Academic Edi o : Panagio is
Geo gianos
Recei ed: 1 Feb ua y 2025
Re ised: 25 Feb ua y 2025
Accep ed: 27 Feb ua y 2025
Published: 4 Ma ch 2025
Ci a ion: Ge aci, G.; So ce, A.; Zanoli,
L.; Cu one, G.; Calab ese, V.; Pallo i,
F.; Pa e nò, V.; Fe a a, P.; Dominguez,
L.J.; Polosa, R.; e al. Rela ionship
Be ween 8-iso-p os aglandin-F2αand
P edic ed 10-Yea Ca dio ascula Risk
in Hype ensi e Pa ien s. Li e 2025,15,
401. h ps://doi.o g/10.3390/
li e15030401
Copy igh : © 2025 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license
(h ps://c ea i ecommons.o g/
licenses/by/4.0/).
A icle
Rela ionship Be ween 8-iso-p os aglandin-F2αand P edic ed
10-Yea Ca dio ascula Risk in Hype ensi e Pa ien s
Giulio Ge aci 1, Alessand a So ce 2, Luca Zanoli 3, Giuseppe Cu one 1, Vincenzo Calab ese 1,
F ancesco Pallo i 1, Valen ina Pa e nò4, Pie o Fe a a 5,6 , Ligia J. Dominguez 1, Ricca do Polosa 1,7 ,
Jacob Geo ge 8, Giuseppe Mulè2and Ca e ina Ca ollo 2,*
1Depa men o Medicine and Su ge y, Ko e Uni e si y o Enna, 94100 Enna, I aly;
[email p o ec ed] (G.G.); giuseppe.cu one@uniko e.i (G.C.); incenzo.calab [email p o ec ed] (V.C.);
[email p o ec ed] (F.P.); [email p o ec ed] (L.J.D.); [email p o ec ed] (R.P.)
2Uni o Neph ology and Dialysis, Hype ension Excellence Cen e, Depa men o Heal h P omo ion,
Mo he and Child Ca e, In e nal Medicine and Medical Special ies (PROMISE), Uni e si y o Pale mo,
90133 Pale mo, I aly; alessand a.so ce@communi y.unipa.i (A.S.); [email p o ec ed] (G.M.)
3
Neph ology, Depa men o Clinical and Expe imen al Medicine, Uni e si y o Ca ania, 95124 Ca ania, I aly;
[email p o ec ed]
4Ope a i e Uni o Diabe ology, Umbe o I Hospi al, P o incial Heal h Au ho i y (ASP) o Enna, 94100 Enna, I aly
5
Cen e o Public Heal h Resea ch, Uni e si y o Milan–Bicocca, 20900 Monza, I aly; pie [email p o ec ed]
6Labo a o y o Public Heal h, IRCCS Is i u o Auxologico I aliano, 20149 Milan, I aly
7Cen e o Excellence o he Accele a ion o Ha m Reduc ion, Uni e si y o Ca ania, 95124 Ca ania, I aly
8Ca dio ascula Medicine and The apeu ics, Uni e si y o Dundee Medical School, Ninewells Hospi al,
Dundee DD1 9SY, UK; [email p o ec ed]
*Co espondence: ca e ina.ca [email p o ec ed]
Abs ac : Backg ound: 8-iso-p os aglandin-F
2α
(8-iso-PGF
2α
) is a ecognized ma ke o
oxida i e s ess. P e ious s udies sugges ed ha 8-iso-PGF
2α
plays an impo an ole in
he pa hogenesis o hype ension and ca dio ascula (CV) diseases. Howe e , limi ed da a
exis on he p ognos ic ole o 8-iso-PGF
2α
in hype ensi e pa ien s unde going p ima y
p e en ion. The aim o his s udy was o assess he ela ionship be ween 8-iso-PGF
2α
and
10-yea CV isk, as p edic ed by alida ed equa ions in hype ension pa ien s wi hou CV
diseases. Ma e ials and me hods: A o al o 432 indi iduals aged 40–75 yea s we e en olled.
Plasma 8-iso-PGF
2α
was assessed h ough he ELISA me hod. CV isk was calcula ed by us-
ing he F amingham Risk Sco e (F -S) and he A he oscle osis Ca dio ascula Disease Risk
Sco e (ASCVD-S). Low, mode a e, o high CV isks we e de ined acco ding o alida ed
cu o s. Resul s: Indi iduals wi h highe CV isk had signi ican ly g ea e 8-iso-PGF
2α
alues compa ed o hose wi h low o mode a e CV isk (p< 0.001). 8-iso-PGF
2α
co ela ed
s ongly wi h F -S and ASCVD-S in he en i e popula ion and in pa ien s wi h no mal
enal unc ion (all p< 0.001) bu no in pa ien s wi h eGFR < 60 mL/min/1.73 m
2
. These
associa ions emained signi ican a e adjus men o adi ional ac o s included in he CV
isk equa ions in he o e all popula ion and in pa ien s wi h no mal enal unc ion. The
8-iso-PGF
2α
cu o s ha bes dis inguished pa ien s wi h high CV isk we e 310 pg/mL o
F -S and 264 pg/mL o ASCVD-S in he o e all popula ion, wi h signi ican di e ences be-
ween he g oups di ided by eGFR (all p< 0.001). Conclusions: These indings highligh he
po en ial u ili y o 8-iso-PGF
2α
as a bioma ke o e ining ca dio ascula isk s a i ica ion
in hype ensi e pa ien s, pa icula ly hose wi h p ese ed enal unc ion. Fu u e s udies
should explo e i s p ognos ic alue in longi udinal coho s and assess i s in eg a ion in o
clinical isk models o enhance ea ly p e en ion s a egies o ca dio ascula disease.
Keywo ds: oxida i e s ess; 8-iso-p os aglandin-F
2α
ca dio ascula isk; hype ension;
ch onic kidney disease; in lamma ion; p e en ion; p ognosis
Li e 2025,15, 401 h ps://doi.o g/10.3390/li e15030401
Li e 2025,15, 401 2 o 14
1. In oduc ion
The 8-iso-p os aglandin-F
2α
(8-iso-PGF
2α
) is a bioac i e compound mainly o med
in humans ia he ee adical-media ed pe oxida ion o a achidonic acid in memb ane
phospholipids [
1
]. I se es as a aluable bioma ke o
in i o
lipid oxida ion and a
su oga e indica o o inc eased eac i e oxygen species p oduc ion and educed ni ic
oxide bioa ailabili y. As such, i is conside ed a sensi i e and speci ic index o oxida i e
s ess [
2
,
3
]. P e ious s udies ha e demons a ed ha 8-iso-PGF
2α
induces asocons ic ion,
pla ele ac i a ion, and smoo h muscle p oli e a ion in blood essels [
4
]. These e ec s
con ibu e o he impai men o endo helium-media ed asodila a ion and p omo e a
p o- h ombo ic and p o-in lamma o y s a e [3–6].
The e is conside able e idence ha F
2
-isop os anes a e in ol ed in he pa hogene-
sis o hype ension and a he oscle osis, and hei impo an ole in he de elopmen o
ca dio ascula diseases has also been desc ibed [
7
–
10
]. Oxida i e s ess con ibu es o
he ad e se e ec s o ca dio ascula isk ac o by inducing endo helial dys unc ion and
mo pho unc ional changes in mic oci cula ion, bo h o which a e s ong p edic o s o o gan
damage and ca dio ascula ou comes [5,6,11,12].
O e he yea s, se e al ma hema ical models ha e been de eloped o es ima e global
isk o ca dio ascula e en s by in eg a ing he pa ial in o ma ion o each majo isk ac o .
Among hese, he F amingham Risk Sco e (F -S) and he A he oscle osis Ca dio ascula
Disease Risk Sco e (ASCVD-S) ha e become widely adop ed due o hei simplici y and
alida ion ac oss di e se popula ions [
13
–
15
]. De eloped om longi udinal ial da a,
hese sco es can es ima e he 10-yea isk o ca dio ascula diseases, and hei use is
ecommended o assess o e all ca dio ascula isk, p o iding a comp ehensi e app oach
o managing hype ensi e pa ien s [15–17].
The ea ly de ec ion o ca dio ascula isk in hype ensi e pa ien s is c ucial o im-
plemen ing imely in e en ions ha can educe he p og ession o ca dio ascula disease
and associa ed complica ions. Iden i ying high- isk indi iduals a an ea ly s age allows
o a ge ed li es yle modi ica ions, op imized pha macological ea men , and pe son-
alized p e en i e s a egies. The use o eliable bioma ke s, such as 8-iso-PGF
2α
, as a
ma ke o
in i o
oxida i e s ess, can enhance isk s a i ica ion by p o iding objec i e
measu es o oxida i e s ess, a key con ibu o o ascula dys unc ion [
1
]. In eg a ing such
bioma ke s in o ou ine clinical assessmen s may imp o e isk p edic ion, acili a e ea ly
he apeu ic decisions, and ul ima ely con ibu e o he p e en ion o hype ension- ela ed
ca dio ascula e en s [7–9,18].
In his con ex , 8-iso-PGF
2α
eme ges as a po en ial media o be ween oxida i e
s ess and ca dio ascula isk assessmen , po en ially se ing as a p edic o o ca dio-
ce eb o ascula diseases ac oss di e se popula ions [
7
–
9
]. While some s udies suppo
his associa ion, con lic ing da a emain [
18
]. Fo example, a sys ema ic e iew by Zhang
e al., summa izing indings om 20 s udies, epo ed a signi ican co ela ion be ween
ele a ed F
2
-isop os anes le els in u ine o blood and ca dio ascula disease [
9
]. Howe e ,
he au ho s emphasized he need o u he esea ch o cla i y he ole o F2-isop os anes
as a non-speci ic indica o o ca dio ascula disease.
Gi en he limi ed e idence on he p ognos ic alue o 8-iso-PGF
2α
, a speci ic F
2
-
isop os ane, in hype ensi e pa ien s, pa icula ly in he con ex o p ima y p e en ion, ou
s udy seeks o in es iga e i s po en ial as a bioma ke o p edic ing 10-yea ca dio ascula
isk. Impo an ly, no p io esea ch has explo ed he ela ionship be ween oxida i e s ess,
as measu ed by 8-iso-PGF
2α
, and ca dio ascula isk p edic ions de i ed om alida ed
isk models in hype ensi e pa ien s. Add essing his gap, ou s udy aims o p o ide
new insigh s in o he clinical ele ance o oxida i e s ess ma ke s in ca dio ascula isk
s a i ica ion.
Li e 2025,15, 401 3 o 14
2. Ma e ials and Me hods
2.1. S udy Design and Popula ion
This c oss-sec ional obse a ional design was pe o med on 432 essen ial hype ensi e
pa ien s selec ed om Caucasian pa ien s consecu i ely a ending he Neph ology and
Hype ension Sec ion o he Uni e si y Hospi al o Pale mo, I aly, o specialis ad ice,
be ween Janua y 2024 and Oc obe 2024. Pa ien s mee ing he ollowing c i e ia we e
excluded om his esea ch (see Supplemen a y Figu e S1):
−
Aged <40 and >75 yea s old, o align wi h he applica ion ange o F -S and ASCVD-S;
−
Reno ascula , endoc ine, o malignan hype ension o hype ension associa ed wi h
obs uc i e sleep apnea synd ome, as desc ibed in de ail in p e ious s udies [19,20];
−Renal eplacemen he apy ( ansplan ed o dialysis pa ien s);
−
Pha macological ea men o ca diac hy hm o conduc ion abno mali ies, in o de
o minimize po en ial con ounde s;
−
Use o nons e oidal o s e oidal an i-in lamma o y medica ions wi hin 4 weeks be o e
he s a o he s udy.
−
His o y o ce eb o ascula disease, co ona y hea disease, o symp oma ic pe iphe al
a e ial disease;
−Hospi aliza ion o CV cause in he p e ious 6 mon hs;
−
Majo non-ca dio ascula diseases (his o y o li e ci hosis, ch onic obs uc i e lung
disease, o neoplasms).
The s udy p o ocol con o med o he e hical guidelines o he Decla a ion o Helsinki on
e hical p inciples o medical esea ch in ol ing human subjec s (REF) and was app o ed by
he Local Re iew Boa d. W i en in o med consen was ob ained om each pa ien .
2.2. Clinical and Labo a o y E alua ion
Ca e ul clinical his o y and physical examina ion we e pe o med in all pa ien s. Indi-
iduals who epo ed smoking ciga e es egula ly du ing he pas yea we e conside ed
cu en smoke s. Body weigh and heigh we e measu ed by a nu se, and body mass index
(BMI) was calcula ed as body weigh di ided by squa ed heigh (kg/m
2
). Pa ien s wi h a
his o y o diabe es (o on ea men wi h an idiabe ic d ugs) o wi h as ing se um glucose
le els o
≥
126 mg/dL we e conside ed diabe ics. Fo indi iduals wi h as ing se um
glucose le els o be ween 100 and 125 mg/dL, he diagnosis o diabe es was con i med
based on ei he glyca ed hemoglobin o 2 h plasma glucose du ing an o al glucose ole ance
es . Clinic blood p essu e (BP) was eco ded by a doc o as he mean o h ee consecu-
i e measu emen s ob ained a 2 min in e als using a alida ed elec onic oscillome ic
de ice (Wa chBP O ice, Mic oli e AG, Widnau, Swi ze land), a e 5 min o es in a si ing
posi ion. Acco ding o he 2023 Eu opean Socie y o Hype ension/Eu opean Socie y o
Ca diology guidelines, hype ension was de ined as a BP
≥
140/90 mmHg o ea men
wi h an ihype ensi e d ugs [17].
A 08:30 h on he day o he s udy, he o e nigh - as ed pa ien s we e placed in a
supine posi ion, and blood samples we e ob ained om an indwelling o ea m enous
ca he e . Rou ine biochemical pa ame e de e mina ion was pe o med in all pa ien s wi h
s anda d echniques using an au oanalyze (Boeh inge Mannheim o Hi achi sys em
911, Mannheim, Ge many). Low-densi y lipop o ein (LDL) choles e ol was calcula ed
using he F iedewald o mula. Es ima ed glome ula il a ion a e (eGFR) was de e mined
using he Ch onic Kidney Disease Epidemiology Collabo a ion (CKD-EPI) equa ion. The
8-iso-PGF
2α
was measu ed by a solid-phase, speci ic enzyme-linked immunoso ben assay
(ELISA) using a comme cial ki (Assay Design Inc., Ann A bo , MI, USA), wi h pa icula
a en ion o minimizing in e e ence om o he se um componen s. A e cen i uga ion a
4
◦
C, blood samples we e ozen a
−
80
◦
C and p ocessed wi hin 2 mon hs o collec ion.
Li e 2025,15, 401 4 o 14
Acco ding o he manu ac u e ’s ecommenda ions, he es sensi i i y was 16.3 pg/mL,
and he in e -assay coe icien o a ia ion was <9%. High-sensi i i y C- eac i e p o ein
(CRP) was also measu ed using a comme cially a ailable ELISA ki (Diagnos ic Biochem,
London, On a io, Canada), wi h a sensi i i y o 10 ng/mL, an in e -assay coe icien o
a ia ion o <10%, and an in a-assay coe icien o a ia ion o <8%.
Ca dio ascula isk sco e: Pas medical his o y, clinical da a, and labo a o y es s we e
collec ed in all pa ien s o p edic he 10-yea isk o ca dio ascula e en s using alida ed
equa ions o F -S and ASCVD-S. These ma hema ical sex- and ace-speci ic models p o ide
an es ima e o o e all 10-yea ca dio ascula isk, and we e, espec i ely, de i ed by he
F amingham coho s udy and pooled coho s o pa icipan s om se e al la ge s udies,
including he A he oscle osis Risk in Communi ies (ARIC) s udy, he Ca dio ascula
Heal h S udy, and he Co ona y A e y Risk De elopmen in Young Adul s (CARDIA)
s udy. Based on speci ic cu -o s, he pa ien s we e classi ied in o low CV isk (F -S < 10%;
ASCVD < 7.5%), in e media e CV isk (F -S
≥
10% and <20%; ASCVD
≥
7.5% and <15%),
o high CV isk (F -S ≥20%; ASCVD ≥15%) [15–21].
2.3. S a is ical Analysis
S a is ical analyses we e pe o med using he IBM SPSS S a is ics so wa e pack-
age, e sion 23, o Macin osh (SPSS, Chicago, IL, USA). S a is ical analysis was ini ially
pe o med on he en i e s udy popula ion. Gi en he well-es ablished link be ween 8-iso-
PGF
2α
and kidney unc ion, as no ed in p e ious s udies [
22
,
23
], s a is ical analysis was
subsequen ly conduc ed on wo subg oups based on eGFR:
≥
60 mL/min/1.73 m
2
(n= 279)
and <60 mL/min/1.73 m
2
(n= 153). Fo u he analyses, he popula ion was di ided in o
h ee g oups acco ding o alida ed 10-yea ca dio ascula isk cu o alues (10% and 20%
o F -S; 7.5% and 15% o ASCVD-S) [15–21].
The no mal dis ibu ion o con inuous a iables was assessed using he Kolmogo o –
Smi no es . Con inuous a iables we e epo ed as means
±
s anda d de ia ion (SD).
T iglyce ides, F -S, and ASCVD-S, which had skewed dis ibu ions, we e log- ans o med
o sa is y dis ibu ional assump ions be o e applying pa ame ic es s. These a iables we e
p esen ed as median and in e qua ile ange (IQR). Ca ego ical a iables we e exp essed as
pe cen ages. Compa isons o con inuous a iables be ween g oups we e conduc ed using
S uden ’s - es o unpai ed da a o analysis o a iance (ANOVA) wi h he Holm–Sidak
es o mul iple compa isons, as app op ia e. Fo he ca ego ical a iables, compa isons
we e pe o med using he
χ2
es , wi h he Mon e Ca lo me hod employed o compu e
exac wo- ailed α- alues.
Uni a ia e eg ession analyses wi h Pea son’s co ela ion coe icien s we e used o
examine he ela ionships be ween 8-iso-PGF
2α
wi h F -S, ASCVD-S, and he o he a i-
ables. S epwise mul i a ia e eg ession analyses we e pe o med wi h F -S (o al e na i ely
ASCVD-S) as he ou come a iable. Co a ia es included: age, sex (0 = emales; 1 = males),
diabe es (0 = no; 1 = yes), cu en smoking habi (0 = no; 1 = yes), an ihype ensi e he apy
(0 = no; 1 = yes), BMI, se um o al choles e ol, HDL and LDL-choles e ol, clinic sys olic
BP, eGFR, and 8-iso-PGF
2α
. To u he assess he in luence o enal unc ion, ea ed as
con inuous a iable (eGFR), on he ela ionship be ween F -S (o al e na i ely ASCVD-S)
and 8-iso-PGF
2α
, addi ional mul i a ia e models we e analyzed in he popula ion di ided
in o wo g oups based on eGFR alues (
≥
60 mL/min/1.73 m
2
o <60 mL/min/1.73 m
2
). A
backwa d s epwise p ocedu e was used in all analyses, wi h
α
equal o 0.15 as he cu o o
a iable en y o emo al. Collinea i y was assessed by calcula ing he a iance in la ion
ac o (VIF): a iables wi h VIF
≥
2 we e excluded om he models. The null hypo hesis
was ejec ed wi h a wo- ailed p- alue ≤0.05.
Li e 2025,15, 401 5 o 14
Recei e -ope a ing cha ac e is ic (ROC) cu es we e buil o he en i e popula ion and
o he wo g oups di ided by eGFR o e alua e he accu acy o 8-iso-PGF
2α
in de ec ing
a 10-yea isk o ca dio ascula disease
≥
20% wi h F -S o
≥
15% wi h ASCVD-S. The
signi icance o di e ences be ween ROC cu es was assessed using he Hanley and McNeil
me hod. The null hypo hesis was ejec ed a a p- alue o ≤0.05.
3. Resul s
A o al o 432 hype ensi e pa ien s we e en olled. The mean age o he o e -
all s udy popula ion was 60
±
10 yea s; 59.0% we e male and 35.4% had an eGFR o
<60 mL/min/1.73 m
2
. Table 1p esen s he cha ac e is ics o he o e all s udy popula ion
and he wo g oups di ided by eGFR.
Table 1. 8-iso-PGF
2α
in pa ien s wi h low, mode a e, o high ca dio ascula isk calcula ed by he
F amingham Risk Sco e o ASCVD Risk Sco e.
Va iable * O e all Popula ion
(n= 432)
eGFR ≥60
(n= 279)
eGFR < 60
(n= 153) p-Value ˆ
Age (yea s) 60 ±10 57 ±10 65 ±8<0.001
Male sex, n(%) 255 (59) 173 (64.0) 82 (53.6) NS
Smoking habi , n(%) 109 (25.3) 59 (21.15) 50 (32.8) NS
Diabe es, n(%) 111 (25.7) 63 (22.6) 48 (31.4) NS
An ihype ensi e he apy, n(%) 415 (96.1) 270 (96.8) 145 (94.8) NS
Clinic sys olic BP (mmHg) 142 ±21 143 ±21 140 ±20 NS
Clinic dias olic BP (mmHg) 84 ±13 86±14 80 ±11 <0.001
Clinic mean BP (mmHg) 103 ±14 105 ±15 100 ±12 0.001
Clinic pulse p essu e (mmHg) 58 ±16 57 ±15 60 ±18 NS
Clinic hea a e (bpm) 73 ±10 73 ±10 72 ±11 NS
Biochemical pa ame e s
Se um glucose (mg/dL) 110.1 ±36.1 108.6 ±31.7 112.8 ±42.9 NS
Se um u ic acid (mg/dL) 6.43 ±1.65 6.39 ±1.70 6.48 ±1.59 <0.001
Se um o al choles e ol (mg/dL) 191.5 ±43.6 193.6 ±40.3 187.6 ±48.9 NS
LDL-c (mg/dL) 119.06 ±38.80 121.69 ±37.65 114.27 ±40.32 NS
HDL-c (mg/dL) 46.11 ±12.44 47.22 ±11.79 44.10 ±13.35 <0.05
Se um iglyce ides (mg/dL) 118 (86–161) 105 (81–152) 136 (104–177) <0.001
Se um c ea inine (mg/dL) 1.43 ±1.14 0.92 ±0.16 2.36 ±1.53 <0.001
eGFR (ml/min/1.73 m2)65.9 ±27.5 83.5 ±12.8 33.8 ±16.1 <0.001
Se um sodium (mEq/L) 139 ±3 140 ±3 139 ±3NS
Se um po assium (mEq/L) 4.35 ±0.40 4.33 ±0.38 4.37 ±0.43 NS
Endo helial dis unc ions and ca dio ascula isk
8-iso-PGF2α(pg/mL) 292.6 ±125.7 247.2 ±104.7 375.4 ±118.7 <0.001
CRP (mg/dL) 2.40 (1.60–3.30) 2.00 (1.39–2.70) 3.17 (2.40–3.80) <0.001
F amingham Risk Sco e (%) 7.46 (4.17–14.06) 6.49 (3.60–11.76) 9.44 (6.00–17.83) 0.001
F amingham Risk Sco e < 10%, n
(%) 272 (63.0) 193 (69.2) 79 (51.6) <0.001
F amingham Risk Sco e ≥20%,
n(%) 61 (14.1) 36 (12.9) 25 (16.3) NS
ASCVD Risk Sco e (%) 10.92 (4.92–21.43) 8.25 (4.24–17.28) 15.83 (9.59–28.27) <0.001
ASCVD Risk Sco e < 7.5%, n(%) 157 (36.3) 129 (46.2) 28 (18.3) <0.001
ASCVD Risk Sco e ≥15%, n(%) 167 (38.7) 87 (31.2) 80 (52.3) <0.001
* Con inuous a iables a e epo ed as ei he mean
±
s anda d de ia ion o median wi h in e qua ile ange, based
on hei dis ibu ion. ˆ Compa ison be ween eGFR-based g oups; non-signi ican (NS): p> 0.05. Abb e ia ions:
eGFR—es ima ed glome ula il a ion a e; BP—blood p essu e; LDL-c—low-densi y lipop o ein choles e ol;
HDL-c—high-densi y lipop o ein choles e ol; 8-iso-PGF
2α
—8-iso-p os aglandin F
2α
; CRP—C- eac i e p o ein;
ASCVD—a he oscle o ic ca dio ascula disease.
Mos o he indi iduals had a low ca dio ascula isk, and none had a his o y o
p e ious ca dio ascula e en s. Pa ien s wi h low eGFR had signi ican ly highe alues o
Li e 2025,15, 401 6 o 14
8-iso-PGF, F -S, and ASCVD-S compa ed o hose wi h no mal eGFR (all p< 0.001), while
no signi ican di e ences in an ihype ensi e he apy we e obse ed be ween g oups.
Subjec s wi h highe ca dio ascula isk had signi ican ly g ea e alues o 8-iso-PGF
2α
compa ed o hose wi h low o mode a e ca dio ascula isk (Figu e 1).
Li e 2025, 15, x FOR PEER REVIEW 6 o 15
ASCVD Risk Sco e < 7.5%, n (%) 157 (36.3) 129 (46.2) 28 (18.3) <0.001
ASCVD Risk Sco e ≥ 15%, n (%) 167 (38.7) 87 (31.2) 80 (52.3) <0.001
* Con inuous a iables a e epo ed as ei he mean ± s anda d de ia ion o median wi h
in e qua ile ange, based on hei dis ibu ion. ^ Compa ison be ween eGFR-based g oups; non-
signi ican (NS): p > 0.05. Abb e ia ions: eGFR—es ima ed glome ula il a ion a e; BP—blood
p essu e; LDL-c—low-densi y lipop o ein choles e ol; HDL-c—high-densi y lipop o ein
choles e ol; 8-iso-PGF2α—8-iso-p os aglandin F2α; CRP—C- eac i e p o ein; ASCVD—
a he oscle o ic ca dio ascula disease.
Mos o he indi iduals had a low ca dio ascula isk, and none had a his o y o
p e ious ca dio ascula e en s. Pa ien s wi h low eGFR had signi ican ly highe alues
o 8-iso-PGF, F -S, and ASCVD-S compa ed o hose wi h no mal eGFR (all p < 0.001),
while no signi ican diffe ences in an ihype ensi e he apy we e obse ed be ween
g oups.
Subjec s wi h highe ca dio ascula isk had signi ican ly g ea e alues o 8-iso-
PGF2α compa ed o hose wi h low o mode a e ca dio ascula isk (Figu e 1).
Figu e 1. 8-iso-P os aglandin F2α le els in pa ien s wi h low, mode a e, o high ca dio ascula isk
(CV) calcula ed by he F amingham Risk Sco e o A he oscle o ic Ca dio ascula Disease Risk
Sco e.
The main uni a ia e co ela ions o 8-iso-PGF2α, F -S, and ASCVD-S in he o e all
popula ion a e p esen ed in Table 2.
257.7
233.3
328.9
292.7
389.3
348.3
200
220
240
260
280
300
320
340
360
380
400
F amingham
Risk Sco e
ASCVD
Risk Sco e
8-iso-PGF2
α
(pg/ml)
ANOVA: p < 0.001
Low CV Risk
Mode a e CV Risk
High CV Risk
ANOVA: p < 0.001
Figu e 1. 8-iso-P os aglandin F
2α
le els in pa ien s wi h low, mode a e, o high ca dio ascula isk
(CV) calcula ed by he F amingham Risk Sco e o A he oscle o ic Ca dio ascula Disease Risk Sco e.
The main uni a ia e co ela ions o 8-iso-PGF
2α
, F -S, and ASCVD-S in he o e all
popula ion a e p esen ed in Table 2.
Table 2. Main co ela ions o 8-iso-PGF
2α
and ca dio ascula isk sco es wi h o he a iables in he
en i e s udy popula ion.
8-Iso-PGF2α
F amingham
Risk Sco e
ASCVD
Risk Sco e
Age (yea s) 0.383 *** 0.778 *** 0.859 ***
Se um glucose (mg/dL) 0.202 *** 0.377 *** 0.345 ***
Se um u ic acid (mg/dL) −0.051 NS 0.234 *** 0.273 ***
Se um o al choles e ol (mg/dL) −0.131 ** −0.301 *** −0.160 ***
LDL-c (mg/dL) −0.165 *** −0.090 * −0.156 **
HDL-c (mg/dL) −0.027 NS −0.288 *** −0.256 ***
Se um iglyce ides (mg/dL) 0.090 NS 0.088 NS 0.147 **
Se um c ea inine (mg/dL) 0.466 *** 0.127 ** 0.177 ***
eGFR (mL/min/1.73 m2)−0.520 *** −0.254 *** −0.338 ***
Se um sodium (mEq/L) −0.024 NS −0.085 NS −0.009 NS
Se um po assium (mEq/L) 0.086 NS 0.088 NS 0.084 NS
Sys olic BP (mmHg) 0.188 *** 0.236 *** 0.156 ***
Dias olic BP (mmHg) −0.015 NS −0.163 *** −0.247 ***
Mean BP (mmHg) 0.083 NS 0.014 NS −0.076 NS
Pulse P essu e (mmHg) 0.250 *** 0.430 *** 0.395 ***
Hea Ra e (bpm) −0.046 NS −0.074 NS −0.094 *
CRP (mg/dL) 0.717 *** 0.407 *** 0.404 ***
***: p
≤
0.001; **: p
≤
0.01; *: p
≤
0.05; NS:p> 0.05. Abb e ia ions: ASCVD—a he oscle o ic ca dio ascula disease;
LDL-c—low-densi y lipop o ein choles e ol; HDL-c—high-densi y lipop o ein choles e ol; eGFR—es ima ed
glome ula il a ion a e; BP—blood p essu e; 8-iso-PGF
2α
—8-iso-p os aglandin F
2α
; CRP—C- eac i e p o ein.
Li e 2025,15, 401 7 o 14
8-iso-PGF
2α
was signi ican ly associa ed wi h he a iables included in he equa ions
used o p edic 10-yea ca dio ascula isk. Fu he mo e, 8-iso-PGF
2α
showed a s ong
co ela ion wi h bo h F -S o ASCVD-S (all p< 0.001) (Figu e 2), and hese ela ionships
emained signi ican a e adjus men o eGFR alues ( = 0.361 and p< 0.001 wi h F -S;
= 0.306 and p< 0.001 wi h ASCVD-S). When hese ela ionships we e assessed sepa a ely
in he wo g oups o pa ien s di ided by eGFR, 8-iso-PGF
2α
was signi ican ly associa ed
wi h F -S and ASCVD-S only in subjec s wi h eGFR
≥
60 mL/min/1.73 m
2
( espec i ely
= 0.667 and = 0.580; all p< 0.001). In con as , hese co ela ions we e no obse ed in
subjec s wi h lowe eGFR< 60 mL/min/1.73 m2.
Li e 2025, 15, x FOR PEER REVIEW 8 o 15
Figu e 2. Uni a ia e co ela ions be ween8-iso-P os aglandin F2α le els nd F amingham Risk Sco e
(uppe plo ) o A he oscle o ic Ca dio ascula Disease Risk Sco e (lowe plo ) in he en i e s udy
popula ion.
A he mul i a ia e analyses in he o e all popula ion, 8-iso-PGF2α was signi ican ly
associa ed wi h F -S (o al e na i ely ASCVD-S) independen ly o o he co a ia es,
including eGFR and a iables used o calcula e he 10-yea ca dio ascula isk (Table 3).
110100
0
100
200
300
400
500
600
700
800
900
8-iso-PGF2
α
(pg/ml)
F amingham Risk Sco e
ALL PATIENTS
= 0.474
p < 0.001
0,1 1 10 100
0
100
200
300
400
500
600
700
800
900
8-iso-PGF2
α
(pg/ml)
ASCVD Risk Sco e
ALL PATIENTS
= 0.465
p < 0.001
0.1
Figu e 2. Uni a ia e co ela ions be ween8-iso-P os aglandin F
2α
le els nd F amingham Risk Sco e
(uppe plo ) o A he oscle o ic Ca dio ascula Disease Risk Sco e (lowe plo ) in he en i e
s udy popula ion.
Li e 2025,15, 401 8 o 14
A he mul i a ia e analyses in he o e all popula ion, 8-iso-PGF
2α
was signi ican ly
associa ed wi h F -S (o al e na i ely ASCVD-S) independen ly o o he co a ia es, includ-
ing eGFR and a iables used o calcula e he 10-yea ca dio ascula isk (Table 3).
Table 3. Independen mul i a ia e co ela es o F amingham Risk Sco e [A] and ASCVD Risk Sco e
[B] in he o e all s udy popula ion.
[A]
Ou come Va iable:
F amingham Risk Sco e
Reg ession Coe icien s
S anda dized
Bβ p-Value
Model (R2= 0.938)
Age 0.024 0.683 45.810 <0.001
Diabe es 0.274 0.326 24.988 <0.001
Sys olic BP 0.005 0.277 21.928 <0.001
Sex (male) 0.178 0.240 18.354 <0.001
Smoking habi 0.166 0.165 12.780 <0.001
HDL choles e ol 0.002 0.079 5.844 <0.001
Se um o al choles e ol 0.001 −0.059 −4.357 0.001
eGFR <0.001 0.066 4.128 0.001
8-iso-PGF2α<0.001 0.052 3.236 0.001
Cons an −1.582 - −27.712 <0.001
[B]
Ou come Va iable:
ASCVD Risk Sco e
Reg ession Coe icien s
S anda dized
Bβ p-Value
Model (R2= 0.969)
Age 0.038 0.891 82.357 <0.001
Diabe es 0.245 0.244 26.431 <0.001
Sex (male) 0.207 0.232 25.019 <0.001
Sys olic BP 0.005 0.216 24.131 <0.001
Se um o al choles e ol 0.002 0.177 18.455 <0.001
HDL choles e ol −0.006 −0.168 −17.513 <0.001
Smoking habi 0.072 0.060 6.562 <0.001
An ihype ensi e he apy 0.129 0.057 6.482 <0.001
eGFR <0.001 0.036 3.150 0.002
8-iso-PGF2α<0.001 0.026 2.285 0.023
Cons an −2.384 - −43.679 <0.001
Abb e ia ions: BP—blood p essu e; HDL—high-densi y lipop o ein choles e ol; eGFR—es ima ed glome u-
la il a ion a e; 8-iso-PGF
2α
—8-iso-p os aglandin F
2α
; ASCVD—a he oscle o ic ca dio ascula disease.
B—uns anda dized coe icien , β—s anda dized eg ession coe icien , — - alue, R2—coe icien o de e mina ion.
Addi ional mul i a ia e models we e cons uc ed o subg oups wi h eGFR
≥
60 mL/min/1.73 m
2
and <60 mL/min/1.73 m
2
, and 8-iso-PGF
2α
was independen ly
associa ed wi h F -S and ASCVD-S only in indi iduals wi h eGFR ≥60 mL/min/1.73 m2
(all p< 0.001), whe eas no signi ican ela ionship was obse ed in indi iduals wi h enal
impai men .
The ROC cu es c ea ed o assess he global accu acy o 8-iso-PGF
2α
in de ec ing
pa ien s wi h high ca dio ascula isk (F -S
≥
20%; ASCVD-S
≥
15%) a e shown in Figu e 3.
The 8-iso-PGF
2α
cu o s ha bes dis inguished pa ien s wi h high ca dio ascula isk we e
310 pg/mL o F -S (AUC: 0.767) and 264 pg/mL o ASCVD-S (AUC: 0.718) (Figu e 3A,B).
Li e 2025,15, 401 9 o 14
Li e 2025, 15, x FOR PEER REVIEW 10 o 15
(A) (B)
Figu e 3. Recei e ope a ing cha ac e is ic (ROC) cu es o 8-iso-P os aglandin F2α le els o he
de ec ion o high ca dio ascula isk calcula ed by F amingham Risk Sco e o A he oscle o ic
Ca dio ascula Disease Risk Sco e in he o e all s udy popula ion (A,B).
When ROC cu es we e compa ed in pa ien s s a i ied by eGFR, highe AUC alues
we e obse ed in pa ien s wi h eGFR ≥ 60 mL/min/1.73 m2 compa ed o hose wi h lowe
eGFR, wi h signi ican diffe ences (all p < 0.001).
Pa ien s wi h highe p edic ed ca dio ascula isk had signi ican ly ele a ed le els
o 8-iso-PGF2α, which s ongly co ela ed wi h he wo isk sco es conside ed,
pa icula ly in hose wi h no mal enal unc ion. The associa ion emained signi ican
a e adjus ing o adi ional isk ac o s bu was no obse ed in pa ien s wi h impai ed
kidney unc ion, sugges ing a po en ial in luence o enal s a us on oxida i e s ess
ma ke s.
4. Discussion
A key inding o ou s udy is ha 8-iso-PGF2α, a eliable ma ke o oxida i e s ess,
is independen ly associa ed wi h 10-yea ca dio ascula isk, as p edic ed by alida ed
equa ions in hype ensi e pa ien s wi hou o e ca dio ascula disease. The e is
expe imen al e idence ha oxida i e s ess con ibu es o he pa hogenesis o
hype ension [3,11,12], and p e ious s udies ha e in es iga ed he po en ial ole o 8-iso-
PGF2α in he p ocess o a he oscle osis and ca dio ascula diseases [7–10,22]. Minuz e al.
demons a ed he inc eased u ina y exc e ion o 8-iso-PGF2α in 75 hype ensi e
indi iduals compa ed o 75 pai -ma ched heal hy con ols [23], and o he au ho s
simila ly ound ele a ed u ina y F2-isop as anes in hype ensi e pa ien s and indi iduals
a isk o u u e ca dio ascula e en s [4,10]. Co one e al. obse ed highe se um le els
o 8-iso-PGF2α in indi iduals wi h essen ial hype ension compa ed o heal hy con ols,
con i ming ha oxida i e s ess is inc eased in his popula ion [3]. High le els o F2-
isop os anes ha e also be p oposed as a bioma ke o ca dio ascula disease, and he ole
o 8-iso-PGF2α in ca dio ascula e en s has also been in es iga ed by se e al au ho s. In
a la ge gene al popula ion s udy, Keaney e al. epo ed ha u ina y 8-epi-PGF2α le els
we e associa ed wi h p e ious ca dio ascula diseases [24]: in his s udy, app oxima ely
13% o pa icipan s had a his o y o p io ca dio ascula e en s, and only one- hi d o
pa ien s had hype ension. In con as , in ou s udy, none o pa icipan s had o e
0 20406080100
0
20
40
60
80
100
Sensi i i y
100-Speci ici y
CUT-OFF VALUE
8-iso-PGF2α>310 pg/ml
AUC = 0.767
0 20406080100
0
20
40
60
80
100
CUT-OFF VALUE
8-iso-PGF2α> 264 pg/ml
AUC = 0.718
Sensi i i y
100-Speci ici y
Figu e 3. Recei e ope a ing cha ac e is ic (ROC) cu es o 8-iso-P os aglandin F
2α
le els o he
de ec ion o high ca dio ascula isk calcula ed by F amingham Risk Sco e o A he oscle o ic Ca dio-
ascula Disease Risk Sco e in he o e all s udy popula ion (A,B).
When ROC cu es we e compa ed in pa ien s s a i ied by eGFR, highe AUC alues
we e obse ed in pa ien s wi h eGFR
≥
60 mL/min/1.73 m
2
compa ed o hose wi h lowe
eGFR, wi h signi ican di e ences (all p< 0.001; Figu e 3A,B).
When ROC cu es we e compa ed in pa ien s s a i ied by eGFR, highe AUC alues
we e obse ed in pa ien s wi h eGFR
≥
60 mL/min/1.73 m
2
compa ed o hose wi h lowe
eGFR, wi h signi ican di e ences (all p< 0.001).
Pa ien s wi h highe p edic ed ca dio ascula isk had signi ican ly ele a ed le els o
8-iso-PGF
2α
, which s ongly co ela ed wi h he wo isk sco es conside ed, pa icula ly
in hose wi h no mal enal unc ion. The associa ion emained signi ican a e adjus ing
o adi ional isk ac o s bu was no obse ed in pa ien s wi h impai ed kidney unc ion,
sugges ing a po en ial in luence o enal s a us on oxida i e s ess ma ke s.
4. Discussion
A key inding o ou s udy is ha 8-iso-PGF
2α
, a eliable ma ke o oxida i e s ess, is
independen ly associa ed wi h 10-yea ca dio ascula isk, as p edic ed by alida ed equa-
ions in hype ensi e pa ien s wi hou o e ca dio ascula disease. The e is expe imen al
e idence ha oxida i e s ess con ibu es o he pa hogenesis o hype ension [
3
,
11
,
12
],
and p e ious s udies ha e in es iga ed he po en ial ole o 8-iso-PGF
2α
in he p ocess
o a he oscle osis and ca dio ascula diseases [
7
–
10
,
22
]. Minuz e al. demons a ed he
inc eased u ina y exc e ion o 8-iso-PGF
2α
in 75 hype ensi e indi iduals compa ed o
75 pai -ma ched heal hy con ols [23], and o he au ho s simila ly ound ele a ed u ina y
F
2
-isop as anes in hype ensi e pa ien s and indi iduals a isk o u u e ca dio ascula
e en s [
4
,
10
]. Co one e al. obse ed highe se um le els o 8-iso-PGF
2α
in indi iduals
wi h essen ial hype ension compa ed o heal hy con ols, con i ming ha oxida i e s ess
is inc eased in his popula ion [
3
]. High le els o F
2
-isop os anes ha e also be p oposed
as a bioma ke o ca dio ascula disease, and he ole o 8-iso-PGF
2α
in ca dio ascula
e en s has also been in es iga ed by se e al au ho s. In a la ge gene al popula ion s udy,
Keaney e al. epo ed ha u ina y 8-epi-PGF
2α
le els we e associa ed wi h p e ious
ca dio ascula diseases [
24
]: in his s udy, app oxima ely 13% o pa icipan s had a his o y
