Cardiac radiotherapy transiently alters left ventricular electrical properties and induces cardiomyocyte-specific ventricular substrate changes in heart failure.

AIMS: Ongoing clinical trials investigate the therapeutic value of stereotactic cardiac radioablation (cRA) in heart failure patients with ventricular tachycardia. Animal data indicate an effect on local cardiac conduction properties. However, the exact mechanism of cRA in patients remains elusive. Aim of the current study was to investigate in vivo and in vitro myocardial properties in heart failure and ventricular tachycardia upon cRA. METHODS AND RESULTS: High-density 3D electroanatomic mapping in sinus rhythm was performed in a patient with a left ventricular assist device and repeated ventricular tachycardia episodes upon several catheter-based endocardial radio-frequency ablation attempts. Subsequent to electroanatomic mapping and cRA of the left ventricular septum, two additional high-density electroanatomic maps were obtained at 2- and 4-month post-cRA. Myocardial tissue samples were collected from the left ventricular septum during 4-month post-cRA from the irradiated and borderzone regions. In addition, we performed molecular biology and mitochondrial density measurements of tissue and isolated cardiomyocytes. Local voltage was altered in the irradiated region of the left ventricular septum during follow-up. No change of local voltage was observed in the control (i.e. borderzone) region upon irradiation. Interestingly, local activation time was significantly shortened upon irradiation (2-month post-cRA), a process that was reversible (4-month post-cRA). Molecular biology unveiled an increased expression of voltage-dependent sodium channels in the irradiated region as compared with the borderzone, while Connexin43 and transforming growth factor beta were unchanged (4-month post-cRA). Moreover, mitochondrial density was decreased in the irradiated region as compared with the borderzone. CONCLUSION: Our study supports the notion of transiently altered cardiac conduction potentially related to structural and functional cellular changes as an underlying mechanism of cRA in patients with ventricular tachycardia.

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.