The bradykinin hypothesis and COVID – what is it and what can it tell us?

The last few months have seen numerous investigations regarding the pandemic-level development of COVID and its wide-ranging array of symptoms that can vary significantly from one individual to the next. Now, findings from a recent study that explore the erratic mechanisms this virus possesses that can overtake our body, and in some cases our brain, point to what’s known as a bradykinin storm.*

Bradykinin are essentially protein molecules that play a significant role in inflammation. In combination with other naturally occurring chemicals in our system, bradykinin are capable of smoothing muscles and increasing blood flow. This increased blood flow and accompanying sensitization of nerve endings responsible for pain are the components of the inflammation process. As a result, bradykinin causes an increase in vasodilation, blood-brain barrier (BBB) permeability, and pain.1

But first, how does COVID actually get into our system?

As we had discussed in a previous blog this year, the entry point for SARS-CoV-2 or COVID 19 is through ACE2 receptors; it is thought that in most cases, the entry point is the nose where ACE2 receptors are very abundant. Here, ACE2 acts as a cellular doorway for the virus that causes COVID 19. The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, brain (glial cells and neurons) and the heart.2,3

Once inside, COVID 19 actively hijacks the body’s own systems, tricking it into upregulating ACE2 receptors in places where they’re usually expressed at low or medium levels, including and especially the lungs.   

Much has been written about the virus and effects of cytokines, which are proteins secreted by certain cells of the immune system that have an effect on other cells. When released, they signal the immune system to function and affect the growth of all blood and other cells that support the body's immune and inflammation responses. But, when the immune system is over-activated in the presence and in the aftermath of disease, such as COVID, cytokine storms can wreak havoc with our health.

The Bradykinin Theory.

This latest and very interesting theory posits that it is not just a cytokine storm at work, but a bradykinin storm, where the bradykinin molecules begin to run rampant in our system. As such, it actually may be the bradykinin storm that is responsible for the downstream effects with this virus. According to the team’s analysis, when the virus tweaks the renin-angiotensin system (RAS), it causes the body’s mechanisms for regulating bradykinin to go haywire and increases both the vascular and BBB permeability in the body and the brain. COVID 19 also increases hyaluronic acid in the lungs, which causes the lungs to fill with fluid, which as the study noted, is why ventilators don't work - the lungs in the presence of the virus simply become a “water balloon.” Given that bradykinin are known to affect our BBB, this gives us even more cause for concern that brain health could be additionally compromised by this virus.

ACE2 vs RAS vs Bradykinin
ACE2 is a component of the counteracting hypotensive axis of RAS, which controls many aspects of the circulatory system including the body’s levels of bradykinin. As part of the vasopressor system that induces hypotension and vasodilation, bradykinin is degraded by the angiotensin converting enzyme (ACE) and enhanced by the angiotensin produced by ACE2.

So what does this have to do with the risk of COVID?

Chronic exposure to cardiovascular risk factors and oxidative stress creates an environment that favors reduced vasodilation and a pro-inflammatory and pro-thrombotic state. The vascular endothelium is intimately involved in vascular and immune homeostasis. Two pathways that play a major role in endothelial homeostasis, and consequently endothelial dysfunction, are those of the RSA and bradykinin–nitric oxide (NO) systems. Bradykinin storms could create arrhythmias and low blood pressure. I think one reason high dose vitamin C may help is because:
•    It improves immune function with many different mechanisms.
•    It disrupts the ability of endothelial cells to release t-PA and produce a pro-thrombotic state.
Additionally, vitamin D is thought to help reduce bradykinin and it is highly recommended we add this supplement to our dietary regimen now – especially since so many of us are deficient under ordinary circumstances.4

I think this theory likely explains why those with chronic conditions such as underlying cardiovascular disease (CVD), arteriosclerosis cardiovascular disease (ASCVD), prior strokes, diabetes, obesity, metabolic syndrome, smokers, and others often manifest severe COVID illness. There is already in place a systemic “setup” that puts these patients at greater risk.
 
What is metabolic syndrome and why is it important now?

Metabolic syndrome is a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes. These conditions reflect increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. Hispanic women appear to be at the greatest risk of developing metabolic syndrome.  Studies find that your risk of CVD doubles if you have metabolic syndrome and you are more likely to die from the condition if you also have metabolic syndrome.

The “danger zone” numbers:
*A waist measurement of more than 35 inches around (more than 40 inches in men).
*A fasting blood glucose level of 100 mg/dL or higher; or you're already taking medication because you have high blood glucose levels.
*A triglyceride level at or above 150 mg/dL. Triglycerides are a form of fat in your blood.
*An HDL cholesterol level (the "good" cholesterol) below 50 mg/dL (below 40 mg/dL in men); or you're already taking medication to increase your HDL level.
*A blood pressure at or above 130 mm Hg systolic (the top number) or 85 mm Hg diastolic (the bottom number); or you're already taking medication to treat high blood pressure.

The U.S. has an epidemic of metabolic syndrome and obesity, where one out of three adults considered obese and two out of three are overweight. But truly, metabolic syndrome is now a GLOBAL problem.
 
Dr. Robert Lustig, a renowned pediatric endocrinologist and professor emeritus at the University of California – San Francisco, states, “Eighty percent of the population with obesity do in fact have metabolic disease (57 million). However, what typically isn’t recognized is that forty percent of the population without obesity also has metabolic disease (67 million)."  
And, 50 percent of those 60 years of age or older were estimated to have the metabolic syndrome in 2011-2012, according to results published from a cross-sectional population study conducted using NHANES data.5 What’s more, there is also evidence that metabolic syndrome can even affect adults who are of normal weight, making this a critical health factor of which we all need to be aware.

More to ponder…

COVID 19 has taught us many things in what is a relatively short period of time and we are still learning more about this disease as well as how to best treat it. But, what we also should be most concerned about is the PANDEMIC of chronic disease that preceded COVID and the collective impact over the years to global health. And we need to do what we can to improve that state of health in every way possible.  

We have to wonder too...could this virus have been engineered to act in a different manner? Perhaps nature through the advent of this new virus has given all 7+ billion of us on this planet a collective wakeup call and sounded the alarm to raise our collective consciousness now – while we can still affect positive change going forward for our and our children’s futures. Stay curious, commit to getting healthy and, as always, remember we are here for you if you need us.

In hope and healing,
Dr. Suzanne Gazda

References and additional reading:

*The Scientist:
https://www.the-scientist.com/news-opinion/is-a-bradykinin-storm-brewing-in-covid-19--67876

1 Pirahanchi Y, Sharma S. Physiology, Bradykinin. [Updated 2019 Jan 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020
https://www.ncbi.nlm.nih.gov/books/NBK537187/

2 Samavati Lobelia, Uhal Bruce D. Much More Than Just a Receptor for SARS-COV-2. Frontiers in Cellular and Infection Microbiology. (2020) Vol. 10, p. 317. ISSN=2235-2988   
doi: 10.3389/fcimb.2020.00317.
https://www.frontiersin.org/articles/10.3389/fcimb.2020.00317/full

3 https://www.suzannegazdamd.com/scientifically-speaking1/covid-19-news-could-the-virus-also-affect-the-nervous-system

4 Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020;3(9):e2019722. doi:10.1001/jamanetworkopen.2020.19722
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157

5 Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the Metabolic Syndrome in the United States, 2003-2012. JAMA. 2015;313(19):1973–1974. doi:10.1001/jama.2015.4260
https://jamanetwork.com/journals/jama/fullarticle/2293286

Dr. Robert Lustig: https://robertlustig.com/metabolic-education