Two groups within AstraZeneca’s IMED Biotech Unit have published novel studies providing new insights to underlying processes in heart disease. The studies, both published in the European Heart Journal, show that inflammatory processes are an important disease driver in a common form of heart failure as well as coronary artery disease (CAD), and measuring these has potential to stratify risks and improve diagnosis. These discoveries can help in the development of effective new treatments and diagnostic methods.
AstraZeneca has a long history of shaping cardiovascular medicine including statins, beta blockers and ACE inhibitors. Despite the resulting improvements on patient outcomes, heart disease remains the leading cause of death worldwide. As part of our strategy for developing the next wave of effective drugs, the IMED Biotech Unit no longer view heart disease in isolation, but in the context of many complex underlying causes. The two new studies present key roles for inflammation as a driving factor in heart disease, and show how it can affect individual patient disease profiles.
In the most recent of the two studies, PROMIS, IMED scientists along with collaborators in Sweden, Singapore, Finland and the US identified a new potential diagnostic marker in heart failure with preserved ejection fraction (HFpEF), a difficult-to-diagnose condition that accounts for half of patients with heart failure. PROMIS is the largest ever study of its kind, taking measurements from 200 patients at five different centres whereof two in Sweden. It showed for the first time that dysfunction of the small vessels supplying the heart, often caused by inflammation, is very common in patients with HFpEF. It also described a new patient-friendly detection method based on echo and ultrasound imaging. The technique used equipment already found in most medical centres, meaning it could be used in almost any clinic worldwide.
Professor Li-Ming Gan, Chief Scientist at IMED CVRM, said: “We have shown that small artery disease is closely linked with HFpEF, and how it could be measured with a new, patient-friendly technique. Understanding the underlying mechanisms will help us develop future targeted therapies, and developing a profile of disease hallmarks with potential to improve outcomes through earlier diagnosis.”
The HFpEF population is diverse with few obvious commonalities between patients, which has made it challenging to study and diagnose. Here, researchers were able to classify patients and correlate heart disease severity with small artery dysfunction and other factors such as systemic endothelial dysfunction. This detailed patient profiling will make it easier to identify patients with HFpEF, and better define trial populations for future studies in heart failure. The results from the PROMIS study were also presented as late-breaking clinical science presentation at the European Society for Cardiology meeting on 27th August.
In the other study, IMED scientists along with collaborators in Australia, New Zealand and Singapore, showed that an inflammatory enzyme, myeloperoxidase (MPO) had potential as both a therapeutic target and a diagnostic biomarker in high-risk CAD. CAD is the most common form of heart disease, and is characterised by atherosclerotic plaques – deposits of fat, cholesterol and calcium that build up inside arteries. In some cases, the plaques can restrict blood flow, but remain stable or ‘dormant’. In other cases, unstable plaques can rupture, causing formation of blood clots that block blood vessels, leading to heart attack and stroke. Although this risk is well established, the events are still highly unpredictable and often strike without warning.
MPO has been shown to be involved in various cardiovascular disorders, and MPO inhibitors have been an important asset in the IMED cardiovascular research toolkit. However, until now, its role in CAD was unknown. Using a mouse model for unstable plaques, the researchers showed that plaques with higher MPO levels were more likely to rupture, with the risk being significantly decreased when MPO was inhibited. This study further supports our understanding that MPO plays an important role in vascular inflammation, including both endothelium and atherosclerotic lesions.
Erik Michaëlsson, Principal Scientist, Bioscience Heart Failure, IMED CVRM, said: “Currently, a high medical need remains for CAD, and when acute events strike is down to chance. This pre-clinical proof-of-principle study provides compelling new data in our understanding of CAD. If we can build upon these studies and find a way of managing these risks, it could make a significant difference to the lives of patients.”
The two studies exemplify IMED’s approach to combating heart disease by carefully characterising patient populations and molecular disease drivers. As science evolves, it is becoming clear that uncovering the root causes and building detailed population maps is essential for developing effective therapies, and targeting them to the right patients.