Patrick F.H. Lai

Role of KATP Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts

Rationale: Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF. Objective: We addressed the hypotheses that there is regional disease-related expression of KATP channels in human cardiomyopathic hearts and that KATP channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness. Methods and Results: In a human Langendorff model, electric mapping of 6 control and 9 treatment (10 &mgr;mol/L glibenclamide) isolated cardiomyopathic hearts was performed. Spontaneous defibrillation was studied and mean VF cycle length was compared regionally at VF onset and after 180 seconds between control and treatment groups. KATP subunit gene expression was compared between LV endocardium versus epicardium in myopathic hearts. Spontaneous VF termination occurred in 1 of 6 control hearts and 7 of 8 glibenclamide-treated hearts (P=0.026). After 180 seconds of ischemia, a transmural dispersion in VF cycle length was observed between epicardium and endocardium (P=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP subunit on the endocardium compared with the epicardium (P<0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (&Dgr;ERPTransmural=ERPEpicardium−ERPEndocardium) was verified with pacing protocols. &Dgr;ERPTransmural in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (&Dgr;ERPTransmural for glibenclamide+ischemia=4.9±4 ms, P=0.019 versus control ischemia). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Background— The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. Methods and Results— Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio–renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. Conclusions— RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.

Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF.

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrodes buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.

Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping

Background: Low-voltage–guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (Vpp) from variations in wavefront direction relative to electrode orientation and from fractionation and collision events. We aim to compare bipole Vpp with novel omnipolar peak-to-peak voltages (Vmax) in sinus rhythm (SR) and AF. Methods and Results: A high-density fixed multielectrode plaque was placed on the epicardial surface of the left atrium in dogs. Horizontal and vertical orientation bipolar EGMs, followed by omnipolar EGMs, were obtained and compared in both SR and AF. Bipole orientation has significant impact on bipolar EGM voltages obtained during SR and AF. In SR, vertical values were on average 66±119% larger than horizontal (P=0.004). In AF, vertical values were on average 31±96% larger than horizontal (P=0.07). Omnipole Vmax values were 99.9±125% larger than both horizontal (99.9±125%; P<0.001) and vertical (41±78%; P<0.0001) in SR and larger than both horizontal (76±109%; P<0.001) and vertical (52±70%; P value <0.0001) in AF. Vector field analysis of AF wavefronts demonstrates that omnipolar EGMs can account for collision and fractionation and record EGM voltages unaffected by these events. Conclusions: Omnipolar EGMs can extract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation, compared with contemporary bipolar techniques.

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Background— After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+ current to inactivate leads to intracellular Ca2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+ current, on ventricular refibrillation. Methods and Results— Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967–treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967–treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+ alternans (P=0.03). Conclusions— Late Na+ current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.

Analysis of reliability metrics and quality enhancement measures in current density imaging

Low frequency current density imaging (LFCDI) is a magnetic resonance imaging (MRI) technique which enables calculation of current pathways within the medium of study. The induced current produces a magnetic flux which presents itself in phase images obtained through MRI scanning. A class of LFCDI challenges arises from the subject rotation requirement, which calls for reliability analysis metrics and specific image registration techniques. In this study these challenges are formulated and in light of proposed discussions, the reliability analysis of calculation of current pathways in a designed phantom and a pig heart is presented. The current passed is measured with less than 5% error for phantom, using CDI method. It is shown that Gausss law for magnetism can be treated as reliability metric in matching the images in two orientations. For the phantom and pig heart the usefulness of image registration for mitigation of rotation errors is demonstrated. The reliability metric provides a good representation of the degree of correspondence between images in two orientations for phantom and pig heart. In our CDI experiments this metric produced values of 95% and 26%, for phantom, and 88% and 75% for pig heart, for mismatch rotations of 0 and 20 degrees respectively.

Physiological Assessment of Ventricular Myocardial Voltage Using Omnipolar Electrograms

Background Characterization of myocardial health by bipolar electrograms are critical for ventricular tachycardia therapy. Dependence of bipolar electrograms on electrode orientation may reduce reliability of voltage assessment along the plane of arrhythmic myocardial substrate. Hence, we sought to evaluate voltage assessment from orientation‐independent omnipolar electrograms. Methods and Results We mapped the ventricular epicardium of 5 isolated hearts from each species—healthy rabbits, healthy pigs, and diseased humans—under paced conditions. We derived bipolar electrograms and voltage peak‐to‐peak (Vpps) along 2 bipolar electrode orientations (horizontal and vertical). We derived omnipolar electrograms and Vpps using omnipolar electrogram methodology. Voltage maps were created for both bipoles and omnipole. Electrode orientation affects the bipolar voltage map with an average absolute difference between horizontal and vertical of 0.25±0.18 mV in humans. Vpps provide larger absolute values than horizontal and vertical bipolar Vpps by 1.6 and 1.4 mV, respectively, in humans. Bipolar electrograms with the largest Vpps from either along horizontal or vertical orientation are highly correlated with omnipolar electrograms and with Vpps values (0.97±0.08 and 0.94±0.08, respectively). Vpps values are more consistent than bipoles, in both beat‐by‐beat (CoV, 0.28±0.19 versus 0.08±0.13 in human hearts) and rhythm changes (0.55±0.21 versus 0.40±0.20 in porcine hearts). Conclusions Omnipoles provide physiologically relevant and consistent voltages that are along the maximal bipolar direction on the plane of the myocardium.

The need for and the challenges of measuring renal sympathetic nerve activity.

Renal denervation (RDN) was primarily developed to treat hypertension and is potentially a new method for treating arrhythmias. Because of the lack of a standardized protocol to measure renal sympathetic nerve activity, RDN is administered in a blind manner. This inability to assess efficacy at the time of treatment delivery may be a large contributor to the ambiguity of RDN outcomes reported in the hypertension literature. The advancement of RDN as a treatment of hypertension or arrhythmias will be hampered by the lack of delivery assessment, a deficiency that the cardiovascular electrophysiology community, with its expertise in recording and mapping, may have a role in addressing and overcoming. The development of endovascular recording of renal nerve action potentials may provide a useful accessory tool for RDN. Innovation in this area will be crucial as we as a community reconsider the therapeutic value of RDN.