Targeting multiple mechanisms in heart failure

Growing scientific understanding of the differences between HFpEF and HFrEF is driving rapid progress in development of novel treatments.

While patients with HFpEF and HFrEF have similar symptoms, ultrasound scans of their heart show different types of disease.¹

As HFrEF usually occurs after a heart attack, scans often show loss of muscle cells and visible scarring.¹ The heart does not contract properly to push blood out around the body.

In HFpEF, the heart does not fill properly, and this is also visible on scans.^1,3 People with HFpEF are typically elderly and have other related diseases such as coronary disease, obesity, diabetes, high blood pressure, and chronic kidney disease.^1,4

These comorbidities appear to cause widespread inflammation in small blood vessels^2,4-6 so they do not relax and contract normally. This microvascular dysfunction means that blood flow to the heart and other vital organs is impaired.

Through our PROMIS-HFpEF multicentre clinical trial, we are identifying key proteins involved in microvascular dysfunction, inflammation and the co-morbidities that are linked with HFpEF. This could potentially enable better diagnosis of HFpEF, and aid development of new and personalised therapeutics.⁷ Our expanded research efforts also include a key international collaboration between AstraZeneca’s scientists in Sweden and China, Gothenburg University, Sweden and Zhongshan Hospital, China to better understand the diversity in populations of patients with distinct patterns of disease in HFpEF.

The Heart Bus – taking HFpEF research to patients

Over the next three years, 200 patients in south-west Sweden will take part in an important research study of HFpEF. On the Heart Bus, they will have in-depth assessments including heart function, blood chemistry, exercise capacity and quality of life. Through this crucial collaboration with Sahlgrenska Hospital, we hope the study data will shed new light on different subtypes of HFpEF. In addition, local physicians will be able to use their patients’ test results to help guide the type of care they offer them.

Dig deeper into microvascular inflammation and dysfunction and you enter a fascinating world of interconnected mechanisms leading to HFpEF.

With AstraZeneca’s expertise in developing preclinical models for investigating such mechanisms, our scientists are making substantial progress in identifying promising targets and working towards making potential new medicines.

One target is an enzyme called myeloperoxidase (MPO) which the body uses as part of the immune response against infection.⁸ However, if MPO gets into blood vessel walls it catalyses production of free radicals, indirectly leading to microvascular dysfunction.⁸

AstraZeneca is developing MPO inhibitors with the aim of reducing free radical production, breaking the cycle of microvascular dysfunction, fibrosis and remodelling, and potentially improving heart function.⁹

Up to half of people with heart failure also have kidney disease,¹⁰ so the mechanisms which connect and drive the two conditions are under intense scientific scrutiny.

“Breaking the connections in this cardiorenal axis has potential advantages for patients with HFpEF and for those with chronic kidney disease,” explains Krister Bamberg, Principal Scientist, AstraZeneca R&D.

One interesting target is the mineralocorticoid receptor (MR) which is found in several organs including the kidneys¹¹, heart and colon but also in vascular smooth muscle and endothelial cells.¹⁰ Given the importance of inflammation and fibrosis in heart failure, our preclinical research is exploring how MR modulation could have potential benefits for patients with HFrEF and HFpEF, and for those with chronic kidney disease (CKD).¹²

AstraZeneca’s early clinical programmes in CKD and heart failure are also being designed to allow the evaluation of common disease drivers of HFpEF as a serious comorbidity. This could potentially provide new insights into how patient outcomes change in heart failure when kidney function improves and uncover new targets that may benefit patients with both HFrEF and HFpEF, and those with CKD.

At AstraZeneca, we are building preclinical models designed to predict the effects of our potential medicines so that only the most promising agents move into clinical trials.

A heart in a jar

In a laboratory jar, a miniature ventricle, no bigger than the end of a finger, hangs from a probe, beating rhythmically. Engineered from ventricular muscle cells derived from human stem cells, together with fibroblasts and collagen, the 3D structure has a pumping action just like a normal ventricle.¹³

Building on this sophisticated technology, AstraZeneca is collaborating with global stem cell biotechnology company, Novoheart, to develop the world’s first in vitro, functional model of HFpEF.

Heart failure in a dish

Individual heart muscle cells are shedding new light on the faulty mechanisms that prevent them from relaxing and contracting efficiently in heart failure. Derived from stem cells from patients whose heart failure is linked to one of two common genetic mutations, these cardiomyocytes are visibly larger and stiffer than normal heart muscle cells and they take longer to relax between contractions.

“With this heart failure in a dish model, we want to learn why HFpEF cardiomyocytes don’t relax as well as normal cells, understand more about how they generate and use energy, and test the effects of potential new medicines on them,” explains Malin Jonsson Boezelman, Associate Principal Scientist at AstraZeneca.

Nearly five years into a successful collaboration between AstraZeneca and the National Heart Centre Singapore (NHCS), we now have a very useful cell model system to study how healthy cardiomyocytes generate energy compared to diseased cells.¹⁴

“Healthy heart muscle cells are very flexible in how they generate the energy they need and can use many different substrates. But diseased cells are much more restricted in the way they produce the energy they need to function,” says Jonsson Boezelman.

Studies have shown that the mitochondrial networks that generate energy in normal cells are disrupted in heart failure and become inefficient. The next question is to find out whether such disruption is different in HFpEF from HFrEF and how this may affect future drug targets.

The cardiomyocyte studies being conducted by AstraZeneca and NHCS researchers are providing valuable preclinical insights that are relevant to the clinical heart failure setting.

A greater understanding of the complex mechanisms of HFpEF and other cardiovascular, renal and metabolic diseases will help identify the right targets for novel medicines. Building functional preclinical models to effectively test drug candidates has the potential to help us move forward with the most promising agents and enhance our success in the clinic.