You are all familiar with the warning, "high blood pressure and cardiovascular disease increase your risk of death from COVID-19". You have also probably read, "certain blood pressure medications increase your risk of death from COVID-19". So which is it, high blood pressure, or high blood pressure medications? It's important to know. Either we need to be more aggressive controlling blood pressure, or we need to stop these medications. Why are we getting conflicting recommendations?
Observational evidence
Recommendations like this start with observational studies. They are relatively easy to perform: take characteristics of patients who die from COVID-19, and compare them with the characteristics of patients who have a milder course. From these studies, several risk factors or co-morbidities have surfaced that seem to increase your chance of death from COVID-19. These include: heart disease, high blood pressure, diabetes, and lung disease. These conditions, in turn, are associated with other variables such as: advanced age, male sex, obesity, smoking, high cholesterol, genetics, low grade inflammation, sedentary lifestyle, stress, and poor diet. Any one of these factors could be causing the problem or just associated with the problem. How can we tell?. This is known as the problem of confounding, or "association is not causation".
Moreover, these high risk COVID-19 patients take many medications (like blood pressure medications, NSAIDs, etc). It is inevitable that these medications will be implicated in increasing death from COVID-19 as well. This is another type of confounding called confounding by indication. For instance, PPI acid medications were recently blamed for causing dementia and kidney failure. However, most of the time, these medications are innocent by-standards - association not causation.
Pathophysiological evidence
The best way to prove causation is through a randomized controlled trail. When this is not feasible, doctors turn to pathophysiological evidence. Pathophysiological evidence is evidence from the laboratory - test-tube studies, animal models, and autopsy. This kind of evidence has lead to some of the greatest discoveries in medicine, including the germ theory of disease. However, it is far from perfect and often leads us astray. This is because pathophysiological evidence is deductive in nature, and is usually dependent on a series of weak premises. Consequently, it is malleable, and can be used to support anything the researcher desires. You can find a pathophysiologic pathway to justify just about any idea.
You can find a pathophysiologic pathway to justify just about any idea.
For COVID-19, I can provide pathophysiological evidence that high blood pressure medications improve COVID-19, and I can also provide pathophysiological evidence to the contrary, high blood pressure medications worsen COVID-19. Which one is true? (Note: it is possible that neither are true - neither are causative - both just associations; however, I won't get into this here).
In this post, I will explain what pathophysiological evidence is, provide a brief history of its development, and show how it can arrive at conflicting results with respect to COVID-19. Lets first look at the beginnings of pathophysiologic evidence. The time in history when we decided to make a crucial leap - peering inside dead bodies...
Anatomy - the first time we peered inside dead bodies
If your car or computer is broken down, you need to know the internal workings of it to fix it. You need to know what each part is for (hardware), and how each part communicates with the other parts (software). Yet, prior to the 1400's there was almost no record of human anatomy or autopsy (except for Herophilus of Alexandria). No one actually peered inside the human body to see how it worked. With a strong belief in the afterlife, autopsy and study of the dead was considered immoral, and a desecration of the sacred. It was illegal in almost all cultures. How could doctors learn to fix the human body without understanding the basics, such as: cell theory, chromosomal theory, germ theory, or the rudimentary function of organs like the circulatory system? (This cannot be ignored when we try to incorporate knowledge from traditional medical systems into our current medical practices such as: Humoral medicine from Greece, Ayurvedic medicine from India, and Traditional Chinese Medicine.)
One of the greatest leaps in the history of medicine occurred when we finally decided to peer into the human body. It started during the Renaissance and was driven by the Catholic Church. It turns out the church's doctrine of dualism made autopsy and anatomical dissection allowable. They believed the body was merely a vehicle for the soul; thus, very soon after death, the soul leaves to heaven, and the remaining body is essentially a worthless lump of flesh. The church began to allow anatomical study and autopsy in the 1400's. There were two ulterior motives: they were eager to determine the cause of death when a Pope mysteriously died, and they wanted artists like Leonardo to display perfect anatomical accuracy for church paintings and sculpture.
The first and greatest anatomist was Andreas Vesalius from the University of Padua. He wrote the canonical textbook of anatomy, De Humani Corporis Fabrica (Of the fabric of the human body). It was published in 1543 and became the foundation of medical training for centuries. The illustrations were superb and, in fact, drawn by a student of Titian. (see below. Note the contrapposto position of the corpse)
The birth of pathophysiology and clinicopathological correlation
Once it was deemed okay to dissect humans, the next step was to dissect the bodies of the diseased. This gave birth to pathophysiology - learning the mechanism of disease using samples from the body. Giovanni Morgagni, also from the University of Padua, provided us with the first attempt. He complied a series of 700 patients that he followed from clinic to autopsy. He detailed the symptoms and signs of these sick patients; if and when they died, he performed an autopsy. This allowed him to correlate the symptoms he saw in the clinic with the autopsy findings. This is known as clinicopathological correlation. For example, he is first to describe a case of appendicitis: a man dies with right lower quadrant abdominal pain and fever; Morgagni opens up his abdomen and finds putrid smelling pus in the right lower quadrant. His book, De Sedibus et Causis Morborum per Anatomen Indagatis (The Seats and Causes of Diseases Investigated by Anatomy), was published in 1761. The importance of this cannot be overstated. It introduced one of the principle sources of knowledge in medical science. Take apart the body of a sick person, see how it differs from a well person, and generate a hypothesis about the mechanism of disease. That is pathophysiology.
Moving back to 2020, pathophysiological principles have not changed much. But now instead of eyes, we use electron microscopes, and instead of noses, we use biochemical assays. Let's review the pathophysiological evidence for the role of blood pressure and blood pressure medications in COVID-19.
High blood pressure medications make COVID-19 worse
The Lancet published a small paper last month. Using pathophysiological evidence, it hypothesized that blood pressure medications like ACE inhibitors, and Advil make COVID-19 infections worse. This launched hundreds of news reports, chain emails, and fear amongst the hundred of millions of patients that use these kinds of medications. The deductive reasoning in the paper relies on several premises. Let me break it down for you: ( I don't expect you to follow the logic; just to appreciate the convoluted nature of it)
Premise 1 - The SARS-CoV-2 virus gets into the human cell through a receptor called the ACE2 receptor. Without this receptor the virus could not invade.
Premise 2 - The more ACE2 receptors, the more likely the virus will infect, and the more likely the virus will replicate.
Premise 6. The more a virus replicates the worse the infection.
Premise 3 - This ACE2 receptor is also part of the renin-angiotensin pathway. A pathway responsible for controlling blood pressure.
Premise 4 - Several medications work by affecting the renin-angiotensin pathway; including ACE inhibitors, ARB's, diuretics, and NSAIDs like Advil.
Premise 5 - Taking these medications leads to more ACE2 receptors on cells. (This is due to a feedback mechanism called up-regulation.)
Conclusion - ACE inhibitors, ARB's, diuretics, and NSAIDS make patients more susceptible to COVID-19 and the infection worse.
To avoid a non-sequitur all 6 premises must be true for the conclusion to be true. This is how deductive reasoning works. However, in this case, many of the premises may be wrong. For example, how many ACE2 receptors does the virus require to infect the cell? Would an increase from 10,000 receptors to 11,000 receptors really make a difference? In addition, the small basic science experiments these premises are based on may be irreproducible. We know that when we try to replicate the results of small basic science experiments like these, well over 50% fail to replicate.
High blood pressure makes COVID-19 worse, high blood pressure medications can help
On Friday, The Lancet published another small paper. Using pathophysiological evidence, it hypothesized that high blood pressure makes COVID-19 worse and blood pressure medications can actually help. Their deductive reasoning also relies on a series of several premises. Let me break it down for you:
Premise 1 - ACE2 receptors are found in many organs but particularly in the lining of blood vessels - known as the endothelium.
Premise 2 - The SARS-CoV-2 virus can infect endothelial cells: this has been shown in test tubes, and in three patients from an autopsy series (see picture below of pathology slides)
Premise 3 - Infected endothelial cells leads to inflammation of the endothelium - "endotheliitis"
Premise 4 - Endothelial inflammation leads to endothelial dysfunction.
Premise 5 - Endothelial dysfunction leads to vasoconstriction (clamping down of blood vessels).
Premise 6 - Vasoconstriction leads to poor organ perfusion, decline in organ function and blood clotting.
Premise 7 - Patients with high blood pressure and other cardiovascular issues already have underlying endothelial dysfunction.
Conclusion 1 - Patients with high blood pressure and other cardiovascular issues will have worse outcomes when infected by COVID-19.
Conclusion 2 - Agents like ACE inhibitors, ARB's, statins, and aspirin improve endothelial function, prevent clotting, and will improve outcomes in COVID-19 patients.
Summary
Both high blood pressure, and high blood pressure medications are associated with worse prognosis in COVID-19. Which one is causative? The same journal published separate papers with pathophysiological evidence to support both claims: high blood pressure medications help COVID-19, and high blood pressure medications worsen COVID-19. These are mutually exclusive propositions. Both cannot be true at the same time.
Pathophysiological evidence is a wonderful thing. It has taken us out of the dark, and out of the dark ages; but, it has major limitations. It can help us generate ideas, but not confirm them.
Please continue your blood pressure medications for now. Since we don't know, it's best to continue them. Poor control of blood pressure could lead to worse problems than COVID-19.