Myocardial Fluid Homeostasis in the Era of COVID-19: Understanding the Dynamics and Pathological Disruptions


The intricate nature of myocardial fluid homeostasis and its disruption under pathological conditions forms a critical aspect of cardiovascular health. This system, essential for maintaining the physiological function of the heart, involves a delicate balance between microvascular filtration and absorption, interstitial hydration, cellular water management by cardiomyocytes, and lymphatic fluid removal.

Pathological conditions such as ischaemia, ischaemia-reperfusion injury, inflammation, and hypertension critically disrupt this balance, leading to dysregulated myocardial fluid dynamics. This dysregulation manifests as tissue oedema, marked by water accumulation in both interstitial and intracellular compartments, which in turn leads to cardiomyocyte injury, dysfunction, and consequent cardiac remodelling.

Myocardial oedema (MO) has been identified as a significant factor in various cardiac diseases, including heart failure, ischaemia-reperfusion injury, and myocarditis. The development of MO involves several mechanisms: disruption of the microvascular barrier, leading to increased endothelial permeability; changes in the myocardial extracellular matrix (mECM); alterations in the cardiac lymphatic system; and dysregulation of cardiomyocyte homeostasis. These changes are not only due to physical disruptions but also involve complex biochemical signaling pathways.

The myocardium is especially susceptible to oedema due to its high metabolic demand and low oxygen extraction reserve, coupled with the reliance on autoregulation of blood flow. This susceptibility means that MO can significantly contribute to myocyte ischaemia by expanding the interstitial space, thereby increasing the distance for oxygen transport.

The mECM plays a crucial role in the physiological functioning of the myocardium. Its primary components, collagen types I and III, provide not only structural support but also play a role in signaling pathways that regulate cellular behavior. Disruption in the balance of mECM, through increased collagen deposition and degradation, can lead to myocardial fibrosis, which is a hallmark of chronic heart failure and acute myocarditis. Myocardial oedema actively promotes these processes by influencing the expression of key proteins involved in collagen synthesis.

Endothelial dysfunction, another critical factor in MO, can be exacerbated by infections such as SARS-CoV-2. This dysfunction leads to increased inflammation, a pro-thrombotic state, and contributes to MO formation. Additionally, the cascade of events initiated by MO, including inflammation, endothelial cell dysfunction, and the release of reactive oxygen species, create a feedback loop that exacerbates the condition, ultimately leading to tissue necrosis, fibrosis, and organ failure.

The Starling forces and the revised Starling equation offer a framework for understanding the regulation of microvascular fluid exchange and its dysregulation in MO. These forces, influenced by various factors such as capillary hydraulic conductivity, hydrostatic pressure differences, and osmotic pressure gradients, determine the rate of fluid filtration. Alterations in these forces, whether due to hypoalbuminaemia, inflammation, or other factors, can lead to enhanced fluid filtration and MO.

The endothelial glycocalyx, a critical component of the endothelial barrier, plays a vital role in regulating microvascular fluid dynamics. Comprising proteoglycans, glycoproteins, and glycosaminoglycans, the glycocalyx modulates immune cell interactions, inflammation, and the permeability of the endothelial barrier. Its disruption or shedding can significantly increase microvascular permeability, contributing to MO.

In summary, the balance of myocardial fluid homeostasis is a complex interplay of various physiological mechanisms and pathophysiological alterations. Understanding these dynamics is crucial for developing effective therapeutic strategies to manage and treat conditions leading to myocardial oedema and its associated complications. This intricate system highlights the importance of maintaining cardiovascular health and the potential impacts of systemic diseases on cardiac function.


The discussion on the impact of viral infections, notably SARS-CoV-2, on myocardial fluid homeostasis highlights the intricate interplay between viral pathophysiology and cardiovascular complications. This complex relationship underscores the significant role of systemic inflammatory processes in disrupting microvascular homeostasis, with profound implications for myocardial health.

During the acute phase of viral infections, rapid cellular entry is facilitated through the destabilization of the endothelial glycocalyx. This breakdown of the endothelial barrier enhances permeability, allowing inflammatory processes to affect adjacent tissues, including the myocardium. The chronic phase is characterized by viral persistence and sub-clinical inflammation, which triggers a cascade of events leading to immunothrombosis, oedema formation, tissue necrosis, and myocardial remodelling, ultimately resulting in heart failure.

Viruses exert additional stress on the endoplasmic reticulum by hijacking cellular machinery for the production of viral proteins and replication intermediates. This stress activates various pro-inflammatory pathways, including those mediated by pattern recognition receptors (PRRs) and toll-like receptors (TLR-4). Notably, the activation of nuclear factor erythroid-2-related factor 2 (NRF2) and the induction of antioxidant enzymes such as superoxide dismutase 1 (SOD-1) and heme oxygenase 1 (HO-1) illustrate the body’s defensive response to mitigate reperfusion injury and oedema formation.

SARS-CoV-2 infection, in particular, activates immunothrombosis pathways through TLR signaling. This involves the formation of extracellular traps (ETs) and the release of nuclear and mitochondrial DNA and histones, which are recognized as damage-associated molecular patterns (DAMPs). These DAMPs promote thrombin generation, leading to platelet activation and the formation of platelet aggregates, which are central to the development of microthrombotic complications during infection.

The role of the TLR-von Willebrand factor (vWF)-NETosis axis in destabilizing microvascular integrity during SARS-CoV-2 infection is noteworthy. This axis is implicated in various organ-specific manifestations, such as pulmonary permeability oedema in acute lung injury/acute respiratory distress syndrome, and vasogenic oedema in the brain of COVID-19 patients with neurological symptoms. The disruption of the blood-brain barrier, characterized by a breakdown of pericyte homeostasis and perivascular inflammation, further exemplifies the systemic impact of SARS-CoV-2.

Here’s an explication of the sentence “The role of the TLR-von Willebrand factor (vWF)-NETosis axis in destabilizing microvascular integrity during SARS-CoV-2 infection is noteworthy” broken down into simpler parts:

Key Words:

  • TLR: Toll-like receptors, proteins on immune cells that recognize pathogens.
  • vWF: von Willebrand factor, a protein in blood that helps platelets stick together.
  • NETosis: A process where immune cells release sticky webs called nets to trap pathogens.
  • Microvascular integrity: The strength and stability of small blood vessels.
  • SARS-CoV-2: The virus that causes COVID-19.

Sentence Breakdown:

  • “The role of…axis”: This refers to the interaction between TLRs, vWF, and NETosis.
  • “in destabilizing microvascular integrity”: This means that this interaction weakens and damages small blood vessels.
  • “during SARS-CoV-2 infection”: This happens when someone is infected with the virus that causes COVID-19.
  • “is noteworthy”: This means that this interaction is important and deserves attention.

Simplified Explanation:

When someone gets infected with the virus that causes COVID-19, certain immune cells called TLRs activate vWF and NETosis. This makes the sticky webs in the blood vessels, which can clog them and weaken their walls. This can lead to serious problems like blood clots and organ damage.

The cardiac implications of SARS-CoV-2 are profound, affecting not only pericytes but also cardiomyocytes and fibroblasts. In animal models, the occurrence of fibrin-rich microthrombi and pericyte loss has been associated with oedematous cardiomyocyte swelling. The virus’s impact on human cardiac pericytes, mediated through the CD147 receptor and ERK1/2 pathway, reveals a complex interplay of viral mechanisms affecting cardiac health.

In conclusion, the maintenance of microvascular homeostasis, including the integrity of the glycocalyx and pericytes, is crucial for preserving the endothelial barrier and interstitial fluid balance. The impairment of these systems during SARS-CoV-2 infection, due to inflammation and ischaemia, significantly enhances vascular permeability and leads to oedema formation. This intricate relationship between viral pathophysiology and myocardial health necessitates further research to gain deeper insights into unique signaling pathways and therapeutic opportunities for managing both acute and chronic SARS-CoV-2 infection. This research will be pivotal in developing targeted treatments to mitigate the cardiovascular impacts of such viral infections.

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