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Background: Continuous flow left ventricular assist devices have improved outcomes in patients with end-stage heart failure that require mechanical circulatory support. Current devices have an adverse event profile that has hindered widespread application. The EVAHEART®2 left ventricular assist device (EVA2) has design features such as large blood gaps, lower pump speeds and an inflow cannula that does not protrude into the left ventricle that may mitigate the adverse events currently seen with other continuous flow devices., Methods: A prospective, multi-center randomized non-inferiority study, COMPETENCE Trial, is underway to assess non-inferiority of the EVA2 to the HeartMate 3 LVAS when used for the treatment of refractory advanced heart failure. The primary end-point is a composite of the individual primary outcomes: Survival to cardiac transplant or device explant for recovery; Free from disabling stroke; Free from severe Right Heart Failure after implantation of original device. Randomization is in a 2:1 (EVA2:HM3) ratio., Results: The first patient was enrolled into the COMPETENCE Trial in December of 2020, and 25 subjects (16 EVA2 and 9 HM3) are currently enrolled. Enrollment of a safety cohort is projected to be completed by third quarter of 2022 at which time an interim analysis will be performed. Short-term cohort (92 EVA2 subjects) and long-term cohort is expected to be completed by the end of 2023 and 2024, respectively., Conclusions: The design features of the EVA2 such as a novel inflow cannula and large blood gaps may improve clinical outcomes but require further study. The ongoing COMPETENCE trial is designed to determine if the EVA2 is non-inferior to the HM3., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background Gastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia. Methods and Results Clinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm 2 , n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers ( P<0.0001) into low-molecular-weight VWF multimers ( P<0.0001) and VWF fragments ( P<0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated ( P=0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders ( P=0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length ( P=0.04) and migration ( P=0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length ( P<0.001) and migration ( P=0.01). Conclusions LVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.

Background: Recent data suggest that hemolysis contributes to left ventricular assist device (LVAD) thrombosis, but the mechanism is unknown. In a clinical study, we measured plasma free hemoglobin (pfHgb) and the incidence of LVAD thrombosis. In an in vitro study, we examined biophysical relationships between shear stress, pfHgb and von Willebrand factor (vWF) metabolism toward understanding mechanisms of LVAD thrombosis., Methods: In the clinical study, blood samples were obtained from continuous-flow LVAD patients (n = 30). Plasma free hemoglobin was measured via enzyme-linked immunosorbent assay. Plasma lactate dehydrogenase (LDH) was measured with a fluorimetric assay. In the in vitro study, to investigate mechanism, human plasma (n = 10) was exposed to LVAD-like shear stress (175 dyne/cm 2 ) with and without free hemoglobin (30 mg/dL). ADAMTS-13 (the vWF protease) activity was quantified with Förster resonance energy transfer. vWF size was quantified with immunoblotting. vWF clotting function was quantified with an enzyme-linked immunosorbent assay., Results: In the clinical study, LVAD support caused subclinical hemolysis. In all patients, LDH increased significantly from 213 ± 9 U/L to 366 ± 31 U/L at 10 days of support (p < 0.0001) and remained significantly elevated at 280 ± 18 U/L at 1 month of support (p < 0.01). In 21 patients that did not develop LVAD thrombosis, pfHgb increased early but decreased over time (pre-LVAD: 5.2 ± 0.8 mg/dL; 1 week: 19.8 ± 4.4 mg/dL, p < 0.01; 3 months: 9.3 ± 2.2 mg/dL, p = 0.07). In 9 patients that developed LVAD thrombosis, pfHgb was significantly elevated versus patients without thrombosis before (p < 0.001) and after 3 months (p < 0.05) of support (pre-LVAD: 20.2 ± 6.3 mg/dL; 1 week: 17.3 ± 3.7 mg/dL; 3 months: 21.5 ± 7.8 mg/dL). Similarly, after 3 months, patients that did not develop LVAD thrombosis had an LDH of 271 ± 28 U/L, whereas patients that later developed LVAD thrombosis had a significantly higher LDH of 625 ± 210 U/L (p = 0.02). In the in vitro study, shear stress degraded vWF similarly to an LVAD. Free hemoglobin inhibited ADAMTS-13 activity during shear stress (633 ± 27 ng/mL to 565 ± 24 ng/mL; p < 0.001). vWF was thereby protected from degradation, 4 vWF fragments decreased significantly (p ≤ 0.05), and vWF clotting function increased (1.15 ± 0.09 U/mL to 1.29 ± 0.09 U/mL, p = 0.06)., Conclusions: These are the first data to demonstrate mechanistic relationships between subclinical hemolysis and a procoagulant state during continuous-flow LVAD support. Patients with high pfHgb and LDH were more likely to develop LVAD thrombosis. In vitro experiments demonstrated that free hemoglobin inhibited ADAMTS-13, protected vWF from degradation, increased vWF clotting function, and created a procoagulant state. As such, pfHgb may be a clinical target to prevent LVAD thrombosis., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Background: Supraphysiologic shear stress from continuous-flow left ventricular assist devices (LVADs) accelerates von Willebrand factor (vWF) degradation and predisposes patients to nonsurgical bleeding. It is unknown whether unique design characteristics of LVADs differentially affect vWF degradation. We tested the hypothesis that the centrifugal-flow EVAHEART (Evaheart, Houston, TX) left ventricular assist system (LVAS), which was designed to minimize shear stress (low operational revolutions per minute [rpm], larger flow gaps, low shear stress, flat H-Q curve), reduced vWF degradation versus the axial-flow HeartMate II (Thoratec, Pleasanton, CA) LVAD., Methods: Whole human blood was obtained from volunteer donors (n = 22). Blood was circulated for 12 hours in mock circulatory loops through a HeartMate II (n = 10; 11,400 rpm, 6.3 ± 0.8 L/min, 76 ± 2 mm Hg) or an EVAHEART LVAS (n = 12; 2,300 rpm, 5.7 ± 0.1 L/min, 80 ± 1 mm Hg). vWF degradation was characterized with electrophoresis and immunoblotting for large vWF multimers and 11 vWF degradation fragments., Results: The HeartMate II eliminated large vWF multimers and significantly (p < 0.05) increased 10 of 11 vWF degradation fragments at 6 and 12 hours. The increase was approximately 2.0-fold at 6 hours and 2.2-fold at 12 hours. In contrast, the EVAHEART LVAS modestly reduced large vWF multimers and significantly increased 5 of 11 and 8 of 11 vWF degradation fragments at 6 and 12 hours, respectively. The increase was approximately 1.5-fold at 6 hours and 1.7-fold at 12 hours. The EVAHEART LVAS caused significantly less degradation (p < 0.01) than the HeartMate II of the 140 kDa vWF fragment (cleavage product of ADAMTS-13, the vWF protease)., Conclusions: The EVAHEART LVAS caused significantly less vWF degradation than the HeartMate II in a mock circulatory loop with whole human blood. LVAD design features may minimize vWF degradation. These data may inform the design and operation of next-generation LVADs to minimize blood trauma., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Nonsurgical bleeding is a frequent complication of continuous-flow left ventricular assist device (LVAD) support. Abnormal von Willebrand factor (vWF) metabolism plays a major role. However, the relationship between LVAD speed and vWF degradation is unknown. Recent evidence has demonstrated that supraphysiologic shear stress from continuous-flow LVADs accelerates vWF degradation and causes an acquired vWF deficiency and bleeding. To manage LVAD-associated bleeding, it has been proposed that reduced LVAD speed may decrease shear stress and thereby reduce pathologic vWF metabolism. However, there are little published data to support this clinical practice. We tested the hypothesis that reduced continuous-flow LVAD speed decreases vWF degradation., Methods: Whole blood was collected from patients before and after the implantation of a HeartMate II continuous-flow LVAD (n = 10) to quantify in vivo vWF degradation. In parallel, to evaluate the relationship between LVAD rpm and vWF degradation, whole blood was collected from human donors (n = 30). Single-donor units of blood circulated in an ex vivo HeartMate II mock circulatory loop for 12 hours at 11,400, 10,000, or 8600 rpm (n = 10/each rpm group). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblot analysis. Paired Student t tests were performed within each group. ANOVA with Tukey post hoc test was performed across groups., Results: In patients, LVAD support reduced large vWF multimers and significantly (P < .05) increased vWF degradation fragments. The profile of vWF degradation was nearly identical between LVAD patients and blood circulated in the LVAD mock circulatory loop. At 11,400, 10,000, and 8600 rpm, decreased large vWF multimers and significantly increased vWF degradation fragments were noted. vWF degradation fragments were not statistically different across the 3 rpm groups or versus LVAD patients, which suggested that LVAD rpm did not influence vWF degradation., Conclusions: Reduced LVAD speed (within the clinical operational range) did not significantly decrease vWF degradation in a mock circulatory loop with human blood. During bleeding events, reduced LVAD speed, itself, may not diminish vWF degradation., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Bleeding is an important source of morbidity in patients with a left ventricular assist device. Evidence suggests a major role for von Willebrand factor. However, limited data exist to explain the mechanism(s) of von Willebrand factor degradation during left ventricular assist device support. We investigated whether left ventricular assist device-related shear stress and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13, the von Willebrand factor protease) altered von Willebrand factor metabolism., Methods: Whole blood was collected from patients (n = 8) with a left ventricular assist device. von Willebrand factor multimers and degradation fragments were characterized with electrophoresis and immunoblotting. To investigate mechanisms, an in vitro model was developed to generate the supraphysiologic shear stress of a continuous-flow left ventricular assist device. Normal human blood (n = 8) was cycled in a laboratory vortexer (∼2400 rpm, shear stress ∼175 dyne/cm(2), 4 hours) to reproduce the pathologic degradation of von Willebrand factor that occurs during left ventricular assist device support. To investigate the specific mechanistic roles of shear stress and ADAMTS-13 in von Willebrand factor degradation, purified von Willebrand factor protein ± ADAMTS-13 protease were exposed to supraphysiologic shear stress in the vortexer. von Willebrand factor multimers and 11 von Willebrand factor degradation fragments were characterized with electrophoresis and immunoblotting., Results: Left ventricular assist device support reduced large von Willebrand factor multimers and significantly increased 10/11 von Willebrand factor degradation fragments (P < .05). Normal human blood exposed to supraphysiologic shear stress in the vortexer demonstrated the same profile of von Willebrand factor degradation fragments as in a patient with a left ventricular assist device. Supraphysiologic shear stress alone caused modest mechanical demolition of large von Willebrand factor multimers into smaller multimers but did not greatly generate von Willebrand factor fragments. In the presence of supraphysiologic shear stress, ADAMTS-13 completely eliminated large von Willebrand factor multimers and generated statistically significant amounts of 11/11 von Willebrand factor degradation fragments (P < .05). The profile of von Willebrand factor fragments generated was identical to the profile that was observed in vivo in patients with a left ventricular assist device., Conclusions: Supraphysiologic shear stress alone causes physical demolition of large von Willebrand factor multimers into smaller von Willebrand factor multimers. In the setting of supraphysiologic shear stress, ADAMTS-13 cleaves large von Willebrand factor multimers into von Willebrand factor degradation fragments. ADAMTS-13 may be a therapeutic target to reduce von Willebrand factor degradation and bleeding complications in patients with a left ventricular assist device., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular assist device (LVAD) thrombosis is a life-threatening complication that remains a major clinical problem. Consensus diagnostic criteria do not exist. We investigated whether hematologic, echocardiographic, or pump parameters reliably change during LVAD thrombosis., Methods: A retrospective analysis of 20 consecutive cases of continuous-flow LVAD thrombosis (Thoratec HeartMate II n = 16, HeartWare HVAD n = 4) was performed. Hematologic markers (lactate dehydrogenase, plasma-free hemoglobin, hemoglobin, creatinine), echocardiographic parameters (left ventricular end-systolic and end-diastolic diameter, mitral regurgitation, aortic insufficiency, inflow-cannula velocity), and pump characteristics (speed, power, estimated flow, pulsatility index) were analyzed with one-way repeated measures ANOVA with Tukey post-test or paired Student t-tests., Results: Lactate dehydrogenase and plasma-free hemoglobin were significantly (p < 0.05) elevated at admission for LVAD thrombosis. Hemoglobin and creatinine were not significantly different at admission but changed significantly after admission. Left ventricular end-systolic and end-diastolic diameter, mitral regurgitation, aortic insufficiency, inflow-cannula velocity, LVAD speed, power consumption, estimated flow, and pulsatility index were not significantly different at admission for LVAD thrombosis., Conclusion: Hematological markers of hemolysis, but not echocardiographic or pump parameters, reliably changed during LVAD thrombosis. Markers of hemolysis are the best early predictors of LVAD thrombosis., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Counterpulsation with an intra-aortic balloon pump (IABP) has not achieved the same success or clinical use in pediatric patients as in adults. In a pediatric animal model, IABP efficacy was investigated to determine whether IABP timing with a high-fidelity blood pressure signal may improve counterpulsation therapy versus a low-fidelity signal., Methods: In Yorkshire piglets (n = 19; weight, 13.0 ± 0.5 kg) with coronary ligation-induced acute ischemic left ventricular failure, pediatric IABPs (5 or 7 mL) were placed in the descending thoracic aorta. Inflation and deflation were timed with traditional criteria from low-fidelity (fluid-filled) and high-fidelity (micromanometer) blood pressure signals during 1:1 support. Aortic, carotid, and coronary hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption was calculated from coronary sinus and arterial blood samples. Left ventricular myocardial blood flow and end-organ blood flow were measured with microspheres., Results: Despite significant suprasystolic diastolic augmentation and afterload reduction at heart rates of 105 ± 3 beats per minute, left ventricular myocardial blood flow, myocardial oxygen consumption, the myocardial oxygen supply/demand relationship, cardiac output, and end-organ blood flow did not change. Statistically significant end-diastolic coronary, carotid, and aortic flow reversal occurred with IABP deflation. Inflation and deflation timed with a high-fidelity versus low-fidelity signal did not attenuate systemic flow reversal or improve the myocardial oxygen supply/demand relationship., Conclusions: Systemic end-diastolic flow reversal limited counterpulsation efficacy in a pediatric model of acute left ventricular failure. Adjustment of IABP inflation and deflation timing with traditional criteria and a high-fidelity blood pressure waveform did not improve IABP efficacy or attenuate flow reversal. End-diastolic flow reversal may limit the efficacy of IABP counterpulsation therapy in pediatric patients with traditional timing criteria. Investigation of alternative deflation timing strategies is warranted., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: Despite progress with adult ventricular assist devices, limited options exist to support pediatric patients with life-threatening heart disease. Extracorporeal membrane oxygenation remains the clinical standard. To characterize (patho)physiologic responses to different modes of mechanical unloading of the failing pediatric heart, extracorporeal membrane oxygenation was compared to intra-aortic balloon pump, pulsatile-flow ventricular assist device, or continuous-flow ventricular assist device support in a pediatric heart failure model., Design: Experimental., Setting: Large animal laboratory operating room., Subjects: Yorkshire piglets (n = 47; 11.7 ± 2.6 kg)., Interventions: In piglets with coronary ligation-induced cardiac dysfunction, mechanical circulatory support devices were implanted and studied during maximum support., Measurements and Main Results: Left ventricular, right ventricular, coronary, carotid, systemic arterial, and pulmonary arterial hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption and total-body oxygen consumption were calculated from arterial, venous, and coronary sinus blood sampling. Blood flow was measured in 17 organs with microspheres. Paired Student t tests compared baseline and heart failure conditions. One-way repeated-measures analysis of variance compared heart failure, device support mode(s), and extracorporeal membrane oxygenation. Statistically significant (p < 0.05) findings included 1) an improved left ventricular blood supply/demand ratio during pulsatile-flow ventricular assist device, continuous-flow ventricular assist device, and extracorporeal membrane oxygenation but not intra-aortic balloon pump support, 2) an improved global myocardial blood supply/demand ratio during pulsatile-flow ventricular assist device and continuous-flow ventricular assist device but not intra-aortic balloon pump or extracorporeal membrane oxygenation support, and 3) diminished pulsatility during extracorporeal membrane oxygenation and continuous-flow ventricular assist device but not intra-aortic balloon pump and pulsatile-flow ventricular assist device support. A profile of systems-based responses was established for each type of support., Conclusions: Each type of pediatric ventricular assist device provided hemodynamic support by unloading the heart with a different mechanism that created a unique profile of physiological changes. These data contribute novel, clinically relevant insight into pediatric mechanical circulatory support and establish an important resource for pediatric device development and patient selection.

We describe a 36-year-old male with a HeartWare LVAD and a Medtronic Virtuoso DR pacemaker in whom increased intrathoracic impedance preceded suction events, low LVAD flows, symptoms of a heart failure exacerbation, and hospitalization. Measurement of intrathoracic impedance may identify fluid shifts prior to symptoms and predict adverse events in patients with an LVAD., (© 2013 Wiley Periodicals, Inc.)

A counterpulsation device (Symphony) is being developed to provide long-term circulatory support for advanced heart failure (HF) patients. In acute animal experiments, flow waveform patterns in the aortic, carotid, and coronary arteries were compared during Symphony and intra-aortic balloon pump (IABP) support. Human data were examined for similarities. The 30-mL Symphony was compared to a 40-mL IABP in calves with cardiac dysfunction (80-100 kg, n = 8). Aortic pressures and aortic, carotid, and coronary artery flows were simultaneously recorded at baseline (devices off) and during 1:1 and 1:2 support. Forward, retrograde, and mean flows were calculated and compared for each test condition. Findings were also compared to aortic flow measurements recorded in HF patients (n = 21) supported by 40-mL IABP. IABP caused significant retrograde flows in the aorta, coronary (IABP: -24 ± 8 mL/min, Symphony: -6 ± 2 mL/min, baseline: -2 ± 1 mL/min, P < 0.05), and carotid arteries (IABP: -30 ± 5 mL/min, Symphony: -0 ± 0 mL/min, baseline: -0 ± 0 L/min, P < 0.05) during ventricular systole compared to the Symphony. IABP support produced higher diastolic pressure and flow augmentation compared to Symphony. Due to retrograde flows during IABP support, Symphony provided higher overall coronary, carotid, and aortic flows. Similar reduction in total aortic flows due to retrograde flow was observed in HF patients during IABP support. Counterpulsation with an IABP via aortic volume displacement produces retrograde flows during rapid balloon deflation that reduces total flow. Counterpulsation with Symphony via volume removal eliminates retrograde flow and improves total flow more than that achieved with IABP. The Symphony may provide long-term hemodynamic benefits in HF patients., (© 2012, Copyright the Authors. Artificial Organs © 2012, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The recent, widespread success of mechanical circulatory support has prompted the development of numerous implantable devices to treat advanced heart failure. It is important to raise awareness of novel device systems, the mechanisms by which they function, and implications for patient management. This article discusses devices that are being developed or are in clinical trials. Devices are categorized as standard full support, less-invasive full support, partial support: rotary pumps, partial support: counterpulsation devices, right ventricular assist device, and total artificial heart. Implantation strategy, mechanism of action, durability, efficacy, hemocompatibility, and human factors are considered. The feasibility of novel strategies for unloading the failing heart is examined., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32-mL stroke volume CPD with a standard 40-mL intra-aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant (P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32-mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40-mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions.

The circadian rhythm of varying blood pressure and heart rate is attenuated or absent in patients with severe heart failure. In 28 patients supported by a left ventricular assist device (LVAD) for at least 30 days, a restoration of the circadian rhythm was demonstrated by a consistent nocturnal decrease, and then increase, of the LVAD flow while at a constant LVAD speed. The return of the circadian rhythm has implications for cardiac recovery, and the observation indicates that the continuous-flow LVAD has an intrinsic automatic response to physiologic demands., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Continuous-flow left ventricular assist devices (LVADs) cause an acquired von Willebrand factor (VWF) deficiency and bleeding. Models to risk-stratify for bleeding are urgently needed. We developed a model of continuous-flow LVAD bleeding risk from patient-specific severity of VWF degradation. In a prospective, longitudinal cohort study, paired blood samples were obtained from patients (n = 67) with a continuous-flow LVAD before and during support. After 640 ± 395 days, patients were categorized as all-cause bleeders, gastrointestinal (GI) bleeders, or nonbleeders. VWF multimers and VWF clotting function were evaluated to determine bleeding risk. Of 67 patients, 34 (51%) experienced bleeding, 26 (39%) experienced GI bleeding, and 33 (49%) did not bleed. In all patients, LVAD support significantly reduced high-molecular-weight VWF multimers (P <.001). Bleeders exhibited greater loss of high-molecular-weight VWF multimers (mean ± standard deviation, –10 ± 5% vs –7 ± 4%, P =.008) and reduced VWF clotting function versus nonbleeders (median [interquartile range], –12% [–31% to 4%] vs 0% [–9 to 26%], P =.01). A combined metric of VWF multimers and VWF function generated the All-Cause Bleeding Risk Score, which stratified bleeders versus nonbleeders (86 ± 56% vs 41 ± 48%, P <.001) with a positive predictive value of 86% (95% confidence interval, 66%-95%) and diagnostic odds ratio of 11 (95% confidence interval, 2.9-44). A separate GI Bleeding Risk Score stratified GI bleeders versus nonbleeders (202 ± 114 vs 120 ± 86, P =.003) with a positive predictive value of 88% (64%-97%) and diagnostic odds ratio of 18 (3.1-140). The severity of loss of VWF multimers and VWF clotting function generated Bleeding Risk Scores with high predictive value for LVAD-associated bleeding. This model may guide personalized antithrombotic therapy and patient surveillance. [Display omitted] [ABSTRACT FROM AUTHOR]

Evidence suggests a major role for von Willebrand factor (vWF) in left ventricular assist device (LVAD)-associated bleeding. However, the mechanisms of vWF degradation during LVAD support are not well understood. We developed: (i) a simple and inexpensive vortexer model; and (ii) a translational LVAD mock circulatory loop to perform preclinical investigations of LVAD-associated vWF degradation. Whole blood was obtained from LVAD patients (n = 8) and normal humans (n = 15). Experimental groups included: (i) blood from continuous-flow LVAD patients (baseline vs. post-LVAD, n = 8); (ii) blood from normal humans (baseline vs. 4 h in vitro laboratory vortexer, ∼ 2400 rpm, shear stress ∼175 dyne/cm2, n = 8); and (iii) blood from normal humans (baseline vs. 12 h HeartMate II mock circulatory loop, 10 000 rpm, n = 7). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting. Blood from LVAD patients, blood exposed to in vitro supraphysiologic shear stress, and blood circulated through an LVAD mock circulatory loop demonstrated a similar profile of decreased large vWF multimers and increased vWF degradation fragments. A laboratory vortexer and an LVAD mock circulatory loop reproduced the pathologic degradation of vWF that occurs during LVAD support. Both models are appropriate for preclinical studies of LVAD-associated vWF degradation. [ABSTRACT FROM AUTHOR]

Ventricular assist devices ( VADs) have emerged as a successful treatment option for advanced heart failure. The objective of this study was to develop a clinically relevant model of chronic ischemic cardiomyopathy to investigate functional, histological, and molecular changes during mechanical circulatory support. In calves ( n = 17, 94 ± 7 kg), 90 μm microspheres were injected percutaneously into the left coronary artery. Serial echocardiography was performed weekly to evaluate cardiac function. Sixty days after coronary microembolization, a terminal study was performed via thoracotomy to measure hemodynamics. Regional myocardial and end-organ blood flows were quantified with 15-μm fluorescent-labeled microspheres. Myocardial fibrosis, myocyte size, and myocardial apoptosis were quantified with histological stains. Eleven animals survived coronary microembolization and exhibited clinical and statistically significant echocardiographic and hemodynamic signs of severe systolic dysfunction. Statistically significant decreases in regional myocardial blood flow and increases in myocardial fibrosis, myocyte size, total myocardial apoptosis, and cardiac myocyte-specific apoptosis were observed. End-organ hypoperfusion was observed. Coronary microembolization induced stable and reproducible chronic left ventricular failure in calves. The anatomical size and physiology of the bovine heart and thorax are appropriate to study novel interventions for the clinical management of heart failure. This model is an appropriate physiological substrate in which to test VAD and adjunctive biological therapies. [ABSTRACT FROM AUTHOR]

A response by Carlo R. Bartoli and colleagues to a letter to the editor about their article "A Novel Subcutaneous Counterpulsation Device: Acute Hemodynamic Efficacy During Pharmacologically Induced Hypertension, Hypotension, and Heart Failure," in the 2010 issue is presented.