Padget Rachel L, Zeitz Michael J, Blair Grace A, Wu Xiaobo, North Michael D, Tanenbaum Mira T, Stanley Kari E, Phillips Chelsea M, King D Ryan, Lamouille Samy, Gourdie Robert G, Hoeker Gregory S, Swanger Sharon A, Poelzing Steven, Smyth James W
Graduate Program in Translational Biology, Medicine, and Health (R.L.P., G.A.B., K.E.S., D.R.K.), Virginia Tech, Blacksburg.
Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke (R.L.P., M.J.Z., G.A.B., X.W., K.E.S., C.M.P., D.R.K., S.L., R.G.G., G.S.H., S.A.S., S.P., J.W.S.).
Circ Res. 2024 Mar 29;134(7):892-912. doi: 10.1161/CIRCRESAHA.122.322437. Epub 2024 Feb 28.
Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species specificity, models of infection are lacking, and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse adenovirus type-3 was previously reported as cardiotropic, yet it has not been utilized to understand the mechanisms of cardiac infection and pathology.
We have developed mouse adenovirus type-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart before an appreciable immune response or gross cardiomyopathy.
Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43 are protected against mouse adenovirus type-3-induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of mouse adenovirus type-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased and current density. Turning to human systems, we find human adenovirus type-5 increases phosphorylation of Cx43 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes, indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data.
Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
病毒性心脏感染是一项重大的临床挑战，涉及多种病原体、疾病阶段、复杂的临床表现，以及由此导致的对发病机制缺乏了解。心肌炎是年轻成年人心脏性猝死的主要原因，目前该领域的知识主要集中在疾病后期阶段和病理性免疫反应。然而，对于感染如何在显著的免疫反应之前急性诱导致心律失常基质，人们知之甚少。腺病毒是心肌炎的主要病因，但由于物种特异性，缺乏感染模型，并且不清楚腺病毒感染如何导致心脏骤停。先前报道小鼠3型腺病毒具有嗜心性，但尚未用于了解心脏感染和病理机制。
我们已将小鼠3型腺病毒感染开发为一种模型，以研究在明显的免疫反应或严重心肌病出现之前急性心脏感染及受感染心脏的分子改变。
对受感染心脏的光学标测显示，传导速度降低，同时Cx43磷酸化增加，Cx43是已知调节缝隙连接功能的一个残基。在Cx43处具有磷酸化缺失突变的动物心脏可免受小鼠3型腺病毒诱导的传导速度减慢影响。除了缝隙连接改变外，对小鼠3型腺病毒感染的成年小鼠心室心肌细胞进行膜片钳记录发现，由于 电流密度降低，动作电位时程延长。在人类系统中，我们发现人类5型腺病毒增加Cx43的磷酸化，并破坏人类诱导多能干细胞衍生心肌细胞的同步性，这表明与我们的小鼠全心和成年心肌细胞数据具有共同机制。
总之，这些发现表明腺病毒感染通过直接靶向心脏中的缝隙连接和离子通道功能来产生致心律失常基质。已知这种改变会引发心律失常，并可能导致急性感染患者的心脏性猝死。
