Engineered heart tissue: Design considerations and the state of the art.

Originally developed more than 20 years ago, engineered heart tissue (EHT) has become an important tool in cardiovascular research for applications such as disease modeling and drug screening. Innovations in biomaterials, stem cell biology, and bioengineering, among other fields, have enabled EHT technologies to recapitulate many aspects of cardiac physiology and pathophysiology. While initial EHT designs were inspired by the isolated-trabecula culture system, current designs encompass a variety of formats, each of which have unique strengths and limitations. In this review, we describe the most common EHT formats, and then systematically evaluate each aspect of their design, emphasizing the rational selection of components for each application.

TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.

Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals with dilated cardiomyopathy (DCM) or other disorders of impaired cardiac contractility. Two reports in this issue of the JCI shed light on a potential mechanism involving truncated TTN sarcomere integration and the potential for disruption of sarcomere structural integrity. Kellermayer, Tordai, and colleagues confirmed the presence of truncated TTN protein in human DCM samples. McAfee and authors developed a patient-specific TTN antibody to study truncated TTN subcellular localization and to explore its functional consequences. A "poison peptide" mechanism emerges that inspires alternative therapeutic approaches while opening new lines for inquiry, such as the role of haploinsufficiency of full-length TTN protein, mechanisms explaining sarcomere dysfunction, and explanations for variable penetrance.