Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices.

Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder (n = 12) and non-bleeder (n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c (Cyt.c), platelet mitochondrial membrane potential (Δψ m), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non-bleeder group (p < 0.05). Platelet pro-survival proteins (Bcl-2, Bcl-xL) were significantly reduced in the bleeder group in comparison to the non-bleeder group (p < 0.05). Translocation of Bax into platelet mitochondria membrane and subsequent release of Cyt.c were more prevalent in the bleeder group. Platelet mitochondrial damage, activation of caspases, gelsolin cleavage, and ultimate platelet apoptosis in the bleeder group were observed. Oxidative stress and activation of both intrinsic and extrinsic pathways of platelet apoptosis may be linked to NSB in CF-LVAD patients. Additionally, biomarkers of oxidative stress, examination of pro-survivals and pro-apoptotic proteins in platelets, mitochondrial damage, caspase activation, and platelet apoptosis may be used to help identify HF patients at high risk of NSB post-implant.

Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure.

BACKGROUND: Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. METHODS AND RESULTS: Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. CONCLUSIONS: Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.

Blood trauma testing of CentriMag and RotaFlow centrifugal flow devices: a pilot study.

Mechanical circulatory assist devices that provide temporary support in heart failure patients are needed to enable recovery or provide a bridge to decision. Minimizing risk of blood damage (i.e., hemolysis) with these devices is critical, especially if the length of support needs to be extended. Hematologic responses of the RotaFlow (Maquet) and CentriMag (Thoratec) temporary support devices were characterized in an in vitro feasibility study. Paired static mock flow loops primed with fresh bovine blood (700 mL, hematocrit [Hct] = 25 ± 3%, heparin titrated for activated clotting time >300 s) pooled from a single-source donor were used to test hematologic responses to RotaFlow (n = 2) and CentriMag (n = 2) simultaneously. Pump differential pressures, temperature, and flow were maintained at 250 ± 10 mm Hg, 25 ± 2°C, and 4.2 ± 0.25 L/min, respectively. Blood samples (3 mL) were collected at 0, 60, 120, 180, 240, 300, and 360 min after starting pumps in accordance with recommended Food and Drug Administration and American Society for Testing and Materials guidelines. The CentriMag operated at a higher average pump speed (3425 rpm) than the RotaFlow (3000 rpm) while maintaining similar constant flow rates (4.2 L/min). Hematologic indicators of blood trauma (hemoglobin, Hct, platelet count, plasma free hemoglobin, and white blood cell) for all measured time points as well as normalized and modified indices of hemolysis were similar (RotaFlow: normalized index of hemolysis [NIH] = 0.021 ± 0.003 g/100 L, modified index of hemolysis [MIH] = 3.28 ± 0.52 mg/mg compared to CentriMag: NIH = 0.041 ± 0.010 g/100 L, MIH = 6.08 ± 1.45 mg/mg). In this feasibility study, the blood trauma performance of the RotaFlow was similar or better than the CentriMag device under clinically equivalent, worst-case test conditions. The RotaFlow device may be a more cost-effective alternative to the CentriMag.

Miniaturization of mechanical circulatory support systems.

Heart failure (HF) is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care, prognosis with HF remains poor, especially in advanced stages. The large patient population with advanced HF and the limited number of donor organs stimulated the development of mechanical circulatory support (MCS) devices as a bridge to transplant and for destination therapy. However, MCS devices require a major operative intervention, cardiopulmonary bypass, and blood component exposure, which have been associated with significant adverse event rates, and long recovery periods. Miniaturization of MCS devices and the development of an efficient and reliable transcutaneous energy transfer system may provide the vehicle to overcome these limitations and usher in a new clinical paradigm in heart failure therapy by enabling less invasive beating heart surgical procedures for implantation, reduce cost, and improve patient outcomes and quality of life. Further, it is anticipated that future ventricular assist device technology will allow for a much wider application of the therapy in the treatment of heart failure including its use for myocardial recovery and as a platform for support for cell therapy in addition to permanent long-term support.

Coronary artery fistula: 64-slice computed tomographic delineation and correlation with multiplane transesophageal echocardiography and surgical findings.

A 49-year-old female who presented with 3 weeks of exertional chest pain had an abnormal mediastinal finding at chest x-ray imaging. Conventional, nongated computed tomography of the chest revealed a "mass" in proximity to the right atrium. 64-slice, cardiac gated computed tomographic coronary angiography, and transesophageal echocardiography delineated the "mass" as a coronary artery fistula structure. The fistula originated from the left main as a tubular vessel that continued into an aneurysmal sac-like cavity that emptied into the superior vena cava near the right atrium. Computed tomographic coronary angiography showed otherwise normal coronary arteries. Findings were ultimately confirmed at cardiac catheterization. Coronary steal was clinically diagnosed and she underwent surgical ligation and resection of the fistula and aneurysm. Her subsequent course was uncomplicated.

Blood trauma testing for mechanical circulatory support devices.

Preclinical hemolysis testing is a critical requirement toward demonstrating device safety for U.S. Food and Drug Administration (FDA) 510(k) approval of mechanical circulatory support devices (MCSD). FDA and ASTM (formerly known as the American Society for Testing and Materials) have published guidelines to assist industry with developing study protocols. However, there can be significant variability in experimental procedures, study design, and reporting of data that makes comparison of test and predicate devices a challenge. To overcome these limitations, we present a hemolysis testing protocol developed to enable standardization of hemolysis testing while adhering to FDA and ASTM guidelines. Static mock flow loops primed with fresh bovine blood (600 mL, Hematocrit = 27±5%, heparin titrated for ACT >300 sec) from a single-source donor were created as a platform for investigating test and predicate devices. MCSD differential pressure and temperature were maintained at 80 mmHg and 25°±2° C. Blood samples (3 ml) were collected at 0, 5, 90, 180, 270, 360 minutes to measure CBC and plasma free hemoglobin. This protocol led to 510(k) approval of two adult MCSD and has been used to test novel cannulae and a pediatric MCSD. Standardization of hemolysis testing procedures and transparency of results may enable better blood trauma characterization of MCS devices to facilitate the FDA 510(k) and PMA submission processes and improve clinical outcomes.

Destination therapy: one-year outcomes in patients with a body mass index greater than 30.

Left ventricular assist devices (LVADs) are slowly gaining acceptance as the treatment of choice in appropriately selected patients with end-stage heart failure who are not transplant candidates. Obesity is a well-known risk factor for increased cardiovascular morbidity and mortality, and frequently can be the reason some patients are turned down for heart transplantation. Because of this experience in transplant patients, many centers have also been reluctant to offer these patients an LVAD for destination therapy (DT). Subsequently, the 1-year outcomes of obese patients receiving LVADs for DT at our center were reviewed. Fifty-eight consecutive patients (83% men) were implanted with HeartMate XVE (n = 22) or HeartMate II (n = 36) LVAD. Patients were divided into normal (body mass index [BMI] or= 30 kg/m(2), n = 20) groups according to their BMI. Preoperatively, there were statistically significant differences (P < 0.05) between normal and obese groups in age (65.9 years vs. 54.7 years), weight (72.9 kg vs. 107.5 kg), BMI (24.1 kg/m(2) vs. 35.2 kg/m(2)), and incidence of diabetes (37% vs. 60%). At 1-year follow-up, there were no statistically significant differences (P > 0.5) between normal and obese groups: creatinine levels (1.4 vs. 1.5), New York Heart Association classification (1.2 vs. 1.6), and survival (63% vs. 65%). Our initial results demonstrate that morbidly obese patients with end-stage heart failure with a contraindication for transplant may successfully undergo implantation of an LVAD for DT.

Shear stress and blood trauma under constant and pulse-modulated speed CF-VAD operations: CFD analysis of the HVAD.

Modulation of pump speed has been proposed and implemented clinically to improve vascular pulsatility in continuous flow ventricular assist device patient. The flow dynamics of the HVAD with a promising asynchronous pump speed modulation and its potential risk for device-induced blood trauma was investigated numerically. The boundary conditions at the pump inlet and outlet were defined using the pressure waveforms adapted from the experimentally recorded ventricular and arterial pressure waveforms in a large animal ischemic heart failure (IHF) model supported by the HVAD operated at constant and modulated pump speeds. Shear stress fields and hemolysis indices were derived from the simulated flow fields. The overall features of the computationally generated flow waveforms at simulated constant and pulse-modulated speed operations matched with those of the experimentally recorded flow waveforms. The simulations showed that the shear stress field and hemolysis index vary throughout the cardiac cycle under the constant speed operation, and also as a function of modulation profile under modulated speed operation. The computational model did not demonstrate any differences in the time average hemolysis index between constant and modulated pump speed operations, thereby predicting pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma. Graphical abstract The streamline inside the HVAD pump and the wall shear stress distribution on the impeller surface at six discrete time instants over one cardiac cycle under constant speed operation (3000 rpm) (a) and under pulse-modulated speed operation (b). c Computationally predicted flow rate waveform under pulse-modulated speed operation. d Computationally predicted time-varying HI generated by the HVAD pump under the two operation modes constant speed (dash line) and pulse-modulated speed (solid line). These figures indicate that the pulse-modulated speed operation may help to restore vascular pulsatility without any further increased risk of blood trauma.

Reducing emboli in cardiac surgery: does it make a difference?

Particulate embolization remains a serious complication of cardiac surgery. Adverse events associated with particulate embolization affect patient morbidity and long-term survival, and increase the length of hospital stay and the cost of health care. Today, atherosclerosis plays a role in at least two-thirds of all adverse events after coronary artery revascularization, and postoperative stroke is the second most common cause of operative mortality. Because many lower-risk patients now undergo interventional revascularization, higher-risk patients are now typically referred for surgical revascularization. These patients are older and sicker, and have multiple comorbidities, making them more susceptible to adverse events. For these high-risk patients, surgeons should be proactive in attempting to reduce the possibility of emboli. Patients must be carefully assessed before surgery to determine their risk, and if the risk is high, surgeons should consider using newer, innovative devices, and techniques in their operative strategy that have proven to be effective in mitigating some of the potential embolic adverse events. A multifaceted, preventive strategy can make a difference, not only in reducing particulate emboli, but also in reducing morbidity and in lowering the economic burden on the health-care system. This brief review will address three areas of focus that are important for the prevention of particulate embolization: (i) prevalence and morbidity of atherosclerotic disease; (ii) risk factors for adverse neurologic events; and (iii) prevention/mitigation of adverse events for patients undergoing cardiac surgery.

Low incidence of neurologic events during long-term support with the HeartMate XVE left ventricular assist device.

Neurologic events during left ventricular assist device (LVAD) support are associated with significant morbidity and death. To evaluate this problem, we analyzed neurocognitive function and the frequency and incidence of neurologic events in 21 consecutive patients who were undergoing long-term support with the HeartMate XVE LVAD (Thoratec Corporation; Pleasanton, Calif). The mean duration of LVAD support was 531 days (range, 55-1, 309 d); the cumulative support time was 11,188 days (30.7 yr). No patients received anticoagulant therapy, and most received aspirin. None experienced strokes or transient ischemic attacks. Twenty patients were discharged from the hospital; 2 were later readmitted because of transient changes in neurologic status (metabolic encephalopathy) that ultimately resolved. Neurologic function, as measured by the National Institutes of Health Stroke Scale (NIHSS) and the Modified Rankin Score (MRS), was abnormal before LVAD implantation but normal 6 and 12 months after (mean NIHSS, 23.6 before vs 0 after; mean MRS, 0.68 before vs 0.18 after). Neurocognitive function, as evaluated by the Boston Naming Test, Trail Making Test part B, and Block Design Test, also improved during LVAD support. Together, these findings indicate that few neurologic events occur during long-term HeartMate XVE LVAD support in the absence of anticoagulation therapy. They also suggest that modifications made to the HeartMate LVAD since the REMATCH trial have resulted in fewer complications, and that better patient selection and supportive care have improved outcomes.

Hemodynamic Benefits of Counterpulsation, Implantable, Percutaneous, and Intraaortic Rotary Blood Pumps: An In-Silico and In Vitro Study.

Mechanical circulatory support (MCS) devices have become a standard therapy for heart failure (HF) patients. MCS device designs may differ by level of support, inflow and/or outflow cannulation sites, and mechanism(s) of cardiac unloading and blood flow delivery. Investigation and direct comparison of hemodynamic parameters that help characterize performance of MCS devices has been limited. We quantified cardiac and vascular hemodynamic responses for different types of MCS devices. Continuous flow (CF) left ventricular (LV) assist devices (LVAD) with LV or left atrial (LA) inlet, counterpulsation devices, percutaneous CF LVAD, and intra-aortic rotary blood pumps (IARBP) were quantified using established computer simulation and mock flow loop models. Hemodynamic data were analyzed on a beat-to-beat basis at baseline HF and over a range of MCS support. Results demonstrated that all LVAD greatly diminished vascular pulsatility (P) and LV external work (LVEW). LVAD with LA inflow provided a greater reduction in LVEW compared to LVAD with LV inflow, but at the potential risk for blood stasis/thrombosis in the LV at high support. Counterpulsation provided greater coronary flow (CoF) augmentation, but had a lower reduction in LVEW compared to partial percutaneous LVAD support. IARBP diminished LVEW, but at the expense of diminished CoF due to coronary steal. The hemodynamic benefits for each type of mechanical circulatory support system are unique and clinical decisions on device selection to maximize end organ perfusion and minimize invasiveness needs to be considered for an individual patients' presentation.

Surgical Technique for Ventricular Device Exchange: From HeartMate II to HVAD.

Implantable continuous-flow left ventricular assist devices (LVADs) have improved the survival of end-stage heart failure patients. Recent studies have shown an increased occurrence of device replacement in the axial flow pumps particularly for thrombosis. In some patients, to try and avoid recurrent pump thrombosis, it might be advantageous to switch from the axial flow LVAD to a newer generation centrifugal flow LVAD. Technically, this requires some adaption of the LVAD inflow and outflow connections. We describe our technique and outcomes in patients who underwent the conversion from an axial flow LVAD to a centrifugal flow LVAD.

Infection, Oxidative Stress, and Changes in Circulating Regulatory T Cells of Heart Failure Patients Supported by Continuous-Flow Ventricular Assist Devices.

The objective of this study was to investigate the changes in oxidative stress (OS) and circulating regulatory T cells (Tregs) of the immune system in patients supported by continuous-flow ventricular assist device (CF-VAD) with or without infection. We recruited 16 CF-VAD patients (5 with infection and 11 without infection) and 7 healthy volunteers. Generation of reactive oxygen species (ROS) from lymphocytes, superoxide dismutase (SOD) in erythrocyte, total antioxidant capacity (TAC), and oxidized low-density lipoprotein (oxLDL) in plasma were measured. Circulating Tregs were evaluated by flow cytometry. Heart failure (HF) patients had elevated OS than healthy volunteers as evident from higher lymphocyte ROS, elevated oxLDL, as well as depleted SOD and TAC levels. At baseline, HF patients had decreased percentage of Tregs (5.12 ± 1.5% vs. 8.14 ± 3.01%, p < 0.01) when compared with healthy volunteers. Postimplant patients with infection illustrated 35% and 44% rise in ROS and oxLDL, respectively, 31% decrease in TAC, and marked rise in percentage of Tregs (14.27 ± 3.17% vs. 9.38 ± 3.41%, p < 0.01) when compared with the patients without infection. Elevated OS and rise in Tregs were more prominent in CF-VAD patients with infection. In conclusion, OS and compromised immune system may be important indicators of systemic response of the body to CF-VAD among HF patients with infection.

Continuous-Flow Left Ventricular Assist Device Support Improves Myocardial Supply:Demand in Chronic Heart Failure.

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.

Efficacy of Subcutaneous Electrocardiogram Leads for Synchronous Timing During Chronic Counterpulsation Therapy.

Counterpulsation devices (CPDs) require an accurate, reliable electrocardiogram (ECG) waveform for triggering inflation and deflation. Surface electrodes are for short-term use, and transvenous/epicardial leads require invasive implant procedure. A subcutaneous ECG lead configuration was developed as an alternative approach for long-term use with timing mechanical circulatory support (MCS) devices. In this study, efficacy testing was completed by simultaneously recording ECG waveforms from clinical-grade epicardial (control) and subcutaneous (test) leads in chronic ischemic heart failure calves implanted with CPD for up to 30 days. Sensitivity and specificity of CPD triggering by R-wave detection was quantified for each lead configuration. The subcutaneous leads provided 98.9% positive predictive value and 98.9% sensitivity compared to the epicardial ECG leads. Lead migration (n = 1) and fracture (n = 1) were observed in only 2 of 40 implanted leads, without adversely impacting triggering efficacy due to lead redundancy. These findings demonstrate the efficacy of subcutaneous ECG leads for long-term CPD timing and potential use as an alternative method for MCS device timing.

Left ventricular assist device weaning: hemodynamic response and relationship to stroke volume and rate reduction protocols.

Clinical evidence of myocardial recovery in a small cohort of patients supported with a left ventricular assist device (LVAD) has been reported. Development of an optimal LVAD weaning protocol is needed for these patients to sustain recovery after device explant. In this study, we tested the hypothesis that LVAD stroke volume reduction produces a steady-state mechanical reloading of left ventricular (LV) pressures and volumes compared with LVAD rate reduction that results in transient mechanical reloading of the heart due to beat-to-beat variation in LV pressures and volumes. The relationship of LVAD flow to LVAD stroke volume and systolic interval over a range of LVAD rates (60, 80, 100, 120, and 140 bpm) was validated in a mock circulatory flow loop. In six acute experiments, calves were implanted with a pneumatic paracorporeal LVAD (PVAD, Thoratec, Pleasanton, CA). The PVAD was operated asynchronously in the auto volume mode (full decompression) for 30 minutes to establish a baseline control condition. The calf hearts were then mechanically reloaded by LVAD rate reduction (80, 60, and 40 bpm) or LVAD stroke volume reduction (100, 120, and 140 bpm) protocols consisting of 30 minutes of support at each LVAD beat rate. The order of weaning protocols was randomized with a 30-minute recovery period (LVAD volume mode to fully decompress heart allowing it to rest) between protocols to enable return to baseline control state. Aortic pressure and flow, LV pressure and volume, pulmonary artery flow, and LVAD flow waveforms were recorded for each test condition. The LVAD stroke volume reduction protocol produced steady-state mechanical reloading compared with VAD rate reduction that resulted in transient LV mechanical reloading. This distinction is due to differences in their temporal relationships between LVAD and LV filling and emptying cycles. The acute hemodynamic benefit of LVAD stroke volume reduction was greater reduction in LV end-diastolic pressure and increase in LV segmental shortening than LVAD rate reduction. The long-term effects of steady-state and transient LV mechanical reloading on myocardial structure and function toward achieving sustained myocardial recovery warrant further investigation.

Embol-X intra-aortic filtration system: capturing particulate emboli in the cardiac surgery patient.

We sought to evaluate the effectiveness of using an intra-aortic filtration system for the prevention of particulate emboli transport and the minimization of significant postoperative complications associated with particulate emboli. Between October of 2000 and October 2001, a total of 146 patients were enrolled at Advocate Christ Medical Center as part of the multi-institutional randomized trial (1289 patients at 22 centers). A total of 74 patients (51%) received the Embol-X intra-aortic filter and 72 patients (49%) were enrolled in the control group. Patients were evaluated for neurological deficit, myocardial infarction, renal insufficiency/failure, limb ischemia, and death at 12-hour, 24-hour, 72-hour, 7-day, and 30-day postoperative intervals. All filters received histological examination for particulate matter. Particulate matter was isolated in 70 (94.5%) of the filters successfully deployed. There was no statistically significant difference in the device related events between the filter and conventional cannulation groups (9/74 = 12.1% vs. 7/72 = 9.7%). Although not clinically evident, the primary event for both groups was ascending aortic intimal tears. There was one death in each of the groups not related to the filter or cannula used. The use of the Embol-X intra-aortic filter system has proven to be a safe and effective means to reduce the introduction of particulate emboli into the systemic circulation. Clearly, the reduction of particulate matter by as much as 95% justifies its use in cardiac surgery patients identified with an increased pre-operative embolic risk.

Left Ventricular Assist Device-Associated Carbon Monoxide and Iron-Enhanced Hypercoagulation: Impact of Concurrent Disease.

Left ventricular assist device (LVAD) therapy is associated with thrombophilia despite anticoagulation. Of interest, LVAD patients have increased carboxyhemoglobin, a measure of upregulated heme oxygenase (Hmox) activity that releases carbon monoxide (CO) and iron. Given that CO and iron enhance plasmatic coagulation, we determined if LVAD patients had hypercoagulability and decreased fibrinolytic vulnerability with measurable CO and iron-mediated effects. Blood samples were obtained a month or more after implantation of the LVAD. Thrombelastographic methods to assess coagulation kinetics, fibrinolytic kinetics, formation of carboxyhemefibrinogen, and iron-mediated enhancement of clot growth were utilized. Coagulation and fibrinolytic parameter normal individual (n = 30) plasma values were determined. Sixteen LVAD patients were studied. CO and iron enhancement of coagulation were observed in the majority of LVAD patients, contributing to hypercoagulation. However, most patients demonstrated abnormally increased rates of clot lysis. Critically, hemolysis as assessed by circulating lactate dehydrogenase activity was small in this cohort, and only four patients without comorbid states (e.g., obesity, diabetes, sleep apnea) were hypercoagulable with evidence of Hmox upregulation. However, seven patients with comorbidities were hypercoagulable with Hmox upregulation. Future investigation of CO and iron-related thrombophilia and comorbid disease is warranted to define its role in LVAD-related thrombosis.

Feasibility of Pump Speed Modulation for Restoring Vascular Pulsatility with Rotary Blood Pumps.

Continuous flow (CF) left ventricular assist devices (LVAD) diminish vascular pressure pulsatility, which may be associated with clinically reported adverse events including gastrointestinal bleeding, aortic valve insufficiency, and hemorrhagic stroke. Three candidate CF LVAD pump speed modulation algorithms designed to augment aortic pulsatility were evaluated in mock flow loop and ischemic heart failure (IHF) bovine models by quantifying hemodynamic performance as a function of mean pump speed, modulation amplitude, and timing. Asynchronous and synchronous copulsation (high revolutions per minute [RPM] during systole, low RPM during diastole) and counterpulsation (low RPM during systole, high RPM during diastole) algorithms were tested for defined modulation amplitudes (±300, ±500, ±800, and ±1,100 RPM) and frequencies (18.75, 37.5, and 60 cycles/minute) at low (2,900 RPM) and high (3,200 RPM) mean LVAD speeds. In the mock flow loop model, asynchronous, synchronous copulsation, and synchronous counterpulsation algorithms each increased pulse pressure (ΔP = 931%, 210%, and 98% and reduced left ventricular external work (LVEW = 20%, 22%, 16%). Similar improvements in vascular pulsatility (1,142%) and LVEW (40%) were observed in the IHF bovine model. Asynchronous modulation produces the largest vascular pulsatility with the advantage of not requiring sensor(s) for timing pump speed modulation, facilitating potential clinical implementation.