ACE and ARB blood pressure meds (i.e losartan) and coronavirus concern

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Excerpted from Chris Masterjohn's, PhD newsletter:

A preprint* released yesterday by collaborators from the medical schools of Stanford, Columbia, University of Minnesota, UC San Diego, and Taiwan's China Medical School provided the first evidence of the expression of ACE2 in the upper respiratory tract among humans with different risk factors and found that it is slightly lower in those using ACE inhibitors than in controls, but no different from controls in those using angiotensin receptor blockers (ARBs).

This contradicts the longstanding and controversial concern that these drugs may increase the expression of ACE2 and thereby worsen the risk of contracting COVID-19, since the coronavirus that causes the disease, SARS-CoV-2, uses ACE2 as the portal of entry to infect cells. Conversely, it is consistent with recent studies showing that COVID-19 outcomes are no worse and perhaps better among hypertension patients who use these drugs than among those who don't. Nevertheless, it remains to be seen whether the drugs within these classes are all the same or whether some increase risk and others decrease risk.

Please note that I am not a medical doctor and none of this is medical advice. I have a more detailed disclaimer at the bottom of the page.

Background on ACE2 in Normal Physiology
The role of ACE2 in normal physiology is as part of the renin-angiotensin system. In this system, low blood pressure or low blood volume cause a decreased flow of blood through the kidneys, and the kidneys respond by making renin. Baroreceptors in the aorta and carotid artery also sense the low blood pressure and respond by increasing sympathetic tone (the “fight-or-flight” part of the nervous system), which also increases the kidney's production of renin. Renin is an enzyme that converts angiotensinogen, released by the liver, into angiotensin I. Angiotensin-converting enzyme (ACE, not to be confused with ACE2) in the blood vessels of the lung and kidney then convert angiotensin I to angiotensin II.

Angiotensin II acts on angiotensin receptors to cause vasoconstriction, and causes the adrenals to release aldosterone, which causes the retention of sodium and the urinary loss of potassium. Together, vasoconstriction and sodium retention both increase blood pressure, restoring homeostasis. Chronic elevation of angiotensin II also causes cellular proliferation and fibrosis (the laying down of scar tissue).

ACE2 functions as a counterbalance to ACE, leading to the conversion of angiotensin II to angiotensin 1-7 or, in conjunction with other enzymes, the conversion of angiotensin I to angiotensin 1-7 instead of its conversion to angiotensin II. Angiotensin 1-7 opposes the effects of angiotensin II on blood pressure, cellular proliferation, and fibrosis. Once antiogensin 1-7 is formed, ACE converts it back to angiotensin II, so the relative activity of ACE and ACE2 will dynamically regulate the ratio of angiotensin II to angiotensin 1-7.

In other words, ACE2 is a counterbalance to ACE, and angiotensin 1-7, the product of ACE2, is a counterbalance to angiotensin II, the product of ACE. ACE2 and angiotensin 1-7 support healthy blood pressure and cardiovascular function.

Background on ACE Inhibitors, ARBs, and COVID-19
ACE inhibitors inhibit ACE, not ACE2. Angiotensin-receptor blockers (ARBs) stop angiotensin II from carrying out its function. They also do not directly target ACE2. In fact, both of these classes of drugs are aligned with ACE2 in the sense that they decrease the ACE/angiotensin II axis, which ACE2 and angiotensin 1-7 exist to counterbalance.

An early letter to the editor in the British Medical Journal first popularized the concern that these drugs might increase the risk of COVID-19 by pointing out that lisinopril, an ACE inhibitor, increases the mRNA expression of ACE2 in the heart, while losartan, increases both mRNA expression and activity of ACE2 in the heart.

It is important to distinguish between mRNA expression and activity. mRNA stands for “messenger RNA,” and is a copy of the information contained within a gene that is directly used to synthesize a protein. However, there are many factors that influence the rate at which proteins are synthesized from mRNA, the rate at which they are degraded, what location they make it to within a cell, and to what degree they are switched on and off. Measuring the amount of protein tells you if there is more of the protein. Specific staining techniques can tell you where in the cell there is more or less protein. Measuring the activity of the enzyme takes all of the foregoing factors into account and tells you whether you actually get more of the physiological effect of the enzyme. Measuring mRNA does not tell you that. It just tells you that you might get more of the physiological effect. Or, if you show that mRNA, protein, and activity are all increased the mRNA measurement helps to explain part of why the activity was increased.

In fact, mRNA levels often have no correlation with protein levels.

This is the statement raising the concerns about ACE inhibitors and ARBs from the BMJ:

…it could be shown in animal experiments that both the ACE-inhibitor lisinopril and the angiotensin-receptor blocker losartan can significantly increase mRNA expression of cardiac ACE2 (5-fold and 3-fold, respectively) [5]. Further, losartan also significantly increases cardiac ACE2 activity [5].

Hiding within that statement is the fact that lisinopril did not have any effect on ACE2 activity, suggesting that its effect on the mRNA either did not lead to an increase in the protein, or that the protein was inactive. However, the authors do not draw any attention to that fact. Instead, they strengthen the perception that lisinopril is increasing ACE2 by pointing out that the mRNA was increased 5-fold, which is a very large difference.

A closer look at the study they cite reveals their analysis as even more misleading.

First, it is conducted in rats, which they didn't even mention.

Second, although it is true that lisinopril caused a very large increase in ACE2 mRNA and losartan caused a still large but lesser increase, combining the two drugs brought the cardiac ACE2 levels back down to the level of controls. By contrast, lisinopril had no effect on ACE2 activity, while losartan increased ACE2 activity even when it was combined with lisinopril.

These findings show that there is basically no relationship whatsoever between the drug's effect on mRNA expression and its effect on enzymatic activity. Lisinopril alone, which caused the largest increase in mRNA, did nothing for activity. Losartan increased mRNA when given alone but not when combined with lisinopril, but it increased activity regardless of whether it was combined with lisonopril.

The authors commented on this in the discussion:

The absence of parallelism between gene expression and protein levels has been documented in many studies; therefore, it is not surprising that we did not find a direct correlation between cardiac ACE2 mRNA and cardiac ACE2 activity.

It's bizarre that there could be such a potent demonstration that the effects on mRNA do not say anything about the effects on activity and yet the authors of the BMJ letter would emphasize the mRNA findings without even mentioning this.

Some of the effects of the drugs are not that hard to explain:

  • Lisinopril blocked ACE, which converts angiotensin I and angiotensin 1-7 to angiotensin II. Therefore, it decreased plasma angiotensin II and increased plasma angiotensin 1-7. Less angiotensin II meant less activation of the angiotensin receptor. Activation of the angiotensin receptor ordinarily suppresses ACE2 mRNA production, so the decreased activation of this receptor led to an increased level of ACE2 mRNA. However, since the ACE inhibitor already favored a decrease in angiotensin II and an increase in angiotensin 1-7, increased ACE2 activity was not needed and some unknown factor prevented the increased mRNA level from resulting in increased enzymatic activity.
  • Losartan did not block ACE. Instead, it blocked the angiotensin receptor. This caused the system to compensate by making more angiotensin II, the activator of the receptor. Blocking the receptor increased ACE2 mRNA, just as with lisinopril (which decreased the activator of the receptor). In contrast to lisinopril, which decreased angiotensin II, the large increase in angiotensin II signaled to the system that more ACE2 activity was needed; therefore, unlike lisinopril, which did not increase ACE2 activity, losartan did.
The unknown is the precise mechanism by which activity is controlled, as it is obviously not primarily controlled by the amount of mRNA, and it might not be controlled by the amount of protein either.

In the context of COVID-19, it is critical to distinguish between mRNA, protein, and activity.

In the context of SARS, it was shown that the active site of the ACE2 enzyme, which is responsible for its activity, is not involved in viral entry. So, it is the protein content, not the amount of mRNA or the activity of the enzyme, that matters.

More to the point, in the airway, where viral infection takes place, large amounts of ACE2 are shed from the membrane and become soluble. Soluble ACE2 acts as a decoy for the virus and prevents viral entry. So it is specifically the amount of ACE2 protein located on the surface of cells within the airway that matters.

A paper published on April 23 in the New England Journal of Medicine argued that this issue is very complex because animal models have shown conflicting results about whether these drugs increase ACE2, and the few human studies that exist suggest the drugs are not all the same and have conflict effects. Among the human findings:

  • Intravenous use of ACE inhibitors (different inhibitors were used in different patients) had no effect on angiotensin 1-7.
  • Six-month, but not shorter treatment, with captopril increased angiotensin 1-7, though that could be from decreasing ACE activity rather than increasing ACE2 activity.
  • In patients with heart failure, atrial fibrillation, aortic stenosis, or coronary artery disease, plasma ACE2 was no higher among those using ACE inhibitors and ARBs than those not using them.
  • In Japanese patients with hypertension, urinary ACE2 was higher among those using the ARB olmesartan, but not with other ARBs (losartan, candesartan, valsartan, or telmisartan), or with the ACE inhibitor enalapril.
None of these studies looked at the amount of ACE2 protein located on the surface of the cells within the airway.

Recent Studies on ACE Inhibitors, ARBs, and COVID-19
On May 10, a review was released as as a preprint* that identified nine studies examining the association between ACE inhibitors, ARBs, and COVID-19 outcomes.

The nine studies cover 58,615 patients from China, the United States, the United Kingdom, Italy, and one international group.

All six out of six studies that reported mortality found a reduced risk. Eight of the nine studies reported severity of outcome: two found an increased risk (a 56% increase that was statistically significant in one, a 67% increase that was not significant in the other), one found no effect, and five reported decreased risk (three of which found statistical significance).

The authors performed a meta-analysis pooling the five studies that reported odds ratios (a statistic comparing the risk of being exposed versus not being exposed), and found a 78% decreased risk of severe or critical outcome.

Ace Inhibitors and ARBs Do Not Increase Airway ACE2
Had we had good reason to believe these drugs consistently increase the amount of ACE2 protein on the surface of the cells of the airway, these findings would be deeply puzzling.

However, we never had that.

The new preprint reports the first study to use immunofluorescence to look at airway ACE2 in humans who do and do not use these drugs. Immunofluorescence is a technique that uses antibodies to attach fluorescent molecules to cellular proteins to image how much of the protein is present and where it is found within the cell.

Across several models of the upper and lower respiratory tract, they found that ACE2 is mainly found in the cilia of the airway. Cilia are little hairlike projections that move mucous and debris along, clearing the way for clean air.

To examine risk factors that may associate with ACE2 expression in these cilia, they looked at tissues of the nasal passages from volunteers in three separate cohorts: Stanford, National Taiwan University, and China Medical University.

ACE2 protein was slightly decreased in patients taking ACE inhibitors, who were only represented in the Stanford cohort. ARBs, by contrast, were not associated with ACE2 levels in any of the three cohorts.

This first analysis controlled for age, sex, and smoking status, but not hypertension. In a second analysis controlling for hypertension, the reduced number of subjects caused statistical significance to get lost when they kept the cohorts divided. However, when they pooled the three cohorts together, they found similar results as in the first analysis: hypertension patients who used ACE inhibitors, but not ARBs, had somewhat lower airway ACE2.

Angiotensin II Causes Clotting
One of the less commonly noted effects of angiotensin II's activation of the angiotensin receptor is to promote clotting. If the complications of severe COVID-19 are largely driven by blood clotting (as I've argued here, here, and here), the fact that hypertension doubles the risk of requiring ventilation might be rather simply explained by its association with the pro-clotting effects of angiotensin II. ACE inhibitors and ARBs are, at a minimum, keeping a major risk factor, blood pressure, under control. They may well be having anti-thrombotic effects that underlie the general association with better outcomes in COVID-19.

Different Drugs May Have Different Effects on ACE2
With that said, the “background” section toward the beginning of this article provides ample reason to believe that ACE inhibitors and ARBs do not all have the same effects on ACE2. The studies discussed in this newsletter have all at least grouped the ACE inhibitors together as a class and the ARBs together as a class. Some have even grouped both classes together. None have looked at the individual effects of the specific drugs.

Therefore, I believe the jury is out on any particular drug until it is studied individually.

Still, the available evidence does not support going off of these drugs to prevent or treat COVID-19.

The Bottom Line
The bottom line at this time is that there are no randomized controlled trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes, nor are there studies that look at each drug individually, but they do not appear to increase ACE2 on the surface of cells in the upper respiratory tract in humans, and for people with hypertension, treatment with ACE inhibitors and ARBs in general appears to be associated with a lower risk of critical or fatal disease.

While much remains to be studied, there is currently no basis to go on or off these drugs for the sake of preventing or treating COVID-19. As always, please discuss your own medication use with your own doctor.

Stay safe,
Chris
 
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