COVID-19 Is, in the End, an Endothelial Disease

Peter Libby; Thomas Lüscher

Disclosures

Eur Heart J. 2020;41(32):3038-3044. 

In This Article

Abstract and Introduction

Abstract

The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

Introduction

The vascular endothelium provides the crucial interface between the blood compartment and tissues. The endothelial monolayer that lines the intima of arteries, veins, and microvessels measures up to 7000 m2 in surface area.[1] The endothelium possesses a series of remarkable properties that contribute capitally to homeostasis (Figure 1, left). The endothelium furnishes one of the only surfaces, either natural or synthetic, that under physiological conditions maintains blood in a liquid state during prolonged contact. The endothelium displays a tightly regulated palette of functions that control vasomotion, inflammation, oxidative stress, vascular permeability, and structure.[2] The endothelial cells also provide a crucial interface in host defences, forming the front line of encounter with bloodborne pathogens, thus sensing danger threatening the organism in a concerted fashion, sending early warning signals of infection, invasion, or injury.[3] While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host (Figure 1, middle and right).[4,5]

Figure 1.

The left side of the diagram depicts a resting endothelial monolayer with the endothelial cells of squamous morphology resting on an intact basement membrane. The homeostatic mechanisms displayed by the resting endothelium include the listed properties as detailed in the text. When the endothelial cells undergo the cytopathic effect of a viral infection such as SARS-CoV-2, or encounter pathogen-associated molecular patterns (PAMPs) derived from viruses or bacteria such as lipopolysaccharide, proinflammatory cytokines such as IL-1 or TNF, or damage-associated molecular patterns (DAMPs) derived from dead or dying cells, the endothelial cells become activated. The endothelial cells display more columnar morphology. They can express adhesion molecules that attract leucocytes and chemokines that direct their migration into the subendothelial space. Sloughing of endothelial cells uncovers the thrombogenic basement membrane. Adherent neutrophils can undergo formation of neutrophil extracellular traps that provide an amplifier for endothelial damage mediated in part by IL-1α. Inflammatory activation of endothelial cells can disrupt VE-cadherin largely responsible for the integrity of the endothelial barrier function.62 Activated endothelial cells can also express matrix metalloproteinases that can degrade the basement membrane and further interrupt endothelial barrier function. In small vessels, such as those that embrace alveoli in the lung, this impaired barrier function can lead to capillary leak. These various disturbances in endothelial function, depicted in the middle part of the diagram, lead to end organ damage including adult respiratory distress syndrome and thrombosis in the lungs, predispose to plaque rupture and thrombosis in coronary arteries, and affect the microvasculature leading to myocardial ischaemia and damage. The thrombotic diathesis provoked by endothelial dysfunction can also predispose towards strokes. Microvascular as well macrovascular injury can potentiate acute renal failure. Hepatic dysfunction can also result from microvascular thrombosis among other mechanisms. Deep venous thrombosis can occur as endothelial disfunction represents an important part of Virchow's triad, and sets the stage for pulmonary embolism. Thus, loss of the endothelial protective and unleashing of the mechanisms depicted can lead to multiorgan system failure that characterizes the advanced stages of COVID-19.

SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems, in particular the lungs, heart, brain, kidney, and vasculature. This essay will explore the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. This concept not only provides a unifying pathophysiological picture of this raging infection but also furnishes a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

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