Automatic measurement of short-term variability of repolarization to indicate ventricular arrhythmias in a porcine model of cardiac ischaemia.

AIMS: An automated method for determination of short-term variability (STV) of repolarization on intracardiac electrograms (STV-ARIauto) has previously been developed for arrhythmic risk monitoring by cardiac implantable devices, and has proved effective in predicting ventricular arrhythmias (VA) and guiding preventive high-rate pacing (HRP) in a canine model. Current study aimed to assess (i) STV-ARIauto in relation to VA occurrence and secondarily (ii-a) to confirm the predictive capacity of STV from the QT interval and (ii-b) explore the effect of HRP on arrhythmic outcomes in a porcine model of acute myocardial infarction (MI). METHODS AND RESULTS: Myocardial infarction was induced in 15 pigs. In 7/15 pigs, STV-QT was assessed at baseline, occlusion, 1 min before VA, and just before VA. Eight of the 15 pigs were additionally monitored with an electrogram catheter in the right ventricle, underwent echocardiography at baseline and reperfusion, and were randomized to paced or control group. Paced group received atrial pacing at 20 beats per min faster than sinus rhythm 1 min after occlusion. Short-term variability increased prior to VA in both STV modalities. The percentage change in STV from baseline to successive timepoints correlated well between STV-QT and STV-ARIauto. High-rate pacing did not improve arrhythmic outcomes and was accompanied by a stronger decrease in ejection fraction. CONCLUSION: STV-ARIauto values increase before VA onset, alike STV-QT in a porcine model of MI, indicating imminent arrhythmias. This highlights the potential of automatic monitoring of arrhythmic risk by cardiac devices through STV-ARIauto and subsequently initiates preventive strategies. Continuous HRP during onset of acute MI did not improve arrhythmic outcomes.

A Heart too Drunk to Drive; AV Block following Acute Alcohol Intoxication.

Acute excessive alcohol consumption is associated with heart rhythm disorders like atrial fibrillation but also premature ventricular contractions, collectively known as the "holiday heart syndrome". More rarely but clinically significant are reports of atrioventricular (AV) conduction disturbances in binge drinkers with no underlying heart disease or chronic alcohol consumption. To obtain better insights into common denominators and the potential underlying mechanisms we collected and compared individual case reports of AV block following acute alcohol intoxication in otherwise healthy people. By screening PubMed, Google Scholar, Scopus and JSTOR, fifteen cases were found of which eight were sufficiently documented for full analysis. Blood alcohol levels ranged from 90 to 958 mg/dl (19 to 205 mM). Second and third degree AV block was observed most (6/8) albeit that in two of these patients a vagal stimulus led to deterioration from first into higher order AV block. In all cases, patients reverted to normal sinus rhythm upon becoming sober again. Mildly lowered body temperature (35.9 ± 0.5°C) was observed but can be excluded as a major cause of conduction blockade. We hypothesize that ethanol induced partial inhibition of calcium and potentially also sodium currents in conductive tissue structures may be one of the mechanisms of conduction slowing and block that may become exaggerated upon increased vagal tone. An impairment of gap junction function cannot be excluded as a contributing factor. In conclusion, cases of documented alcohol induced AV block are very rare but events can occur at relatively low serum alcohol levels which should prompt to awareness of this phenomenon in alcohol intoxicated patients.

High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model.

Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog. Methods: Dofetilide (25 µg/kg in 5 min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats/minute for 2 min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60retro). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDRcubic). Results: In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 ± 33 vs. 0 ± 0, p < 0.05 and vs. 12.5 ± 25 and 25 ± 50, both p > 0.05). The reduction in TdP score was reflected by a significant decrease in SDRcubic (125 ± 46 ms before TdP vs. 49 ± 18 ms during RVA100, p < 0.05), and SDR was smaller than in the RVA60retro animals (101 ± 52 ms, p < 0.05 vs. RVA100). Conclusion: In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.

Detection of Ischemic ST-Segment Changes Using a Novel Handheld ECG Device in a Porcine Model.

Background: Portable, smartphone-sized electrocardiography (ECG) has the potential to reduce time to treatment for patients suffering acute cardiac ischemia, thereby lowering the morbidity and mortality. In the UMC Utrecht, a portable, smartphone-sized, multi-lead precordial ECG recording device (miniECG 1.0, UMC Utrecht) was developed. Objectives: The purpose of this study was to investigate the ability of the miniECG to capture ischemic ECG changes in a porcine coronary occlusion model. Methods: In 8 animals, antero-septal myocardial infarction was induced by 75-minute occlusion of the left anterior descending artery, after the first or second diagonal. MiniECG and 12-lead ECG recordings were acquired simultaneously before, during and after coronary artery occlusion and ST-segment deviation was evaluated. Results: During the complete occlusion and reperfusion period, miniECG showed large ST-segment deviation in comparison to 12-lead ECG. MiniECG ST-segment deviation was observed within 1 minute for most animals. The miniECG was positive for ischemia (ie, ST-segment deviation ≥1 mm) for 99.7% (Q1-Q3: 99.6%-99.9%) of the occlusion time, while the 12-lead was only positive for 79.8% (Q1-Q3: 81.1%-98.7%) of the time (P = 0.018). ST-segment deviation reached maxima of 10.5 mm [95% CI: 6.5-14.5 mm] vs 5.0 mm [95% CI: 2.0-8.0 mm] for the miniECG vs 12-lead ECG, respectively. Conclusions: MiniECG ST-segment deviation was observed early and was of large magnitude during 75 minutes of porcine transmural antero-septal infarction. The miniECG was positive for ischemia for the complete occlusion period. These findings demonstrate the potential of the miniECG in the detection of cardiac ischemia. Although clinical research is required, data suggests that the miniECG is a promising tool for the detection of cardiac ischemia.

The canine chronic atrioventricular block model in cardiovascular preclinical drug research.

Ventricular cardiac arrhythmia is a life threating condition arising from abnormal functioning of many factors in concert. Animal models mirroring human electrophysiology are essential to predict and understand the rare pro- and anti-arrhythmic effects of drugs. This is very well accomplished by the canine chronic atrioventricular block (CAVB) model. Here we summarize canine models for cardiovascular research, and describe the development of the CAVB model from its beginning. Understanding of the structural, contractile and electrical remodelling processes following atrioventricular (AV) block provides insight in the many factors contributing to drug-induced arrhythmia. We also review all safety pharmacology studies, efficacy and mechanistic studies on anti-arrhythmic drugs in CAVB dogs. Finally, we compare pros and cons with other in vivo preclinical animal models. In view of the tremendous amount of data obtained over the last 100 years from the CAVB dog model, it can be considered as man's best friend in preclinical drug research. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Quantitative Analysis of the Cytoskeleton's Role in Inward Rectifier K IR 2.1 Forward and Backward Trafficking.

Alteration of the inward rectifier current I K1, carried by KIR2.1 channels, affects action potential duration, impacts resting membrane stability and associates with cardiac arrhythmias. Congenital and acquired KIR2.1 malfunction frequently associates with aberrant ion channel trafficking. Cellular processes underlying trafficking are intertwined with cytoskeletal function. The extent to which the cytoskeleton is involved in KIR2.1 trafficking processes is unknown. We aimed to quantify the dependence of KIR2.1 trafficking on cytoskeleton function. GFP or photoconvertible Dendra2 tagged KIR2.1 constructs were transfected in HEK293 or HeLa cells. Photoconversion of the Dendra2 probe at the plasma membrane and subsequent live imaging of trafficking processes was performed by confocal laser-scanning microscopy. Time constant of green fluorescent recovery (τg,s) represented recruitment of new KIR2.1 at the plasma membrane. Red fluorescent decay (τr,s) represented internalization of photoconverted KIR2.1. Patch clamp electrophysiology was used to quantify I KIR2.1. Biochemical methods were used for cytoskeleton isolation and detection of KIR2.1-cytoskeleton interactions. Cytochalasin B (20 µM), Nocodazole (30 µM) and Dyngo-4a (10 nM) were used to modify the cytoskeleton. Chloroquine (10 µM, 24 h) was used to impair KIR2.1 breakdown. Cytochalasin B and Nocodazole, inhibitors of actin and tubulin filament formation respectively, strongly inhibited the recovery of green fluorescence at the plasma membrane suggestive for inhibition of KIR2.1 forward trafficking [τg,s 13 ± 2 vs. 131 ± 31* and 160 ± 40* min, for control, Cytochalasin B and Nocodazole, respectively (*p < 0.05 vs. control)]. Dyngo-4a, an inhibitor of dynamin motor proteins, strongly slowed the rate of photoconverted channel internalization, whereas Nocodazole and Cytochalasin B had less effect [τr,s 20 ± 2 vs. 87 ± 14*, 60 ± 16 and 64 ± 20 min (*p < 0.05 vs. control)]. Cytochalasin B treatment (20 µM, 24 h) inhibited I KIR2.1. Chloroquine treatment (10 µM, 24 h) induced intracellular aggregation of KIR2.1 channels and enhanced interaction with the actin/intermediate filament system (103 ± 90 fold; p < 0.05 vs. control). Functional actin and tubulin cytoskeleton systems are essential for forward trafficking of KIR2.1 channels, whereas initial backward trafficking relies on a functional dynamin system. Chronic disturbance of the actin system inhibits KIR2.1 currents. Internalized KIR2.1 channels become recruited to the cytoskeleton, presumably in lysosomes.

High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model.

BACKGROUND: The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP. OBJECTIVE: The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias. METHODS: Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STVICD) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STVRV,EGM/LV,MAPD). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STVICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STVICD threshold was reached. RESULTS: In experiment 1, 8 of 8 dogs had repetitive TdP, and STVICD increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P <.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STVRV,EGM/LV,MAPD from 2.02 ± 1.12 ms to 0.78 ± 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs. CONCLUSION: STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

Short-Term Variability of the QT Interval Can be Used for the Prediction of Imminent Ventricular Arrhythmias in Patients With Primary Prophylactic Implantable Cardioverter Defibrillators.

Background Short-term variability of the QT interval (STVQT) has been proposed as a novel electrophysiological marker for the prediction of imminent ventricular arrhythmias in animal models. Our aim is to study whether STVQT can predict imminent ventricular arrhythmias in patients. Methods and Results In 2331 patients with primary prophylactic implantable cardioverter defibrillators, 24-hour ECG Holter recordings were obtained as part of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators) study. ECG Holter recordings showing ventricular arrhythmias of >4 consecutive complexes were selected for the arrhythmic groups (n=170), whereas a control group was randomly selected from the remaining Holter recordings (n=37). STVQT was determined from 31 beats with fiducial segment averaging and calculated as [Formula: see text], where Dn represents the QT interval. STVQT was determined before the ventricular arrhythmia or 8:00 am in the control group and between 1:30 and 4:30 am as baseline. STVQT at baseline was 0.84±0.47 ms and increased to 1.18±0.74 ms (P<0.05) before the ventricular arrhythmia, whereas the STVQT in the control group remained unchanged. The arrhythmic patients were divided into three groups based on the severity of the arrhythmia: (1) nonsustained ventricular arrhythmia (n=32), (2) nonsustained ventricular tachycardia (n=134), (3) sustained ventricular tachycardia (n=4). STVQT increased before nonsustained ventricular arrhythmia, nonsustained ventricular tachycardia, and sustained ventricular tachycardia from 0.80±0.43 ms to 1.18±0.78 ms (P<0.05), from 0.90±0.49 ms to 1.14±0.70 ms (P<0.05), and from 1.05±0.22 ms to 2.33±1.25 ms (P<0.05). This rise in STVQT was significantly higher in sustained ventricular tachycardia compared with nonsustained ventricular arrhythmia (+1.28±1.05 ms versus +0.24±0.57 ms [P<0.05]) and compared with nonsustained ventricular arrhythmia (+0.34±0.87 ms [P<0.05]). Conclusions STVQT increases before imminent ventricular arrhythmias in patients, and the extent of the increase is associated with the severity of the ventricular arrhythmia.