TABLE 1.
Comparison of maturation state of selected cardiac tissue models
| Model | Calcium dynamics | Action potential (AP) | Action potential duration (APD90) | Metabolism/Maturation | References |
|---|---|---|---|---|---|
| Human heart in vivo | • Myofilament calcium sensitivity | • 4 phases: Upstroke (0); early fast repolarization (1); plateau (2); repolarization (3), diastole (4); | ∼250 ms (atrium) | • Reliance on oxidative phosphorylation (80% of cardiac ATP production fatty acid β‐oxidation); | Zhao et al., 2019 EL‐Armouche & Eschenhagen, 2009 |
| EC50 = 701 nM. | • Atrial AP is shorter than ventricular AP. | ∼350–400 ms (ventricle). | • Lactic acid metabolism; | Lopaschuk & Jaswal, 2010 | |
| • β ‐adrenergic stimulation by β‐adrenergic receptors (β1‐ is the most abundant subtype). | Torres, Varian, Canan, Davis, & Janssen, 2013 | ||||
| Organoids | • Changes in the gene expression of calcium‐handling‐related genes (e.g., decrease in: ATP2A2, RYR2, CACNA1C, and SLC8A1, and increase in ITPR3). | • The atrium‐like regions exhibited significantly shorter APD90 than the ventricle‐like region. | 75 ms (atrial‐like) and 140 ms (ventricle‐like). | • Physiologically relevant metabolism–basal respiration ∼100 pmol/min; | J Et al., 2020 |
| • Presence of the K+ channel Kir2.1. | Richards et al., 2020 | ||||
| Muscular thin films (MTFs) | • Faster cycling of Ca2+ in comparison with 2D cultures. | • Contractile wave through MTFs, takes 160 ms, and back to its diastolic state‐360 ms; | Not presented. | • Increase in parallel registration of the sarcomeres at the Z‐disc. | Nishimura et al., 2004 |
| • Under isometric conditions, the duration of contraction shortened by 10‐fold; | Alford, Feinberg, Sheehy, & Parker, 2010 | ||||
| • Increase in peak systolic stress in comparison with 2D cultures. | Denning et al., 2016 | ||||
| Feinberg et al., 2012 | |||||
| Cell sheets | • Regular calcium transients proven. | • Conduction velocities of up to 25 cm/s (mESC‐CM/fibroblast); | 247 ms. | • Basal respiration‐46.1 pmol/min; | P. Lee et al., 2012 |
| • Contractile forces of up to 2 mN/tissue (mESC‐CM/fibroblast); | • Increase in inward sodium current density and a decrease in funny current densities; | Liau, Christoforou, Leong, & Bursac, 2011 | |||
| • Unidirectional action potential propagation, coupling with neighboring cell sheet; | • Presence of IKr and Na + channel (∼60% of the Na + current is inactivated); | Yoshida et al., 2018 | |||
| • A positive force–length and a negative isometric force–frequency relationship. | • Presence of gap junctions with connexin 43. | Shaheen et al., 2018 | |||
| Laksman et al., 2017 | |||||
| Wong et al., 2020 | |||||
| Engineered heart tissue (EHTs) | • Calcium‐handling proteins (L‐type calcium channels, LTCC; Na+/Ca2+−exchanger, NCX1; Na+/K+ ‐ATPase; Na+/H+ ‐exchanger, NHE1; SR Ca2+‐ATPase, SERCA; PLN are detected); | • Possibility to compare APD between atrial and ventricular EHTs. | 230 ms (atrial) and 420 ms (ventricular). | • More oxidative metabolism of glucose, lactate, and fatty acid and less glycolysis, and generated 2.3‐fold more ATP by oxidation than in 2D models; | Saleem et al., 2020 |
| Mannhardt et al., 2016 | |||||
| Ulmer et al., 2018 | |||||
| Lemme et al., 2018 | |||||
| Heart‐on‐a‐chip | • Contraction of CMs is strongly related to the transition of the intracellular calcium ion concentration; | • Possibility to mimic hypoxia influence on APD (a substantial reduction in mean APD50 (−46%) and APD90 (−34%)). | 236 ms. | • Basal respiration‐373.38 pmol/min and ATP production‐225.27 pmol/min; | Sakamiya et al., 2020 |
| • Spontaneous and synchronous calcium transient. | • Elongated cardiomyocytes with well‐developed sarcomeric structure and connexin‐43 positive gap junctions. | Pasqualini et al., 2018 | |||
| Sidorov et al., 2017 | |||||
| De/Recellularized heart | • Reduction in the duration of CaT90 and calcium upstroke time; | • Improved cardiac commitment; | 408 ms. | • Ion channel formation of CMs in cECM; | Garreta et al., 2016) |
| • Expression of calcium‐handling genes. | • Reduction of the conduction velocity. | • Sarcomere formation; | |||
| • Sarcomeric α‐actinin, cardiac troponin T, connexin‐43, N‐cadherin and myosin heavy chain expression; | Guyette et al., 2016 | ||||
| • Increases in the expression of different cardiac channels, such as SNCA5, KCNJ2, KCNA4, CACNA1C, SERCA2, KCNQ1, and KCNQ2. | |||||
| In vivo mouse heart model | • Full functional development of calcium storage system; | • Differences in ion channels affects APD90: both KV4.2 and KV4.3 are responsible for a fast transient outward current Ito,f in mouse; in human, only KV4.3. | 20–50 ms (atrial) and 52–54 ms (ventricular); almost ten‐fold shorter than in human heart in vivo. | • Basal respiration in young mice (2–3 months old)‐450 625 pmol/min; in old mice (22–28 months old)‐625 pmol/min. | Das & Muniyappa, 2013 |
| • Lack of voltage‐gated calcium channel CaV3.3 in mouse. | Lomax, Kondo, & Giles, 2003 | ||||
| Tanner & Beeton, 2018 | |||||
| Ying et al., 2016 |