Making the connection:

Targeting multiple mechanisms in heart failure

Overview

Exciting results from AstraZeneca’s long-term heart failure research are opening up numerous opportunities for exploring novel targeted therapies. Through a deep understanding of the shared mechanisms that connect heart failure with other cardiovascular, renal and metabolic (CVRM) diseases, potential medicines might be emerging that could help slow down, halt and ultimately reverse heart failure progression.

Patients with heart failure due to inadequate filling of the heart with blood (heart failure with preserved ejection fraction [HFpEF]) are in great need of effective treatment options. Targeting key mechanisms of HFpEF including widespread inflammation, fibrosis and microvascular dysfunction is a major priority. Understanding mechanisms that drive coexisting disorders in heart failure and kidney disease is another key objective – an approach with potential therapeutic implications for other heart, circulatory and kidney disorders as well as HFpEF.

To achieve these ambitious goals, 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. By collaborating with global leaders in heart failure research, and using the most advanced technologies, we are helping to redefine medical science in heart failure.

Introduction


Heart failure is a common and potentially life-threatening disease which occurs when the heart cannot pump enough blood around the body.1

There are two main types of heart failure – heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).1 Research suggests that as people live longer – often with multiple other diseases – HFpEF is becoming more common.2

In recent years, new therapies have been introduced for HFrEF which reduce deaths and hospitalisation due to the disease.1 But these drugs do not work as well in HFpEF1 and research is needed to identify alternative strategies.



People with HFpEF do not respond to standard of care for HFrEF, possibly because the biology of the two diseases is so different. At AstraZeneca, we recognise the urgent need to learn more about the underlying mechanisms of HFpEF in our ambition to develop targeted therapies for this largely untreated population of patients.

Regina Fritsche-Danielson Senior Vice President, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D
01

What makes HFpEF different from HFrEF?

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 vessels2,4-6 so they do not relax and contract normally. This microvascular dysfunction means that blood flow to the heart and other vital organs is impaired.



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.


HFpEF is a syndrome in which there is an imbalance between the output of the heart and the demands of the body. Despite a heart with apparently normal pumping capacity, it leads to patients´ typical symptoms such as fatigue, breathlessness, congestion etc. The root cause of the syndrome may be the heart but it may also be the kidneys, lungs, liver or fat deposits. However, based on recent research, the most common likely theme is microvascular dysfunction and it is this which is associated with poor outcomes.

Li-Ming Gan Head of Early Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D

02

Targeting blood vessel inflammation and fibrosis

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.7 However, if MPO gets into blood vessel walls it catalyses production of free radicals, indirectly leading to microvascular dysfunction.7

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.8


We believe MPO has an important role in a number of cardiovascular diseases, including coronary artery disease and HFpEF. We know that circulating levels are raised in patients with HFpEF and we have chosen to focus on this disease because of the clear unmet need for new treatments.

Erik Michaëlsson Principal Scientist, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D


03

Uncovering connections with kidney disease

Up to half of people with heart failure also have kidney disease,9 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 kidneys, 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).11

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.


By considering different common molecular mechanisms of CKD and HFpEF, our aim is to improve outcomes in patients with one specific diagnosis before comorbidities emerge. Our focus is to really understand different subpopulations of patients for these two incredibly complex diseases, so we can work towards developing the right treatment for the right patients.

Regina Fritsche-Danielson Senior Vice President, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D

04

Future directions

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.12

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.13

“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.




References

1. Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975.

2. Lourenço AP, Leite-Moreira AF, Balligand JL et al. An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail. 2018 Feb;20(2):216-227.

3. Butler J, Fonarow GC, Zile MR et al. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail. 2014 Apr;2(2):97-112.

4. Shah SJ, Lam CSP, Svedlund S et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. 2018 Oct 1;39(37):3439-3450.

5. Hage C, Svedlund S, Saraste A et al. Coronary microvascular dysfunction in HFpEF is associated with heart failure hospitalizations and cardiovascular mortality. Poster presentation at Heart Failure Association Discoveries 2020. Available at: https://esc365.escardio.org/Congress/222411-coronary-microvascular-dysfunction-in-hfpef-is-associated-with-heart-failure-hospitalizations-and-cardiovascular-mortality#abstract (Last accessed September 2020)

6. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013 Jul 23;62(4):263-71.

7. Ndrepepa G. Myeloperoxidase - A bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta. 2019 Jun;493:36-51.

8. Cheng D, Talib J, Stanley CP et al. Inhibition of MPO (Myeloperoxidase) Attenuates Endothelial Dysfunction in Mouse Models of Vascular Inflammation and Atherosclerosis. Arterioscler Thromb Vasc Biol. 2019 Jul;39(7):1448-1457. 

9. Ter Maaten JM, Damman K, Verhaar MC et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail. 2016 Jun;18(6):588-98.

10. Bauersachs J, Jaisser F, Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension. 2015 Feb;65(2):257-63.

11. Bamberg K, Johansson U, Edman K et al. Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion. PLoS One. 2018 Feb 23;13(2):e0193380. doi: 10.1371/journal.pone.0193380. eCollection 2018.

12. Li RA, Keung W, Cashman TJ et al. Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells. Biomaterials. 2018 May;163:116-127. 

13. Ramachandra CJA, Mehta A, Wong P et al. Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes. Int J Cardiol. 2018 Dec 1;272:288-297.