Conditions leading to myocardial dysfunction and heart failure often have mechanical origins. Myocardial infarction and heart failure are characterized by maladaptive remodeling of the cardiac tissue wall and are often accompanied by diffuse fibrosis. At the cellular level, changes in shape (aspect ratio) are seen in a number of clinical conditions associated with various forms of cardiomyopathy. The overarching hypothesis is that remodeling and reorganization of the myocyte-cytoskeletal (CSK) architecture is a collective (structurally integrative) process, requiring instructive extracellular signals (e.g., cell-ECM and cell-cell contact). Damaged tissue cannot provide the requisite mechanical microenvironment (e.g., anisotropic) dependent cues

The intracellular architecture plays a critical role in transducing mechanical signals into biochemical processes responsible for regulating cell function. Mechanical control of the microenvironment (structural anisotropy, topography) provides both the cues and means for affecting cell fate (see Figure). This mechanobiological perspective forms the basis for viewing the heart (tissue) as a mechanotransducing anisotropic continuum, exhibiting constant mechanosensory-driven self-recurrent adjustment of the cytoskeleton through a tight interplay between its force generation activity and concurrent architecture (sarcomerogenesis / myofibrillogenesis). It is becoming increasingly clear that changes in cardiac function accompanying tissue remodeling associated with heart failure are brought about by the disruption of the mechanotransduction continuum (e.g., disorganized cells alignment and altered cell phenotype).  The ability to surgically engineer (reverse remodel) the mechanical milieu of cells provides a compelling rationale for advancing novel biomaterial-based therapeutic strategies (e.g., injectable scaffolds).

A – Fibronectin-microprinted adhesive patterns (‘mechano-alphabet’), representing the spectrum of the anisotropic and isotropic adhesion imposed conditions (top) and corresponding myocyte cytoskeleton (CSK) architectural features (bottom). B – Polarity of myofibrils (MFs) induced by the anisotropic adhesion feature (arrows) follows the tensile field (crossbow). Myocytes demonstrate the continual MF formation, revealing the spatial integrity of CSK even over the non-adhesive zones. Stress-fibers in the fibroblast are localized at the cell edges and demonstrate their longitudinal integrity.

Selected Publications

“Pacing-Induced Cardiac Gap-Junction Remodeling”
Matsushita S, Tran VN, Pelleg A, Wechsler AS, Kresh JY
Amer. J. Therapeutics, Vol. 16, 224-230, 2009

“Of Mice and Men (and Effects of Gene Silencing)"
Wechsler AS, Kresh JY
Circulation, Vol. 120, 1027-1028, 2009

“Anti- and Proarrhythmic Effects of Cardiac Resynchronization Therapy: Point of View”
DiPalma JR, Kutalek SP, Eisen H, Kresh JY, Pelleg A
Amer. J. Therapeutics, Vol. 15, 190-195, 2008

“Real-Time Monitoring of Adhesion and Aggregation of Platelets using Thickness Shear Mode (TSM) Sensor”
Ergezen E, Appel M, Shah P, Kresh JY, Lec RM, Wootton, DM
Biosens Bioelectron. Vol. 23, 575-82, 2007

“Risk Stratification of Obstetric Patients Undergoing Spinal Anesthesia”
Chamchad D, Arkoosh AV, Horrow JC, Buxbaum JL, Izrailtyan I, Nakhamchik L, Hoyer D, Kresh JY
Anesthesia & Analgesia, Vol. 99, 1818-21, 2004

Complex Systems Science in BioMedicine
Deisboeck TS., Kresh JY (eds): Springer, New York, NY, USA. 2006

"Cell replacement therapy: the functional importance of myocardial architecture and intercellular gap-junction distribution"
Kresh JY
J Thorac Cardiovasc Surg. Vol. 131, 1310-3, 2006

“Physiologic and Hemodynamic Basis of Ventricular Assist Devices”
Bolno PB, Kresh JY,
Cardiology Clinics, Vol. 21, 15-27, 2003

“Cardiomyocyte-Mediated Contact Programs Human Mesenchymal Stem Cells to Express Cardiogenic Phenotype”
Rangappa S, Entwistle JW, Wechsler AS, Kresh JY
J Thorac and Cardiovas Surg. Vol. 126, 124-132, 2003

"A Novel approach to Robotic Cardiac Surgery Using Haptics and Vision"
Kennedy CW, Hu T, Desai JP, Wechsler AS, Kresh JY
Cardiovascular Engineering: An International Journal, Vol. 2 No. 1, 15-22 , 2002

"Early detection of acute allograft rejection by linear and nonlinear analysis of heart rate variability"
Izrailtyan I, Kresh JY, Morris RJ, Brozena SC, Kutalek SP, Wechsler AS
J Thorac Cardiovasc Surg. Vol. 120, 737-45, 2000

Patents

Pacing System and Method for Cardiac Pacing As a Function of Determined Myocardial Contractility: U.S. Patent # 4,936,304

Myocardial Contractility-Sensitive Pacer: French and German Patents # 0244446 / 3673643

Acoustic Blood Analyzer for Assessing Coagulation Status U.S. Patent # (Pending)