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“We’re on a road to nowhere ...”
In early March of this year, Fang and colleagues published a letter noting that patients with diabetes and/or hypertension treated with ACE inhibitors or angiotensin II type-1 receptor blockers [i.e. ARBs] increase their expression of the ACE2 enzyme. Parenthetically, they also stated that ACE2 is upregulated by thiazolidinediones and ibuprofen. They then speculated that because SARS-CoV2 gains intracellular entry via ACE2 binding, the association between diabetes and hypertension and adverse COVID-19 outcome is, potentially, mediated by medication-induced ACE2 over-expression.
About a week later, another brief report by Sommerstein made similar conjecture. Should clinicians think twice about patients taking life-saving drugs [i.e. ACEIs and ARBs] during the SARS-CoV2 pandemic when these drugs may enhance cellular invasion?
In what feels like a different human epoch, and synchronous with the aforementioned letters, I briefly covered the topic of the angiotensin system in COVID-19. With a helpful cartoon by Dr. Carla Canepa, we illustrated that the relationship between the angiotensin system and COVID-19 severity is not straightforward. Since those early days of the North American COVID-19 onslaught, others have published on this topic; this entry provides a brief update.
The Molecular Basics
Of interest, ACE2 is also the portal of entry for SARS-CoV. Yet, the affinity of SARS-CoV-2 for ACE2 is 10–20-fold more than that of SARS-CoV; ostensibly, explaining the greater transmissibility of SARS-CoV-2. In addition to virus spike protein binding to ACE2, proteolytic cleavage of ACE2 by transmembrane serine protease 2 [TMPRSS2] enhances virus cell entry. TMPRSS2 is well-represented in the lungs and is a potential therapeutic target. That is, there are TMPRSS2 inhibitors such as camostat and nafamostat mesylate.
ACE2 is mostly a membrane-bound enzyme expressed in many organs, including the lungs, heart, and kidneys. Typically, ACE-2 is housed in the vascular endothelium but also in type 2 alveolar epithelial cells.
But what is the role of ACE2? ACE2 enzymatically transforms angiotensin II [Ang II] into Ang[1–7] which acts on the Mas receptor. Ultimately, activation of the Mas receptor causes mild vasodilation, sodium and water excretion and anti-inflammation via nitric oxide. Accordingly, ACE2 antagonizes ACE1–Ang II signalling. Recall that ACE1 generates Ang II [especially in the lung], which acts at the type 1 angiotensin receptor [AT1R] to promote vasoconstriction, myocardial hypertrophy, renal sodium and water absorption, as well as inflammation, fibrosis, bronchoconstriction and vascular permeability [see figure 2 here]. Thus, ACE2 acts as an antidote to Ang II. Given the detrimental effects of unopposed Ang II in ARDS [e.g. inflammation, fibrosis, vascular permeability, vasoconstriction], one may wonder if ACE2 upregulation is actually beneficial?
Evidence that ACEIs and ARBs increase ACE2
If we ignore the above and suppose that excessive ACE2 is harmful because it summons SARS-CoV-2 into the body, what is the evidence that ACEIs and ARBs over-expose the ACE2 enzyme?
First, there is some animal data showing that ACE inhibitors, ARBs and mineralocorticoid receptor antagonists increase cardiac, vascular, and renal ACE2 expression and activity. Second, in patients, 6 months of ACE inhibitor therapy increased plasma Ang[1-7] level and Ang II to Ang[1-7] ratio. As well, spironolactone increased both ACE2 activity and macrophage mRNA from heart failure patients.
Yet there are no investigations demonstrating how ACE inhibitors or ARBs affect ACE2 expression or activity in the lung. Further, other studies have been unable to replicate the aforementioned relationship between ACEI, ARBs and ACE2 upregulation.
Angiotensin II and Inflammation: basic science
While it is unclear that ACEIs and ARBs clearly and consistently upregulate the activity of ACE2, there is no data – not even indirect – supporting the hypothesis that increased ACE2 levels are harmful in COVID-19. By contrast, there is indirect evidence that amplified ACE2 may be beneficial. As briefly described above, the pathway described by ACE1 generating Ang II acting upon AT1R, augments ARDS pathophysiology. By contrast, the pathway of ACE2 acting upon Ang II to generate Ang[1-7] is protective in the lung. Accordingly, Ang II worsens experimental ARDS, while Ang[1-7] and ACEI or ARB administration improves it. This physiology is recapitulated in the myocardium as well; in a murine SARS-CoV-1 model, ACE2 expression is diminished and in patients with myocardial SARS-CoV-1, myocardial inflammation was greater with attenuated ACE2 expression.
And what about aldosterone antagonists [e.g. spironolactone]? Recall that Ang II induces aldosterone release, which encourages vascular damage via mineralocorticoid receptor activation. Aldosterone also exerts multiple pro-inflammatory actions on immune cells, which express the MR. Further, spironolactone also has antiandrogenic actions; interestingly, TMPRSS2 has androgen-dependent expression. Consequently, spironolactone has additional, though highly speculative, mechanisms of benefit in COVID-19 ARDS.
Angiotensin II and Inflammation: suggestive clinical data
If inhibiting Ang II production or blocking its effect on the AT1 receptor calms pulmonary inflammation, one might expect there to exist clinical data revealing diminished incidence of ARDS or pneumonia in patients on these medications. Of note, in two meta-analyses and case control studies in post-stroke and Parkinson’s Disease patients, blocking the renin-angiotensin axis was protective against aspiration pneumonia. While very far from convincing in COVID-19-associated ARDS, these data offer some clinical consistency with the molecular mechanisms described above.
More recently, in a propensity-matching analysis among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower all-cause mortality compared with ACEI/ARB nonusers. Again, as a retrospective, observational analysis, this cannot be used to draw definitive conclusions; but similar to the pneumonia data above, this provides pathophysiological consonance and allays some concern over harm.
When to hold ACEI and ARBs
Do not forget that ceasing ACEI and ARBs in heart failure patients heightens the risk of clinical worsening relatively quickly. In patients with clinical heart failure and New York Heart Association functional class III or IV, holding ACEI or ARB causes plasma angiotensin II, aldosterone, cortisol, and norepinephrine levels to increase to pre-treatment levels within 4-days. Further, in patients with reduced ejection fraction, stopping ACEI therapy for a fortnight returns left ventricular end-diastolic and end-systolic volumes to pre-treatment levels. Thereafter, clinical symptoms and diminished exercise capacity occur within 4–6 weeks of ACE inhibitor withdrawal.
Given the above, there is no good indication to hold ACEIs or ARBs based solely on COVID-19 infection, despite what some have suggested. Indeed, this is echoed in society guidelines. The reasons to hold these medications remain the same as before this pandemic [i.e. expected or concurrent worsening renal failure, hyperkalemia, hypotension, etc]. Thus, we should heed the warnings of others – let us follow scientific rigour before speculation; sound science before quick judgement.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org