Heart Disease

Lead Researcher: Dr Paz Tayal

Supported by the Cardiovascular Theme

Hypertrophic cardiomyopathy (HCM) is a condition where the heart muscle becomes abnormally thick, making it harder for the heart to pump blood. It is one of the most common genetic heart diseases and can lead to serious complications such as heart failure, arrhythmias, or even sudden cardiac death. While a lot is known about the genetic causes of HCM, we do not know how other factors such as hormones may affect patients with HCM.

Previous research has suggested that women and men experience HCM differently: women tend to have more severe disease by the time of diagnosis. Hormonal differences between the sexes, particularly related to oestrogen and testosterone, may play a role in these differences, but this has not been studied in detail.

In this project, we examined how sex hormones might impact the severity of HCM in both men and women.

Our research aimed to answer a key question:

• How do hormone levels impact heart function and scarring in patients with HCM?

To explore these questions, we studied a group of HCM patients, measuring their hormone levels and comparing this data with the progression of their disease assessed on scans of their hearts.

Key Findings:

• Sex Hormones and Heart Function:We found that lower levels of oestrogen were associated with more scarring in the heart in patients with HCM. Testosterone levels were not associated with the amount of scarring.
• Differences Between Men and Women:These effects were most obvious for male patients.

Conclusion:

This research highlights the importance of considering sex hormones in the management of hypertrophic cardiomyopathy. By better understanding how hormones like oestrogen and testosterone affect the heart, we may be able to develop more personalised treatments for patients.

Lead Researcher: Prof Martin Wilkins

Supported by the Cardiovascular Theme

Imatinib is used to treat certain blood cancers and there is interest in using this drug as a treatment for pulmonary arterial hypertension (PAH). A previous study has shown that doses as high as 400mg daily have a beneficial effect on blood pressure in the lungs of patients with PAH but not many patients tolerate these doses. We looked at the safety, tolerability and usefulness of lower doses of imatinib (100mg to 400mg daily) in a small group of patients, some of whom had sensors implanted in their pulmonary arteries providing daily measurements of the blood pressure in their lungs. The study showed that doses lower than 400mg daily are better tolerated and also reduce blood pressure in the lungs in patients with PAH with a dose-dependent relationship. The inclusion of patients with sensors implanted in their pulmonary arteries provided a more detailed picture of the time course of response and the data collected from this study will be useful in building a computer model (a digital twin) of how the heart and blood vessels in the lung respond to drug treatment. It is hoped that this computer model will help personalise the treatment of patients in the future.

Lead Researcher: Prof Prapa Kanagaratnam

Supported by the Cardiovascular Theme

Atrial fibrillation (AF) is a common heart condition where the heart beats irregularly, often leading to symptoms like palpitations, shortness of breath, and fatigue. If left untreated, AF can increase the risk of stroke and other serious complications. One of the most common treatments for AF is a procedure called ablation, where doctors use specialized equipment to treat the areas of the heart that cause these irregular beats. However, current ablation procedures are not always successful, especially in complex cases.

Our project has focused on developing the Tau20 system, a new technology designed to improve the effectiveness of AF treatments. The Tau20 system combines advanced hardware and software, including a unique tool called RETRO-Mapping, which helps doctors identify the specific areas in the heart responsible for causing AF. This technology has the potential to make ablation procedures more accurate and effective for patients.

Key Achievements:

1. Integration into Clinical Settings:
   The Tau20 system was successfully integrated into the Cardiac Catheter Laboratory at Imperial College Healthcare NHS Trust. Working closely with a clinical team, we connected the system with other key medical instruments and collected electrogram data from 15 AF patients. This data is currently being analysed and will be used to further refine the system for future clinical applications. While the Tau20 system has not yet been used during ablation procedures, the integration and data collection represent important steps toward making the system ready for clinical use.
2. RETRO-Mapping Technology for Ablation Guidance:
   We applied the RETRO-Mapping software, which is part of the Tau20 system, to identify the areas of the heart causing AF. The software was updated with a new, user-friendly interface that allows clinicians to pinpoint these areas with greater accuracy during ablation. Although not yet used directly in patient procedures, this tool holds promise for improving how doctors treat AF, making it easier to target problem areas and potentially enhancing patient outcomes.
3. Development of a New Algorithm Using Machine Learning:
   A new version of the RETRO-Mapping algorithm was developed using machine learning techniques. This updated algorithm has significantly reduced the time needed to process the heart’s electrical signals, making it quicker to identify the problematic areas causing AF. Although this progress is promising, further funding and research are required to explore the use of deep learning to improve the system’s real-time performance. More data is also needed to fully optimize the technology and ensure its effectiveness in guiding ablation procedures in clinical practice.

Looking Ahead:

Our work on the Tau20 system represents a major step forward in using technology to improve AF treatment. By making ablation procedures more precise and efficient, this technology has the potential to benefit many AF patients. We are committed to continuing our research, improving the system’s capabilities, and eventually making it available for wider use in hospitals, which could lead to better outcomes and quality of life for patients with AF.

Lead Researcher: Dr Andrew Cowburn

Supported by the Cardiovascular Theme

Pulmonary arterial hypertension (PAH) is a rare, debilitating disease, affecting all ages. It is caused by structural changes in the blood vessels of the lung that lead to their narrowing and destruction, resulting in increased blood pressure in the lungs and ultimately right-heart failure. If untreated PAH is often fatal in 3-5 years and treatments for the disease are very limited.

Studies have revealed a role for a white blood cell, called the neutrophil, and its blood vessel damaging cargo, neutrophil elastase in PAH. These neutrophils appear to behave differently in PAH patients, being continuously switched-on or activated.

We use a machine that tests the deformability, or how squishy, the cells are to an external force. Generally, the greater the stiffness, the more activated the cell and more prone to causing damage to blood vessels in the lungs. In this project, we have shown that neutrophils in PAH patients are stiffer than those from healthy people of the same age, and after neutrophils travel through the diseased blood vessels in the lungs of PAH patients, they become even stiffer. We think that these stiff neutrophils are more likely to get stuck in the narrow lung blood vessels and cause more damage. We have also found that patients who have more severe disease have neutrophils with a more ruffled outer lining (membrane), which is another indicator of neutrophil activation.

Based on these results, we believe that inappropriately activated neutrophils in PAH contribute to worsening of the disease process. Our future work will look at protein and genetic signatures in the blood of these patients to see if we can identify what is causing the neutrophils to become stiff. We aim to find a way to return PAH patient neutrophils to behave like healthy cells, which could open up a new avenue for developing treatments for PAH.

We have been setting up additional work as part of this project. With our scientific partner in Germany, we have developed a new technique that can be used with our machine to measure how well neutrophils can travel through a device that mimics lung blood vessels. This will allow us to measure how stiff neutrophils need to be to get stuck, and see if this maps to the severity of disease in PAH patients.

We have also partnered with a group at Birmingham university who have developed a new way to look at neutrophil elastase activity in the blood. Elastase is a protein that can damage blood vessels and is secreted by activated neutrophils. We have collected blood samples from PAH patients to measure elastase activity and will see if this matches neutrophil stiffness and disease severity.

Overall, we have found that neutrophils from PAH patients are stiff and overactive which we think increases blood vessel damage and makes the disease process worse. Our future work will provide more detail about neutrophil activation status and blood vessel damage capability. We hope that our work will lead to the development of completely new treatments for PAH.