rotigaptide and Tachycardia--Ventricular

Existing anti-arrhythmic therapy is hampered by lack of efficacy and unacceptable side effects. Thus, ventricular tachycardia and fibrillation remains the strongest predictor of in-hospital mortality in patients with myocardial infarction. In atrial fibrillation, rhythm control with conventional ion channel blockers provide no therapeutic benefit relative to rate control. Several lines of research indicate that impaired gap junctional cell-to-cell coupling between neighbouring cardiomyocytes is critical for the development of cardiac re-entry arrhythmias. Rotigaptide is the first drug that has been developed to prevent arrhythmias by re-establishing gap junctional intercellular communication. During conditions with acute cardiac ischaemia, rotigaptide effectively prevents induction of both ventricular and atrial tachyarrhythmia. Moreover, rotigaptide effectively prevents ischaemia reperfusion arrhythmias. At the cellular level, rotigaptide inhibits ischaemia-induced dephosphorylation of Ser297 and Ser368, which is considered important for the gating of connexin43 gap junction channels. No drug-related toxicity has been demonstrated at plasma concentrations 77,000 times above therapeutic concentrations. In rats and dogs, rotigaptide reduces infarct size following myocardial infarction. A series of phase I trials has been completed in which rotigaptide has been administered intravenously to ~200 healthy persons. No drug-related side effects have been demonstrated in healthy human beings. Clinical safety, tolerability and efficacy in patients with heart disease are being evaluated in ongoing clinical trials. Rotigaptide represents a pioneering pharmacological principle with a highly favourable preclinical and clinical safety profile, which makes this molecule a promising drug candidate for the prevention of cardiac arrhythmias.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Gap Junctions; Humans; Oligopeptides; Tachycardia, Ventricular

Spiral-wave (SW) reentry is a major organizing principle of ventricular tachycardia/fibrillation (VT/VF). We tested a hypothesis that pharmacological modification of gap junction (GJ) conductance affects the stability of SW reentry in a two-dimensional (2D) epicardial ventricular muscle layer prepared by endocardial cryoablation of Langendorff-perfused rabbit hearts. Action potential signals were recorded and analyzed by high-resolution optical mapping. Carbenoxolone (CBX; 30 μM) and rotigaptide (RG, 0.1 μM) were used to inhibit and enhance GJ coupling, respectively. CBX decreased the space constant (λ) by 36%, whereas RG increased it by 22-24% (n = 5; P < 0.01). During centrifugal propagation, there was a linear relationship between the wavefront curvature (κ) and local conduction velocity (LCV): LCV = LCV(0) - D·κ (D, diffusion coefficient; LCV(0), LCV at κ = 0). CBX decreased LCV(0) and D by 27 ± 3 and 57 ± 3%, respectively (n = 5; P < 0.01). RG increased LCV(0) and D by 18 ± 3 and 54 ± 5%, respectively (n = 5, P < 0.01). The regression lines with and without RG crossed, resulting in a paradoxical decrease of LCV with RG at κ > ~60 cm(-1). SW reentry induced after CBX was stable, and the incidence of sustained VTs (>30 s) increased from 38 ± 4 to 85 ± 4% after CBX (n = 18; P < 0.01). SW reentry induced after RG was characterized by decremental conduction near the rotation center, prominent drift and self-termination by collision with the anatomical boundaries, and the incidence of sustained VTs decreased from 40 ± 5 to 17 ± 6% after RG (n = 13; P < 0.05). These results suggest that decreased intercellular coupling stabilizes SW reentry in 2D cardiac muscle, whereas increased coupling facilitates its early self-termination.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Carbenoxolone; Cell Communication; Disease Models, Animal; Electrophysiologic Techniques, Cardiac; Gap Junctions; Heart Conduction System; Oligopeptides; Perfusion; Rabbits; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation; Voltage-Sensitive Dye Imaging

The border zone of healing myocardial infarcts is an arrhythmogenic substrate, partly the result of structural and functional remodeling of the ventricular gap junction protein, Connexin43 (Cx43). Cx43 in arrhythmogenic substrates is a potential target for antiarrhythmic therapy.. We characterized Cx43 remodeling in the epicardial border zone (EBZ) of healing canine infarcts 5 days after coronary occlusion and examined whether the gap junction-specific agent rotigaptide could reverse it. Cx43 remodeling in the EBZ was characterized by a decrease in Cx43 protein, lateralization, and increased Cx43 phosphorylation at serine (S) 368. Rotigaptide partially reversed the loss of Cx43 but did not affect the increase in S368 phosphorylation, nor did it reverse Cx43 lateralization. Rotigaptide did not prevent conduction slowing in the EBZ, nor did it decrease the induction of sustained ventricular tachycardia by programmed stimulation, although it did decrease the EBZ effective refractory period.. We conclude that partial reversal of Cx43 remodeling in healing infarct border zone may not be sufficient to restore normal conduction or prevent arrhythmias.

Topics: Animals; Disease Models, Animal; Dogs; Electrophysiological Phenomena; Gap Junctions; Heart Conduction System; Myocardial Infarction; Oligopeptides; Pericardium; Recovery of Function; Tachycardia, Ventricular

Altered conduction is associated with increased atrial fibrillation (AF) vulnerability in canine models of chronic mitral regurgitation (MR) and heart failure (HF). Rotigaptide (ZP123) augments gap junction conductance, improving cell-to-cell coupling. We studied the effects of rotigaptide on atrial conduction and AF vulnerability in the canine MR and HF models.. Twenty-one dogs in 3 groups were studied: control (n=7), chronic MR induced by mitral avulsion (n=7), and HF induced by ventricular tachypacing (n=7). Epicardial mapping of both atria was performed with a 512-electrode array at baseline and at increasing rotigaptide doses (10, 50, and 200 nmol/L). Conduction velocity increased in both atria in control animals and MR animals (maximum percentage increase: 24+/-5%, 38+/-6% [P<0.001, <0.001] in the left atrium and 19+/-9%, 18+/-3% [P<0.001, <0.001] in the right atrium). Conduction velocity did not change in the left atrium of the HF group and increased minimally in the right atrium (3+/-3%, 17+/-5% [P=NS, P=0.001]). AF duration was increased at baseline in MR and HF animals (control: 16+/-25 seconds, MR: 786+/-764 seconds, HF: 883+/-684 seconds; P=0.013). At 50 nmol/L of rotigaptide, duration of AF markedly decreased in the MR animals (96% reduction, P<0.001), reducing AF duration to that of control animals (control: 9+/-11 seconds, MR: 14+/-16 seconds, HF: 1622+/-355 seconds; P=0.04).. Gap junction modulation with rotigaptide reduces AF vulnerability in a canine MR model of AF to a level similar to control animals but does not affect AF vulnerability in the canine HF model. This may be a novel therapeutic target in some forms of AF.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Disease Models, Animal; Disease Susceptibility; Dogs; Gap Junctions; Heart Atria; Heart Conduction System; Oligopeptides; Tachycardia, Ventricular

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in alpha-chloralose-anesthetized, open-chest dogs 1-4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 +/- 0.1 nM, 77 vs. 75%; 7.8 +/- 0.4 nM, 86 vs. 77%; and 78.8 +/- 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

Topics: Animals; Cell Communication; Dogs; Female; Gap Junctions; Heart; Male; Myocardial Ischemia; Oligopeptides; Tachycardia, Ventricular

The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion.. Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by 69% +/- 20% in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in alpha-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline: 1.0 +/- 0.2 nM: 6/12 vs 0/12; 7.7 +/- 0.6 nM: 7/13 vs 1/12; and 69.2 +/- 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size.. The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.

Topics: Animals; Blood Pressure; Cell Membrane; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Female; Gap Junctions; Heart Block; Heart Conduction System; Incidence; Infusions, Intravenous; Male; Models, Cardiovascular; Myocardial Ischemia; Myocytes, Cardiac; Oligopeptides; Reproducibility of Results; Statistics as Topic; Tachycardia, Ventricular