Angiotensin II Induced Cardiac Dysfunction on a Chip

Abstract

In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.

The Right Ventricle in COVID-19

“…As discussed previously, the increased degradation of ACE2 in response to SARS-CoV2 infection may result in a theoretical unopposed ATII signaling [122] with negative actions on the heart, comprising inflammation, oxidative stress, negative inotropic effects, and adverse remodeling [134]. Whether ATII contributes to myocardial damage and dysfunction in COVID-19, and whether RAS-interfering drugs have therapeutic advantages, remain speculative so far and are the focus of several ongoing clinical investigations.…”

Electrospun Fibrous PVDF‐TrFe Scaffolds for Cardiac Tissue Engineering, Differentiation, and Maturation

“…Moreover, derivation of cardiomyocytes from human‐induced pluripotent stem cells (hiPSCs), enables construction of patient specific tissues, increasing the therapeutic potential of engineered cardiac patches, and their clinical relevance as in vitro models for pharmacological studies . The functional readouts from the engineered tissues include video tracking of their mechanical contraction followed by calculation of contractile stress, extracellular potentials using microelectrode arrays, or calcium transients measured using calcium sensitive dyes . These methods usually involve disruption of the cells culture since they are carried out outside the incubator, and the obtained readouts often require complex processing of heavy data files.…”

Organs-on-chips: into the next decade

“…[H2] Stem cells and tissue chips -powerful partners While many OoCs have been developed to model disease phenotypes using primary or cell line sources, the increasing use of iPSCs, plus the novel option of using the mass production of organoid technology as a way to source adult stem cells in biomedical research, has also led to the increased development of an array of diseases-on-chips including: cardiac (atrial and ventricular) myopathies 72,93,94 ; asthma 95 ; vascular abnormalities ; polycystic kidney disorders 97 ; as well as neural disorders -including ones mimicking aspects of neurodegenerative and psychiatric disorder phenotypes 98,99 -and rare pediatric diseases such as Hutchinson-Gilford Progeria Syndrome 100 . However, a limitation associated with using stem cell-derived cells in OoCs include difficulties in producing an adequate number of mature, differentiated cells with the necessary purity for many tissues (for more see Box 2).…”