Deciphering phospholamban cardiomyopathy
Deciphering phospholamban cardiomyopathy
Heart failure is a major cause of illness and death worldwide, and occurs when the heart is no longer able to pump enough blood to meet the demand of the body. In some patients, heart failure is caused by inherited changes in the DNA that affect how the heart muscle functions. One example is a change in the phospholamban (PLN) gene, known as the PLN p.Arg14del (R14del) variant. This variant can lead to a severe and unpredictable heart disease and commonly occurs in the Netherlands, affecting approximately 1 in 5.000 to 10.000 individuals.
This thesis of Frits Deiman investigates how the PLN R14del variant causes heart disease and how this knowledge can improve diagnosis and treatment. First, an overview is provided of current knowledge of PLN-related heart disease and available treatment options. Next, the DECIPHER-PLN cohort is established, in which PLN R14del carriers across the disease spectrum are followed over time to improve understanding of the disease.
Using advanced techniques, this thesis identifies proteins and metabolites in the blood that may help predict which PLN R14del carriers are at increased risk of disease progression. In addition, changes in proteins and their regulation are found to lead to disruptions in calcium handling and contraction of the heart muscle. Subsequently, a novel treatment strategy is investigated: RNA therapy. In a human heart cell model, this therapy reduced harmful aggregation of the PLN protein and improved heart cell function. Lastly, the potential of RNA therapy for heart failure beyond PLN R14del is explored.
Together, these findings contribute to a better understanding of inherited heart diseases such as PLN R14del and to the development of personalized treatments for patients with inherited heart disease.