Molecular and cellular pathophysiology of circulating cardiomyocyte-specific cell free DNA (cfDNA): Biomarkers of heart failure and potential therapeutic targets

Pathological cardiac damage during heart failure is associated with cell death and damage associated molecular patterns (DAMPs) release which triggers a viscous cycle of sterile inflammation to mediate maladaptive cardiac tissue remodelling during the progression to heart failure. DAMPs like cytokines, chemokines, and nuclear or mitochondrial genomic fragments are released in the pathological myocardium. Interestingly, circulating or cytosolic DNA fragments can play a role in the disease by interaction with nucleic acid sensors expressed in cardiomyocyte and non-myocyte neighbouring cells. The circulating cell free DNA (cfDNA) fragments have been clinically reported as markers for various diseases including cardiovascular pathophysiology. Such cfDNA within the DAMP pool can mediate intra- and inter-cellular signalling cascade to upregulate transcriptional expression of inflammatory mediators and trigger oxidative stress within cells. The cellular role of such genomic equivalents varying with chronic or acute stress might be correlated with the cell death forms encountered in myocardium during disease progression. Thus, cfDNA can be phenotypically correlated as a critical player towards upregulation of pathological processes like interstitial fibrosis, cardiomyocyte contractile dysfunction and cell death. Herein, we review the association of cfDNA with heart failure and analyse their potential usage as novel and effective therapeutic targets towards augmentation of cardiac function.& COPY; 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Automated summary

Pathological cardiac damage during heart failure is associated with the release of cell death and damage associated molecular patterns (DAMPs), which leads to sterile inflammation and maladaptive cardiac tissue remodeling. Circulating or cytosolic DNA fragments, including cell free DNA (cfDNA), can interact with nucleic acid sensors in neighboring cells, triggering intra- and inter-cellular signaling cascades that upregulate inflammatory mediators and induce oxidative stress. This can result in interstitial fibrosis, cardiomyocyte contractile dysfunction, and cell death. This review focuses on the association of cfDNA with heart failure and explores its potential as a therapeutic target for improving cardiac function.