Cardiac Fibrosis Is a Risk Factor for Severe COVID-19.

Julian Mustroph,Benedikt Seither,Lars S Maier,Stefan Wagner,Christoph Brochhausen,Katharina Broeker,Katja Evert,Julian Hupf,Carsten Jungbauer,Christine Meindl,Matthias Evert,Maria J Baier

doi:10.3389/fimmu.2021.740260

Abstract

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor β1 (TGF-β1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-β1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-β1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-β1 mRNA performed at the time of first medical contact.

Highlights

During the 2020 coronavirus disease 2019 (COVID-19) pandemic, direct cardiac manifestations of infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), such as heart failure, arrhythmias [1,2,3], and general ischemic events, were increasingly detected [4, 5]
This study demonstrates that patients who have died from COVID-19 have increased myocardial fibrosis
We postulate that this myocardial fibrosis is likely to be a pre-existing risk factor for severe disease courses of COVID-19, whereby increased expression of sIL1-RL1 induces NRP-1 expression that facilitates angiotensin-converting enzyme 2 (ACE2)-mediated SARS-CoV-2 entry into the lung

Summary

Introduction

During the 2020 coronavirus disease 2019 (COVID-19) pandemic, direct cardiac manifestations of infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), such as heart failure, arrhythmias [1,2,3], and general ischemic events, were increasingly detected [4, 5]. Myocardial magnetic resonance imaging (MRI) of patients with COVID-19 and patients who were post-recovery revealed increased levels of myocardial fibrosis, in patients who had experienced severe COVID-19 disease courses [6, 7]. Cardiac injury and fibroblast activation via TGF-b1 induce the soluble form of interleukin-1 receptor-like 1 (sIL1-RL1 [ known as sST2]), which serves as a decoy receptor for IL-33 and inhibits the cardioprotective effects of IL-33/IL1-RL1 interaction [9, 10, 12]

Methods

Results

Conclusion