Cardiovascular disease is the leading cause of deaths in Australia and other developed countries. Over 300，000 Australians have heart failure with 400 new cases being added each week. Most commonly， it can be due to an enlargement in cardiomyocyte size in response to chronic increased pressure overload， a process called left ventricular hypertrophy (LVH). It is an adaptive response to chronic increase workload or to defects in the efficiency of the contractile machinery. However， in the long term it contributes to the development of heart failure and sudden death. Despite advances in our management for these disorders， they remain key factors for the development of premature death and disability. Factors regulating contractility， including neurohumoural activation via catecholamines and cardiomyocyte 冄- and 円-adrenergic receptors (ARs)， can initiate pathological hypertrophy and influence cardiac remodelling.

    Under physiological conditions， enhanced inotropy (contractility) as a result of increased sympathetic nerve activity is mainly medicated by 円1-ARs. 冄1-ARs are believed to play roles in the induction of cardiac hypertrophy， protection from apoptosis and increased contractility under pathological conditions， such as ischemia and heart failure when the 円-AR signalling is compromised. Understanding the mechanisms regulating cardiac contractility and cardiac hypertrophy， physiologically and in disease， has become a key to the development of novel therapies and treatment strategies for these disorders. We have developed transgenic mice with cardiac-restricted 冄1A-AR overexpression (CRα1A-AR TG) and surprising found that these animals did not develop LVH， but exhibited enhanced left ventricular contractility.
We hypothesized that hypercontractility in CRα1A-AR TG mice in vivo might be due to a high basal sympathetic activity. To test this hypothesis， we assessed contractility in isolated hearts and myocytes from CRα1A-AR mice. Because previous evidence implicating 冄1-ARs in LVH was derived from neonatal myocytes， we also generated CRα1A-AR TG rats to test the hypothesis that this effect was species dependant.

    Our results showed that isolated TG myocytes revealed reduced shortening with no change in basal or peak Ca2+ levels， but hypersensitive to phenylephrine (PE)， α1A-AR agonist stimulation， with increased shortening driven by increased calcium release. Isolated perfused TG hearts documented basal hypocontractility， but stimulated hypersensitivity to α1A-AR agonist stimulation. CRα1A-AR rats also failed to develop LVH at 3- and 8-month age， and perplexingly had a hypocontractile phenotype. Interestingly， CRα1A-AR TG rats showed an acute agonist-induced inotropic hyper-responsiveness and displayed a unique sudden death phenotype initiated by acute receptor activation endogenously or exogenously. The possibility exists that despite increased receptor expression， insufficient agonist is available to stimulate these receptors. To test this possibility， we treated WT and CRα1A-AR TG rats with a sub-maximal dose of PE (at 0.175mg/kg/d) for 14 days via a mini-pump. CRα1A-AR TG rats developed LVH in response to α1A-AR agonist in vivo.

    We concluded that adult rats with CRα1A-AR overexpression， like CRα1A-AR mice， do not develop LVH. This is consistent with our previous data indicating that the α1A-AR is neither a mediator nor a modulator of pathological hypertrophy， although a role in physiological hypertrophy cannot be excluded. The similar contractility phenotypes of isolated mouse hearts/myocytes and the rat heart in vivo are consistent with the enhanced LV contractility of CRα1A-AR mice in vivo being due to enhanced basal sympathetic activity.

    The fact is that I have selected 10 clinicians and researchers from Harbin to Faculty of Medicine， University of new South Wales (I did my PhD and post-doc  fellow there， one of the top 100 universities in the world， our Institute belongs to UNSW). I would like to take this opportunity to look at any collaboration between China and VCCRI during the conference.