- Cardiovascular disease (CVD)
- Use of anti-hypertension medications

Smith College

Michigan State University

University of Michigan - Ann Arbor

Angiotensin-converting enzyme 2 (ACE2)is a membrane bound protein that functions as a receptor for SARS-CoV-2. Since ACE2 is found in the lungs and heart, systemic inflammatory response triggered by the virus will target those tissues, leading to damage in myocardial cells. This will lead to an increase in cardiovascular symptoms in COVID-19 patients. 

- RAAS and COVID-19 
- ACE Inhibitors and Angiotensin Receptor Blockers 
- Troponin 

Molecular Underpinnings of COVID-19 and the Cardiovascular System

- drug mediators
- non-drug mediators
- genetic mediators
- disease states

Mediators that Infleunce ACE2 Expression

Zheng, Y. Y., Ma, Y. T., Zhang, J. Y., & Xie, X. (2020). COVID-19 and the cardiovascular system. Nature reviews. Cardiology, 17(5), 259–260. https://doi.org/10.1038/s41569-020-0360-5

COVID-19 and the Cardiovascular System

Factors that can potentially increase ACE2 expression in the Cardiovascular System 

Inhibitors of the Renin-Angiotensin-Aldosterone pathway (ie. ACE inhibitors, angiotensin-receptor blockers) are commonly used to treat hypertension. Previous animal studies, which have shown that these inhibitors can increase the level of ACE2 expression in one's body, coupled with the cardiovascular comorbidities, lead to speculation amongst clinicians and researchers that these widely-used drugs may be harmful for patients with COVID-19. Current studies (June 2020) have shown no evidence of harm with continued use of RAAS inhibitors in COVID-19 patients. 

- database study involving 8910 patients from 11 countries
- case control study in the Lombardy region of Italy
- study based on data from the electronic health records in the New York University Langone Health system


Inhibitors of the Renin–Angiotensin–Aldosterone System (RAAS) and COVID-19

In a retrospective analysis, researchers investigated whether patients with hypertension who received ACEIs/ARBs experienced heightened complications of the illness or were at a greater risk of mortality during COVID-19 infection. 


Studying the effect of ACE inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in COVID-19 Patients with Hypertension (Wuhan, China)

- Troponin found circulation in the heart is an indicator of a myocardial injury
- Myocardial injury causes inflammation
- Troponin levels are elevated in COVID-19 patients
- Mortality rates of those with COVID-19 are greater in those with cardiovascular disease
- COVID-19 patients experiencing ARDS are at greater risk of developing nonischemic myocardial injury and type 2 myocardial infarction

Troponin and cardiovascular disease in relation to COVID-19

Other chemical exposures besides drugs such as ACE inhibitors (ACE-Is) and angiotensin II receptor blocker (ARBs) can influence the expression of ACE2.  The following have been shown to increase ACE2 expression levels:

- increased dietary potassium
- intermittent fasting
- nicotine
- Vitamin D
- compounds that interact with SIRT1

Non-Drug Exposures that Increase ACE2 Expression

Sirtuin 1 (SIRT1) is a gene that is expressed next to the promoter region of the ACE2 gene.  Increased expression or activation of SIRT1 is positively associated with ACE2 expression.  Factors that increase SIRT1 expression or activation include:

- calorie restriction
- resveratrol
- Vitamin C
- aspirin
- metformin
- vitamin B3

This may explain why a large Vitamin C dose can possibly have a rescuing effect for COVID-19 patients with severe acute respiratory distress syndrome.

SIRT1 Modulates ACE2 Expression

miRNAs that are homologous to the 3' end of the ACE2 gene were assessed using the data set from the Wang research group to determine if ACE2 expression was modulated by smoking.  miR-1246 is complementary to the  3′ untranslated region (3′UTR) of ACE2 mRNA.  Predicted base pairing was assessed using TargetScanHuman 7.2 (http://www.targetscan.org/vert_72/).  Affymetirx miRNA 2.0 arrays and TaqMan PCR reveal that miR-1246 expression is significantly decreased in smokers compared to nonsmokers (**P < 0.01 and ***P < 0.001).  This miRNA may be involved in the mechanism that regulates ACE2 expression in the SAE. 

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