Table 2.

NICMs modelled with patient iPSC-CMs.

NICM	Culture environment	CM disease readouts∗	Selected interventions (effect)∗	Reference
Dilated cardiomyopathy	Embryoid bodies (EBs)	Disturbed sarcomeric organisation. ↑Sensitivity to positive inotropic and biomechanical stress (cyclic stretch). ↓Sarcoplasmic reticulum (SR) Ca2+ storage and altered Ca2+ handling. ↓CM contraction forces.	Overexpression of Serca2a (↑[Ca2+]i transients and CM contraction forces). Beta-1-adrenergic blockade (resistance to biomechanical stress and improved myofilament organisation)	Sun et al. (2012) [120]
Hypertrophic cardiomyopathy	EBs	CM hypertrophy. Disturbed sarcomeric organisation. ↑Multinucleation. ↑Hypertrophy-related genes. Expression of atrial natriuretic peptide. ↑Beta-/alpha-myosin ratio. Calcineurin activation. NFATc4. ↑Myofibril content. ↑Membrane capacitance. Presence of arrhythmic waveforms. ↑Irregular beating frequencies. CM hypercontractility. Irregular Ca2+ transients. ↓SR Ca2+ release and ↑[Ca2+]i	Blockade of calcineurin-NFAT interaction (40% reduction in CM cell size). Beta-adrenergic stimulation (↑irregular Ca2+ transients and arrhythmia). Coadministration of beta-adrenergic blocker + beta-adrenergic agonist (↓hypertrophy, Ca2+ handling deficiencies, and arrhythmia). Inhibition of Ca2+ influx (eliminated Ca2+ handling abnormalities and arrhythmia, and restoration of normal beating frequency)	Lan et al. (2013) [121]
Arrhythmogenic right ventricular cardiomyopathy	EBs	↓PKP2 and plakoglobin. ↓Cx43. ↑Maximum width in CM. Disorganised Z-bands. ↑Distorted desmosomes#. Altered lipid droplet morphology. ↑Lipid droplets and accumulation. ↑PPAR-gamma and -alpha. ↑Susceptibility to apoptosis. ↓Beta-catenin. Abnormal [Ca2+]i handling capability. ↓Serca2a and Na+/Ca2+ exchanger 1	Activation of canonical Wnt signalling (↓lipid droplet accumulation). Induction of adult-like energy metabolism and overactivation of PPAR-gamma signalling (increased apoptosis and lipid accumulation). Lentiviral transduction of WT PKP2 (redistribution of plakoglobin to cell membrane and nucleus, ↓apoptosis, and lipogenesis). Scavenging of reactive oxygen species (↓apoptosis). Enrichment for right ventricle-like CMs (↑lipogenesis and apoptosis)	Ma et al. (2013) [122], Caspi et al. (2013) [123], and Kim et al. (2013) [124]
Long QT syndrome 1	EBs	Longer action potentials with slower repolarisation velocities in ventricular- and atrial-like CMs. ↓K+ currents. Translocation of KCNQ1 from the cell surface to the endoplasmic reticulum	Transduction of WT KCNQ1 (redistribution to the cell surface of H9c2 cells). Beta-adrenergic stimulation (impaired rate adaptation of the AP and EADs), rescued by nonselective beta-blockade	Moretti et al. (2010) [74]
Long QT syndrome 2	iPSC coculture with END-2 cells [75]. EBs [125]. Directed differentiation method [126]	↑Field potential durations on microelectrode arrays. Prolonged cardiac repolarisation phase of the AP (ventricular-like CMs).↑Arrhythmogenicity. Presence of EADs. Prolonged [Ca2+]i transients. ↓Densities of rapid delayed potassium channels. ↑Sensitivity to the antiarrhythmic drug, sotalol and the human Ether-à-go-go-related gene (hERG) blocker E-4031. ↑Sensitivity to beta-adrenoreceptor agonism	Nonspecific beta-adrenergic agonist (↑chronotropy). Pharmacological QT prolongation (arrhythmogenic behaviour). K+ channel enhancement (shortened APs and prevention of EADs). Ca2+ channel blockade (shortened APs)	Lahti et al. (2012) [76], Matsa et al. (2011) [126], and Spencer et al. (2014) [127]
Long QT syndrome 3 (Brugada syndrome)	iPSC coculture with END-2 cells	↓Inward Na+ current density. Defective biophysical properties of Na+ channel. Prolonged inactivation of Nav1.5. Mild prolongation of after-depolarising potential. Altered SR Ca2+ release. DADs and arrhythmias	None	Davis et al. (2012) [128] and Fatima et al. (2013) [129]
Timothy syndrome	EBs	Slower (30 bpm) and more irregular contraction rates. ↓Voltage-dependent inactivation of the L-type Ca2+ channel current. Longer APs (only in ventricular-like CMs). Presence of DADs. Larger and prolonged Ca2+ elevations	Pharmacological ↑ of voltage-dependent inactivation (↓irregular timing and amplitude of Ca2+ transients, and AP duration)	Yazawa et al. (2011) [130]
Catecholaminergic polymorphic ventricular tachycardia	iPSC coculture with END-2 cells	↑Ca2+ amplitudes and longer durations of spontaneous Ca2+ release events (persisted after repolarisation). DADs and arrhythmias	Catecholaminergic stimulation (↑diastolic [Ca2+], ↓SR Ca2+ content, DADs, and arrhythmias). ↑Cytosolic cAMP levels (prevented Ca2+ induced Ca2+ release events). Pharmacological stabilisation of the closed state of RyR channels (normalised Ca2+ spark properties)	Fatima et al. (2011) [131] and Jung et al. (2012) [132]
LEOPARD syndrome	EBs	↑Median CM surface area. ↑Sarcomere assembly. ↑NFATc4 nuclear translocation. ↑Phosphorylation of EGFR and MEK1 (in iPSCs)	None	Carvajal-Vergara et al. (2010) [133]
Hypoplastic left heart syndrome	Directed differentiation method	Less organised sarcomeres. ↓Cardiac progenitor marker Mesp1. Retarded but persistent GATA4 expression. ↑MYH6 (fast isoform). ↓cTnT and Cx43 expression. ↑Atrial natriuretic peptide. ↓Numbers and beating rates of contractile areas. Accelerated rate of Ca2+ transient decay. RyR and SR dysfunction. ↑Inositol trisphosphate receptor	Beta-adrenergic receptor agonism (lower increases in beat frequency)	Jiang et al. (2014) [134]
Duchenne muscular dystrophy	EBs [135]. Directed differentiation method [136, 137]. Staged: days 1–16 EBs + directed differentiation, days 20–24 maturation on hydrogel substrate with a physiological stiffness [138]	↓Dystrophin expression. Abnormal Ca2+ handling. ↓Numbers of spontaneously contracting embryoid bodies and cTnT-positive CMs. ↑Apoptotic markers: Ca2+ overload, mitochondrial damage, caspase-3 activation, and cell death	Beta-adrenergic receptor agonism (↑beating rates). Antisense oligonucleotides exon skipping (exon skipping and dystrophin expression). Minidystrophin gene construct (restored dystrophin expression). Human artificial chromosome carrying the whole dystrophin genomic locus (restored dystrophin expression including multiple isoforms and correct subcellular localisation). Oxidative stress (earlier mitochondrial permeability pore opening). Hypotonic stress (↑susceptibility). Membrane sealing (↓apoptotic markers)	Dick et al. (in press) [136], Guan et al. (2014) [138], Zatti et al. (2014) [137], and Lin et al. (2015) [139]

^∗Or in other cell types where specified.

^#Desmosomal widening correlated with lipid droplet accumulation.