Harold H. Bien

4th Year Medical Student

Department: School of Medicine

Graduate Program: Biomedical Engineering

Advisor: Dr. Emilia Entcheva

Abstract:

Title: Cardiac Arrhythmogenesis In Urban Air Pollution: Optical Mapping In A Tissue-Engineered Model

Recent epidemiological evidence has implicated particulate matter air pollution in cardiovascular disease. We hypothesized that inflammatory mediators released from lung macrophages after exposure to particulate matter predisposes the heart to disturbances in rhythm. Using a rational design approach, a fluorescent optical mapping system was devised to image spatiotemporal patterns of excitation in a tissue engineered model of cardiac tissue. Algorithms for automated data analysis and characterization of rhythm stability were developed, implemented, and verified. Baseline evaluation of spatiotemporal instability patterns in normal cardiac tissue was performed for comparison to an in-vitro model of particulate matter air pollution exposure. Exposure to particulate-matter activated alveolar macrophage conditioned media resulted in paradoxical functional changes more consistent with improved growth and increased resistance to arrhythmias. These findings might be indicative of a “stress” response to particulate-matter induced pulmonary inflammation, or may be specific to the animal model (neonatal rat) employed. In the pursuit of elucidating the proposed pathway, we have also furthered our understanding of fundamental behaviors of arrhythmias in general and established a model where further testing might ultimately reveal the mechanism for urban air pollution associated cardiovascular morbidity.

Publications:
(MSTP-supported publications indicated with an *)

*1. Jia Z, Bien H and Entcheva E, Detecting space-time alternating biological signals close to the bifurcation point. 2008 (in review).

*2. Bien H, Kalkhoran S and Entcheva E, Hysteresis in rhythm patterns during electric field stimulation of cardiac tissue. Chaos, Solitons & Fractals, 2008 (in press).

*3. Chung CY, Bien H and Entcheva E, The role of cardiac tissue alignment in modulating electrical function. Journal of Cardiovascular Electrophysiology, 18: 1323-1329, 2007.

*4. Bien H, Parikh P and Entcheva E, Lenses and effective spatial resolution in optical mapping. Physics in Medicine and Biology, 52(4):941-960, 2007.

*5. Bien H, Entcheva E, Pertsov A, Mironov S, Vetter F, Spatial frequency content in optical mapping of cardiac cell monolayers. Am J Physiol – Heart & Circ Physiol, 291(3):H484-5, 2006.

*6. Bien H, Yin L and Entcheva E, Calcium instabilities in mammalian cardiomyocyte networks. Biophysical Journal, 90(7): 2628-40, 2006.

*7. Entcheva E and Bien H, Macroscopic optical mapping of excitation in cardiac cell networks with ultra-high spatiotemporal resolution. Progress in Biophysics and Molecular Biology, 92(2):232-57, 2006. *Article featured in Biophotonics International – November 2006.

*8. Zong X, Bien H, Chung CY, Yin L, Fang D, Chu B, Hsiao BS, and Entcheva E, Electrospun fine-textured scaffolds for heart tissue constructs. Biomaterials 26(26):5330-5338, 2005.

*9. Entcheva E and Bien H. Acoustic micromachining of three-dimensional surfaces for biological applications. Lab on a Chip, 5(2): 179-184, 2005.*Selected as a “hot article” by the Royal Society of Chemistry (RSC); featured in RSC Chem Technol 2004 (1) T7

*10. Yin L*, Bien H*, Entcheva E. Scaffold topography alters intracellular calcium dynamics in cultured cardiomyocyte networks. American Journal of Physiology - Heart & Circulatory Physiology. 283(3): H1276-85, 2004. (*equal contribution)

*11. Entcheva E, Bien H, Yin L, Chung C-Y, Farrell M, and Kostov Y. Functional cardiac cell constructs on cellulose-based scaffolding. Biomaterials. 25: 5753-5762, 2004.

*12. Entcheva E and Bien H. Tension development and nuclear eccentricity in topographically controlled cardiac syncytium. Biomedical Microdevices. 5(2): 165-70, 2003.

*13. Bien H, Yin L, Entcheva E. Cardiac cell networks on elastic microgrooved scaffolds. IEEE Engineering in Medicine and Biology. 22(5): 5753-62, 2004.

14. Cuenca A, Cheng F, Wang H, Brayer J, Horna P, Gu L, Bien H, Borrello IM, Levitsky HI, Sotomayor EM. “Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens.” Cancer Res. 63(24):9007-15, 2003.

15. Sotomayor EM. Borrello I. Tubb E. Rattis FM. Bien H. Lu Z. Fein S. Schoenberger S. Levitsky HI. “Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40” Nature Medicine. 5(7):780-7, 1999.

Peer reviewed short proceedings

16. Jia Z, Bien H, and Entcheva E, A sensitive algorithm for automatic detection of space-time alternating signals in cardiac tissue, Proceedings of IEEE Engineering in Medicine and Biology Society, Vancouver, Canada, 2008.

17. Singh R, Bien H and Entcheva E, Inherent dispersion of restitution properties over space, Proceedings of IEEE Engineering in Medicine and Biology Society, New York City, NY, 2006.

18. Shah U, Bien H and Entcheva E, Cardiac arrhythmogenesis and temperature, Proceedings of IEEE Engineering in Medicine and Biology Society, New York City, NY, 2006.

19. Zong X, Bien H, Chung C-Y, Yin L, Kim K, Fang DF, Chu B, Hsiao BS and Entcheva E. Electrospun non-woven membranes as scaffolds for heart tissue constructs. Fall Meeting of the American Chemical Society, New York, NY, September 2003.

20. Bien H, Yin L, Entcheva E. Optical mapping of complex electrical activity in engineered cardiac tissue constructs. ASME Summer Bioengineering Conference, Sonesta Beach FL, June 2003.

21. Bien H, Yin L, Entcheva E. Cardiac cell networks on elastic microgrooved scaffolds. Proceedings of IEEE Engineering in Medicine and Biology Society and BMES Annual Conference, Houston TX, 2002. *First place in the Student Paper Competition by IEEE-EMBS.

Peer Reviewed Abstracts

22. Jia Z, Bien H and Entcheva E, Automatic detection of spatiotemporal fine-scale alternans in paced cardiac tissue, Annual BMES Meeting, St. Louis, MI, October 2008.

23. Entcheva E, Jia Z and Bien H, Asynchrony in spatiotemporal calcium dynamics and cardiac arrhythmias, APCTP Workshop on Self-Organization in Biological Systems, Pusan, South Korea, November 2007.

24. Entcheva E, Jia Z and Bien H, Spatially discordant alternans in paced cardiac tissue, Gordon Research Conference on Cardiac Arrhythmias, Ventura, CA, March 2007.

25. Jia Z, Bien H and Entcheva E, Spatially discordant alternans in quasi-1D cardiac tissue constructs, Dynamics Days, Boston, MA, January 2007.

26. Wang W, Gao J, Bien H, Entcheva E, Cohen IS and Mathias RT, Transmural gradient in Na/K pump activity leads to regional differences in calcium handling, Biophysical Society Meeting, Baltimore, MD, March 2007.

27. Shah U, Chung CY, Bien H and Entcheva E, Microtopographical effects of natural scaffolding on cardiac function, Annual BMES Meeting, Chicago, IL, October 2006.

28. Bien H, Parikh P and Entcheva E, Optics’ limitations on spatial resolution in fluorescence optical mapping, Frontiers in Live Cell Imaging Meeting, Washington, DC, April 2006.

29. Bien H and Entcheva E, Co-existence of reentrant waves with spatially discordant alternans, Annual Heart Rhythm Society Meeting, Boston, MA, May 2006.

30. Bien H, Varghese L and Entcheva E, Optical mapping reveals direct cardiac arrhythmogenicity by inflammatory cytokines, Annual BMES Meeting, Baltimore, MD, October 2005.

31. Bien H, Chung CY and Entcheva E, Uncovering temperature dependencies of excitability and connectivity in cardiomyocyte networks, Annual BMES Meeting, Baltimore, MD, October 2005.

32. Chung CY, Bien H and Entcheva E, Anisotropy and propagation patterns influence voltage and calcium in assembled cardiac cell networks, Annual BMES Meeting, Baltimore, MD, October 2005.

33. Varghese L, Bien H and Entcheva E, Multiparameter analysis of cardiac response to TNF-α and adrenergic stimulation, Annual BMES Meeting, Baltimore, MD, October 2005.

34. Entcheva E and Bien H, Imaging calcium dynamics and reentrant arrhythmias in cardiac cell networks, Gordon Research Conference (GRC) on Cardiac Arrhythmias, Santa Ynez Valley, CA, February, 2005.

35. Wang W, Gao J, Bien H, Entcheva E, Cohen IS and Mathias RT, A contraction gradient across the ventricular wall is determined by the transmural gradient in Na/K pump current, Biophysical Society Meeting, Long Beach, CA, February 2005.

36. Kostov Y, Rao G, Bien H, Farrell M, Yu H-J and Entcheva E. Miniaturized fluorescence lifetime system for oxygen measurements in cardiac cell constructs. Annual BMES Meeting, Philadelphia PA, October 2004.

37. Chung CY, Zong X, Bien H, Yin L, Fang DF, Chu B, Hsiao BS and Entcheva E. Functional cardiac tissue grown on electrospun non-woven scaffolds. Annual BMES Meeting, Nashville TN, October 2003.

38. Bien H, Farrell M, Yu H-J, Kostov Y and Entcheva E. Lifetime fluorescence measurements of oxygen uptake in cardiac cell networks using oxygen-sensitive scaffolds. Annual BMES Meeting, Nashville TN, October 2003.

39. Entcheva E, Kostov Y, Bien H, Yin L, Chung CY, Dasari V and Farrell M. Versatile cellulose-based scaffolding for growing functional cardiac cell networks. Annual BMES Meeting, Nashville TN, October 2003.

40. Entcheva E, Bien H and Tchernev E. Acoustic micromachining for three-dimensional anisotropy control in engineered cardiac tissue. Annual BMES Meeting, Nashville TN, October 2003.

41. Entcheva E and Bien H, Analysis of propagation patterns in engineered cardiac tissue, Gordon Research Conference (GRC) on Cardiac Arrhythmia Mechanisms, New London, NH, August 2003.

42. Bien H, Dasari V, Farrell M, Yu H-J, Yin L, Chung C-Y and Entcheva E. Mechanical and spatial determinants of cytoskeletal geodesic dome formation in cardiac fibroblasts, ASM Conference on Bio-, Micro- and Nanosystems, New York, NY, July 2003.

43. Entcheva E, Bien H and Tchernev E. Acoustic micromachining for controlled cell growth. Fourth Annual BioMEMs and Biomedical NanoTECH World 2003, Washington DC, 2003.

44. Entcheva E, Bien H and Yin L. Electromechanical performance of engineered cardiac constructs. ET 2003: Engineering Tissues, 7th Hilton Head Workshop & Annual ET Conference, March 2003.

45. Entcheva E, Yin L, and Bien H. [Ca2+]i changes in cardiac tissue constructs on 3D elastic matrices. PACE-Pacing and Clinical Electrophysiology 26(4 (Part II)):1107, 2003.

46. Entcheva E and Bien H. Tension development and nuclear eccentricity in topographically controlled cardiac syncytium. Third Annual BioMEMs and Biomedical NanoTECH World 2002, Columbus OH, 2002.

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