Blood-contacting magnetic levitation bearing design using computational fluid dynamics for haemocompatibility.

The Hemocompatibility Assessment Platform (HAP) is a testing rig that will allow for the evaluation of blood trauma caused by individual components of rotary blood pumps including the NeoVAD - a proposed paediatric Left Ventricular Assist Device (LVAD). It is important that the HAP itself is only minimally haemolytic such that the plasma free haemoglobin measured can be assumed to come from the test component. In this study, Computational Fluid Dynamics simulations have been carried out to inform the design of a magnetically levitated motor bearing gap. Simulations show that issues with the original design, namely stagnation regions and large recirculation zones can be mitigated with the introduction of a pipe that introduces blood-flow to the centre of the bearing and disrupts the secondary flow patterns that cause these issues.Clinical relevance- The consequent reduction in shear exposure time will reduce heamolsyis from the HAP. The redesign of the bearing will result in reduced baseline blood trauma from the HAP, thus allowing quantification of test component haemolysis and will therefore aid the design of future paediatric LVADs.

A Two-Step Transcriptome Analysis of the Human Heart Reveals Broad and Disease-Responsive Expression of Ectopic Olfactory Receptors.

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (n = 18) and non-failing heart samples (n = 4) were subjected to a two-step transcriptome analysis consisting of the quantification of 372 distinct OR transcripts on real-time PCR arrays and simultaneous determination of global cardiac gene expression by RNA sequencing. This strategy led to the identification of >160 ORs expressed in the human heart, including 38 receptors differentially regulated with heart failure. Co-expression analyses predicted the involvement of dysregulated ORs in the alteration of mitochondrial function, extracellular matrix remodeling, and inflammation. We provide this dataset as a resource for investigating roles of ORs in the human heart, with the hope that it will assist in the identification of new therapeutic targets for the treatment of heart failure.

Machine learning based on computational fluid dynamics enables geometric design optimisation of the NeoVAD blades.

The NeoVAD is a proposed paediatric axial-flow Left Ventricular Assist Device (LVAD), small enough to be implanted in infants. The design of the impeller and diffuser blades is important for hydrodynamic performance and haemocompatibility of the pump. This study aimed to optimise the blades for pump efficiency using Computational Fluid Dynamics (CFD), machine learning and global optimisation. Meshing of each design typically included 6 million hexahedral elements and a Shear Stress Transport turbulence model was used to close the Reynolds Averaged Navier-Stokes equations. CFD models of 32 base geometries, operating at 8 flow rates between 0.5 and 4 L/min, were created to match experimental studies. These were validated by comparison of the pressure-flow and efficiency-flow curves with those experimentally measured for all base prototype pumps. A surrogate model was required to allow the optimisation routine to conduct an efficient search; a multi-linear regression, Gaussian Process Regression and a Bayesian Regularised Artificial Neural Network predicted the optimisation objective at design points not explicitly simulated. A Genetic Algorithm was used to search for an optimal design. The optimised design offered a 5.51% increase in efficiency at design point (a 20.9% performance increase) as compared to the best performing pump from the 32 base designs. An optimisation method for the blade design of LVADs has been shown to work for a single objective function and future work will consider multi-objective optimisation.

Continuous-Flow Ventricular Assist Device Support in Adult Congenital Heart Disease: A 15-Year, Multicenter Experience of Temporary and Durable Support.

Heart failure (HF) is common in adult congenital heart disease (ACHD) patients; however, use of continuous-flow ventricular assist devices (CF-VADs) remains rare. We reviewed outcomes of patients with congenital heart disease greater than or equal to 18 years of age at the time of CF-VAD implant at the affiliated pediatric and adult institutions between 2006 and 2020. In total, 18 ACHD patients (15 with great anatomical complexity) received 21 CF-VADs. Six patients (median age 34 years) received seven percutaneous CF-VADs with a median duration of support of 20 days (3-44 days) with all patients survived to hospital discharge and two patients were bridged to durable CF-VADs. Fourteen patients (median age 38 years) received durable CF-VADs. Thirteen patients (93%) survived to hospital discharge and the median duration of support was 25.8 months (6.4-52.1 months). Estimated survival on durable CF-VAD at 1, 3, and 5 years was 84%, 72%, and 36%, respectively. Three patients were successfully bridged to transplantation. Device-related complications include cerebrovascular accident (n = 5), driveline infection (n = 3), device infection requiring chronic antibiotic therapy (n = 4), gastrointestinal bleeding (n = 6), and presumed pump thrombosis (n = 5). These results show percutaneous and durable CF-VADs can support ACHD patients with advanced HF.

The Jarvik 2000 Left Ventricular Assist Device: Results of the United States Bridge to Transplant Trial.

The Jarvik 2000 bridge to transplant investigational device exemption study was a multicentered, prospective study of 150 UNOS status I patients implanted with the Jarvik 2000 between 2005 and 2012. During the study period, there were numerous modifications of the system that included converting from pin to cone bearings. Results were analyzed for three cohorts: total (n = 150), pin (n = 128), and cone (n = 22). Baseline demographics included age (52 ± 13), gender (79% male), size (BSA 1.98), and etiology (37% idiopathic dilated cardiomyopathy; 43% Ischemic). Seventy percent of patients were either INTERMACS 1 or 2. The primary endpoint-defined as successful transplantation or listing at 180 days (prespecified at 65%; 95% lower CI: 57%)-was successfully achieved for the total cohort (67.3%; 95% CI: 59.5%-74.3%; p = 0.006). In subgroup analysis of the more contemporary, cone-bearing group, the primary endpoint was met in 91% (95% CI: 72%-97.5%; p = 0.001). Compared with pin patients, cone-bearing patients had less hemolysis as well as decreased end-organ dysfunction. Functional and quality of life scores improved after implantation independent type of bearing. In conclusion, despite a particularly sick patient population, the Jarvik 2000 was shown to be effective in supporting the advanced HF patient.

Experience with the HeartMate II Left Ventricular Assist Device in Patients Older than 60 Years.

BACKGROUND: Advanced age is a relative contraindication for heart transplantation, but no age cutoff has been defined for patients receiving mechanical circulatory support. METHODS: Between November 1, 2003 and November 1, 2012, we implanted the HeartMate II (HMII) left ventricular assist device (LVAD) in 319 patients. One hundred seven patients (89 men, 18 women) were over 60 years old (mean, 66 ± 4 years, range, 61-78 years) and received the HMII as a bridge to transplantation (n = 45) or as destination therapy (n = 62). We evaluated their experience by performing a retrospective analysis. RESULTS: Seventy-two patients had ischemic cardiomyopathy, and 34 had idiopathic cardiomyopathy. Three patients (2.8%) already had a HeartMate XVE LVAD, 54 (50.5%) were receiving intra-aortic balloon pump support, 52 (48.6%) had undergone a previous cardiac procedure, and 9 (8.4%) had received renal replacement therapy (RRT) (continuous venovenous hemofiltration, hemodialysis, or both) before HMII implantation. The median duration of HMII support was 313 days (range, 1-3339 days). After device implantation, 36 patients (33.6%) had gastrointestinal bleeding, 24 (23%) required RRT, 18 (17.5%) had ventricular arrhythmias, and 24 (22.4%) had LVAD-related infections, and 9 (8.4%) had right ventricular failure requiring mechanical support, and 28 (26.2%) had neurologic complications. The actual survival rate was 69% at 6 months, 63% at 1 year, and 54% at 2 years. Eighty-one patients died, 9 are still receiving HMII support, and 17 are alive after heart transplantation. CONCLUSIONS: Older patients can benefit from LVAD therapy, and advanced age should not preclude LVAD implantation.

In Vitro Hemocompatibility Evaluation of Ventricular Assist Devices in Pediatric Flow Conditions: A Benchmark Study.

Development of pediatric ventricular assist devices (VADs) has significantly lagged behind that of adult devices. This frustrating reality is reflected by the fact that the Berlin Heart EXCOR VAD is currently the only approved pediatric-specific device in the USA. An alternative option is an off-label use of adult continuous-flow VADs, such as HeartMate II (HMII), which inevitably causes patient-device size mismatch in small children. We sought to conduct in vitro hemocompatibility testing in a pediatric flow condition, with a specific aim to provide benchmark values for future pediatric device development. Given the aforementioned fact that both pulsatile and continuous-flow devices are being used in the pediatric population, we opted to test both types of devices in the present study. The EXCOR and HMII blood pumps were tested using bovine blood under constant hemodynamic conditions (flow rate, Q = 2.5 ± 0.25L/min; differential pressure across the pump, ΔP = 68 ± 5mm Hg). Hemolysis was measured by Harboe assay. There was a steady increase in plasma free hemoglobin during in vitro testing, with a statistically significant difference between 5 and 360 min for both EXCOR (P < 0.0001) and HMII (P < 0.001). However, the degree of an increase in plasma free hemoglobin was more significant with HMII (P < 0.001). Normalized index of hemolysis for EXCOR and HMII were 0.003 ± 0.0026g/100 L and 0.085 ± 0.0119g/100 L, respectively. There was also a steady increase in platelet activation detected by CAPP2A antibody using flow cytometry, with a statistically significant difference between 5 and 360 min for both devices (P < 0.05). The degree of an increase in platelet activation was similar between the two devices (P = 0.218). High molecular weight von Willebrand factor (HMW vWF) multimer degradation measured by immunoblotting was evident for both devices, however, it was more pronounced with the EXCOR. EXCOR blood samples from all three time points (120, 240, and 360 min) were significantly different from the baseline (5 min), whereas only 360 min samples had a significant difference from the baseline with the HMII. In conclusion, we have observed similarities and differences in hemocompatibility profiles between the EXCOR and HMII, both of which are commonly used in the pediatric population. We anticipate the benchmark values in the present study will facilitate future pediatric VAD development.

Building a Total Bioartificial Heart: Harnessing Nature to Overcome the Current Hurdles.

Engineering a bioartificial heart has become a possibility in part because of the regenerative medicine approaches to repairing or replacing damaged organs that have evolved over the past two decades. With the advent of inducible pluripotent stem cell technology, it is now possible to generate personalized cells that make the concept of autologous tissue engineering imaginable. Scaffolds that provide form, function, and biological cues to cells likewise potentially enable the engineering of biocompatible vascularized solid organs. Decellularized organs or tissue matrices retain organ complexity and structure at the macro and micro scales, contain biologically active molecules that support cell phenotype and function, and are vascularized allowing full thickness tissue generation. There is also dynamic reciprocity between the extracellular matrix and cells, which does not occur with synthetic scaffolds and allows both to evolve as functional need changes, making it a unique scaffold. Yet, building a whole heart from decellularized scaffolds and cells requires delivering hundreds of billions of multiple types of cardiac cells appropriately and providing a milieu where they can survive and mature. We propose a novel type of in vivo organ engineering utilizing pre-clinical models where decellularized hearts are heterotopically transplanted with the intent to harness the capability of the body to at least in part repopulate the scaffold. By adding load and electrical input, possibly via temporary mechanical assistance, we posit that vascular and parenchymal cell maturation can occur. In this study, we implanted porcine decellularized hearts acutely and chronically in living recipients in a heterotopic position. We demonstrated that the surgical procedure is critical to prevent coagulation and to increase graft patency. We also demonstrated that short-term implantation promotes endothelial cell adhesion to the vessel lumens and that long-term implantation also promotes tissue formation with evidence of cardiomyocytes and endothelial cells present within the graft. Utilizing endogenous repair capabilities of the recipient in response to a naked ECM, we allowed the transplanted scaffold to direct host cells-both organizationally and functionally. Thus, the scaffold provided necessary cues for cell organization and remodeling within the transplanted organ. Future work would involve culturing partially recellularized engineered organs in bioreactors where mechanical and electrical stimulation can be controlled to promote organ development and then transplanting these after a minimal level of maturation has been achieved.

Sca-1+ cardiac fibroblasts promote development of heart failure.

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45- CD31- CD29+ mEF-SK4+ PDGFRα+ Sca-1+ periostin+ (Sca-1+ ) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1+ periostin+ cardiac fibroblasts (PostnCre Il17rafl/fl ) protected mice from post-infarct heart failure and death. Moreover, PostnCre Il17rafl/fl mice had significantly fewer GM-CSF-producing Sca-1+ cardiac fibroblasts and inflammatory Ly6Chi monocytes in the heart. Sca-1+ cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1+ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.

Continuous-Flow Left Ventricular Assist Device Implantation in Patients With a Small Left Ventricle.

BACKGROUND: Having a preoperative small left ventricle (LV) has been associated with higher complication and mortality rates after left ventricular assist device (LVAD) implantation; however, the outcomes after continuous-flow LVAD implantation have not been well studied. This is the first large-scale analysis of long-term survival after continuous-flow LVAD implantation in patients with a preoperative small LV. METHODS: Our cohort comprised 511 patients who underwent primary implantation of a HeartMate II (n = 393 [Thoratec, Pleasanton, CA]) or HeartWare HVAD (n = 118 [HeartWare International, Framingham, MA]) at our institution between November 2003 and March 2016. Preoperative small LV was defined as having an LV end-diastolic diameter of 5.5 cm or less. HeartMate II and HVAD recipients with a small LV were compared with patients not having a small LV in terms of perioperative characteristics, complications, and long-term survival. RESULTS: The HeartMate II was implanted in 393 patients (non-small LV, n = 352; small LV, n = 41), and the HVAD was implanted in 118 patients (non-small LV, n = 94; small LV, n = 24). For the HeartMate II recipients, the 24-month survival rate was 66.8% for the non-small LV patients and 56.1% for the small LV patients (p = 0.17); non-small LV patients had significantly better overall survival (p = 0.02). For the HVAD recipients, the 24-month survival rate was 71.3% for the non-small LV patients and 70.8% for the small LV patients (p = 0.96); these groups showed no significant difference in overall survival (p = 0.89). CONCLUSIONS: Although the indications for implantation are different for these two devices, our study suggests that the survival advantage associated with HVAD implantation should be considered when selecting a device for small LV patients.

Rapid Speed Modulation of a Rotary Total Artificial Heart Impeller.

Unlike the earlier reciprocating volume displacement-type pumps, rotary blood pumps (RBPs) typically operate at a constant rotational speed and produce continuous outflow. When RBP technology is used in constructing a total artificial heart (TAH), the pressure waveform that the TAH produces is flat, without the rise and fall associated with a normal arterial pulse. Several studies have suggested that pulseless circulation may impair microcirculatory perfusion and the autoregulatory response and may contribute to adverse events such as gastrointestinal bleeding, arteriovenous malformations, and pump thrombosis. It may therefore be beneficial to attempt to reproduce pulsatile output, similar to that generated by the native heart, by rapidly modulating the speed of an RBP impeller. The choice of an appropriate speed profile and control strategy to generate physiologic waveforms while minimizing power consumption and blood trauma becomes a challenge. In this study, pump operation modes with six different speed profiles using the BiVACOR TAH were evaluated in vitro. These modes were compared with respect to: hemodynamic pulsatility, which was quantified as surplus hemodynamic energy (SHE); maximum rate of change of pressure (dP/dt); pulse power index; and motor power consumption as a function of pulse pressure. The results showed that the evaluated variables underwent different trends in response to changes in the speed profile shape. The findings indicated a possible trade-off between SHE levels and flow rate pulsatility related to the relative systolic duration in the speed profile. Furthermore, none of the evaluated measures was sufficient to fully characterize hemodynamic pulsatility.

New continuous-flow total artificial heart and vascular permeability.

BACKGROUND: We tested the short-term effects of completely nonpulsatile versus pulsatile circulation after ventricular excision and replacement with total implantable pumps in an animal model on peripheral vascular permeability. METHODS: Ten calves underwent cardiac replacement with two HeartMate III continuous-flow rotary pumps. In five calves, the pump speed was rapidly modulated to impart a low-frequency pulse pressure in the physiologic range (10-25 mm Hg) at a rate of 40 pulses per minute (PP). The remaining five calves were supported with a pulseless systemic circulation and no modulation of pump speed (NP). Skeletal muscle biopsies were obtained before cardiac replacement (baseline) and on postoperative days (PODs) 1, 7, and 14. Skeletal muscle-tissue water content was measured, and morphologic alterations of skeletal muscle were assessed. VE-cadherin, phospho-VE-cadherin, and CD31 were analyzed by immunohistochemistry. RESULTS: There were no significant changes in tissue water content and skeletal muscle morphology within group or between groups at baseline, PODs 1, 7, and 14, respectively. There were no significant alterations in the expression and/or distribution of VE-cadherin, phospho-VE-cadherin, and CD31 in skeletal muscle vasculature at baseline, PODs 1, 7, and 14 within each group or between the two groups, respectively. Although continuous-flow total artificial heart (CFTAH) with or without a pulse pressure caused slight increase in tissue water content and histologic damage scores at PODs 7 and 14, it failed to reach statistical significance. CONCLUSIONS: There was no significant adherens-junction protein degradation and phosphorylation in calf skeletal muscle microvasculature after CFTAH implantation, suggesting that short term of CFTAH with or without pulse pressure did not cause peripheral endothelial injury and did not increase the peripheral microvascular permeability.

A PKM2 signature in the failing heart.

A salient feature of the failing heart is metabolic remodeling towards predominant glucose metabolism and activation of the fetal gene program. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor used for the treatment of highly vascularized tumors. In diabetic patients, sunitinib significantly decreases blood glucose. However, a considerable proportion of sunitinib-treated patients develop cardiac dysfunction or failure. We asked whether sunitinib treatment results in shift towards glycolysis in the heart. Glucose uptake by the heart was increased fivefold in mice treated with sunitinib. Transcript analysis by qPCR revealed an induction of genes associated with glycolysis and reactivation of the fetal gene program. Additionally, we observed a shift in the enzyme pyruvate kinase from the adult M1 (PKM1) isoform to the fetal M2 (PKM2) isoform, a hallmark of the Warburg Effect. This novel observation led us to examine whether a similar shift occurs in human heart failure. Examination of tissue from patients with heart failure similarly displayed an induction of PKM2. Moreover, this phenomenon was partially reversed following mechanical unloading. We propose that pyruvate kinase isoform switching represents a novel feature of the fetal gene program in the failing heart.

A hybrid mock circulation loop for a total artificial heart.

Rotary blood pumps are emerging as a viable technology for total artificial hearts, and the development of physiological control algorithms is accelerated with new evaluation environments. In this article, we present a novel hybrid mock circulation loop (HMCL) designed specifically for evaluation of rotary total artificial hearts (rTAH). The rTAH is operated in the physical domain while all vasculature elements are embedded in the numerical domain, thus combining the strengths of both approaches: fast and easy exchange of the vasculature model together with improved controllability of the pump. Parameters, such as vascular resistance, compliance, and blood volume, can be varied dynamically in silico during operation. A hydraulic-numeric interface creates a real-time feedback loop between the physical and numerical domains. The HMCL uses computer-controlled resistance valves as actuators, thereby reducing the size and number of hydraulic elements. Experimental results demonstrate a stable interaction over a wide operational range and a high degree of flexibility. Therefore, we demonstrate that the newly created design environment can play an integral part in the hydraulic design, control development, and durability testing of rTAHs.

MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart.

BACKGROUND: Mechanical unloading of the failing human heart induces profound cardiac changes resulting in the reversal of a distorted structure and function. In this process, cardiomyocytes break down unneeded proteins and replace those with new ones. The specificity of protein degradation via the ubiquitin proteasome system is regulated by ubiquitin ligases. Over-expressing the ubiquitin ligase MAFbx/Atrogin-1 in the heart inhibits the development of cardiac hypertrophy, but the role of MAFbx/Atrogin-1 in the unloaded heart is not known. METHODS AND RESULTS: Mechanical unloading, by heterotopic transplantation, decreased heart weight and cardiomyocyte cross-sectional area in wild type mouse hearts. Unexpectedly, MAFbx/Atrogin-1(-/-) hearts hypertrophied after transplantation (n=8-10). Proteasome activity and markers of autophagy were increased to the same extent in WT and MAFbx/Atrogin-1(-/-) hearts after transplantation (unloading). Calcineurin, a regulator of cardiac hypertrophy, was only upregulated in MAFbx/Atrogin-1(-/-) transplanted hearts, while the mTOR pathway was similarly activated in unloaded WT and MAFbx/Atrogin-1(-/-) hearts. MAFbx/Atrogin-1(-/-) cardiomyocytes exhibited increased calcineurin protein expression, NFAT transcriptional activity, and protein synthesis rates, while inhibition of calcineurin normalized NFAT activity and protein synthesis. Lastly, mechanical unloading of failing human hearts with a left ventricular assist device (n=18) also increased MAFbx/Atrogin-1 protein levels and expression of NFAT regulated genes. CONCLUSIONS: MAFbx/Atrogin-1 is required for atrophic remodeling of the heart. During unloading, MAFbx/Atrogin-1 represses calcineurin-induced cardiac hypertrophy. Therefore, MAFbx/Atrogin-1 not only regulates protein degradation, but also reduces protein synthesis, exerting a dual role in regulating cardiac mass.

Pre-operative risk factors of bleeding and stroke during left ventricular assist device support: an analysis of more than 900 HeartMate II outpatients.

OBJECTIVES: This study sought to determine the pre-operative risk factors related to late bleeding, stroke, and pump thrombosis in patients with HeartMate II (HMII) left ventricular assist devices (LVADs) (Thoratec Corporation, Pleasanton, California) that might influence tailored improvements in patient management. BACKGROUND: Adverse events in LVAD patients remain high. It is unclear whether pre-operative characteristics influence the likelihood of the development of post-operative hemorrhagic or thrombotic complications. Knowing which patients are at greater risk might assist in tailoring anticoagulation therapy for certain patients. METHODS: Advanced heart failure patients (n = 956) discharged from the hospital after LVAD implantation in the HMII bridge to transplantation (n = 405) and destination therapy (n = 551) clinical trials were retrospectively evaluated. Bleeding requiring surgery or transfusion of >2 U of packed red blood cells, stroke (hemorrhagic and ischemic), and pump thrombosis were tracked from hospital discharge until patient outcome. RESULTS: Adverse event rates for post-discharge bleeding (0.67 events/patient-year) were higher than those for hemorrhagic stroke (0.05), ischemic stroke (0.04), and pump thrombosis (0.03). The main sites of bleeding included gastrointestinal (45% of events), wound (12%), and epistaxis (4%). Older age (>65 years) (hazard ratio [HR]: 1.31), lower pre-operative hematocrit (≤31%) (HR: 1.31), ischemic etiology (HR: 1.35), and female (HR: 1.45) were statistically significant multivariable risk factors for bleeding. Female (HR: 1.92) and 65 years of age and younger (HR: 1.94) were multivariable risk factors for hemorrhagic stroke, whereas female (HR: 1.84) and history of diabetes (HR: 1.99) were risk factors for ischemic stroke. Female (HR: 1.90) and higher body mass index (HR: 1.71/10 kg/m(2) increase) were also multivariable risk factors for pump thrombosis. CONCLUSIONS: The risk of bleeding and thrombotic events during LVAD support differs by patient demographics, including sex, age, body mass index, and etiology of heart failure. Further studies should focus on the potential of tailored anticoagulation strategies in these subgroups.

Pulsatile operation of the BiVACOR TAH - Motor design, control and hemodynamics.

Although there is limited consensus about the strict requirement to deliver pulsatile perfusion to the human circulatory system, speed modulation of rotary blood pumps is an approach that may capture the benefits of both positive displacement and continuous flow blood pumps. In the current stage of development of the BiVACOR Total Artificial Heart emphasis is placed on providing pulsatile outflow from the pump. Multiple pulsatile speed profiles have been applied in preliminary in-vivo operation in order to assess the capability of the TAH to recreate a physiologic pulse. This paper provides an overview about recent research towards pulsatile BiVACOR operation with special emphasis on motor and control requirements and developments.

Outcomes of pediatric patients supported by the HeartMate II left ventricular assist device in the United States.

OBJECTIVE: The HeartMate II (HMII; Thoratec, Pleasanton, CA) continuous-flow left ventricular assist device (LVAD) is an established treatment modality for advanced heart failure in adults. The objective of this study was to evaluate outcomes of pediatric patients supported by the HMII LVAD. METHODS: This was a retrospective review of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) of patients supported with a HMII from April 2008 to September 2011. The primary cohort comprised pediatric patients aged 11 to 18 years. Outcomes were compared with a group of young adults aged 19 to 39 years who underwent HMII implant during the same period. Ischemic etiologies for heart failure were excluded. RESULTS: There were 28 pediatric patients, of whom 19 (68%) were males, 14 (46%) were African American, and 7 (25%) underwent device placement in a pediatric hospital. Competing outcomes analysis showed that at 6 months of follow-up, the composite of survival to transplantation, ongoing support, or recovery was 96% for the pediatric group, which was not significantly different from the young adult group (96%, p = 0.330). The 2 groups had similar INTERMACS profiles but differed in diagnosis, weight, and morbidities. Bleeding complications requiring surgical intervention were more common in the pediatric group. CONCLUSIONS: Pediatric outcomes with a HMII LVAD are comparable to that of young adults. As we continue to monitor this growing group, more sophisticated characterization and comparisons will be possible. Also, as technology progress and second- and third-generation devices are introduced, the number of children who will benefit from mechanical support will continue to grow.

Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart.

BACKGROUND: Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose-6-phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6-phosphate (G6P) accumulation. METHODS AND RESULTS: We subjected the working rat heart ex vivo to a high workload in the presence of different energy-providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4-phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2-deoxy-d-glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro-PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. CONCLUSIONS: We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load-induced mTOR activation and ER stress.