Since the beginning of the pandemic, everything and its opposite has been said about antihypertensive medications. Used in patients suffering from high blood pressure, these medications were first thought to aggravate the consequences of COVID-19 before being considered as a new therapeutic avenue for the same disease.
As a PhD candidate in pharmaceutical sciences at the faculty of pharmacy and the Institute for Research in Immunology and Cancer in Montréal, I believe it is important to observe the need for rigorous scientific research before disseminating conclusions on such a subject, especially during a health crisis.
The different roles of ACE2
This enzyme acts as a receptor for SARS-CoV-2. The virus binds to ACE2 — like a key that fits into a lock — and is then able to enter the cells to replicate and infect the body. Although SARS-CoV-2 has a significant impact on cells in the lungs, it is now clear that other organs are affected, such as the esophagus, kidney and heart.
But it turns out that the role of the ACE2 is not limited to providing SARS-CoV-2 with a passkey for the body. It works in concert with its close counterpart ACE1 to keep blood pressure in balance.
ACE1 produces angiotensin-2, a protein involved in vasoconstriction (narrowing, or constricting, of blood vessels), which increases blood pressure. ACE2 then takes over to transform this protein into a derivative called angiotensin 1-7, which is, conversely, a powerful vasodilator, and opens — or dilates — blood vessels and lowers pressure.
Conditions such as being overweight, having high stress levels or having kidney disease can lead to high blood pressure (hypertension) and cause increased vessel constriction. This forces the heart to work harder to pump blood through the arteries. Two types of antihypertensive drugs can lower blood pressure: ACE inhibitors, which target ACE1, and angiotensin 2 receptor blockers, which prevent angiotensin 2 from binding to its receptor and acting as a vasoconstrictor.
Nevertheless, the COVID-19 pandemic has raised many concerns among patients on antihypertensive therapy about the risks associated with taking these drugs and the development of complications following viral infection.
Two studies carried out on rats in 2004 — thus outside the context of COVID-19 — showed that taking these antihypertensive drugs induced an increase in the presence of ACE2 in the kidney and the heart.
This observation led to the hypothesis that these treatments would multiply the doorways by which the SARS-CoV-2 virus enters the body, leading to more severe effects such as kidney and heart failure. The fears associated with taking antihypertensive medication reported in some media have been as viral as SARS-CoV-2 itself and have spread internationally. So much so that messages have been disseminated by various relevant health authorities such as the American College of Cardiology and the European Society of Cardiology to prevent the discontinuation of these drugs.
The American College of Cardiology states that at this time, “there is no experimental or clinical evidence to demonstrate the benefits or dangers of taking antihypertensive drugs in patients with COVID-19.” The statements at the root of these controversies are based on a mixture of results from both animal and human experiments.
Moreover, the results of these studies are not reproducible and one study shows no change in the presence of ACE2 after taking antihypertensive drugs. These studies also alternate the administration of the two types of antihypertensive drugs described above, ACE inhibitors and angiotensin-2 receptor blockers, resulting in inconsistent physiological effects.
This may be the reason why some clinical studies in humans further qualify their judgement, suggesting that only some antihypertensive drugs would increase the amount of this receptor and should therefore be evaluated individually or by type. Health authorities believe that hypertensive patients are at risk because they have other conditions, such as diabetes and cardiovascular diseases, that occur with age.
In addition, stopping treatment is risky. It can lead to stroke or heart failure. Furthermore, even if the presence or activity of ACE2 was altered by antihypertensive medication, there are no relevant clinical studies to date that indicate that this would result in increased SARS-CoV-2 infection.
A hope for treatment
The debate took a new twist when some researchers hypothesized that, in reality, the use of antihypertensives may actually be beneficial in COVID-19 patients.
The universities of Minnesota and Kansas have launched two clinical studies to evaluate the therapeutic benefits of losartan, a generic angiotensin-2 receptor blocker, in these patients.
These hypotheses are based on the results of studies conducted on a related virus, SARS-CoV that caused the SARS outbreak in 2003. As both viruses bind to the same receptor (ACE2), it seems relevant to transpose the results observed in SARS-CoV to the new coronavirus.
One study has shown that binding of SARS-CoV to ACE2 results in a decrease in the presence of ACE2. That leads to an accumulation of angiotensin-2. Because angiotensin-2 is a vasoconstrictor, this accumulation increases the risk of vasoconstriction and hypertension.
This phenomenon has been identified as one of the main reasons for pulmonary hypertension, contributing to major damage to the lungs after infection with various viruses, including SARS-CoV, H5N1 and syncitial virus.
Countering the effect of the virus
If the same process exists for SARS-CoV-2, infection would lead to a decrease in the presence of ACE2 in the different organs where the receptor is normally expressed. This phenomenon could significantly increase blood pressure in these organs and cause acute damage to the lungs or heart.
The increase in ACE2 caused by antihypertensive drugs seems paradoxical in this context, but some researchers believe it may actually be life-saving by counteracting the effect of the virus on the receptor. By blocking angiotensin-2 receptors in patients with COVID-19, antihypertensive drugs such as losartan may be able to counteract the exacerbated vasoconstriction that occurs after viral infection. Angiotensin-2 would no longer be able to exercise its vasoconstrictor activity, but would become a vasodilator through its conversion to angiotensin 1-7 by the enzyme ACE2.
To support this hypothesis, a study found elevated levels of angiotensin-2 in the plasma of patients with COVID-19, correlated with high total viral load and significant lung damage. The study suggests that increased angiotensin-2 activity may be partly responsible for organ damage in these patients. However, this study is a small sample of patients and the authors call for larger cohorts in future studies.
The results of the clinical studies in Kansas and Minnesota will provide the first concrete information to clarify the real involvement of losartan, and perhaps this type of antihypertensive in general, in the evolution of COVID-19. At the same time, they will also provide the first answers as to whether this antihypertensive drug is taken at risk or, on the contrary, beneficial in the current context.