Projects

Ongoing

New Generation of Intracardiac Visualization Catheters

Radiofrequency ablation (RFA) targets reentrant circuits or ectopic sources that cause atrial fibrillation. Today, there are limited means for real-time visualization of cardiac muscle tissue injury during RFA procedures. We found that hyperspectral autofluorescence imaging greatly improves the visualization of terminally injured cardiac tissue caused by thermal ablations. The ultimate goal of the STTR phase II proposal is to integrate hyperspectral imaging technology into the design of new percutaneous visualization catheters.

Funded by the National Institutes of Health, NHLBI, STTR Phase II award, PI - Sarvazyan

Tissue Engineered Pumps Aiding Flow of Biological Fluids

We are developing novel approaches to treat the insufficient flow of biological fluids. If successful, these approaches can aid the treatment of chronic deep venous disease and other causes of limited flow, including direct injury and paralysis of lower limb muscles. The approach is based on using patient's own stem cells to create a rhythmically beating sheath of cardiac muscle cells that wrap around soft vessels. Such tissue-engineered 'mini hearts' can contain valves as well as be valveless (ie., be based on Liebau principle).

Funded by the American Heart Association, National Institutes of Health, and National Science Foundation, PI - Sarvazyan.

Hyperspectral Imaging to reveal text and images on ancient ostraca and frescoes

In collaboration with the American University of Armenia (Prof. Gregory Areshian) and GW Archeological Institute (Profs. Christopher Rollston and Eric Cline), our lab is using advanced imaging tools to help reveal images and text on ancient objects that for thousands of years have been exposed to the elements.

Funded by the GW Office of Vice President of Research and American University of Armenia, PIs: Sarvazyan (GW) & Areshian (AUA).

Past Projects

Bringing Tissue Engineering Protocols to Armenia

The purpose of this project was to facilitate the development and dissemination of scientific expertise in Tissue Engineering and Regenerative Medicine (TERM) protocols, aiming specifically at young professionals from basic science and clinical institutions of the Republic of Armenia. A hands-on-course on tissue engineering protocols was developed and conducted. It covered the most common TERM methods including cultivation and maintenance of stem cells, derivation of bioscaffolds, and tissue decellularization methods.

Funded by the U.S. Department of State Fulbright Program, US Scholar Award to Sarvazyan

Light Controlled Muscle Pumps

Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins. The goal of this collaborative project is to use light to modulate function of tissue-engineered muscle cuff pumps.

Funded by the GW Office of Vice President of Research, Cross-Disciplinary Research Fund. PIs - Entcheva, Sarvazyan, Posnack

Cardiac Effect of Snake Venoms

The main goal of this project is to examine pharmacological effects of crude venom and disintegrins from Macrovipera lebetina obtusa and Montivipera raddei venoms on cardiac myocyte network morphology and behavior.

Funded by the GW Office of Vice President of Research, International Research Program. PI - Sarvazyan, Collaborator - Ayvazyan, Karabekian

Stem Cells and Cardiac Arrhythmias

Arrhythmias are a major cause of death after a myocardial infarction, but preliminary studies suggest that the transplantation of stem cell-derived cardiomyocytes can reduce the incidence of post-infarct arrhythmias. We will investigate the mechanistic basis for this anti-arrhythmic effect and explore new strategies to further enhance the electrical integration of stem-cell-derived cardiomyocytes in injured hearts.

Funded by the National Institutes of Health R01 HL117991, PI - Laflamme, Sarvazyan - co-PI on GW contract.

Engineering Immunocompatible Tissues

Embryonic stem cells (ESC) provide a unique opportunity to modify the original source of differentiated cells that can allow to subsequently circumvent their rejection by the host. We are testing a novel strategy of diminishing the expression of Major Histocompatibility Complex class I molecules (MHC I) and up-regulating Fas ligand (FasL) expression in order to minimize rejection of ESC-derivatives by the host. The modified ESC can then be differentiated and seeded into decellularized scaffolds from target tissues, followed by testing their immunogenicity in non-autologous hosts.

Funded by the National Science Foundation, EAGER award, CBET 1231549, PI - Sarvazyan, Co-PI - Karabekian

Plasticizers and Cardiac Function

The cardiac effects of plasticizers remain largely understudied. We have recently shown that one of the most commonly used one - DEHP - markedly decreases the conduction velocity, diminishes the amount of connexin-43 and impairs cell adhesion in cardiomyocyte cultures. DEHP treatment has also disrupted expression of a large number of genes, pointing to pathways contributing to an arrhythmogenic phenotype and made cardiac cells increase their dependence on fatty acids for energy production. Our current studies include assessment of in vivo DEHP effects and examining cardiotoxicity of other plasticizers, such as BPA.

Funded by the National Institutes of Health K99 ES023477 award. PI - Posnack, Sarvazyan- Mentor and Collaborator

Heterogeneity of Flow & Reperfusion Arrhythmias

Tachyarrhythmias within the settings of unstable angina can be deadly as they are the common culprits of sudden cardiac death. The broad goal of our studies is to further understand how the dynamic heterogeneity of tissue metabolism that results from unstable angina breeds arrhythmias. We aim to study mechanisms of ischemia and reperfusion arrhythmias from a new perspective: that of connecting local changes in tissue metabolism caused by perturbations in coronary flow to the resulting disturbances in electrical activity. Ultimately, this will provide new insights into possible therapeutic interventions to prevent sudden cardiac death.

Funded by the National Institutes of Health R01 HL095828 award, PI - Kay, Sarvazyan - co-PI

Origins of Non Reentry Arrhythmias: Ectopic Nexus Hypothesis

Our studies have revealed that development of ectopic arrhythmias proceeds via an essential step, which we named an ectopic nexus (EN). It refers to a functional state of an injured cardiac tissue in which multiple poorly-coupled ectopic sources form a transient "breeding" microenvironment in which ectopic activity develops from individual cells into slowly propagating ectopic waves confined to the area of injury. The waves of excitation from surrounding healthy tissue fail to invade the EN, allowing slow ectopic waves to co-exist side-by-side with normal propagation pattern. Subsequent relief of EN conditions results in an escape of the ectopic waves leading to an arrhythmia. The EN is a novel concept, which, if it does occur in vivo, has important implications for both understanding and clinical treatment of arrhythmias and ventricular fibrillation.

Funded by the National Institutes of Health R01 HL076722 award. PI - Sarvazyan

Role of N-Cadherin in Stem Cell Engraftment to Cardiac Muscle

Multiple studies have shown that transplantation of embryonic stem cells (ESC) into failing or ischemic heart tissue is beneficial. The mechanisms behind such benefit may include paracrinal and angiogenic factors, as well as direct regeneration of a functional cardiac network from differentiating ESC. The main goal of this project was to test a novel hypothesis that overexpression of N-cadherin will improve the electrical and mechanical connectivity of cardiomyocytes derived from ESC to the host myocardium, leading to decreased arrhythmogenicity of these cells.

Funded by the National Institutes of Health NIH F32HL087529 award. Postdoctoral trainee - Karabekian, Sponsor - Sarvazyan

Antracycline Cardiotoxicity: Oxidative Stress and Protein Kinase C

Administration of anthracyclines, a family of highly effective anticancer drugs, is associated with a cumulative dose-related cardiomyopathy, the etiology of which remains poorly understood. We have discovered that administration of the anthracyclines leads to a marked inhibition of membrane-associated calcium-independent phospholipase A(2) both in vitro and in vivo. Because membrane iPLA(2) represents the majority of myocardial PLA(2) activity, its inhibition by anthracyclines would critically impair the ability of cardiomyocytes to repair oxidized phospholipids. The results suggested that iPLA(2) inhibition may be the initial step in a chain of events leading to chronic cardiotoxicity of the anthracyclines.

Funded by the National Institutes of Health R01 HL62419 award. PI - Sarvazyan

Ischemia-Reperfusion in a Two Dimensional Cardiomyocyte Network

We developed a new experimental approach to study the effects of local injury in a multicellular preparation and tested the ability of the method to induce reperfusion arrhythmias in cardiomyocyte monolayers. The model holds a potential to reveal both micro-and macroscopic features of propagation, conduction, and cell coupling in the normal and diseased myocardium and to serve as a new tool to test antiarrhythmic protocols in vitro.

Funded by the National American Heart Association AHA Established Investigator Award. PI - Sarvazyan

Visualization of Doxorubicin Induced Oxidative Stress

Doxorubicin is an important anticancer drug with prominent cardioxicity, etiology of which remains poorly understood. We loaded cardiac myocytes with an oxidant-sensitive fluorescent probe and exposed them to clinically relevant concentrations of the drug. The data confirmed an oxidative mechanism of doxorubicin cardiotoxicity and demonstrated the capability of live confocal imaging to monitor intracellular oxidation in living cardiomyocytes.

Funded by the American Heart Association, Texas Affiliate Grant-in-Aid. PI - Sarvazyan

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