed. Importantly, the incorporation of NVP did not affect the thromboresistance, bioactivity, or biostability of the hydrogel layer. In addition to eliminating complications due to hydrogel particle generation in our multilayer graft design, this defect tolerant hydrogel formulation has broad potential use in many cardiovascular and soft tissue applications. STATEMENT OF SIGNIFICANCE: Small-caliber vascular grafts used in coronary artery bypass procedures typically fail due to development of intimal hyperplasia or thrombosis. Our laboratory has developed a multilayered vascular graft with an electrospun polyurethane outer layer with improved compliance matching and a hydrogel inner layer that is both thromboresistant and promotes endothelialization. However, hydrogel particulates were dislodged from the hydrogel layer during suturing in vivo. This work describes a hydrogel formulation based on poly(ethylene glycol) that is resistant to suture-induced damage. The introduction of sacrificial, hydrogen bonds by co-polymerization with n-vinyl pyrrolidone (NVP) resulted in an increase fracture energy without affecting the thromboresistance, bioactivity, or biostability. This defect-tolerant hydrogel formulation and the methodology to assess hydrogel defect tolerance has broad potential use in cardiovascular and soft tissue applications.

Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue.

BACKGROUND: Aberrant vagal stimulation may promote the generation and propagation of atrial fibrillation (AF). Researchers have suggested that botulinum toxin (BTX), a neurotoxin that decreases neural vagal stimulation, may decrease the incidence of postoperative AF. The exact electrophysiologic mechanism underlying the observations and histopathologic alterations associated with BTX are unclear. OBJECTIVE: To investigate the electrophysiologic, functional, and histopathologic effects of BTX on fibrillation induction in ovine atria. METHODS: Eight sheep underwent BTX injections into their pulmonary veins, atrial fat pads, and ventricular walls. Electrophysiology with pacing was performed at baseline and 7 days after injection to evaluate the atrial effective refractory period (ERP) and vulnerability to AF with and without vagal stimulation. Echocardiography was performed at baseline and day 7. After euthanasia, histopathologic analysis was performed. RESULTS: Seven sheep completed the study. For both atria, there was significant shortening in the ERP with vagal stimulation versus no stimulation on day 0 but not on day 7. More aggressive pacing was required to induce AF in the left atrium on day 7 than on day 0. Echocardiography on day 7 showed no significant changes in ejection fraction or new wall-motion abnormalities of the left and right ventricle. Histopathologic analysis showed no significant adverse effects. CONCLUSION: The subacute BTX effect reduced the vulnerability of atrial tissue to AF induction and reduced the vagal influence on atrial ERP shortening compared to baseline levels. Direct BTX injection did not cause myocardial dysfunction or histologic adverse effects.

Comparison of shape memory polymer foam versus bare metal coil treatments in an in vivo porcine sidewall aneurysm model.

The endovascular delivery of platinum alloy bare metal coils has been widely adapted to treat intracranial aneurysms. Despite the widespread clinical use of this technique, numerous suboptimal outcomes are possible. These may include chronic inflammation, low volume filling, coil compaction, and recanalization, all of which can lead to aneurysm recurrence, need for retreatment, and/or potential rupture. This study evaluates a treatment alternative in which polyurethane shape memory polymer (SMP) foam is used as an embolic aneurysm filler. The performance of this treatment method was compared to that of bare metal coils in a head-to-head in vivo study utilizing a porcine vein pouch aneurysm model. After 90 and 180 days post-treatment, gross and histological observations were used to assess aneurysm healing. At 90 days, the foam-treated aneurysms were at an advanced stage of healing compared to the coil-treated aneurysms and showed no signs of chronic inflammation. At 180 days, the foam-treated aneurysms exhibited an 89-93% reduction in cross-sectional area; whereas coiled aneurysms displayed an 18-34% area reduction. The superior healing in the foam-treated aneurysms at earlier stages suggests that SMP foam may be a viable alternative to current treatment methods. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1892-1905, 2017.

Aortic pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

Aortic pulse pressure arises from the interaction of the heart, the systemic arterial system, and peripheral microcirculations. The complex interaction between hemodynamics and arterial remodeling precludes the ability to experimentally ascribe changes in aortic pulse pressure to particular adaptive responses. Therefore, the purpose of the present work was to use a human systemic arterial system model to test the hypothesis that pulse pressure homeostasis can emerge from physiological adaptation of systemic arteries to local mechanical stresses. First, we assumed a systemic arterial system that had a realistic topology consisting of 121 arterial segments. Then the relationships of pulsatile blood pressures and flows in arterial segments were characterized by standard pulse transmission equations. Finally, each arterial segment was assumed to remodel to local stresses following three simple rules: 1) increases in endothelial shear stress increases radius, 2) increases in wall circumferential stress increases wall thickness, and 3) increases in wall circumferential stress decreases wall stiffness. Simulation of adaptation by iteratively calculating pulsatile hemodynamics, mechanical stresses, and vascular remodeling led to a general behavior in response to mechanical perturbations: initial increases in pulse pressure led to increased arterial compliances, and decreases in pulse pressure led to decreased compliances. Consequently, vascular adaptation returned pulse pressures back toward baseline conditions. This behavior manifested when modeling physiological adaptive responses to changes in cardiac output, changes in peripheral resistances, and changes in local arterial radii. The present work, thus, revealed that pulse pressure homeostasis emerges from physiological adaptation of systemic arteries to local mechanical stresses.

In vitro and in vivo evaluation of a shape memory polymer foam-over-wire embolization device delivered in saccular aneurysm models.

Current endovascular therapies for intracranial saccular aneurysms result in high recurrence rates due to poor tissue healing, coil compaction, and aneurysm growth. We propose treatment of saccular aneurysms using shape memory polymer (SMP) foam to improve clinical outcomes. SMP foam-over-wire (FOW) embolization devices were delivered to in vitro and in vivo porcine saccular aneurysm models to evaluate device efficacy, aneurysm occlusion, and acute clotting. FOW devices demonstrated effective delivery and stable implantation in vitro. In vivo porcine aneurysms were successfully occluded using FOW devices with theoretical volume occlusion values greater than 72% and rapid, stable thrombus formation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1407-1415, 2016.

The complex distribution of arterial system mechanical properties, pulsatile hemodynamics, and vascular stresses emerges from three simple adaptive rules.

Arterial mechanical properties, pulsatile hemodynamic variables, and mechanical vascular stresses vary significantly throughout the systemic arterial system. Although the fundamental principles governing pulsatile hemodynamics in elastic arteries are widely accepted, a set of rules governing stress-induced adaptation of mechanical properties can only be indirectly inferred from experimental studies. Previously reported mathematical models have assumed mechanical properties adapt to achieve an assumed target stress "set point." Simultaneous prediction of the mechanical properties, hemodynamics, and stresses, however, requires that equilibrium stresses are not assumed a priori. Therefore, the purpose of this work was to use a "balance point" approach to identify the simplest set of universal adaptation rules that simultaneously predict observed mechanical properties, hemodynamics, and stresses throughout the human systemic arterial system. First, we employed a classical systemic arterial system model with 121 arterial segments and removed all parameter values except vessel lengths and peripheral resistances. We then assumed vessel radii increase with endothelial shear stress, wall thicknesses increase with circumferential wall stress, and material stiffnesses decrease with circumferential wall stress. Parameters characterizing adaptive responses were assumed to be identical in all arterial segments. Iteratively predicting local mechanical properties, hemodynamics, and stresses reproduced five trends observed when traversing away from the aortic root towards the periphery: decrease in lumen radii, wall thicknesses, and pulsatile flows and increase in wall stiffnesses and pulsatile pressures. The extraordinary complexity of the systemic arterial system can thus arise from independent adaptation of vessels to local stresses characterized by three simple adaptive rules.

Assessment of aortic valve pressure overload and leaflet functions in an ex vivo beating heart loaded with a continuous flow cardiac assist device.

OBJECTIVES: Aortic valve regurgitation, fusion and thrombosis are commonly reported clinical complications after continuous flow ventricular assist device implantations; however, the complex interaction between reduced pulsatile flow physiology and aortic valve functions has not been studied experimentally. To address this, a continuous flow left ventricular assist device was implanted in four swine ex vivo beating hearts and then operated at baseline (device off, no flow) and at device speeds ranging between 8500 and 11,500 rpm under healthy and experimentally created failing heart conditions. METHODS: At baseline and after each speed increase, aortic, left ventricular, left atrial and pulse pressure signals were monitored to assess the haemodynamic status of the ex vivo heart, aortic valve opening time and the transvalvular pressure changes. Aortic root and device flows were recorded with flow probes. Left ventricular pressure-volume loops were measured with a conductance catheter. Changes in aortic leaflet motion and end-diastolic aortic root diameter were recorded with epicardial echocardiography. RESULTS: A two-chamber healthy and failing ex vivo beating heart model was successfully created. At increasing device flows, aortic valve open time steadily decreased from 36±7% of the baseline cardiac cycle to 0% at 11,500 rpm in the healthy heart and from 18±16 to 0% in failing heart mode (P<0.05). Aortic transvalvular pressure increased from 25±5 mmHg (baseline) to 67±7 mmHg (11,500 rpm) in the healthy heart and from 10±9 mmHg (baseline) to 73±8 mmHg (11,500 rpm) in failing heart mode (P<0.05). Aortic root diameters were significantly increased at speeds exceeding 10 500 rpm in the healthy heart mode (P<0.05 vs baseline) and approached statistical significance in failing hearts. CONCLUSIONS: Increasing assist device flows resulted in pressure overload above the aortic leaflets, impaired leaflet functions, caused aortic root dilatation and altered leaflet coaptation at the central portion of the aortic valve in both modes. We conclude that the deleterious effect of the reduced pulsatile flow on the aortic valve functions and haemodynamics is immediate and such an insult may explain the structural changes of the aortic valve causing leaflet fusion and/or regurgitation in the chronic phase.

The effects of continuous and intermittent reduced speed modes on renal and intestinal perfusion in an ovine model.

The effects of the continuous-flow output on renal and intestinal microcirculation have not been extensively studied. To address this, the Heartware HVAD pump loaded with continuous and intermittent reduced speed (IRS) modes was implanted in four sheep and then operated at low and high speeds to mimic partial and complete unloading of the left ventricle. Then microsphere and positron emission tomography/computed tomography (PET/CT) studies were used to assess renal and intestinal tissue perfusion at various pump speeds and flow modes as compared with baseline (pump off). Arterial and venous oxygen (T02) and carbon dioxide (TCO2) contents were measured to assess changes in intestinal metabolism. Renal and intestinal regional blood flows did not produce any significant changes compared with baseline values in either continuous or IRS modes and speeds. The venous TO2 and TCO2 significantly increased in continuous and IRS modes and speeds compared with baseline. Our data suggested that renal and intestinal tissue perfusions were not adversely affected by continuous and IRS modes either in partial or complete unloading. Intestinal venous hyperoxia and increased TCO2 may be the evidence of intestinal arteriovenous shunting along with increased intestinal tissue metabolism. Longer-term studies are warranted in chronic heart failure models.

In vivo response to an implanted shape memory polyurethane foam in a porcine aneurysm model.

Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane-based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology, and low vacuum scanning electron microscopy imaging after 0, 30, and 90 days. Clotting was initiated within the SMP foam at time 0 (<1 h exposure to blood before euthanization), partial healing was observed at 30 days, and almost complete healing had occurred at 90 days in vivo, with minimal inflammatory response.

MR angiography of carotid artery aneurysms in a porcine model at 3 Tesla: comparison of two different macrocyclic gadolinium chelates and of dynamic and conventional techniques.

PURPOSE: To evaluate the differences in image quality of two macrocyclic gadolinium-based contrast agents, gadobutrol and gadoterate meglumine, using time-resolved, contrast-enhanced MR angiography (CE-MRA) in a porcine carotid artery aneurysm model and to compare image quality between dynamic and conventional, single acquisition CE-MRA. MATERIALS AND METHODS: Bilateral carotid aneurysms were created surgically in this Institutional Animal Care and Use Committee approved study. Dynamic CE-MRA studies optimized for high temporal resolution were performed at 3 Tesla. Scans using equivalently dosed (on a per mmol basis) gadobutrol and gadoterate meglumine were compared qualitatively and quantitatively in terms of contrast-to-noise ratio (CNR). Higher spatial resolution dynamic and conventional CE-MRA were also compared. RESULTS: N = 16 aneurysms were assessed. Qualitative evaluation of dynamic CE-MRA scans demonstrated a preference for gadobutrol over gadoterate meglumine. Significantly higher aneurysm CNR was found with gadobutrol (133 ± 44) versus gadoterate meglumine, the latter at both equivalent and double injection rates (94 ± 35 and 102 ± 38). In a blinded assessment, conventional CE-MRA was preferred qualitatively when compared with dynamic CE-MRA. However, dynamic CE-MRA was generally capable of providing diagnostic image quality. CONCLUSION: Gadobutrol is preferred to gadoterate meglumine for high temporal resolution dynamic CE-MRA, a fact with important clinical implications for low dose CE-MRA protocols in patients at risk for nephrogenic systemic fibrosis. Conventional high resolution CE-MRA provides superior image quality when compared with dynamic CE-MRA.

Pulsatile venous waveform quality in Fontan circulation-clinical implications, venous assists options and the future.

OBJECTIVE: Functionally univentricular heart (FUH) anomalies are the leading cause of death from all structural birth defects. Total cavopulmonary connection (TCPC) is the last stage of the palliative surgical reconstruction with significant late hemodynamic complications requiring high-risk heart transplantation. Alternative therapeutic options for these critically ill patients are crucial. In Phase I, we investigated the effect of pulsatility of venous flow (VF) waveform on the performance of functional and "failing" Fontan (FF) patients based on conduit power loss. In phase 2, the effect of enhanced external counter pulsation on Fontan circulation flow rates is monitored. METHODS: In phase 1, Doppler VFs were acquired from FF patients with ventricle dysfunction. Using computational fluid dynamics (CFD), hemodynamic efficiencies of the FF, functional and in-vitro generated mechanically assisted VF waveforms were evaluated. In phase 2, Fontan circulation on sheep model was created and enhanced external counter pulsation (EECP) applied. RESULTS: Variations in the pulsatile content of the VF waveforms altered conduit efficiency notably. High frequency and low amplitude oscillations lowered the pulsatile component of power losses in FF VF waveforms. The systemic venous flow, pulmonary artery and aorta flows increased by utilizing EECP. CONCLUSION: Our data highlighted the significance of VF pulsatility on energy efficiency inside SV circulation and the feasibility of VF waveform optimization. EECP assist in Fontan circulation can result in venous flow augmentation.

In vivo testing of an intra-annular aortic valve annuloplasty ring in a chronic calf model.

OBJECTIVE: To increase applicability and stability of aortic valve repair, a three-dimensional aortic annuloplasty ring has been developed for intra-annular placement. The goal of this study was to test the safety of this device with in vivo implantation in the calf model. METHODS: In 10 chronic calves, the HAART annuloplasty ring was sutured to the aortic valve annulus using cardiopulmonary bypass. The animals were recovered and followed for 1-2 months. Serial echocardiography was used to evaluate valve competence, and contrast aortograms and CT angiograms were obtained in selected animals. After completion of follow-up, each animal was euthanized, and aortic endoscopy was performed under water distension in five. Full autopsies with histologic examinations were performed. RESULTS: All animals survived surgery. Two were euthanized in the first week for complications, and the remaining eight calves were followed uneventfully for the 1-2 months. Serial echocardiography showed completely competent valves in all but one animal, in which the ring was intentionally up-sized to test the sizing strategy. Contrast aortographic and CT angiographic findings were similar to the echocardiograms. Postmortem examination showed proper seating of all rings with endothelialization at 1-2 months. All valves demonstrated good leaflet coaptation and no abnormalities. CONCLUSIONS: In vivo testing of a three-dimensional aortic annuloplasty ring in a chronic calf model proved to be very successful and safe. Using the sizing and implant strategies developed, human trials seem indicated.

In vivo performance evaluation of the innovamedica pneumatic ventricular assist device.

We evaluated the short- and mid-term in vivo performance of the Innovamedica ventricular assist device (VAD), a new, low-cost, paracorporeal, pneumatically actuated, pulsatile blood pump. We implanted the VAD in six healthy sheep by inserting the stainless-steel inflow cannula into the left ventricular apex and suturing the outflow graft to the descending thoracic aorta. The anesthetized animals were supported for 6 hours, and pump performance, hemodynamic parameters, and hemolysis were monitored. The pump maintained a blood flow of 4.4 ± 0.8 L/min and an arterial blood pressure of 76 ± 15 mm Hg. At 6 hours, the plasma free hemoglobin concentration was 5.11 ± 0.6 mg/dl (baseline value, 4.52 ± 0.7 mg/dl). The VAD was easy to implant and deair and performed well during the 6 hour period. After successful short-term results, we similarly implanted the VAD in two healthy sheep for 30 days. The animals reached the scheduled end point without device-related problems. Postmortem examination of the explanted organs revealed small infarcted areas in the kidneys of one animal, but renal function was unaffected; the animal also had two thrombi (3 and 7 mm) on the outlet valve. This device may offer a simple, economical alternative to currently available VADs.

Stent treatment of inferior vena cava compression in an ovine with a total artificial heart.

Although current continuous-flow total artificial hearts (CFTAHs) are much smaller than previous models, venous kinking may still occur after device implantation, especially in smaller animals. By inserting a self-expanding stent at the site of venous narrowing in a sheep model implanted with a CFTAH, we were able to restore the normal venous geometry and dramatically increase the CFTAH output. Because this percutaneous approach avoids the challenges associated with reoperation in these cases, it may be useful to other CFTAH investigators.

Ventricular assist device outflow-graft site: effect on myocardial blood flow.

BACKGROUND: Recent advances in left ventricular assist device (LVAD) technology have resulted in small, durable, energy-efficient, continuous-flow blood pumps that can support patients with end-stage heart failure. However, the effects of reduced or nonpulsatile flow on end-organ function are unclear. We performed a pilot study in calves with a continuous-flow LVAD to assess the effects of the pump's outflow-graft location (ascending versus descending aorta) on myocardial blood flow. MATERIALS AND METHODS: In 8 healthy calves, we implanted the Jarvik 2000 LVAD in the left ventricular apex without the use of cardiopulmonary bypass. We anastomosed the outflow graft to either the ascending aorta (group 1; n = 4) or the descending aorta (group 2; n = 4). Hemodynamic parameters, myocardial oxygen consumption, and regional myocardial blood flow (analyzed with colored microspheres) were assessed at baseline (pump off) and during pump operation at 8000, 10,000, and 12,000 rpm. RESULTS: No intergroup differences were found in the aortic pressure, heart rate, central venous pressure, pump-flow to total-cardiac-flow ratio, or blood flow in the left anterior descending and right posterior descending coronary arteries at increasing pump speeds. Neither myocardial oxygen consumption nor myocardial tissue perfusion differed significantly between the two groups. CONCLUSIONS: Regardless of the outflow-graft location (ascending versus descending aorta), the continuous-flow LVAD unloaded the left ventricle and did not adversely affect myocardial perfusion in either the right or left ventricle. Owing to the small number of animals studied, however, the most we can conclude is that neither outflow-graft location appeared to be inferior to the other.

Continuous-flow cardiac assistance: effects on aortic valve function in a mock loop.

BACKGROUND: As the use of left ventricular assist devices (LVADs) to treat end-stage heart failure has become more widespread, leaflet fusion--with resul-tant aortic regurgitation--has been observed more frequently. To quantitatively assess the effects of nonpulsatile flow on aortic valve function, we tested a continuous-flow LVAD in a mock circulatory system (MCS) with an interposed valve. MATERIALS AND METHODS: To mimic the hemodynamic characteristics of LVAD patients, we utilized an MCS in which a Jarvik 2000 LVAD was positioned at the base of a servomotor-operated piston pump (left ventricular chamber). We operated the LVAD at 8000 to 12,000 rpm, changing the speed in 1000-rpm increments. At each speed, we first varied the outflow resistance at a constant stroke volume, then varied the stroke volume at a constant outflow resistance. We measured the left ventricular pressure, aortic pressure, pump flow, and total flow, and used these values to compute the change, if any, in the aortic duty cycle (aortic valve open time) and transvalvular aortic pressure loads. RESULTS: Validation of the MCS was demonstrated by the simulation of physiologic pressure and flow waveforms. At increasing LVAD speeds, the mean aortic pressure load steadily increased, while the aortic duty cycle steadily decreased. Changes were consistent for each MCS experimental setting, despite variations in stroke volume and outflow resistance. CONCLUSIONS: Increased LVAD flow results in an impaired aortic valve-open time due to a pressure overload above the aortic valve. Such an overload may initiate structural changes, causing aortic leaflet fusion and/or regurgitation.