THE WORSLEY TIMES

What Does The Renin-Angiotensin-Aldosterone System (RAAS) Have To Do With Long COVID?

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Worsley Times

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Zak Muggleton, Year 3

Patients with ‘long’ COVID-19 end up with a variation of symptoms, involving a large array of systems. This includes respiratory system (cough, breathlessness), cardiovascular system (chest pain, palpitations), MSK system (joint and muscle pain), ENT symptoms (permanent loss of smell/taste, tinnitus, earache), gastrointestinal system (abdominal pain, nausea), neurological system (brain fog, delirium, visual disturbance) and psychological symptoms (anxiety, PTSD, depression). This is not an extensive list (NHSInform, 2023). 

Approximately 15% of all adults who caught COVID reported experiencing long COVID symptoms for some period of time, with the most being women aged 45-54 reporting long covid symptoms (Walker et al, 2021). According to some recent studies, an antibody attacking the mediator of the renin-angiotensin-aldosterone system (RAAS) may be the culprit for these symptoms. 

The RAAS system is initiated, as low blood pressure is detected by the kidneys, so renin is released. Renin converts angiotensinogen into angiotensin I. Then angiotensin I travels to the lungs or the kidneys, where angiotensin converting enzyme (ACE), converts angiotensin I into angiotensin II. Angiotensin II then stimulates the adrenal cortex to release aldosterone, as well as the pituitary gland being stimulated to release antidiuretic hormone (ADH). This, in combination, leads to increased salt retention that raises blood pressure. It also leads to vasoconstriction (blood vessels becoming smaller to increase blood pressure), hypertension and cardiac hypertrophy (increase in cardiac muscle due to strain of pumping blood around the body). 

In opposition, in a non-affected individual, angiotensin-converting enzyme 2 (ACE2) converts angiotensin I (AT1) into angiotensin 1-9 (AT1-9) (further converted into angiotensin 1-7 (AT1-7) by ACE) and ACE2 converts angiotensin II (AT2) into AT1-7. This AT1-7 leads to vasodilation (expansion of the vessels to decrease blood pressure) and hypotension. This system allows the RAAS system to not overwork the body, and lead to systemic effects. 

In COVID, an antibody begins to attack ACE2. ACE2 is an enzyme that can be found either on the membrane of cells (membraneACE2 (mACE2)) or soluble in the body (solubleACE2 (sACE2)). These mACE2 cells are the main passageway of entry for COVID molecules into the cell, and they can be found on the intestines, kidneys, testis, gallbladder or in the heart. As these COVID molecules attach to these ACE2 molecules, the body can no longer vasodilate as effectively, and the RAAS system is allowed to work on overdrive. Therefore the immune system is not activated, and vasodilation does not occur, so damaged tissues do not get adequate blood flow, and there is a less effective delivery of oxygen and nutrients. (DAIC, 2021). Further precipitating the problem is the kallikrein-kinin system which regulates sodium channels using bradykinin, lowering blood pressure and producing reactive oxygen species. COVID has been shown to increase bradykinin levels, leading to further vasoconstriction (Beyerstedt S, 2021). 

Although there are no studies confirming this link, does this lack of vasoconstriction lead to the development of long COVID? What is certain is that the suppression of ACE2 leads to harmful hypertension in these COVID patients. There is also evidence that oestrogen regulates the expression of ACE2 in the body, so potentially patients who have decreased oestrogen, for reasons such as menopause,  become exponentially more at risk of long COVID due to the lack of ACE2 (American Physiological Society, 2020). This could explain why middle-aged women are seemingly most likely to be affected by long COVID.  

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