Breakthrough: DNA Methylation’s Role in Heart Failure

The leading cause of death in the United States is currently cardiovascular disease, with heart failure contributing to “about 36% of all cardiovascular disease” (HFSA). Although, in recent decades our knowledge about heart disease has grown insurmountably, there is still a lot not known about it. Specifically, the precise triggers that lead to the development or worsening of heart failure in some individuals. While certain risk factors are known (e.g high blood pressure, coronary artery disease, and diabetes) the exact mechanisms by which these factors contribute to heart failure in some individuals are still being investigated. 

However, fairly recently, some scientists have made a breakthrough on what could be a potential trigger for heart failure at the cellular level. Specifically, they have been looking at the connection between epigenetics and heart failure with preserved ejection fraction (HFpEF). HFpEF is a type of heart failure where the heart’s pumping action isn’t as strong as it should be, however, the amount of blood pumped out of the heart with each beat (this is called the ejection fraction) is normal, or near normal. In HFpEF, the heart has trouble relaxing and filling with blood properly, particularly in the left ventricle, the main pumping chamber of the heart. This causes a backlog of blood in the lungs and other parts of the body, which can lead to symptoms like shortness of breath, fatigue, and swelling in the legs. HFpEF is responsible for nearly half of the current cases of heart failure, and the reason why it is so hard to treat is because it causes multiple abnormalities in the body, including diastolic disfunction, impaired relaxation, increased stiffness of the heart muscle, etc. Targeting these multiple pathways simultaneously poses a serious challenge.

It was shown in many studies that DNA methylation has a potential connection to triggering HFpEF. DNA methylation is a biochemical process where a methyl group is added to a DNA strand. It is a process completely controlled through enzymes, specifically the DNA methyltransferases (DNMTs). There are different types of DNMTs, but some of the most important ones are DNMT3A and DNMT3B, since they have the ability to actually add methyl groups to our DNA wherever they are needed. In the heart, these enzymes are especially crucial since heart cells do not replicate their DNA often, so any changes made by these enzymes tend to stay for a long time. By adding or removing methyl groups, genes can either “turn on” or “turn off”, depending on where it happens. If a promoter region (which helps start the process of making a protein from a gene) gets methylated, it can block certain proteins called transcription factors from attaching to DNA, thus turning the gene “off”.  On the other hand, if a gene loses its methylation, it can become more active and start producing proteins. 

In individuals that have HFpEF, the heart becomes stiff due to increased levels of collagen and proteins like titin. This stiffness is the reason why their hearts cannot completely relax and fill up with blood properly. Collagen is a tough, fibrous protein, and when too much of it is produced it accumulates in the spaces between the heart muscle cells, causing them to become still and less flexible. This excessive collagen deposition leads to the formation of scar-like tissue, known as fibrosis, within the heart muscle.  Increased DNA methylation and high expression of DNMT1 and DNMT3b have been linked to the development of fibrosis in the heart tissue since they can affect certain genes involved in fibroblast action and fibrosis development.

Another way that cardiac fibrosis can develop is through myocardial inflammation. Myocardial inflammation simply occurs when the heart muscles become inflamed, which hinders their ability to pump blood effectively throughout the body. People that have HFpEF, are found with heart walls containing macrophages that produce a growth factor called TGF-𝛽, which promotes fibrosis. This also leads to an increased level of collagen in the heart tissue, and a reduction in enzymes that normally break down collagen. There is a direct relationship between the number of inflammatory cells and how severe the diastolic dysfunction is (the heart’s ability to relax and fill with blood properly). It has been found that when DNA methylation is inhibited by 5-azacytidine, the macrophages no longer promote inflammation, instead they have an anti-inflammatory effect. 5-azacytidine works by changing a protein called interferon regulatory factor -1 (IRF1) into macrophages, which helps to reduce cardiac fibrosis. In other words, by preventing DNA methylation from occurring, we can decrease inflammation and fibrosis in the heart. 

However, HFpEF doesn’t only occur through fibrosis, it can also develop through causes involving the sarcoplasmic reticulum Ca2+-ATPase (SERCA). SERCA is a crucial protein that is responsible for removing calcium from the heart muscle when it is relaxing. This process is crucial since if the heart doesn’t relax completely, it won’t be able to completely fill the ventricles up with blood, thus causing blood-backup throughout the body. When there is a deduction of SECRA activity, calcium isn’t properly removed from the celled, which causes the heart muscle to not completely relax, thus diastolic dysfunction. It has been found through other studies that patients that have diastolic dysfunction have high levels of the TNF-ɑ and interleukin-6 (IL-6) cytokines, and by decreasing the levels of these cytokines have results in better diastolic function. This is because these cytokines reduce the expression of the SECRA gene, and when there is an increase in DNA methylation of the SECRA gene promoter (which is stimulated by the TNF-ɑ cytokine), there are decreased levels of the SECRA protein. 

This understanding of DNA methylation’s role in HFpEF is truly exciting because it opens up possibilities for finding a solution for HFpEF. Insights into DNA methylation changes associated with heart failure can lead to the development of targeted therapies. Drugs that can change DNA methylation patterns or target specific genes affected by methylation changes can help change and provide better treatment options for heart failure patients. Perhaps these drugs could help prevent fibrosis from happening at all, which would also help prevent HFpEF. In addition, by analyzing DNA methylation patterns, we can begin to identify certain patterns as biomarkers for heart failure. Detecting specific methylation changes in patients can help diagnose heart failure early, predict disease progression, and assess treatment response. In addition by understanding individual differences in DNA methylation patterns we can start using personalized treatment approaches for heart failure patients. By tailoring treatments based on a patient’s unique methylation profile could improve therapeutic outcomes and reduce side effects. This way we can analyze specifically what type of HFpEF the patient is experiencing and use treatments to help suppress either collagen production or increase SECRA activity. 

Works Cited

Heart Failure Facts & Information, https://hfsa.org/patient-hub/heart-failure-facts-information. Accessed 28 March 2024.

“Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding.” NCBI, 18 January 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016826/. Accessed 28 March 2024.

“Myocarditis - Symptoms and causes.” Mayo Clinic, 20 May 2022, https://www.mayoclinic.org/diseases-conditions/myocarditis/symptoms-causes/syc-20352539. Accessed 28 March 2024.

Rabkin, Simon W. “Epigenetics in Heart Failure: Role of DNA Methylation in Potential Pathways Leading to Heart Failure with Preserved Ejection Fraction.” NCBI, 17 October 2023, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604152/. Accessed 28 March 2024.