Table 8.
Murine genetic models of structural disorders associated with ventricular or atrial arrhythmia
| Gene Product | Model | Features | Reference Nos. |
|---|---|---|---|
| Fibrotic change | |||
| TGF-β1 | Cardiac-specific TGF-β1 overexpression (MHC-TGFcys33 ser) | Atrial fibrosis and AF inducibility | 1193 |
| TNF-α | Cardiac-specific TNF-α overexpression | Atrial dilation, fibrosis, thrombosis, spontaneous AF in ambulant mice | 598, 974 |
| Angiotensin I converting enzyme (ACE) | ACE 8/8 | Atrial dilatation, fibrosis, and spontaneous AF in ambulant mice | 1280 |
| Cardiac-specific overexpression of ACE | |||
| Adenosine (A1 or A3) receptors | Cardiac-specific A3AR overexpression of at high (A3high) or low (A3low) adenosine levels | Bradycardiomyopathy | 300 |
| Ras homolog gene family member A (RHOA) | Cardiac-specific (αMhc promoter) overexpression of WT or activated form of RHOA | Atrial enlargement, cellular hypertrophy, interstitial fibrosis, AF susceptibility, atrioventricular block, premature death | 991 |
| Mitogen-activated protein kinase kinase 4 (Mkk4), | Atrial cardiomyocyte-specific conditional knock-out Mkk4-acko-Nppa-Cre4 | AF, atrial fibrosis, upregulated TGF-β1 signaling and dysregulation of matrix metalloproteinases | 245 |
| Hypertrophic cardiomyopathy (HCM) | |||
| α-Myosin heavy chain (Myh6) | Mhc-R403Q/+ | QT dispersion, conduction heterogeneity, inducible VT, sudden death, variable degree of hypertrophy | 112, 347, 1266 |
| Myosin binding protein C (Mybp-C3) | MyBP-C-t/+ and MyBP-C-t/t; (t = truncated Mybp-C3) | Hypertrophy, fibrosis, ventricular ectopic activity | 113 |
| Troponin T (Tnnt2) | Severity: Tnnt2-I79N >TnnT-F110I>TnnT-R278C | Altered Ca2+ sensitivity, spontaneous VT, reduced IK1 | 83, 580, 583 |
| Myosin light chain (coded by Mlc17) | Mlc-17-M149V | Hypertrophy | 1185 |
| Ras (HRAS) | Targeted, chronic Ras-Raf–MAPK pathway activation and αMHC-loxp-GFP-loxp-H-RasV12 | Hypertrophy, ventricular arrhythmia, atrial fibrillation, conduction block | 969, 1346 |
| Dilated cardiomyopathy (DCM): sarcomeric protein mutations | |||
| α-Myosin heavy chain (Myh6) | Mhc-F764L/+, Mhc-S532P/+, Mhc-F764L/F764L and Mhc-S532P/S532P) | Dilatation | 1018 |
| Mammalian-enabled protein and vasodilator-stimulated phosphoprotein (Vasp) | Cardiac myocyte-restricted, α-myosin heavy chain promoter-directed expression of the dominant-negative VASP-EVH1 domain | Dilatation, hypertrophy, bradycardia, sudden death | 293 |
| Neuron-restrictive silencer factor (Nsrf) | α-MHC-dnNRSF (dominant-negative knock-in) | Dilatation, heart block, sudden death | 608 |
| Dilated cardiomyopathy (DCM): cytoskeletal protein mutations | |||
| Lamin (coded by LMNA) | LMNA+/− | AV nodal disease, atrial arrhythmia, VT | 1267 |
| Lmna-N195K | Dilatation, fibrosis bradycardia, SA node exit block | 807 | |
| Lmna-H222P/H222P | Models Emery-Dreifuss syndrome; dilatation, increased PR interval, variable conduction block, QRS prolongation, ventricular extrasystoles | 45 | |
| Dilated cardiomyopathy (DCM): SR Ca2+-cycling protein mutation | |||
| Phospholamban (Pln) | Pln-R14Del | Dilation, fibrosis, VT sudden death | 397 |
| Pln-R9C/R9C | Reduced protein kinase A activity, delayed SERCA-Ca2+ reuptake, dilated cardiomyopathy, congestive heart failure | 1019 | |
| Dilated cardiomyopathy (DCM): developmental gene mutations | |||
| Cardiac homeobox gene product (Nkx-2.5) | Ventricle-restricted deficiency: Nkx2-5-f/f/cre+ | Hypertrabeculation, noncompaction, conduction disturbance | 871 |
| Vinculin (VCL) | Cardiac-restricted Vclfl/fl MLC-2vCre/+ knockout | Dilatation, VT, sudden death | 1324 |
| Troponin I (TNNI3) | cTnI-R192H | Atrial dilatation, decreased LV volume, decreased EF, delayed relaxation | 278, 279 |
| Arrhythmogenic right ventricular dysplasia (ARVD): desmosomal protein gene mutations | |||
| Plakophilin-2 (Pkp2) | Pkp2−/− | Lethal | 376 |
| Pkp2+/− | Normal cardiac phenotype | 376 | |
| Plakoglobin (Pg) | Pg−/− | Lethal | 647 |
| Cardiac specific Pgf/f-αMHCcre | RV enlargement, fibrosis, slowed RV conduction, spontaneous VT of right ventricular origin. Phenotype exacerbated by training | 571, 647, 973 | |
| Desmoplakin (Dsp) | Dsp−/− | Embryonic lethal | 339, 475 |
| Dsp+/− | Slowed conduction and inducible VT prior to adult structural changes | 366 | |
| Cardiac overexpression of flag-tagged Dsp cDNA carrying Dsp-R2834H-Tg COOH-terminal mutation | Apoptosis, fibrosis, RV and LV dilatation, reduced ventricular function, widened intercalated disks | 1296 | |
| Cardiac specific Dsp-f/f- (MLC2v-Cre) | Cardiomyopathic changes, ventricular arrhythmias accentuated by exercise and catecholaminergic challenge, slowed RV conduction | 706 | |
| Desmoglein (Dsg2) | Cardiac overexpression of flag-tagged dominant Dsg2-N271S mutant (homologous with human DSG2–N266S ARVC mutation) | Myocyte necrosis, calcification and fibrous tissue replacement, spontaneous ventricular arrhythmias, conduction slowing, ventricular dilatation and aneurysms, replacement fibrosis and SCD | 896 |
| Arrhythmogenic right ventricular dysplasia (ARVD): laminin receptor mutations | |||
| Laminin receptor 1 (Lamr1) | KK/Rvd (knock-down) | Right ventricular fibrosis, QRS prolongation | 48 |
| Left ventricular noncompaction cardiomyopathy (LVNC) | |||
| Cypher/Zasp | Mutations in Cypher/Zasp | LVNC with DCM and HCM phenotype, early postnatal death | 1345, 1350 |