(A) Cardiovascular diseases are complex clinical phenotypes that involve many different endophenotypes (e.g., inflammation, thrombosis inflammation, thrombosis, calcification, fibrosis) that cannot be explained solely by a single pathogenic variant. (B) Heterogeneity in cardiovascular diseases is evident as shown by the relationships among genetic variants (genotypes), the biochemical and cellular consequences of harboring these variants (endophenotypes), and clinically observed pathophenotypes. (C) In a model based on big data and network analyses, specific endophenotypes are determined by modules or a (sub)network of protein-protein interactions within a larger disease network. Crosstalk between pathways that regulate different endophenotypes via a critical gene may occur. In this way, post-transcriptional and epigenetic mechanisms that are important in the pathogenesis of disease endophenotypes are emphasized and, collectively, converge to produce a complex pathophenotype. DCM, dilated cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; LDL, low-density lipoprotein; LV, left ventricle; MI, myocardial infarction; RV, right ventricle; VSMC, vascular smooth muscle cell; VT, ventricular tachycardia. Adapted with permission from the Journal of the American College of Cardiology (network image in Figure 2C of, and bottom right panel of central illustration of, ref. 31).