Written by:
VP & Head of Translational Sciences & Early Clinical Development
Global Project Leader
Senior Medical Director
Developing a next-generation medicine starts with understanding a disease at its biological roots. In cardiovascular research, we’re moving beyond disease management strategies and are exploring the molecular and genetic mechanisms that drive complex conditions, like cardiomyopathies.
The burden of cardiomyopathy
Cardiomyopathies represent a group of diseases that affect the heart muscle, known as the myocardium, leading to enlargement, stiffening, or scarring, which impairs the heart’s ability to pump blood. This can result in fatigue, breathlessness, and even heart failure.1,2
Cardiomyopathy is estimated to affect about 2.5 million people globally3, with dilated cardiomyopathy (DCM) as the most prevalent form. While symptoms typically manifest between ages 20 and 60,2 DCM also occurs in children where it accounts for the majority of childhood cardiomyopathies.1 DCM is a leading cause of non-ischaemic heart failure (that is, heart failure not caused by artery blockages) and is often diagnosed late, after damage to the heart has already occurred. DCM is a major reason for heart transplants worldwide.4
In people living with DCM, the heart muscle stretches and thins, hindering its ability to effectively pump blood. The disease typically begins in the left ventricle, the heart’s main pumping chamber. Progressive enlargement of the left ventricle weakens contractile strength and reduces blood flow throughout the body. As DCM advances, the damage can spread to other heart chambers, further compromising cardiac function.
As a cardiologist, I’ve seen firsthand how DCM can affect patients differently. Although existing treatments - medication, devices and lifestyle strategies - have helped many patients live fuller lives, the variability is striking. While some experience significant improvement or stabilization of disease with available treatment, many others do not. Beyond managing the arrhythmias and heart failure that can result in advanced stages of the disease, we need targeted therapies that can address the underlying biology driving DCM.
Uncovering the genetics behind the disease
One of the biggest challenges with DCM is that it’s highly heterogeneous, both in its presentation and its underlying aetiology.1 While environmental factors, such as infections or exposure to certain toxins, are linked with DCM, genetics also play a role: up to 35% of DCM cases have an identifiable genetic cause.5
Research shows that genetic variants associated with DCM typically disrupt the structure and function of cardiomyocytes (the specialized cells that form heart muscle). Many of these genetic changes can affect calcium cycling, an essential process that enables the heart to contract and relax with each beat. Certain genetic variants, such as mutations in TTN, LMNA, or PLN genes, are linked with DCM incidence and subsequent heart failure.1
Genetics are already shaping clinical decisions in DCM, with relatives of affected individuals offered genetic testing and closer follow-up, while genotype and molecular profiling are incorporated into risk assessment.1 While some DCM patients improve or remain stable for many years on standard-of-care treatment, others deteriorate more quickly and may need more intensive monitoring and follow-up care. This variability highlights a critical gap: no targeted therapies currently exist for DCM.
The role of PLN and the R14del mutation in calcium handling
PLN is an essential protein that helps regulate calcium flow in heart muscle cells, crucial for cardiac contraction and relaxation, which allows the heart to pump.6
PLN regulates the activity of SERCA2a, a critical pump involved in the cardiac calcium cycle. SERCA2a shuttles calcium from the cytoplasm into the sarcoplasmic reticulum, a cellular ‘storage chamber’ for these ions. By removing calcium from the cytoplasm, SERCA2a enables muscle fibres to relax between heartbeats. The pump’s activity is directly tied to cardiac performance and is reduced in many forms of heart failure.7
In some forms of cardiomyopathy, PLN malfunctions and interferes with the normal activity of SERCA2a, disrupting calcium flow in the heart. Several PLN mutations have been identified that are linked with cardiomyopathies, with the most extensively studied being the R14del variant. This mutation can lead to aggregates within cardiomyocytes and affect calcium transport, with clinical manifestations including dangerous arrhythmias, a weaker and scarred heart, and eventually heart failure in many patients.6
Certain mutations to PLN are more prevalent in specific populations. The PLN R14del mutation is especially prevalent in patients in the Netherlands, where it accounts for a major share of heart transplants.6
Moving towards more precise, targeted care
Given the heterogeneity, diagnosis and treatment of cardiomyopathies remain challenging, as many cases are not diagnosed early and are often classified and treated as broader forms of heart failure. This can lead to missed opportunities for earlier, more targeted interventions.8
One class of next-generation medicines includes nucleotide-based therapies, which use nucleic acids to modulate genes and potentially change the course of disease. A major challenge with this approach is that many nucleotide-based therapies, including oligonucleotides, predominantly target the liver instead of reaching other organs, like the heart. At AstraZeneca, we are investigating the use of novel targeting approaches that can direct oligonucleotides to specific cell types, including cardiomyocytes. By targeting the transferrin receptor – a protein that regulates iron uptake in the heart – we are aiming to deliver gene-mediating therapies directly to cardiac cells to ultimately improve the heart’s ability to relax and contract.
Key genetic drivers that underlie cardiomyopathies were identified years ago, but these molecular players have been considered undruggable as they are hard to reach, residing in cardiomyocytes. Utilising breakthrough targeting technologies, we are bringing novel next-generation strategies for DCM into the clinic, unlocking previously inaccessible therapeutic pathways.
Through unravelling the underlying biology of DCM, we hope to fundamentally change the treatment paradigm: moving beyond management of heart failure toward targeted strategies that address the disease at a genetic level, which could ultimately enable more patients to live healthier, more fulfilling lives.
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