Gq-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gαq/Gα11-family (Gq). Besides pro-fibrotic and pro-inflammatory effects, Gq-mediated signaling induces inositol trisphosphate receptor (IP3R)-mediated intracellular Ca2+ mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic Gq-mediated signaling is absent. METHODS AND RESULTS: To define the role of Gq in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gαq/Gα11-deficiency (Gq-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in Gq-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in Gq-KO mice-both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from Gq-KO and control mice and electrically stimulated to study Ca2+-mobilization during excitation-contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca2+ waves and sarcoplasmic reticulum content-corrected Ca2+ sparks were less frequent in Gq-KO mice. Interestingly, nuclear but not cytosolic Ca2+ transient amplitudes were significantly decreased in Gq-KO mice. CONCLUSION: Gq-signaling promotes arrhythmogenic atrial Ca2+-release and AF in mice. Targeting this pathway, ideally using Gq-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the Gq-effector IP3R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.

COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab.

BACKGROUND: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. AIMS AND METHODS: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1ß antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. RESULTS: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. CONCLUSION: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

Femtosecond laser tuning of silicon microring resonators.

Femtosecond laser modification is demonstrated as a possible method for postfabrication tuning of silicon microring resonators. Single 400 nm femtosecond laser pulses were used to modify the effective index of crystalline silicon microring waveguides by either amorphization or surface nanomilling depending on the laser fluence. Both blue- and redshifts in the microring resonance could be achieved without imparting significant degradation to the device quality factor.

Compact silicon microring-assisted directional couplers for optical signal processing applications.

We propose and demonstrate a compact microring-assisted directional coupler in the silicon-on-insulator material system. An analytical model based on the strongly coupled mode theory shows that the device can be designed to have a wide range of spectral characteristics, including sharp asymmetric Fano line shapes, which can be used for WDM, switching, and sensing applications. The measured transmission spectra of the fabricated device with a 5-mum-radius microring resonator exhibited an asymmetric spectral response characteristic of the Fano resonance as predicted by the analytical model.

Experimental determination of coupled microring filter parameters via pole-zero extraction.

A method for directly extracting the coupling coefficients, the resonant frequency detunings and the loss of an N(th)-order serially-coupled microring resonator filter from the measured power spectral responses is presented. The device parameters are obtained from the through-port complex transfer function, which is constructed from the experimentally extracted poles and zeros of the filter. We applied the method to determine the parameters of a symmetric microring doublet fabricated in the Silicon-on- Insulator material platform. Simulated spectral responses using the extracted parameters showed good agreement with the measured data. The extracted parameters along with the poles and zeros of the device provide important information about the fabrication process and can be used to guide the post-fabrication trimming of high-order microring filters.

Realization of asymmetric optical filters using asynchronous coupled-microring resonators.

General filter architectures based on asynchronously-tuned, coupled-microring resonators are proposed for realizing optical filters with asymmetric spectral responses. Asymmetric filters enable more complex spectral shapes to be realized which can better meet the demands of more advanced applications than symmetric filters. By adjusting individual transmission zeros of the filter transfer function, the transition bands on the low and high-frequency sides of the passband can be separately optimized to achieve an optimum filter response. A method for synthesizing asymmetric spectral responses based on the energy coupling matrix will also be presented along with numerical examples of high-order asymmetric optical filters. These devices represent new microring-based architectures that can be explored for advanced applications in optical spectral shaping and dispersion engineering.