A change of heart: Individual genetic factors could lead to customized cardiac therapies

In an era of precision medicines, it's perhaps no surprise that scientists are looking at how they tailor therapies to treat conditions of one of the body's most vital organs: the heart. New research indicates that individual genetic factors could lead to differing pathways to heart failure, a discovery that paves the way for potential customizable therapies.

The findings, published Aug. 4 in the journal Science, uproot the pervasive belief that heart failure—a hard-to-treat and often fatal condition—occurs from a common final pathway, while also providing new potential targets for developing therapies and personalized medicines.

The research is based on an analysis by 53 scientists across the world, including investigators from Brigham and Women’s Hospital and Harvard Medical School, of 880,000 single heart cells from 18 healthy and 61 failing human hearts. The scientists focused on tissue from patients with dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), conditions that frequently lead to heart failure and subsequent heart transplant.

The international team performed a single-nucleus RNA-sequencing (snRNAseq) analysis, which created a genetic readout for each heart tissue cell and enabled them to determine cellular and molecular changes in each cell type.

The team identified 10 key cell types and 71 distinct transcriptional states, noting that patients with DCM or ACM had depleted cardiomyocytes—cells responsible for the heart muscle contracting—and increased endothelial and immune cells. Looking across various hearts with mutations in certain disease genes—such as TTN, PKP2 and LMNA—the researchers also noted molecular and cellular differences, as well as some shared responses.  

When cross-referenced with patient medical records, the analysis found that, on average, individuals with a mutated RBM20 gene experienced heart failure and needed a transplant much earlier than those with other genetic forms of DCM.   

Other findings include muscle cells increasingly replaced by fat and connective tissue cells, especially in the right ventricle, in the hearts of ACM patients.

Overall, the heart of the research is this—different genetic mutations induce specific and sometimes shared responses that can trigger cardiac failure. "This network showed remarkably high prediction of the genotypes for each cardiac sample, thereby reinforcing our conclusion that genotypes activate very specific heart failure pathways,” the authors wrote.

The analysis let the scientists see that cardiomyopathies don’t uniformly trigger the same pathological pathways, according to co-author Christine Seidman, M.D., director of the Cardiovascular Genetics Center at Brigham and professor at Harvard.

“Our findings hold enormous potential for rethinking how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that may alter how the heart functions,” said Seidman.

More research must be done to further understand the molecular paths behind cardiomyopathies across certain demographics, different areas of the heart and earlier stages of disease, the researchers concluded.

The team has made their data set available online in the hope that others use the information to develop new heart failure prevention treatments. The end goal is to create individualized, genotype-specific therapies for heart disease patients, with the potential to be more effective and with fewer side effects than available treatments, according to the study's authors.