Our focus is on how the brain controls breathing and blood pressure. We are interested in what goes wrong in the brain to result in the development of cardiovascular disease. We study peptides and their receptors in cardiovascular, autonomic, centres of the brain. Our current research aims to understand the central mechanisms driving the sympathetically mediated increases in blood glucose and blood pressure in models of sleep apnoea. By understanding the mechanisms driving the cardiovascular consequences of sleep apnoea, we aim to identify new therapeutic targets to treat sufferers and reduce disease burden.
Cardiovascular disease (CVD) is a complex, multifactorial disease and remains the leading cause of death in Australia, and worldwide. It is often present with other confounding conditions such as obesity or obstructive sleep apnoea (OSA), both of which are independent risk factors for CVD.
The global burden of OSA is recently estimated as approximately 1 billion people and is comorbid in 30–80% of cardiovascular (particularly hypertension) conditions and in approximately 70% of diabetics. The associated Australian healthcare and economic costs due to comorbid disease and lost productivity are over $5 billion per year and are largely attributed to undiagnosed OSA. While once regarded as a disease of the obese, it is now estimated that 20–30% of individuals with OSA are not obese. Worryingly, normal weight OSA sufferers are four times more likely to develop hypertension and have a much higher risk of early atherosclerosis compared to obese OSA sufferers, even though normal weight patients have less severe OSA. Metabolic dysfunction can also be detected in otherwise healthy young men who were screened and found to have mild OSA. Diagnosed OSA sufferers in the normal weight range are also much less tolerant of conventional therapies, making them more difficult to treat. In conditions such as OSA, excess sympathetic activity may trigger development of cardiometabolic diseases, but research, and concrete evidence is lacking.
We aim to significantly advance this research area. Our unique models and techniques are designed to uncover a previously unexplored mechanism that suggests OSA induces autonomic plasticity, which is important in the pathogenesis of CVD. If our hypotheses are correct, the adverse sympathetic effects of intermittent hypoxia may begin with the first episode. As the duration of the insult increases, the autonomic plasticity may become “permanent,” providing an explanation for why current OSA therapies are ineffective at reversing cardio-metabolic derangements in some patients and why 80% of resistant hypertension cases (the most dangerous form) also have OSA.
Results have the potential to dramatically expand our knowledge into the effects of intermittent stimulation and the capacity for plasticity to occur in primitive, life-sustaining areas of the brain. This will identify new approaches to ultimately show causality between OSA and CVD, and how these may be managed.
Farnham MMJ, et al (2008) PACAP is expressed in sympathoexcitatory C1 neurons of the brainstem and increases sympathetic nerve activity in vivo. Am J Physiol 294:R1304-1311.
Farnham MMJ, et al (2011) Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat. Am J Physiol 300:H214-22.
Inglott MA, et al (2012) Activation of PAC1 and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetised rat. Br J Pharmacol 167:1089-98.
Farnham MMJ, et al (2012) PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rat. Am J Physiol 303:H9210-7.
Bhandare A, et al (2015) Antagonism of PACAP or microglia function worsens the cardiovascular consequences of kainic acid induced seizures in rats. J Neurosci 35: 2191 - 2199.