NT Probnp Pada Sepsis

8/12/2019 NT Probnp Pada Sepsis

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[Frontiers in Bioscience 18, 1237-1243, June 1, 2013]

BNP and NT-proBNP leels in patients !it" sepsis

Nan #i1, $u %"an&1, 'on&tao Fan2, Jin& (in&1, )on&*an& #iu1

1The First Hospital Affiliated to Dalian Medical University, Emergency Department, Dalian, Liaoning, China 11!11" #The FirstHospital Affiliated to Dalian Medical University, $phthalmology Department, Dalian, Liaoning, China 11!11

T+B# F .NTNT'

1% A&stract

#% 'ntrod(ction)% *iologic characteristics of *+ and +T-pro*+

)%1% 'ntrod(ction)%#% .ene str(ct(re and e/pression of *+ and +T-pro*+

)%)% 0ynthesis and secretion of *+ and +T-pro*+)%% Mechanism of *+ in h(mans)%2% Degradation and inactivation of *+ and +T-pro*+

% Assay of *+

2% hysiologic f(nction% *+ and +T-pro*+ in sepsis

%1% The level of *+ and +T-pro*+ in sepsis%#% The possi&le mechanism (nderlying increased *+ and +T-pro*+ in sepsis

%)% The clinical application of *+ and +T- pro*+ in sepsis

3% Concl(sions4% Ac5no6ledgments7% 8eferences

1/ +B'T+.T

Sepsis is a severe complication of critically ill

patients that is characterized by the systemic inflammatoryresponse syndrome (SIRS). The increased levels of B-type

natriuretic peptide (BN) and N-terminal prohormone ofbrain natriuretic peptide (NT-proBN) are related !ith

dysfunction of the cardiovascular system and systemicinflammation. In recent years" BN and NT-proBN have

been the focus of studies evaluatin# the severity andpro#nosis of sepsis. In this study" !e !ill revie! the role of

BN and NT-proBN in sepsis.

2/ NT.TN

Sepsis is a severe complication of critically illpatients !ith severe trauma" e$tensive burns" shoc%" or

severe infections. Sepsis is characterized by the systemicinflammatory response syndrome (SIRS)" !hich developsinto the multiple or#an dysfunction syndrome (&'S)!hen complicated by infection. The occurrence and

development of sepsis depends on ris% factors" includin#infection" inflammation" and abnormal immune andcoa#ulation function" reflectin# a series of

pathophysiolo#ic chan#es. Sepsis develops rapidly and

leads to a hi#h mortality rate ("*). In the +nited States"appro$imately ," patients develop sepsis each year"amon# !hich **" die" resultin# in hi#h treatment costs(/"0).

It is crucial to evaluate the severity of sepsis andprovide early intervention to patients to reduce sepsis

mortality. There have been many studies involvin# theindicators by !hich the severity and pro#nosis of sepsis can

be evaluated. rocalcitonin (1T) (-2)" 1-reactive protein(1R) (3")" and protein 1 (1) 4activated protein 1

(51) (-/) have been !idely identified as predictors ofsepsis. In recent years" brain natriuretic peptide (BN)"no! %no!n as B-type natriuretic peptide (also BN)"and N-terminal prohormone of brain natriuretic peptide

(NT-proBN) have become better %no!n" and studiesinvolvin# BN or NT-proBN in the evaluation of the

severity and pro#nosis of sepsis have been on the rise(0).

3/ B#. .)++.T'T.' F BNP +N

NT-PBNP

3/1/ ntroduction

The natriuretic peptide (N) system includes 5-"B- (BN)" 1-" and -type natriuretic peptide ("6). BN!as ori#inally identified in e$tracts of porcine brain bySudoh in 322 (,)" and sho!n to be similar to atrial

natriuretic peptide (5N). 5N causes diuresis" natriuresis"an e$pansion of blood vessels" and a reduction of blood

pressure (,).3/2/ ene structure and e5pression o6 BNP and NT-

proBNP

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The BN #ene is located on human chromosome

" and is in series !ith the 5N #ene" !hich is in the 2"bases upstream of the BN #ene. In 323" the complete

nucleotide se7uence of BN !as described" and the8untranslated re#ion se7uence !as described by a

molecular analysis and tissue-specific #ene e$pressionstudy in 336.The BN #ene is 3** bp !ith / e$ons and

* introns" includin# a hi#hly-conserved se7uence(T5TT5T). In the human BN #ene" both enhancer

elements e$ist in the vicinity of the promoter and have apositive effect" such as 95T5 bindin# and S elements"!hich can up-re#ulate #ene transcription" and sub-elements!ith a ne#ative effect" !hich can do!n-re#ulate

transcription (2-*).

The BN #ene reverse transcribes into cN5"!hich is composed of 3 nucleotides" and then

synthesizes mRN5 encodin# the precursor protein of BN(pre-proBN) !ith /0 amino acids. In the pre-proBN

protein" a *6-amino acid si#nal peptide is immediatelyremoved" resultin# in the formation of a 2-amino acid

peptide (proBN). Then" proBN is decomposed into t!o

parts by the proteolytic enzymes" protease furin and corin.'ne part is the N-terminal fra#ment" NT-proBN"includin# ,6 amino acids !ithout biolo#ic activity: the

other part is BN" !hich is composed of /* amino acids!ith biolo#ical activity. BN is characterized by a ,-

amino acid rin#" !hich is connected !ith cysteine disulfideand is si#nificant for its biolo#ical activity (*"**).

3/3/ '*nt"esis and secretion o6 BNP and NT-proBNP

In humans" BN and NT-proBN are mainlysynthesized and secreted from ventricles by the coronarysinus. In ventricles" the reserve of BN and NT-proBNare as lo! as ,; of 5N. In addition" BN can also be

synthesized and secreted from the adrenal medulla. Inpatients !ith primary aldosteronism" the level of BN

mRN5 in the adrenal #land is increased" as !ell as thesynthesis and secretion of BN (*/). 5n in vitro study

demonstrated that the e$pression of the BN #ene can bestimulated by many factors" such as stress" ischemia"mechanical tension" and cyto%ines (includin# tumornecrosis factor" interleu%in" and endothelin). " and 1-type natriuretic factor receptor

=NR1>) have been identified. NR5 and NRB aretransmembrane receptors !ith #uanylate cyclase (91)activity and can synthesize cyclic #uanosinemonophosphate (c9&)" !hich can mediate most

biolo#ical effects of BN" such as diuresis" natriuresis"dilation of blood vessels" reduction of blood pressure"re#ulation of body fluid volume" and maintainin#electrolyte balance. NR1 is a removal receptor !ith a

short cytoplasmic domain of /, amino acid residues" !hich

participates in the clearance of BN in the circulation.

NR5" NRB" and NR1 are distributed !ithin tar#etor#ans" includin# the %idneys" heart" vessels" adrenal

#lands" and central nervous system. hosphorylation anddephosphorylation re#ulate the activity of NR. ?hen NR

is phosphorylated" NR becomes sensitive to its li#and.?hen NR dephosphorylates" sensitivity to the li#and is

decreased (/*-/0).

3/9/ e&radation and inactiation o6 BNP and NT-

proBNP

The half-life of BN is ** min in humans. Thema@ority of BN is de#raded in the lun#s and %idneys. The

mechanisms underlyin# BN de#radation are as follo!sABN is de#raded by brea%in# the 1ys,-he2 bond in itsrin# structure by neutral metal endopeptidase !ith zinc: andBN binds !ith NR1 and is de#raded by NR1-mediated

intracellular chemota$is (2"/). 'f note" it has not beenconfirmed !hich mechanism of BN de#radation isdominant" or !hether the mechanisms are e7uivalent(


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Fi&ure 1/ e#radation inactivation of BN. The BN de#radations include t!o path!ays. 'n one path!ay" BN is de#raded bybrea%in# the 1ys,-he2 bond in its rin# structure by neutral metal endopeptidase !ith zinc. 'n the other path!ay" BN binds

!ith NR1 and is de#raded by NR1-mediated intracellular chemota$is.

9/ P)$'#. FN.TN

In humans the physiolo#ic functions of BN areas follo!sA BN rela$es vessels" reduces the cardiac

preload and sympathetic activity" and rela$es arteries andveins" resultin# in fluid transfer from the blood vessels to

the e$travascular tissues: BN reduces sympathetic activityby inhibitin# the secretion of catecholamines and the spreadof sympathetic impulses" and also reduces the activatedthreshold of passin# impulses in the va#us nerve" resultin#

in inhibition of vasoconstriction and a bradycardic refle$ tocardiac preload reduction: BN resists mitotic activityleadin# to inhibition of vascular smooth muscle andendothelial cell proliferation: the role of BN in sodium

and !ater metabolism is similar to 5N: In the %idneys"BN increases renal blood flo! by diuresis and natriuresis"and inhibits the renin-an#iotensin-aldosterone (R55)system and direct tubular action: BN rela$es afferent

arterioles and constricts efferent arterioles to increase the#lomerular filtration rate" resultin# in an inhibition ofreabsorption of sodium and !ater in the pro$imalconvoluted tubule mediated by an#iotensin II: in the renal

collectin# duct" BN anta#onizes vasopressin to retain!ater and sodium: BN directly inhibits the secretion ofrenin and aldosterone: and in the central nervous system"BN reduces the sympathetic activity of brainstem" directly

inhibits the secretion of vasopressin" and inhibits salt

appetite and thirst of central nervous system centers. 5ll ofthese effects result in a sustained natriuretic effect:ho!ever" a further study on the relationship bet!een BN

in the central nervous system and in the renal andcardiovascular systems is needed (0*).

:/ BNP +N NT-PBNP N 'P''

Studies !hich have focused on BN and NT-

proBN in cardiovascular diseases have sho!n that BNand NT-proBN indicate the pro#nosis of acute myocardial

infarction and heart failure" !hile BN and NT-proBN inthe pro#nosis of sepsis has not been confirmed. Sepsis is a

serious complication of acute critical illnesses" such assevere trauma" lar#e-area burns" shoc%" and severe

infections. Sepsis is characterized by SIRS" usuallycomplicated by infections" !hich can develop into &'S

and result in a hi#h mortality rate and a poor pro#nosis(0/). In assessin# sepsis" 1T and 1R have been usedtraditionally" !hile BN and NT-proBN have receivedmore attention in recent years (0).

:/1/ T"e leel o6 BNP and NT-proBNP in sepsis

The incidence of sepsis and septic shoc% hasincreased in recent years. atients !ith sepsis and septic

shoc% are usually complicated by cardiac insufficiency. InSIRS" an abundance of inflammatory media !ith cardiacto$icity is produced in patients !ith sepsis. Comeostasis ofthe cardiovascular system is disturbed !hen inflammation

is stron#" resultin# in septic shoc%. 1ardiac insufficiency isone of the most si#nificant clinical manifestations of septicshoc% (00). &yocardial in@ury is considered as one of theearly characteristics of septic shoc%" leadin# to hypo$ia in

peripheral tissues and patient death. It has beendemonstrated that ventricular systolic dysfunction occurs inthe early sta#e of patients !ith septic shoc%.

Several studies have sho!n increased levels of

BN and NT-proBN in the plasma of patients !ith septicshoc%" especially patients !ith ventricular contractileinsufficiency (0). The BN level is ne#atively correlated

!ith left ventricular e@ection fraction (DF


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myocardial depression. The BN concentration on day

may be used as a pro#nostic mar%er to identify patients!ith an elevated ris% for an adverse outcome. 1harpentier

and collea#ues (0,) reported similar findin#s. on# andcollea#ues (02) have studied the levels of BN and NT-

proBN in 36 ne!borns !ith neonatal septicemia The 36patients !ere divided into a myocardial in@ury #roup and a

non-myocardial in@ury #roup" and !ere tested for the levelsof BN and NT-proBN in the plasma on the *nd" th" and

th days of septicemia and in infants of different#estational a#es. The results !ere compared to creatine%inase isoenzyme and troponin I. on# and collea#ues (02)found that the levels of BN and NT-proBN in plasma

increased in neonates !ith myocardial in@ury and sepsis"especially in premature infants. Rudi#er and collea#ues(03) found an increased level of BN in *0 patients !ithsepsis" septic shoc%" or con#estive heart failure. These

findin#s raise the issue of !hether or not the increased BNlevel is related to inflammation or cardiac insufficiencysecondary to sepsis. This issue is in need of further study.

:/2/ T"e possi;le ec"anis underl*in& increased BNP

and NT-proBNP in sepsis&ultiple factors lead to increased levels of BN

and NT-proBN in patients !ith sepsis. Indeed" primary

cardiac insufficiency or systemic inflammation is a possiblecause of the increased levels of BN and NT-proBN in

patients !ith sepsis. In recent years" it has been acceptedthat the increased levels of BN and NT-proBN in the

plasma of septic shoc% patients is due to cardiacinsufficiency secondary to sepsis (). ar%er and

collea#ues () reported that the left and ri#ht ventricles areacutely dilated in patients !ith sepsis. In in vivo and invitroe$periments" ar%er and collea#ues () found that6;-2; of BN in plasma !as from ventricular

myocytes" and the overload ventricular pressure" overloadvolume" or ventricular dilatation is an important cause of

BN release.

In addition to cardiovascular function" systemicinflammation is related to increased BN in the peripheralcirculation. &eader and collea#ues reported that BNlevels !ere E p# 4ml in 2 sepsis patients !ith normal

left ventricular function" and confirmed by Renana andcollea#ues (*). These findin#s su##est that the increased

BN level can be e$plained by another mechanism.5nother possible cause of the increased BN level in

patients !ith sepsis may be the release of lar#e amounts ofinflammatory cyto%ines (interleu%ins and tumor necrosis

factor) and endoto$in. The inflammatory cyto%ines not onlyplay a direct role in cardiac to$icity" but also participate inthe e$pression of the BN #ene. 5n in vitrostudy sho!edthat e$pression of the BN #ene !as increased h after

lipopolysaccharide stimulation (/). In sepsis patients" theBN level in blood !as increased !ithout cardiacinsufficiency" !hile the level of BN !as positivelycorrelated !ith the 1R level" su##estin# the role of

inflammation in the increase of BN (0). In addition" pro-inflammatory cyto%ines can promote the heart to secreteBN. It has been reported that pro-inflammatory cyto%ines(interleu%in (ID)-) can promote the increase of BN in

sepsis" and the e$pression of BN in myocardial cells is

increased after stimulation of ID-beta in vitro. In sepsis"

the level of ID-6 increased times #reater than heartfailure" su##estin# an important role of ID-6 in re#ulatin#

BN secretion in sepsis. Because inflammation can induceincreased secretion and decreased de#radation of BN" the

BN level is increased in severe sepsis and septic shoc%.

:/3/ T"e clinical application o6 BNP and NT- proBNP insepsis

Sepsis is common in clinics !ith a hi#h mortalityand poor pro#nosis. In recent years" BN and NT-proBNhave been applied in predictin# the pro#nosis of patients!ith severe sepsis or septic shoc%. Rivers and collea#ues

() measured BN levels " /" 6" *" *0" /6" 02" 6" and ,*h after admission in ** patients !ith severe sepsis andseptic shoc%" and found that elevated BN levels (E

p#4mD) occurred in 0*; and 63; of patients at the time of

presentation and at *0 h. They also found that a BN E *p#4mD at *0 h !as the most si#nificant independentindicator of increased mortality (sensitivity" ,3; andspecificity" 3;)" and the mortality !as increased as the

level of BN increased. Thus" serial BN levels may be a

useful ad@unct in the early detection" stratification"treatment" and pro#nostication of hi#h-ris% patients.Bruec%mann and collea#ues (6) tested NT-proBN in ,

patients !ith severe sepsis usin# an enzyme-lin%edimmunosorbent assay (DIS5)" and found an increased

plasma level of NT-proBN. Bruec%mann and collea#ues(6) also found that the mortality increased /.3-fold !henthe level of NT-proBN !as E 0 pmol4D. Thus" NT-

proBN can be used as an inde$ to @ud#e the severity of

sepsis. Handil and collea#ues (,) e$amined therelationship bet!een BN levels and the severity of sepsisindependent of con#estive heart failure. Handil andcollea#ues (,) divided 03 sub@ects into the follo!in# /

#roupsA / patients !ith septic shoc%: 2 patients !ith earlysepsis: and 2 a#e-matched healthy controls. None of the

sub@ects had co-morbid conditions (con#estive heart failureor renal failure) and !ere follo!ed for * days. The serum

BN levels !ere determined at the time of dia#nosis ofsepsis and at the time of patient improvement ordeterioration. The results sho!ed that patients !ith septicshoc% had si#nificantly hi#her BN levels on admission

compared !ith the other * #roups (G.)" and plasmaBN levels for patients !ith septic shoc% !ere positively

correlated !ith Se7uential 'r#an


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proBN levels are fre7uently elevated in patients !ith

severe sepsis and septic shoc%" !hich is related toinhibitory factors in myocardial cells. levated NT-proBN

levels can be due to a syner#istic effect !ith TN


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messen#er ribonucleic acid e$pression alon# !ith that of

atrial nat riuretic peptide are enhanced in patients !ithprimary aldosteronism. 9 Clin Endocrinol Meta&,3 ()"

0,6*02*. (330)

*0. &artinez-Rumayor 5" Richards 5&. Biolo#y of thenatriuretic peptides.Am 9 Cardiol(/5)" /-2. (*2)

*. 'mland T. 5dvances in con#estive heart failuremana#ement in the intensive care unitA B-typenatriuretic peptides in evaluation of acute heart failure.Crit Care Med ):1 0(ppl


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. &cDean 5S" Tan# B" Nalos &. Increased B - type

natriuretic peptide ( BN) level is a stron# predictor forcardiac dysfunction inintensive care unit patients .Anaesth

'ntensive Care/" *-*,. (*/)

. ar%er &&" &c1arthy H" '#nibene < . Ri#htventricular dys*function and dilatation" similar to left

ventricular chan#es" charac*terize the cardiac depression ofseptic shoc% in humans. Chest3," *6 - /. (33)

*. Renana Shor" Ooseph Rozenman B" 5haronBolshins%y. BN in septic patients !ithout systoli cmyocardial dysfunction. E(ropean 9o(rnal of 'nternal

Medicine ," /6 -0. (*6)

/. Tomaru HI" 5rai &" Oo%oyama T. Transcriptionalactivation of the BN #ene by lipopolysaccharide is

mediated throu#h 95T5 elements in neonatal rat cardiacmyocytes.9 Mol Cell Cardiol /0" 603-63. (**)0. Shor R" Rozenman O" Bolhins%y 5. BN in septic

patients !ithout systolic myocardial dysfunction. E(r 9

'ntern Med ," /6-0. (*6)

.Rivers " &c1ord M " 'tero R. 1linical utility of B-

type natriuretic peptide in early severe sepsis and septicshoc%.9 'ntensive Care Med ** (6)" /6/*/,/. (*,)

6. Coffmann +" Bruec%mann &. 5 ne! lan#ua#e ofnatriuretic peptides in sepsisP Crit Care Med/6(3)" *626-,.(*2)

,. mad Handil" Moshua Burac%. 5 Biomar%er for theia#nosis and Ris% Stratification of atients ?ith SepticShoc%.Arch 0(rg0/(/)" *0*-*06. (*2)

2. +eda S " Nishio H" 5%ai O. ro#nostic value of

increased plasma levels of brain nat riuretic peptide inpatient s !ith septic shoc%. 0hoc5*6 (*)" /0-/3. (*6)

3. ?ieczore% SM" ?u 5C" 1hristenson R. 5 rap id B -type natriuretic peptide assay accurately dia#noses leftventricular dysfunction and heart failureA a multicenter

evaluation.Am Heart 900 ()" 2/0 2/3. (**)

6. Hotanidou 5" Harsalia%os % ro#nostic importance ofincreased plasma amino-terminal pro-brain natriuretic

peptide levels in a lar#e noncardiac" #eneral intensive careunit population. 0hoc5/(0)" /0*-,. (*3)

6. Farpula &" ul%%i H" Harlsson S% redictive value ofN-terminal pro-brain natriuretic peptide in severe sepsisand septic shoc%. Crit Care Med/()" *,,-2/. (*,)

+;;reiations? SIRSAsystemic inflammatory responsesyndrome:BNA B-type natriuretic peptide: NT-proBNA

N-terminal prohormone of brain natriuretic peptide:

&'SA multiple or#an dysfunction syndrome: 1TArocalcitonin: 1RA 1-reactive protein: 1A protein 1:5NA atrial natriuretic peptide: 1#mpA cyclic #uanosinemonophosphate: 1C
http://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndromehttp://en.wikipedia.org/wiki/Systemic_inflammatory_response_syndrome

NT Probnp Pada Sepsis

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