Defibrillation effectiveness and safety of the shock waveform used in a contemporary wearable cardioverter defibrillator: Results from animal and human studies.

INTRODUCTION: The wearable cardioverter defibrillator (WCD) is used to protect patients at risk for sudden cardiac arrest. We examined defibrillation efficacy and safety of a biphasic truncated exponential waveform designed for use in a contemporary WCD in three animal studies and a human study. METHODS: Animal (swine) studies: #1: Efficacy comparison of a 170J BTE waveform (SHOCK A) to a 150J BTE waveform (SHOCK B) that approximates another commercially available waveform. Primary endpoint first shock success rate. #2: Efficacy comparison of the two waveforms at attenuated charge voltages in swine at three prespecified impedances. Primary endpoint first shock success rate. #3: Safety comparison of SHOCK A and SHOCK B in swine. Primary endpoint cardiac biomarker level changes baseline to 6 and 24 hours post-shock. Human Study: Efficacy comparison of SHOCK A to prespecified goal and safety evaluation. Primary endpoint cumulative first and second shock success rate. Safety endpoint adverse events. RESULTS: Animal Studies #1: 120 VF episodes in six swine. First shock success rates for SHOCK A and SHOCK B were 100%; SHOCK A non-inferior to SHOCK B (entire 95% CI of rate difference above -10% margin, p < .001). #2: 2,160 VF episodes in thirty-six swine. Attenuated SHOCK A was non-inferior to attenuated SHOCK B at each impedance (entire 95% CI of rate difference above -10% margin, p < .001). #3: Ten swine, five shocked five times each with SHOCK A, five shocked five times each with SHOCK B. No significant difference in troponin I (p = 0.658) or creatine phosphokinase (p = 0.855) changes from baseline between SHOCK A and SHOCK B. Human Study: Thirteen patients, 100% VF conversion rate. Mild skin irritation from adhesive defibrillation pads in three patients. CONCLUSIONS: The BTE waveform effectively and safely terminated induced VF in swine and a small sample in humans. TRIAL REGISTRATION: Human study clinical trial registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04132466.

Molecular remodeling of Cx43, but not structural remodeling, promotes arrhythmias in an arrhythmogenic canine model of nonischemic heart failure.

BACKGROUND: Both gap junctional remodeling and interstitial fibrosis have been linked to impaired electrical conduction velocity (CV) and fatal ventricular arrhythmias in nonischemic heart failure (HF). However, the arrhythmogenic role of the ventricular gap junctional Cx43 in nonischemic HF remains in debate. Here, we assessed this in a newly developed arrhythmogenic canine model of nonischemic HF. METHODS AND RESULTS: Nonischemic HF was induced in canines by combined aortic valve insufficiency and aortic constriction. Left ventricular (LV) myocardium from HF dogs showed similar pathological changes to that of humans. HF dogs had reduced LV function, widened QRS complexes, and spontaneous nonsustained ventricular tachycardia. CV was measured in intact LV epicardium with high-density grid mapping. Total (Cx43-T) and nonphosphorylated Cx43 (Cx43-NP) and histological interstitial fibrosis were assessed from these mapped LV tissues. Longitudinal CV, which was slowed in HF (49 ± 1 vs. 65 ± 2 cm/s in Ctl), was positively correlated with reduced total junctional Cx43 and negatively correlated with markedly increased junctional Cx43-NP (2-fold) in HF. Cx43 dephosphorylation in HF was associated with enhanced colocalization of PP2A at the level of Cx43. Unchanged action potential upstroke and transverse CV were associated with unaltered Cx43 lateralization and interstitial fibrosis in the nonischemic HF canine LV. CONCLUSION: Our unique arrhythmogenic canine model of HF resembles human nonischemic HF (prior to the end stage). Cx43 remodeling occurs prior to the structural remodeling (with lack of fibrosis) in HF and it is crucial in slowed CV and ventricular arrhythmia development. Our findings suggest that altered Cx43 alone is arrhythmogenic and modulation of Cx43 has the anti-arrhythmic therapeutic potential for HF patients.

Left atrial appendage electrical isolation and concomitant device occlusion: A safety and feasibility study with histologic characterization.

BACKGROUND: Left atrial appendage (LAA) electrical isolation is reported to improve atrial fibrillation ablation outcomes. However, loss of mechanical function may increase thromboembolic risk. OBJECTIVE: The aim of this study was to evaluate the feasibility and safety of LAA occlusion after electrical isolation in a canine model. METHODS: Nine canines underwent LAA isolation with irrigated radiofrequency ablation after pulmonary vein (PV) isolation. Entrance and exit block were confirmed with intravenous adenosine after 30 minutes. The LAA was then occluded with a Watchman device. Device position was assessed at 10 days by using transthoracic echocardiography. At 45 days, LAA isolation was assessed epicardially. Hearts were then examined macroscopically and histologically. RESULTS: All 36 PVs and 8 of 9 LAAs (89%) were electrically isolated. Acute LAA reconnection occurred in 4 of 8 LAAs (50%). All were reisolated. The mean ablation time was 51 ± 19 minutes, including 24 ± 18 minutes for LAA isolation. LAA occlusion was successful in all cases. One animal died of a primary intracranial bleed due to anticoagulant hypersensitivity 36 hours after the procedure. Transthoracic echocardiography at 10 days confirmed satisfactory device positions and no pericardial effusion. At 45 days, 7 of 8 (88%) had persistent LAA electrical isolation. All devices were stable without evidence of erosion. Microscopy revealed complete device-tissue apposition and a mature connective tissue layer overlying the device surface in all cases. CONCLUSION: LAA electrical isolation and mechanical occlusion can be performed concomitantly in this animal model, with no displacement or mechanical erosion of the appendage at 45 days. This technique can potentially improve success rates and obviate the need for chronic anticoagulation. Future studies should address efficacy, safety, and feasibility in humans.

Chymase inhibition prevents fibronectin and myofibrillar loss and improves cardiomyocyte function and LV torsion angle in dogs with isolated mitral regurgitation.

BACKGROUND: The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR. METHODS AND RESULTS: We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a >40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P<0.05) and normalized in MR+CI dogs (4.85±0.44%). MRI with tissue tagging demonstrated an increase in LV torsion angle in MR+CI versus MR dogs. CI normalized the significant decrease in fibronectin and FAK phosphorylation and prevented cardiomyocyte myofibrillar degeneration in MR dogs. In addition, total titin and its stiffer isoform were increased in the LV epicardium and paralleled the changes in fibronectin and FAK phosphorylation in MR+CI dogs. CONCLUSIONS: These results suggest that chymase disrupts cell surface-fibronectin connections and FAK phosphorylation that can adversely affect cardiomyocyte myofibrillar structure and function. The greater effect of CI on epicardial versus endocardial titin and noncollagen cell surface proteins may be responsible for the increase in torsion angle in chronic MR.

Mast cell stabilization decreases cardiomyocyte and LV function in dogs with isolated mitral regurgitation.

BACKGROUND: Mast cells are increased in isolated mitral regurgitation (MR) in the dog and may mediate extracellular matrix loss and left ventricular (LV) dilatation. We tested the hypothesis that mast cell stabilization would attenuate LV remodeling and improve function in the MR dog. METHODS AND RESULTS: MR was induced in adult dogs randomized to no treatment (MR, n = 5) or to the mast cell stabilizer, ketotifen (MR + MCS, n = 4) for 4 months. LV hemodynamics were obtained at baseline and after 4 months of MR and magnetic resonance imaging (MRI) was performed at sacrifice. MRI-derived, serial, short-axis LV end-diastolic (ED) and end-systolic (ES) volumes, LVED volume/mass ratio, and LV 3-dimensional radius/wall thickness were increased in MR and MR + MCS dogs compared with normal dogs (n = 6) (P < .05). Interstitial collagen was decreased by 30% in both MR and MR + MCS versus normal dogs (P < .05). LV contractility by LV maximum time-varying elastance was significantly depressed in MR and MR + MCS dogs. Furthermore, cardiomyocyte fractional shortening was decreased in MR versus normal dogs and further depressed in MR + MCS dogs (P < .05). In vitro administration of ketotifen to normal cardiomyocytes also significantly decreased fractional shortening and calcium transients. CONCLUSIONS: Chronic mast cell stabilization did not attenuate eccentric LV remodeling or collagen loss in MR. However, MCS therapy had a detrimental effect on LV function because of a direct negative inotropic effect on cardiomyocyte function.

Activation patterns of Purkinje fibers during long-duration ventricular fibrillation in an isolated canine heart model.

BACKGROUND: The roles of Purkinje fibers (PFs) and focal wave fronts, if any, in the maintenance of ventricular fibrillation (VF) are unknown. If PFs are involved in VF maintenance, it should be possible to map wave fronts propagating from PFs into the working ventricular myocardium during VF. If wave fronts ever arise focally during VF, it should be possible to map them appearing de novo. METHODS AND RESULTS: Six canine hearts were isolated, and the left main coronary artery was cannulated and perfused. The left ventricular cavity was exposed, which allowed direct endocardial mapping of the anterior papillary muscle insertion. Nonperfused VF was induced, and 6 segments of data, each 5 seconds long, were analyzed during 10 minutes of VF. During 36 segments of data that were analyzed, 1018 PF or focal wave fronts of activation were identified. In 534 wave fronts, activation was mapped propagating from working ventricular myocardium to PF. In 142 wave fronts, activation was mapped propagating from PF to working ventricular myocardium. In 342 wave fronts, activation was mapped arising focally. More than 1 of these 3 patterns could occur in the same wave front. CONCLUSIONS: PFs are highly active throughout the first 10 minutes of VF. In addition to retrograde propagation from the working ventricular myocardium to PFs, antegrade propagation occurs from PFs to working ventricular myocardium, which suggests PFs are important in VF maintenance. Prior plunge needle recordings in dogs indicate activation propagates from the endocardium toward the epicardium after 1 minute of VF, which suggests that focal sites on the endocardium may represent foci and not breakthrough. If so, in addition to reentry, abnormal automaticity or triggered activity may also occur during VF.

Quantification of activation patterns during ventricular fibrillation in open-chest porcine left ventricle and septum.

BACKGROUND: A single stationary mother rotor has been hypothesized to be responsible for maintenance of ventricular fibrillation (VF) in the guinea pig. Previous studies have pointed to the ventricular septum as a possible location for a mother rotor in the pig heart. OBJECTIVES: The purpose of this study was to test the hypothesis that a mother rotor is located in the septum. METHODS: In seven open-chest pigs, we mapped the first 20 seconds of electrically induced VF simultaneously from the posterior left ventricle (LV) and right side of the septum with two electrical arrays. Each array contained 504 electrodes (21 x 24) spaced 2 mm apart in the LV and 1.5 mm apart in the septum. RESULTS: The percentage of VF wavefronts that formed reentrant circuits was significantly lower in the septum (1% +/- 1% [mean +/- SD]) than in the LV (2% +/- 1%). The peak frequency during VF also was significantly smaller in the septum (8.6 Hz +/- 3.0 Hz) than in the LV (10.4 Hz +/- 3.4 Hz). The mean direction of spread of activation of VF wavefronts was away from the region where the posterior LV free wall intersects the posterior septum in both the LV and septum. CONCLUSIONS: The lower incidence of reentry and lower peak frequency in the mapped region of the septum than in the LV indicate that a mother rotor is not present in swine on the RV side of the septum. The mean directions of the VF activation sequences in the LV and septum suggest that if a mother rotor is present during the first 20 seconds of VF, it exists where the posterior LV free wall joins the septum, the region where the posterior papillary muscle inserts.

Regional differences in ventricular fibrillation in the open-chest porcine left ventricle.

It has been hypothesized that during ventricular fibrillation (VF), the fastest activating region, the dominant domain, contains a stable reentrant circuit called a mother rotor. This hypothesis postulates that the mother rotor spawns wavefronts that propagate to maintain VF elsewhere and implies that the ratio of wavefronts propagating off a region to those propagating onto it (propoff/propon) should be >1 for the dominant domain but <1 elsewhere. To test this prediction in the left ventricular (LV) epicardium of a large animal, most of the LV free wall was mapped with 1008 electrodes in 7 pigs. VF activation rate was faster in the posterior than in the anterior LV (10.0+/-1.3Hz versus 9.3+/-1.3Hz; P<0.001). The anterior LV had a higher fraction of wavefronts that blocked than did the posterior LV and had a propoff/propon ratio <1 (P<0.001). The mean conduction velocity vectors of the VF wavefronts pointed in the direction from the posterior to the anterior LV. Although these findings favor a dominant domain in the posterior LV, the facts that the anterior LV had a higher incidence of reentry than did the posterior LV and that the posterior LV did not have propoff/propon significantly different from 1 do not. Thus, quantitative regional differences are present over the porcine LV epicardium during VF. Although these differences are not totally consistent with the presence of a dominant domain within the LV free wall, the mean conduction velocity vector is consistent with one in the septum.

Left ventricular resynchronization therapy in a canine model of left bundle branch block.

Positive responses to left (LV) and biventricular (BV) stimulation observed in heart failure patients with left bundle branch block (LBBB) suggest a possible mechanism of LV resynchronization. An anesthetized canine LBBB model was developed using radio frequency ablation. Before and after ablation, LV pressure derivative over time (dP/dt) and aortic pulse pressure (PP) were assessed during normal sinus rhythm with right ventricle (RV), LV, or BV stimulation combined with four atrioventricular delays in six dogs. In three more dogs, M-mode echocardiograms of septal and LV posterior wall motion were obtained before and after LBBB and during LV stimulation. LBBB caused QRS widening and hemodynamics deterioration. Before ablation, stimulation alone worsened LV dP/dt and PP. After ablation, LV and BV stimulation maximally increased LV dP/dt by 16% and PP by 7% (P < 0.001), whereas little improvement was observed during RV stimulation. M-mode echocardiogram showed that LBBB resulted in a paradoxical septal wall motion that was corrected by LV stimulation. In conclusion, LV and BV stimulation improved cardiac function in a canine LBBB model via resynchronization of LV excitation and contraction.