Recei ed: 2 Augus 2021 Re ised: 30 Sep embe 2021 Accep ed: 2 Oc obe 2021
DOI: 10.1111/jch.14376
OPINION
Pos COVID e ec on endo helial unc ion in hype ensi e
pa ien s: A new esea ch oppo uni y
Luis Giménez-Mi anda Luis Bel án-Rome o Da id León-Jimenez Pablo S ie el
Unidad Clínica de A ención Médica In eg al
(UCAMI) y Labo a o io de Epidemiología
Clínica y Riesgo Vascula . Ins i u o de
Biomedicina de Se illa (IBiS), Hospi al
Uni e si a io Vi gen del
Rocío/CSIC/Uni e sidad de Se illa, Se ille,
Spain
Co espondence
Pablo S ie elMD,PhD,UnidadClínicade A en-
ciónMédicaIn eg al(UCAMI)y Labo a o io
deEpidemiologíaClínica yRiesgo Vascula ,
Ins i u odeBiomedicina deSe illa(IBiS), Se -
icioAndaluzde Salud/ ConsejoSupe io de
In es igacionesCien í icas /Uni e sidadde
Se illa,Hospi alUni e si a ioVi gendel Rocío,
A enidaManuelSiu o s/n, Se ille41013,
Spain.
Email:[email p o ec ed]
Abs ac
SARS-CoV-2iscausingde as a ionbo hinhumanli esand economic esou ces. When
he wo ld seems o s a o e coming he pandemics scou ge, he h ea o long- e m
complica ions o COVID-19 is ising. Repo s show ha some o hese long- e m
e ec s may con ibu e o he main cause o mo bimo ali y wo ldwide: he ascula
diseases. Gi en he e idence o damage in he endo helial cells due o SARS-CoV-2 and
ha endo helialdys unc ionp ecedes hede elopmen o a e ioscle osis, heau ho s
p opose o measu e endo helial unc ion a ound 6–12 mon hs a e acu e disease in
hype ensi e pa ien s, especially i hey ha e o he ca dio ascula isk ac o s o o e
ascula disease. The me hods he au ho s p opose a e cos -e ec i e and can be made
a ailable o any hype ension uni . These me hods could be he “in i o” assessmen o
endo helial unc ion by low media ed asodila a ion a e ischemia by Lase -Dopple
lowme y and he measu emen o plasma ee ci cula ing DNA and mic opa icles o
endo helial o igin.
KEYWORDS
ci cula ing ee DNA, endo helial dys unc ion, endo helial mic opa icles, Lase -Dopple lowme-
y, SARS CoV-2
1INTRODUCTION
A ecen posi ion pape o he Eu opean Socie y o Ca diology (ESC)
Wo king G oup o A he oscle osis and Vascula Biology, and he
ESC Council o Basic Ca dio ascula Science s a es ha (1) “Fu he
esea ch is u gen ly needed o comba he COVID-19 pandemic and
we emphasize ha he ole o ascula endo helium equi es close
sc u iny. The e a e oday se e al ou s anding ques ions ha need o
be add essed o elucida e mo e p ecisely he ole o endo helial cells
in COVID-19 and o in es iga e po en ial ou es o clinical ansla-
ion” and (2) “A be e unde s anding o he e ec s o SARS-CoV-2
on endo helial biology in bo h he mic o- and mac o- ascula u e is
equi ed, and endo helial unc ion es ing should be conside ed in he
ollow-up o con alescen COVID-19 pa ien s o ea ly de ec ion o
long- e m ca dio ascula complica ions”.1
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided
he o iginal wo k is p ope ly ci ed.
© 2021 The Au ho s. The Jou nal o Clinical Hype ension published by Wiley Pe iodicals LLC
In his espec , endo helial dys unc ion (ED) is hough o be a
p ima y s ep in a he oscle osis and ca dio ascula disease. Se e al
ca dio ascula isk ac o s p omo e endo helial dys unc ion including
hype ension, obesi y o insulin esis ance among o he s. ED quan i i-
ca ion has become a isk ma ke ha p edic s he de elopmen o ca -
dio ascula disease and ca dio ascula disease- ela ed mo ali y.2
2MEASURENMENT OF ENDOTHELIAL
FUNCTION
2.1 Flow media ed asodila a ion in esponse o
he ischemia
Endo helial unc ion can be measu ed by assessing he hype emic
esponse o ischemia caused by in la ing a blood p essu e (BP) cu ,
200 wileyonlinelib a y.com/jou nal/jch J Clin Hype ens. 2022;24:200–203.
GIMÉNEZ-MIRANDA ET AL.201
FIGURE 1 Endo helial mic opa icles in s able co ona y a e y disease and ime o majo ad e se ca dio ascula and ce eb al e en s ( aken
om Eu Hea J 2011; 32(16):2034-41 wi h pe mission o he au ho )
20 mm Hg abo e he pa ien ’s sys olic BP. The magni ude o he
esponse can be assessed ei he by high- esolu ion ul asonog aphy o
ple hysmog aphy.3
One o he mos ecen and inno a i e echniques o assess he
magni ude o esponse is Lase -Dopple lowme y, which mainly
allows he de e mina ion o he mic oci cula ion s a us. This is a
nonin asi e echnique, bu i s measu emen s a e p obably mo e inde-
penden o heobse e since he esul sa e au oma icallyob ained by
so wa e. This so wa e assesses many pa ame e s bo h in gene al and
adjus ed analysis o he esponse. Al hough some pa ame e s measu e
he speed o he esponse, such as he slope o he ime o maximum
hype emia, o he s a e ela ed o he du a ion o his esponse, such
as he ime o each he hal alue a e he maximum hype emia.
A p e ious s udy o ou g oup ound ha he a ea o hype emia
was he pa ame e wi h highe sensi i i y and speci ici y o iden i-
ica ion o pa ien s wi h co ona y a e y disease, because he a ea
depends on he speed as well as on he in ensi y and du a ion o he
esponse.4
2.2 Cell- ee DNA measu emen
Al hough ini ially ela ed o neoplas ic diseases cell- ee DNA (c-
DNA) le els, has mo e ecen ly been ela ed o pa hologies in ol ing
ischemia such as acu e co ona y synd ome,5ischemic hea ailu e,6
s oke,7and mesen e ic ischemia,8as well as in pa ien s who ha e
su e ed ca diac a es ou side he hospi al.9Simila ly, inc eases in
ci cula ing c- DNA ha e been documen ed in si ua ions in ol ing
hypoxia, suchas expe imen alacu e pulmona y h omboembolism10 o
obs uc i e sleep apnea/ hypopnea synd ome.11
Ou g oup ha e also obse ed highe le els o c- DNA in pa ien s
wi h p eeclampsia (PCL, a disease ela ed o placen al ischemia) ha
also inc eases wi h he se e i y o disease, being highe in pa ien s
wi h HELLP synd ome, ac onym Hemolysis, Ele a ed Li e enzymes
and Low Pla ele coun . Acco ding o ou da a, we p oposed a cu -
o poin o 950 ng/ml o c- DNA as being suspicious o se e e illness
because hese alues had high sensi i i y and speci ici y o de ec ing
se e e PCL and HELLP synd ome12,13 (Figu e 2).
202 GIMÉNEZ-MIRANDA ET AL.
FIGURE 2 Ci cula ing c- DNA in con ols and pa ien s wi h
p eeclampsia acco ding o he se e i y o disease ( aken om Am J
Hype ens 2013; 26 (12): 1377–80)
Finally, Al a ado Vasquez and cowo ke s14 ha e desc ibed ha ci -
cula ing cell- ee mi ochond ial DNA migh be he p obable induce o
ea ly endo helial dys unc ion.
2.3 Ci cula ing endo helial mic opa icles
Ci cula ing mic opa icles (MPs) a e small esicles ha a e eleased
in esponse o se e al inju ies. The le el o ci cula ing MPs in pe iph-
e al blood has been epo ed o be inc eased in ce eb o ascula dis-
ease, hype ension, diabe es, smoking, co ona y disease, and obs uc-
i e sleep apnea (OSA) synd ome. The e exis s a posi i e co ela ion
be ween ci cula ing le els o MPs and noc u nal hypoxemia se e i y.15
We ha e also p e iously epo ed ha changes in MPs a e con inu-
ousposi i eai wayp essu ein OSA pa ien swe e g ea e in hosewi h
a mo e se e e disease, de ined acco ding o he oxygen desa u a ion
and apnea-hypopnea indexes, sugges ing ha in mo e se e e pa ien s
he bene i is g ea e .16 Finally, Sinning and cowo ke s17 de e mined
CD31+/Annexin V+MPs by low cy ome y in 200 pa ien s (age 66.1
+10.4 yea s) wi h angiog aphically p o en s able co ona y a e y dis-
ease and co ela ed wi h ca dio ascula ou comes. The median ollow-
up ime o majo ad e seca dio ascula and ce eb al e en s(MACCE)
was 6.1 (6.0/6.4) yea s. A i s MACCE occu ed in 72 pa ien s (37%).
MPs le els we e signi ican ly highe in pa ien s wi h MACCE compa ed
wi hpa ien s wi hou e en (p=0.004).Inmul i a ia e analysis(ca dio-
ascula isk ac o s, numbe o diseased essels, use o angio ensin-
con e ing enzyme-inhibi o s, and s a ins), high MPs le el we e asso-
cia ed wi h a highe isk o ca dio ascula dea h [Haza d a io (HR)
4.0, 95% con idence in e al (CI) 1.1–14.6; p=.04], he need o e as-
cula iza ion (HR 2.4, 95% CI 1.3–4.4; p=.005), and he occu ence
o a i s MACCE (HR 2.3, 95% CI 1.4–3.8; p<.001). Inclusion o he
MP le el in o a classical isk ac o model subs an ially inc eased c-
s a is ics om 0.637 (95% CI: 0.557–0.717) o 0.702 (95% CI: 0.625–
0.780) (p=.03). The e o e, hey concluded ha he le el o ci cula ing
CD31+/Annexin V+MPS is an independen p edic o o ca dio ascu-
la e en s in s able co ona y pa ien s and may be use ul o isk s a i-
ica ion.
3CLINICAL AVAILABILITY OF THE
AFOREMENTIONED ENDOTHELIAL FUNCTION
ASSESSMENT
A Lase -Dopple lowme e is a ela i ely inexpensi e de ice (a ound
20,000 eu os) easy o handle by any nu se a e minimal aining. I is
also ela i ely well ole a ed by he pa ien and could be done in abou
20 min including he ime necessa y o elaxing he pa ien . I only
equi es a com o able chai in a low-s ess en i onmen and, he e-
o e, i could be used in any hype ension uni , whe e, on he o he
hand, we a end pa ien s who, apa om hype ension, usually ha e
o he ac o s o ascula isk and e en o e ascula diseases (sec-
onda y p e en ion)
Measu emen o c DNA is used in he clinical ou ine o ea ly can-
ce de ec ion, de ec ion o ecu ence in localized cance , p edic ion
o esponse o ea men in me as a ic cance , iden i ica ion o esis-
ance mechanisms in e ac o y cance s, and moni o ing he esponse
in me as a ic cance . In addi ion, i is used o moni o he ea men
o sys emic lupus e y hema osus. I is also a bioma ke o solid o gan
ansplan ejec ion. Mo eo e , i is also used o e alua e he p ognosis
and moni o ing o auma isms.
Ci cula ing ee e al DNA is ou inely analyzed o de e mine hesex
o he e us, he e al RhD ac o when he mo he is Rh- o ule ou
hemoly ic disease o he newbo n, o diagnosis o e al monogenic dis-
eases, dominan inhe i ance diseases, ecessi e inhe i ance diseases,
and e al aneuploidy s udies.
The measu emen o ci cula ing mic opa icles equi es only
ained pe sonnel and a low cy ome e ha is a ailable in mos hos-
pi als o he diagnosis o ollow-up o pa hologies such as leukemia,
lymphoma, p ima y immunode iciency, moni o ing o he hema ologi-
cal s a us o pa ien s wi h HIV in ec ion, as well as he de ec ion o any
cell line.
As hese esea ch s udies will be on human beings, local e hics com-
mi ee app o al mus be ob ained and pa ien s should be in o med
o he possible ad e se e ec s o hese echniques which will include
hose de i ed om enipunc u e and keeping he cu in la ed on he
a m o 4 min.
4THE NEW PROPOSAL
P ac ically all hype ension uni s a e loca ed in hospi als ha ha e o
could ha e he h ee echniques men ioned abo e. The inding by Sin-
ning and cowo ke s ha is ep oduced in Figu e 1(wi h he au ho ’s
pe mission) shows how, om p ac ically he i s 6–12 mon hs, bo h
cu es ( hose ha p esen e en s and hose ha do no ) begin o di -
e .
GIMÉNEZ-MIRANDA ET AL.203
Ou p oposal is e y simple: all hype ensi e pa ien s who ha e su -
e ed an episode o SARS-CoV-2 in ec ion -and e en mo e so i hey
ha e o he associa ed ascula isk ac o s o al eady mani es ed as-
cula disease- should be e alua ed om he poin o iew o hei
endo helial unc ion a leas once 6–12 mon hs a e he episode, by
any o he h ee a o emen ioned me hods.
We encou age all in e es ed esea che s. o design a compa a i e
s udy, age-sex- isk ac o ma ched s udy o hype ensi e pa ien s wi h
and wi hou his o y o SARS-CoV-2. Bo h g oups should be compa ed
o decide whe he he e a e signi ican di e ences, and in such case,
es ablish cu -o poin s om which o es ablish measu es aimed a
imp o ing he u u e ascula p ognosis in in ec ed pa ien s who ha e
wo sened hei ascula isk due o de e io a ion o endo helial unc-
ion.
CONFLICTS OF INTEREST
The e is no any con lic o in e es .
FUNDING STATEMENT
This wo k was suppo ed by Conseje ia de Salud, Jun a de Andalucía,
Spain [g an numbe PI 0456-2018].
ORCID
Luis Giménez-Mi anda h ps://o cid.o g/0000-0003-2588-5557
Pablo S ie el h ps://o cid.o g/0000-0002-6668-5466
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How o ci e his a icle: Giménez-Mi anda L, Bel án-Rome o
L, León-Jimenez D, S ie el P. Pos COVID e ec on endo helial
unc ion in hype ensi e pa ien s: a new esea ch oppo uni y.
J Clin Hype ens. 2022;24:200–203.
h ps://doi.o g/10.1111/jch.14376