HomeScience and ResearchScientific ResearchHere's How Genetic Defects Lead To Heart Failure In Different Ways

Here’s How Genetic Defects Lead To Heart Failure In Different Ways

Published on

Cardiomyopathy isn’t the same for everyone. An international group writes in Science that various genetic defects cause heart failure in different ways.

According to newly released research based on the first thorough single-cell examination of cardiac cells from healthy and failing hearts, the precise gene mutation that each patient inherits determines the molecular and cellular pathways that cause heart failure in persons with cardiomyopathy.

The research, which was published in the journal Science, was done by 53 scientists from six North American, European, and Asian nations.

The study demonstrates that genetic polymorphisms alter the gene activation profiles and cell type compositions. The researchers say that the results can be used to help make targeted therapies that take into account each patient’s specific form of cardiomyopathy and the gene defect that causes it.

880,000 single heart cells were analyzed

It was a challenging task that needed an interdisciplinary team to examine the genes active in over 880,000 single cells from 61 failing hearts and 18 healthy donor hearts as a reference.

The Brigham and Woman’s Hospital in Boston, Massachusetts, the Heart and Diabetes Center North Rhine-Westphalia in Bad Oeynhausen, Ruhr University Bochum in Germany, and Imperial College London, United Kingdom, all obtained the organs.

A condition with multiple causes

The researchers concentrated their efforts on dilated cardiomyopathy (DCM), the most prevalent form of cardiac failure that results in the need for heart transplants.

It includes the expansion (dilation) of the heart chamber’s walls, particularly in the left ventricle, which serves as the organ’s primary pumping chamber. Heart failure results from the heart’s muscles weakening, which impairs their capacity to contract and pump blood.

The team analyzed samples from patients with cardiomyopathies caused by a variety of genetic abnormalities. These changes happened in proteins that do different things in the heart, and tests show that these changes led to different reactions.

“We investigated pathogenic gene variants in heart tissue at the single-cell level,” says co-senior author Norbert Hübner, “which allowed us to map precisely how specific pathogenic variants drive cardiac dysfunction.”

“To our knowledge, this is the first such analysis conducted in cardiac tissue, and we hope this approach can be used to study other types of genetic heart diseases.”

The experts carefully described the different mutations in each heart and compared them with each other, with healthy hearts, and with hearts where the causes of dilation and dysfunction were unknown.

Using single-cell sequencing techniques, every type of cardiac cell and its myriad subtypes were examined one by one. No lab could handle the enormous amount of data collected on its own, but close cooperation among experts from several fields allowed for the construction of a cohesive structure out of each individual puzzle piece.

This research is also a part of the global Human Cell Atlas (HCA) consortium’s efforts to map every type of human cell in order to better understand human health and to identify, track, and treat diseases.

According to co-senior author Christine Seidman, “Only this level of resolution allows us to see that cardiomyopathies do not uniformly trigger the same pathological pathways. Rather, different mutations evoked 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.”

Hyperactive connective tissue cells

Matthias Heinig, who conducted computer calculations, states “For example, we discovered that fibrosis – the abnormal growth of connective tissue – observed in DCM is not caused by an increased number of fibroblasts in the heart.” 

These cells continue to exist in the same quantity. However, the current cells become more active and make more extracellular matrix, which fills the space between the connective tissue cells,” Eric Lindberg continues. Thus, rather than an excess of fibrotic cells, the researchers only saw a change in the distribution of cell subtypes, as evidenced by an increase in the number of fibroblasts with a focus on extracellular matrix formation.

The effect was particularly prominent in the hearts of patients with a mutant RBM20 gene, according to the authors. The medical histories of the individuals confirmed this observation. Patients who had this particular mutation typically experienced heart failure and required a transplant significantly sooner than those who had other hereditary forms of DCM. In dilated hearts, single-cell sequencing identified numerous such genotype-specific variations.

Change patterns that are specific

The investigation also revealed that, particularly in the right ventricle, muscle cells are being gradually replaced by fat and connective tissue cells in the hearts of persons with arrhythmogenic cardiomyopathies (ACM), which result in serious heart rhythm problems. The researchers concentrated its analysis on the gene for the protein plakophilin-2, or PKP2, even though this type of cardiomyopathy can also result from mutations in other genes. They compared cells taken from the right and left ventricles’ cell signaling pathways. The findings explain why persons with this kind of cardiomyopathy produce more cell fat in their heart muscle.

“The precise molecular signatures obtained for the highly specialized cells of the heart allowed us to predict cell-to-cell communication pathways,” Michela Noseda adds. 

“The team found that different genetic causes of cardiomyopathies were associated with specific aberrations of the cellular communication networks. “This is clear evidence of specified mechanisms driving the disease.” 

Finally, the researchers created a model using all of these data using artificial intelligence. Based on the specific patterns of molecular changes in the different types of cells, the algorithm can predict with a high degree of certainty which mutation is present. This shows that pathogenic variants of certain genes are linked to differences in how genes and cells are turned on.

Biomarkers for specialized treatments

Researchers said that the ultimate goal is to come up with personalized treatments for heart disease. Treatments that are tailored to a person’s genotype could be more effective and have fewer side effects. The scientific community can access all of the consortium’s findings online. Seidman thinks that this resource would encourage additional research into developing novel treatments for heart failure, which is now an incurable illness.

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

The research team, meanwhile, has decided on its next project.

According to Daniel Reichart, one of the first authors, “The heart tissue that we studied came from people in the final stage of a disease.” 

“We are excited to see what changes we discover in earlier stages of the disease, for example, based on endomyocardial biopsies.” 

Gavin Oudit says that it’s possible that biomarkers and pathways will be found that will show how a disease develops in a very specific way, allowing truly personalized medicine.

Image Credit: Anissa Viveiros and Dr. Gavin Oudit, University of Alberta

You were reading: Here’s How Genetic Defects Lead To Heart Failure In Different Ways

Latest articles

Here’s How and When Mount Everest-sized ‘Devil Comet’ Can Be Seen With Naked Eye

Mount Everest sized Comet 12P/Pons-Brooks, also known as "devil comet" which is making its...

Something Fascinating Happened When a Giant Quantum Vortex was Created in Superfluid Helium

Scientists created a giant swirling vortex within superfluid helium that is chilled to the...

The Science of Middle-aged Brain and the Best Thing You Can Do to Keep it Healthy, Revealed

Middle age: It is an important period in brain aging, characterized by unique biological...

Science Shock: Salmon’s Food Choices Better at Reducing Risk of Heart Disease and Stroke

Salmon: Rich in Health Benefits, Yet May Offer Less Nutritional Value - This is...

More like this

Here’s How and When Mount Everest-sized ‘Devil Comet’ Can Be Seen With Naked Eye

Mount Everest sized Comet 12P/Pons-Brooks, also known as "devil comet" which is making its...

Something Fascinating Happened When a Giant Quantum Vortex was Created in Superfluid Helium

Scientists created a giant swirling vortex within superfluid helium that is chilled to the...

The Science of Middle-aged Brain and the Best Thing You Can Do to Keep it Healthy, Revealed

Middle age: It is an important period in brain aging, characterized by unique biological...