Research Overview

Cardiovascular diseases are the major cause of death in the developed world. Our research aims at providing insights into structure and function of tissues, cells and proteins of the normal and diseased heart. This research is motivated by our interest in combining science, engineering and medicine to advance our understanding of cardiac diseases and therapies.

Research in our laboratory is focused on the following topics:

Tissue Remodeling in Heart Failure and Restoration after Therapy

tissue remodeling

We made contributions to understanding of subcellular and cellular remodeling in heart failure and restoration after cardiac therapy. Using confocal microscopy and image processing, we identified heterogeneous subcellular depletion of the transverse tubular system and alterations of its spatial relationship with ryanodine receptors in synchronous and dyssynchronous heart failure. We linked this structural remodeling to remodeling of excitation-contraction coupling. Furthermore, we demonstrated partial restoration of structures and function after cardiac resynchronization therapy, which sheds light on cellular mechanisms underlying the clinical success of this therapy. The studies were performed in collaboration with Dr. John Bridge, University of Utah, and Drs. Gordon Tomaselli and David Kass, Johns Hopkins University.

With Drs. Stavros Drakos and Craig Selzman, University of Utah, we extended our methods to gain insights into subcellular remodeling in heart failure patients before and after left ventricular assist device (LVAD) therapy. This work promises to have a major impact on basic understanding of cellular remodeling in disease and recovery after therapy.

Fiber-Optics Confocal Microscopy of the heart

Fiber optics confocal microscopy

In collaboration with Drs. Robert Hitchcock, University of Utah, and Aditya Kaza, Boston Children’s Hospital, we explore fiber-optics confocal microscopy for applications in pediatric heart surgery. Patents on our imaging approach and several of its collateral methods were published or are pending. We evaluated the imaging in a small mammal model. We showed that tissues can be discriminated in the living arrested heart using fiber-optics confocal microscopy. We currently work on clinical translation of the developed approach. A feasibility study on 6 patients undergoing intra-operative imaging at Boston Children’s Hospital was recently completed.

With Dr. Nassir Marrouche, University of Utah, we introduced an approach for imaging of subendocardial cardiac tissue based on a catheterized fiber-optics confocal microscopy. The approach was tested in beating in situ hearts. We integrated the imaging with clinical electrical mapping, ablation and navigation technology. Based on these developments, we perform a clinical assessment of endomyocardial tissue microstructure. Our long-term aims are to support diagnosis and treatment of atrial fibrillation and heart failure patients.

Localization and Function of Transient Receptor Cation Channels In Cardiac Myocytes

transient receptor potential cation channels

TRPC channels are thought to reside in the sarcolemma and contribute to mechano-electrical feedback in myocytes. Using scanning confocal microscopy and immunoelectron-microscopy on adult rabbit myocytes we provided evidence that TRPC channels are located at the sarcoplasmic reticulum. This finding points at a role of TRPC channels in excitation-contraction coupling. Using methods for adenoviral infection of myocytes for TRPC overexpression and silencing, we found that TRPC1 channels contribute to calcium leak from the sarcoplasmic reticulum. Currently, we explore methods for super-resolution imaging and are measuring calcium signals in infected cells in different strain conditions.

Computer Modeling

3D reconstruction

We develop and apply computational models to gain insights into ion channels and their role in cardiac electrophysiology. A focus is on ion channel mutations, their effects on cellular electrophysiology, and potential drug treatment. We use molecular dynamics and Markovian modeling to investigate structure-functional relationships of ion channels. For instance, in collaboration with Dr. Michael Sanguinetti, University of Utah, we investigated mechanisms of blockers and activators on the human ether-à-go-go (hERG) channels responsible for repolarization of cardiac myocytes. Recent work with Dr. Martin Tristani-Firouzi, University of Utah, and Dr. Gunnar Seemann, University of Freiburg, was related to effects of voltage sensitivity of muscarinic acetylcholine receptors on autorhythmicity of pacemaker cells.

Computational and experimental approaches enable us to investigate structures and function of normal and diseased tissue. We characterized modulation of mechano-electrical signaling in experimental and computational studies on small muscle preparations and isolated cells. With Drs. Junior Abildskov and Alonso Moreno, University of Utah, and Dr. Gunnar Seemann, we developed electrophysiological models of cardiac fibroblasts and a new class of multi-domain models for computational studies of tissue electrophysiology. We introduced and applied image-based computational models to predict effects of fibrosis, in particular, arrhythmogenesis. The developed approaches provide a unique basis for modeling of various cardiac diseases.

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