AUTHOR=Iop Laura TITLE=Toward the Effective Bioengineering of a Pathological Tissue for Cardiovascular Disease Modeling: Old Strategies and New Frontiers for Prevention, Diagnosis, and Therapy JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=Volume 7 - 2020 YEAR=2021 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.591583 DOI=10.3389/fcvm.2020.591583 ISSN=2297-055X ABSTRACT=Cardiovascular diseases still represent the primary cause of mortality worldwide. Preclinical modeling by recapitulating human pathophysiology is fundamental to advance the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and treatment. In silico, in vivo, and in vitro models have been applied to dissect many cardiovascular pathologies. Computational and bioinformatic simulations allow developing algorithmic disease models considering all known variables and severity degrees of disease. In vivo studies based on small or large animals have a long tradition and largely contributed to the current treatment and management of CVDs. In vitro studies with two-dimensional cell culture demonstrated their suitability to study the behavior of single diseased cellular types. The introduction of induced pluripotent stem cell technology and the application of bioengineering principles raised the bar towards in vitro three-dimensional modeling by enabling the development of pathological tissue equivalents. This review article intends to describe the advantages and disadvantages of past and present modeling approaches applied to provide insights on some of the most relevant congenital and acquired cardiovascular diseases, as rhythm disturbances, bicuspid aortic valve, cardiac infections and autoimmunity, cardiovascular fibrosis, atherosclerosis, and calcific aortic valve stenosis.