Transgenerational Epigenetic Inheritance of Cardiovascular Diseases: A Network Medicine Perspective

Introduction The ability to identify early epigenetic signatures underlying the inheritance of cardiovascular risk, including trans- and intergenerational effects, may help to stratify people before cardiac symptoms occur. Methods Prospective and retrospective cohorts and case–control studies focusing on DNA methylation and maternal/paternal effects were searched in Pubmed from 1997 to 2023 by using the following keywords: DNA methylation, genomic imprinting, and network analysis in combination with transgenerational/intergenerational effects. Results Maternal and paternal exposures to traditional cardiovascular risk factors during critical temporal windows, including the preconceptional period or early pregnancy, may perturb the plasticity of the epigenome (mainly DNA methylation) of the developing fetus especially at imprinted loci, such as the insulin-like growth factor type 2 ( IGF2 ) gene. Thus, the epigenome is akin to a “molecular archive” able to memorize parental environmental insults and predispose an individual to cardiovascular diseases onset in later life. Direct evidence for human transgenerational epigenetic inheritance (at least three generations) of cardiovascular risk is lacking but it is supported by epidemiological studies. Several blood-based association studies showed potential intergenerational epigenetic effects (single-generation studies) which may mediate the transmittance of cardiovascular risk from parents to offspring. Discussion In this narrative review, we discuss some relevant examples of trans- and intergenerational epigenetic associations with cardiovascular risk. In our perspective, we propose three network-oriented approaches which may help to clarify the unsolved issues regarding transgenerational epigenetic inheritance of cardiovascular risk and provide potential early biomarkers for primary prevention. Significance What is already known on this subject? Many maternal risk factors, including dyslipidemia, hypertension, smoking, diabetes, and obesity have been associated with CVDs risk in the offspring. Paternal factors are emerging as risk factors contributing to transgenerational effects. From a molecular point of view, DNA methylation may be responsible, at least in part, for early modifications during fetal development which set CVD risk trajectories during post-natal life. What this study adds? Big data availability supports the importance of Network Medicine approaches for integrating environmental exposures, clin