Heart failure news and stories
Precision medicine in heart failure
R&DMaking heart failure a global health priority to transform patient care
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Heart failure
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Home / Our therapy areas / Cardiovascular, Renal and Metabolism (CVRM) / Heart failure
Heart failure is a condition that worsens over time and affects about 64 million people worldwide.1
What is heart failure?
Heart failure (HF) is a complex syndrome which occurs when the heart cannot pump enough blood around the body.2 It is often complicated by multiple interrelated diseases ‒ so it requires a deep understanding of the potential disease drivers for every individual heart. It affects over 64 million people across the globe and is the leading cause of hospitalisation for those over the age of 65.1,3 HF is often closely linked with other cardiovascular, renal and metabolic (CVRM) diseases such as chronic kidney disease (CKD), hypertension, type 2 diabetes and amyloidosis.
Current HF treatments follow a “one-size-fits-all” approach. However, due to the wide range of mechanisms by which HF can occur, one size does not fit all; up to 50% of HF patients die within five years of diagnosis.4 That’s why our scientists are dedicated to uncovering the underlying disease biology of heart failure to identify novel disease drivers. By harnessing the power of next generation therapeutics we aim to halt and reverse HF, restore organ damage and, one day, pave the way to a cure.
There are several types of HF that are defined by the measurement of the percentage of blood leaving the left ventricle of the heart each time it contracts, which is called left ventricle ejection fraction (LVEF):5
- HF with reduced ejection fraction (HFrEF, LVEF ≤40%; pumping capacity is impaired by coronary artery disease, myocardial infarction or dilated cardiomyopathy)5
- HF with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%)5
- HF with preserved ejection fraction (HFpEF, LVEF, ≥50%; inadequate filling of the heart due to microvascular dysfunction, fibrosis, or transthyretin amyloid cardiomyopathy [ATTR-CM]).5,6
[#news]
[#HFpEF]
Unravelling the complexity of HF and CVRM diseases
The heart and kidneys are so closely connected that identifying risk factors, like CKD, and intervening early can help slow disease progression and reduce cardiovascular (CV) events.7
The connections between CVRM continue to be elucidated as studies have found:
- Significant percentages of HF patients also have diabetes; 8
- Cardiovascular disease (CVD) can lead to HF, and accounts for around 40% to 50% of all deaths in patients with late-stage chronic kidney disease (CKD) (stages 4-5);9 and
- Many patients with HF or CKD experience hyperkalaemia.10,11
We are advancing research into interconnected disease drivers where we can intervene early, such as systemic chronic inflammation, a key driver of disease and influenced by several factors, including obesity and dyslipidaemia.12 Our early clinical programmes in CKD and HF 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 HF when kidney function improves and uncover new targets that may benefit patients with both HFrEF and HFpEF, and those with CKD.
With the advances in genomics and other omics technologies, we are uncovering genetic disease drivers in specific subpopulations to enable us to better tailor treatment regimens. By considering different common molecular mechanisms of CVRM diseases, 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 incredibly complex diseases, so we can work towards developing the right treatment for the right patients.
Uncovering the various types of amyloidosis
Amyloidosis is a group of complex rare diseases caused by abnormal proteins that misfold and clump together to form toxic amyloids that deposit in tissues or organs, including the heart, kidneys and peripheral nerves.13-17 The build-up of these toxic amyloids can result in significant organ damage and organ failure that can severely impact quality of life and ultimately be fatal.14,15 Signs and symptoms of amyloidosis often resemble other diseases and lead to misdiagnosis and/or delayed diagnosis and treatment, and most existing therapies focus on preventing or suppressing the formation of new toxic amyloids.18,19
Transthyretin-mediated amyloidosis (ATTR) is one type of amyloidosis and occurs when the liver produces transthyretin (TTR) proteins that are unstable, leading to a breakdown into its individual monomer components that are prone to misfolding and aggregating, forming amyloid deposits.20,21 ATTR can be either hereditary (ATTRv) or non-hereditary (wild-type) (ATTRwt).14
Two types of ATTR are ATTR-CM, which can cause heart failure (cardiomyopathy) and ATTRv-PN, which affects function of the peripheral nerves (polyneuropathy).15,16 ATTR-cardiomyopathy (CM) is a systemic, progressive and fatal condition that can lead to heart failure within several years of onset.15 As the TTR protein fibrils accumulate, more tissue damage occurs, the heart gets stiffer and the disease worsens, resulting in poor quality of life and eventually death.14,15,22,23
By exploring diverse yet complementary mechanisms of action to stabilise, silence or deplete toxic amyloids in organs and tissues, we seek for ways to halt and reduce organ damage for as many patients as possible – regardless of disease state, stage or phenotype.
[#nextwave]
Next wave of innovative therapeutics for HF
Being able to precisely target the underlying molecular cause of an individual’s disease in HF would be a fundamental change from current clinical management paradigms which rely mainly on clinical signs and symptoms. We are collaborating with world-leading experts to build a growing understanding of the genetic drivers of HF. This is helping us identify novel targets and biomarkers to discover and develop precision medicine in life-threatening diseases of the heart muscle, such as ischaemic cardiomyopathy (ICM) and idiopathic dilated cardiomyopathy (IDCM.)24,25
Molecular fingerprints of HF
Molecular fingerprints of HF
By harnessing the power of artificial intelligence and omics analysis, our aim is to unravel the complex disease biology of HF at the molecular level in individual patients. We are using machine learning to analyse large quantities of gene expression data from cardiac biopsy samples and stratify patients with HF into novel molecular sub-classes, irrespective of their clinical signs and symptoms. We are also using gene expression data from past trials, linked with clinical data, to see whether they correspond to clinically meaningful phenotypes. Using this wealth of new information, our aim is to identify novel therapeutic targets that will form the basis of a precision medicine approach to the care of patients with different molecular signatures of HF.
Improving heart muscle contraction
Improving heart muscle contraction
Among the genetic drivers of the stretched and weakened heart muscle seen in dilated cardiomyopathy (DCM) is a mutation in the gene for phospholamban (PLN).26 Excessive PLN activity is linked to cellular calcium dysregulation and impaired heart muscle contraction and relaxation.27 Whilst a key target for drug discovery, the structure of the protein has proven hard to target with conventional drugs.
Research carried out in collaboration with Ionis Pharmaceuticals and global heart failure scientists at University Medical Center Groningen and Karolinska Institute, shows that nucleotide-based therapies can be used to deplete the formation of PLN linked to DCM.28
Encouraging preclinical results are making this a promising precision medicine approach in cardiomyopathy and possibly other forms of HF.
Miniature beating hearts
Miniature beating hearts
In the development of ‘miniature organs’ to recreate the mechanical and electrical properties in a beating heart, we are working with Novoheart to use the world’s first human-specific, in vitro functional model of HfpEF. HfpEF mini-hearts could provide a powerful tool for discovery, screening and advancement to clinical trials of novel therapeutics for heart failure.
Rare genetic drivers
Rare genetic drivers
In a recent collaboration, scientists at our Centre for Genomics research identified variants in 21 different genes linked to cardiomyopathy, irrespective of whether patients had heart failure with preserved or reduced ejection fraction – the main clinical categories of the disease.29 This means that, although patients may go to their doctor with different symptoms, their underlying genetic drivers may be similar, with environment and comorbidities playing a bigger role than previously thought.
[#collab]
Collaborations to support HF innovation
We are proud to be working with healthcare professionals, patients, governments and policy makers to improve access to healthcare, remove barriers to diagnosis and optimal treatment, changing how CVRM diseases are detected, diagnosed and treated to accelerate medical practice change together to make a difference for patients.
[#people]
Our people
Built on an impressive legacy in CVRM research, we are uniquely positioned to build a healthier and longer future for people with these diseases. Our team of over 1,000 people spans more than 23 functions including early and late R&D, medical and commercial.
Our employees are accomplished and experienced scientists, researchers, clinicians, and healthcare and commercial professionals dedicated to advancing novel science and driving practice change to benefit patients with CVRM diseases.
References
1. Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017;390(10100):1211-1259.
2. Mayo Clinic [Internet]. Heart Failure [Last Accessed: February 2025]. Available from: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.
3. Azad N, et al. Management of chronic heart failure in the older population. J Geriatr Cardiol. 2014;11(4):329-337.
4. Tsao CW, et al. Heart disease and stroke statistics – 2023 update: A report from the American Heart Association. Circulation. 2023;147(8):e93-e621.
5. Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032.
6. Bilak JM, et al. Microvascular dysfunction in heart failure with preserved ejection fraction: pathophysiology, assessment, prevalence and prognosis. Cardiac Failure Review. 2022;8:e24
7. Shlipak MG, et al. The case of early identification and intervention of chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2021;99(1):34-47.
8. Paolillo S, et al. Role of comorbidities in heart failure prognosis Part I: Anaemia, iron deficiency, diabetes, atrial fibrillation. Eur J Prev Cardiol 2020;27(Suppl 2):27-34.
9. Jankowski J, et al. Cardiovascular disease in chronic kidney disease: Pathophysiological insights and therapeutic options. Circulation. 2021;143:1157-1172.
10. Thomsen RW, et al. Elevated potassium levels in patients with congestive heart failure: Occurrence, risk factors, and clinical outcomes: A Danish population-based cohort study. J Am Heart Assoc. 2018;7(11):e008912.
11. Furuland H, et al. Serum potassium as a predictor of adverse clinical outcomes in patients with chronic kidney disease: New risk equations using the UK clinical practice research datalink. BMC Nephrol. 2018;19(1):211.
12. Furman D, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832.
13. Oghina S, et al. The impact of patients with cardiac amyloidosis in HFpEF trials. JACC Heart Fail. 2021;9(3):169-178.
14. Ando Y, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.
15. Law S, et al. Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage. ESC Heart Fail. 2020;7(6):3942–3949.
16. Adams D, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122.
17. Nijst P and Tang WW. Recent advances in the diagnosis and management of amyloid cardiomyopathy. Fac Rev. 2021;10:31.
18. Papingiotis G, et al. Cardiac amyloidosis: Epidemiology, diagnosis and therapy. e-Journal of Cardiology Practice. 2021;19(19).
19. Desport E, et al. AL amyloidosis. Orphanet J Rare Dis. 2012;7:54.
20. Gonzalez-Duarte A and Ulloa-Aguirre A. A brief journey through protein misfolding in transthyretin amyloidosis (ATTR amyloidosis). Int J Mol Sci. 2021;22(23):13158.
21. Ellahham S.H. [Internet] American College of Cardiology. Emerging therapeutics for cardiac transthyretin amyloidosis. American College of Cardiology [Last Accessed: February 2025].
22. American Heart Association [Internet]. Transthyretin amyloid cardiomyopathy (ATTR-CM) [Last Accessed: February 2025]. Available from https://www.heart.org/en/health-topics/cardiomyopathy/what-is-cardiomyopathy-in-adults/transthyretin-amyloid-cardiomyopathy-attr-cm
23. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16:70.
24. Povysil G, et al. Assessing the role of rare genetic variation in patients with heart failure. JAMA Cardiol. 2021;6(4):379-386.
25. Mantziari L, et al. Differences in clinical presentation and findings between idiopathic dilated and ischaemic cardiomyopathy in an unselected population of heart failure patients. Open Cardiovasc Med J. 2012;6:98-105.
26. Mavrogeni S, et al. Cardiac involvement in Duchenne and Becker muscular dystrophy. World J Cardiol. 2015;7(7):410-414
27. Schultheiss HP, et al. Dilated cardiomyopathy. Nat Rev Dis Primers. 2019;5(1):32.
28. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198-205.
29. Grote Beverborg N, et al. Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy. Nat Commun. 2021;12(1):5180.
30. AZ Workplace [Internet]. Act on CKD Internal Programme and Metrics [Last Accessed: February 2025]. Available from: https://astrazeneca.workplace.com/100025043435576/videos/684605172857664/.
31. AstraZeneca (2023). Advancing UK Life Sciences Through Innovation and Collaboration. [Brochure]
32. ClinicalTrials.gov [Internet]. Optimising a Digital Diagnostic Pathway for Heart Failure in the Community (OPERA) [Last Accessed: February 2025]. Available from: https://clinicaltrials.gov/ct2/show/NCT04724200.
33. University of Glasgow [Internet]. Landmark Partnership Aims to Improve Scotland’s Health [Last Accessed: February 2025] Available from: https://www.gla.ac.uk/news/headline_876209_en.html.
Veeva ID: Z4-69682
Date of preparation: May 2025