Focus Area: Heart and Regenerative Medicine

Heart disease is the nation’s leading killer. The heart can be damaged suddenly or over time. Why does electrical conductivity in the heart stop abruptly? How do arteries become blocked? What strategies might scientists develop to help correct these problems?

Scientists at the Virginia Tech Carilion Research Institute’s Center for Heart and Regenerative Medicine Research aim to improve understanding of exactly how the heart functions, why it sometimes fails to work properly, and what to do to repair any damage.


CHAPPELL LABORATORY

Blood vessels deliver oxygen and distribute inflammatory cells to nearly every tissue in the human body, among other essential functions. Regulation of vascular growth must therefore be tightly controlled, and when this regulation is disrupted, numerous diseases can occur or become worsened such as cancer growth and metastasis. Dr. John Chappell and his research team study how the blood vasculature develops during early organ formation and during certain diseases such as tumor progression and neurological disorders. Increased insight into the basic mechanisms of blood vessel formation will guide the design of clinical therapies for vascular-related pathologies.

Pericytes are cells that wrap around blood vessels to maintain their stability and integrity. Disruptions in pericyte contribution to the vascular wall can lead to disease progression including diabetic retinopathy. Trained as a biomedical engineer, Dr. Chappell uses computational modeling approaches in conjunction with real-time imaging of ex vivo and in vitro models of blood vessel formation to understand pericyte behavior during blood vessel formation in health and disease. Understanding the mechanisms behind pericyte recruitment and investment will provide rationale and guidance for targeting pericyte-endothelial cell interactions for therapeutic benefit.


GOURDIE LABORATORY

The components of the cardiac pacemaking and conduction system are the heart’s “smart” tissues, responsible for initiating and regulating coordinated cardiac electrical activation. Yet developmental defects in pacemaking and conduction system tissues can lead to arrhythmias and sudden death in children and adults.

Dr. Robert Gourdie’s main area of focus over the past two decades has been to elucidate the developmental processes of cardiac conduction and its implications for birth defects of the heart. Dr. Gourdie has used replication-incompetent retroviruses expressing LacZ to demonstrate that, contrary to a long-held hypothesis, conduction cells are not derived from neural progenitors, but share a common cellular lineage with working myocytes. His group went on to show that whether an embryonic myocyte selects a conduction cell or a working myocyte, lineage—that is, fate—is determined by endothelin signaling by endothelial cells.

Dr. Gourdie has also demonstrated that, consistent with the mechano-sensitive characteristics of endothelin signaling, patterns of biomechanical force are critical to patterning the conduction system. He found that neural crest cells migrating into the embryonic heart determine insulation of the cardiac conduction system. Mutations of the cardiac transcription factor Nkx2.5 were among the first genes to be identified as contributing directly to heart defects in humans, including deficits in the pacemaking and conduction system. Dr. Gourdie’s group provided an understanding of the mechanistic basis of these genetic-determined birth defects by showing that Nkx-2.5 is upregulated in conduction cells and demonstrating that this upregulation was necessary for differentiation of the conduction system.


POELZING LABORATORY

Sudden cardiac death in adolescence is increasingly identified with genetic mutations in cardiac proteins. Mutations in the principal ventricular gap junction protein have been linked not only to such diseases as Brugada syndrome, right ventricular dysplasia, and Naxos disease, but also to a high risk of sudden death in children.

Connexin43, or Cx43, is the principal ventricular gap junction protein that allows spread of electrical activity between cardiac myocytes for the purpose of coordinating uniform and synchronized contraction. Conventional theory suggests that reducing Cx43 expression should slow the spread of electrical activity—conduction—in the heart and increase risk of arrhythmias leading to sudden death. The experimental relationships between conduction slowing, sudden cardiac death, and loss of Cx43 is not straightforward, however, and conflicting laboratory findings have led to a lack of experimental agreement on the degree of conduction slowing expected from a quantifiable reduction of Cx43.

Dr. Steven Poelzing hypothesizes that the spread of electrical activity between cardiac myocytes is not only mediated through connexins, but also through electric fields between myocytes. His laboratory has demonstrated that the hydration state of the heart can mask or unmask conduction slowing in the presence of reduced Cx43 expression. Dr. Poelzing’s group uses high-resolution optical mapping, isolated cellular electrophysiological measurements, and immunohistochemistry to determine the mechanisms of non-gap junction–mediated conduction and its dependence on Cx43 and the gap junction. In particular, Dr. Poelzing is seeking to determine how pathological insults such as cardiac inflammation and edema modulate the risk of sudden death in the young and how age changes this relationship.


SMYTH LABORATORY

Dr. James Smyth researches exactly how heart cells communicate, as well as why and how transferring information between cells can change. Cardiac cells communicate by sending and receiving messages, all which are controlled by gap junctions. Existing for only a few hours, gap junctions have a high turn over rate. Each new generation faces mutations and break downs that can deregulate intercellular communication.

Dr. Smyth is also interested in cardiac structures that overlap in the heart and how that affects communication between the cells. Scientists might be able to develop interventional therapeutics to encourage one gap junction to compensate for another gap junction if it becomes dysfunctional, once they understand the molecular mechanism of communication. Dr. Smyth uses powerful microscopes and advanced imaging technology to observe the overlaping cardiac cells dynamically at a high resolution to learn more about this process.


The Center for Heart and Regenerative Medicine Research was established in 2012 to encourage innovative and significant research into matters of the heart. Four outstanding institute researchers are now leading the expedition to discover new methods for treating damaged hearts.

Directed by Robert Gourdie, PhD, the center encompasses a range of individual yet intricately linked projects. The researchers study electrical currents in the heart, the growth of new blood vessels, and disruptions to normal systems. They also use what they learn to help create interventions to treat these problems.

The center’s researchers seek to:
• Understand the intricacies of how the heart conducts electricity at the molecular level;
• Research gene mutations in cardiac cells that can cause sudden cardiac death;
• Examine the process of blood vessel growth and regrowth after cardiac injury;
• Advance anti-arrhythmic treatments;
• Invent new remedies for cardiac blockages;
• Develop novel therapeutic approaches to repair injured cardiac tissue; and
• Investigate how to apply those treatments to other parts of the body.