Individual genetic defects lead to heart failure in different ways, consortium reports

Cardiomyopathy is not a uniform disease. Rather, individual genetic defects lead to heart failure in different ways, reports an international consortium in Sciences.

The molecular and cellular mechanisms that lead to heart failure in people with cardiomyopathy are determined by the specific genetic variant that each patient carries, according to recently published research based on the first comprehensive analysis of cardiac cells from healthy and diseased hearts.

The work, published in the magazine Sciences, It was conducted by 53 scientists from six countries in North America, Europe and Asia.

The study shows that cell type compositions and gene activation profiles change according to genetic variants. The researchers say the findings may inform the design of targeted therapies that take into account each patient’s underlying genetic defect responsible for their particular form of cardiomyopathy.

The team studied 880,000 individual heart cells

Examining the activated genes in approximately 880,000 individual cells from 61 defective hearts and 18 healthy donor hearts as a reference was a complex task that required an interdisciplinary team. The organs were purchased from Brigham and Woman’s Hospital in Boston, USA, the University of Alberta in Canada, the Heart and Diabetes Center North Rhine-Westphalia in Bad Oeynhausen, Ruhr University Bochum in Germany, and Imperial College London, United Kingdom.

The lead authors who spearheaded the project are Christine Seidman, a professor of medicine and genetics at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital; Jonathan Seidman, professor of genetics at Harvard Medical School; Norbert Hübner, Professor of Cardiovascular and Metabolic Sciences at the Max-Delbrück Center for Molecular Medicine of the Helmholtz Association (MDC) and Charité – Universitätsmedizin Berlin, as well as Dr. Gavin Oudit, University of Alberta, Canada; Professor Hendrik Milting, Heart and Diabetes Center NRW, Bad Oeynhausen, Ruhr University Bochum, Germany; Dr. Matthias Heinig, Helmholtz Munich, Germany; Dr Michela Noseda from the National Heart and Lung Institute at Imperial College London, UK; and Professor Sarah Teichmann from the Wellcome Sanger Institute in Cambridge, UK. The first joint authors are Daniel Reichart, MD (Harvard), Eric Lindberg, and Henrike Maatz, MD (both MDC).

A disease with many causes

The scientists focused on dilated cardiomyopathy (DCM), the most common form of heart failure leading to heart transplants. It involves an expansion (dilation) of the heart chamber walls, especially in the left ventricle, the main pumping chamber of the heart. The heart muscles weaken, compromising their ability to contract and pump blood, ultimately leading to heart failure. The consortium studied tissues from patients with different genetic mutations that commonly cause cardiomyopathies. These mutations occurred in proteins with different functions in the heart, and analyzes indicate that they triggered different responses.

We investigated pathogenic gene variants in cardiac tissue at the single-cell level, allowing us to precisely map how specific pathogenic variants drive cardiac dysfunction. 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.”

Norbert Huebner, Co-Lead Author

The scientists precisely characterized the various 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. Each cardiac cell type and the numerous subtypes were analyzed one by one, using single cell sequencing methods. No single laboratory could handle the huge amount of data generated, but close collaboration between specialists from different disciplines made it possible to put together a coherent picture of each individual piece of the puzzle. This study is also part of the efforts of the international Human Cell Atlas (HCA) consortium, which aims to map every cell type in the human body as a basis for understanding human health and for diagnosing, monitoring and treating disease.

“Only this level of resolution allows us to see that cardiomyopathies do not uniformly trigger the same pathological pathways,” says co-senior author Christine Seidman. “Rather, different mutations elicited specific and some shared responses that lead to heart failure. These genotype-specific responses point to therapeutic opportunities that may inform the development of precisely targeted interventions,” says Seidman.

overactive connective tissue cells

“For example, we found that the fibrosis (the abnormal growth of connective tissue) seen in DCM is not caused by an increased number of fibroblasts in the heart,” says Matthias Heinig, who carried out the computational analyses. “The number of these cells remains the same. But the existing cells become more active and produce more extracellular matrix, which fills the space between the connective tissue cells,” adds Eric Lindberg. Therefore, instead of an overproduction of fibrotic cells, the researchers observed only a change in the proportion of cell subtypes, marked by an increase in the number of fibroblasts that specialize in the production of extracellular matrix.

“The phenomenon was especially pronounced in the hearts of patients with a mutated RBM20 gene,” explains Henrike Maatz. This observation was also reflected in the clinical records of the patients. On average, patients with this specific mutation developed heart failure and needed a transplant much sooner than people with other genetic forms of DCM. Single-cell sequencing revealed a whole host of genotype-specific differences in dilated hearts.

Specific patterns of change

The analysis also showed that in the hearts of people with arrhythmogenic cardiomyopathies (ACMs), which cause dangerous heart rhythm disturbances, muscle cells are increasingly replaced by fat and connective tissue cells, particularly in the right ventricle. Although this form of cardiomyopathy can also be caused by a mutation in several genes, the team focused their analysis on the gene for the protein plakophilin-2, or PKP2 for short. They compared the cell signaling pathways of cells obtained from the right and left ventricles. The findings identify the cause behind the increased production of cellular fat in the heart muscle of people with this type of cardiomyopathy.

“The precise molecular signatures obtained for the highly specialized cells of the heart allowed us to predict cell-to-cell communication pathways,” says Michela Noseda. The team found that different genetic causes of cardiomyopathies were associated with specific aberrations of cellular communication networks. “This is clear evidence of the specific mechanisms driving the disease.”

Finally, the scientists used artificial intelligence to develop a model from all this data. Based on the specific patterns of molecular changes in different cell types, the algorithm can predict with a high degree of confidence which mutation is present, confirming that differences in gene and cell activation are associated with pathogenic variants of specific genes. .

Biomarkers for targeted therapies

The ultimate goal is to develop individualized therapies for heart disease, the researchers said, because genotype-specific treatment may be more effective and have fewer side effects. The consortium has made all of its results available to the scientific community online. Seidman hopes that this resource will prompt studies by other groups to define new treatments to prevent heart failure, which is now an incurable disease.

“We investigated tissue from patients who needed a heart transplant; it was their last option,” says Hendrik Milting. “We hope that future drug treatments will at least slow the progression of the disease, and that the data from our study will help make this happen.”

In the meantime, the research team has identified their next task. “The heart tissue we studied came from people in the final stage of a disease,” says Daniel Reichart, one of the first authors. “We are excited to see what changes we discover in the early stages of the disease, for example, based on endomyocardial biopsies.” Perhaps biomarkers and pathways will be found that shed light on very precise disease pathogenesis that will truly enable personalized medicine, adds Gavin Oudit.


Magazine Reference:

Reichhart, D. et al. (2022) Pathogenic variants damage cellular compositions and single cell transcription in cardiomyopathies. Sciences.

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