Date of Award

2025

Degree Name

Doctor of Philosophy (College of Medicine)

Schools and Centres

Medicine

First Supervisor

Professor David Playford

Second Supervisor

Professor Gregory M. Scalia

Third Supervisor

Professor Geoff Strange

Abstract

Pulmonary hypertension (PH) is a common, complex, and potentially lethal haemodynamic condition with many underlying aetiologies. It is poorly understood, and diagnosis is usually made late in the disease process resulting in poor outcomes even in the developed world. An innovative universal framework is required to achieve early and accurate diagnosis for improved outcomes, especially in remote and rural areas. The thesis documents my substantial body of work that unlocks a collective framework to assist patients with PH, particularly in areas not classically serviced by tertiary level PH care.

The first chapter of my thesis outlines the history, important milestones in evolution of current knowledge on PH, major breakthroughs in diagnostic and imaging techniques as well as treatments. Evolving definitions, diagnostic criteria, classification systems and emerging therapeutics throughout time as well as rationale for the current study were discussed. To bridge significant gaps between patients being cared in tertiary PH centres and those from remote regions, a thorough literature review of PH in disadvantaged population was undertaken and discussed in the chapter 2. This work uncovered and documented a substantial gap in our understanding of PH in the disadvantaged population.

Chapter 3 consists of the findings from the original epidemiological study performed in the Top End region of Australia (the top part of Northern Territory) which is a remote and rural region with a high proportion of Indigenous people. The results of this study confirmed for the first time that PH is highly prevalent in the region at approximately 1% of general population having PH, which is comparable to current global estimate of PH. The prevalence was higher for Indigenous population at about 1.5% of Indigenous people in the Top End suffering from PH. Presence of PH was also associated with a high mortality of 40% in a median (IQR) follow-up of 5.1 (2.9-7.4) years, especially for the Indigenous people with hazard ratio of 1.796 (1.496-2.155), p=0.001. These data highlighted an alarming disease burden, and substantial treatment and outcome gaps for disadvantaged population. A high burden of modifiable risk factors and treatable underlying conditions such as valvular heart diseases were also identified, reinforcing the need for a proactive approach.

To confirm our central hypothesis of PH being a universally prevalent disease and to contextualise the findings in Top End Pulmonary Study, another study was performed in Mackay, chosen because it was an urban area, more densely populated than the population in our Top End study, but less than the major cities which are typically studied in PH research. In addition, Mackay offers further insights by being a regional Australian city with different population profile from the Top End. This study again proved that PH is common with minimal indicative prevalence of 433 individuals per 100,000 (0.4%) and lethal (21% mortality in median follow-up of 487 (IQR 335-657) days. A prognostically important proportion of these patients (16%) have no formal diagnosis of PH, and thus no management plan toward potentially life-saving treatment.

Based on the evidence and experience garnered from these unique and insightful studies in chapters 3 and 4, a simple diagnostic algorithm suited for remote and disadvantaged populations is proposed in the chapter 5. This work was published in the Internal Medicine Journal of Royal Australian College of Physicians, carefully selected to receive a wide readership among physicians with different speciality interests given the multidisciplinary nature required to look after patients with PH. This provides the framework that, if widely adopted in clinical practice, has the potential to simplify diagnosis, point toward appropriate management steps, and improve the lives of many Australians. From a global perspective, this simple step-by-step process of PH diagnosis and management can be deployed in many countries (with only basic validation required for specific populations). To further enhance diagnostic processes into the future, chapter 6 outlines the roadmap to precision medicine for every PH patient using modern technology and artificial intelligence. In the appendix, the review on heart failure with preserved ejection fraction (HFpEF) which is a major cause of PH globally as well as a cohort study to investigate the impact of PH on patients with severe aortic stenosis who were undergoing transcatheter aortic valve implantation in a major Australian cardiac centre were included to supplement this thesis.

In this body of work, the high prevalence and complexity of PH have been confirmed by performing original studies in two remote Australian regions. Based on the experience and results from these studies, a simple framework as well as more comprehensive approach using modern technologies were thoroughly discussed to reach improved and equitable health outcomes for all PH patients.

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