Patients Taking Angiotensin-Converting Enzyme Inhibitors/Angiotensin II Type I Receptor Blockers: Higher Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection but Milder Clinical Manifestations?
The COVID-19 pandemic has brought unprecedented attention to the role of angiotensin-converting enzyme 2 (ACE2) in the pathogenesis of SARS-CoV-2 infection. ACE2 serves as the primary receptor for the virus to enter host cells, making it a critical factor in the disease’s progression. Among the many questions raised, the impact of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type I receptor blockers (ARBs) on COVID-19 outcomes has been a subject of intense debate. These drugs, commonly prescribed for hypertension and cardiovascular diseases, are known to influence the renin-angiotensin system (RAS), which includes ACE2. This article explores the complex relationship between ACEIs/ARBs, ACE2 expression, and COVID-19, addressing both the potential risks and benefits of these medications in the context of SARS-CoV-2 infection.
The Role of ACE2 in SARS-CoV-2 Infection
ACE2 is a membrane-bound enzyme that plays a dual role in the RAS. It converts angiotensin II, a potent vasoconstrictor, into angiotensin-(1-7), which has vasodilatory and anti-inflammatory effects. SARS-CoV-2 exploits ACE2 as its entry point into host cells. Upon binding to ACE2, the virus initiates its replication cycle, leading to cellular damage and systemic inflammation. The expression levels of ACE2, therefore, are critical in determining the susceptibility to and severity of COVID-19.
ACEIs/ARBs and ACE2 Expression
One of the primary concerns regarding ACEIs/ARBs in COVID-19 is their potential to upregulate ACE2 expression. Animal studies have shown that these drugs can increase ACE2 levels in various tissues, including the heart and lungs. For instance, Ferrario et al. demonstrated that lisinopril (an ACEI) and losartan (an ARB) increased cardiac ACE2 activity in animal models. However, the doses used in these studies were significantly higher than those typically prescribed in clinical practice, limiting their direct applicability to humans.
The biological significance of ACE2 upregulation depends on the form of ACE2 that is elevated. Membrane-bound ACE2 facilitates viral entry, potentially increasing susceptibility to SARS-CoV-2 infection. In contrast, soluble ACE2, which is cleaved from the cell surface, may act as a competitive inhibitor, preventing the virus from binding to membrane-bound ACE2. The balance between these two forms of ACE2 could determine the overall impact of ACEIs/ARBs on COVID-19 outcomes.
Clinical Implications of ACEIs/ARBs in COVID-19
The potential risks and benefits of ACEIs/ARBs in COVID-19 patients have been the subject of ongoing research. On one hand, increased ACE2 expression could theoretically heighten the risk of SARS-CoV-2 infection. On the other hand, ACEIs/ARBs may mitigate the severity of COVID-19 by modulating the downstream effects of ACE2 and reducing angiotensin II-mediated inflammation.
Several studies have explored these hypotheses. Zhang et al. conducted a retrospective analysis of hospitalized COVID-19 patients with hypertension and found that those treated with ACEIs/ARBs had lower all-cause mortality compared to non-users. Importantly, the blood pressure levels were similar between the two groups, suggesting that the observed benefits were independent of blood pressure control. Reynolds et al. performed a propensity score-matched analysis and found no significant difference in the likelihood of testing positive for SARS-CoV-2 or developing severe illness between ACEIs/ARBs users and non-users.
Mechanisms Underlying the Potential Benefits of ACEIs/ARBs
The potential protective effects of ACEIs/ARBs in COVID-19 may be attributed to their ability to modulate the RAS and reduce inflammation. ACE2 downregulation following SARS-CoV-2 binding can lead to an accumulation of angiotensin II, which exacerbates lung injury through its pro-inflammatory and vasoconstrictive effects. ACEIs inhibit the production of angiotensin II, while ARBs block its binding to the angiotensin II type 1 receptor (AT1R). Both mechanisms can attenuate the inflammatory response and mitigate acute lung injury.
Animal studies have provided evidence supporting this hypothesis. For example, Kuba et al. demonstrated that ACE2 deficiency exacerbates lung injury in SARS-CoV-infected mice, while ACE2 overexpression protects against severe lung damage. Similarly, Imai et al. found that ACE2 plays a crucial role in protecting against acute lung failure in animal models of viral infections.
Genetic Factors and ACE2 Polymorphisms
In addition to pharmacological interventions, genetic factors may influence the susceptibility to and outcomes of COVID-19. Polymorphisms in the ACE2 gene have been associated with variations in ACE2 expression and function, potentially affecting the risk of SARS-CoV-2 infection and disease severity. For instance, Marshall et al. identified an insertion/deletion polymorphism in the ACE2 gene that is associated with susceptibility to acute respiratory distress syndrome (ARDS), a severe complication of COVID-19. Stawiski et al. further explored the role of ACE2 polymorphisms in predicting SARS-CoV-2 susceptibility, highlighting the potential for personalized medicine in managing COVID-19.
Clinical Recommendations and Future Directions
Despite the ongoing debate, most professional societies, including the European Society of Cardiology and the American Heart Association, recommend that patients continue taking ACEIs/ARBs unless advised otherwise by their physicians. The current evidence does not support the discontinuation of these medications due to concerns about increased COVID-19 risk. Instead, the potential benefits of ACEIs/ARBs in mitigating severe outcomes should be considered.
Future research should focus on elucidating the precise mechanisms by which ACEIs/ARBs influence ACE2 expression and activity in humans. Large-scale, well-designed clinical studies are needed to provide definitive answers regarding the role of these drugs in COVID-19. Additionally, the impact of genetic factors, such as ACE2 polymorphisms, on disease susceptibility and outcomes should be further explored to inform personalized treatment strategies.
Conclusion
The relationship between ACEIs/ARBs, ACE2, and COVID-19 is complex and multifaceted. While concerns have been raised about the potential for these drugs to increase ACE2 expression and susceptibility to SARS-CoV-2 infection, the available evidence suggests that they may also confer protective benefits by modulating the inflammatory response and mitigating lung injury. Clinical studies have not demonstrated a significant increase in COVID-19 risk among ACEIs/ARBs users, and some have even shown improved outcomes in these patients. As the scientific community continues to investigate this topic, current recommendations emphasize the importance of continuing ACEIs/ARBs therapy for patients who require it, while closely monitoring for emerging evidence.
doi.org/10.1097/CM9.0000000000000996
Was this helpful?
0 / 0