Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.

With the COVID-19 pandemic infecting millions of people, large-scale isolation policies have been enacted across the globe. To assess the impact of isolation measures on deaths, hospitalizations, and economic output, we create a mathematical model to simulate the spread of COVID-19, incorporating effects of restrictive measures and segmenting the population based on health risk and economic vulnerability. Policymakers make isolation policy decisions based on current levels of disease spread and economic damage. For 76 weeks in a population of 330 million, we simulate a baseline scenario leaving strong isolation restrictions in place, rapidly reducing isolation restrictions for non-seniors shortly after outbreak containment, and gradually relaxing isolation restrictions for non-seniors. We use 76 weeks as an approximation of the time at which a vaccine will be available. In the baseline scenario, there are 235,724 deaths and the economy shrinks by 34.0%. With a rapid relaxation, a second outbreak takes place, with 525,558 deaths, and the economy shrinks by 32.3%. With a gradual relaxation, there are 262,917 deaths, and the economy shrinks by 29.8%. We also show that hospitalizations, deaths, and economic output are quite sensitive to disease spread by asymptomatic people. Strict restrictions on seniors with very gradual lifting of isolation for non-seniors results in a limited number of deaths and lesser economic damage. Therefore, we recommend this strategy and measures that reduce non-isolated disease spread to control the pandemic while making isolation economically viable.

Histology and immunohistochemistry. Immunohistochemistry was performed on paraffin-embedded sections. Gross heart morphology and collagen content were examined using Masson's trichrome stain (American MasterTech Scientific). Wheat germ agglutinin staining was used to visualize cell membranes and enable quantification of CM cell size. Microelectrode recordings. Investigators were blinded to the sample group allocation during the experiment and analysis of experimental outcome. Mouse hearts were Langendorff perfused and were recorded while in sinus rhythm and when stimulated at 10 Hz (approximately 600 beats per minute). Using glass sharp microelectrodes, single LA CMs were sampled near the epicardial surface. To decrease noise from motion artifacts, blebbistatin (0.2 mg/mL) was used to arrest motion and allow for stable microelectrode recording without requiring the use of floating electrodes. Additional information. All methods related to mouse RT-qPCR (Supplemental Table 14) and RNA-sequencing and analysis are detailed in the Supplemental Methods. Expanded methods for human tissue acquisition, CMN isolation, histology and immunohistochemistry, and microelectrode recordings are also supplied in the Supplemental Methods. RA RNA-sequencing accession number. RA RNA-sequencing data discussed in this manuscript have been deposited in the National Center for Biotechnology Information's (NCBI) Gene Expression Omnibus (GEO) database and are accessible through GSE100244. LA RNA-sequencing accession number. LA RNA-sequencing data discussed in this manuscript have been deposited in NCBI's GEO and are accessible through GSE138253. Human RNA-sequencing accession number. Data have been deposited in NCBI's GEO and are accessible through GSE138252. Statistics. All data are expressed as mean ± SEM. Statistical analyses were performed after assessing for normal distribution using either paired or unpaired Student's 2-tailed t tests for comparison of 2 groups with a Welch's correction. Values of P < 0.05 were considered statistically significant. Study approval. Animal protocols were approved by the Animal Studies Committee at Washington University in St. Louis, and animals were handled in accordance with the NIH's Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011). Protocols involving human tissue acquisition were approved by the Washington University in St. Louis IRB. Informed consent was obtained for all tissue before inclusion in this study. Methods described in this manuscript were performed in accordance with all human research guidelines. Author contributions SLR was responsible for conceptualization of the study. SLR, CEL, JJ, and QG contributed to experimental design. CEL, JJ, QG, TY, and SB conducted experiments, acquired data, and performed data analysis. SCH conducted histology staining. GL contributed to data analysis. CEL, JJ, QG, GL, TY, SCH, DMZ, UG, KT, and BDB contributed to human tissue acquisition. RDN and CPC performed mouse RNA-sequencing and statistical analysis. SL and BZ perfo...

With the COVID-19 pandemic infecting millions of people, large-scale isolation policies have been enacted across the globe. To assess the impact of isolation measures on deaths, hospitalizations, and economic output, we create a mathematical model to simulate the spread of COVID-19, incorporating effects of restrictive measures and segmenting the population based on health risk and economic vulnerability. Policymakers make isolation policy decisions based on current levels of disease spread and economic damage. For 76 weeks in a population of 330 million, we simulate a baseline scenario leaving strong isolation restrictions in place, rapidly reducing isolation restrictions for non-seniors shortly after outbreak containment, and gradually relaxing isolation restrictions for non-seniors. We use 76 weeks as an approximation of the time at which a vaccine will be available. In the baseline scenario, there are 235,724 deaths and the economy shrinks by 34.0%. With a rapid relaxation, a second outbreak takes place, with 525,558 deaths, and the economy shrinks by 32.3%. With a gradual relaxation, there are 262,917 deaths, and the economy shrinks by 29.8%. We also show that hospitalizations, deaths, and economic output are quite sensitive to disease spread by asymptomatic people. Strict restrictions on seniors with very gradual lifting of isolation for non-seniors results in a limited number of deaths and lesser economic damage. Therefore, we recommend this strategy and measures that reduce non-isolated disease spread to control the pandemic while making isolation economically viable.

With the COVID-19 pandemic infecting millions of people, large-scale quarantine policies have been enacted across the globe. To assess the impact of quarantine measures on deaths, hospitalizations, and economic output, we expand the classical SEIR model to simulate the spread of COVID-19, incorporating effects of restrictive measures and segmenting the population based on health risk and economic vulnerability. For 76 weeks in a population of 330 million, we simulate a baseline scenario leaving current quarantine restrictions in place, rapidly reducing quarantine restrictions for non-seniors shortly after outbreak containment, and gradually relaxing quarantine restrictions for non-seniors. In the baseline scenario, there are 207,906 deaths and the economy shrinks by 34.0%. With a rapid relaxation, a second outbreak takes place, with 788,815 deaths, and the economy shrinks by 28.2%. With a gradual relaxation, there are 221,743 deaths, and the economy shrinks by 29.4%. Additionally, hospitalizations, deaths, and economic output are quite sensitive to disease spread by asymptomatic people. Strict restrictions on seniors with very gradual lifting of quarantine for non-seniors results in a limited number of deaths and lesser economic damage. Therefore, we recommend this strategy and measures that reduce non-quarantined disease spread to control the pandemic while making quarantine economically viable.