Abstract
We have developed murine models of viral myocarditis induced by encephalomyocarditis (EMC) virus in which severe myocarditis, congestive heart failure and dilated cardiomyopathy occur in high incidence. From these models, we have learned the natural history and pathogenesis and assessed not only new diagnostic methods but also therapeutic and preventive interventions. Autoantibodies against cardiac troponin I appeared in spontaneously developing autoimmune myocarditis in PD-1 deficient mice, who lack the T-cell receptor costimulatory molecule PD-1. The passive transfer of this antibody induced myocardial dysfunction. Later, this autoantibody was found in patients with myocarditis. Mast cell deficiency had beneficial effects in the viral myocarditis model, and anti-allergic agents prevented viral myocarditis. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blocker and an aldosterone receptor antagonist improved viral myocarditis, suggesting that the renin–angiotension–aldosterone system may play an important role in the pathogenesis of viral myocarditis. Differential modulation of cytokine production was seen with various calcium channel blockers, and some calcium channel blocker improved viral myocarditis. Viral infection could lead to increased synthesis of immunoglobulin light chains (FLC). Serum levels of FLC were increased in myocarditis, and exogenously given FLC inhibited viral replication and improved myocarditis. We suggest that a strategy of drug development specifically addressing inflammation in myocarditis may provide increased benefit in terms of target organ damage.
Zusammenfassung
Im tierexperimentellen Modell der murinen Enzephalovirusmyokarditis sind schwere Herzmuskelentzündung, kongestive Herzinsuffizienz und dilatative Kardiomyopathie besonders ausgeprägt. In diesem Modell konnten der Spontanverlauf, die Pathogenese sowie neue diagnostische, therapeutische und präventive Interventionen detailliert erforscht werden. In PD-1-defizienten Mäusen, denen das T-Lymphozyten-kostimulatorische Molekül PD-1 fehlt, fanden sich Antikörper gegen kardiales Troponin I bei der sich spontan entwickelnden autoimmunen Myokarditis. Der passive Transfer dieser Antikörper induzierte eine myokardiale Funktionsstörung. Nachfolgend konnten wir die gegen Troponin I gerichteten Antikörper auch bei Patienten mit Myokarditis nachweisen. Eine Reduktion von Mastzellen und die Behandlung mit Antiallergika wirkten sich in diesem Virusmyokarditismodell günstig aus. ACE-Inhibitoren, AT-II-Rezeptor-Blocker und der Einsatz von Aldosteronrezeptorantagonisten verbesserten den Verlauf der Virusmyokarditis. Dies legt eine zentrale Rolle des Renin-Angiotensin-Aldosteron-Systems bei der Viruspathogenese der Myokarditis nahe. Eine differenzielle Modulation der Zyotkinproduktion fand sich unter dem Einfluss diverser Kalziumantagonisten, wobei einige den Verlauf der Myokarditis verbesserten. Die Virusinfektion könnte zu einer vermehrten Synthese von Immunglobulinleichtketten (FLC) führen. FLCs waren bei Myokarditis erhöht nachweisbar, inhibierten, wenn von extern zugeführt, zusätzlich die Virusreplikation und beeinflussten die Ausprägung der Myokarditis günstig. Wir regen deshalb an, Medikamente zu entwickeln, die gezielt die Entzündung bei Myokarditis beeinflussen, um die Schädigung der Zielorgane, insbesondere des Herzens, zu vermindern.
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Matsumori, A. Lessons learned from experimental myocarditis. Herz 37, 817–821 (2012). https://doi.org/10.1007/s00059-012-3692-z
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DOI: https://doi.org/10.1007/s00059-012-3692-z
Keywords
- Encephalomyocarditis (EMC) virus
- Renin–angiotension–aldosterone system (RAAS)
- Troponin I antibodies
- Light chain immunoglobulins
- Treatment