Cardiovascular disease is the number one killer in the world, taking an estimated 17.9 million lives each year. Numbers are expected to rise, due to a growing aging population with cardiometabolic disease – a cluster of conditions that includes obesity and diabetes. This places a huge burden on the economy as well as the healthcare system.
In response to heart disease the heart enlarges (pathological cardiac hypertrophy). Ventricular enlargement predisposes to heart failure (HF) and atrial enlargement predisposes to atrial fibrillation (AF). The heart also enlarges in response to regular aerobic exercise (physiological cardiac hypertrophy) but this typically protects against HF and AF. Our research has focused on understanding and targeting key differences between the pathological failing heart and physiological exercise-trained heart to identify new drug targets and biomarkers for cardiac pathology. We have identified the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) signalling pathway as a master regulator of physiological hypertrophy and exercise-induced protection. Increased IGF1-PI3K provides cardiac protection, whereas decreased IGF1-PI3K leads to accelerated HF and AF. This work has focused on the ventricle to date.
We will expand this research to the atria, and develop novel therapies for both HF and AF. Markers of reduced PI3K can also be measured for earlier detection of cardiotoxicity. This work has additional implications for preventing disease in other tissues. A recent discovery from our team revealed that a failing heart can release factors into the circulation that can cross-talk with distal organs to cause pathology. We propose here that the healthy physiological heart also releases factors that protects against metabolic disorders.
The aims of this research are to:
- Develop innovative therapies targeting the IGF1-PI3K pathway to treat HF, AF and cardiometabolic disturbances
- Define differences between physiological and pathological atrial enlargement to inform strategies for the prevention and treatment of AF and/or stroke
- Assess the potential of PI3K-related lipids to predict cardiotoxicity and AF
- Understand heart-organ cross-talk to prevent cardiometabolic disease and other complications.
The outcome of this research is to discover new fundamental knowledge on mechanisms responsible for heart-tissue cross-talk and how these mechanisms can be targeted to prevent multi-organ damage.