Б
том ХXXI, 2025, № 2
ДРУЖЕСТВО
НА КАРДИОЛОЗИТЕ
В БЪЛГАРИЯ
ОБЗОРИ
REVIEWS
ABSOLUTE AND FUNCTIONAL IRON DEFICIENCY IN HEART FAILURE – NOVEL
ABSOLUTE AND FUNCTIONAL IRON DEFICIENCY IN HEART FAILURE – NOVEL
DEFINITIONS AND THERAPEUTIC APPROACH – REVIEW OF LITERATURE
DEFINITIONS AND THERAPEUTIC APPROACH – REVIEW OF LITERATURE
G. Go ano 1, V. Go ano a2
1Sec ion o Ca diology, Fi s Depa men o In e nal Medicine, Medical Uni e si y – Plo di
2Sec ion o Haema ology, Fi s Depa men o In e nal Medicine, Medical Uni e si y – Plo di
АБСОЛЮТЕН И ФУНКЦИОНАЛЕН ЖЕЛЕЗЕН ДЕФИЦИТ ПРИ СЪРДЕЧНА
АБСОЛЮТЕН И ФУНКЦИОНАЛЕН ЖЕЛЕЗЕН ДЕФИЦИТ ПРИ СЪРДЕЧНА
НЕДОСТАТЪЧНОСТ – СЪВРЕМЕННИ ДЕФИНИЦИЯ И ТЕРАПЕВТИЧЕН ПОДХОД.
НЕДОСТАТЪЧНОСТ – СЪВРЕМЕННИ ДЕФИНИЦИЯ И ТЕРАПЕВТИЧЕН ПОДХОД.
ЛИТЕРАТУРЕН ОБЗОР
ЛИТЕРАТУРЕН ОБЗОР
Г. Горанов1, В. Горанова2
1Секция по кардиология, Първа катедра по вътрешни болести, Медицински университет – Пловдив
2Секция по хематология, Първа катедра по вътрешни болести, Медицински университет – Пловдив
Abs ac . Absolu e and unc ional i on de i ciency (ID) is a c i ical ac o con ibu ing o a ious ca diac issues, including mi ochond ial
dys unc ion, myoca dial emodeling, and signi i can sys olic and dias olic impai men s. These condi ions inc ease he
isk o le en icula hype ophy, pulmona y conges ion, ca diac i b osis, and dec eased exe cise ole ance in pa ien s
wi h hea ailu e (HF). The e o e, imely and accu a e diagnosis o ID is essen ial, as i can be a p ima y o seconda y
ea men goal. Cu en diagnos ic c i e ia o en ely on se um e i in le els, which can be misleading and a e de i ed om
p e ious clinical ial eligibili y c i e ia. This e iew examines mul iple andomized clinical ials, s udies, and me a-analyses
ha ad oca e o a ede i ni ion o ID. I p oposes new diagnos ic c i e ia based p ima ily on ans e in sa u a ion (TSAT)
le els below 20%, which demons a e high speci i ci y and sensi i i y o iden i ying candida es o ea men . These c i e ia
co ela e signi i can ly wi h su i al a es and ca dio ascula ou comes. Addi ionally, eme ging indica o s o ID, such as
se um soluble ans e in ecep o (sT R) and he sT R- e i in index, a e discussed. These indica o s p o ide insigh s in o
mi ochond ial i on s a us and help di e en ia e be ween absolu e i on de i ciency (AID) and unc ional i on de i ciency (FID).
Key wo ds: absolu e/ unc ional i on de i ciency, diagnos ic c i e ia, hea ailu e, ea men
Add ess
o co espondence: Geo gi Go ano , MD, e-mail: [email p o ec ed]
Резюме.Абсолютният (АЖ) и функционалният железен дефицит (ЖД) са независими патогенетични фактори за нарушена
митохондриална структура, миокардно ремоделиране, тежка систолна и диастолна дисфункция, повишен риск от
хипертрофия и дилатация на лявата камера, белодробен застой, сърдечна фиброза и ограничен физически капа-
цитет. ЖД е успоредна и самостоятелна терапевтична цел при пациенти със СН, която изисква ранно и точно диаг-
ностициране. Съществуващите традиционни показатели за доказване на ЖД се базират на спорни и подвеждащи
серумни нива на феритина (най-често в референтния интервал), механично взети от критериите за допустимост
в клинични проучвания (КП). В литературния обзор се анализират редица КП, научни разработки и метаанализи,
които обосновават необходимостта от редефиниция на ЖД. Посочени са предложенията за нови критерии за ЖД,
основани предимно на TSAT < 20%. Подобен диагностичен подход притежава висока специфичност и чувствител-
ност, идентифицира по-точно подходящите за лечение пациенти и притежава значимо прогностично и предиктивно
значение, т.е. корелира с преживяемостта и сърдечните събития, както и с честотата и качеството на терапев-
тичния отговор. Разгледани са и някои нови диагностични показатели за ЖД – разтворим феритинов рецептор в
серума (sT R), съотношенията sT R mg/L и log на феритин в μg/L (феритинов индекс) и sT R:хепцидин, отразяващи
митохондриалния железен статус и разграничаващи АЖД от ФЖД.
Ключови думи:абсолютен/функционален железен дефицит, диагностични критерии, сърдечна недостатъчност, лечение
Адрес
за кореспонденция:д-р Георги Горанов, e-mail: [email p o ec ed]
This is an open access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY 4.0), which pe mi s un es ic ed
use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal au ho and sou ce a e c edi ed.
doi: 10.3897/bgca dio.31.e150462
G. Go ano , V. Go ano a
36
I
Hea ailu e (HF) is a widesp ead condi ion and
p esen s a majo heal hca e challenge wo ldwide. I is
he leading cause o hospi aliza ion in pa ien s abo e
65 yea s o age and has a 75% mo ali y a e a 5 yea s
o diagnosis. Gi en he aging popula ion in wes e n
coun ies, HF is no only becoming mo e common bu
also p esen s a p og essi ely inc easing i nancial bu -
den on heal hca e sys ems. One o he main cha ac-
e is ics o HF pa ien s is he high incidence o como -
bidi ies. Abou hal o he adul pa ien s wi h HF ha e
a leas 5 o mo e como bidi ies such as o e weigh ,
me abolic synd ome, diabe es melli us, a e ial hype -
ension, ce eb o ascula disease, COPD, PAD, CKD,
degene a i e-in l amma o y join diseases, anaemia,
cance , e c. The abo e ha e a nega i e impac on HF
and, by modula ing he he apeu ic esponse, wo sen
he p ognosis and su i al o pa ien s [1]. Among all
como bidi ies, i on de i ciency bo h absolu e and unc-
ional (AID/FID) and i on de i ciency anaemia (IDA)
ha e a dis u bingly high ela i e incidence. The ue
incidence o ID in gene al popula ion is unknown,
which is e iden om he e y wide ange epo ed in
he li e a u e: 4-18% in Wes e n Eu ope and 9-50% in
Eas e n Eu opean coun ies. Mani es IDA is signi i -
can ly less common – 2.6-5%. In gene al, ID is much
mo e common han IDA. In pa ien s wi h ch onic and
acu e HF i occu s in 50-57% o men, and in abou
80% o women, p opo ional o hei NYHA class [2].
ID in HF has been widely discussed in specialized li -
e a u e o decades. Nume ous andomized clinical
ials (RCTs) and publica ions ha e demons a ed ha
ID i espec i e o haemoglobin (Hb) le els is an inde-
penden p ognos ic indica o o educed exe cise ca-
paci y, inc eased isk o dea h, eadmission, impai ed
quali y o li e, and iden i i es pa ien s wi h he highes
isk o dea h a e an episode o acu e hea ailu e
[3]. Because o he abo e ID is o be iewed no only
as a concomi an condi ion bu also as a signi i can
pa hogene ic ac o in he e olu ion o HF, subjec o
manda o y he apeu ic co ec ion.
B
I on (Fe) is a mic oelemen o g ea impo ance
o he gas exchange. I is a s uc u al elemen o
Hb and a co- ac o o o e 30 key enzyme sys ems
esponsible o ene gy p oduc ion in all human cells
and o he syn hesis o impo an o ganic com-
pounds (Table 1) [1].
Enzyma ic Fe is o key impo ance o no mal mi o-
chond ial unc ion, especially o cells wi h high ene gy
needs, high me abolic ac i i y and mi ogenic po en ial
– ca diomyocy es, skele al muscles, neu ons, hepa o-
cy es, kidney cells, hema opoie ic and immune cells
[4]. On he o he hand, quan i a i e de ia ions o Fe
in ID and i on o e load, especially in ca diomyocy es
could cause se ious dys unc ion posing a he apeu ic
challenge. Fe is an example o he well-known “phys-
iological pa adox” – on he one hand, i is i al o gas
anspo and ene gy p oduc ion in he cell, on he o he
– I ca alyses he o ma ion o oxic adicals and oxida-
i e cell damage.
M
F
In p ac ice, Fe has a “closed” me abolism and
u ilises almos he same i on a oms, due o he nu-
me ous p ocesses o euse o “aged” cells and i on
accumula ion si es. App oxima ely 90% he Fe e-
qui ed daily is ob ained h ough ecycling and only
abou 10% h ough in es inal abso p ion [5]. The ox-
ici y o Fe++/Fe+++ ions is physiologically minimized
by hei almos comple e binding o he in acellula
p o ein e i in o o he ex acellula ans e in. The
mechanisms and main pa icipan s in he eso p ion,
anspo , s o age and u iliza ion o Fe ha e been
well s udied (Fig. 1 and Fig. 2). In he epi helial cells
o he duodenum and he ini ial pa o he small in-
es ine, Fe binds o a speci i c p o ein – apo e i in
and e i in is o med. Fe is s o ed in mac ophages
and hepa ocy es in his o m.
Table. 1. Biological signi i cance o i on
Pa icipa es in he syn hesis o :
hem
lipids and choles e ol
ca echolamines and neu o ansmi e s
collagen, ca ni ine
hy oid ho mones
p os aglandins, h omboxane
pu ines
RNA, DNA eplica ion and egene a ion
T anspo and s o age o О2
Hypoxia egula ion
In l amma o y eac ions
Immune eac ions (p oli e a ion o immune cells and immune
esponse)
An ioxidan de ence
Oxida i e s ess
D ug inac i a ion
Apop osis
О2 anspo in CNS (neu oglobin)
(adap a ion o Alnuwaysi RIS and co-au ho s, BioRende .com)
37
Absolu e and unc ional i on de i ciency in hea ailu e...
I on passes om en e ocy e mucosa in o he
blood h ough a special anspo p o ein – e opo -
in. The anspo o inac i e Fe3+ in o he ci cula ion
is ca ied ou by he glycop o ein ans e in, which
binds Fe abso bed and eleased om mac ophages
and hepa ocy es wi h high affi ni y. A cell memb ane
complex o ans e in and ans e in ecep o p o-
ein (T R1) ensu es, he con e sion o Fe3+ in o bi-
ologically ac i e cy osolic Fe2+ h ough endocy osis.
The abo e is necessa y o he syn hesis o ATP and
hem om e y h oid p ecu so s. Excess cy osolic Fe2+
ca alyses he oxida ion o memb ane phospholipids
wi h subsequen cell dea h by e op osis. Fe i-
in-media ed egula ion o cy osolic Fe2+ is c ucial in
he balance be ween e i inophagy and e op osis
[6]. In heal hy adul s, se um e i in le els a e ypical-
ly main ained a ≈ 20-300 μg/L in men and ≈ 20-200
μg/L in women.
Fig. 1. (Adap ed om And ews NC. New Engl J Med, 1999)
Fig. 2. Sys emic i on homeos asis (Ganz T, Physiological Re iews. 2013) [7]
G. Go ano , V. Go ano a
38
H –
The expo o Fe ia e ipo in om he basal side
o he en e ocy e in o he blood is egula ed by he ci -
cula ing polypep ide ho mone hepcidin. I is syn he-
sized mainly by hepa ocy es and is he i s ho mone
p o en o egula e Fe homeos asis. A high le els o
Fe in ans e in o inc eased s o es in e i in, hepcidin
blocks he “ga e” in he memb anes o en e ocy es and
mac ophages, espec i ely he anspo unc ion o
e opo in, which limi s he mobiliza ion o Fe om en-
e ocy es, hepa ocy es and mac ophages [7] (Fig. 2).
The same mechanism supp esses he en y o ali-
men a y and medicinal Fe. Con e sely, when se um Fe
dec eases, hepcidin p oduc ion is supp essed, which
s imula es Fe eso p ion and elease. P oin l amma o y
cy okines (IL-6, IL-1) ha e a signi i can nega i e impac
on Fe homeos asis: hey inc ease hepcidin sec e ion,
dec ease he esponse o e y h opoie in (EPO), induce
apop osis o e y h oid p ecu so s, dec ease ans e -
in exp ession and supp ess e opo in mRNA [6, 7].
The impo ance o in l amma o y p ocesses has been
demons a ed in he s udies o Jankowska E. A e al.,
Za i sky J. e al., Mecklenbu g I e al., who ound in-
c eased le els o hepcidin: up o 98 ng/mL in pa ien s
wi h mild CKD 270 ng/ml; 218 ng/mL in CKD s ages 2-4
and 577 ng/mL in ac i e in l amma o y bowel disease
[6, 8, 9]. This is 10-20 old highe han he no mal ange
o 11.4 ng/mL in p emenopausal women and 21.8 ng/
mL in men, and shows some co ela ion wi h CRP [10].
I
In acellula i on s a us and anspo – up ake,
u iliza ion, s o age and exc e ion by ca diomyocy es
is egula ed by speci i c mechanisms ha ensu e su -
i cien cy osolic Fe, limi he elease o ac i e Fe2+ and
lipid pe oxida ion [1, 11]. I on homeos asis in he myo-
ca dium is go e ned by a ansc ip ional sys em o he
i on egula o y p o ein (IRP-1/-2) and co esponding
changes in i on anspo e s – ans e in ecep o -1
(TFR-1), di alen me al anspo e -1 (DMT-1) and
e opo in (FPN) [11]. The ans e in – ans e in e-
cep o p o ein (T R1) complex unde goes endocy osis
and in acellula Fe3+ is con e ed o biologically ac i e
cy osolic Fe2+, which in excess is seques e ed in he
e i in nanocage in he un eac i e Fe3+ o m. I ca diac
e i in is o e exp essed, Fe emains apped in e i in
and HF occu s. Excess cy osolic Fe2+ is seques e ed
in he e i in nanos uc u e in he un eac i e Fe3+ o m,
om whe e i is eleased as needed by e i inophagy.
When cy osolic Fe2+ is low, e i inophagy is enhanced,
and con e sely, when Fe2+ is ele a ed, cellula e o-
p osis occu s [6]. When e i in is o e exp essed, Fe
emains seques e ed in he e i in nanoshell, causing
cellula HF. Ca diac hepcidin is egula ed in ac inely
by damage o in l amma ion o ca diomyocy es, and
i s exp ession is inc eased in cases o die a y Fe de i -
ciency ( he opposi e o sys emic hepcidin). I should be
no ed ha in HF, myoca dial ID does no co ela e wi h
s anda d bioma ke s assessing sys emic i on homeo-
s asis. Ano he mechanism o ID-induced HF is neu-
oho monal ac i a ion, which educes myoca dial Fe.
In an expe imen al s udy, i was ound ha dec eased
TFR1 exp ession was associa ed wi h inc eased ac i-
a ion o he neu oendoc ine sys em, especially aldo-
s e one and no epineph ine [12].
C
As al eady indica ed, a e en e ing he cell, Fe3+ is
con e ed in o a highly eac i e Fe2+ ion, necessa y o
he syn hesis o haemoglobin o as a majo componen
in Fe-S clus e s and he elec on anspo chain (ETC).
Hao Zhang and co-wo ke s iden i i ed a numbe o mi-
ochond ial me abolic dys unc ions and dis u bances
in he enzyma ic ac i i y o he espi a o y chain in
HF. The enzyma ic ac i i y o ETC co ela es wi h he
le els o Fe in he myoca dium, and in ID emodelling
is impai ed and cha ac e ised by inc eased oxida i e
s ess. Dila ed ca diomyopa hy o example is cha ac-
e ised by subcellula dys egula ion in Fe me abolism:
educed memb ane and cy osolic le els o anspo e s
o Fe up ake and inc eased le els o he Fe expo e
in he sa colemma. In ID, ega dless o e y h opoiesis
and sys emic Fe s a us, ca diomyocy es ha e impai ed
sys olic and dias olic unc ion due o s uc u al chang-
es wi h imp ope o ganiza ion o he sa colemma, mi o-
chond ial swelling, inc eased anae obic p ocesses and
glycolysis wi h accumula ion o lac ic acid, impai ed ox-
ida i e phospho yla ion, dec eased an ioxidan ac i i y,
ul ima ely esul ing in hype ophy and dila a ion o he
le en icle, pulmona y conges ion and ca diac i b o-
sis [12]. The damaging eff ec o he excess Fe should
no be unde es ima ed as well - pe manen o ansien
excesses o cy osolic Fe (a e boluses o in a enous
Fe) inc ease he le els o malondialdehyde (lipid pe -
oxida ion) and oponin [13].
C
The main mechanisms o i on de i ciency a e in
gene al: 1) educed i on in ake, 2) educed abso p ion
and 3) inc eased loss. In HF, he mos common caus-
es o i on de i ciency a e mo e peculia . Acco ding o
li e a u e, 35% o 78% o pa ien s wi h HF suff e om
malnu i ion, associa ed wi h a igue, dyspnoea, swal-
39
Absolu e and unc ional i on de i ciency in hea ailu e...
lowing diso de s, nausea, anxie y, mono onous ood,
educed appe i e, dyspepsia a e ea ing and ea ly sa i-
e y, and equen use o an acid medica ions wo sening
abso p ion [14]. Consump ion o ligh e o plan -based
ood is no a solu ion – non-hem i on is eabso bed
mo e diffi cul ly, and s udies ha e shown ha a ege-
a ian die leads o 2.5- old inc ease in he incidence o
i on de i ciency. Secondly, he in amous gas oin es inal
conges ion in CHF is associa ed wi h non-occlusi e
in es inal ischemia, mucosal oedema, inc eased pe -
meabili y, al e ed mic obiome, and impai ed abso p ion
[14]. Ano he impo an cause o ID is occul blood loss
om he conges i e and ulne able mucosa o he gas-
oin es inal ac in he p esence o an ipla ele and an-
icoagulan ea men (o en in combina ion) in pa ien s
wi h CHF [12].
C
ID is a condi ion in which he Fe a ailable in he
body is insuffi cien , bo h o he enzyme sys ems and
o no mal e y h opoiesis. ID can lead o a a ie y o
clinical mani es a ions, aff ec ing mul iple sys ems. The
se e i y o symp oms o en co ela es wi h he deg ee
o de i ciency and he indi idual’s o e all heal h. The
p ima y clinical mani es a ions associa ed wi h i on
de i ciency a e: ID anemia, cogni i e impai men s, de -
ma ological changes (hai loss, b i le nails, glossi is),
ca dio ascula symp oms ( achyca dia, a igue and
weakness) and gas oin es inal symp oms (dysphagia,
abdominal discom o ).
Acco ding o he Eu opean Socie y o Ca diology
ID is de i ned as se um e i in < 100 ng/mL, o be ween
100-299 ng/mL, bu wi h TSAT < 20%. Cu en ly, ID is
classi i ed in o 2 o ms based on i s speci i c pa hophys-
iological ole and independen ly om anemia – abso-
lu e (AID) and unc ional (FID). AID is cha ac e ized by
educed i on s o es in bone ma ow mac ophages, li e
and spleen, espec i ely wi h low le els o se um e i-
in, se um Fe and TSAT < 20%. The gold s anda d o
iden i ying AID is se um e i in le el < 15-20 μg/L, TSAT
< 20%, ele a ed soluble ans e in ecep o (sT R) le -
els, and dec eased hepcidin sec e ion. Con e sely, in
FID, he le els o s o ed i on a e no mal o ele a ed
(no mal o ele a ed e i in), bu Fe canno be eleased
due o blockage o e opo in by hepcidin, i.e. subop i-
mal anspo . Such a cons ella ion is mos commonly
obse ed in in l amma o y, in ec ious, and neoplas ic
condi ions [15] Due o low TSAT, e i inophagy and Fe
elease om he e i in nanos uc u e dec ease in pa -
allel wi h cy osolic i on le els, while in acellula and se-
um e i in le els inc ease. FID is usually cha ac e ised
by no mal se um Fe, TSAT < 20% and e i in le els o
a leas > 15-20 μg/L, bu in eali y hey a e o en highe
and ou he e e ence ange, which excludes AID [13].
In an analysis by G o e Be e bo g N e al o he EFINE-
HF and BIOSTAT-CHF s udies including 2357 pa ien s,
he wo o ms o ID we e de i ned as LIS (Low I on S o -
age) – low s o age o Fe ( ans e in sa u a ion below
20% and se um e i in concen a ion ≤ 128 ng/mL) and
DIU (De ec i e I on U iliza ion) - de ec i e u iliza ion o
Fe ( ans e in sa u a ion below 20% and se um e i in
concen a ion abo e 128 ng/mL). LIS co ela es wi h a
highe incidence o IDA and a wo se quali y o li e, and
DIU wi h highe le els o in l amma o y ma ke s. Bo h
o ms o ID showed an abno mal 6-minu e walk es ,
bu only LIS was an independen p edic o o all-cause
mo ali y o ( e)hospi aliza ions o wo sening HF (haz-
a d a io, 1.47; 95% CI, 1.26-1.71; P < 0.001) [16].
E iden ly, bo h de i ni ions lea e oom o possible
misin e p e a ions. They a e bo h based on e i in le -
els wi hin a wide e e ence ange. Fu he mo e, e i in
is no only an indica o o i on s o es, bu also an acu e
phase p o ein. Unlike e i in, TSAT inc eases o a less-
e deg ee in esponse o in l amma ion and co ela es
well wi h a ailable Fe [17].
Anemia in i on de i ciency is also diff e en ia ed
depending on he p eceding e iopa hogene ic mecha-
nisms esul ing in ID. I is classi i ed in o 2 o ms: classic
ID and he so-called anaemia seconda y o ch onic dis-
ease. The well-known classic ID anaemia de elops as
a esul o pe sis en i on de i ciency. I is cha ac e ised
by low se um Fe, e i in, e y h ocy e indices (mic ocy-
osis, hypoch omia) and high IBC. Anemia in ch onic
diseases is mos o en he esul o FID, in which Fe is
una ailable o use, and a low le el o e y h opoie in
a e o en obse ed; The e y h ocy e indices a e usually
unchanged (no mocy osis wi h no moch omemia), and
he se um Fe and TSH a e low, while e i in le el is
mos o en no mal o ele a ed. I is e iden ha bo h
o ms o ID, as well as bo h ypes o anaemia pa hoge-
ne ically associa ed wi h hem, ha e a diff e en clinical
p o i le and hence equi e a diff e en he apeu ic ap-
p oach [15]. The s anda d blood coun es s and e y h-
ocy e indices a e insuffi cien o he diagnosis o ID.
P
ID
Mos de i ni ions o ID in HF u ilise e i in and ans-
e in sa u a ion (TSAT). Acco ding o he Eu opean
Socie y o Ca diology ID is de i ned as se um e i in <
100 ng/mL, o be ween 100-299 ng/mL, bu wi h TSAT
< 20%. I is e iden ha such a de i ni ion off e s inaccu-
a e and misleading in o ma ion, due o he use o e -
i in, which is mos o en wi hin he e e ence ange o
could ha e de ia ions e en in heal hy indi iduals. Sec-
ondly, an impo an ac is no aken in o conside a ion,
namely, e i in is an indica o o i on a ailabili y, bu
G. Go ano , V. Go ano a
40
also an acu e phase p o ein, i.e. i can unde go signi i -
can quan i a i e l uc ua ions, un ela ed o i on me ab-
olism. Unlike e i in, TSAT changes o a lesse deg ee
in esponse o in l amma ion and co ela es well wi h Fe
a ailabili y [15]. This ac has long been discussed in
specialized li e a u e and has been he subjec o eas-
sessmen in ecen yea s [18].
No el indica o s o i on me abolism and de i -
ciency. Se um soluble e i in ecep o (sT R) and
sT R– e i in index [19-21]. sT R is pa o he e y h oid
memb ane p o ease, a ma ke o e y h opoie ic ac i i y
and o he size o e y h oid p ecu so s. I s concen a-
ion depends on age, al i ude, e hnici y, e y h opoie in
adminis a ion, bu is no di ec ly aff ec ed by in l amma o-
y p ocesses. Sie pinski R e al. ound ha sT R ≥ 1.25
mg/L occu s in 47% o pa ien s wi h HF, in 56% and
46% o anemic and non-anemic pa ien s, espec i ely
(p < 0.05). sT R is an indica o o ID wi h a sensi i i y
o 84% and speci i ci y o 100%. The au ho s ound ha
se um sT R ≥ 1.41 mg/L was a signi i can ly mo e accu-
a e p ognos ic indica o o 3-yea mo ali y compa ed
o plasma N- e minal p o-B- ype na iu e ic pep ide and
o he a iables. In a mul i a ia e p ognos ic model o
3-yea all-cause mo ali y, he addi ion o sT R abolished
he p ognos ic alue o se um e i in and TSAT [20].
sT R le els a e inc eased in he p esence o i on de i -
ciency, dec eased in pa ien s wi h i on o e load, and a e
no mal o low in in l amma ion [39]. The a io o sT R (in
mg/L) and log e i in (in μg/L) o he so-called sT R– e -
i in index dis inguishes FID in in l amma o y condi ions
and anemia in ch onic disease [21]. In AID, he sT R–
e i in index is > 1.5 (Dade-Beh ing) o > 3.2 (Roche),
in FID (CRP > 5 mg/L) and ACD ( educed Hb and CRP
> 5 mg/L) > 0.8 (Dade-Beh ing) o > 2.0 (Roche) [15].
Leszek e al. epo ed ha se um sT R signi i can ly co -
ela ed wi h myoca dial and mi ochond ial Fe s a us, un-
like e i in, se um Fe and TSAT [22].
Hepcidin is no only a majo egula o o sys emic
i on me abolism, bu also co ela es wi h ID, al hough
no s ic ly ela ed. Ele a ed le els o IL-6, IL-1, and
TNF-α (cha ac e is ic o como bidi ies in HF) a e asso-
cia ed wi h low se um Fe and high hepcidin [18]. The
abo e ela ionship is mo e cha ac e is ic o FID han o
AID [6]. Ele a ed ci cula ing hepcidin le els a e cha ac-
e is ic o ea ly s ages o HF and a e no accompanied
by anaemia o in l amma ion. In pa ien s wi h s able HF,
an in e se ela ionship be ween hepcidin le els and HF
se e i y has been es ablished, wi h hepcidin le els in
pa ien s wi h NYHA class IV being signi i can ly lowe
e en compa ed o heal hy con ols. HF p og ession is
associa ed wi h a dec ease in ci cula ing hepcidin and
he de elopmen o ID [6].
The sT R:hepcidin a io has been p oposed as
an in o ma i e indica o o ID. Acco ding o Jankows-
ka E.A e al., pa ien s wi h low hepcidin and high sT R
had pe iphe al oedema, high NT-p oBNP, u ic acid, low
haemoglobin (p < 0.05), and 5% highe in-hospi al and
12-mon h mo ali y [6].
CRP is no used o he diagnosis o ID bu indi-
ca es he se e i y o in l amma ion and he cause o e -
Fig. 3
41
Absolu e and unc ional i on de i ciency in hea ailu e...
i in inc ease he la e being an acu e phase p o ein.
A signi i can nega i e co ela ion was ound be ween
CRP and e i in and CRP and he pe cen age o Fe
de i ciency [23].
T2* MRI is o g ea bene i o non-in asi e as-
sessmen o myoca dial Fe in he managemen o i on
o e load in ans usion-dependen homozygous β- hal-
assemia. In pa ien s wi h HF, his modali y yields a ela-
i ely accu a e assessmen o myoca dial Fe le els [11].
In a sys ema ic e iew, Dhaliwal S and Kaloge o-
poulos AP iden i i ed se e al bioma ke s o i on me ab-
olism ha showed signi i can co ela ion wi h HF: se um
e i in < 15-20 μg/L indica ed AID, TSAT was a good
p edic o o o e all mo ali y, as well as he long- e m isk
o hospi aliza ions o HF; inc eased sT R le els we e
associa ed wi h wo se exe cise ole ance and QoL; low
se um Fe was associa ed wi h an inc eased isk o ca -
dio ascula e en s; hepcidin was o p ognos ic alue o
o e all mo ali y in HF.39 On he o he hand, ID in HF
co ela ed wi h a signi i can numbe o biochemical pa-
ame e s and clinical symp oms. Fo example, a s udy
by Van de Wal H.H e al., conduc ed in 2357 HF pa-
ien s analyses 92 ca dio ascula pa ame e s and hei
co ela ion wi h HF and hei signi i cance o su i al and
i s ehospi aliza ion. ID was ound in 61.6% o pa ien s
and co ela ed wi h lowe p o ein in ake, achyca dia, pe-
iphe al oedema, o hopnoea, hypoalbuminemia, CKD,
low haemoglobin, high CRP le els, and use o P2Y12
inhibi o s (p < 0.05). None o hese indica o s we e gen-
de -speci i c, al hough ID was mo e common in women
[24]. Acco ding o he Ge man p ospec i e obse a ion-
al PReP egis y (P ä alenz des Eisenmangels bei Pa-
ien en mi He zinsuffi zienz) in 1198 pa ien s, ID was an
independen indica o o educed exe cise ole ance in
HF, adjus ed o age, sex, anaemia, se um c ea inine,
C- eac i e p o ein, LVEF, and NP le el [3].
R ?
The li e a u e on he impo ance o e i in and
TSAT in he assessmen o ID in pa ien s wi h HF, ac-
co ding o ca diology guidelines, is oo con adic o y o
in e p e . In ac , he indica o s o ID used a e inclusion
c i e ia, empi ically de i ed om he nume ous s udies
o ID and i s impac on HF. In p ac ice, he adop ed
de i ni ion includes condi ions wi h bo h AID and FID. I
is unaccep able and misleading o pa ien s wi h e i in
< 100 ng/mL (no mal le el, also ound in heal hy peo-
ple) o be au oma ically diagnosed wi h ID. Con e sely,
he common clinical scena io o FID wi h high se um
e i in le els (≥ 300 μg/L), low se um Fe concen a-
ions (≤ 13 μmol/L) and low TSAT (< 20%) is no ad-
d essed by he HF guidelines [18].
The e e ence anges p o ided in he guidelines
a e clea ly no accu a e. A e i in < 100 ng/mL, nei-
he ID no suffi cien i on a ailabili y a alues > 400
ng/mL (hype e i inemic synd omes) can be excluded,
no can AID be dis inguished om FID. The gene al-
ly accep ed de i ni ion has a sensi i i y o 82.4% and a
speci i ci y o 72% o de ec ing ID in pa ien s wi h HF
compa ed o he gold s anda d [25] De i ni ions based
solely on TSAT ≤ 19.8% o se um i on ≤ 13 μmol/L,
howe e , ha e a sensi i i y o 94% and a speci i ci y o
88%, (p < 0.05) [21, 25]. On he o he hand, i da a om
clinical ials a e analysed, i is e iden ha e i in has
no p ognos ic signi i cance and does no co ela e wi h
a numbe o indica o s o HF and ca diac mo ali y. In
a s udy conduc ed among 4422 ou pa ien s wi h HF,
Masini G e al ound ha only TSAT < 20% and se um
i on ≤ 13 μmol/L we e associa ed wi h highe 5-yea
mo ali y (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and
HR: 1.37; 95% CI: 1.22-1.54; P < 0.001). Se um e i in
< 100 ng/mL showed a end o lowe mo ali y wi hou
s a is ical signi i cance (HR: 0.91; 95% CI: 0.81-1.01; P
= 0.09) [18]. Acco ding o Ri a Del Pin o e al, low TSAT
(< 20%) and i on le els (≤ 72.6 μg/dL), bu no e i in (<
100 ng/mL), e l ec bone ma ow Fe deple ion and a e
associa ed wi h inc eased o e all mo ali y in HF [21].
Simila esul s we e ob ained by Palau P e al in a e -
ospec i e s udy o 1701 pa ien s wi h decompensa ed
HF: lowe TSAT (< 20%) bu no e i in was associa ed
wi h he isk o 30-day eadmission o dea h [26]. R. I.
S. Alnuwaysi e al. ound ha se um Fe (≤ 13 μmol/L)
and TSAT (≤ 19.8%) we e signi i can ly be e a p edic -
ing ID han he FAIR-HF de i ni ion, wi h a eas unde
he cu es (AUC) o 0.922 and 0.932, espec i ely [12].
The addi ion o e i in o ei he de i ni ion did no lead o
a signi i can inc ease in AUC, i.e. e i in does no con-
ibu e o a mo e accu a e iden i i ca ion o pa ien s wi h
ID and HF and has no p ognos ic signi i cance. Cleland
e al. demons a ed ha high e i in le els a e associ-
a ed wi h a highe isk o all-cause and ca dio ascu-
la mo ali y [27]. Such esul s could be explained by
he mul i ac o ial pa hogenesis o ID in he con ex o
a ious como bidi ies, mos o which a e cha ac e ised
by in l amma ion, esul ing in highe e i in, inc eased
hepcidin le els and dec eased Fe abso p ion. E en el-
a i ely common condi ions such as obesi y, hype - and
dyslipidemia a e p o-in l amma o y. Fo example, in FID
dynamic changes in e i in le els could be obse ed
wi hou ecip ocal al e a ions in i on me abolism. On
he o he hand, e i in l uc ua ions in FID a e p opo -
ional o p o-in l amma o y cy okine le els and o he
se e i y o HF. Along wi h o he acu e phase p o eins
such as C- eac i e p o ein (CRP) and alpha-1-acid
glycop o ein (AGP), e i in inc eases apidly wi h in-
c eased exp ession o p o-in l amma o y cy okines (IL-
6) [28]. The p edic i e alue o e i in in e ms o he a-
peu ic esponse in clinical ials is also deba able. Wi h
an inclusion c i e ion o e i in < 100 (20-99) μg/L in
G. Go ano , V. Go ano a
42
he HEART-FID and IRONMAN s udies, no all pa ien s
showed a eliable educ ion in ad e se HF ou comes
wi h in a enous Fe adminis a ion [29, 30]. Li e a u e
sugges s ha TSAT is a mo e in o ma i e indica o o
o al Fe deple ion and demons a es smalle a ia ions
in esponse o in l amma o y p ocesses and hepcidin.
TSAT co ela es wi h inc eased o e all mo ali y and
ehospi aliza ion a e in pa ien s wi h HF, ega dless o
ejec ion ac ion [14]. Acco ding o Be e bo g NG e al.
TSAT is a p edic o o he he apeu ic esponse o IV
i on ca boxymal ase as well [25]. Analyses show ha
in pa ien s included in clinical ials based on adi ional
ecommenda ions, he isk o ca dio ascula mo ali y
and hospi aliza ion is educed by an a e age o 13%.
(0.75-1.01) [31]. A me a-analysis o 4 double-blind, an-
domized ials in 839 pa ien s, as well as he IRON-
CRT ial, ound ha in a enous e ic ca boxymal ase
signi i can ly educed ehospi aliza ions, ca dio ascula
mo ali y, and imp o ed le en icula ejec ion ac ion
in pa ien s wi h TSAT < 20.1% compa ed wi h pa ien s
wi h TSAT > 20.1% [32]. Ano he me a-analysis o 10
ials in pa ien s wi h inclusion c i e ia o TSAT < 20%
and e i in < 400 μg/L epo ed a 33% educ ion in he
isk o ca dio ascula dea h [33]. The IRONMAN ial,
demons a ed ha pa ien s wi h TSAT < 20% had a
20% isk educ ion wi h in a enous Fe – haza d a io
0.80 (0.63-1.02), compa ed wi h a 4% isk educ ion in
subjec s wi h e i in < 100 μg/L-TSAT > 20% – isk a io
0.96 (0.69-1.34). Analy ical a iabili y ( echnical?) and
diff e en e e ence anges (54% diff e ence in a com-
pa a i e s udy by B. A. Fo d e al.) o e i in should
also be conside ed [34].
Unlike sys emic Fe me abolism, he assessmen
o myoca dial i on me abolism is nei he easy no he-
o e ically clea . Li e a u e indica es ha abou 50% o
pa ien s wi h HF and educed ejec ion ac ion ha e
ID by gene ally accep ed c i e ia, bu low myoca dial
Fe is de ec ed by MRI in only 20-25% [35]. On he
o he hand, se um Fe and se um e i in le els do no
clea ly dis inguish pa ien s wi h and wi hou myoca -
dial i on de i ciency. The dynamics o myoca dial and
bone ma ow Fe do no show a s ic co ela ion – Fe
s o es assessed by endomyoca dial biopsy do no
co ela e wi h blood bioma ke s, and o al myoca dial
Fe does no accu a ely e l ec cy osolic Fe2+ [36]. This
jus i i es he ecommenda ion o a ede i ni ion o ID
in HF using mo e p ecise c i e ia based on TSAT and
se um Fe [37-40]. Acco ding o Packe M e al. ID can
be de i ned by TSAT < 20% and se um e i in < 400
μg/L; se um e i in < 100 μg/L should be disca ded as
a s and-alone diagnos ic c i e ion [40]. Such a ede -
ini ion iden i i es pa ien s a high isk o ID who would
bene i om in a enous ea men .
ID HF
The ea men o HF wi h educed ejec ion ac ion
aims o p e en ehospi aliza ion and imp o e exe -
cise ole ance, clinical s a us and QoL and o educe
mo ali y. None o hese goals a e achie able wi hou
co ec ion o ID, ega dless o e y h opoiesis [41]. The
2021 ESC HF Guideline ecommenda ions o i on e-
placemen he apy include [42]:
• Symp oma ic pa ien s who ha e a le en icula
ejec ion ac ion (LVEF) < 45% o elie e symp oms,
imp o e exe cise ole ance and QoL (Class IIa ecom-
menda ion, Le el o E idence A).
• P e- and pos -discha ge ollow-up o pa ien s hos-
pi alized o acu e HF o imp o e symp oms and educe
ehospi aliza ion (Class IIa ecommenda ion, Le el o
E idence B).
• Symp oma ic pa ien s ecen ly admi ed o HF
wi h an LVEF < 50% o educe he isk o hospi aliza-
ion o HF (Class IIa ecommenda ion, Le el o E i-
dence B).
The main he apeu ic p oblem is o e coming/
bypassing hepcidin blockage, edis ibu ion, seques-
a ion and impai ed i on anspo in HF and/o sec-
onda y anaemia in pa ien s wi h HF and mul iple co-
mo bidi ies. Fe ic ca boxymal ose is he mos widely
s udied IV Fe and he only Fe compound speci i cally
ecommended o he ea men o HF in he 2021
ESC guidelines [42]. Re iculocy es inc ease a e only
24-48 hou s, and Hb le els no ea lie han 1–2 weeks.
A apid inc ease in e i in > 400 μg/L may signal a
sho - e m o e load o cy osolic Fe, which p o okes
lipid pe oxida ion (malonaldehyde ↑) and ca diomyo-
cy e inju y ( oponin ↑) [13]. In he IRONMAN [29]
s udy, e i in le els inc eased 10- old wi hin 4 weeks
and emained > 500 μg/L o he nex 4 mon hs. In
he AFFIRM-AHF [43] and HEART-FID [30] s udies,
se um e i in le els inc eased o ≈ 350 μg/L wi hin
6 weeks, wi h simila alues main ained o up o 6
mon hs. The he apeu ic p o ocol ecommends no
mo e han 1000-2000 mg o i on ca boxymal ose
du ing he i s 6 weeks, egula assessmen o i on
le els, and 500 mg e e y 3-4 mon hs as needed. The
esul s o ea men , acco ding o me a-analyses o 10
RCTs, a e unidi ec ional: educ ion o hospi aliza ions
o decompensa ed HF, imp o emen o NYHA class
and QoL, 6-minu e walk es , le en icula ejec ion
ac ion, NT-p oBNP and CRP, educ ion o he isk
o dea h by any cause. Howe e , no signi i can di -
e ence in su i al be ween ea ed and un ea ed
pa ien s has been demons a ed [21]. The bene i o
long- e m ea men wi h IV Fe emains unclea , gi en
he diffi cul - o-co ec e iology o i on de i ciency in HF.
I seems logical o main ain i on s o es, espec i ely
he e i in le el, wi hin he ange o abou 400 μg/L.
43
Absolu e and unc ional i on de i ciency in hea ailu e...
Inde i ni e IV Fe he apy e e y 4-6 mon hs was es ed
in he IRONMAN, HEART-FID and AFFIRM-AHF ials
wi h cu -off alues o e i in > 400 μg/L o TSAT ≥ 25%
and > 300 μg/L o TSAT ≥ 20%, espec i ely [29, 30,
43]. I is easonable o ecommend ha such he apy
be conside ed only i e i in and TSAT le els emain
low. Wi h ega d o o al he apy, he IRONOUT HF i-
al [44] did no epo any clinical bene i due o slow
pha macokine ics and he po en ial o Fe seques a-
ion in mac ophages and hepa ocy es. O al p epa a-
ions a e cu en ly no ecommended o he co ec-
ion o i on de i ciency in HF, al hough i on de i ciency
can be co ec ed o ally wi h bi alen i on d ugs. No
eff ec has been demons a ed a e he adminis a ion
o e y h opoie in ( he isk o h omboembolic e en s is
inc eased).
N
The main goal o inc easing i on abso p ion and
mobiliza ion o seques e ed Fe can be achie ed
h ough he educ ion o hepcidin syn hesis and/o
unc ion and manipula ion o he hepcidin- e ipo -
in link. Di ec agen s agains hepcidin (LY2787106,
Lexap epid pegol o an icalins), blocking IL-6 wi h he
an i-IL-6 ligand an ibody zil i ekimab, supp ession o
bone mo phogenic p o ein wi h LY3113593, as well as
he use o di ec e opo in an ibodies ha e been es -
ed in phase 1 and 2 clinical ials [45]. Inhibi ion o he
p olyl hyd oxylase/hypoxia-inducible ac o (PHD/HIF)
domain is ano he he apeu ic s a egy being in es i-
ga ed. Phase 3 clinical ials a e es ing he HIF s abi-
lize s Vadadus a , Dap odus a , and Roxadus a , and
ini ial analyses indica e ha PHD inhibi o s inc ease
haemoglobin le els, se um ans e in, inc ease in-
es inal Fe abso p ion, and educe hepcidin le els in
anaemic pa ien s wi h CKD, ega dless o in l amma-
ion [46, 47].
C
Absolu e and unc ional i on de i ciency (ID), along
wi h he classical i on de i ciency anemia and anemia o
ch onic disease, exhibi dis inc clinical ea u es and bio-
chemical ma ke s o diagnosis. T adi ional ca diology
guidelines ha e elied on se um e i in le els o diag-
nosing ID; howe e , hese le els can be con o e sial
and o en misleading, as hey ypically all wi hin he e -
e ence ange and a e based on c i e ia de eloped om
clinical ials ocused on ea ing ID in hea ailu e (HF).
Recen li e a u e sugges s new diagnos ic c i e ia o ID,
p ima ily ocusing on ans e in sa u a ion (TSAT) le els
below 20%. This app oach demons a es high speci i ci y
and sensi i i y, allowing o mo e accu a e iden i i ca ion
o pa ien s who could bene i om ea men . Mo eo e ,
i holds signi i can p ognos ic and p edic i e alue, co -
ela ing wi h su i al a es, ca dio ascula e en s, and
he likelihood and eff ec i eness o he apeu ic espons-
es. Ne e heless, e i in es ing emains impo an ; i no
only helps de i ne absolu e i on de i ciency when le els
a e below 15-20 μg/L bu also se es as an indica o o
i on o e load. Addi ionally, as an acu e phase p o ein,
e i in co ela es wi h in l amma o y ma ke s, p o iding
aluable insigh s o diff e en ial diagnosis.
Table 2
Clinical T ial Objec i e Findings Key ou comes No es
IRONMAN [29]
E alua e he effi cacy
o in a enous e ic
ca boxymal ose in hea
ailu e pa ien s wi h i on
de i ciency.
Signi i can educ ion
in hospi aliza ions o
decompensa ed hea
ailu e.
Imp o ed NYHA class,
QoL, educed NT-p oBNP
and CRP le els.
Fe i in le els
inc eased 10- old
wi hin 4 weeks.
AFFIRM-AHF [43]
Assess he eff ec s o
in a enous i on on pa ien s
wi h acu e hea ailu e and
i on de i ciency.
Fe ic ca boxymal ose
imp o ed symp oms
and educed hospi al
eadmissions.
Se um e i in le els
inc eased o ~350 μg/L
wi hin 6 weeks.
Simila esul s wi h
HEART-FID.
HEART-FID [30]
In es iga e he impac o
i on eplacemen he apy on
clinical ou comes in hea
ailu e pa ien s.
Pa ien s expe ienced
imp o ed exe cise
capaci y and educed
symp oms o hea ailu e.
Reduc ion in
hospi aliza ions and
imp o ed quali y o li e.
Fe i in le els
main ained a ound
350 μg/L o up o 6
mon hs.
IRONOUT HF [44]
E alua e he eff ec i eness
o o al i on eple ion in hea
ailu e pa ien s wi h educed
ejec ion ac ion.
No signi i can clinical
bene i obse ed om o al
i on supplemen a ion.
Slow pha macokine ics;
po en ial o i on
seques a ion.
O al i on is no
ecommended
o hea ailu e
managemen .
Phase 3 T ials
(Vadadus a ,
Dap odus a ,
Roxadus a ) [45-47]
Tes p olyl hyd oxylase
inhibi o s o anemia in CKD
pa ien s.
Inc eased hemoglobin
le els, enhanced in es inal
i on abso p ion, educed
hepcidin le els.
Po en ial o imp o e i on
me abolism and anemia
managemen .
In es iga ional d ugs
showing p omise o
u u e he apies.
No con l ic o in e es was decla ed
