Heart failure (HF) is a chronic heart disease that prevents this organ from properly pumping blood and is one of the main causes of mortality and hospital admission. New research has identified molecules and signaling pathways involved in heart failure that occurs due to genetically based pathologies such as dilated and arrhythmogenic cardiomyopathy, a finding that may help improve the treatment of heart failure and facilitate the use of medicine personalized in these patients so that individualized therapies can be administered depending on their genetic profile.
Dilated cardiomyopathy is the most common cause of heart failure leading to heart transplantation and is characterized by an expansion of the heart chamber walls, especially the left ventricle, causing the muscle to weaken and reduce its ability to function. ability to contract and pump blood, which ultimately causes heart failure.
“Currently we treat all patients with heart failure and reduced systolic function with the same drugs, regardless of the cause that is giving rise to impaired cardiac function,” explained Fernando Domínguez, deputy of the Unit, in statements to Diario Médico. of Familial Heart Diseases of the Puerta de Hierro University Hospital. The objective of this study was to identify the changes at the cellular and molecular level that lead to heart failure in MCD and ACM and have verified that, depending on the underlying genetic disease, there are different patterns in gene expression and cell signaling pathways .
Influence of genetic variants in heart failure
The study has been led by scientists from Brigham and Women’s Hospital and Harvard Medical School (HMS) who have analyzed 880,000 individual heart cells, with the collaboration of 53 scientists from six countries in North America, Europe and Asia. The research focused on the study of patients with dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM).
The molecular and cellular mechanisms that trigger heart failure are determined by the specific genetic variant that each patient carries
To carry out the work, which has been published in Science, the activated genes were examined in almost 900,000 individual cells from 61 hearts from diseased individuals and 18 from healthy individuals. Heart tissue samples and organs were provided by Brigham and Woman’s Hospital in Boston, the University of Alberta, Canada, the North Rhine-Westphalia Heart and Diabetes Center in Bad Oeynhausen, the University of Ruhr of Bochum (Germany) and the Imperial College of London (United Kingdom).
Norbert Hübner, co-lead author of the study, explained: “We investigated heart tissue at the single-cell level in subjects with pathogenic genetic variants, which allowed us to verify that these drive cardiac dysfunction,” explains study co-lead author Norbert Hübner. “To our knowledge, this is the first analysis of its kind done on heart tissue, and we hope that this approach can be used to study other types of genetic heart disease,” he adds.
The researchers identified 10 major cell types and 71 different transcriptional states and found that in tissue from MCD or MCA patients, cardiomyocytes were reduced, while endothelial and immune cells were increased. Another important finding was that the fibroblasts did not increase, but showed altered activity, as reported by Matthias Heinig, who carried out the computational analyses.
Personalized therapies based on genetic defects
In the opinion of the authors of the research, its results can contribute to the design of targeted therapies in which the underlying genetic defects that cause each particular form of cardiomyopathy are taken into account, that is, personalized medicine could be used in the management of heart failure, since the molecular and cellular mechanisms that trigger HF are determined by the specific genetic variant carried by each patient.
The researchers precisely characterized the different mutations in each of the hearts and compared them with each other, as well as with healthy hearts and with hearts in which the causes of dilation and dysfunction were unknown. They thus discovered that the composition of cell types and the activation profiles of genes change according to genetic variants.
“Only this level of resolution allows us to see that cardiomyopathies do not uniformly trigger the same pathological pathways,” explains co-author Christine Seidman. “Rather, different mutations evoke specific and some shared responses that lead to heart failure. These genotype-specific responses point to therapeutic opportunities that may inform the development of precision-targeted interventions,” Seidman concludes.
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