Monique M.J. de Jong

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias.

BACKGROUND Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. METHODS Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. RESULTS The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up. CONCLUSIONS Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Reduced ventricular proarrhythmic potential of the novel combined ion-channel blocker AZD1305 versus dofetilide in dogs with remodeled hearts.

Background— AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results— AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective IKr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290±7 to 397±15 ms (+37%, P<0.0001) and from 603±22 to 778±32 ms (+29%, P=0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535±28 to 747±36 ms (+40%, P<0.0001), similar to the QT prolongation by dofetilide (511±22 to 703±45 ms [+38%, P<0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3±0.2 to 6.3±0.7 ms; P<0.0001) but not after AZD1305 (2.8±0.3 to 3.7±0.3 ms; P=0.20) despite similar left-ventricular monophasic-action-potential duration prolongations. Conclusions— Despite causing similar degrees of repolarization delay as the selective IKr blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart.

Short intra-aortic balloon pump in a swine model of myocardial ischaemia: a proof-of-concept study

OBJECTIVES This proof-of-concept study examined the haemodynamic performance as well as the coronary and visceral organ perfusion using a new short balloon for intra-aortic counterpulsation (IABP) in a swine model of myocardial ischaemia. METHODS Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned into 3 groups undergoing IABP implantation with a 35-ml short balloon (n = 6), a 40-ml short balloon (n = 6) or no IABP implantation (controls, n = 6). Haemodynamics, and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively. RESULTS Mesenteric and renal flows increased significantly at tR1 only in the IABP groups (all, P < 0.001) and were significantly higher than controls throughout the reperfusion periods (P < 0.001). Coronary systolic and diastolic blood flows increased only at tR1 in the IABP groups (all, P < 0.001) but were higher than controls at tR1-tR6. The IABP was associated with enhanced haemodynamics compared with controls. No difference was detected using different balloon volumes (all, P > 0.05). CONCLUSIONS The new short balloon significantly increased visceral flow, enhanced haemodynamics and improved coronary circulation during reperfusion following myocardial ischaemia in our experimental model.

In-vivo evaluation of reduced-lead-systems in noninvasive reconstruction and localization of cardiac electrical activity

Noninvasive imaging of electrical activity of the heart has increasingly gained attention last decades. Heart-surface potentials are reconstructed from a torso-heart geometry and body-surface potentials recorded from tens to hundreds of body-surface electrodes. However, it remains an open question how many electrodes are needed to accurately reconstruct heart-surface potentials. In a canine model, we reconstructed epicardial electrograms and activation locations, investigating the use of a full-lead system, consisting of 169 well connected body-surface electrodes, and reduced-lead systems: using half or a third of the electrodes, or a minimalistic set of the default 12-lead ECG. Correlation coefficients indicate that the quality of the reconstructed electrograms remains stable to a third of the electrodes, and decreases with fewer electrodes. Similarly, the mismatch between the detected origin of a beat and known pacing location decreases when fewer body-surface electrodes are used. However, when only 9 or 10 electrodes are available for pacing localization, the median mismatch is 30mm, only marginally higher than when half of the electrodes are used, although with a significant error spread up to 65mm. These results indicate that for specific purposes (such as detecting the origin of an extrasystolic beat), a lower number of body-surface electrodes can provide noninvasive electrocardiographic imaging results that might still be useful for a clinical purpose.

Comparing short versus standard-length balloon for intra-aortic counterpulsation: results from a porcine model of myocardial ischaemia–reperfusion

OBJECTIVES We compare a short and a standard-size balloon with same filling volumes to verify the differences in terms of visceral flow, coronary circulation and haemodynamic performance during aortic counterpulsation in an animal model of myocardial ischaemia-reperfusion injury. METHODS Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned to have intra-aortic balloon counterpulsation (IABP) with a 40-ml short-balloon (n = 6) or a 40-ml standard-length balloon (n = 6), or to undergo no IABP implantation (controls, n = 6). Haemodynamics and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively. RESULTS Mesenteric flows increased significantly at tR1 only in the short-balloon group (P < 0.001) and it was constantly higher than in the standard-balloon group regardless of mean arterial pressure, systemic vascular resistance and cardiac output (CO; all, P < 0.001). Renal blood flows were significantly increased during IABP treatment with values constantly and significantly higher in short balloons at any following experimental step (all, P < 0.05). IABP improved CO and coronary blood flow, and reduced afterload, myocardial resistances and myocardial oxygen consumption without differences between the short and the standard-length balloon (all, P > 0.05). CONCLUSIONS The short balloon prevents visceral ischaemia and, compared with the standard-size balloon, it does not lose IABP beneficial cardiac and coronary-related effects. Further studies are warranted to confirm our findings.

Is visceral flow during intra-aortic balloon pumping size or volume dependent?

Aim: We evaluated the influence of intra-aortic balloon size and volume on mesenteric and renal flows. Methods: Thirty healthy swine underwent 120-minute ligation of the left anterior descending coronary artery followed by 6 hours of reperfusion. Then, they were randomly assigned to the following five groups of animals, with six animals in each group: no intra-aortic balloon pump (IABP), a short 35-mL IABP, a short 40-mL IABP, a long 35-mL IABP and a long 40-mL IABP. Superior mesenteric artery (SMA) and renal flows were measured at baseline (t0), at 2-hour ischemia (t1) and every hour thereafter until 6 hours of reperfusion (from tR1 to tR6). Results: SMA flows increased significantly at tR1 only in the two short IABP groups (p<0.001) and balloon volume did not appear to affect flows which, at any experimental time-point, were comparable using 35 mL or 40 mL balloons (p>0.05). Renal flows appeared to be influenced by balloon length, but not by volume. Indeed, flows in the renal arteries rose during IABP treatment; the increase was significantly higher in the short balloon groups and throughout the whole reperfusion (all, p<0.001). Conclusions: Changes in visceral perfusion during IABP assistance were significantly related to balloon length, but not to its volume. This could be relevant for the evolution of balloon engineering design in order to reduce the incidence of mesenteric ischemia following IABP. Further research is necessary to confirm these findings.