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.

Quantitative evaluation of different high-density 3D mapping modes for atrial and ventricular substrate assessment of cardiac arrhythmias with the HD grid catheter.

BACKGROUND: Atrial and ventricular arrhythmias significantly contribute to morbidity and mortality of patients with cardiac disease. Ablation of these arrhythmias has shown to improve clinical outcomes, yet targeted ablation strategies rely on proper mapping capabilities. In the present study, we compare different modes of high-resolution mapping in clinically relevant arrhythmias using HD grid. METHODS AND RESULTS: Using the Advisor™ HD Grid Mapping Catheter in either the standard, the wave (bipolar along spline and bipolar orthogonal) or the wave diagonal setting, low-voltage areas were determined. Low-voltage was defined as local electrograms with an amplitude <0.5 mV (bipolar; atria/ventricle) or <4 mV (unipolar; ventricle). Ultra high-density mapping in 47 patients with ventricular tachycardia, ventricular premature beats, atrial fibrillation and atrial tachycardia provided reliable information for the understanding of the arrhythmia mechanism resulting in safe ablation procedures. Regions of low voltage were significantly decreased by 14 ± 2% and 31 ± 3% with wave and wave diagonal settings as compared to standard settings, respectively. CONCLUSION: Substrate mapping and risk stratification relies on proper low voltage discrimination. Even though the Advisor™ HD Grid Mapping Catheter was safely used in all cases, the extent of low voltage areas was mapping-mode dependent.

Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB.

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with zinc sulfate (ZnSO4) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-κB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

Does the extent of left atrial arrhythmogenic substrate depend on the electroanatomical mapping technique: impact of pulmonary vein mapping catheter vs. ablation catheter.

AIMS: In persistent atrial fibrillation (AF), left atrial low-voltage areas and complex fractionated atrial electrograms (CFAEs) have been thoroughly discussed as critical substrate points for AF perpetuation. Thus, in patients undergoing pulmonary vein isolation, these sites are often considered additional ablation targets. Currently, mapping techniques for these substrate indicators are still under discussion. The aim of this study was to evaluate the impact of different mapping catheters on the detection of low-voltage areas and CFAE. METHODS AND RESULTS: Two bipolar voltage maps and two CFAE left atrial maps were obtained each in 30 patients undergoing catheter ablation of AF using the following two different catheters: A four-pole ablation catheter (MAP, mapping and ablation catheter) (electrode size: tip: 4 mm, band: 1 mm; inter-electrode spacing: 0.5-5-2 mm) and a 10-pole circular pulmonary vein mapping catheter (CMC) (electrode size: 1 mm; inter-electrode spacing: 7-7-7 mm). Successively, low-voltage and CFAE area sizes were then compared between the two catheters. Areas with a bipolar voltage of <0.5 mV were significantly smaller when obtained with the CMC compared with the MAP (8.9 ± 8.9 vs. 17.4 ± 11.7 cm², P < 0.001). This was also significantly different for a bipolar voltage of <0.2 mV (2.3 ± 4.6 vs. 6.2 ± 9.6 cm², P < 0.001). Complex fractionated atrial electrogram area sizes were significantly larger when obtained with the CMC compared with the MAP group (14.6 ± 10.9 vs. 19.4 ± 9.4 cm², P = 0.011). CONCLUSION: Low-voltage and CFAE area size varies significantly between different mapping catheters. Mapping electrode settings have to be taken into consideration for the assessment of electroanatomical substrate of AF.

The Lewis Lead for Detection of Ventriculoatrial Conduction Type.

BACKGROUND: Identification of a possible ventriculoatrial (VA) dissociation in wide QRS complex tachycardias is one of the most reliable criteria for differentiation of tachycardia origin. The Lewis lead has been proposed for detection of atrial activity during ventricular tachycardias. HYPOTHESIS: A modified Lewis-lead-ECG will be superior to the standard-lead ECG for detection of ventriculoatrial conduction during ventricular tachycardia. METHODS: Forty-seven patients underwent electrophysiological study, stimulated with a fixed cycle length of 400 ms in the ventricle. During stimulation, a standard-lead ECG and a modified Lewis-lead ECG were recorded. Simultaneously, VA conduction was documented by intracardiac electrograms. Surface ECGs were presented to 6 blinded examiners for VA conduction assessment. RESULTS: Type of VA conduction was correctly diagnosed in significantly more ECGs in the Lewis-lead ECG group (mean, 35.0 [75%]) than in the standard-lead ECG group (mean, 29.2 [62%]; P = 0.045). Ventriculoatrial dissociation also was significantly more often correctly diagnosed in the Lewis-lead ECG group (mean, 17.7 [71%]) than in the standard-lead ECG group (mean, 12.7 [49%]; P = 0.014). Interobserver agreement was moderate in both groups (κ = 0.45 and κ = 0.49, respectively). CONCLUSIONS: Compared with standard-lead ECG, modified Lewis-lead ECG is associated with significantly improved detection of VA conduction type during fast ventricular pacing and thus may help improve ECG diagnosis.