Table 1. Animal models of genetic arrhythmia channelopathies.
Models are separated by disease, listing the animal species, orthologous human gene and protein, mutation, notable arrhythmia phenotypes/findings, and reference. Abbreviations: wild type (WT), double knockout (DKO), knockout (KO), homozygous (hom), heterozygous (het), heart rate (HR), monomorphic/polymorphic ventricular tachycardia (MVT, PVT, VT), nonsustained ventricular tachycardia (NSVT), supraventricular tachycardia (SVT), premature ventricular complexes (PVCs), isoproterenol (iso), caffeine (caff), ventricular fibrillation (VF, VF), atrial fibrillation (AF), programmed electrical stimulation (PES), loss of function (LoF), gain of function (GoF), dominant negative (DN), action potential duration (APD), early afterdepolarization (EAD), delayed afterdepolarization (DAD), atrioventricular (AV), action potential duration (AP, APD), ischemia-reperfusion (IR), heart failure (HF), right bundle branch block (RBBB).
| Disease, Type, Animal | Human Ortholog Gene (Protein) | Mutation | Notes | Ref. |
|---|---|---|---|---|
| Catecholaminergic polymorphic ventricular tachycardia (CPVT) | ||||
| CPVT1 | ||||
| Mouse | RYR2 (RyR2) | R4496C+/− | Catecholamine/exercise-induced arrhythmia; phenotype not as penetrant as some other models | 31 |
| Mouse | RYR2 (RyR2) | V2475F+/− | Homs are embryonic lethal, catecholamine-induced arrhythmia | 343 |
| Mouse | RYR2 (RyR2) | R2474S+/− | Seizures, exercise-induced arrhythmia, sudden death | 344 |
| Mouse | RYR2 (RyR2) | P2328S+/− | Iso-induced PVCs, VT, VF | 345 |
| Mouse | RYR2 (RyR2) | R2474S/V3599K | GoF + LoF; protective- no arrhythmia | 346 |
| Mouse | RYR2 (RyR2) | R4496C+/− with E4872Q+/− | GoF + LoF; protective- no arrhythmia | 32 |
| Mouse | RYR2 (RyR2) | L433P+/−, N2386I+/− | Mutations from patients with CPVT; no report of CPVT in mouse models; mice also develop AF with pacing protocol | 347 |
| Mouse | RYR2 (RyR2) | R176Q+/− | CPVT-like phenotype; AF | 348 |
| Mouse | RYR2 (RyR2) | exon3del+/− | Homs embryonic lethal, hets did not develop CPVT; patients with exon3del have exercise-induced VT | 33 |
| C. elegans |
RYR2 (RyR2), CASQ2 (Casq2) |
R4743C, Casq2 KO |
Enables optogenetic pacing, observed defect with mutations | 349 |
| CPVT2 | ||||
| Mouse | CASQ2 (Casq2) | KO | Severe CPVT, ultrastructure changes, catecholamine/exercise-induced arrhythmia | 38 |
| Mouse | CASQ2 (Casq2) | D307H/D307H, D309deltaE9/D309deltaE9 (Casq2−/−) | Both mutations result in loss of Casq2 protein, catecholamine/exercise-induced arrhythmia | 350 |
| Mouse | CASQ2 (Casq2) | ventricular/Purkinje KO | Subtissue-selective knockout | 351 |
| Mouse | CASQ2 (Casq2) | ventricular/Purkinje KO | Subtissue-selective knockout | 352 |
| Mouse | CASQ2 (Casq2) | R33Q/R33Q | Reduction of Casq2 protein, ultrastructure changes, arrhythmia | 353 |
| Mouse | CASQ2 (Casq2) | K180R+/− | Autosomal dominant inheritance; iso-induced arrhythmias | 354 |
| CPVT4 | ||||
| Zebrafish | CALM (CaM) | N53I and N97S | Increased iso-induced HR (indicated dominant negative effect) | 355 |
| Zebrafish | CALM (CaM) | E105A | Arrhythmias, tachycardia, altered RyR2 binding | 356 |
| CPVT5 | ||||
| Mouse | TRDN (Triadin) | KO | Ultrastructure changes; iso-induced arrhythmias; overlap syndrome with LQT? | 36 |
| CPVT? | ||||
| Mouse | KCNJ2 (Kir2.1) | R67Q+/−, cardiac-specific | Structurally normal heart, iso-induced VT, no LQT | 357 |
| Calcium release deficiency syndrome (CRDS) | ||||
| Mouse | RYR2 (RyR2) | A4860G+/− | VF with sympathetic stimulation, homs embryonic lethal | 45 |
| Mouse | RYR2 (RyR2) | D4646A+/− | RyR2 Ca2+ release deficiency syndrome (CRDS); homs are embryonic lethal | 44 |
| Long QT syndrome (LQTS) | ||||
| LQT1 | ||||
| Mouse | KCNQ1 (Kv7.1) | KO | Deaf, shaker/waltzer phenotype; LQT | 53 |
| Mouse | KCNQ1 (Kv7.1) | truncated isoform, cardiac-specific overexpression | LQT, sinus node dysfunction, occasional AV block | 358 |
| Mouse | KCNQ1 (Kv7.1) | A340V−/− | Homs have LQT, hets do with gene dose dependence; PVCs after feeding (linked to diabetes) | 359 |
| Rabbit | KCNQ1 (Kv7.1) | Y315S cardiac-specific overexpression | LQT; sympathetic stimulation induces EADs and VT; rabbits die within 3 weeks of AV node ablation; | 54 |
| LQT2 | ||||
| Rabbit | KCNH2 (Kv11.1/hERG) | G628S cardiac-specific overexpression | LQT, spontaneous PVT, sudden death; prolonged APD | 54 |
| Zebrafish | KCNH2 (Kv11.1/hERG) | I462R, M521K | 2:1 block (phenotype) | 360 |
| Zebrafish | KCNH2 (Kv11.1/hERG) | I59S−/− | 2:1 block (phenotype); prolonged APD; EADs | 361 |
| Zebrafish | KCNH2 (Kv11.1/hERG) | Morpholino KD of WT + expression of hERG +/− mutants | Tested 40 pathogenic and 10 non-pathogenic hERG mutants in the zERG background | 55 |
| LQT3 | ||||
| Mouse | SCN5A (Nav1.5) | ΔKPQ/+ | 1505–1507 deletion; prolonged QT/QTc; prominent T wave; prolonged APD; arrhythmias; sudden death | 57 |
| Mouse | SCN5A (Nav1.5) | ΔQKP/+ | 1507–1509 deletion; long QTc, wide QRS, AV block; spontaneous PVCs, VT, and VF with sudden death; no atrial arrhythmias | 56 |
| Mouse | SCN5A (Nav1.5) | N1325S cardiac-specific overexpression | LQT; arrhythmia; sudden death; also other non-LQT3 features like shorter PR and elevated heart rate | 362 |
| Mouse | SCN5A (Nav1.5) | 1795insD | LQT and Brugada in family; homs embryonic lethal; sinus node dysfunction, conduction slowing, bradycardia, and LQT | 76 |
| Guinea Pig | SCN5A (Nav1.5) | cellular model, isolated cells tx | Isolated cardiomyocytes treated with anthopleurin; rescued by mexillitine | 58 |
| Minor Types | ||||
| Mouse | ANK2 (Ankyrin-B) | KO | LQT with HR deceleration, sinus node dysfunction | 62 |
| Mouse | ANK2 (Ankyrin-B) | +/− | Bradycardia, variable HR, slow conduction, AV dissociation, long QTc; iso/exercise-induced PVT & death | 63 |
| Mouse | KCNA1 (Kv1.1) | N-term fragment overexpression | Long QTc; spontaneous PVC, couplets, ventricular tachycardia | 67 |
| Mouse | KCNA5 (Kv1.5) | W461F cardiac-specific overexpression | Long QTc | 363 |
| Mouse | KCNB1 (Kv2.1) | N216 cardiac-specific overexpression | Long QTc | 364 |
| Mouse | KCND2 (Kv4.2) | W362F cardiac-specific overexpression | Subtle bradycardia, prolonged QTc | 365 |
| Mouse | KCND2 x KCNA4 | W362F x KO | QRS widening, prolonged QTc, AV block/dropped beats, spontaneous ventricular arrhythmia | 366 |
| Rabbit | KCNE1 (minK) | G52R dominant negative overexpression | Long QTc; drug-induced arrhythmia (Torsades) | 65 |
| Mouse | KCNE1 (minK) | KO | LQT with HR deceleration | 64 |
| Mouse | KCNE2 (MiRP1) | KO | Long QTc with age, mice had hyperkalemia | 367 |
| Mouse | KCNE3 (MiRP2) | KO | Females have long QTc at 9 months (hyperaldosteronism); increased susceptibility to IR arrhythmias | 69 |
| Mouse | KCNJ2 (Kir2.1) | KO | Bradycardia, LQT | 60 |
| Mouse | KCNJ2 (Kir2.1) | T75R cardiac-specific overexpression | Long QTc; spontaneous VT; iso-induced PVCs, VT, atrial flutter/fibrillation | 61 |
| Mouse | KCNIP2 (KChIP2) | KO | Significant reduction in Ito; elevated ST segment, atrial flutter and VT with PES; prolonged APD in cells | 368 |
| Mouse | CACNA1C (Cav1.2) | −/−, +/− | KO embryonic lethal, hets survive and are just like WT | 369 |
| Mouse | CACNA1C (Cav1.2) | G406R cardiac-specific overexpression | Long QTc, exercise-induced PVCs and Torsades; crossing with AKAP150 KO protected against all phenotypes of the G406R mutant | 66 |
| Zebrafish | CALM (CaM) | D129G | Bradycardia; conduction abnormality; LQT | 370 |
| Mouse | SCN1B (Scn β1) | KO | Bradycardia, prolonged APD/QTc, slowed repolarization; sodium channel expression increased | 59 |
| Mouse | SLC18A2 (VMAT2) | +/− | LQT | 371 |
| Mouse | ATP1A3 (NaK ATPase α3) | human isoform overexpression | LQT, steeper QT rate dependence, T wave alternans, VT | 372 |
| Short QT syndrome (SQTS) | ||||
| SQTS1 | ||||
| Rabbit | KCNH2 (Kv11.1/hERG) | N588K cardiac-specific overexpression | Shortened APs and QTc, normal T wave height, ex vivo perfused hearts inducible VT/VF | 73 |
| Zebrafish | KCNH2 (Kv11.1/hERG) | L499P | SQT | 71 |
| SQTS8 | ||||
| Zebrafish | SLC4A3 (AE3) | Knockdown | SQT and systolic duration; WT SLC4A3 expression rescued phenotype, but R370H did not | 72 |
| Mouse | SLC8A1 (NCX) | KO | SQT | 373 |
| Mouse | CAV3 (Caveolin 3) | WT cardiac-specific overexpression | Short QTc, bradycardia, prolonged PR | 374 |
| Kangaroo | Unknown | None Reported | Kangaroos have LV hypertrophy, SQT, and are highly susceptible to VF and sudden death, especially under light anesthesia | 375 |
| Brugada Syndrome (BrS) | ||||
| Pig | SCN5A (Nav1.5) | E558X+/− | Conduction abnormalities, QRS widening, reduced conduction velocity, ex vivo hearts have increased susceptibility to VF | 375 |
| Mouse | SCN5A (Nav1.5) | +/− | KO is embryonic lethal; hets have sick sinus, slowed conduction, pacing-induced VT; QTS widening & fibrosis with age | 74 |
| Mouse | SCN5A (Nav1.5) | 1795insD | LQT and BrS in family; hom mice embryonic lethal; sinus node dysfunction, conduction slowing, bradycardia, and LQT | 76 |
| Mouse | SCN5A (Nav1.5) | ΔSIV/+ | C-term truncation; SA, AV, and His conduction slowing; one human patient with V2016M diagnosed with Brugada | 376 |