CORRELATION OF SYSTEMIC INFLAMMATORY STATUS & CARDIAC MYONECROSIS IN PATIENTS UNDERGOING ...

8/13/2019 CORRELATION OF SYSTEMIC INFLAMMATORY STATUS & CARDIAC MYONECROSIS IN PATIENTS UNDERGOING PERCUT

1/76

1

CORRELATION OF SYSTEMIC INFLAMMATORY STATUS &

CARDIAC MYONECROSIS IN PATIENTS UNDERGOING

PERCUTANEOUES CORONARY INTERVENTION

MSc In Diagnostic & Interventional Cardiology Thesis

Under University of Dublin (Trinity College)

YEAR -2006

STUDENT

DR MD KHALED MOHSIN

MBBS, MD in Cardiology (Dhaka University) MRCPI

SUPERVISOR:

DR NIALL T MULVIHILL

MBChB, MD, FRCPI

CONSULTANT CARDIOLOGIST

ST JAMESS HOSPITAL,DUBLIN-8


2/76

2

DECLARATION

I hereby declare that

This is entirely my own work

This work has not been submitted as an exercise for a degree at this

(Trinity College) or any other university.

I agree that the library may lend or copy the thesis upon request (single

copies made for study purposes,subject to normal condition of

acknowledgement)

(MD KHALED MOHSIN)

MSc In Cardiology student (Number 04159560, Course-223)

Trinity College Dublin


3/76

3

1. ABSTRACT

Objective of study: To the evaluate the influence of pre-procedural highsensitivity C reactive protein (hsCRP) on percutaneous coronary intervention

related cardiac myonecrosis.

Design: Prospective observational study.

Setting: Tertiary referral hospital

Patients:Total of 38 patients with normal serum troponin T (60%

patients undergoing elective PCI.This was further increased to >65% after

PCI.Median value of of hsCRP before PCI was 3.61, range (0.21-47.2)

mg/L.This value increased to 4.58, range (0.44-39.2) mg/L after PCI (p


4/76

4

2. ACKNOWLEDGEMENTS

At the very beginning I would like to express my warmest thanks and sincere

gratitude to my supervisor (and the coordinator of MSc in Cardiology course

under TCD) Dr Niall Mulvihill Consultant Cardiologist St Jamess Hospital Dublin

for his continued guidance & cooperation from the very beginning.Despite being

a busy and leading Cardiologist (clinical & interventional) of Ireland he always

provided me his valuable time for encouragement feedback & constructive

criticism.I also recall with gratitude his help in getting the study approved by the

regional ethics committee of SJH/AMNCH and also by the authority of St

Jamess Hospital.

I take this opportunity to thank all the consultants of the Cardiology department

of St Jamess Hospital for the kind permission to recruit their patients in this

study as well as their interest .For this reason I am indebted to Prof Michael

Walsh,Dr Peter Crean,Dr Brendan Foley,Dr Ross Murphy & Dr Angie Brown.I

also want to thank the Registrars of Cardiology department and other staffs

working in the cathterisation laboratories for their help.

I want to express my gratitude to Dr Kathleen Bennett (statistician of Trinity

Institute of Health Sciences) & Dr Zubair Kabir (presently post doctoral fellow in

epidemiology at Harvard University,Boston USA) for their generous help in

study design & statistical analysis.

I also recall with utmost respect the encouragement and financial help from my

father Professor M A Khaleque (FRCP-London,Edin & Glasgow) and theblessings of my ailing mother Mrs Anjuman Ara Begum (who was diagnosed to

have breast cancer during my course).I am also grateful to my wife Dr

Rukhsana Parveen for her encouragement & support to our family, my daughter

Nazrana and son Sadman for their affection.

Finally I want to express my sincere gratitude to all the patients who graciously

consented to participate in this study.I wish them all long life and good health


5/76

5

3.AIMS OF THE STUDY

To investigate the correlation of baseline systemic inflammatory status(measured by hsCRP) on post PCI myonecrosis (evaluated by specific cardiac

enzyme TnT and CKMBM)

To evaluate the influence of PCI on the the systemic inflammatory

status(hsCRP) as well as the serum level of TnT and CKMBM (by comparing

pre and post PCI levels).

To look at the influence of some additional related factors (certain

demographic factors , duration & pressure of balloon/stent inflation,procedure

related comlication & peri-proceduoral medications) on post PCI myonecrosis.


6/76

6

4.INTRODUCTION

Coronary artery disease is a dynamic process combining enhanced

inflammatory and thrombotic activity (Ross 1999).The role of C reactive protein

has been implicated and its plasma concentration has been found to be

increased in many instances (Libby et al 1999) Pre PCI plasma hsCRP

concentration has been reported to influence both short and long term outcome

after PCI (Buffon et al 1999 & Chew at al 2001)Recent observational studies

have shown that statin therapy decrease the risk of adverse cardiac events post

PCI in patients with elevated CRP (Chan et al 2002)Statin induced decrease in

plasma CRP suggests that CRP probably plays an important role in the

outcome of PCI (Albert et al 2001).One study has reported association between

pre PCI CRP and PCI induced cardiac myonecrosis evaluated by sensitive

marker of myocardial injury (Saadeddin et al 2002).

In addition to CRP, procedural factors such as number & duration of balloon

inflations,stent deployment and complications (side branch

occlusion,dissection,spasm,slow flow) has been suggested as possible causesof increased release of cardiac markers after PCI (Oh et at 1980 & Garbaz et al

1999). In addition, complexity of the target coronary lesion has also been

implicated (Ellis et al 1999)

Post PCI cardiac myonecrosis incidence is variable depending on the method of

detection .When CKMB is used 15 to 26% patients are reported to have

elevated levels after the procedure.(Stone at al 2001)Troponins (more sensitive

& cardiospecific) are reported to be elevated in 29-48% after PCI(Saadeddin et

al 2000 & Warren et al 2002).In most of these cases these myocardial injury is

small & asymptomatic with variable prognosis(Tardiff et al 1999 & Akkerhuis et

al 2002)

The present study attempts to evaluate the the influence of prePCI CRP

levels,factors related to the procedure,& ongoing medications on the event of

post PCI cardiac myonecrosis.


7/76

7

5.REVIEW OF LITERATURE

5a.Post-PCI cardiac myonecrosis (PCM)

Coronary balloon angioplasty was first successfully performed by Gruntzig in

1977(Gruntzig ,1978). Since then percutaneous coronary intervention (PCI) has

been arguably recognized as the ultimate strategy in the management coronary

artery disease (CAD) . There has been steady improvement in interventional

techniques and expertise of the operators. With introduction of devices such as

stents, the incidence of major peri-procedural complications [Q-wave acute

myocardial infarction (AMI), coronary artery bypass grafting (CABG), and

cardiac death] has significantly reduced initial 9% to current figures of less than

2%.(Togni et al 2004) But regrettably, the incidence of reflected by post

procedure cardiac marker elevation has not substantially declined since its

initial reporting (Oh et al,1985). These marker elevations are now considered

to reflect post-PCI cardiac myonecrosis (Califf et al 1998)

5a,1.Definition and diagnosis

Myocardial injury implies any impairment of normal myocardial homeostasis,

which can lead to reversible/irreversible changes in myocardial structure and

function. A number of different factors are implicated , including mechanical,

trauma infectious, toxic, and metabolic injury. In the setting of PCI, myocardial

injury is predominantly of metabolic origin, resulting in ischaemia. Presently

available diagnostic modalities cannot not detect all the myocardial alterationstaking place. For example, peripheral blood TnT concentrations significantly

lower than coronary sinus cTnT concentrations following percutaneous

transluminal coronary angioplasty (PTCA) (Katoh et al.2000) . Studies also

have indicated that reversible injury might give positive cardiac marker results (

Feng et al 1998) It has been , demonstrated that the majority of cTnT

elevations within 24 h after PCI persist at 96 h after PCI, indicating ongoing

release of cTnT from the contractile apparatus and hence irreversible

myocardial injury. (Remppis et al 2000)Recent magnetic resonance imaging


8/76

8

study identified areas of myocardial infarction as the site of cardiac serum

marker release after PCI (Selvanayagam et al 2005) Thus, PCM is

synonymous with peri-procedural myocardial infarction in majority of post-

procedural cardiac serum marker elevation. According to current ESC/ACC

guidelines, any cardiac serum marker elevation above the upper limit of normal

(ULN) after PCI is suggestive of PCM Owing to its high specificity and

sensitivity, cTnI and cTnT are the preferred serum markers of myocardial injury

with peak values to be expected around 2448 h after PCI.(Alpert et al,2000)

CKMB mass assay is the preferred alternative with peak values occurring

around 24 hour after PCI.

5a.2.Magnitude of the problem of PCM

Wide variation in Incidence of PCM has been reported depending on the choice

of biomarker, laboratory methods of marker assay, cut off value of upper limit of

normal and frequency of blood analyses. All these possibly have influenced the

difference among the various studies.

In non-selective, multimarker series, reported post-procedural (over ULN)

elevation of CKMB mass has been 047% (mean+/-SD: 23 +/- 12) , cTnT 7

69%(mean+/-SD 23 +/- 11), and cTnI 553%(mean+/-SD: 27 +/-12) (Herrmann

2005).

5a.3.Factors influencing PCM

5a.3.1 Factors related to patient (undergoing PCI)Extensive coronary artery

disease (CAD) has been associated with a higher incidence and larger

magnitude of PCM. Intervention of multivessel CAD increases the risk of PCM

by 1.31.8-fold . It has been identified that systemic atherosclerosis is a

stronger clinical predictor of PCM compared to multivessel and diffuse CAD

with odds ratios (ORs) 1.89 vs. 1.31 and 1.41, respectively (Kini et al 1999).

Older age is frequently associated with PCM with ORs just above one

(Herrmann 2005).

The reported incidence of CKMB elevation was overall highest (33.3%) in

patients with renal failure compared to 18.7% in the entire cohort (Kini et al

1999)Most of the studies (including the present one) have excluded patients


9/76

9

with renal failure because of its potentially confounding impact on cardiac

marker assessment. It was shown that the incidence of non- Q-wave PCM

(CKMB . >5ULN) was significantly higher in chronic and end-stage kidney

diseases than in patients with normal renal function (Gruberg et al 2002)

After saphenous vein graft (SVG) intervention, a reported increase in the

incidence of PCM was increased by a factor of 1.6, which also influenced

reduction of creatinine clearance from >70 to


10/76

10

adverse peri-procedural events like thrombosis , threatened or complete acute

closure and in-hospital MI. occurred exclusively in nearly one out of four

patients with a pre-procedural CRP serum concentration of >0.3 mg/dL(Buffon

et al 1999.) It has been reported that 30-day post PCI event rate of MI was

minimum (3.9%) in lowest CRP quartile (9.5 10

6

/L (Gurm etal,2003).

5a.3.2.Procedural factors

Complex coronary artery lesions often pre-dispose to procedural complications.

Side-branch occlusion has been implicated with PCM quite frequently with ORs

ranging from 1.7 to 7.9. Coronary dissection is the next most frequently noted

procedural complication with adjusted OR 1.2 to 1.8. Resultant

threatened/acute vascular closure, itself bears an adjusted ORs between 1.9

and 8.0. No-reflow/slow flow has reported ORs from 4.5 to 5.8 for PCM . Distal

embolization is another strong predictor of PMI (adjusted ORs 4.4 to 6.0)

(Herrmann ,2005)..

Obvoiusly complex lesions usually necessitate complex intervention.

Intervention parameters such as number, pressure, and duration of balloon

inflations as well as procedural time and the type of intervention appears to

influence the PCM. Higher incidence of PCM has been reported with directional

coronary atherectomy (DCA) (Tardiff et al 1999) .

Reported risk of PCM was 2 fold higher with atherectomy procedures and

about 1.2 fold higher risk with stenting compared with plain PTCA. A

significantly higher incidence of PCM in multivessel intervention was also

reported (Kini et al ,1999).

Though angiographic complications are the strongest predictors of PCM yet

occur only in the minority of procedures, Cause of majority of post-procedural

cardiac marker elevations are therefore cryptogenic.


11/76

11

5a.3.3.Lesion-related risk factors

Iintervention of de novo lesions is associated with a higher risk of PCM

compared t restenotic lesions (ORs 1.61.8). SVG disease associated with a

high risk of PCM (adjusted ORs 2.22.4), but a markedly reduced PCM

incidence can be seen with intervention of SVG in-stent restenoses.(Ashby et

al, 2003) Lipid accumulation is characteristic in primary atherosclerosis, leading

to friable atheroma formation, whereas extracellular matrix accumulation,

leading to firm neointimal proliferation, characterizes restenosis, (particularly in-

stent) (Chung et al 2002). Lesion characteristics that possibly pre-dispose to

PCM include eccentric lesion, greater plaque and thrombus burden, plaquerupture, and adjacent side branch occlusion.

5a.4.Underlying mechanism of PCM

All types of coronary intervention causes local plaque distribution and trauma,

which has definite occlusion potential on the epicardial and myocardial

microvascular bed. MR imaging has classified, two basic patterns of PCM: type

I (proximal), which is close to the target lesion and commonly due to side-

branch occlusion, and type II (distal), which is downstream of the treated

coronary lesion mainly due to structural and functional microvascular

obstructions (Selvanayagam et al 2005)The latter accounts for 5075% of all

PCM.

5a.4.1 Platelet activation and thrombosis

It has been demonstrated that plaque disruption by PTCA and/or stenting

causes shedding of debris as well as release of tissue factor (TF) into the

coronary circulation leading to microvascular thrombosis and no-reflow

(Bonderman et al,2002). Coronary sinus concentration of TF was reported to

plateau 424 h after PTCA, followed by an increase in coronary sinus

concentration of thrombinantithrombin III complex, (Mizuno et al,2000) In the

plaque, TF activity resides in shed membrane microparticles of apoptotic

macrophages and leukocytes. These microparticles has potent procoagulant

potential (Mallat et al,1999) High levels of shed membrane microparticles (of

endothelial cell origin) were found in patients with ACS, leading to impaired

endothelium dependent vasodilatation Activated platelets are important source


12/76

12

of microparticles (platelet dust), which promote adhesion of platelets to the

subendothelium and promote leukocyteendothelial cell and leukocyte

leukocyte binding (Vanwijk et al 2003). Elevated levels of plateletmonocyte

aggregates prior to PCI were shown to increase the incidence of post-

procedural cTnI elevation by a factor of 2.5 (Ray et al 2005).

Compared with PTCA, DCA and RA are also associated with more extensive

platelet activation,leading to a reduction in myocardial perfusion contributing

significantly in the pathogenesis of PCM ( Koch et al 1999) It was also

demonstrated that patients with impaired TIMI myocardial perfusion grade had a

10-fold higher incidence of post-procedural CKMB elevation (Gibson et al2002).. This observation was valid when patients with sidebranch occlusion

were excluded and was also noted in the presence of normal epicardial

coronary flow .

5a.4.2 Embolism of atheromatous and thrombotic debris

PTCA, results in plaque redistribution alone while both stenting and rotablation

involve an additional decrease in plaque volume due to plaque embolization,

compression, or fragmentation, leading to higher incidence of PMI .(Ahmed et

al 2000) It was shown in a study that post-procedural CKMB relates to

intraprocedural reduction of plaque volume, pointing towards the athero-

embolization pathophysiology (Prati et al,2003;Topol EJ et al.2000) Autopsy-

based studies support for this concept, by finding plaque debris in the

myocardial microvasculature after PCI.(Saber et al 1993) Studies with distal

protection devices confirmed mobilization of plaque material in almost any type

of intervention (Rogers et al ,2004; & Angelini et al,2004) The average volume

of retrieved debris was 20 L. The average particle sizes were 200 80 m with

the PercuSurge balloon occlusion system and 520240 m with the

AngioGuard filter system. Particle size, ranging from 600 m,.No

significant correlation has been found between angiographic plaque area and

extent of particle retrieval. Debris are predominantly comprised of thrombotic

followed by atheromatous debris; neutrophils and foam cells.


13/76

13

5a.4.3 Oxidative stress

Increase in TNF- expression in myocardium may be potentially the

consequence of increased oxidative stress secondary to ischaemia. Increased

concentration of isoprostanes in coronary sinus blood samples was reported

after PTCA .(Iuliano et al 2001)This might suggest that angioplasty is

associated with ischaemia related increase in oxidative stress leading to

release of isoprostanes from the culprit lesion enhancing platelet adhesion and

coronary vasoconstriction. Increased production of free radical species in the

setting of myocardial ischaemia can lead to the formation of ischaemia-modified

albumin (IMA), which serve as a marker of reactive oxygen species (ROS)production. Indeed, It was demonstrated that increase in isoprotane

concentration in peripheral plasma samples within 30 min after PCI occurred in

only 9 out of 19 patients but increase in IMA was seen in 18 out of 19 patients

who developed chest pain and ECG changes during angioplasty. However

cTnT concentrations remained


14/76

14

(Taylor et al 2004), ET-1 can prolong acute coronary vasoconstriction effects

mediated by a-adrenergic stimulation.

Another important factor involved is angiotensin II, adding on vasoconstricting

effect of the sympathetic nervous system.(Maruyama et al 2000) Post-

procedural vasoconstriction can be seen not only in the culprit vessel but also in

other coronary artery territory and even in the upstream circulation.(Indolfi et al

1995) These observations suggest a thoracic-spinal cardio-excitatory reflex,

(symphathetic) which can be triggered by stretching of the coronary arterial wall

as well as by myocardial ischaemia.(Gregorini et al 1998)It has been reported

that non-selective & selective -adrenoreceptor blockade reversedvasoconstriction proximal and distal to the target lesion following PTCA,

stenting, and rotational atherectomy.(Gregorini et al 2002)It has been reported

that microembolization can also result in increase coronary blood flow,

attributable to the release of adenosine from the myocardium around the

embolized regions (Hori et al 1986.), In patients with normal coronary flow

reserve (CFR) before intervention and reduced CFR shortly after stenting,

vasoconstriction can be observed along with diffuse left ventricular dysfunction.

Adrenoreceptor inhibition potentiated by the effect of adenosine, leading to CFR

normalization.(Gregorini et al 1998)Two patterns of post-procedural coronary

flow velocity reserve (CFVR) impairment has been identified the first related to a

significantly higher baseline average peak velocity (APV) value within 10 +/- 2

min after the last balloon inflation and normalized within 24 h after PCI and the

second is related to a lack of increase in hyperemic APV in the setting of a

normal post-procedural baseline APV (Dupouy et al.2002) The first pattern

was mainly seen in patients undergoing stenting and the latter in patients

undergoing PTCA, highlighting differences in embolization. Patients with

baseline impairment of the myocardial microcirculation seem to be more prone

to develop post-procedural CFVR impairment, An initial study reporting post-

procedural cTnT and CK elevation, patients with no normalization of absolute

and relative CFVR had a higher plaque burden prior to intervention.(Herrmann

et al 2001)The link between post-procedural CFVR impairment and PCM was

subsequently confirmed in other studies (Skyschally et al 2002) TNF- has


15/76

15

also been identified as a key mediator in these situations.It was found that

methylprednisolone, given shortly before or after procedure, prevented both

myocardial TNF- increase and progressive contractile dysfunction,

independent of leukocyte infiltration and infarct size.(Skyschally et al 2004)

Particles released from atherosclerotic plaques are diverse, larger in size, and

not biologically inert. In UAP, an immunologicaly mediated inflammatory

response of the myocardial microcirculation can be seen. (Neri Serneri et

al,2003)

5a.4.5.Role of inflammation

Inflammation is the cardinal response to injury, and evidence of increasedneutrophil activation in coronary sinus blood samples has been described and

appears to be more prominent with newer device intervention and in treating

type C coronary lesions (GottsaunerWolf et al 2000). Serum CRP

concentration increases following the increase in serum IL-6 concentration by

1236 h, peaking 24 h after the procedure.It was found that the increase in the

serum concentrations of both IL-6 and CRP were more pronounced in patients

with concomitant post-procedural cTnT elevation (Bonz et al 2003). But it was

also reported that , even after excluding patients with any post-procedural

cardiac marker elevation there was CRP elevation of >0.5 mg/dL within 48 h

after PCI in almost all patients (Gaspardone et al 1998).

5a.5 Clinical presentation and significance of PCM

5a.5.1 Acute presentation of PCM

PCM remains clinically silent in the majority of patients. Most common

presentation is post-procedural chest pain, which was described as related to

epicardial artery stretching (Jeremias et al 1998). Studies have indicated an

association between postprocedural chest pain and PCM and reported that the

incidence of post-procedural cardiac marker elevation is about 2.54 fold higher

among patients with chest pain after PCI.(Kini et al 2003) EPISTENT trial,

showed that the 30-day event rate of MI was about 7 fold higher in patients with

post-procedural chest pain 12 fold higher if post-procedural chest pain occurred

within the first 4 h and 22 fold higher when associated with ST-T wave changes


16/76

16

.(Robbins et al 1999)Nearly similar observations were found in another study

which reported post-procedural CK elevation was 2 fold higher among those

patients with post-procedural chest pain and 10 fold. higher if associated with

ECG changes (Mansour et al 1992).

In about two-thirds of the patients with post-procedural chest pain, a procedural

complication can be clearly identified.(Kini et al 2003)In the remaining third, it

may relate to microembolization , vessel wall stretch and injury leading to

vasoconstriction via the thoracic cardiac reflex pathway. Changes in the

autonomous tone and ischaemia may also cause cardiac arrhythmias. reported

to occur within a window from 4 to 32 h after myocardial microvascularembolization(Skyschally et al 2004)

5a.5.2.Management of acute PCM

Current guidelines suggest monitoring of all patients with serial cardiac

biomarker assessment at 612 and 24 h and ECGs immediately after PCI and

in the event of post-procedural chest pain.(Mahmud et al 2003; & Levine et al

2003)It has been reported that ST-T changes found with post-procedural chest

pain are 100% sensitive but only 66% specific for abnormal post-PCI

angiography findings necessciating repeat intervention just more than half of

these abnormalities (Mansour et al 1992.). In contrast to dissections (with and

without abrupt closure) side branch occlusion and distal embolization are less

amendable to repeat intervention and may resolve over time.(Ijima et al 2005)

For no-reflow phenomena haemodynamic support, oxygenation, treatment of

chest pain and vagal reactions are important along with intracoronary

vasodilator therapy (Klein et al 2003). GP IIb/IIIa inhibitors are being

increasingly used in these situations & its benefit in randomised control trials is

under evaluation (Fuchs et al 2000)Most patients with acute PCM does not

require repeat angiography and conservative standard management is usully

sufficient for majority. Current clinical recommendations favour one or more

days of additional monitoring especially in the setting of higher levels of cardiac

biomarker elevation. (Levine et al 2003) Owing to their proven benefit,

discharge medications should include aspirin, clopidogrel, beta-blocker, HMG-


17/76

17

CoA reductase inhibitors, and ACE-inhibitors.(Frilling et al 2004;Saw et al

2004; Otsuka et al 2004)

5a.5.3 Long-term implications of PCM

The CAVEAT-I trial first demonstrated a correlation between post-procedural

cardiac enzyme elevation and future major adverse cardiac events, which was

also valid for patients with chronic kidney disease and UAP.Similar findings

were echoed by some other study (Jeremias et al 2002 )Overall, prognosis

seem to relate mainly to cardiac mortality, (higher incidence of sudden cardiac

deaths).Prognostic yield seems to be more established with CKMB than withcTnT/cTnI.(Topol et al 1999)During follow-up of at least 6 months, majority of

studies using CKMB as a cardiac marker indicated increased long-term cardiac

mortality (ORs 1.15) compared with only three out of 28 studies using

cTnT/cTnI as a cardiac marker, which seems to have greater association with

recurrent MI, chest pain, and repeat revascularization.(Herrmann 2005)Another

study indicated reduced target vessel revascularization in patients with PCM,

probably due to the presence of necrotic and less symptomatic

myocardium.(Narins et al 1999) Another study considered post-procedural

cardiac marker (CKMB) elevation as a retrospective evidence of optimal stent

deployment and indicated an overall lower 1-year mortality in these patients this

group.(Iakovou et al 2003)A similar analysis indicated that the relative increase

in 6-month mortality with increase in post-procedural peak CKMB level is

similar for spontaneous and PCI-related myonecrosis.(Akkerhuis et al 2002)A

meta-analysis of seven studies, showed a 1.5, 1.8, and 3.1 times higher long-

term (upto I34 months) mortality risk for patients with post-procedural CKMB

elevation 13ULN, 35ULN, and >5ULN, respectively.(Ioannidis et al 2003)

A recently published study indicates a linear relationship between post-

procedural CKMB elevation and 2-year mortality, but fail to confirm a similar

prognostic value for post-procedural cTnI elevation.(Cavallini at al 2005) The

current guidelines, consider post-procedural CKMB elevations >3 ULN

clinically relevant.(Califf et al 1998 &Smith et al 2001)


18/76

18

5a.6.Prevention of PCM

5a.6.1.Mechanical Approach

5a.6.1.1.Direct stenting

Stenting without pre-dilation leads to less manipulation and wall injury.Direct

stenting is a recognized strategy to reduce PCM. A three times lower incidence

of d cTnI elevation (0.20.9 ng/mL) was found after direct stenting of native

coronary artery lesions (Nageh T et al 2003) Other reports state a 1.7 times

lower incidence of CKMB elevation (>4 ULN) after direct stenting of SVG

lesions. ( Nageh et al 2003 & Leborgne et al 2003)However at present there is

no firm evidence that direct stenting prevents PCM.

5a.6.1.2.Distal protection devices

Initial report on the Percu-Surge distal balloon occlusion device in SVG

intervention showed that the amount of retrieved particular matter was less with

direct stenting compared to conventional stenting, which was attributed to a

greater release of plaque material by balloon pre-dilatation.(Carlino et al 1999)

Another study reported the incidence of no-reflow after SVG intervention was

66% lower with the distal balloon protection with a 40% reduction in 30-day

myocardial infarction rate and lower 30-day mortality (Ballarino et al 2003). No

significant differences in efficacy has been found between balloon and filter

devices reported so far & it can be concluded at the present moment that distal

protection devices can reduce but not fully prevent PCM.(Mehilli at al 2004)

5a.6.1.3.Ischaemic pre-conditioning

It has been assessed that mechanical ischaemic preconditioning leads to 70%

relative reduction in the incidence of post-procedural CKMB elevation (Laskey

,1999). Protective effects of pharmacological pre-conditioning is yet to be

established (Kato et al 2003).


19/76

19

5a.6.2.Pharmacological approaches

5a.6.2.1.HMG-CoA reductase inhibitors (Statins)

Pre-procedural statin therapy reduces the incidence of non-Q-wave PCM, and

improves long-term outcome (Chang et al 2004).

Activation of the PI3K/Akt signaling pathway seems to be crucial in the

cardioprotective effects of statins, leading to increased levels adenosine

generation as well as increased eNOS activity resulting in higher NO tissue

bioavailability,. (Bell et al 2003 & Sanada et al 2004) Adenosine and NO

synergistically lead to decreased platelet activation and aggregation, decreased

leukocyte activation and decreased vasoconstriction . Prolonged treatment withstatins reported to wane its acute cardioprotective benefit (Mensah et al 2005)

In patients on long term statin therapy the role of plaque consolidation in

prevention of PCM is questionable(Okazaki et al 2004)

5a.6.2.2 Beta-blocker.

Oral beta-blocker therapy prior to PCI reduces the incidence of minor (1

3ULN) but not major (.>3ULN) post-procedural CKMB elevation by 45%

along with a similar reduction in post-procedural chest pain and ST-T changes

on post-procedural ECGs. Oral beta-blocker therapy before PCI was

associated with lower long-term mortality, mainly among patients without

postprocedural CKMB elevation. (Sharma et al 2000). Subsequent studies

confirmed that patients who were on oral beta-blocker therapy at the time of PCI

had better long-term survival but not a lower PCM ( Ellis et al 2002;Chan et al

2002) Propanolol, experimentally injected distal to the target lesion, was

reported to reduce post-procedural CKMB and cTnTelevation by 53 and 61%,

respectively.(Wang et al 2003)Beta-blocker therapy may be given for its acute

cardioprotective effects as well as for long-term benefit.

5a.6.2.3. Antiplatelet agents

Considering the role of platelet activation and resultant arterial thrombosis in

the pathogenesis of PCM, antiplatelet therapy is mandatory and aspirin the

standard. Aspirin resistance is reported in about 20% which increases the risk

of post-procedural cardiac marker elevation nearly three fold.(Chen et al 2004)


20/76

20

Aspirin , limit inflammation, and endothelial dysfunction, which may exert

additional benefit in PCI.(Kharbanda et al 2002) For example there is reported

44% relative survival benefit at 1 year with aspirin use at the time of PCI(Chan

etal 2002)Platelet activation can be ongoing during PCI despite aspirin therapy

and synergistic antiplatelet pre-treatment. with ticlopidine was emphasized in

PCI setting When ticlopidine was started on the day of the procedure, the

incidence of PCM, (defined as a post-procedural CKMB elevation >1ULN)

4%. It was 48% lower when ticlopidine was started 12 days before and 82%

lower if started >3 days before the procedure (Steinhubl et al1998) . Similar

results were reported in another study with a 70% reduction in the incidence of12-h post-stenting cTnT elevation when ticlopidine was added to aspirin 3 days

before the procedure (Berglund et al 2002). A comparable reduction of 12-h

post-stenting cTnT elevation was found with a loading dose of 300 mg

clopidogrel on the day of the procedure, & effectiveness of which being outlined

in different trials (Steinhubl et al 2002 & Atmaca et al 2003) A recently

published randomized trial failed to show any difference in postprocedural

elevation of CKMB / cTnI elevation in the background of initiation of clopidogrel

3 days prior to or on the day of PCI (van der Heijden et al 2004) Up to 30% of

patients may have insufficient platelet inhibition 24 h after a loading dose of 300

mg of clopidogrel, which may be reduced to 11% by a 600mg loading dose

Loading dose of 600 mg achieves plateau levels of inhibitionin in 2 h compared

with 6 h with the 300 mg and provides additional platelet inhibition in patients

already on clopidogrel.( Gurbel et al 2005). In the randomized ARMYDA-2 trial,

a 600-mg loading dose of clopidogrel resulted in a 46 and 41% reduction of

post-procedural CKMB and cTnI elevation compared with a standard pre-

procedural loading dose of 300 mg.(Pratti etal 2005) The potent early

clopidogrel therapy in may even reduce the need of platelet glycoprotein IIb/IIIa

receptor inhibitor therapy in elective interventions (Kastrati et al 2004; Claeys

et al 2005)Periprocedural tirofiban reduced post-procedural cTnI elevations by

66% but not the absolute increase in cTnI and peak post-procedural CK/CKMB

serum concentration.(Bonz et al 2002) High-dose tirofiban bolus/infusion

continued at least 48h after and 6 h pre-treatment with ticlopidine/clopidogrel,


21/76

21

respectively, resulted in a significant (33%) reduction in the incidence of post-

procedural cTnI elevation and a 70 and 60% reduction in the absolute post-

procedural peak levels of cTnI and CKMB (Valgimigli et al 2004). A study on

mainly UAP patient population and the TARGET trial reported significant

reductions in the event rate of 30-day MI if clopidogrel was started more than 6

h before the procedure. (Chan et al 2003)Relative superiority of abciximab over

tirofiban was reported in the TARGET trial in the background of the GP IIb/IIIa

blockage mediated reduction of procedure-related ischaemic complications

(Stone at al 2002). Abciximab was shown to reduce plateletmonocytes

aggregation prior to PCI and leukocyteplatelet interaction after ischaemia andimprove microvascular flow with resultant cardioprotective effects in

experimental models (Kunichika et al 2004)

GPIIb/IIIa inhibitors (Iincluding abciximab) improve endothelium-dependent

vasofunction and preserve coronary blood flow response to acetylcholine after

stenting.(Heitzer at al 2003) These effects may account for the relative risk

reduction in post-procedural CKMB elevation with abciximab use EPISTENT

trial also reported a significant relative risk reduction of angiographic

complications of PCI owing to the use of abciximab. (Islam etal 2002) The

TEAM study results also indicate a lower incidence of angiographic

complications with abciximab compared to tirofiban and eptifibatide.,This

however, did not influence a significant difference in post-procedural cardiac

marker elevation.(Kini et al 2002) In high-risk lesions, .90% of platelet

aggregation inhibition may be optimum, whereas in low-risk lesions 25%

inhibition with aspirin & upto 50% inhibition with additional clopidogrel loading.

may be sufficient (Claeys et al 2005)

5a.6.2.4. Anticoagulants

Post-PCI cTnI elevation is higher in patients without pre-procedural heparin use,

but randomized trials are yet to show a reduction of PCM by full

anticoagulation.(ten Berg et al 2000)Low-molecular- weight heparin seems to

confer no additional benefit over unfractionated heparin.( Bhatt et al 2003)

Direct thrombin inhibitor bivalirudin is not inferior to the combination of heparin

and GP IIb/IIIa inhibitor, irrespective of clopidogrel pre-treatment (Lincoff et al


22/76

22

2003 & Saw et al 2004)Bivalirudin confers lower haemorrhagic risk, but this

benefit appears to be lost when combined with GP IIb/IIIa inhibitors (Lincoff et

al 2004) Direct thrombin inhibitors are an essential alternative in heparin-

induced thrombocytopenia. Current guidelines states that anticoagulants in

PCI, are essential and none is clearly superior to unfractionated heparin at

present (Popma et al 2004).

5a.6.2.5 Miscellaneous agents

Calcium channel blocker and ACE-inhibitors/angiotensin receptor blockers have

not yet shown to reduce PCM .


23/76

23

5b.High-Sensitivity C-Reactive Protein:

About a half of all myocardial infarctions (MI) occur in individuals without overt

hyperlipidemia. More than three quarters of all cardiovascular events occurs

among those with low-density lipoprotein (LDL) cholesterol levels below 160

mg/dL, and just less than half occurred among those with LDL cholesterol levels

below 130 mg/dL(Ridker et al 2002)About 20% of all coronary events occur in

the absence of any major risk factor(Wilson et al 1998). In one recent analysis

patients with CHD, 15% of the men and 19% of the women had no evidence of

any major risk factor, and more than 50% had only 1 of these factors.(Khot et

al 2003)

In background of this some novel risk factors, including high sensitivity C-

reactive protein (hsCRP) , lipopro-tein(a), homocysteine, fibrinogen, D-dimer,

tissue plasminogen activator, and plasminogen activator inhibitor-1 antigen has

attracted the attention in recent years. Among these hsCRP is the most

promising biomarker in terms of clinical utility.( Pearson et al 2003)

hsCRP emerged as the most powerful single predictor of cardiovascular riskincluding CHD death, nonfatal MI, stroke, coronary revascularization &

outcome of peripheral arterial disease. ( Ridker et al 2001)

Inflammation is characteristic in all phases of atherothrosclerosis and provides a

link between early fatty streak formation upto plaque rupture leading to

occlusion and infarction.(Libby et al 2002)Proinflammatory cytokines such as

interleukin-l(IL-1) and tumor necrosis factor(TNF). potentiate the expression of

adhesion molecules on vascular endothelial cells, leading to the recruitment of

leucocytes to the arterial wall,. IL-1 & TNF also activate chemokines that

promote migration of monocytes into the subendothelial space. Mononuclear

cells release growth factors that stimulate the proliferation of smooth muscle

cells and lead to plaque progression. Mediators such as CD40 ligand induce

tissue factor expression and promote thrombus formation. Primary

proinflammatory cytokines also stimulate the expression of interleukin-6, which

create enhancement of inflammatory response, which leads to the production

of CRP.


24/76

24

5b.1.What is CRP

CRP is a member of the pentraxin family of innate immune response proteins

(composed of 5 23-kd subunits,) synthesized by the liver in response to

interleukin-6, Recent evidence suggests that CRP is also produced by smooth

muscle cells of coronary arteries (particularly diseased vessels).(Calabro et al

2003 )It has been reported that levels of CRP in atherosclerotic plaque were 7-

and 10-fold higher than that in the liver and normal blood vessels (Yasojima et

al 2001). CRP influence vascular vulnerability (in vitro) by enhanced

expression of endothelial cell surface adhesion molecules,(Pasceri et al 2000)monocyte chemoattractant protein-(Ridker et al 2002) endothelin (Verma et al

2002) and endothelial plasminogen activator inhibitor (Devraj et al 2003)

reduced endothelial nitric oxide activity;( Verma et al 2002) and increased LDL

uptake by macrophages (Zwaka et al 2001) Recent data also indicate that

expression of human CRP enhances intravascular thrombosis in endothelial

disruption.(Danenberg et al 2003)

Serum hsCRP concentrations are lower than the tissue CRP concentrations

(which promote atherogenic responses) Serum hsCRP levels less than 1 mg/L

labeled as low , 1 to 3 mg/L labeled as intermediate, and greater than 3 mg/L

labeled as high-risk. CRP at the cellular level usually range from 5 to 900

mg/Lduring inflammatory responses .On the other hand CRP concentrations as

low as 5 mg/L have been implicated to decrease nitric oxide production (Verma

et al 2002)One study suggests that low concentrations of hsCRP (1 mg/L.


25/76

25

5b.2.hsCRP and Cardiovascular Risk

hsCRP predicts future cardiovascular risk in a wide variety of populations,

including healthy individuals patients with acute coronary syndromes, stable

angina , after MI, after percutaneous coronary intervention (PCI) and patients

with the metabolic syndrome, diabetes, or renal disease.

5b.2.1.hsCRP and Subclinical Atherosclerosis

Epidemiologic studies on general populations have found inconsistent

associations between hsCRP and evidence of subclinical atherosclerosis suchas carotid intimal-medial thickness (IMT) and coronary calcification as

measured by electron beam computed tomography (EBCT). In a subset of

Framingham Study, the top quartile of hsCRP was associated with relative risk

(RR) of carotid stenosis (25%) of 3.90 (95% CI, 2.44-6.44) among women and

1.62 (95% CI, 1.12-2.36) among men (Wang et al 2002) . hsCRP level also

correlated positively with the extent of coronary artery calcification in healthy

participants evaluated with EBCT(Wang et al 2002) Another study reported

that persons with hsCRP level in the top tertile of the sample distribution were

twice as likely to have moderate or severe carotid plaques than were persons in

the bottom tertile (>2.77 vs


26/76

26

5b.2.2.Acute coronary syndromes. A study reported that patients presenting

with unstable angina and elevated plasma levels of hsCRP and serum amyloid

A suffered higher adverse outcomes than did patients without the same, even

in the absence of troponin elevation (Liuzzo et al 1994). TIMI investigators

reported that the increased cardiac risk associated with high hsCRP levels may

be evident as early as 14 days after presentation with an acute coronary

syndrome.(Morrow etal 1998)CAPTURE trial of abciximab in unstable angina

poulations found that, hsCRP predicted risk of mortality or MI at 6 months

(Heeschen et al 2000)and at 4 years.(Lenderink et al 2003) FRISC trial (on

low-molecular-weight heparin) reported the risk associated with elevatedhsCRP levels at the time of the index event (unstable angina in 61% and MI in

39% of participants) continued to increase during a 3-year follow-up (Lindahl et

al 2000)

In the TIMI, CAPTURE, and FRISC studies, the predictive value of hsCRP was

shown to be independent of, and additive to, troponin. An approach using

hsCRP, troponin I, and B-type natriuretic peptide has been shown to improve

risk prediction in patients with acute coronary syndromes.(Sabatine et al 2002)

In patients of the TIMI trial (categorized on the basis of the number of elevated

biomarkers at presentation), there was nearly doubled 30-day mortality risk for

each additional biomarker elevation. Similar relations also existed for the

endpoints of MI and congestive heart failure, and for the composite of the 3

outcomes, at 30 days and at 10 months.

5b.2.3.Stroke. Recent reports suggest that hsCRP may be useful in predicting

risk of subsequent cardiovascular events among persons with ischemic stroke.

hsCRP levels were measured in ischemic stroke patients within 24 hours after

onset. Compared with those in the bottom hsCRP quartile (33 mg/L) and middle two quartiles (5-

33 mg/L) had RRs of 4.04 and 1.37 respectively, of a future cardiovascular

event in 2 years of follow-up. (Di Napoli et al 2002)


27/76

27

5b.2.4.After percutaneous coronary intervention.

It has been reported that hsCRP strongly predicted early complications (30-day

risk of death or MI) after PCI in patients with a high percentage of use of stents

and glycoprotein IIb/IIIa inhibitors; with the RR was 3.68 for the highest(>10

mg/L) vs lowest (3 mg/L vs 3 vs 5vs3vs


28/76

28

scores with the lowest hsCRP levels despite a higher prevalence of traditional

coronary risk factors.(Zebrack etal 2002).

Inflammation appears to be systemic rather than localized in patients with acute

coronary syndromes but the precise source of CRP elevations remains unclear.

(Boffon etal 2002) It has been documented that hsCRP levels did not change

after PTCA in patients with stable or unstable angina with normal preprocedural

CRP levels but did increase after PTCA in patients with unstable angina and

elevated hsCRP levels at baseline.(Liuzzo et al 1998)Plaque rupture may not

be the source of elevated hsCRP levels in unstable angina, but elevated hsCRP

in this setting may be suggestive of hyper-responsiveness of the inflammatorysystem to smaller stimuli. As sirolimus and similar coatings present an

antiproliferative, anti-inflammatory surface interface with the endothelium.

These coated stents are likely to decrease event rates among individuals with

elevated levels of hsCRP. hsCRP may be an important factor in the decision to

use the drug eluting stents in certain patients, thereby potentially reducing the

economic burden associated with widespread nonselective use of drug eluting

stents.On the contrary if inflammatory activity is is widespread and not limited to

the lesion site drug eluting stents may not decrease future events.

5b.2.5.Chronic phase after Myocardial Infarction.

It has been reported in the CARE study that, patients with elevated hsCRP

levels at 3 to 20 months after the MI were at higher risk of recurrent events

during the 5-year follow-up period.(Ridker etal 1998)Another study of patients

with premature MI also found hsCRP to be a strong predictor of future cardiac

death. The 10-year RR of cardiac mortality doubled with increasing CRP

quartiles. Patients in the top quartile had 6 times the risk of cardiac death than

did patients in the bottom quartile(adjusting age, left ventricular ejection

fraction, serum cholesterol, fibrinogen, smoking, and hypertension) (Retterstol

et al 2002)Another study found that, hsCRP levels measured 2 months after

the index MI significantly predicted the risk of recurrent coronary events but the

association lost the significant after adjustment for ejection fraction and

presence of pulmonary oedema (Harb et al 2002).


29/76

29

In another study, hsCRP levels were measured in stable angina patients with

or without exercise induced ischemia Individuals with levels of 3.8 mg/L or

above were far more likely to have exercise-induced ischemia ( RR, 4.2; 95%

CI, 1.6-11.0) (Bettie et al 2003).. Thresholds used to define an abnormal or

elevated CRP level among patients with documented coronary disease range

from 3 mg/L to 5 mg/L(Chew et al 2001,de Winter et al 2002) CAPTURE

investigators found that a threshold of 10 mg/L maximized the predictive value

of CRP in patients with unstable angina.(Heeschen et al 2000) Lowest

distribution has been among healthy individuals, an intermediate range in stable

CAD, and the highest range in acute coronary syndromes (Bassuk et al 2004).

5b.3.Practical Considerations of hsCRP

5b.3.1 hsCRP Assays

Traditionally CRP has been used to monitor active infection & inflmmmation.

related to musculoskeletal systemThese assays are automated and

reproducible and have a lower detection limit of 3 to 8 mg/L and is not sensitive

enough to detect the lower levels for prediction of cardiovascular risk. To

improve the sensitivity of CRP assays, the useful approach has been to amplify

the light-scattering properties of the antigen-antibody complex by covalently

coupling latex particles to a specific antibody. Most of the nearly 30 types of

hsCRP assays, presently used employ this commercially available approach

(Ledue et al 2003). Commonly used methods achieved sensitivities of less

than or equal to 0.3 mg/L, and had analytic variabilities of less than 10% (

reproducibility . >90%).(Roberts et al 2001)

5b.3.2.Biologic Properties of CRP

hsCRP exhibits a relatively low range of variability in the same stable patients.

In a study it was reported that , two separate measurements of hsCRP in the


30/76

30

same individual 90 days apart classified of 90% of values in the same or

immediately adjacent biomarker tertile.(Ockene et al 2001) The CARE trial,

reported moderate positive correlation (r= 0.6) between two hsCRP

measurements 5 years apart,(Ridker et al 1999)

If a value less than 10 mg/L is obtained, it is believed that a single hsCRP

assessment is sufficient. The CDC and AHA recommend two hsCRP

measurements taken 2 or more weeks apart, and the mean value is used to

predict vascular risk.(Pearson et al 2003) hsCRP levels may increase upto

100-fold or more in response to acute infections or trauma, Levels above 10

mg/L should be ignored initially and the test repeated after stabilization. Ifelevation persists, then connective tissue disease, inflammatory bowel disease,

or endocarditis should be excluded (particularly with elevated erythrocyte

sedimentation rate). It has been reported, that individuals with persistent &

significant elevations of hsCRP appear to have exceptionally high coronary

risk(Ridker et al 2004). In clinical studies, fewer than 2% of hsCRP values

exceeds15 mg/L, and persistent elevations are rare. hsCRP levels are not

influenced by food intake or circadian rhythm, .(Ockene et al 2001 )Owing to its

pentraxin structure, hsCRP has a long plasma half-life (18 to 20 hours),

Measurements can be made accurately from fresh or frozen blood

(serum/plasma) without the need for special collection procedures. (Ledue TB

et al 2003). CRP has been shown to be stable at 4C for 60 day s,(Kebler A et al

1994)at 70C for longer than 20 years, (Wilkins et al 1998)and in liquid nitrogen

for an indefinite period.(Rifai et al 2003) hsCRP levels have demonstrated

specificity for vascular events and not predictive of cancer.(Rifai et al 2002)A

population-based cohort study of women (>65 years) reported that an elevated

CRP level strongly predicted cardiovascular mortality (CRP >3 vs


31/76

31

moderate-, and high-risk groups for primary cardiovascular prevention (Ridker

et al 2003& Pearson et al 2003 ), Individuals with the lowest hsCRP levels

(10mg/L) are at very high risk. (Ridker et al

2004)

5b.3.3.1.Genetic influence:Different studies suggest that CRP concentrations

are in part genetically determined & heritability of serum CRP level is

approximately 40% to 50% .( MacGregor et al 2004).

5b.3.3.2.Sex:Circulating hsCRP concentrations, measured by high-sensitivity

assays, appears comparable among men and women with the 50th percentilefor both sexes being approximately 1.5 mg/L. .(Rifai et al 2003), hsCRP levels

are higher in women who use oral HRT which may be partly responsible for the

increased risk of thrombotic events associated with oral HRT use.(Manson JE

et al 2003). Selective estrogen receptor modulators do not raise hsCRP

levels,(Herrington et al 2001) nor do transvaginal or transdermal

estrogens.(Vongpatanasin et al 2003)

5b.3.3.3. Age. Most studies report a modest relation between age and serum

CRP concentrations. (Rifai et al 2003; Ledue et al 2003)Reported median

hsCRP concentrations for individuals aged 45 to 54, 55 to 64, 65 to 74, and 75

years or older were 1.31, 1.89, 1.99, and 1.52 mg/L, respectively. (Rifai et al

2003)

5b.3.3.4.Race/ethnicity. There was no reported significant differences in the

distributions of hsCRP levels among European-American, African-American,

Mexican-American men. and Japanese men. (Ford et al 2003) In contrast,

hsCRP concentrations are reportedly higher in Mexican-American women than

in European-American women. (Ford et al 2004) African-American women

(compared to whites) had higher hsCRP levels and Asian-American women had

lower level of hsCRP (compared to Hispanics).(Albert et al 2004)

5b.4.Therapeutic Interventions

It has not yet been conclusively proved that that lowering hsCRP levels leads to

reduction in future cardiovascular events. many behavioral and pharmacologic


32/76

32

interventions known to reduce the risk of clinical cardiovascular events have

been linked to lower hsCRP levels. The goal of cardiovascular screening

programs is the identification of high-risk individuals who can be targeted for

weight loss,smoking cessation, increased physical activity, blood pressure

control, and, where necessary, pharmacologic therapy. A patients compliance

with recommended interventions depends at least in part on his or her

perception of absolute disease risk. Because the addition of hsCRP to lipid

evaluation improves the prediction tool, hsCRP screening may be useful for this

reason alone.

5b.4.1.Pharmacologic Interventions

Several pharmacologic agents with demonstrated ability to reduce hsCRP

levels.

5b.4.1.1.Lipid-lowering agents. Lipid-modulating medications reported to

affect hsCRP levels favorably include HMGCoA reductase inhibitors (statins),

fibrates, and niacin. Statins are by far the most effective.

5b.4.1.1.1.Statins. Cardiovascular benefits of statins extend beyond LDL

cholesterol reduction. Benifits of statin therapy comes sooner than expected

(even when LDL cholesterol has not started to reduce). Patients taking statins

have a better prognosis than patients not taking the same even when LDL

cholesterol levels are matched.Statins reduce ambulatory ischemia and

symptomatic angina, events not generally explained by LDL reduction alone;.

Statins also reduce risk of stroke although LDL cholesterol is not a major risk

factor.,The CARE trial.first reported the hsCRP lowering ability of statins

(pravastatin) because of its possible anti-inflammatory effects in addition of

lipid-lowering (Ridker et al 1998 & 1999). Confirmatory work showed that effect

of statins on hsCRP was a consistent and important class effect. A meta-

analytic review of the effects of statins on CRP, fibrinogen, homocysteine,

oxidised LDL cholesterol, tissue plasminogen activator, plasminogen activator

inhibitor, and platelet aggregation concluded that, among these, only hsCRP

appears to be reduced by statins(Balk et al 2003) . All statins (pravastatin,


33/76

33

lovastatin, cerivastatin, simvastatin, and atorvastatin) have shown to reduce

median CRP levels by 15% to 25% as early as 6 weeks after initiation of

therapy in different subsets of CAD patients (Balk et al 2003 &;Kinlay et al

2003) This reduction in CRP levels (and improving lipid profiles) is augmented

by the addition of ezetimibe, (a cholesterol absorption inhibitor not affecting

triglycerides and fat-soluble vitamins.(Ballantyne et al 2003 )Though ezetimibe

alone had no reported effect on hsCRP. Magnitude of LDL cholesterol reduction

due to statin therapy is minimally correlated with the magnitude of hsCRP

reduction. (Balk et al 2003) It has been reported that the cardiovascular risk

reduction attributable to statin therapy may be most marked in those havingelevated hsCRP levels at baseline. In the CARE trial, recurrent events

prevented by pravastatin was 54% among persons with elevated hsCRP levels

but only 25% among persons with lower hsCRP levels, though baseline lipid

profile were nearly identical in both groups.(Ridker et a 1999) In a primary

prevention trial, lovastatin therapy was associated with a 42% reduction in first

cardiovascular events among participants with LDL cholesterol levels 1.6 mg/L . (Ridker etal2001) It has been reported

that high hsCRP confers a dramatic increase in cardiovascular risk even in the

absence of elevated LDL cholesterol, The randomized JUPITER trial is

underway investigating the effect of rosuvastatin vs placebo on men and

women with LDL cholesterol levels below 130 mg/dL but hsCRP levels above 2

mg/L in 4 year follow up to see the effect on first vascular events (Ridker et

al2003) The JUPITER trial will also provide important data on the relative

benefit (or lack of benefit) of hsCRP reduction as compared with LDL

cholesterol reduction.

5b.4.1.1.2.Fibrates.

Small trials have shown that fibrates may also decrease plasma concentrations

of hsCRP and other inflammatory markers in dyslipidemic patients (Wang et al

2003 & Despres et al 2003) CRP-lowering ability of fenofibrate (200 mg/d)

was compared with that of atorvastatin (10 mg/d) and fenofibrate treatment was

found to be more effective,(Melenovsky et al 2002) In a double-blind trial

fenofibrate and simvastatin (20 mg/d) found to be equally effective.(Wang et al


34/76

34

2003) Gemfibrozil, was shown to lower cardiovascular event rates without a

significant reduction in LDL cholesterol(Rubins et al 1991).

5b.4.1.1.3.Niacin.

It has been shown that combination of niacin and lovastatin (1000 & 20-mg

respectively), reduced median hsCRP levels in dyslipidemic patients by 4% at 8

weeks and doubling the dose reduced hsCRP by 24% at one year (P .

.01).(Kashyap et al 2002) In another double-blind randomized trial on type 2

diabetic patients niacin (at doses of 1000 or 1500 mg/d,) reduced median

hsCRP levels by 11%, and 20% compared to placebo.(Grundy et at 2002).

5b.4.1..2.Aspirin and other antiplatelet agents. A large primary prevention

trial reported that the risk of future MI was reduced 56% by aspirin (325 mg on

alternate days) in those with baseline CRP levels in the highest quartile and

reduction was only 14% among those in the lowest quartile of CRP.This

observation might suggest that aspirin may prevent ischemic events through

anti-inflammatory as well as antiplatelet effects (Ridker et al 1997). Published

data indicate that the effects of clopidogrel and abciximab may be strongest in

patients with elevated CRP levels before PCI.(Chew et al 2001 & Lincoff et al

2001) In contrast, ticlopidine conferred a significant reduction in subsequent

cardiovascular events after ischemic stroke with admission hsCRP levels in the

bottom 2 tertiles.. Nonsignificant excess risk was evident among those in the

highest CRP tertile.(Di Napoli et al 2002)Whether aspirin or other antiplatelet

agents can lower CRP directly is uncertain. One trial found that six weeks of

aspirin therapy (300 mg/d) significantly reduced CRP levels in patients with

stable angina,(IkonomidisI et a 1999)

5b.5.Clinical Recommendations

Persons for whom National Cholesterol Education Program guidelines call for

therapeutic intervention (based on serum LDL) an elevated hsCRP level should

provide a strong impetus to improve compliance with diet and pharmacologic


35/76

35

therapy. Whether or not patients with normal levels of LDL cholesterol but high

levels of hsCRP will benefit from statin therapy is being tested in the JUPITER

trial. CDC and the American Heart Association, recommends to measure

hsCRP in individuals determined to be at intermediate cardiovascular risk on

the basis of traditional risk factors (Pearson et al 2003).

hsCRP predicts early and late mortality rates in acute coronary ischemia,

adding to the prognostic value of cardiac troponin, and predicts outcomes after

coronary stent placement. At present, apparently healthy individuals with

elevated levels of hsCRP should be advised to lose excess weight, increase

physical activity , stop smoking, and consult with their physicians concerning theuse of aspirin and lipid-lowering therapies. In the future, novel anti-

inflammatory therapies that directly target the vascular endothelium may

become available.


36/76

36

6.PATIENTS AND METHODS

6.1Hypothesis

Preexisting systemic inflammation (manifested by raised hsCRP) is associated

with increased incidence of post PCI cardiac myonecrosis.

6.2 Inclusion criteria

Patients undergoing elective PCI (angioplasty with or without intracoronary stent

implantation)

6.3 Exclusion criteria

Acute myocardial infarction within two weeks before the procedure..

Pre-PCI raised cardiac enzyme level (TnT >0.03 g/litre). Renal & Hepatic impairment (Creatinine>3mg%, 3 fold raised AST/ALT

value over baseline).

Obviously active inflammatory musculo-skeletal disease

Staged PCI (another PCI within previous two weeks)

6.4 Study population

Approval from the local ethics committee & authority of St James,s Hospital

was obtained beforehand.

After informed consent fifty consecutive patients undergoing elective PCI

during July & August 2006 in St Jamess Hospital were recruited for this

prospective observational study considering above mentioned inclusion &

exclusion criteria.Twelve patients were later excluded from the analysis as the

blood sample taken immediately before PCI showed significantly high value of

TnT


37/76

37

Their demographics, major risk factors for ischaemic heart disease & ongoing

medications were recorded.

Blood sample were taken immediately before the PCI for estimation of hs CRP

,CKMBM & TnT.These three tests were repeated next morning (16-24 hours

after PCI)

6.5 Performance of PCI

PCI was performed as per standard protocol either by femoral or radial

approach as per operators discretion.

All patients received standard dose of Aspirin & Clopidogrel before PCI plus

continuation dose of other ongoing medications.

Patients also received 5000-7000 units of heparin bolus at the beginning of

procedure and additional boluses later depending on the length & complexity of

the procedure (operators discretion)

As per operators discretion patients received other medications like injectable

calcium channel blocker (verapamil),intracoronary GTN,GP IIb/IIIa inhibitor

(abciximab) etc if required.

During the procedure number & types of treated lesions ,devices used with type

& dimensions (balloon/stent),total duration & pressure of inflations was

recorded.

Complications like acute vessel closure,side branch compromise,prolonged

arterial spasm,no/slow flow phenomena,significant hypotension (SBP 5min) were taken into account .Fortunately no such complications

occured in any of the patients

Successful PCI was judged by


38/76

38

6.6 Laboratory analysis

Blood sample were taken before and after the PCI for estimation of hs

CRP,CKMBM & TnT

hsCRP was estimated by paricle enhanced immunonephlometry (by usung BN

II analyzer manufactured by Dade Behring GmBH,Germany). Lower limit of

detection 0.1mg/L.Values were divided into three tertiles stratifying risk (low

3mg/L) (Ridker et al 2003).Immunology

laboratory of SJH coniders a value of >10mg/L significantly high.

TnT was measured by automatic immunoassay (using Elecsys analyzermanufactured by Roche).Lab data of SJH suggests value of 0.05 g/L is suggestive of definite myocardial injury

(ACC/AHA/ESC recommendation for definition of myocardial infarction)

Sensitivity of TnT is 90 to 100% at 12-24 hrs following an event (Katus et al

1991)

CKMBM was estimated by immunometry by monoclonal antibody directed

against MB subunits.Usual reference range is 0-4 g/L. CKMB starts to rise at

2-4 hours and usually peaks between 12-18 hrs returns to normal in 72 hrs.

Sensitivity & specificity is about 98% if sampled appropriately.

6.7 Statistical analysis

Sample size: In order to detect an effect size of 0.5 of greater for a two sided

significance level of 5% and power of 80% required a minimum sample size of

34 (paired observations)

Pre & post hsPCI CKMBM & TnT values as well as pre & post PCI CRP values

were compared by appropriate statistical tests (non-parametric Mann Whitney U

test)

Correlation of post & pre PCI difference of CRP CKMBM & TnT with age,

ongoing medications,predilatation & stent deployment parameters was done by

using correlation co-efficient .(Spearman rho).


39/76

39

Statistical analysis is done on a personal computer by using SPSS (version 12)

statistical software

Results are expressed as meanSD (for normally distributed data) and median

(with interquartile range) for skewed data

A probability (p) value of


40/76

40

7.RESULTS & TABLES

Mean age(SD) of the 38 patients recruited for the study was 6411.5 years

(range 40 to 83) .Majority of them were in their sixth and seventh

decades.86.8% of them were males.

Clinical background: 17(44.7%) had unstable angina,12 (31.6%) stable

angina,8(21.1%) myocardial infarction (>2 weeks old) & 1 (2.6%) had silent

myocardial ischaemia.

Dyslipidaemia was the most common risk factor present in 18 (47.4%) patients

followed by hypertension in 17(44.7%) and current smoking in 11 (28.9%).

One major risk factor was found in 28.9%, 26.3% had two and same percentage

had three risk factors.However 15.8% had no identifiable risk factor.

100% of patients were on Aspirin & Clopidogrel at the time of PCI.97.4% were

on statin,78.9% were on beta blockers & 50% were on angiotensin converting

enzyme inhibitors or angiotensin receptor blockers.Less than 30% were having

low molecular weight heparin,less than 25% oral nitrate & less than 20% oral

calcium channel blockers.

24 (63.2%) underwent the procedure via femoral route and 14 (36.8%) via radialapproach.

Left anterior descending was the most commonly treated artery (47.4 %)

followed by right coronary (36.8%) and left circumflex (34.2%).Single vessel

stenting was performed on 25 patients (65.8%)

23(60.5%) individuals had type B (ACC/AHA class) coronary artery

lesions,7(18.4%) had type A lesions, 8 (21.1%) both type of lesions.

71.1% individuals underwent predilatation & stenting & rest had direct stenting.

Median number of predilatation inflation was 3/patient..Median pressure was 13

atm and median time was 48 seconds A total number of 75 stents were

deployed in 38 patiens.56% of the stents were sirolimus eluting (Cypher),36%

were paclitaxel eluting (Taxus) & 8% were bare metal stents.Median number of

stents per patient was two.Median length of a stent was 19.8 cm .Median stent

deployment pressure was 16 atm and stent deployment time 39 (per patient) .


41/76

41

All the values in interquartile range was higher in post PCI hsCRP.compared to

pre PCI hsCRP.Median value was 4.58 and 3.61.This difference was

statistically significant(p3mg/L) pre PCI.This

figure went up to 65.8% post PCI.This is suggestive of significant systemic

inflammation further enhanced by the performance of PCI.

TnT values in 50th& 75thpercentile showed significantly higher values post PCI

(median 0.015 vs 0.01 g/L p


42/76

42

Of the ongoing medications calcium channel blockers significantly influenced

CKMBM difference (p


43/76

43

Table 4: Showing prevalence of major risk factors for coronary artery disease in

the study population

Risk factor Frequency Percentage

Dyslipidaemia 18 47.4

Hypertension 17 44.7

Family history 13 34.2

Current smoking 11 28.9

Diabetes Mellitus 04 10.4

Table 5: Showing the number of number of risk factors per individual patient

Number of risk factors Frequency Percentage

0 6 15.8

1 11 28.9

2 10 26.3

3 10 26.3

4 1 2.6

Total 38 100

Table 6 : Showing the ongoing cardiac medications at the time of PCI

Medication Frequency Percentage

Aspirin 38 100

Clopidogrel 38 100

Statin 37 97.4Beta-blocker 30 78.9

ACEI/ARB 19 50.0

Heparin (low molecular ) 11 28.9

Nitrate (oral) 09 23.7

Calcium blocker 07 18.4

Alpha-blocker 03 07.9

Nicorandil 03 07.9


44/76

44

Table 7:Showing the the route of PCI.

Route Frequency Percentage

Femoral 24 63.2

Radial 14 36.8

Total 38 100

Table 8: Showing the target arteries of PCI

Artery Frequency Percentage

Left main (protected) 02 5.3

Left anterior descending 18 47.4

Left circumflex 13 34.2

Right coronary 14 36.8

Graft vessel 02 5.3

Table 9 Showing single & multivessel intervention

Number Percentage

Single vessel 25 65.8

Multivessel 09 23.7

Others (left main/graft) 04 10.5

Table 10: Shows type of coronary artery lesion (ACC/AHA type) treated by PCI

Lesion type Frequency Percentage

A 07 18.4

B 23 60.5

A & B in same patient 08 21.1

Total 38 100


45/76

45

Table 11: Showing the PCI strategy in the study population

PCI Strategy Frequency PercentageDirect stenting 11 28,9

Predilatation & stenting 27 71.1

Total 38 100

Table 12: Showing balloon preditatation parameters of the 27 subjects

Parameter Minimum Maximum Median

Infation number 01 13 03

Pressure (atm) 08 22 13

Time (seconds) 10 206 48.0

Table 13: Showing the types of stents deployed

Type of stent Numbers deployed Percentage

Sirolimus eluting (Cypher) 42 56.0

Paclitaxel eluting (Taxus) 27 36.0

Bare metal (Driver) 06 8.0

Total 75 100

Table 14: Showing different parameters for stent deployment in study

population

Parameter Minimum Maximum Median

Number 01 05 02

Length(mm) 08 33 19.8

Pressure(atm) 12 18 16

Time (secs) 10 98 39


46/76

46

Table 15: Showing trend of TnT before and after PCI(numbers in parenthesis

indicate percentage)

TnT(g/L) Pre PCI Post PCI

4 7(18.4) 23(60.5)

>8 0(0) 07(18.4)

Table :17 Shows trend of hsCRP distribution before and after PCI in the study

population

Pre PCI Post PCIhsCRP tertile

Number Percentage Number Percentage

1(3 mg/L) 23 60.5 25 65.8

Table:18 Showing the distribution of high sensitivity CRP (hsCRP) ,cardiac

troponin T and creatinine phosphokinase myocardial band mass (CKMBM)

before and after PCI.

PercentllesParameter Minimum Maximum25th 50th(median) 75th

Pvalue

(pre PCI)hsCRP 0.21 47.2 1.06 3.61 8.00

(post PCI)hsCRP 0.44 39.2 1.52 4.58 8.11


47/76

47

Table 19 :Showing the influence of the route of PCI on the changed value of

hsCRP, TnT & CKMBM (post PCI minus pre PCI) (Mann Whitney U test)

Radial

(Mean rank)

Femoral

(Mean rank)

Z

value

p

value

hsCRP difference 18.71 19.96 -0.33 0.74(NS)

TnT difference 23.32 17.27 -1.73 0.08(NS)

CKMBM difference 22.00 18.04 -1.06 0.29(NS)

Table 20 :showing correlation of age with difference of hsCRP,TnT,CKMBM

Difference inhsCRP

Difference in TnT Difference in CKMBM

Corr coef P value Corr coef P

value

Corr coef P value

Age 0.26 NS 0.16 NS -0.023 NS

Table 21: showing background influence of unstable angina(17 pts) and stable

angina (12 pts) on difference of hsCRP,TnT,CKMBMDiff hsCRP Diff TnT Diff CKMBM

Chi-square 0.7 0.09 0.008

P value 0.79 0.77 0.92

Table 22: showing the influence of single vs multivessel intervention and direct

vs stenting after predilatation on difference of hsCRP,TnT,CKMBM

Single vs Multivesselintervention

Diff hsCRP Diff TnT Diff CKMBM

147.5 124.5 151.0Mann Whitney U

P value 0.64 0.21 0.72

Direct vs stenting

after predilatation

134.0 140.0 142.5Mann Whitney U

P value 0.66 0.80 0.85


48/76

48

Table 23: Showing correlation of predilatation & stent parameters with

changed value of hsCRP, TnT & CKMBM (by Spearman rho)

hsCRP difference CKMBM difference TnT difference

Corr

coef

P value Corr

coef

P value Corr

coef

P value

Predilatation

Time(secs)

0.117 NS 0.284 NS 0.235 NS

Predilatation

Pressure

-0.043 NS 0.027 NS 0.042 NS

Stentinflation

time (secs)

0.082 NS 0.127 NS 0.094 NS

Stentinflation

Pressure

-0.051 NS 0.048 NS 0.04 NS

Stent

number

0.119 NS 0.218 NS 0.103 NS

Stent

Length

0.062 NS 0.32 NS 0.61 NS

Table 24 :Showing the correlation of pre PCI hsCRP values with post PCI TnT

& CKMBM values (by Spearman rho)

Post PCI TnT Post PCI CKMBM

Correlation

coefficient

P value Correlation

coefficient

P value

Pre PCI hsCRP -0.074 NS 0.036 NS


49/76

49

Table 25 :Showing correlation of difference (post PCI and pre PCI) of hsCRP,

TnT & CKMBM. (by Spearman rho)

CKMBM difference TnT difference

Cor

coefficient

P value Cor

coefficient

P value

hsCRP diff 0.139 0.41 0.117 0.48

TnT

difference

0.52*


50/76

50

8 DISCUSSION

The present study evaluated the presence of preexisting systemic inflammatory

state (estimated by hsCRP) in patients undergoing elective PCI and its

correlation with the changes in specific cardiac enzymes (TnT & CKMBM)

induced by PCI.Change in the systemic inflammatory state after the PCI was

also evaluated.Influence of demographic factors,ongoing medications, &

procedural factors on cardiac enzymes & hsCRP were also investigated

Mean age of the study populaion was 6411.5 years .Nearly same mean age

(6310.7) was reported in a similar study on caucasian subjects by Saleh et alin 2004.Percentatge of female patients another similar study was 20% which is

slightly higher than the present study (13.2%)(Saadeddin et al 2002).In Saleh et

als study reported current smoker percentage was 37 (almost 30% in present

study).Hypertensive patients comprised 37% (44.7%) in present study).

Diabetes Mellitus was present in13% (10.4% in present study).Another related

study reported dyslipidaemia in >80% of their patients (Saadeddin et al 2002)

This figure was 47.4% in the present subject.This might reflect the moreaggressive lipid lowering strategy of present time. This is reflected by ongoing

stain therapy in over 97% in the study.This was more than (73%) reported by

Saleh et al in 2004. However beta blocker usage in that study was slightly

higher than the present one (86% vs 79%).ACEI/ARB use in this study was

50% which is higher than 38% reported by Saadeddin et al.Calcium channel

blocker usage was 33% in that study which is higher than present one

(18.4%).Nitrate use in was only about 24% in this study which was much lower

than 77% reported by Saadeddin et al. Cent percent of patients in present

study received aspirin & clopidogrel which is in keeping with standard PCI

protocol of present time.

Primary unstable angina (Braunwald class B) accounted for nearly 29%

population in this study which is nearly similar (33%) to that reported by Saleh

et al.21% patients of this study had previous myocardial infarction compared to

37% in the study of Saleh et al.


51/76

51

All the patients had angioplasty by femoral approach in the study reported by

Saadeddin et al.But in the present study ,radial approach was used in 36.8%

patients which reflects the changing practice of PCI in recent time.Single vessel

PCI was performed in 65.8% cases which is slightly higher than the

corresponding figure (59%) of Saleh et als series. Left anterior descending was

the target artery in 47.4% which is close to the figure of 52-55% in Saadeddin

et als series.Type B lesion was the overwhelming majority (just over 80%)

which is nearly similar to the figure (75%) reported by Saleh et al.All the

subjects of the present study underwent stent implantation (92% of implanted

stents were drug eluting). But stent use was 82% in the sudy of Saleh et al (noreference of drug eluting stent is found).This difference also reflects the present

day practice of PCI .

Fortunately no significant procedure related complication like side branch

occlusion,so flow/no flow or compication necessitating Abciximab use was

observed in the present study.However side branch occlusion was reported in

nearly 13% in Saadeddin et als series.Overal complication rate was around

9% in Saleh et alsseries. Abciximab use was reported on nearly 7% cases in

Saleh et als series.

Significant systemic inflammatory state (hsCRP >3 mg/L suggested by Ridker

et al 2003)was detected in 60.5% patients before PCI.After PCI this figure rose

to 65.8% indicating worsening of inflammation.In the series of Saadeddin et al

41% had abnormally high hsCRP (cutoff value considered >6. mg/L) Liuzzo et

al in 1998 reported significant increase in hsCRP levels after PCI in patients

with unstable angina and elevated hsCRP at baseline.Gaspardone et alin 1998

& Bonz et al in 2003 also reported significant increase in hsCRP after PCI in

their series.

Median hsCRP in this study before PCI was 3.61 mg/L which increased to 4.58

mg/L after PCI (p


52/76

52

Saleh et al.However this figure was 41% in another study with cutoff value of

>0.04 g/L (Abbas et al 1996).

There was also statistically significant increase in median value of CKMBM

after PCI in this study.(p8

g/L (indicating significant myocardial injury).This figure was 15.6% in Lansky et

als series and 21.3% in Kuchulakanti et als series..

No significant correlation was found between pre PCI hsCRP values and post

PCI TNT (Spearman rho 0.074/p NS) and post PCI CKMBM (Spearman rho

0.036/p NS).Similar trend was observed between post and pre PCI difference of

hsCRP with post and pre PCI difference of TnT & CKMBM.Similar obvervationwas made by Saleh et al in their study where CRP levels before PCI did not

influence myocardial infarction during the procedure.But a contradictory finding

was reported by Saadeddin et al where 46% patients with high hsCRP

developed TnI elevation (compared to 18% without high hsCRP p=0.002).

Post and pre PCI difference of TnT & CKMBM was significantly correlated.

(Spearman r

CORRELATION OF SYSTEMIC INFLAMMATORY STATUS & CARDIAC MYONECROSIS IN PATIENTS UNDERGOING ...

Documents

Transcript of CORRELATION OF SYSTEMIC INFLAMMATORY STATUS & CARDIAC MYONECROSIS IN PATIENTS UNDERGOING ...