Molecular Cardiology

Group Head: Professor Christopher Semsarian

Understanding the basic biology of heart muscle function and therefore defining novel ways to treat heart muscle disorders clearly has wider implications for a variety of cardiovascular disorders, including cardiomyopathies, heart rhythm disorders and coronary artery disease. The potential therapeutic boundaries are limitless. Integration of molecular biology, genetic technologies and clinical medicine will ultimately reduce human heart diseases and prolong life. We hope through our research to realise these goals in the coming years.

Research focus

The Agnes Ginges Centre for Molecular Cardiology is focused on the translation of basic laboratory research to improvements in the diagnosis and treatment of patients with heart disease. While there are several lines of integrated research within the program, the unifying focus is the study of cardiovascular disorders which are caused by underlying genetic abnormalities. There are now over 40 cardiovascular diseases which have been identified to be directly caused by primary genetic abnormalities. Despite the escalation in our knowledge of the genetic causes of cardiac disease, little is known about the molecular steps which determine how an abnormalitiy/alteration in the DNA leads to the clinical disease we see in patients.

Furthermore, studies have shown marked variability in the degree of clinical expression of the abnormal gene. There are many examples of affected individuals within the one family, who are carrying the same gene (DNA) abnormality, having vastly different clinical features and outcomes. This suggests modifying factors, both environmental (e.g. exercise, diet) and secondary genetic influences, play an important role in modifying the clinical phenotype in genetic cardiac disorders.

The aims of the research program are to identify new gene abnormalities in patients with heart disease, to understand the molecular basis of how these gene abnormalities lead to disease and to investigate how these pathogenic mechanisms are influenced by modifying factors. These aims are being addressed in an integrated research program utilising three concurrent sets of studies; in isolated cells, in genetically-modified mice, and in humans with inherited cardiovascular disorders attending the Genetic Heart Disease Clinic at Royal Prince Alfred Hospital. A number of diseases are being studied, ranging from structural heart disorders such as cardiomyopathies to primary arrhythmogenic diseases such as long QT syndrome. A specific area of study is in sudden cardiac death, particularly in the young. These studies include novel gene discovery, genetic diagnosis, understanding disease pathogenesis and initiation of preventative strategies to reduce sudden death in our community.

An example of one of the key diseases which is a focus of the laboratory is hypertrophic cardiomyopathy (HCM) which is the most common structural cause of sudden death in the young, including competitive athletes. HCM is characterised by marked thickening of the heart muscle and occurs in approximately one in 500 people, making it the most common genetic heart disorder known. Our research program has seen and collected clinical information and DNA in over 400 HCM families to enable genetic studies to be performed. To complement the studies in humans, our laboratory has developed two unique transgenic models of HCM, as well as cell culture models to evaluate the cellular effects of specific gene mutations.

Patient information sheets

Hypertrophic Cardiomyopathy
Sudden Cardiac Death
Genes and Inheritance

If you would like more information or are interested in participating in our research program, please contact:
Laura Yeates
Cardiovascular Genetics Coordinator
Phone: 02 9565 6187
Email:

The National Genetic Heart Disease Registry

In this registry, we hope to enrol every family in Australia who have an inherited heart problem, in an effort to learn more about these diseases in Australia (e.g. how many people get symptoms, how many people have defibrillators, how often people see their cardiologist etc).

The registry would also be used as a way to send information out to interested members about any new treatments/ information that may become available. All information gathered would be kept strictly confidential. If you would like to know more or are interested in joining the registry then please visit the registry website at www.registry.centenary.org.au.

Publications

1. Tsoutsman T, Kelly M, Ng D, Tan J, Tu E, Lam L, Bogoyevitch M, Seidman CE, Seidman JG, Semsarian C. Severe heart failure and early mortality in a double mutation mouse model of familial hypertrophic cardiomyopathy. Circulation. 2008; 117: 1820-31.

2. Maron BJ, SpiritoP, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes M, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Prevention of sudden cardiac death and selection of patients for implantable cardioverter-defibrillators in hypertrophic cardiomyopathy. JAMA. 2007; 298: 405-12.

3. Ingles J, Doolan A, Chiu C, Seidman JG, Seidman CE, Semsarian C. Compound and double mutations in hypertrophic cardiomyopathy patients: implications for genetic testing and counselling. J. Med. Genet. 2005; 42: e59-64.

4. Semsarian C, Giewat M, Georgakopoulos D, et al. The L-type calcium-channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J. Clin. Invest. 2002; 109: 1013-20.

5. Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM. Skeletal muscle hypertrophy is mediated by a Ca2+ dependent calcineurin signalling pathway. Nature. 1999; 400: 576-581.

For more publication information, please contact Professor Semsarian or search the available listings on PubMed.