In this episode of Speaking from the Heart, Marzia de Bortoli from Eurac Research discusses how advanced human cardiac models can help researchers study arrhythmogenic cardiomyopathy, a genetic heart disease associated with ventricular arrhythmias and fibrofatty replacement of cardiac tissue.
The conversation explores why patient-derived iPSC models matter for studying inherited cardiac disease, how researchers are moving from 2D cultures to 3D engineered heart tissues, and why functional readouts such as contraction, beating behavior, frequency, and arrhythmia-like activity matter for understanding disease mechanisms.
Marzia also shares how her group uses Cuore to create and monitor 3D human cardiac models in stable incubator conditions, and how early observations of arrhythmia-like behavior open a window for further disease modeling, drug screening, and cardiotoxicity research.
Watch the conversation here:
Dr. Marzia de Bortoli
Her work focuses on cardiovascular research, with a particular interest in genetic cardiomyopathies and arrhythmogenic cardiomyopathy. In this interview, she discusses how her group uses patient-derived iPSC models, 2D and 3D cardiac cultures, and engineered heart tissues to better understand inherited cardiac disease and explore future therapeutic approaches.
By combining patient-derived cells with advanced human cardiac models, her research aims to improve disease modeling and support the development of more predictive platforms for cardiac research, drug screening, and cardiotoxicity studies.
When the first symptom can be sudden cardiac death, what kind of model do researchers need?
Arrhythmogenic cardiomyopathy is difficult to study because it can remain hidden until the consequences are severe. Marzia describes it as an inherited cardiac disease in which ventricular arrhythmias can occur, and cardiomyocytes are gradually replaced by fibrofatty tissue.
That creates an important challenge for researchers. How do you study a disease that is genetic, patient-specific, and closely tied to how heart tissue behaves over time?
For Marzia’s group, the answer starts with patient-derived cells.
By working with patient-derived iPSC lines, researchers can preserve the disease’s genetic background. This matters because arrhythmogenic cardiomyopathy is not only a general cardiac condition. It is inherited, variable, and tied to the patient’s specific biology.
Why move from 2D cultures to 3D cardiac models?
2D cultures can answer important questions, but they also have limitations. In cardiac research, one recurring challenge is maturity. Cells can be derived from patients, but if the model doesn’t closely reflect the structure and function of heart tissue, it may miss key disease behaviors.
This is why Marzia’s group is moving step by step toward more advanced human cardiac models.
In the interview, she explains that 3D engineered heart tissues let researchers work with elongated, aligned cardiomyocytes in a structure that more closely reflects the heart’s organization. The model also allows researchers to consider different cardiac cell types, including cardiomyocytes, cardiac fibroblasts, endothelial cells, and sympathetic neurons.
The goal is not simply to make a model more complex. The goal is to make it more relevant.
If you want to study human disease, how human does the model need to be?
One of the strongest ideas in the conversation is Marzia’s point that if researchers want to study human disease, they need human models.
Animal models remain important in many areas of research, but translation can be difficult. What researchers observe in an animal model may not reflect what happens in a patient.
Advanced human models, including patient-derived 3D cardiac tissues, can help narrow that gap. They let researchers study disease mechanisms in systems that reflect human genetic backgrounds, human cardiac cell types, and measurable functional behavior.
This is especially important for conditions such as arrhythmogenic cardiomyopathy, which is inherited and where patient context can shape the biology being studied.
What changes when researchers can measure the model over time?
A cardiac model becomes more powerful when researchers can track its function over time.
With Cuore, Marzia’s group can measure contraction behavior directly inside the incubator, where temperature, gases, and humidity remain stable. This reduces experimental bias and lets researchers track functional behavior over time.
This is essential for cardiac disease modeling. The question is not only whether the cells are present or whether the tissue has formed. The question is what the tissue does.
How does it beat?
How does contraction change?
How stable is the behavior?
Does the model show disease-relevant patterns?
Can those patterns be followed long enough to test possible interventions?
These are the types of questions that functional 3D models can begin to address.
Seeing arrhythmia-like behavior earlier than expected
One of the most striking moments in the interview comes when Marzia describes observing arrhythmia-like behavior in the engineered heart tissues.
Because her group studies arrhythmogenic cardiomyopathy, this observation was important. What made it especially interesting was the timing. The arrhythmia-like behavior appeared around 7 to 10 days after casting and could be tracked during culture.
That creates a valuable window for research.
If disease-relevant behavior appears early and remains measurable over time, researchers can begin to ask more targeted questions. What drives the phenotype? How does it develop? Can it be rescued? Could the model compare patient lines, healthy controls, or potential therapeutic approaches?
This is where the model becomes more than a structure. It becomes a system for studying disease behavior.
From disease modeling to drug screening and cardiotoxicity
For Marzia, the next step is to characterize the tissues more deeply.
That includes structure, metabolism, calcium handling, and expression profiles. These layers of information can help researchers better understand what the model represents and how closely it reflects the disease.
The longer-term goal is also to use these models for drug screening. If patient-derived tissues show an altered phenotype, researchers can begin to test whether specific compounds can rescue that behavior.
The same platform may also support cardiotoxicity research, where advanced human models could help assess how cardiac tissues respond to new drug candidates.
Why this matters for the future of cardiac research
The conversation points to a broader shift in the field.
Advanced human models, including engineered heart tissues, organ-on-chip systems, and other NAMs, are becoming increasingly important for disease modeling and drug discovery. Their value is not only that they reduce reliance on traditional models. They may also help researchers ask better questions about human biology.
For cardiac research, this means building models that do more than resemble tissue. They need to function, respond, and reveal measurable behavior that is relevant to disease.
Marzia’s work shows why this matters. When patient-derived 3D cardiac models begin to show arrhythmia-like behavior, they can provide a more functional window into inherited cardiac disease and a platform for exploring what might change that behavior in the future.
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