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How disease-causing genetic variants lead to heart failure

How pathogenic gene variants lead to heart failure
In this illustration, the diseased heart is shown as a skin hit by a DNA bat Nata, to represent the genetic influence of the variant studied. Patient cells are depicted as confetti flying out of the heart, in colors reminiscent of the five major genotypes discussed in the paper. Credit: Dr. Eleonora Adami, MDC

Cardiomyopathy is not a uniform disease. Conversely, an international consortium reports in Science that individual genetic defects can lead to heart failure in different ways.

The molecular and cellular mechanisms that lead to heart failure in patients with cardiomyopathy depend on each individual’s specific genetic variation. Patients carry, according to newly published research based on the first comprehensive single-cell analysis of heart cells from healthy and failing hearts.

Work reported in journals Science, by 53 scientists from six countries in North America, Europe and Asia.

Studies show that cell type composition and gene activation profiles change according to genetic variation. The findings could inform the design of targeted therapies that take into account each patient’s underlying genetic defects that are responsible for their specific forms of cardiomyopathy, the researchers said.

Team studied 880,000 single hearts Cell

Examining genes activated at approximately 880,000 single cells from 61 failing hearts and 18 healthy donor hearts as a reference was a complex undertaking that required an interdisciplinary team. The organs were provided by Brigham and Women’s Hospital in Boston, USA; University of Alberta, Canada; North Rhine-Westphalia Heart and Diabetes Center in Bad Oinhausen; Ruhr University Bochum, Germany; and Imperial College London, UK Purchased by the college.

The senior author leading the project is cardiologist Kristin A., professor of medicine and genetics at Harvard Medical School. Christine Seidman, Brigham and Women’s Hospital; Jonathan Seidman, Professor of Genetics, Harvard Medical School; Norbert Hübner, Professor of Cardiovascular and Metabolic Sciences, Max-Delbrück – Center for Molecular Medicine, Helmholtz Consortium (MDC), Charité-Universitätsmedizin Berlin and Dr. Gavin Oudit, University of Alberta, Canada; Prof. Hendrik Milting, NRW Heart and Diabetes Centre, Bad Oeynhausen, Ruhr University Bochum, Germany; Dr. Matthias Heinig, Helmholtz, Munich, Germany; Imperial College London, UK Dr Michela Noseda from the Heart and Lung Institute and Professor Sarah Teichmann from the Wellcome Sanger Institute, Cambridge, UK. Co-first authors are Dr. Daniel Reichart (Harvard), Eric Lindberg, and Dr. Henrike Maatz (all MDC).

Microscopy techniques help to dissect the cellular structure of heart tissue. RNA molecules are labeled with fluorescent molecules that help identify cell types. Cell borders and extracellular matrix are stained green. Nuclei are stained blue. Credit: Eric Lindbergh, MDC
A polycaused disease

Scientists focus on dilated cardiomyopathy (DCM), the cause of heart transplants The most common form of heart failure. It involves dilation (dilation) of the walls of the ventricles, especially in the left ventricle, the main pumping chamber of the heart. The heart’s muscles become weak, affecting its ability to contract and pump blood, eventually leading to heart failure. The consortium studied tissue from patients with different genetic mutations that commonly lead to cardiomyopathy. The mutations occurred in proteins with different functions in the heart, and the analysis showed that the mutations elicited different responses.

“We studied disease-causing genetic variants in cardiac tissue at the single-cell level, which allowed us to accurately to map how specific pathogenic variants drive cardiac dysfunction,” said co-senior author Norbert Hübner. “To our knowledge, this is the first such analysis in cardiac tissue, and we hope this method can be used to study other types of inherited heart disease.”

Scientists have precisely described the various mutations in each heart and compared them with each other, as well as with healthy hearts and hearts with unexplained dilation and dysfunction Compare. A one-by-one analysis was performed for each cardiac cell type and numerous subtypes using single-cell sequencing. No single laboratory can handle the vast amounts of data generated alone, but close collaboration between experts from different disciplines has made it possible to piece together a coherent picture from each individual puzzle. The research is also part of efforts by the International Human Cell Atlas (HCA) consortium to map every cell type in the human body as a basis for understanding human health and diagnosing, monitoring and treating disease.

“Only this resolution allows us to see that cardiomyopathy does not consistently trigger the same pathological pathways, ” says co-senior writer Kristin Seidman. “Instead, different mutations caused specific responses and some common responses that lead to heart failure. These genotype-specific responses point to therapeutic opportunities that may inform the development of precisely targeted interventions,” Seidman said.

Labels tissue with a cell-specific marker. Cells called endothelial cells that line the inside of blood vessels are shown in orange. Cardiomyocytes are gray. Finally, in blue-green, is the nucleus, the structure that contains the DNA (genetic information) of every cell in the body. Image credit: © Sam Barnett and Antonio Manuel Almeida Miranda / Imperial College London

Hyperactive connective tissue cells

” For example, we found that the observed in DCM Fibrosis – abnormal growth of connective tissue not caused by an increase in the number of fibroblasts in the heart,” said Matthias Heinig, who performed the computational analysis. “The number of these cells remained the same. But the existing cells became more active and produced more extracellular matrix, and these cells filled the spaces between the connective tissue cells,” adds Eric Lindberg. Therefore, what the researchers observed was only a change in the ratio of cell subtypes, rather than an overproduction of fibrotic cells, which is marked by an increase in the number of fibroblasts specialized in producing extracellular matrix.

“This phenomenon is particularly evident in the hearts of patients with mutations in the RBM20 gene,” explains Henrike Maatz. This observation was also reflected in the patient’s medical history. On average, patients with this specific mutation developed heart failure and required transplantation earlier than patients with other inherited forms of DCM. Single-cell sequencing reveals a series of genotype-specific differences in the dilated heart.

The specific change mode

The analysis also showed that in patients with proarrhythmic In people with acute cardiomyopathy (ACM) — those that can lead to dangerous heart rhythm disturbances — muscle cells are increasingly replaced by fat and connective tissue cells, especially in the right ventricle. Although this form of cardiomyopathy can also be caused by mutations in several genes, the team focused their analysis on the gene for the protein plakophilin-2, or PKP2 for short. They compared the cellular signaling pathways of cells obtained from the right and left ventricles. The findings identify the cause of increased lipogenesis in cardiomyocytes in patients with this type of cardiomyopathy.

How pathogenic gene variants lead to heart failure
Cell borders are stained green and nuclei are stained blue , the myocardium is stained gray. Image credit: © Anissa Viveiros and Dr. Gavin Oudit, University of Alberta

“Precise molecular signatures obtained for highly specialized heart cells allow us to predict cell-to-cell communication pathways,” says Michela Noseda. The team found that different genetic causes of cardiomyopathy are associated with specific abnormalities in cellular communication networks. “This is clear evidence of a specific mechanism driving the disease.”

Finally, the scientists used artificial intelligence to extract from all these A model is developed from the data. Based on specific patterns of molecular changes in various cell types, the algorithm can predict with high confidence which mutations are present — confirming that differences in gene and cell activation are associated with disease-causing variants in specific genes.

Biomarkers for Targeted Therapy

The ultimate goal is to develop individual Treatment researchers say heart disease is because genotype-specific treatments may be more effective and have fewer side effects. The consortium has made all its results available online to the scientific community. Seidman hopes this resource will spur research by other groups to identify new treatments to prevent heart failure, an incurable disease today.

“We investigated tissue from patients who needed heart transplants; it was their last resort,” says Hendrik Milting . “We hope that future drug treatments will at least slow the progression of the disease – and the data from our study will help achieve that.”

For single-cell sequencing, scientists must first isolate the nucleus. As these nuclei pass through the microfluidic chip, they are packaged into small water droplets along with the barcode. In the droplets, the barcodes then bind to RNA from the nucleus — transcripts produced when genes are read from DNA. In this way, RNA can be assigned to individual nuclei after sequencing. Credit: Eric Lindbergh, MDC

Meanwhile, the research team has already decided on the next mission. “The heart tissue we studied came from people who were in the final stages of the disease,” said Daniel Rechat, one of the first authors. “We’re excited to see what changes we find early in the disease, for example based on endomyocardial biopsies.” Gavin Oudit adds that perhaps the discovery of biomarkers and pathways that can elucidate very precise disease pathogenesis to truly Enable personalized medicine.

More info: Daniel Reichart et al, Pathogenic variants impair cellular composition and single-cell transcription in cardiomyopathy, Science (2022) . DOI: 10.1126/science.abo1984.

All data for this study are available online :

quote: How Pathogenic Gene Variants Contribute to Heart Failure (August 4, 2022) Retrieved August 24, 2022 from https:// 2022-08-genetic-opportunity-personalized-heart-failure.html

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