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BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODS: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTS: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P

The recent discovery of natural biaxial hyperbolicity in van der Waals crystals, such as α-MoO3, has opened up new avenues for mid-IR nanophotonics due to their deep subwavelength phonon polaritons. However, a significant challenge is the lack of active tunability of these hyperbolic phonon polaritons. In this work, we investigate heterostructures of graphene and α-MoO3 for actively tunable hybrid plasmon phonon polariton modes via electrostatic gating in the mid-infrared spectral region. We observe a unique propagation direction dependent hybridization of graphene plasmon polaritons with hyperbolic phonon polaritons for experimentally feasible values of graphene chemical potential. We further report an application to tunable valley quantum interference in this system with a broad operational bandwidth due to the formation of these hybrid modes. This work presents a lithography-free alternative for actively tunable, anisotropic spontaneous emission enhancement using a sub-wavelength thick naturally biaxial hyperbolic material.

In‐plane Hyperbolic Phonon polaritons (HPhPs) are quasiparticles formed via coupling of photons and optical phonons in in‐plane hyperbolic materials and offer unique applications in sensing, thermal emitters and high‐resolution imaging. However, the large momentum mismatch between photons and these in‐plane HPhPs has restricted their technological potential as most experimental demonstrations rely on sophisticated and expensive near‐field detection schemes. In this work, using the example of α‐MoO3, it is demonstrated that by constructing photonic hypercrystals of this material, one can not only excite these in‐plane HPhPs in the far field but also tune the far field response via twisting the hypercrystal lattice with respect the lattice of α‐MoO3. The findings will pave the way for the development of practical in‐plane HPhP devices as well as provide access to new fundamental physics of such materials via conventional and well developed far‐field measurement techniques. [ABSTRACT FROM AUTHOR]

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.15 mmol l(-1) ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2 O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H2 O2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.

BackgroundHypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms.Methods and resultsArrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.0-3.5 mmol/L) in the absence or presence of dofetilide (1 μmol/L). Spontaneous early afterdepolarizations (EADs) and ventricular tachycardia/fibrillation occurred in 50% of hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence. Pretreatment with the Ca-calmodulin kinase II (CaMKII) inhibitor KN-93, but not its inactive analogue KN-92, abolished EADs and hypokalemia-induced ventricular tachycardia/fibrillation, as did the selective late Na current (INa) blocker GS-967. In intact hearts, moderate hypokalemia (2.7 mmol/L) significantly increased tissue CaMKII activity. Computer modeling revealed that EAD generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intracellular Na and Ca overload with consequent CaMKII activation enhancing late INa and the L-type Ca current. K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation were ineffective at causing EADs.ConclusionsWe conclude that Na-K pump inhibition by even moderate hypokalemia plays a critical role in promoting EAD-mediated arrhythmias by inducing a positive feedback cycle activating CaMKII and enhancing late INa. Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback loop.

Myocardial infarction (MI) is the leading cause of death from coronary heart disease and requires immediate reperfusion therapy with thrombolysis, primary percutaneous coronary intervention, or coronary artery bypass grafting. However, myocardial reperfusion therapy is often accompanied by cardiac ischemia/reperfusion (I/R) injury, which leads to myocardial injury with detrimental consequences. The causes of I/R injury are unclear, but are multifactorial, including free radicals, reactive oxygen species, calcium overload, mitochondria dysfunction, inflammation, and neutrophil-mediated vascular injury. Mild hypothermia has been introduced as one of the potential inhibitors of myocardial I/R injury. Although animal studies have demonstrated that mild hypothermia significantly reduces or delays I/R myocardium damage, human trials have not shown clinical benefits in acute MI (AMI). In addition, the practice of hypothermia treatment is increasing in various fields such as surgical anesthesia and intensive care units. Adequate sedation for anesthetic procedures and protection from body shivering has become essential during therapeutic hypothermia. Therefore, anesthesiologists should be aware of the effects of therapeutic hypothermia on the metabolism of anesthetic drugs. In this paper, we review the existing data on the use of therapeutic hypothermia for AMI in animal models and human clinical trials to better understand the discrepancy between perceived benefits in preclinical animal models and the absence thereof in clinical trials thus far. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend consideration for ischemia testing in patients with VT where the clinical presentation or type of arrhythmia suggests coronary artery disease (IIa LOE C). Sustained monomorphic VT (SMVT) usually arises in scar without requiring acute ischemia. Objective: To better characterize the role of ischemic evaluation in VT ablation patients by reviewing ischemic testing and evaluating the prevalence of new or critical coronary disease prior to ablation. Methods: We reviewed records of consecutive patients with SMVT who were referred for VT ablation at two quaternary centers over a two year period. Recent ischemic testing was defined as within one month of the index ablation procedure with the indication being VT. Results: There were 265 VT ablation referrals in 193 patients (mean age 63 yrs, 85% male, BMI 30, history of coronary disease in 58%, prior CABG in 22%). Ischemia testing was performed in 72 patients (37%). Seventeen patients underwent nuclear perfusion stress testing which showed fixed perfusion defects without ischemia. CT angiography was performed in two patients, and was suggestive of significant obstructive disease in one patient and normal in the other. Thirty-nine patients underwent coronary angiography (CA) as the first diagnostic step, and all but seven had obstructive disease. Percutaneous revascularization was performed in 6/72 (8%) patients; three patients continued to have VT following PCI. The other three patients who received PCI all had preexisting scar in the region of the VT with no troponin elevation at presentation. Fourteen patients underwent CA in the EP laboratory prior to epicardial ablation. None of the 193 patients developed ECG or hemodynamic evidence of myocardial infarction during or after the procedure. Conclusion: Testing for ischemia is common in patients with SMVT but the identification of ischemia warranting revascularization is infrequent. These findings suggest that reserving ischemia evaluation for selected patients has the potential to reduce unnecessary testing. [ABSTRACT FROM AUTHOR]