Tackling genetic heart disease at the root – PhD defense Eirini Kyriakopoulou

Heart muscle cells must contract in unison for the heart to pump blood through our bodies. Specialized proteins, called desmosomes, make this possible by connecting heart cells to each other. In patients with ACM, inherited changes in the DNA weaken the desmosomes. Over time, this disrupts the coordinated contraction of the heart, which can lead to abnormal heart rhythms. This can be dangerous and even life-threatening. Current treatments for ACM target the symptoms but not the cause of the disease, and in severe cases, a heart transplant may be necessary.

Laying the foundations for new therapies

During her PhD, Eirini studied how specific genetic changes lead to ACM. “Understanding why desmosomes become defective and how this leads to an abnormal heart rhythm is essential for the development of treatments that address the cause of the disease,” Eirini explains. By studying explanted hearts from ACM patients and models of the disease in the lab, she discovered that the protein EPAS1 contributes to the death of heart muscle cells in ACM.

Eirini also explored whether gene therapy could benefit ACM patients in the future. “The most commonly affected gene in ACM is PKP2, which encodes an essential part of the desmosomes,” she says. “We reasoned that replacing the faulty PKP2 gene with a healthy one in heart muscle cells might strengthen the desmosomes and improve the heart rhythm.” Eirini and her colleagues tested this strategy in several laboratory models of the disease, showing that it improved the desmosomes and contractility of the heart. Building on these results, clinical trials with ACM patients have started in the United States in 2024.

The full spectrum of emotions

Eirini describes her PhD as a journey featuring a wide range of emotions. “It was anything but boredom,” she says. “In the beginning, there’s both excitement and insecurity. Later I gained more confidence, but at times also faced significant disappointments.” The third and fourth years were most fruitful and marked by personal growth, meeting inspiring people and traveling to beautiful places abroad. She fondly remembers doing lab experiments while singing along to ABBA. At the same time, it was challenging to maintain a healthy work-life balance. “In the final year of my PhD, it was rewarding to see my achievements and experiences come together, but there was also the accumulated fatigue of the previous years,” Eirini says.

Despite the challenges, she would not hesitate to do it all again. “Doing a PhD pushed me to recognize both my strengths and my weaknesses, and helped me gain a clearer understanding of myself, my ambitions, and my priorities in life,” she says. Eirini would therefore advise anyone still hesitant about pursuing a PhD to go for it. “Churchill once said: ‘Success is the ability to move from failure to failure without losing enthusiasm.’ Remember that when you encounter disappointments along the way,” Eirini concludes.

A digital version of Eirini’s thesis can be found here.