Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip
Open accessAbstract
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.
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Some cardiomyopathies can exhibit maladaptive tissue remodeling that may result in more circumferential alignments of the musculature.
“some cardiomyopathies can exhibit maladaptive tissue remodeling (14, 15), which may result in more circumferential alignments of the musculature (12, 13, 15).”
From Recreating the heart's helical structure-function relationship with focused rotary jet spinning (2022) · cites this paper as [14]
The Discussion and Chip Design sections describe maladaptive remodeling and local myocyte realignment in a model of failing myocardium, with misalignment resembling that reported in hypertrophic cardiomyopathy. They do not establish that cardiomyopathies produce more circumferential alignment of the musculature; the reported change is local, stretch-induced disorganization. (LLM, conf=0.85)
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- Authors
- McCain, M. L., Sheehy, S. P., Grosberg, A., Goss, J. A., & Parker, K. K.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-28
- Volume
- 110
- Issue
- 24
- Pages
- 9770-9775
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3683774
- OpenAlex
- W2079176005
- Cited by
- 163
- References
- 61
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 13 · 2018: 20 · 2017: 11 · 2016: 20 · 2015: 19 · 2014: 15 · 2013: 1
- FWCI
- 18.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Science Foundation (0213805)
- American Heart Association
- GlaxoSmithKline
- National Institutes of Health (UH2TR000522, UH3TR000522)
- Harvard School of Engineering and Applied Sciences
- Harvard Stem Cell Institute
- Materials Research Science and Engineering Center, Harvard University (DMR-0213805)
- National Heart, Lung, and Blood Institute (R01HL079126)
- Division of Materials Research
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- cardiac remodeling, heart failure, cyclic strain, in vitro heart model, myosin heavy chain isoforms, sarcomere alignment, calcium handling, contractile function, mechanical overload, gene expression
- MeSH terms
- Animals, Animals, Newborn, Calcium, Cells, Cultured, Heart Failure, Humans, Models, Cardiovascular, Myocardial Contraction, Myocardium, Sarcomeres, Systole, Time Factors, Rats, Sprague-Dawley, Myosin Heavy Chains, Ventricular Remodeling, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Ventricular Myosins, Myocytes, Cardiac
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