How pathogenic gene variants lead to heart failure

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

The molecular and cellular mechanisms that lead to heart failure in people with cardiomyopathy are determined by the specific gene variant that each patient carries, according to newly published research based on the first comprehensive single-cell analysis of cardiac cells from healthy and failing hearts. The work, reported in the journal Science, 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 the genetic variants. The investigators say the findings can inform the design of targeted therapies that take into account each patient's underlying gene defect responsible for their particular form of cardiomyopathy.

The team studied 880,000 single heart cells Examining the genes activated in about 880,000 single cells from 61 failing hearts and 18 healthy donor hearts as reference was a complex endeavor which required an interdisciplinary team. The organs were procured by the Brigham and Woman's Hospital in Boston, U.S., 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, UK. Senior authors who spearheaded the project are Christine Seidman, 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 in 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 of the National Heart and Lung Institute at Imperial College London, UK and Professor Sarah Teichmann, Wellcome Sanger Institute in Cambridge, UK. Joint first authors are Dr. Daniel Reichart (Harvard), Eric Lindberg and Dr. Henrike Maatz (both MDC).

In this illustration, the diseased heart is displayed as a piñata being hit by a DNA bat to signify the genetic impact of the variants that were studied. Patient cells are illustrated as confetti flying out of the heart and the colors recall the five main genotypes discussed in the paper. Credit: Dr. Eleonora Adami, MDC Read more

Microscopy technologies help to dissect the cellular landscape of cardiac tissue. RNA molecules are labeled with fluorescent molecules and thereby help to identify cell-types. Cell boundaries and extracellular matrix are stained in green. Cell nuclei are stained in blue. Credit: Eric Lindberg, MDC Read more

The tissue was labeled using markers for specific cells. The cells lining the inside of blood vessels called endothelial cells are shown in orange. Cardiac muscle cells are in grey. Finally, in teal, are the cellular nuclei, the structures that contain the DNA – the genetic information – of each cell in the body. Credit: © Sam Barnett and Antonio Manuel Almeida Miranda / Imperial College London Read more

Cell boundaries are stained in green, nuclei are stained in blue, and heart muscle is stained in grey. Credit: © Anissa Viveiros and Dr. Gavin Oudit, University of Alberta Read more

For single cell sequencing, scientists first have to isolate the cell nuclei. When these nuclei pass over a microfluidic chip, they are packed into small aqueous droplets along with a barcode. In the droplets, the barcode is then coupled with the RNA from the nucleus - the transcripts that are generated when the genes are read from the DNA. This way, the RNA can be assigned to the individual cell nuclei after sequencing. Credit: Eric Lindberg, MDC Read more