Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Orientation of conduction velocity vectors on cardiac mapping surfaces.

AIMS: Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. METHODS AND RESULTS: Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 µm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 µm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. CONCLUSION: Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation.

BACKGROUND: Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. METHODS: After baseline optical mapping, Langendorff-perfused rabbit hearts treated with azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. RESULTS: Pre-treatment with azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with azumolene treatment. CONCLUSION: In a model of ischemic recurrent LDVF, treatment with azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following azumolene treatment may reduce the proarrhythmia risk.

Role of Purkinje-muscle junction in early ventricular fibrillation in a porcine model: Beyond the trigger concept.

BACKGROUND: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. AIM: We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. METHODS: In a healthy, porcine, beating-heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial-endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re-induction and mapping and finally, histological evaluation. RESULTS: Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p < .0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p < .0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p = .0002), respectively]. In controls, epicardial-endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p < .001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p < .001) and to 2.2 ± 0.3 Hz (early VF, p <.001). Endocardial-epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. CONCLUSIONS: Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF.

Exploring the cause of conduction delays in patients with repaired Tetralogy of Fallot.

AIMS: Cardiac dyssynchrony in patients with repaired Tetralogy of Fallot (rToF) has been attributed to right bundle branch block (RBBB), fibrosis and/or the patches that are inserted during repair surgery. We aimed to investigate the basis of abnormal activation in rToF patients by mapping the electrical activation sequence during sinus rhythm (SR) and right ventricular (RV) pacing. METHODS AND RESULTS: A total of 17 patients were studied [13 with rToF, 2 with left bundle branch block (LBBB), and 2 without RBBB or LBBB (non-BBB)] during medically indicated cardiac surgery. During SR and RV pacing, measurements were performed using 112-electrode RV endocardial balloons (rToF only) and biventricular epicardial sock arrays (four of the rToF and all non-rToF patients). During SR, functional lines of block occurred in five rToF patients, while RV pacing caused functional blocks in four rToF patients. The line of block persisted during both SR and RV pacing in only 2 out of 13 rToF patients. Compared to SR, RV pacing increased dispersion of septal activation, but not dispersion of endocardial and epicardial activation of the RV free wall. During pacing, RV and left ventricular activation dispersion in rToF patients were comparable to that of the non-rToF patients. CONCLUSION: The results of the present study indicate that the delayed activation in the right ventricle of rToF patients is predominantly due to block(s) in the Purkinje system and that conduction in RV tissue is fairly normal.

High density intramural mapping of post-infarct premature ventricular contractions and ventricular tachycardia.

BACKGROUND: Spontaneous ventricular premature contractions (PVCs) and ventricular tachycardia (VT) in the acute post infarct milieu is assumed to be due to automaticity. However, the mechanism has not been studied with intramural mapping. OBJECTIVE: To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, and to test the hypothesis that post-infarct PVCs and VT are due to re-entry rather than automaticity. METHODS: In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 20 min of stabilization, recordings were made during the first 10 min of ischemia, and activation maps of individual beats were constructed. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch. RESULTS: In all experiments ST-T alternans was present. Spontaneous ventricular beats occurred in five of 15 dogs where the earliest ectopic activity was manifested in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo-to epicardial spread along the non-ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In three dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. A similar sequence was observed in VT that followed. CONCLUSION: Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium are the mechanism of PVCs and VT in post-infarct myocardium.

Death, discharge and arrhythmias among patients with COVID-19 and cardiac injury.

BACKGROUND: Cardiac injury is common in severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. We aimed to study predictors of in-hospital death, characteristics of arrhythmias and the effects of QT-prolonging therapy in patients with cardiac injury. METHODS: We conducted a retrospective cohort study involving patients with severe COVID-19 who were admitted to Tongji Hospital in Wuhan, China, between Jan. 29 and Mar. 8, 2020. Among patients who had cardiac injury, which we defined as an elevated level of cardiac troponin I (cTnI), we identified demographic and clinical characteristics associated with mortality and need for invasive ventilation. RESULTS: Among 1284 patients with severe COVID-19, 1159 had a cTnI level measured on admission to hospital, of whom 170 (14.7%) had results that showed cardiac injury. We found that mortality was markedly higher in patients with cardiac injury (71.2% v. 6.6%, p < 0.001). We determined that initial cTnI (per 10-fold increase, hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.06-1.66) and peak cTnI level during illness (per 10-fold increase, HR 1.70, 95% CI 1.38-2.10) were associated with poor survival. Peak cTnI was also associated with the need for invasive ventilation (odds ratio 3.02, 95% CI 1.92-4.98). We found arrhythmias in 44 of the 170 patients with cardiac injury (25.9%), including 6 patients with ventricular tachycardia or fibrillation, all of whom died. We determined that patients who received QT-prolonging drugs had longer QTc intervals than those who did not receive them (difference in medians, 45 ms, p = 0.01), but such treatment was not independently associated with mortality (HR 1.04, 95% CI 0.69-1.57). INTERPRETATION: We found that in patients with COVID-19 and cardiac injury, initial and peak cTnI levels were associated with poor survival, and peak cTnI was a predictor of need for invasive ventilation. Patients with COVID-19 warrant assessment for cardiac injury and monitoring, especially if therapy that can prolong repolarization is started. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2000031301.

Trans-myocardial bipolar electrogram: A strategy for mapping and determining efficacy of bipolar ablation of deep foci.

Mapping and ablation of intramural ventricular tachycardia (VT) remain a challenge. We developed a trans-myocardial electrogram recording across distal tips of two separate ablation catheters placed on contralateral sides of the myocardium to record a trans-myocardial bipole and a novel pacing electrode configuration. This trans-myocardial bipole was applied during bipolar ablation in a patient with septal VT. Local activation in this trans-myocardial bipole was similar to the earliest activation recorded from detailed activation maps from both sides of the septum. Pacing from this trans-myocardial bipole resulted in a perfect morphology match. After bipolar ablation, the trans-myocardial bipolar voltage decreased by 82%, and pacing threshold increased by 800%. These findings correlated with VT noninducibility.

Information theory to tachycardia therapy: electrogram entropy predicts diastolic microstructure of reentrant ventricular tachycardia.

There is no known strategy to differentiate which multicomponent electrograms in sinus rhythm maintain reentrant ventricular tachycardia (VT). Low entropy in the voltage breakdown of a multicomponent electrogram can localize conditions suitable for reentry but has not been validated against the classic VT activation mapping. We examined whether low entropy in a late and diversely activated ventricular scar region characterizes and differentiates the diastolic path of VT and represents protected tissue channels devoid of side branches. Intraoperative bipolar electrogram (BiEGM) activation and entropy maps were obtained during sinus rhythm in 17 patients with ischemic cardiomyopathy and compared with diastolic activation paths of VT (total of 39 VTs). Mathematical modeling of a zigzag main channel with side branches was also used to further validate structural representation of low entropy in the ventricular scar. A median of one region per patient (range: 1-2 regions) was identified in sinus rhythm, in which BiEGM with the latest mean activation time and adjacent minimum entropy were assembled together in a high-activation dispersion region. These regions accurately recognized diastolic paths of 34 VTs, often to multiple inducible VTs within a single individual arrhythmogenic region. In mathematical modeling, side branching from the main channel had a strong influence on the BiEGM composition along the main channel. The BiEGM obtained from a long unbranched channel had the lowest entropy compared with those with multiple side branches. In conclusion, among a population of multicomponent sinus electrograms, those that demonstrate low entropy and are delayed colocalize to critical long-protected channels of VT. This information is pertinent for planning VT ablation in sinus rhythm. NEW & NOTEWORTHY Entropy is a measure to quantify breakdown in information. Electrograms from a protected tissue channel can only possess a few states in their voltage and thus less information. In contrast, current-load interactions from side branches in unprotected channels introduce a number of dissimilar voltage deflections and thus high information. We compare here a mapping approach based on entropy against a rigorous reference standard of activation mapping during VT and entropy was assessed in sinus rhythm.

Exit sites on the epicardium rarely subtend critical diastolic path of ischemic VT on the endocardium: Implications for noninvasive ablation.

BACKGROUND: Noninvasive electrocardiographic mapping of ventricular tachycardia (VT) and ablation using stereotactic radiotherapy was recently reported. This strategy does not directly evaluate the critical diastolic components and assumes that the epicardial exit site of VT subtends closely over the endocardial mid-diastolic isthmus. OBJECTIVE: To determine if the epicardial exit site of VT spatially corresponds to the critical diastolic components of ischemic scar-related VT. MATERIALS AND METHODS: Intraoperative simultaneous endocardial and epicardial mapping were performed during VT using a 112-bipole endocardial balloon and 112-bipole epicardial sock array. In eight patients, nine VTs having entire diastolic circuit mapped were included in the study. The diastolic path and VT-exit sites (epicardial and endocardial) were determined. RESULTS: The diastolic path was mapped in the endocardium for all nine VTs (median length, 50; interquartile range [IQR], 28 mm). The tachycardia cycle length ranged from 210-500 ms. The VT-exit site was early in the endocardium for six VTs and on the epicardium for three VTs. The mid-diastolic isthmus and endocardial exit site of the six endocardial VTs were spatially distant from their epicardial exit site by a median distance of 32 and 27 mm, respectively. For the three VTs with an early epicardial exit, the isthmus and endocardial exit sites were distant from the epicardial exit site by a median distance of 34 and 38 mm, respectively. CONCLUSION: The epicardial exit site and the mid-diastolic isthmus sites were spatially distant and discrepant. Surface electrocardiography (ECG)-derived strategy in identifying epicardial exit site to select noninvasive ablation targets is prone to identify epicardial exit sites and may not identify critical targets in ischemic scar VT.

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping.

AIMS: Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. METHODS AND RESULTS: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. CONCLUSION: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model.

INTRODUCTION: Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional following VF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. METHODS: Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. RESULTS: Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. CONCLUSION: Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

The effect of left ventricular pacing on transmural activation delay in myopathic human hearts.

Aims: Left ventricular (LV) epicardial pacing (LVEpiP) in human myopathic hearts does not decrease global epicardial activation delay compared with right ventricular (RV) endocardial pacing (RVEndoP); however, the effect on transmural activation delay has not been evaluated. To characterize the transmural electrical activation delay in human myopathic hearts during RVEndoP and LVEpiP compared with global epicardial activation delay. Methods and results: Explanted hearts from seven patients (5 male, 46 ± 10 years) undergoing cardiac transplantation were Langendorff-perfused and mapped using an epicardial sock electrode array (112 electrodes) and 25 transmural plunge needles (four electrodes, 2 mm spacing), for a total of 100 unipolar transmural electrodes. Electrograms were recorded during LVEpiP and RVEndoP, and epicardial (sock) and transmural (needle) activation times, along with patterns of activation, were compared. There was no difference between the global epicardial activation times (LVEpiP 147 ± 8 ms vs. RVEndoP 156 ± 17 ms, P = 0.46). The mean LV transmural activation time during LVEpiP was significantly shorter than that during RVEndoP (125 ± 44 vs. 172 ± 43 ms, P < 0.001). During LVEpiP, of the transmural layers endo-, mid-myocardium and epicardium, LV endocardial layer was often the earliest compared with other transmural layers. Conclusion: In myopathic human hearts, LVEpiP did not decrease global epicardial activation delays compared with RVEndoP. LV epicardial pacing led to early activation of the LV endocardium, revealing the importance of the LV endocardium even when pacing from the LV epicardium.

Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis.

We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimetre-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted with direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes.

Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allows for the generation of three-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation had markedly increased myofibril ultrastructural organization, elevated conduction velocity and improved both electrophysiological and Ca(2+) handling properties compared to nonstimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.

Design and formulation of functional pluripotent stem cell-derived cardiac microtissues.

Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function.

Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models.

BACKGROUND: Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular fibrillation (VF) by rectifying the calcium dysregulation caused by VF. METHODS AND RESULTS: VF was induced in 26 Yorkshire pigs for 4 minutes. Cardiopulmonary resuscitation was then commenced for 3 minutes, and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation. Animals were defibrillated and observed for 30 minutes. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New Zealand rabbits were Langendorff-perfused. The inducibility of VF after dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic blood pressure ≥60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls (P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful defibrillation (21 ± 6 s versus 181 ± 57 s in controls, P=0.005). The median number of refibrillation episodes was lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic calcium leaks in the form of spontaneous calcium elevations. Administration of 20 µmol/L dantrolene significantly decreased spontaneous calcium elevation amplitude versus controls. (0.024 ± 0.013 versus 0.12 ± 0.02 arbitrary unit [200-ms cycle length], P=0.001). CONCLUSIONS: Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation, improves hemodynamics postdefibrillation, decreases refibrillation, and thus improves survival after cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling.

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 Tyrode's 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.

Mortalité, congé et arythmie chez les patients ayant la COVID-19 et une atteinte cardiaque.

CONTEXTE: Les atteintes cardiaques sont fréquentes dans les cas graves de maladie à coronavirus 2019 (COVID-19) et sont associées à un mauvais pronostic. Notre étude portait sur les facteurs prédictifs de mortalité intrahospitalière, les caractéristiques de l'arythmie et les effets des traitements qui allongent l'intervalle QT chez les patients ayant une atteinte cardiaque. MÉTHODES: Nous avons fait une étude de cohorte rétrospective des cas graves de COVID-19 admis à l'hôpital Tongji, à Wuhan, en Chine, entre le 29 janvier et le 8 mars 2020. En examinant ceux qui avaient une atteinte cardiaque, définie ici comme un taux élevé de troponine I cardiaque (TnIc), nous avons déterminé les caractéristiques biologiques et cliniques associées à la mortalité et au besoin de ventilation invasive. RÉSULTATS: Parmi les 1284 cas graves de COVID-19, 1159 avaient au dossier un taux de TnIc mesuré à l'admission, qui pour 170 (14,7 %) participants indiquait une atteinte cardiaque. Les patients ayant une atteinte cardiaque avaient un taux de mortalité nettement plus élevé que les autres patients (71,2 % c. 6,6 %; p < 0,001). Nous avons constaté que le taux de TnIc initial (pour chaque augmentation d'un facteur 10, rapport de risque [HR] 1,32, intervalle de confiance [IC] à 95 % 1,06­1,66) et le taux de TnIc maximal atteint au cours de la maladie (pour chaque augmentation d'un facteur 10, HR 1,70, IC à 95 % 1,38­2,10) étaient associés à de minces chances de survie. Le taux de TnIc maximal était aussi associé au besoin de ventilation invasive (rapport de cotes 3,02, IC à 95 % 1,92­4,98). Sur les 170 patients ayant une atteinte cardiaque, 44 (25,9 %) présentaient une arythmie. Les 6 qui souffraient de tachycardie ou de fibrillation ventriculaires sont morts. Nous avons remarqué que les patients qui recevaient des médicaments allongeant l'intervalle QT avaient un intervalle QTc plus long que ceux qui n'en recevaient pas (différence entre les médianes 45 ms; p = 0,01), mais que ce traitement n'était pas directement lié à la mortalité (HR 1,04, IC à 95 % 0,69­1,57). INTERPRÉTATION: Chez les patients ayant la COVID-19 et une atteinte cardiaque, les taux initial et maximal de TnIc sont associés à de minces chances de survie, et le taux maximal est un facteur prédictif du besoin de ventilation invasive. Les malades de la COVID-19 doivent subir un dépistage des atteintes cardiaques et être surveillés, surtout si on leur fait suivre un traitement qui peut prolonger la repolarisation. Enregistrement de l'essai : Registre des essais cliniques chinois, n° ChiCTR2000031301.

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

AIMS: Current conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts. METHODS AND RESULTS: Ablation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs. CONCLUSION: By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.