Cardiology Research and Practice

Review Article

Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Afford New Opportunities in Inherited Cardiovascular Disease Modeling

Table 6

Summary of published studies in cardiovascular disease with patient-specific iPSC.


Disease name	Cell type made	Phenotype displayed in iPSC-derived cells	Drug tested	References

Arrhythmogenic right ventricular cardiomyopathy/dysplasia	CMs	Reduced expression of plakophilin-2 and plakoglobin; evidence of myofibril disorganization; elevated lipid content relative to control CMs when they are exposed to adipogenic differentiation media	Nifedipine-inhibited contraction; isoproterenol increased contraction rate	[54]

Barth syndrome	CMs	Impaired cardiolipin biogenesis; ROS production was markedly increased and ATP levels were significantly lower; maximal electron transport chain activity was severely impaired in CMs	Linoleic acid improved sarcomere organization and increased twitch stress to nearly normal levels; mitoTEMPO treatment normalized sarcomere organization and contractility	[93]

Carnitine palmitoyltransferase II (CPT II) deficiency	Myocytes	CPT II-deficient myocytes accumulated more palmitoylcarnitine	Bezafibrate reduced the amount of palmitoylcarnitine	[94]

CPVT	CMs	Immature cardiomyocytes with less organized myofibrils and enlarged sarcoplasmic reticulum cisternae and reduced number of caveolae; DADs; oscillatory arrhythmic prepotentials; after-contractions and diastolic [Ca²⁺ rise	None	[39]

CPVT	CMs	Higher amplitudes and longer durations of spontaneous Ca²⁺ transients; Ca²⁺ release events after repolarization; abnormal Ca²⁺ response to phosphorylation induced by increased cAMP levels	None	[45]

CPVT	CMs	Elevated diastolic Ca²⁺ concentrations, a reduced sarcoplasmic reticulum Ca²⁺ content, and an increased susceptibility to arrhythmias	Dantrolene restored normal Ca²⁺ spark properties and rescued the arrhythmogenic phenotype	[46]

CPVT	CMs	Similar to above, but also evidence of early afterdepolarizations (EADs)	Flecainide and Thapsigargin blocked ads-beta blockers improved Ca²⁺ transient anomalies	[95]

CPVT	CMs	Aberrant Ca²⁺ cycling resulting in DAD and EAD	None	[47]

Familial dilated cardiomyopathy	CMs	Punctate sarcomeric α-actinin distribution; altered Ca²⁺ handling, decreased contractility	Norepinephrine markedly increased the number of CMs with punctate sarcomeric α-actinin distribution from DCM iPSC clones; metoprolol improved myofilament organization and significantly prevented aggravation of the DCM iPSC-CMs that is induced by norepinephrine treatment	[51]

LEOPARD syndrome	CMs	CMs are larger and have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus compared to normal CMs	None	[62]

LQT1	CMs	Longer and slower repolarization velocity; abnormal subcellular distribution of R190Q KCNQ1; reduction of outward K⁺ current	Isoproterenol induced EAD was prevented by propranolol, simulating clinical LQT1	[24]

LQT2	CMs	Prolongation of the action potential duration; reduction of potassium current ; EADs	Nifedipine: complete elimination of EADs; pinacidil: abolished EADs; ranolazine: pronounced anti-EAD effect at both cellular and multicellular level	[26]

LQT2	CMs	Same as above	Nicorandil and PD118057: action potential shortening and reduction of EADs; E4031: induced EADs; isoprenaline induced EADs and was blocked by nadolol and propranolol, simulating clinical treatment	[27]

LQT3	CMs	Dysfunction in Na⁺ channel gating, increase in , right-shifted steady-state channel availability, and faster recovery from inactivation	Mexiletine corrects Na⁺ channel inactivation	[30]

LQT3	CMs	Significantly prolonged APD and in patient-derived V-like hiPSC-CMs during the spontaneous contraction and during electrical pacing. Tetrodotoxin-sensitive late Na⁺current (dA/dF) was significantly larger in patient-derived hiPSC-CMs	Mexiletine reduced the late Na⁺ current, moderate effect of mexiletine in shortening the APD	[31]

LQT8 (Timothy syndrome)	CMs	Irregular contractions; excessive Ca²⁺ influx; prolonged action potentials; irregular electric activity; abnormal Ca²⁺ transients	Roscovitine normalized the Ca²⁺ defects and improved channel inactivation	[5]

Overlap syndrome of cardiac sodium channel disease	CMs	Significant decrease in density and upstroke velocity; a larger persistent leading to an increased persistent	None	[33]

Marfan type 1	Mesenchymal cells	Elevated TGF-β signaling; inhibited osteogenesis and spontaneous chondrogenesis	None	[96]

Pompe disease (infantile onset)	CMs	Glycogen accumulation; ultrastructurally abnormal mitochondria; accumulation of autophagosomes; carnitine deficiency	L-carnitine increased O₂ consumption and suppressed mitochondrial structural phenotype; treatment with rhGAA with autophagy inhibitor 3-MA normalized glycogen content	[97]

SAS	SMCs	Significantly lower level of ELN protein in SMCs and proliferate at a higher rate and migrate significantly faster in response to the chemotactic cytokine platelet-derived growth factor	Recombinant elastin or small GTPase RhoA rescues defective SM α-actin filament bundles	[69]