Introduction
Impulse propagation
Impulse generation and contraction
Ions → action potential duration (APD)
Excitation-contraction coupling
Arrhythmias: abnormal excitation
Triggered arrhythmias
DADs
EADs
Old strategies
New targets for antiarrhythmic treatment
Acute modulation of antiarrhythmic targets
NCX
NCX inhibition
Target | Action | Model | Dose | Block | Author |
INCX
| Inhibition | Ventricular myocytes (guinea pig) | 1 μM | Forward 82.5 % Reverse: 86.2 % | Tanaka et al. 2002 [25] |
INCX
| Inhibition | CAVB myocytes | 1 μM | Forward 50 % Reverse 66 % | Bourgonje et al. 2013 [27] |
INCX
| Inhibition | Ventricular myocytes (pig, mouse) | 0.3–1 μM | Forward 50 % Reverse 70 % | Ozdemir et al. 2008 [28] |
INCX
| Inhibition | Ventricular myocytes (dogs) | 1 μM | Forward 60 % Reverse 80 % | Birinyi et al. 2005 [29] |
ICa,L
| Inhibition | Cardiac tissue (dogs) | 1 μM | 3 % | Nagy et al. 2004 [30] |
ICa,L
| Inhibition | Ventricular myocytes (pig, mouse) | 0.3–1 μM | 25 % | Ozdemir et al. 2008 [28] |
ICa,L
| Inhibition | Ventricular myocytes (guinea pig) | 1 μM | 9 % | Tanaka et al. 2002 [25] |
ICa,L
| Inhibition | CAVB myocytes | 1 μM | 33 % | Bourgonje et al. 2013 [27] |
Model | Inhibitor | Inhibitor administration | Dose | Effect | Author |
In vivo animal model (CAVB dog) | SEA-0400 | After challenge | 0.4 and 0.8 mg/kg | 0.4 mg/kg decreased TdP episodes 7 ± 4 → 3 ± 4 0.8 abolished TdP incidence | Bourgonje et al. 2013 [27] |
Single rabbit ventricular myocytes | SEA-0400 | After challenge | 2 μM | Abolished EADs | Zhao et al. 2012 [18] |
Langendorff perfused rabbit hearts (dofetilide induced arrhythmias) | SEA-0400 | Prior to challenge | 1 μM | No effect on TdP incidence | Farkas et al. 2009 [31] |
Langendorff perfused rabbit hearts (sotalol/veratrinide induced arrhythmias) | SEA-0400 | After challenge | 1 μM | TdP incidence ↓ (16/18 → 1/18, sotolol, 6/13 →0/13 veratrinide) | Milberg et al. 2008 [32] |
Isolated guinea pig myocardium (Ouabain induced arrhythmias) | SEA-0400 | Co-administration | 1 μM | Arrhythmic contractions ↓ (19/26 → 12/26) | Tanaka et al. 2007 [33] |
In vivo animal model (dog ischaemia/reperfusion model and digitalis induced arrhythmias) | SEA-0400 | Prior and co-administration (I/R) and After challenge (Digitalis) | 0.3–3 mg/Kg | Did not change haemodynamics. No antiarrhythmic effect (I/R). Arrhythmic ratio ↓ (digitalis) | Nagasawa et al. 2005 [34] |
Isolated dog Purkinje fibres (dofetilide induced arrhythmias) | SEA-0400 | After challenge | 1 μM | EAD amplitude ↓ (26.6 ± 2.5 → 14.8 ± 1.8 mV) DAD incidence ↓ (6/6 → 3/6) | Nagy et al. 2004 [30] |
In vivo animal model, guinea pigs (aconitine induced arrhythmias) | SEA-0400 | Prior to challenge | 1–10 mg/Kg | Ineffective in suppressing triggered activity | Amran et al. 2004 [35] |
RyR
RyR inhibition
Target | Action | Model | Dose | Block | Author |
Ina
| Inhibition | Ventricular cardiomyocytes (guinea pig) | 1.2 μM | 50 % | Kimura et al. 1999 [44] |
IK1
| Inhibition | Ventricular cardiomyocytes (guinea pig) | 5 μM | 50 % | Kimura et al. 1999 [44] |
ICa
| Inhibition | Ventricular cardiomyocytes (guinea pig) | 3 μM | 50 % | Kimura et al. 1999 [44] |
ICa
| Inhibition | Ventricular cardiomyocytes (rabbit) | 3 μM | 34 % | Loughrey et al. 2007 [43] |
IKr
| Inhibition | Ventricular cardiomyocytes (guinea pig) | 1.2 μM | 50 % | Kiriyama et al. 2000 [45] |
IKr
| Inhibition | Atrial cardiomyocytes (guinea pig) | 1 μM | 50 % | Nakaya et al. 2000 [46] |
IK-ACH
| Inhibition | Atrial cardiomyocytes (guinea pig) | 0.12 μM | 50 % | Nakaya et al. 2000 [46] |
Model | Inhibitor | Inhibitor administration | Dose | Effect | Author |
In vivo rat isoproterenol or I/R induced | K201 | Prior to challenge | 1 mg/kg | Incidence of arrhythmia ↓ 9/10 →2/10 (isoproterenol) 14/14 → 7/15 (I/R) | Otani et al. 2013 [47] |
In vivo dog (CAVB dog) | K201 | Prior to and during challenge | 0.1 and 0.3 mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min iv | No significant anti-arrhythmic but pro-arrhythmic effects were observed | Stams et al. 2011 [48] |
RyRR4496C myocytes +/− ouabain | K201 | Acutely upon DAD incidence, and prior to challenge | 1 μmol/L | No effect on DADs under baseline conditions. But decreased incidence of spontaneous APs during ouabain challenge | Sedej et al. 2010 [49] |
Pulmonary cardiomyocytes, isoprenaline (rabbit) | K201 | Prior to challenge | 0.3 μM | Reduction in spontaneous activity | Chen et al. 2008 [50] |
In vivo rabbit methoxamine and clofilium induced | K201 | After challenge | 50, 200, 400 μg/kg/min | TdP incidence ↓ 6/6 → 4/6, 2/5, 0/6 (dose dependent) | Hasumi et al. 2007 [51] |
RyRR4496C myocytes + in vivo mouse (RyR 4496C+/−) | K201 | Prior to challenge | 1 μmol–10 μmol 18 mg/Kg per day | Failed to limit DADs or arrhythmias | Liu et al. 2006 [52] |
Mouse whole animal (FKBP12.6−/− en FKBP12.6+/−) | K201 | Prior to challenge | 0.5 mg/kg per hour | Prevention of arrhythmias and SCD in FKBP12.6+/− but not FKBP12.6−/− mice. | Wehrens et al. 2004 [42] |
In vivo dog pacing induced | K201 | Prior to challenge | 0.03 mg/kg/min | AF episodes ↓ 4.2 ± 2.9 → 0 ± 0 | Kumagai et al. 2003 [53] |
Isolated guinea pig heart | K201 | After challenge | 0.3 μM and 1 μM | Incidence AF ↓ 2/5 → 0/6 | Nakaya et al. 2000 [46] |
CaMKII
CaMKII inhibition
Target | Action | Model | Dose | Block | Author |
I
ca
| Inhibition | Rabbit cardiomyocytes | 1 μM | 41 % | Anderson et al. 1998 [62] |
I
K
| Inhibition | HEK cells overexpressing Kv1,5 | 3 μM | 50 % | Rezazadeh et al. 2006 [63] |
Model | Inhibitor | Inhibitor administration | Dose | Effect | Author |
In vivo animal model (mdx mice) | KN-93 | After challenge | 1 μM | VT incidence ↓ in presence of KN-93 (7/14 → 2/14) | Ather 2013 [64] |
CAVB dog (dofetilide induced) | W7 | After challenge | 18.87 mg/kg/5 min | Abolished almost all TdPs | Bourgonje et al. 2012 [36] |
Langendorff perfused rat heart (AngII induced arrhythmia) | KN-93 | Prior to challenge | 2 μM | VF incidence ↓ in presence of KN-93 (4/4 → 1/4) | Bapat et al. 2012 [65] |
Langendorff perfused rat heart | KN-93 | Prior to challenge | 2.5 μM | Incidence of premature beats ↓ (71.5 %) | Said et al. 2011 [66] |
Langendorff perfused rat heart (glycolytic inhibition induced arrhythmia) | KN-93 | Prior to and after challenge | 1 μM | Incidence of VT/VF ↓ (6/6 → 4/9) | Morita et al. 2011 [67] |
Whole animal (mouse RyR2-S2814D knock in and aortic banding) | KN-93 | Prior to challenge | 30 μmol/kg | Incidence of VT ↓ (6/12 → 0/12) | Lui et al. 2011 [68] |
Whole animal (heart failure mouse, iso induced arrhythmia) | KN-93 | Prior to challenge | 20 μmol/L/kg | Incidence of arrhythmias ↓ (5/6 → 0/4) | Sag et al. 2009 [69] |
Langendorff perfused rabbit heart | W7 | Co-administration with challenge | 20, 50, 100 μM | EAD incidence ↓ (9/9 → 1/9) TdP incidence ↓ (7/9 → 1/9) | Pu et al. 2005 [70] |
Langendorff perfused mouse heart | W7, KN-93 | After challenge | W7: 25 μM KN–93: 2 μM | W7: pVT incidence ↓ (7/11 → 1/11) KN93: pVT incidence ↓ (5/8 → 1/8) | Kirchhof et al. 2004 [71] |
In vivo animal model (methoxamine rabbit model) | W7 | Prior to challenge | 50 μM/kg | TdP incidence ↓ (12/14 → 1/11) | Gbadebo et al. 2002 [72] |
In vivo animal model (methoxamine rabbit model) | W7 | Prior to challenge | 25, 50 μM/kg | TdP incidence ↓ (6/8 → 1/7) | Mazur et al. 1999 [73] |
Langendorff perfused rabbit heart | KN-93 | Prior to challenge | 0.5 μM | EAD Incidence ↓ (8/8 → 4/10) | Anderson et al. 1998 [62] |
Late inward sodium current
Late INa inhibition
Target | Action | Model | Dose | Block | Author |
---|---|---|---|---|---|
Late I
Na
| Inhibition | Canine wedge preparations | 6 μmol/L | 50 % | Antzelevitch 2004 [76] |
Late I
Ca
| Inhibition | Canine wedge preparations | 2–6 μmol/L | 25–30 % | Antzelevitch 2004 [76] |
I
ks
| Inhibition | Canine wedge preparations | 30 μmol/L | 17 % | Antzelevitch 2004 [76] |
I
Na-Ca
| Inhibition | Canine wedge preparations | 50 μmol/L | 50 % | Antzelevitch 2004 [76] |
I
kr
| Inhibition | Canine wedge preparations | 12 μmol/L | 50 % | Antzelevitch 2004 [76] |
Model | Inhibitor | Inhibitor administration | Dose | Effect | Author |
---|---|---|---|---|---|
Langendorff perfused rat hearts (rapid pacing induced VF and oxidative stress induced VF) | Ranolazine | Prior to challenge | 10 μM | Pacing induced VF shortening >3 min → 12 ± 6 s Oxidative stress induced VF termination and suppression | Morita 2011 [77] |
Transgenic CaMKII mice papillary muscles | Ranolazine | After challenge | 5 μmol/L | Termination of premature arrhythmogenic contractions | Sossalla 2011 [78] |
CAVB dog, dofetilide induced | Ranolazine | After challenge | 4 mg/kg/0.5 min + 0.225 mg/kg/min | TdP episodes ↓ 10 → 3 | Antoons 2010 [79] |
In vivo animal model (rats I/R induced arrhythmias and ischemia induced arrhythmias) | Ranolazine | After challenge (I/R) Prior to challenge (I) | 10 mg/kg iv bolus (I/R) 2, 6, 10 μM (I and I/R) | Sustained VT incidence ↓ 9/12 vs. 1/11 (I/R) VF incidence ↓ 10/12, 8/12, 5/10, 4/12 (control, 2, 8, 10 μM Ranolazine resp.) | Dhalla 2009 [80] |
Clinical trial | Ranolazine | Prior to challenge | Reduced the incidence of VT vs placebo | Scirica 2007 [81] | |
Rabbit and guinea pig isolated ventricular myocytes H2O2 challenge | Ranolazine | After challenge | 10 μM | Suppression of APD prolongation and EAD formation | Song 2006 [82] |
Canine myocytes of normal and HF dogs | Ranolazine | After challenge | 5, 10, 20 μM | Shortening of APD and suppression of EADs | Undrovinas 2006 [83] |
Langendorff perfused guinea pig hearts. ATX-II induced arrhythmias | Ranolazine | Both | 5 μM | Ranolazine abolished ATX-II induced EADs/VTs and prevented ATX-II induced EADs/VTs in pretreated hearts | Wu 2004 [84] |
Langendorff perfused rat hearts I/R ATX-II challenge | Ranolazine | Prior to challenge | 4 μM, 9 μM in perfusate | Reduced Ca2+ overload and LV mechanical dysfunction | Fraser 2006 [85] |
Isolated canine wedge preparations, M cells and Purkinje fibres | Ranolazine | Prior to challenge | 1–100 μmol/L | Abolished TdP and EADs | Antzelevitch 2004 [76] |
Isolated guinea pig ventricular myocytes–ATX-II challenge | Ranolazine | After challenge | 0.1–30 μmol/L | Reduced ATX-II induced EADs | Song 2004 [86] |
Canine Purkinje fibres E-4031, ATX-II and high Ca+ isoproterenol induction | GS-967 | After challenge | 30 nM/100 nM | EAD and DAD incidence ↓ EAD 4/4 → 2/5 → 0/5 (E-4031) EAD 4/4 → 1/4 → 0/4 (ATX-II) DAD 4/4 → 2/4 → 0/5 (high Ca+ isoproterenol) | Sicouri et al. 2013 [87] |
Langendorff perfused rabbit heart ATX-II and E-4031 induction | GS-967 | After challenge | 100 and 600 nmol/L (ATX-II and E-4031 resp.) | Incidence of VT ↓ 6/11 → 0/11 (ATX-II) 5/5 → 0/5 (E-4031) | Belardinelli et al. 2013 [88] |
In vivo animal model (rabbits clofilium/methoxamine and ischaemia induced) | GS-967 | Prior to challenge | 60 μg/kg bolus + 16 μg/kg/min (clofilium) 15 μg/kg + 4 μg/kg/min (ischaemia) | Incidence VT ↓ 5/6 → 1/6 (clofilium) 5/10 → 2/8 (ischemia) | Belardinelli et al. 2013 [88] |
Langendorff perfused guinea pig heart isoprenaline induction | Sophocarpine | After challenge | 300 μmol/L | incidence VT ↓ 6/6 → 0/6 | Yang et al. 2011 [89] |