The average size of ccfDNA is ~170 nucleotides, or the length of one loop of DNA around a nucleosome. However, since DNA sequences are equal in all cell types we need to read these fragments more closely for signatures that provide additional clues. DNA methylation is a modification that provides additional information of the source of ccfDNA. Methylation profiles of ccfDNA allow easy identification of specific cell-status or cell-types associated to the injury. In cardiovascular disease, methylation profiles of ccfDNA could improve diagnosis and evaluation of heart tissue damage linked to myocardial infarction, cardiomyopathy or heart failure. Indeed, preliminary evidence from patients with myocardial infarction suggest that methylated ccfDNA allow successful stratification of acute coronary syndromes. This study aims to expand to include heart failure (HF) patients with both preserved and reduced ejection fraction. By performing whole genome bisulfite conversion sequencing (WGBS) of their plasma, we will identify numerous differentially methylated regions (DMR), which will either match the ones we already identified in ACS patients or unravel distinct new profiles for HF. The improvement of our software pipeline to prioritize the best markers out of hundreds identified in combination with downscaling of input material for a targeted, cost-efficient sequencing approach is in preparation. Our technology will be applicable in many diseases for not only monitoring disease progression or regression such as for cardiovascular-associated diseases like HF and their different comorbidities but also to assess the efficiency of medical treatments. Our long-term goal is to develop an array of cell-free DNA based tests that can observe and/or diagnose various diseases and the respective stages as well as progression or regression upon certain drug treatments. The intended tests will be adjusted to minimum input material and are cost-effective and highly accurate.