Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF, not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months, respectively. These survival rates are approaching those of heart transplant patients. However, bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications, we propose to conduct a series of clinical, biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements.
Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether, a combination of clinical hematology, biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluid dynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic, next generation biocompatible VADs.
Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF, not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. Bleeding is a significant problem for the VAD therapy. The goal of this project is to seek a better understanding of shear-induced hemostatic dysfunction and bleeding in CF-VAD patients. This knowledge can be used by clinicians to match patient specific pre-implant blood profiles with predicted fluid dynamics of CF- VADs to mitigate bleeding risks in patients and by engineers to develop less traumatic, next generation biocompatible VADs. A significant portion of the 250,000 patients with advanced HF in the US will benefit from the improved VAD technology and clinical management.
|Chen, Zengsheng; Jena, Sofen K; Giridharan, Guruprasad A et al. (2018) Flow features and device-induced blood trauma in CF-VADs under a pulsatile blood flow condition: A CFD comparative study. Int J Numer Method Biomed Eng 34:|
|Chen, Zengsheng; Koenig, Steven C; Slaughter, Mark S et al. (2018) Quantitative Characterization of Shear-Induced Platelet Receptor Shedding: Glycoprotein Ib?, Glycoprotein VI, and Glycoprotein IIb/IIIa. ASAIO J 64:773-778|
|Mondal, Nandan K; Chen, Zengsheng; Trivedi, Jaimin R et al. (2018) Association of Oxidative Stress and Platelet Receptor Glycoprotein GPIb? and GPVI Shedding During Nonsurgical Bleeding in Heart Failure Patients With Continuous-Flow Left Ventricular Assist Device Support. ASAIO J 64:462-471|
|Chen, Zengsheng; Jena, Sofen K; Giridharan, Guruprasad A et al. (2018) Shear stress and blood trauma under constant and pulse-modulated speed CF-VAD operations: CFD analysis of the HVAD. Med Biol Eng Comput :|
|Mondal, Nandan K; Sobieski, Michael A; Pham, Si M et al. (2017) Infection, Oxidative Stress, and Changes in Circulating Regulatory T Cells of Heart Failure Patients Supported by Continuous-Flow Ventricular Assist Devices. ASAIO J 63:128-133|
|Mondal, Nandan K; Chen, Zengsheng; Trivedi, Jaimin R et al. (2017) Oxidative stress induced modulation of platelet integrin ?2b?3 expression and shedding may predict the risk of major bleeding in heart failure patients supported by continuous flow left ventricular assist devices. Thromb Res 158:140-148|
|Mondal, Nandan K; Li, Tieluo; Chen, Zengsheng et al. (2017) Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices. Mol Cell Biochem 433:125-137|
|Chen, Zengsheng; Mondal, Nandan K; Zheng, Shirong et al. (2017) High shear induces platelet dysfunction leading to enhanced thrombotic propensity and diminished hemostatic capacity. Platelets :1-8|
|Chen, Zengsheng; Mondal, Nandan K; Ding, Jun et al. (2016) Paradoxical Effect of Nonphysiological Shear Stress on Platelets and von Willebrand Factor. Artif Organs 40:659-68|
|Chen, Zengsheng; Mondal, Nandan K; Ding, Jun et al. (2015) Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress. Mol Cell Biochem 409:93-101|
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