Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                

Strucni Clanci: Professional Articles

Download as pdf or txt
Download as pdf or txt
You are on page 1of 14

Med Pregl 2009; LXII (11-12): 555-568. Novi Sad: novembar-decembar.

555

STRUCNi CLANCI
PROFESSIONAL ARTICLES
Medicinska akademija - US Medical School, Beograd I Strucni clanak
Medicinski fakultet, Kragujevac Professional article
UDK616.124
DOl: lO.2298/MPNS0912555D

EV ALUACIJA RELAKSACIJE MIOKARDA U USLOVIMA REMODELOVANOG SRCA


EVALUATION OF A1YOCARDIAL RELAXATION IN CONDITIONS OF CARDIAC REHODELING

Nina DUKANOVIC 1, Vladimir JAKOVL.JEVIC 2 i Vujadin M. MUJOVIC'


Sazetak - Pojam kardiodinamikc oznacava dinamicke dogadaje koji su povezani sa kontrakcijom i relaksacijorn srca. Nastali talas
ekscitacije siri se veorna brzo duz cele muskulature pretkomora i posle kratkog A V zadrzavanja zahvata sve misicne celije kornora.
Ekscitacija. odnosno sirenje akcionih potencijala prethodi kontrakciji srcanog misica koji se po nasa po zakonu "svc iii nista". Nakon
svake kontrakcije nastaje relaksacija srcanog misica, tako da se kontinuirano smenjuju ciklusi kontrakcije i rclaksacije. Celokupna
kardiodinamika, hernodinamika, tj. signalni mehanizmi srca su prorncnjcni u stanju remodclovanja (prcoblikovanja) miokarda levc
komore, tj. muskulature i celog zida arterije, Rernodelovanjc srcanog zida i slojcva zida artcrije je negativan faktor, jer dovodi do
poremecaja kontrakcije i relaksacije srca i potpornaze progrcsiju arterijskc hipertcnzije. nastanak ateroskleroze i stenoze u arteriji.
Danas se intenzivno proucava genetska baza srcanog rcmodelovanja. Kardiorniopatije su primarni porernecaji srcanog misica
povezane sa abnormalnostima debljine srcanog zida. velicine komore, kontrakcijc. relaksacije, provoda signala i ritmicnosti. One su
glavni uzrok morbiditeta i mortaliteta u svim starosnim strukturama. 0 mchanizmima ovih pojava na molekularnorn nivou bice
diskutovano u ovoj studiji.
Kljucne reci: Remodelovanje kornora; Relaksacija: Hipertrofija lcve komore: Funkcija leve kornore

Summary - The term cardiodynamics refers to dynamic events associated with cardiac contraction and relaxation. The occurring
1-vave ofexcitement spreads very quickly along the entire atrial musculature and after a briefA I' retention it affects all muscle cells
a/the ventricles. Excitation, that is, the increase in action potentials. precedes the contraction ofthe myocardium, whichfollows the
"all or none" rule. Each contraction results in relaxation ofthe mvocardium, so that the contraction and relaxation cycles continu-
allyfollow each other in succession. The entire cardio(h'/l~l/Ilics, ilemodinam ics, i.e. signaling mechanisms ofthe heart are altered
in the remodeling (alternation) condition of the left ventricular mvocardium. i.e. the musculature and the whole arterial wall. Re-
modeling a/the cardiac wall and layers a/the arterial wall is a negative/actor, because it leads to disturbances ofthe cardiac con-
traction and relaxation cycles and incites progression ofthe arterial hypertension, emergence 0/ atherosclerosis and arterial
stenosis. Today the genetic base ofthe cardiac remodeling is the object ofintensive studies. Cardiomyopathies are primary disor-
ders of the myocardium associated with abnormalities a/the cardiac wall thickness, the size ofchambers, contractions, relaxations,
signal conduct and rhythm. They are the major cause of morbidity and mortality/or all age groups. Mechanisms oj these events on
the molecular level will he discussed in the following study.
Key words: Ventricular Remodeling: Relaxation: Hypertrophy, Left Ventricular: Ventricular Function, Left

Uvod Introduction
U poslednje dye decenije ucinjen je znacajan Over the previous 1\\/0 decades significant im-
napredak u rasvetljavanju patogeneze kardiomio- provements have been made and a new light has
patija na molekularnom genetskom nivou [1,2]. been shed on the pathogenesis of cardiomyopathies
Hipertroficna kardiorniopatija moze da nastane mu- at the molecular genetic level [1,2]. Hypertrophic
tacijom gena 11 koji kodira proteine sarkomere, a cardiomyopathy may be caused by mutations of 11
dilataciona (kongestivna) kardiomiopatija je izaz- gene, which encodes sarcomere proteins, while dila-
vana mutacijom hromozoma na lokaciji 25 gde geni tated (congestive) cardiomyopathy is caused by mu-
kodiraju kontraktilne, citoskeletne i kalcijum-regu- tations at 25 chromosome location where genes
latorne proteine. Postoji genetska heterogenost ! encode contractile, cytoskeletal and calcium regula-
brojn i putevi koj i dovode do promena u strukturi 1 tory proteins. There is a genetic heterogeneity and
funkcij i srca [2]. Posebno vazan signal je porernecaj numerous ways leading to changes in cardiac struc-
kinetike i homeostaze kalcijuma. Postoje brojne stu- ture and function [2]. One particularly important
dije 0 kalcijumu i kardiomiopatiji [1,3,4]. Regu- signal is a disorder of kinetics and homeostasis of
lacija ciklusa kalcijuma (Ca 2+). tj. njegovog kruze- calcium. There are also numerous studies of Cal-
nja iz sarkoplazminog retikuluma (SR) do citosola I cium and cardiomyopathy [1,3,4]. Regulation of the
iz citosola do SR, kontrolise ne samo povezanost Calcium (Ca 2 " ) cycling, i.e. its circulation from the
ekscitacije i kontrakcije (ElK) vee i relaksaciju srca.

Adrcsa autora: Mr sc. med. Nina Dukanovic, Medicinska akadernija - US Medical school.
11000 Beograd, Kurncdraska 261. E-mail: ninank1377@yahoo.com

en .J
556 Dukanovic N, i sar. Evaluacija relaksacije miokarda

Skracenice A bbreviutions
SR - sarkoplazmin retikulum SR - sarcoplasmic reticulum
SERCA - Ca 2" ATPaza sarko/cndoplazrninog retikuluma SERCA - sarco/endoplasmic reticulum Ca" /\TPasc
E/K - ekscitacijalkontrakcija E/C - excitation and contraction
PLN - fosfolamban PLN - phospholamban
RyR - rijanodinski receptor RyR - ryanodine receptor
LVR - remodelovanje leve komore LVR - left ventricular remodeling
MI - infarkt miokarda MI - myocardial infarction
RAAS - renin-angiotenzin-aldosteron sistem RAAS - Renin-Angiontensin-Aldosterone System
MMP sistem - metaloproteinazni sistem MMP System - rnetalloproteinase System
AP - akcioni potencijal AP - action potential
TC - terminalne cisterne TC - terminal cisterns
DHP - dihidropiridin DHP - dihydropyridine
CICR - kalcijumom indukovano oslobadanje kalcijuma CICR - Ca 2+ induced Ca 2- release
cADPR - ciklicna ADP-riboza cADPR - cyclic ADP-ribose
ATPaza - adenozin trifosfataza ATPase - adenosinetriphosphatase
NCX - Na+/Ca2+ razmenjivac NCX - natrium-calcium exchanger
EDV - enddijastolni volumen EDV - end-diastolic volume
PV kriva - pritisak-volumen kriva PV curve - pressure volume curve
ESV - endsistolni volumen cAMP - cyclic adenosine monophosphate
cAMP - ciklicni adenozin-monofosfat cGMP - Cyclic guanosine monophosphate
cGMP - ciklicni guanozin-monofosfat TFGB - transformation growth factors of type B
TFGB - transforrnisuci faktori rasta tipa B DAG - diacylglycerol
DAG - diaciglicerol IP, - inositol trisphosphate
IP, - inozitoltrifosfat
TNFa - tumor necrosis factor a
TNFa - tumor nekrozis faktor a
ACE - inhibitors of Angiotensin-Converting Enzyme
ACE - inhibitori angiotenzin-konvertujuceg enzima
AIM - acute myocardial infarction
AIM - akutni infarkt miokarda
EeT - extracellular liquid
ECT - ekstracelularna tecnost
Pi - inorganic phosphorus
Pi - neorganski fosfor
aFGF - kiseli fibroblastni faktori rasta
aFGF - kiseli fibroblastni faktori rasta
bFGF - bazni fibroblastni faktori rasta
bFGF - bazni fibroblastni faktori rasta
Alteracije u povezanosti ekscitacye i kontrakcije ~~­ cytosole to SR, controls not only the connection be-
staju u hipertrofiji sr~a [5-8]. Srcana l~suficIJe~cIJ.a tween excitation and contraction (E/C), but also car-
[1,9,10] se karakterise abnormalnostima Ca' -C}- diac relaxation. Alterations in the connections
klusa odnosno kruzenja kroz SR srca. U tome Je between excitation and contraction originate in the
centr~lna uloga: (a) Ca 2+ ATPaza sarko/endoplaz- cardiac hypertrop.hyJ5-8]. Cardiac. insufficiency [1,
minog retikuluma (SERCA) i njegov regulator fos- 9,10] is charactenze by abnormalities of the Ca cy-
folamban (PLN) u modulaciji relaksacije srca; (b) cling through the heart's SR network..That IS tl~~
kalsekvestrin u regulacij i deponovanja Ca 2+ u S~ i central role of: a) sarco/endoplasmic reticulum Ca-
ATPase (SERCA) and their regulator phospholam-
(c) rijanodinski re~eptor+ (RyR) kao C~2.+ kanali u ban (PLN) in the modulation of cardiac relaxation;
kontroli oslobadanja Ca 2 IZ SR. NIVO ili aktivnost b) calsequestrin m the regulation of despositing Ca~_
ovih kljucnih proteina u kinetici Ca 2+ por~m~eeni s,~ in SR and c) the ryanodine receptor (RyR) as Ca~
u kardiorniopatiji. Ove promene u kruzenju Ca" channels in the control of Ca" release from SR. EI-
glavne su karike u deterioraciji (pogorsanju) srcane ther the level or activity of these key proteins of the
funkcije i remodelovanju. Identifikovane su genet- Ca" kinetics are altered in cardiomyopathies. These
ske varijante u,ovim proteinirna SR Ca" .cik~usa, ~to changes in circulation of Ca" are the main reasons
rnoze da poveca predispoziciju za razvoj srcane tn- for deterioration (worsening) of the. cardiac function
suficijencije iii fatalnih aritmjja. Danas je jasna piv- and remodeling. Genetic yanal:ts 111 these SR C?'
otska uloga proteina SR Ca' ciklusa u zdravlju i cycle proteins have been Identified, which may 111-
bolesti uz specificne genets~e modifikacije. )(0t,1- crease predisposition towards development of car-
ceptualni osnov terapije srcane insuficijencije je diac insufficiency or fatal arrhythmias. Today the
sprecavanje procesa remodelovanja le~e srcane ko- pivotal role of SR Ca 2+ cycle proteins in health and
more (LVR = left ventricular remodelzng). Sistem- disease is clear, with particular genetic rnodifica-
skom ehokardiografijom tokom vremena posle tions. The conceptual baSIS for therapy of cardiac
infarkta miokarda (MI), tj. primarnog ostecenja, insufficiency is prevention of the left ventricular re-
moze da se pratt promena elipsoidnog u sferoidni modeling (LVR). The change from the ellipsoid into
oblik zida leve komore. Ovaj proces promene oblika spheroid form of the left ventricular wall may be
oznacava se kao remodelovanje iIi sekundarno oste- monitored by systematic echocardiography, over a
cenje. Strateski je najbolje spreciti primarno ostece- period of time, after myocardial infarction (MI), i.e.,
nje, ali ako vee do njega dode, valja spreciti re- the primary damage.This process of form alteration
modelovanje, tj. sekundarno ostecenje i time sma- is referred to as remodeling or secondary damage.
njiti mortalitet od srcane insuficijencije. Remode- The best strategy would be to prevent the primary
Med Preg12009; LXII (11-12): 555-568. Novi Sad: novembar-decembar. 557

lovanje leve komore (LVR) posle MI nije povezan damage, but if it has already occurred, an attempt
sa cestirn polimorfizmima u: renin-angiotenzin- should be made to avoid remodeling, i.e., the secon-
aldosteron sisternu (RAAS), adrenergickom sistemu dary damage, and in such a way reduce mortality
i metaloproteinaznom (MMP) sistemu. Medutim, rate cause! by cardiac insufficiency. L VR after MI
dolazi do progresivnog povecanja enddijastolnog is not connected to frequent polymorphisms in:
volumena (EDV) [5]. Renin-Angiontensin-Aldosterone System (RAAS),
adrenergic system and the metalloproteinase (MMP)
Povezanost ekscitacije, kontrakcije i system. However, a progressive increase in end-
relaksacije u srcanom misicu diastolic volume [5J takes place in a prospective
evaluation of left ventricular remodeling after myo-
Povezanost ekscitacije i kontrakcije ukljucuje cardial infarction (MI).
cetiri stepena: (1) sirenje akutnog potencijala (AP)
duz sarkoleme i T-tubula uz oslobadanje Ca2~ iz SR; Correlation between excitation, contraction
(2) vezivanje Ca2+ i aktivacija proteina misica; (3) and relaxation of the myocardium
stvaranje tenzije aktiviranjem proteina i (4) relak-
The correlation between excitation and contrac-
sacija misica.
tion includes four stages: 1) the spreadin? of action
Oslobadanje Ca2" iz terminalnih cisterni (TC)
potential (AP) along the sarcolemma ana T-tubules
sarkoplazminog retikuluma nastaje usled sirenja ta- with the release of Ca 2+ from SR: 2) the binding of
lasa ekscitacije duz sarkoleme. Sarkolema ima bro- Ca 2+ and the activation of muscle proteins; 3) the
jne invaginacije- sistem Tvtubula koji prenose AP creation of tension by protein activation and 4) mus-
radijalno unutar miokardiocita. Sirenje AP dovodi cle relaxation.
do difuzije Ca2+ jona u citosol kroz DHP_Ca 2T ka- Release of Ca 2+ from teminal cysterns (TC) sarco-
nale T-tubula. S obzirom na bliski funkcionalni kon- plasmic reticulum occurs due to the spreading of ex-
takt T-tubula sa SR kao ekstenzivnim intracelular- citation waves along the sarcolemma. The sarcole-
nim membranskim sistemom, sama depolarizacija mma has numerous invaginations - system of T-
T-tubula uzrokuje otvaranje rianodinskih Ca" ka- tubules that transfer AP radially within myocardio-
nala i oslobadanje Ca" iz terminalnih cisterni sarko- cytes. The spreading of AP leads to the diffusion of
plazminog retikuluma. Kolicina Ca2! koji ude u ce- Ca2~ ions in the cytosol throuzh dihydropyridine
. liju kroz T-tubule predstavlja okidac (trigger) oslo- 2T
(DHP)_Ca channels of T-tubules. Regarding the
badanja Ca2+ iz cisterni SR, odnosno depoa kal- close functional contact of T-tubules with SR as an
sekvestrina. Ovaj mehanizam povezanosti E-K extensive intercellular membranous system, the very
ukljucuje kalcijumom indukovano oslobadanje kal- depolarization of T-tubules causes the opening of ry-
cijuma (Ca 2T -induced Ca2+ release - CICR), kao i anoid Ca2+ channels and the release of Ca 2+ from the
Ca2 + signalni J?ut posredovanjem ciklicne ADP-ribo- terminal cisterns of the sarcoplasmic reticulum. The
ze (cADPR) 1 rianodinskih receptora (RyR). Tako quantity of2T Ca2+ that enters a cell through T-tubules
T

dolazi do povecanja koncentracije Ca- u citosolu triggers Ca release from the SR cisterns, i.e., de-
vise od 10 puta kada se poredi sa stanjem POSitS of calsequestrin. This m~~l~anism of cRrrela-
mirovanja. non of E/C includes CICR (Ca induced Ca" rele-
Aktivacija proteina rnisica je druga karika u lan- ase), as well as Ca" signal path by means of cyclic
canom mehanizmu ElK. U miru je interakcija aktina ADP-ribose (cADPR) and ryanoid receptors (RyR).
i miozina inhibisana, a koncentracija Ca2 + u citosolu This results in a higher concentration of Ca2+ in cy-
iznosi oko 0, I mol/I. Pri ekscitaciji i influksu Ca" tosole more than tenfold when compared to resting.
koncentracija Ca2 + u citosolu se znacajno povecava i The muscle protein activation IS another link in
iznosi 1 mol/I. Pri visokoj koncentraciji Ca 2+ u ci- the chain mechanism of E/e. When at rest, the inter-
tosolu, joni kalcijuma se vezuju za troponin C, sto action of actin and myosin is inhibited, and the con-
predstavlja pocetak konformacionih promena regu- centration of Ca2 + in the cytosol equals to about 0.1
latornih proieina i suficijentne aktivacije interakcije
urnol/I. During the excitation and influx of Ca2+, the
concentration of Ca2 + in the cytosol increases signifi-
kontraktilnih proteina aktina i miozina. Troponin C cantly and equals 1 umol/l. With such a high con-
vezuje cetiri Ca 2+ po molekulu. Troponin menja centration of Ca2 + in the cytosol, the calcium ions
oblik, pomera tropomiozin u stranu i otkriva vezna bind to Troponin C, which marks the beginning of
mesta za miozinske glavice na aktinu. Dok misic conformational changes of regulatory proteins and
miruje, tropomiozin pokriva mesta na kojima se sufficient activation of interaction of contractile pro-
miozinske glavice vezuju za aktin. Ekscitacija i teins actin and myosin. Troponin C binds four Ca"
povecanje intracelularne koncentracije Ca 2- od 0,1
°
do 1 umol/l dovoljni su da aktiviraj u proteine unu-
tar misicnih vlakana, otkriju vezna mesta za miozin-
per a molecule. Troponin changes its form, moves
tropomyosin to the side and uncovers binding sites
for myosin heads on the actin. While the muscle
ske glavice i omoguce formiranje poprecnih rnosto- rests, tropomyosin covers the sites on which myosin
va izmedu aktina i miozina. Normalno, say troponin heads bind to actin. The excitation and increase in
nije zasicen Ca2- , pa postoji potencijalna rezerva za the intercellular concentration of Ca2 + of 0.1 umol/l
dodatno formiranje poprecnih mostova. Faktori koj i are a sufficient to activate proteins within muscle fi-
povecavaju intracelularnu koncentraciju Ca2+ obez- bers, to uncover binding sites for myosin heads and
beduju vise mesta za formiranje poprecnih mostova. to allow formation of cross-bridges between actin
and myosin. Of course, all the troponin is not satura-
558 Dukanovic N, i sar. Evaluacija relaksacije miokarda

Stvaranje tenzije aktiviranih proteina rnisica je ted with Ca 2+, so there is a potential reserve for addi-
treci stepen u mehanizmu povezanosti ekscitacije i tional formation of cross-bridges. Factors that in-
kontrakcije (ElK). Aktiviranje proteina prate ponav- crease the intracellular concentration of Ca" provide
ljajuci ciklusi poprecnih mostova, pri cernu se trosi more space for the formation of cross-bridges.
energija nastala hidrolizom ATP. Povecanjem broja Creating tension of activated muscle proteins is
poprecnih mostova povecava se snaga kontrakcije the third stage of the mechanism of excitation and
sto se oznacava kao povecani inotropizam iii po- contraction correlation (EIC). The protein activation
vecanje kontraktilnosti. Glavice molekula miozina is followed by repetitive cross-bridge cycles, during
vezuju se za aktin pod uglom od 90 stepeni i za- which the energy originating from hydrolysis is
veslajem uzrokuju da aktin klizi po miozinu. Gla- spent. As the number of cross-bridges grows. the
vice se zatim odvoje i povezu na sledecem veznom magnitude of contraction also intensifies. which is
mestu, ponavljajuci serijski ovaj proces. Svaki po- defined as an increased inotropism or an increase in
jedinacni ciklus pripajanja, zaveslaja i odvajanja contractility. The myosin molecule heads bind to ac-
skracuje misic i povecava tenziju. Svaki debeli fila- tin at a 90 degree angle and by means of a stroke
ment sadrzi oko 500 miozinskih glavica, a svaka od cause sliding of actin over myosin. The heads then
njih obavi oko 5 ciklusa u sekundi za vreme brze separate and again bind at a new site, thus succes-
kontrakcije. Energija koja se pri tome koristi nastaje sively repeating this process. Each individual cycle
kada adenozin trifosfataza (ATPaza) cepa molekulu of attaching, stroking and separating shortens the
ATP na adenozin difosfat (ADP) i neorganski fosfor muscle and increases the tension. Each thick fila-
(Pi). ATPaza i ATP su lokalizovani na poprecnim ment holds about 500 myosin heads, and each of
mostovima, ali se ATPaza aktivira i hidroliza ATP those performs about 5 cycles per second during a
desava jedino za vreme ciklusa poprecnih mostova, fast contraction. Energy used in this process is cre-
odnosno kada jc miozin vezan za aktin. Za odvaja- ated when adenosinetnphosphatase (ATPase) splits
nje glavice miozina, moraju se iz poprecnih mos- the ATP molecule into adenosine diphosphate
tova ukloniti ADP i Pi i obnoviti molekuli ATP. (ADP) and inorganic phosphorus (Pi). ATPase and
Ako nema ATP molekula, tanki i debeli filamenti ATP are localized on the cross-bridges, but ATPase
ostaju spojeni i ne mogu se odvojiti - rigor mortis. is activated and the ATP hydrolysis occurs only dur-
Cirri se miozin odvoji od aktina, zapocinje ponovna ing the cycle of cross-bridges formation, that is,
hidroliza ATP molekula i vezivanje miozina i aktina when myosin is bound to actin. ADP and Pi must be
tako da se poprecni mostovi vracaju u svoj origi- removed from cross-bridges and ATP molecules
nalni uspravni polozaj i mogu da participiraju u sle- must be restored before a myosin head can detach.
decem ciklusu. Ciklus se odrzava sve dotle dok Je Without ATP molecules, thin and thick filaments re-
Ca 2+ vezan za troponin. Shernatski prikaz zbira do- main attached and cannot be separated - rigor mortis.
gadaja koji dovode do kontrakcije dat je na Slici I As soon as myosin is detached from actin. the hy-
[I I]. drolysis of the ATP molecules and myosin-actin
binding restart, so that the cross-bridges return to
their original upright position and can participate in
I K()NTRAi\:CIJA' jr.----- the next cycle. The cycle lasts tor as long as Ca IS
bound with troponin. The schematic outline of all
the events leading to the contraction is shown in Fig-
ure I [I I].
The question arises as to how this musclerclaxa-
tion occurs. When the concentration of Ca ' 111 the
cytosol decreases to a value less than 0.1 urnol/I, tro-
ponin returns to its original conformational condi-
tion, tropomyosin inhibitsthe reaction of myosin and
actin, so the repetrtton of the cross-bridges cycle IS 2
stopped. With a decrease in the concentration of Ca
in the cytosol, the contraction stops and the relaxa-
tion begins. Active kinetics of Ca" is very important
to control these events. Firstlv, the Ca2~1ATPase
pump in the membrane of sarcoplasmic reticulum
Slika l. Sumiranje dogaetaja za vreme ekscitacije i kontrakcije. (SR) takes over Ca 2 ", from the cytoso! and a~cumu­
TC = terminalne cisterne; SR = sarkoplazmin retikulum lates it inside the SR cisterns 111 the torm ot calse-
Fig. J. Summary of events which occur during excitation and questrin. This pump is activated by phosphorylation
contraction. TC = terminal cisterns: Sf? ~ . sarcoplasmic reticu- of phospholamban (PLB! with the participation of
lum cAPl\1 dependent prote1l1~. kinase. Secondly, the
Postavlja se pitanje koji je mehanizam nastanka quantity ot 1I1tracellular Ca IS regulated by the ex-
relaksacije misica. Kada se smanji koncentracija chance of Na'ICa 2+ (NCX), an antiport mechanism
Ca2-'- u citosolu na vrednosti ispod 0, 1 uol/l, tropo- thrOl~gh the cell membrane carried by gradient Na".
nin se vraca u svoje originalno konformaciono sta- For e'ach 3 Na+- dropped in a cell, I ('a=' is ejected
nje, tropomiozin uspostavlja inhibiciju interakcije from the cytosol into ECT. Thirdly, mitochondria
Med Preg12009; LXII (11-12): 555-568. Novi Sad: novembar-decembar. 559

miozina i aktina pa se zaustavlja ponavljanje ciklusa


poprecnih mostova. Smanjenjem koncentracije Ca 2- RELAKSACIJA

u citosolu dolazi do prestanka kontrakcije i nastanka


TC-K/\.LSEKYESTRI)i
relaksacije. U kontroli ovih dogadaja veomaje vaz- lnaktivacija Mitohondrije

na aktivna kinetika Ca 27. Prvo, Ca 2c_ A TPazna pum-


pa u membrani sarkoplazminog retikuluma (SR) Ca2- pumpa 1
preuzima Ca 27 iz citosola i akumulira ga u cisterna- FOSFOLAMBAN

ma SR u obliku kalsekvestrina. Ova pumpa se akti- Naol Ca2 •


vira fosforilacijom fosfolambana uz ucesce cAMP 3:1
zavisne protein-kinaze. Drugo, kolicina intracclular- kontratransport

nog Ca" regulisana je razmenom Na~Ca2~ (NCX),


antiportnim mehanizmom kroz celijsku membranu - - - - - 1 Inaktivacija poprccnih
nosen gradijentom Na 2+. Za svaka ubacena tri Na u L.- ~ mostova

celiju aktivno se izbacuje jedan Ca 2+ iz citosola u


ekstracelularnu tecnost (ECT). Trece, mitohondrije Stika 2. Shematski prikaz mehanizma relaksacije. TC = terrni-
takode oslobadaju (pasivno) i preuzimaju (aktivno) nalne cisterne -
27, Fig. 2. Schematic outline ofthe mechanism ofrelaxation. TC =
Ca ali je ovaj proces isuvise spor da bi imao
znacaja u brzim procesima ekscitacije, kontrakcije i terminal cisterns
relaksacije. Shematski prikaz mehanizma relaksa- but this process is too slow to have any real signifi-
cije dat je na Slici 2. cance in the fast processes of excitation, contraction
and relaxation. Fourthly, the schematic outline of
Sarkolemalna Ca2+-ATPazna pumpa the mechanism of relaxation is given in Figure 2.
2f
Oslobadanje Ca za vreme relaksacije odvija se Sarcolemmal Ca2+-ATPase Pump
21-ATPaze
u najvecoj meri funkcijom Ca u mern-
brani SR i NCX-a u sarkolemi miokardiocita [12- The release of Ca2~ during the relaxation happens
14]. to the greatest degree by the function of
U srcanom misicu nije moguca ni sumacija niti Cal)ATPase within SR membrane and NCX in the
tetanus. Razume se da to nije mana, vee fizioloska sarcolemma of myocardiocyte [12-14].
prednost srcanog rnisica, koji se mora relaksirati Neither summation nor tetanus is possible in the
posle svake kontrakcije da bi se ornogucila njegova myocardium. This, of course, is not a disadvantage,
restitucija i ponovo punjenje krvlju. Duzina sark- but rather a physiological advantage of the myocar-
omere u srcanorn misicu pre kontrakcije (preload) dium, which must relax after each contraction in or-
zavisi od toga koliko je krvi uslo u srce. Posto je der to enable its restitution and new inflow of blood.
The length of sarcomere in the myocardium prior to
ova kolicina venskog priliva pod fizioloskorn kon-
the contraction (preload) depends on how much
trolom, to je vazan re~ulator snage misicne kontrak- blood has entered the heart. Since this quantity of
cije. Medutirn, snaga kontrakcije moze da varira pri venous inflow is under physiological control, it IS an
27
datoj duzini sarkornere, ako se kolicina ulaska Ca important regulator of the muscYe contraction force.
u celiju prorneni, sto je takode pod stalnom fiziolos- However, the force of contraction may fluctuate
kom kontrolom. along the given length of sarcomere if the quantity
of Ca 2' enterin~ a cell alters, which is also under
Kontrakcija i relaksacija miokarda i njihova constant physiological control.
regulacija
Contraction and Relaxation of Myocardium
Kontraktilnost miokarda predstavlja sposobnost and their Regulation
srcanog misica da radi pri konstantnoj end-dijastol-
noj duzini rnisicnih vlakana, a osnova u kontroli The myocardial contractility is the ability of the
kontraktilnosti je Starlingova kriva [15]. Promene u cardiac muscle to work at a given, constant, end-
kontraktilnosti miokarda skrecu Starlinaovu krivu, diastolic fiber length, while the basis in control of
tako da bilo koja od fizioloskih, farmakoloskih iii contractility is the Starling Curve (15). Changes in
patoloskih intervencija koje uticu na ovu bazicnu the myocardial contractility alter the Starling Curve,
osobenost srca (duzinu misicnih vlakana), stvara so that any physiological, pharmacological or patho-
svoju novu Starlinzovu krivu. Dakle, !ostoji "fa- logical intervention affecting this basic feature of
milija Starlingovih krivulja", a svaka 0 njih prika- the heart (muscle fiber length), creates a new Star-
zuje razlicit stepen kontraktilnosti (Slika 3) [11,15]. ling curve. This means that there is a "family of
Lekovi sa pozitivnim inotropnim dejstvom pove- Starling curves", each of them showing various de-
cavaju radni kapacitet srca pri bilo kom enddija- grees of contractility (Figure 3) [11,15].
stolnom volurnenu, odnosno bilo kojoj pocetnoj Positive inotropic drugs increase the working ca-
duzini misicnih vlakana, ali se srcani misic i dalje pacity of the heart at any end-diastolic volume
ponasa po Frank-Starlingovom zakonu. Isto tako, (EDV), that IS to say, any given muscle fiber length,
lekovi sa negativnim inotropnim dejstvom dovode
560 Dukunovic N, i sar. Evaluacija relaksacijc miokarrla

Radni ucinak povecana


u xi-toli ___ - - kontraktlinost
D
-----
norrnalna
kontraktilnost
Udami
volurnen - MVS --- AKP
smanjena

Freel P1i~"'"
kontraktilnost

srca

lnd-dijastoln: \ «lumen VENSKI PRILIV

Slika 3. Familija Sterlingovih krivulja Slika 4. Fizioloski kontekst razlicitih varijabli odgovornih za
Fig. 3. Starling Curve Famil) , rad lcve komore u intaktnom srcu. Masa i geometrija komore
do redukcije radnog kapaciteta srca i skrecu Starlin- ima centralnu ulogu u clctcrrninuciji afterload-». preload-a i
govu krivu nadesno i nadole. udamoz volurnena. MVS=minutni volurnen srca: AKP=arteri-
Koncept preload-a i afterload-« je od posebnog jski krY~ni pritisak
prakticnog interesa u ispitivanju i vodenju pacije- Fig. 4. Physiological context of various variables responsible
for work. of the left ventricle in intact heart. The ventricular
nata sa oboljenjima srca. Jasna definicija i usvajanje mass and geometry playa central role in the determination of
ovih termina je conditio sine gua non. Preload (pre- aitcrload, preload and impact volume. /1.111' fie art Minute
thodno opterecenje) podrazumeva rastezanje misica Volume. ABP = arterial blood pressure
u mirovanju, pre zapocinjanja kontrakcije. Ostva-
ruje se u poslednje tri faze dijastole komora: fazi but the myocardium continues to behave in accor-
brzog punjenja, fazi laganog punjenja (ili dijastazi) i dance with the Frank-Starling law. In the same way,
presistoli, a dilatacija ventrikula u dijastoli zavisi od negative inotropic drugs lead to a reduction of the
heart working capacity and swerve the Starling
venskog priliva. Afterload (naknadno opterecenje) curve down and to the right.
podrazumeva period od zapocinjanja misicne kon- The concept of preload and afterload is of a very
trakcije. Kada je 0 srcu rec, to je prva faza sistole special practical interest for the process of examin-
komora (izovolumetrijska faza iIi faza izometrijske ing and treating patients with heart diseases. A clear
kontrakc ij e). U ovoj fazi su zatvoreni atrioventriku- definition and acceptance of these terms is condition
larni i semilunarni zalisci, a komore su ispunjene sine qua non. The preload refers to stretching of the
krvlju pri cernu se razvija snazan sistolni pritisak cardiac muscle while resting, before the contraction
dovoljan da se otvore semilunarne valvule i savlada begins. It occurs within the last three phases of dias-
pritisak u aorti, odnosno pulmonalnim arterijama. tole: the phase of rapid filling, the phase of slow fill-
Odnos izmedu duzine misicnih vlakana i volu- ing (or diastasis) and presystolic phase, while the
mena, odnosno tenzije u zidovima i pritiska unutar ventricular dilatation in diastole depends on the ve-
nous inflow. The afterload refers to a period starting
komore zavisi od njene velicine i oblika i definisan
with the muscle contraction initiation. When the
je Laplasovim zakonom. Prema Laplasovom zakonu heart is in question, this is the first systolic phase
tenzija u zidu miokarda se povecava sa povecanjern (an isovolumetric phase or a phase of isometric con-
radijusa krivine ventrikula i obrnuto, pri datorn in- traction). In this phase, the atrioventricular and
traventrikularnom pritisku. Tenzija u miokardnom semilunar valves are snapped shut, while the ventri-
zidu je funkcija unutrasnjeg pritiska i radijusa kri- cles fill with blood. At the same time strong systolic
vine supljine komore. Cinjenica da se tenzija u zidu pressure starts, powerful enough for semilunar valve
miokarda povecava povecanjem volumena komore i to open and overcome the aorta pressure, i.e., the
u slucaju da intaventrikularni pritisak ostane kon- pressure in pulmonary arteries.
stantan posebno je znacajna u razumevanju rada re- The correlation between the length of muscle fi-
modelovanog srca [11]. bers and the volume, i.e., tension in walls and the
End-dijastolni stres zida je analogan preload-is i pressure within the ventricle depends on the size and
predstavlja silu koja dovodi do distenzije misicnih shape of ventricles and is defined by the Laplace's
Law. According to the Laplace's Law, the myocar-
vlakana i duzinu sarkomera neposredno pred svaku
dial wall tension increases together with the radius
kontrakciju. Primen a Laplasovog zakona i povezi- of the ventricle curve and vice versa, with given in-
vanje preload-a kao determinante volumena komore traventricular pressure. The myocardial wall tension
i mase njenog zida kao end-dijastolnog pritiska ima is a function of the inner pressure and of the ven-
svoj prakticni znacaj. Na Slici 4 shernatski su pri- tricular cavity curve radius. The fact that the myo-
kazane varijable performansi leve komore itaktnog cardial wall tension increases together with the
srca. increase of ventricular volume, eve~1 in cases when
the intraventricular pressure remains constant. is es-
Med Pregl 2009; LXII (11-12): 555-568. Novi Sad: novembar-decembar. 561

Regulacija inotropnih svojstava miokarda pecially important in understanding the way in


which the remodeled heart works [11].
Regulacija srcanog rada moze da se posmatra End-diastolic stress of the wall is analogous to
kroz tri potpuno razlicita tipa kontrole: (1) kontrola the preload and represents both the force leading to
na nivou fiziologije organa, (2) na celijskorn nivou the distension of muscle fibers and the sarcomere
biohemije i biofizike kardiocita i (3) na nivou length immediately before each contraction. The ap-
molekularne biologije i ekspresije gena. plication of the Laplace's Law and the connecting
Prva paradigma kontrole na nivou organa pri- of the preload as a determinant of both ventricular
kazana je kroz Frank-Starlingov zakon srca (Slika volume and the mass of its wall as end-diastolic
3). Druga paradigma kontro1e podrazumeva bio- pressure have their practical significance. Figure 4
hemijska i biofizicka svojstva celija miokarda, koja shows a schematic diagram of intact heart lett ven-
se mogu menjati i prilagodavati na razlicite uslove. tricular performance variables.
Nova saznanja da promena u fluksu kalcijuma ima
krucijalnu ulogu u stalnoj regulacij i povezanosti ek- Regulation of myocardial inotropic features
citacije i kontrakcije kao i relaksaciji miokarda, izu-
zetno su znacajna posebno u stratesko-terapijskom The regulation of heart work may be observed
pristupu. Sve veea saznanja 0 trecoj paradigmi kon- through three completely different types of control:
trole da do alteracije ekspresije gena i rernodelo- 1) the control at the level of organ physiology. 2) at
vanja dolazi pri prilagodavanju funkcije srca i the cell level of biochemistry and biophysics of car-
duzem trajanju razlicitih poremecaja, kao sto su mi- diocytes and 3) at the level of molecular biology and
tralna stenoza, aortna insuficijencija, endokrino- gene expression.
patije i miokardiopatije od esencijalnog su znacaja u The first control paradigm at the level of organs
savremenoj kardiologiji. is shown through the Frank-Starling law of the heart
Postoj i mnogo novih naucnih podataka 0 horneo- (Figure 3). The second control paradigm includes
statskim mehanizmima kontraktilnosti miokarda i biochemical and biophysical features of myocardial
adaptacionirn odgovorima na nivou sve tri porne- cells. which may be altered and adjusted in various
nute paradigme [16.17]. "Fazna regulacija" obuhva- ways. Recent discoveries point out that changes in
ta prve dye paradigrne: promene u duzini misicnih calcium flux play an essential role in the continual
vlakana, biohernije i biofizike kardiocita, dinamiku regulation of the correlation between the excitation
misicnih vlakana, biohemije i biofizike kardiocita, and the contraction as well as in the relaxation of
dinamiku kaIcijuma izmedu ekstracelularne tecnos- the myocardium, and they are therefore extremely
ti, citosola, sarkoplazminog retikuluma i mitohon- important. especially for a strategic-therapeutic ap-
drija. Modifikacije u kontraktilnosti miokarda na proach. Ever-increasing breakthrouruhs in relation to
dejstvo neurotransmitera i razlicitih lekova takode the third control paradigm are 0 crucial signi fi-
pripadaju faznoj regulacij i. Medutirn, promene srca- cance in present-day cardiology and lead to a con-
ne funkcije odnosno kontraktilnosti miokarda, usled clusion that the alteration of gene expression and
alteracija u ekspresij i gena, ostvaruju se znatno remodeling occurs during adjustments of the heart
sporije, posle vise nedelja iIi meseci i oznacavaju se function and lengthy presence of various disorders,
kao "tonicka regulacija". such as mitral stenosis, aortic insufficiency, endo-
crinopathy and myocardiopathy.
Regulacija luzitropnih svojstava miokarda There is an abundance of new scientific data
concerning homeostatic mechanisms of the myocar-
Dugo vrernena istrazivaci su posebnu paznju dial contractility and adequate answers on all three
posvecivali mehanizmima kontrakcije miokarda. of the above mentioned control paradigms [16.17].
Kao da se zaboravljalo da pri svakom srcanorn cik- The "phasal regulation" includes first two para-
lusu posle kontrakcije dolazi i do neophodne relak- digms: changes 111 the length of muscle fibers, bio-
sacije miokarda. Stanje komore na kraju sistole chemistry and biophysics of cardiocytes, calcium
odrzava njena inotropna svojstva, a na kraju dijas- dynamics between extracellular fluid, cytosole, sar-
tole (enddijastolni pritisak-volumen) odrazava luzi- coplasmic reticulum and mitochondria. Modifica-
tropna svojstva srcane kornore. Preload (venski tions of the myocardial contractilitv regarding the
priliv) i luzitropno stanje relaksirane komore deter- influence of neurotransmitters and various drugs
also belong to phasal regulation. However, changes
minisu intraventrikularni pritisak i volumen na kraju
of the cardiac function, I.e., the myocardial contrac-
dijastole. Relaksacija leve komore i njeno punjenje
tility, due to alterations in gene expression, develop
zavisi od stanja fibroznog skeleta srca, perikarda, much more slowly, after several weeks or months
kao i od geornetrije i debljine zidova komore. Pored and are referred" to as the "tonic regulation".
toga, fiziolosko-biohernijske varijable kao sto su
brzina disocijacije kontraktilnih proteina, kinetika Regulation of Lusitropic Features of the
Ca 2+ i afinitet kalcijuma za troponin, uticu na luzi- Myocardium
tropno stanje relaksirane komore u dijastoli.
Miokard leve komore pocinje da se relaksira For a very long time. researchers have been pay-
pocetkom dijastole u fazi izovolumetrijske relaksa- ing special attention to mechanisms of the myocar-
cije. U daljim fazama dijastole, posle otvaranja dial contraction. The fact that the necessary rnyocar-
562 Dukanovic N, i sal'. Evaluacija relaksacije miokarda

mitralne valvule (faza brzog punjenja, dijastaza i dial relaxation follows the contraction with every
presistolna faza) dolazi do izotonicke relaksacije cardiac cvcle seems to have been overlooked. Th~
cime se ostvaruje preload za sledecu kontrakciju. condition- of the ventricle at the end of svstole main-
Analogno familiji Starlingovih krivulja (Slika 3), tains its inotropic features. and at the end of diastole
promene luzitropnih (relaksirajucih) svojstava leve (end-diastolic pressure-volume) it maintains ven-
komore mogu se prikazati takode familijom tricular lusitropic features. The preload (venous in-
krivulja, pracenjern odnosa pritiska i volumena u tlow) and lusitropic condition of the relaxed
enddijastoli. Na taj nacin se moze sagledati sposob- ventricle determine the intravetricular pressure and
nost punjenja i restitucije komore miokarda u dijas- volume at the end of diastole. The relaxation of the
toli (Slika 5). left ventricle and its filling depend on the condition
of the fibrous skeleton ofthe heart. pericardium, as
well as on the geometry and thickness of ventricular
walls. In addition to this, physiological-biochemical
variables such as the speed of dissociation of con-
tractile proteins, kinetics of Ca" and calcium affin-
ity for troponin, affect the lusitropic condition of
Pritisak (P) A the relaxed ventricle in diastole.
The left ventricular myocardium starts to relax at
the beginning of diastole, in the phase of isovolu-
-_.......
--_ ...... --- _
""
.... ---B
metric relaxation. In the subsequent diastolic
phases, after the mitral valve opens (fast filling
phase, diastasis and presystolic phase) the isotonic
relaxation begins, thus creating the preload for the
Volumen (V) next contraction. Corresponding to the family of
Starling curves (figure 3). changes in lusitropic (re-
laxation) ventricular features may also be shown by
Stika 5. Familija krivulja punjenja komore. Tri cnddijastolne a family of curves, i.e .. by monitoring the correla-
krive odnosa pritiska (P) i volumena (V). J\=normalna luzitrop- tion between the pressure and volume in end-
nost; Bvpovecana luzitropnost: C=smanjena luzitropnost diastole. The capability of filling and restitution of
Fig. 5. Family of curves of ventricular filling. Three end- the myocardial ventricle in diastole may be scruti-
diastole curves represent the relation between Pressure (P) and nized in such a way (Figure 5).
Volume (I). A = normal lusitropy: B = increased lusitropy: C Changes of peripheral circulation may lead to
-= decreased lusitropy swerving of both the end-systolic and end-diastolic
curve to the left or to the right, that is, they may in-
Promene u perifernoj cirkulaciji mogu da dovedu fluence the inotropic and lusitropic features of the
do skretanja i endsistolicke i enddijastolicke krive heart. Changes or interventions which result in
ulevo iii udesno, tj. da uticu na inotropna i luzi- lesser ability of ventricle to be filled swerve the
tropna svojstva srca. Promene iii intervencije koje end-diastolic curve up and to the left (point C), thus
dovode do smanjene sposobnosti punjenja komore manifesting a negative lusitropic effect. Hemody-
skrecu enddijastolnu krivu ulevo i nagore (tacka C), namic changes or interventions by drugs which fa-
cime se manifestujc negativni luzitropni efekat. cilitate filling of the ventricle swerve the end-dia-
Hernodinamicke promene ili intervencije lekovima stolic pressure-volume ( PV) curve down and to the
koje facilitiraju punjenje komore, skrecu end- right, and lead to the fall of pressure in dilated dias-
dijastolicku pritisak-vaolumen (PV) krivu udesno i tole, thus manifesting a positive lusitropic effect.
nadole, dovode do pada pritiska u dilatiranoj dijas-
toli cime manifestuju pozitivni luzitropni efekat. Indexes of Myocardial Contractility and
Relaxation
Indeksi kontraktilnosti i relaksacije miokarda
Research of cardiac functions is of crucial im-
Ispitivanje funkcije srca je od esencijalnog zna- portance when it comes to mon itoring heart pat i-
caja u pracenju srcanih bolesnika. Posebno je vazno ents. It is especially important to quantify; contrac-
kvantifikovati kontraktilna (inotropna) i luzitropna tile (inotropic) and lusitropic cardiac features, but
svojstva srca, ali i diferentovati uzroke nastanka also to differentiate causes of cardiac dysfunctions
poremecaja funkcije srca kao sto su mitralna such as mitral stenosis, aortic stenosis, aortic insuf-
stenoza, aortna stenoza, aortna insuficijencija iii re- ficiency or regurgitation and many others. However.
gurgitacija i mnoge druge. Medutim, veoma je tesko it is very hard to diagnostically separate disorders of
dijagnosticki odvojiti poremecaje kontraktilnosti mvocardial contractility from relaxation defects, be-
miokarda od porcmecaja relaksacije, jer se periodi cause diastolic and systolic periods take turns cycli-
sistole i dijastole smenjuju ciklicno. Tako smanjena cally. Thus reduced left ventricular contractility,
kontraktilnost leve komore, odnosno inotropna ab- i.e., inotropic abnormality of blood extrusion, leads
normalnost istiskivanja krvi, dovodi do povecanja to an increase of end-systolic volume (ESY). which
ESY, sto otezava punjenje komore, odnosno makes it harder for the ventricle to fill, that is to
Med Pregl 2009; LXII (11-12): 555-568. Novi Sad: novembar-decembar. 563

luzitropnog porernecaja miokarda. Isto tako, komora Tabela 1. Kvantifikacija dijastolnih (luzitropnih) karakteristika
koja se adekvatno ne puni, ne moze se normalno lcve kornore
prazniti. Prema tome, luzitropni porernecaji uzrok Table 1. Quantification of diastolic (lnsitropic) features of the
su inotropnih porernecaja srcanog rada. Na Tabeli 1 left ventricle
Klinicki indeksi dijasrolne funkcijc Komcntar« 'OI1lf}/('IlIcIl)
dati su indeksi u proucavanju luzitropnosti (relak-
("/iIlICLlI IndeXeS (!I" f)ias/o lu: Function
sacije) miokarda. Indeksi u tabelama uglavnom se
I. Auskultacija i registrovanjc treceg i cet- Stctoskop I fllllok;lrdit\grafija,.\'fell/()sC()/h' and
odnose na ispitivanja kontraktilnosti i relaksacije
vrtog srcanog fona A nscnltnnon and F('- [Jh()lJ()canllOgr(lp/~)'
leve komore. Savremena kardiologija se ne moze
cordiJig (~r tlu: third andfourth heart 101Il!
zamisliti bez analize ne samo inotropnog, vee i luzi- :2 Vrcme trajanja izovolumetrijskc faze Dvodimeuzionalna ehokardiografiia - meri sc \TCmC
tropnog stanja miokarda, posle cega se tek provodi rclaksacije!/llfraliol1 of ixovohunctru: rc- ad zatvarania aortne valvule do otvarania mitralne
odreden stratcsko-terapijski tretman. luxatu», phas« 'valvllle./Jl~',)-diJl1(,I/stoll(l/ ('cho(.'ardir)gr(/!)!Jy Ihe
tuncfrom c!oslJIg ot aonic vulve 10 Ihe O/)CfllIf,';.! of
Fizioloska i patoloska hipertrofija nntrolvalve is I1Il\['\"I'('d.

3, Volurnen leve koruor c /I-l!.tl vcntncnkn Evaluacija punjeuja komore ehokardiografski

Hipertrofija srca moze takode da se posmatra


kroz tri pomenute paradigme na nivou organa, celije lillllig.
-.l Penod faze brzog punjenja trakcija pu-
i molekularnom nivou [16-19]. Rast srcaje u nepos- l:'hokardiogratija radionuklcarni °Il cnd-dijastul-

rednoj korelaciji sa njegovim hemodinarnickim rad- njcnja/FuSlft//lI/J.: /1l','/()(.//ill/l'J.:.!rac!iol/ nog punjcnja 1I prvoj trccini dijastolc./I'.-c/wcardio-
gru/,hy and or rctdmnnclnlc ~!-'I! elld-dwslolicji/hlJg
nim ucinkom. Ova korelativnost je prisutna kod
ill Ihc linl tlnrd of filL' dtctstolc.
svake osobe od rodenja do kraja zivota. Tako od-
:' Prorok kroz mitralnu valvulu Odnos izrnedu ranc brzine punjenja (baza brzog pu-
mah posle rodenja dolazi do brzog rasta leve ko- F/o\t fhrough mitrul \'((/\'1.' njenja) i kasnije 1I sisroli prctkomora (presistolicka
more, a kod bolesnika sa hipertenzijom i razlicitim faza); ehokardiografija. mitralna stenoza./Rt!/uf/o)/
valvularnim manama dolazi do znacajnog uvecanja hefIH.. -cn earl» speed '!lli!ling (lasf/Jlling pha\l:;
srca. Pri povecanirn radnim zahtevima, odnosno op- «lid later ill the atria! ,\ySfO/c (pl'e\vs!o!ic phase):
tereccnju (overload), aktivisu se razliciti homeostat- cchocurdiogruphv: mitral SIt!/IO"'.\
ski adaptacijski mehanizmi srca (intrinsic) ivan 6. Hemodinamski indeksi krutost i kom- Mere se u istrazivackim laboratoriiama
njega (extrinsic). U sagledavanju razvoja hipertro- pliansa zida komore/ Hemodvnamu: indc- Measured in research laboratories.
fije srca veoma je vazno razlikovati fizioloske i pa- XL'S: ventricular ngidi~F awl compliance

toloske limite hemodinamickih funkcija, individual-


nost adaptacijskog kapaciteta 11 odnosu na uzrast i say, it leads to a lusitropic myocardial dysfunction.
pol, kao i na duzinu trajanja odredenog stimulusa. In the same way, a ventricle that is not properly
Kada je prekomerno opterecenje srca (overload) filled cannot be properly emptied either. Conse-
hronicnog karaktera, dolazi do rasta i promene or- quently, lusitropic disorders are the cause of ino-
ganizacionih svojstava miokardnih celija (kardio- tropic cardiac dysfunctions. Table I shows indexes
cita) sa smanjenjem kontraktilne funkcije i eventu- used in the study of lusitropy (relaxation) of myo-
alnim nastavkom srcane insuficijencije. Rast, mor- cardium. Indexes of this table mostly refer to studies
foloska transformacija i akumulacija produkata po- of the left ventricular contractilitv and relaxation.
Contemporary cardiology can not even be conceived
jacane sintetske aktivnosti ne manifestuju se samo u to exist without analysIs of not only inotropic, but
celijama radne muskulature srca (kardiocitima), vee also lusitropic condition of the myocardium and
i u nernisicnim celijarna odnosno vezivnom tkivu only then to be followed by a specific strategic-
srca. Ova dva tipa populacije celija, misicne (kar- therapeutic treatment (Table 1).
diociti) i nemisicne (npr. kolagen), odgovaraju
razlicito na dejstvo stirnulusa kao sto su povecan ar- Physiological and Pathological Hypertrophy
terijski krvni pritisak, volumen, hipoksija, preko-
merno opterecenje komore, mitralna i aortna mana. Cardiac hypertrophy may also be viewed through
Kardiociti uvecavaju svoju masu tako sto hipertrofi- a prism of the three paradigms mentioned above and
raju bez deobe, dok se nernisicne celije dele pove- the three levels: organic, cellular and molecular [16-
cavajuci svoj broj, sto se oznacava kao hiperplazija 19]. Heart growth is in direct correlation with its
iIi proliferacija. hemodynamic functional output. Such a correlation
Fundamentalna karakteristika srca je prilagoda- is present in every person from the very beginning
vanje njegove mase hemodinamickorn opterecenju. of life till its end. This means that the left ventricle
Svaka promena hernodinarnicke funkcije, bilo zbog starts growing rapidly immediately after birth. while
fizioloske aktivnosti iii patoloskih alteracija kardio- with patients suffering from hypertension and vari-
vaskularnog sistema, dovodi do promena u odnosu ous valvular dysfunctions heaIi becomes siznifi-
srca i telesne mase. cantly en larged. Whenever the heart must \\'ork
Hipertrofija srca nastala usled fizicke aktivnosti, harder, i.e., when there is an overload. various ho-
odnosno bavljenja sportom, oznacava se kao fizio- meostatic adaptive mechanisms both within the
heart (intrinsic) and those out of it (extrinsic) are ac-
loska hipertrofija i sustinski se razlikuje od hiper- tivated. For any proper analysis of the progress of
trofijskog odgovora na hronicno prekomerno op- cardiac hypertrophy It is very' important to differen-
tereeenje (overload) - patoloska hipertrofija. U tiate betvveen phYSIological and pathological limita-
564 Dukanovic N, i sar. Evaluacija relaksacije miokarda

fizioloskoj hipertrofiji najcesce se ne radi 0 prevazi- tions of hemodynamic functions, individuality of


lazenju homeostatskog adaptacionog kapaciteta jer adaptive capacity in relation to age and gender," and
h ipertrofij ski stimulus u aktivisanju dodatne sinteze the duration of any specific stimulus. When the car-
proteina nije kontinuiran niti dugotrajan. Morfo- diac overload is chronic, organizational features of
loske, funkcionalne i molekulske promene u mio- myocardial cells (cardiocytes) start to grow and
kardu ostaju u fizioloskim granicama od intracelu- change, while the contractile function decreases fol-
larnih energetskih zahteva i balansa sekundarnih lowed by prolonged cardiac insufficiency. Growth.
mesendzera (cAMP, cGMP, Ca", inozitoltrifosfata, morphological transformation and accumulation of
products of intensified synthetic activitv do not
protein-kinaze C) do normofunkcije ekstracelu- manifest themselves onlv within cells of functional
larnih neurotransmitera i hormona kao i ekstracelu- musculature of the heart (cardiocytes), but also in
larnih faktora rasta. Osnovni benefit fizioloske hi- non-muscle cells, i.e .. the heart connective tissue.
pertrofije je akcelerantnost luzitropnih efekata, od- These two types of cells - muscle (cardiocvtes) and
nosno perioda relaksacije leve komore srca. Takode non-muscle (like collagen, for example) - react dif-
je konstatovana akceleracija transporta kalcijuma ferently to stimuli such as increased arterial blood
kroz membranu sarkoplazminog retikuluma kardio- pressure. volume, hypoxia, excessive ventricular
cita, kao i razlicite funkcionalne inotropne i luzi- overload, mitral and aortic defects. Cardiocytes in-
tropne povoljnosti u radu srca osoba sa fizioloskorn crease their mass by undergoing hypertrophy with-
hipertrofijom. Tu ne dolazi do patoloske remode- out cell division. while non-muscle cells divide thus
lacije i hipetrofijske dekompenzacije. Postoje broj- increasing their numbers, the process defined as hy-
ne razlike u rnorfoloskim i molekularnim prorne- perplasia or proliferation.
nama miokarda izmedu fizioloske i patoloske hiper- A fundamental feature of the heart is adaptabilitv
trofije. Osnovna razlika je u prirodi stimulusa za of its mass to the hemodynamic overload. Ever"
rast celije, kao i u vremenu trajanja datog stimulusa. change in hemodynamic function. whether due to
Ook je za razvoj fizioloske hipertrofije najcesci physiological activity or pathological alterations of
stimulus fizicka aktivnost, sportski trening, plivanje the cardiovascular system, leads to changes of the
iIi igranje tenisa - znaci deluju povrerneno, epizo- relation between body mass and the heart.
Cardiac hypertrophy caused bv physical activity
dicno i uglavnom preko simpatickih neurotransmi- such as sports is defined as physiological hypertro-
tera, dotle kod bolesnika sa aortnom stenozom phy and differs significantly from hypertrophic re-
hipertrofijski stimulus permanentno deluje svako- sponse to chronic excessive overload - which i:
dnevno i celodnevno, a prisutan je i u vreme spa- pathological hypertrophy. In most cases, physiologi-
vanja. Pored valvularnih mana, fokalna iIi generali- cal hypertrophy is not about surpassing homeostatic
zovana hipertrofija se cesto konstatuje kod bole- adaptive capacity, because hypertrophic stimulus for
snika sa arterijskom hipertenzijom i ishemijskom the activation of surplus protein synthesis is not
bolescu srca, cija jc glavna karakteristika dilatacio- continual or long-lasting. Morphological, functional
na iii hipertrofijska kardiomiopatija. Da bi se mini- and molecular changes of the myocardium remain
mizirale medicinske greske i na vreme sprecio raz- within physiological bounds, ranging from intracel-
voj patoloske hipertrofije, od krucijalnog znacaja je lular energy demands and balance of secondary
poznavanje molekularnih mehanizama hipertrofije messengers (cAMP, cGMP, Ca2~, inositol triphos-
miokarda. Oko 75% celija u srcu nisu srcani miociti phates, protein kinase C) to nonnofuncton of extra-
(kardiociti), vee fibroblasti, endotelne celije srca i cellular neurotransmitters and hormones, as well as
krvnih sudova, glatke misicne celije, periciti, neu- extracellular zrowth factors. The main benefit of
roni, krvne celije (makrofagi). Mnoge od ovih celija physiological hy,pertrorhy is the ability of Iusitropic
rastu po tipu hiperplazije iIi proliferacije na dejstvo effects - relaxation periods of the left ventricle - to
hipertrofijskog stimulusa. Srcani miociti (kardiociti) accelerate. The accelerated transport of calcium
through the sarcoplasmic reticulum membrane of
cine sarno oko 25% od ukupnog broja celija srca cardiocytes has also been noticed. together with
iako zauzimaju najveci deo volumena ovog organa. other various functional inotropic and lusitropic ad-
Proces rasta kardiocita u hipertrofiji miokarda posle vantages of cardiac function for people with physio-
postnatalnog perioda je po tipu hipertrofije, od- logical hypertrophy, without pathological remode-
nosno uvecanja njihove mase. U produkciji hiper- ling or hypertrophic decompensation.9fhere are nu-
trofije ucestvuje vise molekularnih mehanizama. merous differences concerning morphological and
molecular myocardial changes between pliysiologi-
Ekstracelularni faktori rasta cal and pathological hypertrophy. The main differ-
ence is in the nature of stimulus for cell growth, as
Brojni peptidni faktori rasta imaju ulogu u odgo- well as in duration of the given stimulus. While the
voru srca na prekomerno opterecenjc. Medu njima most common cause of physiological hypertrophy is
su bogato zastupljeni u celijama srca kiseli i bazni physical activity, sports and training sessions, swim-
fibroblastni faktori rasta (aFGF i bFGF) i transfor- ming or tennis, i.e., stimuli which are activated oc-
misuci faktori rasta tipa B (TFGB). S obzirom na casionally, episodically and mainlv through
peptidnu prirodu mnogih faktora rasta, nj ihovo dej- sympathetic neurotransmitters, the corresponding
stvo zapocinje vezivanjem liganda za specificne re- hypertrophic stimuli in patients with aortic stenosis
ceptore celijske membrane. Kompleks ligand-re- are active permanently, all day long and every day,
Med Pregl 2009; LXII (11-12): 555-568. Novi Sad: novembar-decembar. 565

ceptor provodi signalnu kaskadu stimulacijom en- even during sleeping. In addition to valvular dvs-
zirna tirozin-kinaze da fosforilise rezidue tirozina u functions, focal or generalized hypertrophy is often
brojne proteine. U ovoj kaskadi je vazna uloga G- diagnosed in patients suffering hom arterial hyper-
proteina, koji per se irnaju efekte na rast cclije kroz tension and ischemic cardiac disorder, the main
sadejstvo sa kalcijumovim kanalima i modifikaci- characteristic of which is dilatational or hyper-
jorn sinteze intracelularnih mesendzera, kao sto su trophic cardiomyopathy. Knowledge of molecular
cAMP, diacilglicerol (DAG) i inozitol fosfati (IP,). mechanisms of myocardial hypertrophy is of crucial
Ekstracelularni neurotransmiteri, hormoni i faktori importance in minimizing medical errors and pro-
rasta Sll moguci medijatori i moderatori hipertrofij- viding a timely prevention of development of patho-
skih signala i odgovora u prekomerno opterecenorn logical hypertrophy. About 75% of cells in the heart
srcu. Medu njima su identifikovani kateholamini are not card iac myocytes (card iocytcs), but fi bro-
kao faktori rasta za hipertrofiju kardiocita i aJ-adre- blasts, endothelia] cells of the heart and blood ves-
nergicki receptori kao receptori faktora rasta. Pored sels, smooth muscle cells, pericytes, neurons, blood
toga, pokazano je da na rast celije i njenu diferenci- cells (macrophages). Growth of many of these cells
jaciju znacajno uticu a- i B-adrenergicki agonisti, is based on that type of hyperplasia or proliferation
angiotenzin II, honnon rasta, tiroksin, insulin i glu- caused by hypertrophic stimuli. Cardiac myocytes
kokortikoidi. Povecanje hidrolitickih produkata ade- (cardiocytes) make up on Iy about 25% of the total
nozin-trifosfata (ATP) i kreatin-fosfata, ADP, AMP number of heart cells although they occupy the larg-
i kreatina u uslovima prekomernog hemodinamic- est portion of its volume. The process of cardiocyte
kog opterecenja i utroska energije, takode stimulise growth in myocardial hypertrophy after the postna-
rast celije. Vee je ranije naglaseno da mnogi intra- tal period corresponds to the type of hypertrophy,
celularni mesendzeri, kao sto su cAMP, cGMP, dia- i.e., increase in their mass. Several molecular me-
cilglicerol, inozitol fosfati i kalcijum, kroz aktivi- chanisms participate in the production of hypertro-
ranje protein-kinaze imaju ulogu u stimulaciji rasta phy.
celije.
Extracellular Growth Factors
Remodelovanje miokarda leve komore
Numerous peptide growth factors playa role in the
Remodelovanje (preoblikovanje) miokarda pred- response of the heart to excessive overload. Among
stavlja adaptivni fenomen, koji se javlja u sklopu them. heavily present within cells, are acidic and ba-
nekih patofizioloskih procesa u kardiovaskularnom sic fibroblast growth factors (aFGF and bFGF) and
sistemu, kao sto su: miokardiopatije, hipertenzija, transformation growth factors of type B (TFG B).
akutni infarkt miokarda. U krajnjem, ukoliko se na Regarding the peptide nature of various growth fac-
vreme ne spreci odredenim lekovima, remodulacija tors, their influence starts with binding of ligands to
dovodi do srcane insuficijencije. U osnovi patofizi- specific receptors within cell membrane. The Li-
oloskog mehanizma rernodelovanja je losa adapta- gand-receptor complex initiates a signaling cascade
cija krvnih sudova, odnosno miokarda, na gorepo- by stimulating a tyrosine kinase enzyme to phos-
men ute procese. Tako se neposredno utice na struk- phorize tyrosine residues into numerous proteins.
turu srcanih misicnih celija, ito, kako na biohernij- The role of G-proteins is very important in this cas-
ske procese u njima, tako i na sam citoskelet [20, cade, because they per se affect the growth of cells.
21]. together with calcium canals and modification of
Srcani insult (infarkt miokarda, dugotrajna hiper- synthesis of intracellular messengers, such as
tenzija) primarno dovodi do porernecaja funkcije cAMP, diacylglycerol (DAG) and inositol trisphos-
srcanog misica, sto u prvo vreme moze da se phate (lP,). Extracellular neurotransmitters, growth
nadomesti aktivacijom kompenzatornih mehani- hormones and factors are possible mediators and
zama, koji nadoknaduju gubitak funkcije ugrozenog moderators of hypertrophic canals and responses of
dela srcanog misica, Tako, u tom delu srcanog an excessively overloaded heart. Among them are
misica u akutnom infarktu miokarda dolazi do istan- cateholamines, identified as growth factors for hy-
jenja misica leve komore zbog aktivnosti citokina i pertrophy of cardiocytes ancl U 1 - adrenergic recep-
kolagena. Kompenzatorno se 1I preostalom delu tors, identified as growth factor receptors. More-
miokarda razvija volumenska ekstenzija i hipertro- over, it has been shown that a and B adrenergic ago-
fija, cirne se u krajnjem izaziva prosirenje leve ko- nists, angiontensine II. growth hormone, thyroxin,
more. Pored izmenjene funkcionalnosti, leva korno- insul in, and glucocorticoids significantly influence
ra se na taj nacin i anatomski menja u smeru trans- both growth and di ffercntiation of cells. An increase
formacije oblika u sfericnosti, koji vodi hemodi- in products of adenosine triphosphate (ATP) hy-
namickirn porernecaj ima, kako u perifernim organi- drolysis and creatine phosphate, ADP, AMP and
rna, tako i u samom srcu. Ukoliko se ovakav nacin creatine in conditions of excessive hemodvnamic
adaptacije preventivno ne zaustavi u ranoj fazi overload and energy consumption, also stimulates
srcanog insulta, on vodi progresivno u disfunkciju cell growth. It has already been emphasized that
leve komore i razvoj srcane insuficijencije. Kom- many intracellular messengers, such as cAMP,
penzatorni mehanizmi (tahikardija, pojacana kon- cGMP, diacylglycerol, inositol phosphates and cal-
566 Dukanovic N, i sal'. Evaluacija relaksacije miokarda

traktilnost, hipertrofija i dilatacija) stahilizuju mio- cium play their part in stimulatinz cell growth by
kardnu funkciju za veoma kratak period vremena, activating kinase proteins. L

ali njihovo produzeno trajanje dovodi do nepovolj-


nih bioloskih efekata. Tako se inicijalna hipertrofija Left Ventricular Myocardial Remodeling
miokarda tretira kao adapt ivan proces, dok miokard
ne dostigne kriticnu masu, kada se to vee oznacava Myocardial remodeling is an adaptive phenome-
kao bolest [22-24]. non, which origjnates within some pathophysiologi-
Signalni mehanizmi ukljuceni u remodelovanje i cal processes of the cardiovascular system. such as:
progresivnu disfunkciju miokarda su sledeci: adre- myocardiopathy, hypertension, acute myocardial in
nergicki, angiotenzin II, endotelini, TNF, wall- farction. Unless prevented by specific medications.
stress [25-27]. Aktivacija ovih neurohumoralnih, ci- remodulation results in cardiac insufficiency in the
tokinskih i mehanickih signalnih mehanizama do- worst case. At the very basis of the pathophysiologi-
vodi na celijskom nivou do: alteracije genske cal mechanism of remodeling is defective adaptation
ekspresije, gubitka funkcije miocita i remodelacije of blood vessels, i.e .. myocardium, to the above-
same celije, sto za posledicu ima miokardnu disk- mentioned processes. The structure of cardiac mus-
funkciju i srcanu insuficijenciju (Tabela 2). cle cells, together with both biochemical processes
within them and their very cytoskeleton [20 21]
Tabela 2. Signalni mehanizmi ukljuceni u progresivnu mio- is thus directly influenced. '
kardnu disfunkciju i rernodulaciju Cardiac insult (myocardial infarction. long-term
Table 2. Signaling mechanisms integrated in progressive I1lVO- hypertension) primarily leads to myocardial dys-
cardial dysfunction and remodeling function, which III initial phases can be counterbal-
Signalm rneha- Kompcnzatorni efekt Nepovoljni bioloski cfckui) al,lced by the activation of compensatory mecha-
nizam/Si,[,T110Iing ( 'oinpensator; (~!Ii.:cf
nisms. These mechanisms make up for the loss of
mechanisms
functionality of the threatened section of mvocar-
Adrenergicki Porast srcane frckvencije. Toksicni efekti na miocitc. apoptoza.
dium. Acute myocardial infarction is consequently
Adrenergic kontraktilnosti, volumna rast. rernodulacija, promenjena genska
followed bv the thinninu of the left ventricle in that
ckspanzija. hipertrofija ckspresija/Zov«. e.fleel (J1l myocvrc»,
part of myocardium caused bv the activity of cv-
Increase ofcardiac fre- apoptos!», growth, remodulauon, altcrcc)
tokine and collagen. The volume extension' and h\l-
quem),. contractilitv, \'O!UIJlt' gencuc expreSSIOII
pertrophy develop in the remaining sections of
expansion and hypertrophy myocardium as a way of compensation. which ulti-
Angiotenzin II Volumna ekspanzija Apoptoza, rast. remodulacija, prurnenje- mately leads to the enlargement of the left ventricle.
Angiotcnsiue II iolumc ('xj)(.tnsiou
. na genska ekspresija, deponovanje kola- In addition to altered functionalitv. the left ventricle
genaJAjJojJlOsis, growth, rcmodulation. also changes anatomically. becoming spherical in
altered xene expression. co!laKl:1I depo- shape, whicJl in tL~rn leads to hemodynamic dysfunc-
..1 I/()" nons, both III peripheral organs and the heart itself.
Endotelin Hipertrofija Rast. remodulacija, promenjcna gcnska Unless this adaptation mechanism is stopped in the
Eudothelin Hypertoph, ckspresija/r irowth, rcmoduknion. altered early phase of the cardiac insult, as a preventive
gcrn: expression measure, it progressively leads to dysfunction of the
T:-Wa Hipertrofija Apoptoza, inflamacija, rast, remodulaci- left ventricle and development of cardiac insufri-
Hvpertophv ja. prorncnjena genska eksprcsija, aktiva- ciency. Compensatory mechanisms (tachycardia, in-
cija metalprotcin3ZaiA j J()p l rJSI .\ , infla- creased contractility. hypertrophy and dilatation)
nunauon. KI"()H'fh, remodulation. aile red stabilize myocardial function for a very brief period
).:1:111.' expression, acnvatton (4 metal of time, hut their prolongation leads to unwanted
,,,.()Ie/ln,s,, biolo~ical effects. Initial myocardial hypertrophy is
Volurnna ekspanzija hiper- Apoptoza, fast. rernodulacija prorne- thererore regarded as an adaptive process, unti I the
(sires zida) trofija.I 'olmne expansion, njena genska ckspresijaJApojllOsis, myocardium reaches critical mass, but then it is di-
alterc.l j.[C'!I!
,1,TJ·OII'lh, reI110dIlI1l!/()II,
agnosed as a disease [22-24],
Terapijski manevri u sprecavanju remodulacije The following signaling mechanisms take part in
remodeling and progressive myocardial dysfunction:
leve komore podrazumevaju:
adrenergic, angiotensine II, endothelial, TNF. wall-
- U ranoj fazi akutnog infarkta miokarda fibrino- stress [25-27]. At the cellular level, the activation or
liticku i antikoagulantnu terapiju, koja smanjuje in- these neurohormonal. cytokine and mechanical sig-
farciranu zonu i sprecava akutno remodelovanje; nal mechanisms leads to: the alteration of gene ex-
- Prirnenu ACE-inhibitora (ACEI), s obzirorn da pression. loss of myocyte functionality and
je jedan od dominantnih signalnih sistema za re- remodeling of the cell itself, which in turn ends with
modelacij u angiotenzin 11. Pored osnovnog efekta myocardial dysfunction and cardiac insufficiency
inhibitora angiotenzin-konvertujuceg enzima, tkivni (Table 2).
ACEI smanjuje rast i rnigraciju glatkomisicnih Therapy maneuvers aimed at prevention of the
celija, kao i sintezu kolagena tip I i III II fibroblas- left ventricle remodulation include:
tima. Ova grupa lekova ima povoljno dejstvo i na - Fibrinolytic and anticoagulant therapy in the
endotel arterija, odnosno remodelovanje muskula- earlv stage of acute mvocardial infarction, Such
ture i celog zida arterije, ukljucujuci i adventiciju. U therapies '-reduce the infarct zone and prevent acute
remodeling.
Med Pregl 2009; LXII (11-12): 555-568. Novi Sad: novembar-dccembar. 567

odgovoru na vaskularni stres kao sto su distenzija i - The application of ACE-inhibitors (ACEI).
hipoksija, aktiviraju se fibroblasti adventicije i nas- since angiotensine II is one of the more dominant
taju fenotipske promene u vidu proliferacije, difer- signaling systems for remodeling. In addition to its
encijacije i nove regulacije kontraktilnih proteina i main rore of inhibiting the angiotensine-converting
proteina u ekstracelularnom matriksu [28]. Remode- enzyme, tissue ACEI decreases the growth and mi-
lovanje je inace negativan faktor jer potpomaze pro- gration of smooth muscle cells, as well as collagen I
gresiju arterijske hipertenzije, nastanak ateroskle- and III synthesis in fibroblasts. This group of drugs
roze i stenoze u arteriji. Dakle, stetni efekti remode- also has a positive effect on the arterial endotheli-
lovanja su utvrdeni ne samo u miokardu leve ko- um, i.e., remodeling of musculature and the entire
arterial wall, including adventition. In response to
more u toku AIM vee i u zidu perifemih arterija. vascular stress such as distension and hypoxia, ad-
lato su ACE-inhibitori vrlo korisni u lecenju srcane ventition fibroblasts are activated which leads to
insuficijencije i arterijske hipertenzije; phenotypic changes such as proliferation, differen-
- Primena l3-blokatora, koji sprecavaju adrener- tiation and new regulation of contractile proteins
gicki remodulatorni signalni mehanizam, cime se and extracellular matrix proteins [28]. Remodeling
smanjuju svi njegovi nepovoljni bioloski efekti: is actually a negative factor because it supports the
- Primena antioksidantne terapije, kao i lekova progression of arterial hypertension, coming of athe-
koji uticu na modelaciju funkcije edotela.ukljucu- rosclerosis and artery stenosis. So, harmful effects
juci i inhibitore L-arginin: NO sistema, zbog signifi- of remodeling have been detected not only in the
kantne uloge oksidativnog stresa i citokina u left ventricular myocardium during AIM, but also
promeni genske ekspresije miocita. Primena antiok- inside the walls of peripheral arteries. That is why
sidantne terapije je od posebnog benefita u kombi- ACE inhibitors are very useful in treatment of car-
diac insufficiency and arterial hypertension.
naciji sa fibrinolitickom i antikoagulatnom terapi- - The application of l3-blockers, which prevent
jom, zbog reperfuzionih ostecenja koja nastaju us- adrenergic rernodulation signaling mechanism, thus
led pojacane produkcije slobodnih radikala minimizing all of its harmfl~1 biological effects.
kiseonika. U tom smislu se do sada pokazala kao - The application of antioxidant therapy, as well
efikasna primena L-karnitina i koenzima Q-l 0, kao i as drugs which influence endothelial function
antagonista kalcijuma trece generacije iz grupe modulation, including L-arginine inhibitors: NO
dugodejstvujucih dihidropiridina (amlodipin), koji system, due to the significant role of oxidative stress
ima dokazana antioksidantna svojstva, a nema dej- and cytokine in alteration of myocyte gene expres-
stva na neurohumoralnu aktivnost, kao njegovi sion. The application of antioxidant therapy is espe-
kratkodejstvujuci pandani. Oksidativni stres je im- cially beneficial in the combination with fibrinolytic
pliciran u remodelovanju srca. Mi smo pokazali da and anticoagulant therapy, because of reperfusional
damages that occur due to the increased production
inhibicijom ksantin-oksidaze alopurinolom dolazi of free oxygen radicals. In this sense, the application
do smanjenja oksidativnog stresa [29,30]. of the following has been proved efficient: L-
U poslednje vreme jedan kombinovani (X- i 13- carnitine and coenzyme Q-I0, as well as the third
blokator, karvedilol, pokazao je izuzetna povoljna generation calcium antagonist from the group of
dejstva u sprecavanju remodelacije miokarda, slicna long-lasting dihydropyridine (amlodipine), which
onirn koje imaju ACE inhibitori, zbog njegovog, ka- has noticeable antioxidant properties, without any
ko osnovnog, tako i antioksidantog i antiinflamator- Impact on neurohormonal activrty like Its short-
nog dejstva. lasting counterparts do. An oxidant stress is impli-
cated in cardiac remodeling. We have shown that
the inhibition of xanthine oxidase by allopurinol re-
duces oxidant stress (29 and 30).
As of lately. one combined (X- and ~-blocker,
called carvedilol, has turned out to be extraordinar-
ily beneficial in the prevention of myocardial re-
modeling, not unlike ACE inhibitors. due to its both
basic and antioxidant and anti-inflammatory proper-
ties.

Literatura
I. Kranias EG. Bers DM. Calcium and cardiomyopathies. 3. Maier LS, Bcrs DM. Calcium. calmodulin. and calcium-
Subcell Biochcrn 2007:45:523-37. calmodulin kinase 11: heartbeat to heartbeat and beyond . .I Mol
2. Ahmad F. Seidman .JG. Seidman CE. The genetic basis Cell Cardiol 2002:34(8):919-39.
for cardiac remodeling. Annu Rev Gcnornics Hum Genet 2005: 4. Fatkin 0, Graham RM. Molecular mechanisms of inher-
6: 185-216. ired cardiomyopathies. Physiol Rev 2002:82(4 ):945-80.
568 Dukanovic N, i sar. Evaluacija relaksacije miokarda

5. Grybauskiene R. Karciauskaite D. Brazdzionyte J. 19. Mujovic V~1. Jovanovic T. Novine 0 signalnim


Janenaite J. Bertasicne Z. Grybauskas P. ct al. Brain natriuretic mchanizrnirna srca: ligand-receptor kompleks i cfcktorni me-
peptide and other cardiac markers predicting left ventricular re- hanizrni. Kardiologija 1997: I 0( 1-2): 1-10
modeling and function two years after myocardial infarction 20. Severs N). Patophysiology of gap junction in heart dis-
Medicina (Kaunas). 2007:43(9):708-15. case . .I Cardiovasc Electrophysiol 109L5:-1-62-75.
6. Pawlinski R. Tencari M. Hampton CR. Shishido T. 21. Senior R. Basu S. Kinsey C. S'haeffcr S. Lahiri /\.
Bullard TA. Casey LM et a!. Protease-activated receptor-I con- Carvedilol prevents remodeling in patients \\ ith left ventricular
tributes to cardiac remodeling and hypertrophy. Circulation dystuction after acute myocardial infarction. Am Heart J 1990:
2007: 116(20):2298-306. 137: 646-652.
7. Shimokawa .I. Yokoshiki H, Tsutsui H. Impaired activa- 22. Fernandes YR. Edvardscn I. Rosen BD. Carvalho B.
tion of ATP-sensitive K+ channels in endocardial myocytes Campos O. Cordeiro MA. et al. The influence of len: ventricular
from left ventricular hypertrophy. Am J Physiol Heart Circ size and global function on regional myocardial contraction and
Physiol 2007;293( 6):H3643-9. relaxation in an adult population free of cardiovascular disease:
8. Chen-Izu Y. Chen L. Banyasz T, McCulle SL. Norton 13, a tagged CMR study of the MESA cohort. .r Cardiovasc Magn
Scharf SM, et al. Hypertension-induced remodeling of cardiac Reson 2007:9(6):921-30.
excitation-contraction coupling in ventricular myocytes occurs 23. Banters C. Lamblin N. Ennczat PV. Mycinski C. Tricot
prior to hypertrophy development. Am J Physiol Heart Circ 0, Nugue 0, et al. REVE Investigators. A prospective cvalua-
Physio12007;293(6):H3301-10. tion of left ventricular remodeling after inaugural anterior myo-
9. Pinet F, Beserne 0, Cieniewski-Bernard C. Drobecq H, cardial infarction as a function of gene polymorphisms in the
Jourdain S. Lamblin N. et a!. Predicting left ventricular remod- renin-angiotensin-aldosterone, adrenergic. and metalloprotein-
eling after a first myocardial infarction by plasma proteome asc systems. Am Heart J 2()()7:153(41:641-K
analysis. Proteomics 2008:8(9): 1798-808. 24. Rosen BO. Edvardscn T. l.ai S. Castillo E. Pan l..
10. Ulgen MS. Ozturk O. Alan S. Kayrak M, Turan Y. Te- Jerosch-Herold M. et al. Left ventricular concentric remodeling
kes S. et a!. The relationship between angiotensin-converting is associated with decreased global and regional systolic func-
enzyme (insertion/deletion) gene polymorphism and left ven- tion: the multi-ethnic study of atherosclerosis. Circulation
tricular remodeling in acute myocardial infarction. Coron Artery 2005: 112(7):984-91.
Dis 2007:18(3):153-7. 25. Choudhary R. Palm-Leis A. Scott RC 3rd. Gulcria RS.
11. Mujovic VM. Jakovljevic V i Velkovski S. Regulacija Rachut E, Baker KM. et '11. All-trans rctinoic acid prevents de-
rclaksacije i kontrakcije u spccificnim kardiomiopatijama i velopment of cardiac remodeling in aortic banded rats by inhib-
stanju remodelovanog miokarda srca. U: Stamcnkovic Z i sar, iting the renin-angiotensin system. Am .I Physiol Heart Circ
urednici. Kardiomiopatije i disfunkcija srca. Beograd: Elit Physiol 2008:294(2): H588-9.
Medica; 2007. str. 185-212. 26. McConnell PI. del Rio CL. Jacoby DB. Pavlicova 1vl.
12. Bers OM. Altered cardiac myocyte ca regulation in heart Kwiatkowski P. Zawadzka A et al, Correlation of autologous
failure. Physiology 2006:21 :380-7. skeletal myoblast survival with changes in len ventricular re-
13. Bers OM. Calcium, and cardiac rhythms: physiological modeling in dilated ischemic heart failure . .I Thorac Cardiovasc
and pathophysiological. Circ Res 2002:90: 14-7. Surg 2005: 130(4): 100 1.
14. Bers OM. Cardiac excitation-contraction coupling. Na- 27. Kilie A. Bubikat A. Gassner B. l1aba I Ii\, Kuhn M. Lo-
ture 2002:4 15:198-205. cal actions of atrial natriuretic peptide counteract angiotensin 1I
15. Katz AM. Interplay between inotropic and lusitropic ef- stimulated cardiac remodeling. Endocrinology 20()7: 148(9):
fects of cyclic adenosine monophosphate on the myocardial 4162-9.
cell. Circulation 1990:82: 1-7. 28. Stcnrnark KR. Davie N. Frid I'vl. et al. Role of the ad-
16. Mujovic VM. Kardiovaskularni sistem i homeostaza. U: ventitia in pulmonary vascular remodeling. Physiology 2006:
Kardiologija: udzbenik za poslediplornsku nastavu. Beograd: 21: 134-45.
Medicinski fakultet: 1994. str. 14-26. 29. Hayashi K. Kimata 1L Obata K. Matsushita A Fukata
17. Mujovic VM. Funkcija !eve kornorc u stecenirn manama A, Hashimoto K, et '11. Xanthine oxidase inhibition improves
srca. U: Stamenkovic Z, urednik. Stecena oboljenja zalistaka left ventricular dysfunction in dilated cardiornyopathic ham-
levog srca. Beograd: Zavod za izdavanjc udzbenika i nastavna sters . .I Card Fail 2008: 14(3):238-44.
srcdstva: 1996. str. 110-23. 30. Mujovic VM. Zirojevic T. Cernak I. Velkovski S. Rosie
18. Mujovic VM, Jovanovic 1'. Bioloska kaskada u nas- N. Starcevic V. Effects of allopurinol on prostacyclin and
tanku hipertrofije miokarda leve komorc, U: Simpozijurn 0 thrornboxane levels during renal ischemia and reperfusion (ab-
hipertrofij i miokarda leve kornore. N iska Banja 1997. str. 425- stract). XXXIII International Congress of Physiological Sci-
36. ences: 1997 June 30-July 5: St. Petersburg, Russia. St. Peter-
sburg: International Union or Physiologists: 1997: PO 19.12.
Rad je primljen 5. XII 2008.
Prihvacen za stampu 3 I. XII 2008.
BIBLID.0025-81 05:(2009):LXII: 11-12:555-568.

You might also like