Gaurav Girdhar

Device Thrombogenicity Emulation: A Novel Method for Optimizing Mechanical Circulatory Support Device Thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation – mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device – ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers – before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device ‘thrombogenic footprint’, indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops – before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology – demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization – indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.

Design Optimization of a Mechanical Heart Valve for Reducing Valve Thrombogenicity—A Case Study with ATS Valve

Patients implanted with mechanical heart valves (MHV) or with ventricular assist devices that use MHV require mandatory lifelong anticoagulation for secondary stroke prevention. We recently developed a novel Device Thrombogenicity Emulator (DTE) methodology that interfaces numerical and experimental approaches to optimize the thrombogenic performance of the device and reduce the bleeding risk associated with anticoagulation therapy. Device Thrombogenicity Emulator uses stress-loading waveforms in pertinent platelet flow trajectories that are extracted from highly resolved numerical simulations and emulates these flow conditions in a programmable hemodynamic shearing device (HSD) by which platelet activity is measured. We have previously compared two MHV, ATS and the St. Jude Medical, and demonstrated that owing to its nonrecessed hinge design, the ATS valve offers improved thrombogenic performance. In this study, we further optimize the ATS valve thrombogenic performance, by modifying various design features of the valve, intended to achieve reduced thrombogenicity: 1) optimizing the leaflet-housing gap clearance; 2) increasing the effective maximum opening angle of the valve; and 3) introducing a streamlined channel between the leaflet stops of the valve that increases the effective flow area. We have demonstrated that the DTE optimization methodology can be used as test bed for developing devices with significantly improved thombogenic performance.

Thromboresistance Comparison of the HeartMate II Ventricular Assist Device With the Device Thrombogenicity Emulation-Optimized HeartAssist 5 VAD

Approximately 7.5 × 106 patients in the US currently suffer from end-stage heart failure. The FDA has recently approved the designations of the Thoratec HeartMate II ventricular assist device (VAD) for both bridge-to-transplant and destination therapy (DT) due to its mechanical durability and improved hemodynamics. However, incidence of pump thrombosis and thromboembolic events remains high, and the life-long complex pharmacological regimens are mandatory in its VAD recipients. We have previously successfully applied our device thrombogenicity emulation (DTE) methodology for optimizing device thromboresistance to the Micromed Debakey VAD, and demonstrated that optimizing device features implicated in exposing blood to elevated shear stresses and exposure times significantly reduces shear-induced platelet activation and significantly improves the device thromboresistance. In the present study, we compared the thrombogenicity of the FDA-approved HeartMate II VAD with the DTE-optimized Debakey VAD (now labeled HeartAssist 5). With quantitative probability density functions of the stress accumulation along large number of platelet trajectories within each device which were extracted from numerical flow simulations in each device, and through measurements of platelet activation rates in recirculation flow loops, we specifically show that: (a) Platelets flowing through the HeartAssist 5 are exposed to significantly lower stress accumulation that lead to platelet activation than the HeartMate II, especially at the impeller-shroud gap regions (b) Thrombus formation patterns observed in the HeartMate II are absent in the HeartAssist 5 (c) Platelet activation rates (PAR) measured in vitro with the VADs mounted in recirculation flow-loops show a 2.5-fold significantly higher PAR value for the HeartMate II. This head to head thrombogenic performance comparative study of the two VADs, one optimized with the DTE methodology and one FDA-approved, demonstrates the efficacy of the DTE methodology for drastically reducing the device thrombogenic potential, validating the need for a robust in silico/in vitro optimization methodology for improving cardiovascular devices thromboresistance.

Biological effects of dynamic shear stress in cardiovascular pathologies and devices

Altered and highly dynamic shear stress conditions have been implicated in endothelial dysfunction leading to cardiovascular disease, and in thromboembolic complications in prosthetic cardiovascular devices. In addition to vascular damage, the pathological flow patterns characterizing cardiovascular pathologies and blood flow in prosthetic devices induce shear activation and damage to blood constituents. Investigation of the specific and accentuated effects of such flow-induced perturbations on individual cell-types in vitro is critical for the optimization of device design, whereby specific design modifications can be made to minimize such perturbations. Such effects are also critical in understanding the development of cardiovascular disease. This review addresses limitations to replicate such dynamic flow conditions in vitro and also introduces the idea of modified in vitro devices, one of which is developed in the authors’ laboratory, with dynamic capabilities to investigate the aforementioned effects in greater detail.

Thrombogenic Potential of Innovia Polymer Valves versus Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valves

Trileaflet polymeric prosthetic aortic valves (AVs) produce hemodynamic characteristics akin to the natural AV and may be most suitable for applications such as transcatheter implantation and mechanical circulatory support (MCS) devices. Their success has not yet been realized due to problems of calcification, durability, and thrombosis. We address the latter by comparing the platelet activation rates (PARs) of an improved polymer valve design (Innovia LLC) made from poly(styrene-block-isobutylene-block-styrene) (SIBS) with the commercially available Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valve. We used our modified prothrombinase platelet activity state (PAS) assay and flow cytometry methods to measure platelet activation of a pair of 19 mm valves mounted inside a pulsatile Berlin left ventricular assist device (LVAD). The PAR of the polymer valve measured with the PAS assay was fivefold lower than that of the tissue valve (p = 0.005) and fourfold lower with flow cytometry measurements (p = 0.007). In vitro hydrodynamic tests showed clinically similar performance of the Innovia and Magna valves. These results demonstrate a significant improvement in thrombogenic performance of the polymer valve compared with our previous study of the former valve design and encourage further development of SIBS for use in heart valve prostheses.

Thrombogenicity comparison of axial ventricular assist devices by dte methodology: Micromed heartassist 5 and thoratec heartmate II

Mechanical circulatory devices, such as ventricular assist devices (VADs), have become the life-saving alternative for the patients who suffered from severe heart failure (1). These devices were utilized as the bridge-transplant devices; however, due to the fast growing population of cardiovascular diseases and the eligible organ donations are very limited, these devices have been considered for the application of life-long implantation. The continuous-flow VADs offer better hemodynamic performance than the first generations pulsatile flow VADs, its compact design offers surgical advantage; however, due to the non-physiological blood flow past constricted geometrics where platelets are exposed to elevated wall shear stress (2), VADs are burdened with high incidence of thromboembolic events, mandating anticoagulation therapies for its recipients (3).© 2012 ASME

Dynamic Shear Stress Induced Platelet Activation in Blood Recirculation Devices: Implications for Thrombogenicity Minimization

Implantable blood recirculation devices such as ventricular assist devices (VADs) and more recently the temporary total artificial heart (TAH-t) are promising bridge-to-transplant (BTT) solutions for patients with end-stage cardiovascular disease. However, blood flow in and around certain non-physiological geometries, mostly associated with pathological flow around mechanical heart valves (MHVs) of these devices, enhances shear stress-induced platelet activation, thereby significantly promoting flow induced thrombogenicity and subsequent complications such as stroke, despite a regimen of post-implant antithrombotic agents. Careful characterization of such localized high shear stress trajectories in these devices by numerical techniques and corresponding experimental measurements of their accentuated effects on platelet activation and sensitization, is therefore critical for effective design optimization of these devices (reducing the occurrence of pathological flow patterns formation) for minimizing thrombogenicity [1].Copyright

Thrombogenicity assessment of Pipeline Flex, Pipeline Shield, and FRED flow diverters in an in vitro human blood physiological flow loop model: In vitro thrombogenicity of flow diverters

Abstract Endovascular treatment of intracranial aneurysms with endoluminal flow diverters (single or multiple) has proven to be clinically safe and effective, but is associated with a risk of thromboembolic complications. Recently, a novel biomimetic surface modification with covalently bound phosphorylcholine (Shield Technology™) has shown to reduce the material thrombogenicity of the Pipeline flow diverter. Thrombogenicity of Pipeline Flex, Pipeline Shield, and Flow Redirection Endoluminal Device (FRED) in the presence of human blood under physiological flow conditions—in addition to relative increase in thrombogenicity with multiple devices—remains unknown and was investigated here. Thrombin generation (mean ± SD; μg/mL; thrombin–antithrombin complex or TAT) was measured as FRED (30.3 ± 2.9), Pipeline (13.9 ± 4.4), Pipeline Shield (0.4 ± 0.3), and negative control (no device; 0.1 ± 0.0). Platelet activation (mean ± SD; IU/μL; beta‐thromboglobulin or βTG) was measured as FRED (148 ± 45), Pipeline (92.8 ± 41), Pipeline Shield (16.2 ± 3.5), and negative control (2.70 ± 0.16). FRED was significantly more thrombogenic than Pipeline and Pipeline Shield (p < 0.05) for TAT. Additionally, Pipeline Shield had significantly lower TAT and βTG than the other devices tested (p < 0.05) and these were comparable to the negative control (p > 0.05). TAT and βTG scaled proportionately with multiple Pipeline devices (N = 6) but was unaffected by multiple Pipeline Shield (N = 6) devices—the latter being statistically similar to negative control (p > 0.05).

In Vitro Evaluation of Shear-Induced Platelet Activation in the MicroMed DeBakey Ventricular Assist Device With Antiplatelet Therapy

Mechanical circulatory support (MCS) devices, which include ventricular assist devices (VADs), offer an attractive solution to approximately 35,000 end-stage heart failure patients eligible for transplants, of which only 2,000–2,300 are performed annually [1]. These devices are employed to augment the function of the ailing left and/or right ventricle and serve as bridge-to-transplant or destination therapy, but are often accompanied by thrombotic complications. Pathologic flow patterns are characteristic of VADs and increase susceptibility to shear-induced platelet activation, which leads to thrombus formation [2]. Patients implanted with such devices are routinely prescribed antiplatelets to tackle these complications. Despite this concurrent therapy, thromboembolic incident rates of 0.9–13% are reported for the widely-implanted Thoratec HeartMate II and MicroMed DeBakey VADs [3, 4]. This has spurred the development of design optimization techniques to lower or eliminate the incidence of thrombosis and reduce the dependence on pharmacotherapy management.Copyright

Dynamic numerical and experimental evaluation of trileaflet polymer prosthetic heart valves

Valvular heart disease (VHD) continues to be a significant public health issue with an estimated 1–2% of the population affected [1]. Currently, VDH is primarily treated at the end stages with open-heart surgical replacement of the diseased valve with either a tissue or mechanical prosthetic heart valve (PHV), each having deficiencies including low durability and high thrombosis respectively. Polymer trileaflet PHVs have been designed to mimic the native aortic valve (AV) hemodynamics while being more durable and less thrombogenic than current PHVs. Recent advances in polymers and its applications for polymer PHVs, including transcatheter PHVs or use in the Total Artificial Heart (TAH) (Fig. 1), encourage further research and development [2–4]. Paramount to polymer PHV progress is proving equivalence to commercially available FDA approved PHVs.© 2011 ASME