Research

Current Projects

A bionic pacemaker

Heart rate is always variable and much of its variability is causes by the phase coupling to breathing. Smart watches report heart rate variability (HRV) which is enhanced with physical fitness but lost in heart failure with its absence prognostic for sudden cardiac death. We asked the question, why if HRV is natural do cardiac pacemakers pace monotonically which is a sign of poor health. Our early mathematical models indicate that HRV is an energy saving mechanism. After constructing an analogue pacemaker that senses breathing, we paced hearts in animals with heart failure and found a 22% improvement in cardiac pumping, a reduction in apnoeas and reverse re-modeled cardiac myocyte damage. We are now (i) unearthing the mechanisms by which HRV improves cardiac function and reverse remodels the heart; (ii) testing whether HRV pacing improves exercise tolerance and (iii) performing a first-in-human trial to see if the HRV pacemaker works in humans with heart failure.

  Prof Julian Paton

What makes the carotid body tick?

The carotid bodies (CBs) are sensors of blood gases and located at the bifurcation of the common carotid arteries. They connect directly to the brainstem and trigger increases in breathing, blood pressure and sympathetic activity. In cardiovascular disease, the CBs generate unexplained aberrant activity that we have shown causes hypertension and respiratory instability, and worsens heart failure in animal models and human patients. We use genetic and molecular approaches, imaging and chronic radio-telemetry in animal models in vivo to reveal mechanisms underpinning CB hyperexcitability in disease. We are now in the process of identifying these mechanisms and testing to see whether they may offer novel therapeutic treatments for hypertension.

Funded by the Health Research Council of New Zealand.

Dr Igor Felippe, Prof Julian Paton

Revealing heterogeneity within carotid body glomus cells

We hypothesis that there is a high degree of heterogeneity that exists between carotid body glomus cells. This heterogeneity regulates distinct chemoreflex responses upon activating the carotid body. The project focuses on utilising live cell calcium and ATP imaging on dissociated rat glomus cells, and quantifying differences in their response profile to various external stimuli such as acidosis, hypoxia and hypoglycaemia.

Funded by the Health Research Council of New Zealand.

Dr Xin Shen, Prof Julian Paton

Purinergic receptors in the stellate ganglion: role in hypertension and cardiac arrhythmias

Heart beat irregularities are often lethal and can be caused by a group of overactive nerve cells (called stellate) located inside the chest. Removal of stellate cells in humans has been shown to stop life-threatening irregular heartbeats but this involves complex surgery, which is potentially life threatening itself. In both humans with heart disease and rats with susceptibility to heartbeat irregularity, we discovered a novel drug target or ‘receptor’ on these stellate cells which, when blocked, stops irregular heart beating. We propose to identify the precise makeup of this receptor (to refine drug targeting) and the type of stellate cell it resides on. Importantly, we will assess how this receptor makes the stellate cells overactive. In rats, we will use a novel drug to block this receptor to see if this safeguards against irregular heart beating. These studies could be translated to humans as a novel treatment for heartbeat irregularities.

Funded by the Health Research Council of New Zealand.

Dr Carol Bussey, Prof Julian Paton

The carotid body as a novel therapeutic target for treating cardiometabolic disease

Cardiovascular diseases (CVD) are responsible for a third of all deaths in Aotearoa New Zealand. Different cardiovascular conditions often occur together – for example, most (~75%) adults with diabetes also suffer from high blood pressure (hypertension), and around half of patients with hypertension also have diabetes. This comorbid condition (cardiometabolic disease) progressively damages vital organs like the heart, brain, and kidney. A common feature of diabetes and hypertension is a dangerous sustained elevation in sympathetic nerve activity (SNA); we believe that this is, in part, causal and hence offers a potential target for improving patient outcomes. The raised SNA contributes to both blood sugar dysregulation and high blood pressure and impairs the blood supply to vital organs. We have recently shown that small organs located on carotid arteries called carotid bodies (CB) become overactive in cardiometabolic disease. When activated, CBs cause increases in SNA, whereas their removal lowers SNA, which was associated with reductions in both blood sugar and blood pressure. We have identified novel receptors within the CB which can modulate the SNA by acting in the CB. Future studies aligning with this hypothesis will inform a unique and much-needed clinical therapeutic strategy to treat diabetes and hypertension simultaneously.

Funded by the Heart Foundation of New Zealand.

Dr Pratik Thakkar

Gestational Diabetes and Future heart disease risk

Gestational diabetes (GDM) is the most common complications associated with pregnancy and it has a direct impact on the future cardio-metabolic health of the mother and the child. Evidence implies that significant proportion of type 2 diabetes and heart disease in youth may be subsequent to intrauterine exposure to maternal diabetes, with each generation developing CMD at a younger age than the preceding generation. While early detection and intervention of GDM can substantially reduce adverse outcomes, significant inequities exist in screening, diagnosis and management of GDM between Māori, Pasifika and non-Māori women. Understanding the pathophysiology of GDM involving Indigenous women are also scarce. Our research aims to develop a targeted framework for better screening, management and follow-up of Māori and Pasifika women with GDM by utilising community partnership and co-design principles and understand crosstalk between placenta and sympathetic nervous system in the development of GDM. It has the potential to identify ways to prevent and/or treat GDM. Reduced incidence of GDM will break the vicious circle that perpetuates the transmission of CMD to future generations.

  Dr Anna Ponnampalam

Pathophysiology of Endometriosis

Endometriosis is the most common of all gynaecologic disorders, characterised by the presence and growth of endometrium (the lining of the uterus) outside the uterus. Lesions can be found anywhere within the pelvic cavity: on the ovaries, the fallopian tubes, and on the pelvic sidewall. It is a common cause of infertility and chronic abdominal pain in reproductive age women. Untreated endometriosis reduces Health Related Quality of Life and contributes to outcomes such as depression, inability to work, sexual dysfunction and missed opportunity for motherhood.  Annual healthcare costs in New Zealand for endometriosis are greater than that of diabetes and early clinical screening and intervention is crucial for effective treatment and prevention of disease progression. Endometriosis-related pain is serious, debilitating and episodic. There is a clear need to identify novel molecular pathways that can provide early identification of developing resistance, inform current therapies and enable future targeted therapy development. Our research aims objective of this project is to understand the molecular mechanisms, including epigenetic, involved in progesterone resistance generally seen in endometriosis, thereby improving identification and potentially enabling the development of effective therapeutic interventions.

  Dr Anna Ponnampalam

Research expertise and technologies