The pathways that lead to heart failure in patients with cardiomyopathy are determined by the specific genetic variant that each patient carries, concludes this first-ever analysis conducted at the cellular level of heart cells from healthy hearts and failing hearts.
The consortium of 53 scientists from 6 countries in North America, Europe and Asia set out to identify the gene activation profiles of the different cell types, depending on the genetic variants. The results will allow the development of targeted therapies that take into account the underlying genetic defect of each patient, responsible for their particular form of cardiomyopathy.
In total, no less than 880,000 unique heart cells were studied with their gene activation profile, 880,000 individual cells from 61 failing hearts and 18 healthy hearts.
A titanic work to better decipher this disease with multiple causes
Scientists have focused on dilated cardiomyopathy (DCM), the most common form of heart failure that usually requires a heart transplant. The condition is characterized by dilatation of the walls of the heart chamber, particularly in the left ventricle, the main pumping chamber of the heart. The muscles of the heart weaken, which eventually compromises its ability to contract and pump blood, which ultimately leads to heart failure.
The researchers therefore analyzed tissues from patients with different genetic mutations generally leading to cardiomyopathies. These mutations occur in proteins with different functions in the heart. These analyzes indicate that these mutations also trigger different responses: “This study of pathogenic gene variants in cardiac tissue at the cellular level, allowed us to precisely map how specific pathogenic variants lead to cardiac dysfunction”, explains Dr. Norbert Hübner, co-author of the study.
Scientists have characterized the different mutations found in each of the hearts and compared them with each other, as well as with the genetic profiles of healthy hearts and failing hearts whose causes of dysfunction were unknown. Each heart cell type was analyzed, one by one, using single-cell sequencing methods. This level of analysis revealed that
cardiomyopathies do not uniformly trigger the same disease pathways.
Different mutations induce specific responses and also shared responses that lead to heart failure.
- For example, the fibrosis observed in dilated cardiomyopathy is not caused by an increased number of fibroblasts in the heart but rather by a change in the usual proportion of the different cell subtypes, which favors the increase in the number of specialized fibroblasts in the production of extracellular matrix, a typical phenomenon in patients carrying a mutated RBM20 gene…
- As another example, in the hearts of people with arrhythmogenic cardiomyopathy (ACM), a heart condition that causes dangerous heart rhythm disturbances, muscle cells are increasingly replaced by fat cells and connective tissue, a process associated with heart disease. PKP2 gene.
Thus, this work identifies precise molecular signatures for the different types of cardiomyopathies, with the objective, whatever the type, of being able to prevent or treat heart failure. Specific therapeutic targets that will be able to “illuminate” the development of precision cardiac medicine.