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\begin{document}

\title{ACE inhibitors and COVID-19: we don't know yet}



\author[1]{Taqua  Khashkhusha}%
\author[2]{Jeffrey Chan}%
\author[3]{Amer Harky}%
\affil[1]{University of Liverpool}%
\affil[2]{The Chinese University of Hong Kong}%
\affil[3]{Liverpool Heart and Chest Hospital NHS Trust}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\begin{abstract}
The SARS-CoV-2, the causative agent of COVID-19, has been established to
gain access to the human cell via the ACE2 receptor similar to its
familial coronavirus SARS-CoV which led to the outbreak in 2003. A
concern with the newer 2019 coronavirus is its 10-20-fold higher
affinity to the ACE2 receptor that of SARS-CoV, aiding its effective
human-to-human transmission which has led to this pandemic. ACE2
receptor expression is thought to be upregulated in use with ACE
inhibitors. As ACE inhibitors are known to be a used extensively in the
treatment of hypertension it was a concern regarding the risk of using
these medications alongside a SARS-COV-2 infection. ACE inhibitors are
also used in the treatment regime of other common conditions including
diabetes and Cardiovascular disease (CVD). It is worth noting that ACE2
expression has found to be upregulated by the use of thiazolidinediones
and ibuprofen too. Consequently, the increased expression of ACE2 would
facilitate infection with COVID-19. Therefore, it would hypothesise that
diabetes and hypertension treatment with ACE2-stimulating drugs would
increase the risk of developing severe and fatal COVID-19.%
\end{abstract}%



\sloppy


ACE inhibitors and COVID-19: we don't know yet

\emph{Running Head: COVID-19 and ACEi}

Taqua R Khashkhusha1, Jeffrey Shi Kai Chan, MBChB2,3, Amer Harky, MBChB,
MRCS, MSc4*

1 School of Medicine, University of Liverpool, Liverpool, United Kingdom
2 Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong 3 Division of Cardiology, Department of Medicine
and Therapeutics, Prince of Wales Hospital, Shatin, New Territories,
Hong Kong 4 Department of Cardiothoracic Surgery, Liverpool Heart and
Chest Hospital, Liverpool, United Kingdom

* Corresponding author:

Amer Harky

MBChB, MRCS, MSc

Department of Cardiothoracic Surgery

Liverpool Heart and Chest Hospital

Thomas Drive, Liverpool

L14 3PE

United Kingdom

E-mail: aaharky@gmail.com

Phone number: 01516001616

Key words: COVID-19, ACEi, Corona Virus

Abstract:

The SARS-CoV-2, the causative agent of COVID-19, has been established to
gain access to the human cell via the ACE2 receptor similar to its
familial coronavirus SARS-CoV which led to the outbreak in 2003. A
concern with the newer 2019 coronavirus is its 10-20-fold higher
affinity to the ACE2 receptor that of SARS-CoV, aiding its effective
human-to-human transmission which has led to this pandemic. ACE2
receptor expression is thought to be upregulated in use with ACE
inhibitors. As ACE inhibitors are known to be a used extensively in the
treatment of hypertension it was a concern regarding the risk of using
these medications alongside a SARS-COV-2 infection. ACE inhibitors are
also used in the treatment regime of other common conditions including
diabetes and Cardiovascular disease (CVD). It is worth noting that ACE2
expression has found to be upregulated by the use of thiazolidinediones
and ibuprofen too. Consequently, the increased expression of ACE2 would
facilitate infection with COVID-19. Therefore, it would hypothesise that
diabetes and hypertension treatment with ACE2-stimulating drugs would
increase the risk of developing severe and fatal COVID-19.

Dear Editor,

The recent Chinese clinical studies detailing the clinical
characteristics of patients infected by the novel COVID-19 infection
have confirmed many of these concerns \textsuperscript{(1)}. A study
included 1099 patient's laboratory-confirmed Covid-19 from 552 hospitals
in 30 provinces, autonomous regions, and municipalities in mainland
China through January 29, 2020, of which 261 had an associated
comorbidity \textsuperscript{(2).} Hypertension yet again was the most
common comorbidity with 165 patients, followed by 81 patients with
diabetes. A meta-analysis \textsuperscript{(3)} evaluating the
comorbidities associated with COVID19 found similar results, however
noted that in comparison to the prevalence of both diabetes and
hypertension in china, the percentage of each comorbidity presenting
with COVID19 was similar. These statistics raise the question of whether
hypertension itself a high-risk comorbidity is or is the use of ACEI
specifically as treatment responsible for these statistics.

Coronary heart disease (CHD) being the most common chronic condition
worldwide, a small percentage of COVID-19 patients had the disease as a
comorbidity. The lower rates of CHD could be associated with the lower
ACE2 receptor expression found to be supressed in patients with the
development of heart failure \textsuperscript{(4).} Lower ACE2
expression then, would reduce the ability of the COVID-19 virus to bind
and infect the cell. Large cohort studies factoring in ACE2 expression
as a variable while comparing progression of COVID19 infection in
patients would indicate the relevance of the ACE2 receptor in COVID19
mortality and fatality.

According to data from the above study, 23\selectlanguage{ngerman}·7\% of patients with
hypertension were assessed to have a severe COVID19 infection, followed
by diabetes mellitus (16·2\%), coronary heart diseases (5·8\%), and
cerebrovascular disease (2·3\%). A high percentage of 35.9\% of who had
hypertension had an end point at ICU, with the use of mechanical
ventilation or death. 26.9\% of diabetic patients had a similar end
point. As ACE inhibiters are dominantly used in hypertension this could
potentially explain the high percentage of COVID19 positive patients who
develop severe infection. Diabetic patients could also be on ACE
inhibitors slowing down the progression of the vascular complications
associated with diabetes hence, the high percentage of diabetic patients
developing a severe infection. Still, however much less than
hypertension which could be due to the lower use of ACE inhibitors in
diabetes in comparison. It has been shown that contracting COVID19 is
equal in both hypertensive and diabetic, however hypertensive patients
are likely to develop a severe infection in comparison.

On the other hand, studies \textsuperscript{(5)} have suggested the use
of ACE inhibitor might be protective against respiratory complications.
The binding of SARS-CoV-2 to ACE2 exhausts ACE2, leading to an imbalance
of the renin-angiotensin-aldosterone system which spirals into acute
severe pneumonia. Blocking the renin-angiotensin-aldosterone system by
ACEI might therefore reduce inflammation in COVID-19 pneumonia,
potentially reducing mortality. A recent study
\textsuperscript{(5)}compared inflammatory marker found in COVID19
positive patients on ACE inhibitors versus non-ACE inhibitors. It was
found that Interleukin 6 a pro-inflammatory marker levels were reduced
in the ACEI group. Large studies are needed to delineate the role of
ACEI in treating COVID-19, ideally both in patients naïve to ACEI, and
chronic users of ACEI. Since small centres may have difficulty amassing
enough cases, inter-institutional collaborations should be strongly
encouraged. These would indicate whether the use of ACE inhibitors in
COVID-19 positive cause more harm than good or vice versa which would
shine a light on the use of hypertensive medication in these patients.

In short, both the concerns regarding ACE inhibitor use predisposing to
infection by SARS-CoV-2 and the idea that ACEI may help treat COVID-19
have valid theoretical bases. At this point, there is insufficient
clinical evidence pointing to either being true, further studies are
urgently required. Given the known, significant cardiovascular benefits
of ACEI, patients should not stop taking them over the above theoretical
concerns. These guidelines nonetheless are due to lack of evidence for
the use of ACE inhibiters in COVID19 positive patients. Medical workers
and researchers worldwide are strongly encouraged to report any
available data regarding the relationship between ACEI and COVID-19.

The authors wish to disclose no conflict of interest.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the
  recognition of the SARS-CoV-2 by full-length human ACE2. Science.
  2020.
\item
  Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL,
  Hui D, et al. Clinical characteristics of coronavirus disease 2019 in
  China. N Engl J Med. 2020. PMID: 32109013.
\item
  Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, Ji R, Wang H, Wang Y,
  Zhou Y, Prevalence of comorbidities in the novel Wuhan coronavirus
  (COVID-19) infection: a systematic review and meta-analysis,
  International Journal of Infectious Diseases
\item
  Toshiyuki Matsumoto, Ryoji Ozono, Tetsuya Oshima, Hideo Matsuura,
  Taijiro Sueda, Goro Kajiyama, Masayuki Kambe, Type 2 angiotensin II
  receptor is downregulated in cardiomyocytes of patients with heart
  failure,~\emph{Cardiovascular Research} , Volume 46, Issue 1, April
  2000, Pages 73--81,
\item
  Juan Meng, Guohui Xiao, Juanjuan Zhang, Xing He, Min Ou, Jing Bi,
  Rongqing Yang, Wencheng Di, Zhaoqin Wang, Zigang Li, Hong Gao, Lei Liu
  \& Guoliang Zhang~(2020)~Renin-angiotensin system inhibitors improve
  the clinical outcomes of COVID-19 patients with hypertension,~Emerging
  Microbes \&
  Infections,~9:1,~757-760,~DOI:~10.1080/22221751.2020.1746200
\end{enumerate}

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