title: Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip.
abstract: The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structure-function relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α- to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart.
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: McCain
authors.forename: Sean P
authors.initials: SP
authors.lastname: Sheehy
authors.forename: Anna
authors.initials: A
authors.lastname: Grosberg
authors.forename: Josue A
authors.initials: JA
authors.lastname: Goss
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism; D013599:Systole / Q000235:genetics; D013997:Time Factors; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D002118:Calcium
keywords: contraction; mechanotransduction; microarray; muscular thin films; organs on chips