Development of novel precision medicine approach for management of heart failure with preserved ejection fraction
Short description
Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF), knowledge about HFpEF subtypes remains very limited. Even less understood is the ethnical differences in HFpEF mechanisms, onset, manifestation and deterioration.
This project could lay ground for a multinational effort to address this heterogeneous and life-threatening disease. In addition to deepened understanding and more precise segmentation of the population, this project could potentially lead to successful proof of concept study using molecular methods, which eventually may lead to ground breaking novel therapies against this disease condition.
Background
Heart failure is a serious life-threatening disease condition and impacts 1% of the global population. Half of the heart failure patients are diagnosed as heart failure with reduced ejection fraction (HFrEF), which is caused by preceding myocardial infarction due to ischemic heart disease, the other half is called heart failure with preserved ejection fraction (HFpEF).
Heart failure with preserved ejection fraction (HFpEF) is now recognized as the largest unmet medical need in cardiovascular medicine today. Prevalence of the disease is increasing due to the ageing population and massive cardiometabolic comorbidities. Once diagnosed HFpEF, the 5 years mortality rate is almost 50%, which is comparable to the worst cancer forms.
Patients with HFpEF have often very poor quality of life, and are typically suffering from exercise intolerance, fatigue and dyspnea in their daily life. Apart from the high risk of sudden cardiac death, HFpEF patients are also experiencing repeated hospitalization due to decompensation. With the increasing prevalence of this disease condition, it comprises a huge social economic burden also for the society.
Current situation
While recent advances within cardiology have dramatically improved the situation for patients with HFrEF, there is currently no treatment for HFpEF and many recent clinical trials have failed. AstraZeneca has long tradition in developing cardiovascular drugs and has since 5 years been steering its research focus on HFpEF as one of the major CV research areas. This commitment includes research efforts at all levels from clinical and molecular understanding of the disease, hypothesis testing of early drug targets in preclinical models, to early clinical phase I and II studies.
Today, diagnosis of HFpEF is based on various criteria, and the patient population is highly heterogeneous. There is increasing evidences pointing at that the HFpEF population may represent many subgroups with distinct phenotypes, which seem to have unique pattern of disease manifestation and underlying mechanisms.
Recent studies
During the past three years, one interesting and promising hypothesis regarding potential pathophysiological mechanism behind HFpEF has been directed to systemic microvascular inflammation, which could be a consequence of multiple co-morbidities, such as diabetes, dyslipidemia, hypertension, aging etc. Microvascular inflammation can in turn lead to myocardial ischemia, inadequate exercise-induced peripheral vasodilatation, as well as profibrotic events leading to stiffening of myocardium and relaxation disturbance, all hallmarks of HFpEF. However, robust data regarding this hypothesis remains limited, partially due to technical challenges to implement coronary microvascular function measurement in larger scale studies.
We have recently performed the first multi-center trial, in which a comprehensive imaging protocol with focus on diastolic and coronary microvascular function has been developed and validated at our lab. This first larger scale study for the first time proved that microvascular dysfunction is highly prevalent in this population and seems to be an important link between systemic subclinical inflammation and diastolic dysfunction in patients with HFpEF.
Aims and objectives
With this methodological platform, we aim to broaden our knowledge base to include even more patients as well as patients with other ethnical background. Due to fast urbanization of the Chinese society during the past decade and adaptation to a Westernized life style, cardiovascular disease has become No 1 killer in China today. Prevalence of HFpEF is most likely approaching the one observed in the Western world. There is however very limited knowledge about this disease in China today.
The current project aims to establish a precision medicine approach by using the abovementioned comprehensive imaging protocol together with novel molecular methods to deep-phenotype HFpEF patients. We will further confirm the hypothesis that microvascular dysfunction is a key disease driver in HFpEF.
The overall objective of the project is to develop a precision medicine approach aiming at improving diagnosis, risk prediction and tailored drug development to combat this great unmet need in cardiovascular medicine of the 21st century.
Importance
HFpEF is a growing unmet need without treatment today. A precision medicine approach to identify a distinct patient group eligible for potential novel treatment regimens holds the promise to deliver superior clinically meaningfull efficacy.
China is already the top three drug markets in the world and HFpEF is projected to increase in the very near future also in China. Understanding of Chinese HFpEF patient specific phenotype as well as specific disease drivers will help to establish novel precision medicine approaches to improve diagnosis, risk stratification and potentially generate novel precision medicine-based novel treatment strategies against this life-threatening condition.
