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

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

1. ABSTRACT
Objective of study: To the evaluate the influence of pre-procedural high

sensitivity 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 (<0.03 g/litre) undergoing elective PCI.

Results: Significantly high basal levels of

hsCRP was detectable in >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 <0.05).Though there was significant increase in the post PCI median value (compared to pre PCI) of TnT (0.015 vs 0.01 g/L p<0.001) and CKMBM (4.45 vs 2.90 g/L p<0.001) no significant correlation was found between pre PCI hsCRP and post PCI TnT (spearman correlation coefficient 0.074/p=NS) as well as post PCI CKMBM (spearman correlation coefficient 0.036/p=NS).The changed values of TnT & CKMBM showed moderate positive correlation

(spearman correlation coefficient 0.52/p<0.001).Procedural parameters (of balloon dilatation & stent implantation) also did not also have a significant

correlation either.No significant influence of age & ongoing medications was found.

Conclusion: Increased hsCRP levels in serum before PCI was not correlated with significant cardiac myonecrosis detected after PCI.

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 the blessings 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

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.

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 causes of 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.

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 procedure et al 2004) But regrettably, the incidence of reflected by post 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 alterations taking 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

study identified areas of myocardial infarction as the site of cardiac serum marker release after PCI (Selvanayagam et al 2005) Thus, PCM is of post-

synonymous with peri-procedural myocardial infarction in majority 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

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 <30 mL/min. (Gruberg et al 2003) Anaemia (<12 g/dL in women and <13 g/dL in men) has recently been identified as a comorbidity increasing the risk for PMI (OR of 1.35, P = 0.02) but the overall incidence of PMI was low in the anaemic subjects (McKechnie et al 2004) Unstable angina pectoris (UAP) has emerged as an important clinical predictor for PCM (adjusted OR of 1.5). Patients with UAP and cardiac marker elevation on admission, (a high risk predictor of adverse outcome) are excluded in most of the studies anticipating the difficulties of distinguishing between the natural course of evolving AMI and PCI-related myocardial injuries. If patients of UAP with pre-procedural cardiac marker elevation are included in analysis, they were found to have a higher frequency and greater extent of postprocedural cardiac marker elevation (Tardiff et al,1999) A recent analysis of acute coronary syndrome focused trials noted that 44% of ACS patients without pre-procedural CKMB elevation were found to have a postprocedural CKMB elevation, predominantly of milder degree. (Roe et al,2004) Nearly similar percentage (35.6%) of UAP patients had an increase in cTnI concentration by at least 0.1 ng/mL from admission values after intervention within 24-h post-

procedural period (Nageh et al 2002 ) Pre-PCI elevation of high sensitivity Creactive protein (hsCRP) concentration has recently emerged as a clinical predictor of PCM. It has been observed that elevated pre-procedural hsCRP levels in patients with stable angina undergoing PCI, increases the risk of PCM 2.27-fold (Saadeddin et al 2002) Another study reported a nearly four fold higher pre-procedural hsCRP level among patients developing post-procedural CKMB elevation (Ellis et al 2002) Before the hsCRP era, it was noted that

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 (<0.16 mg/dL) and compared to 10.1 11.2% in all other preprocedural CRP quartiles (Chew et al 2001) . A linear correlation between pre-procedural CRP serum concentrations and peak postprocedural CKMB serum activity was noted (Zairis et al 2005). One study has showed that the incidence of post-procedural CKMB increase was 35% higher in patients with a pre-procedural white blood cell count >9.5 106/L (Gurm et al,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.

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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 instent) (Chung et al 2002). Lesion characteristics that possibly pre-dispose to PCM include eccentric lesion, greater plaque and thrombus burden, plaque rupture, 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 sidebranch 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

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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 postprocedural 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 al 2002).. 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 atheroembolization pathophysiology (Prati et al,2003;Topol EJ et al.2000) Autopsybased 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 <56 to >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.

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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 <0.1 ng/mL (<0.05 ng/mL) in all patients within 12 h of PCI. (Sinha et al 2003). Hence, many patients develop myocardial ischaemia and increased oxidative stress during PCI but only a few progress to myocardial injury . 5a.4.4 Altered vascular and myocardial homeostasis by neurohormonal activation Microvascular bed occlusion by plaque debris, thrombus, platelets, and neutrophils, is recognized. Myocardial circulatory derangement can occur due to neurohormonal factors too. Abnormal vasoconstriction at the epicardial and microcirculatory level is a well-known phenomenon in the precipitation of ischaemia in UAP.(Marzilli et al ,2000) Vasoconstriction is frequently seen after PTCA (with and without acute ischaemia), related to abnormal autoregulation and abnormal vasoreactivity to stimuli, like released vasoactive factors from activated platelets. (Fischell t al 1988) Serotonin mediated and vasoconstriction of the distal epicardial bed seems to be pronounced after stenting.(Leosco et al 1999) Endothelin-1 (ET-1) is another potent mediator, generated in

increased amount from plaque deposits in the setting of platelet activation and ischaemia, secondary to procedurerelated mechanical stretch and pressure.

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(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) Postprocedural 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 reversed

vasoconstriction 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 postprocedural 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

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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 increased neutrophil 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

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.(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 microvascular embolization (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 vasodilator therapy (Klein et al 2003). GP IIb/IIIa inhibitors intracoronary 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-

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

et al 2004;Saw

et al

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 with cTnT/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 longterm (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 postprocedural 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)

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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).

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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 with statins 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)

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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 of 12-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 procedural loading dose of 300 mg.(Pratti etal 2005) The pre-

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,

20

respectively, resulted in a significant (33%) reduction in the incidence of postprocedural cTnI elevation and a 70 and 60% reduction in the absolute postprocedural 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 and improve 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

21

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 heparininduced 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 .

22

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 risk including 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.

23

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 7and 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 (<0.5 mg/L) are almost never associated with the future vascular event whereas concentrations greater than 10 mg/L represent very high risk.(Ridker et al 2004).Cut off value for clinically significant circulatory level is >1 mg/L.

24

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 such as 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 <1.11 mg/L: RR, 2.0; 95% CI, 1.3-3.0) after adjustment for BMI and other covariates (van der Meer et al 2002). Autopsy studies have shown that elevated hsCRP is associated with increased macrophage density in atherosclerotic plaque, a higher prevalence of cap thinning , and increased risk of plaque erosions and rupture.(Burke et al 2002) In a 10-year follow-up study on elderly participants who had no history of stroke or atrial fibrillation at baseline, elevated hsCRP was predictive of ischemic stroke, independent of atherosclerosis severity (Cao et al 2003) During followup of the same cohort, there was also a stronger relation between hsCRP and subsequent MI among individuals with evidence of subclinical disease than among those without such evidence.(Tracy et al 1997)

25

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 elevated

hsCRP 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 (<5 mg/L), individuals with an hsCRP level in the top quartile (>33 mg/L) and middle two quartiles (533 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)

26

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 (<1.6 mg/L) quartile comparison The risk associated with

elevated CRP was independent of, but additive to, the ACC/AHA lesion score(Chew et al 2001). It was reported in a study (on patients of stable angina having received elective angioplasty) that hsCRP level (>3 mg/L vs <3 mg/L) was found to be a strong independent predictor of adverse coronary outcomes (death, MI, urgent revascularization, or admission for unstable angina); with a RR of 2.5 .(de Winter et al 2002) hsCRP was reported to be a better predictor than diabetes, hypertension, and ACC/AHA lesion class,. In another report, patients undergoing elective or urgent angioplasty were followed for up to 14 months.In multivariate analyses, elevated CRP level (>3 vs <3 mg/L) was an independent predictor of death or nonfatal MI ( RR, 3.6;) (de Winter et al 2002) Nearly similar results came out of a 1-year follow-up of patients with stable angina who had undergone coronary stenting; Elevated. CRP levels (>5vs<5 mg/L) were associated with a 1.8-fold increase in rate of death or MI but baseline hsCRP levels did not correlate with restenosis (Dibra et al2003). Another follow up study of patients (who had undergone stenting of the culprit lesion). compared individuals with hsCRP levels of 10 mg/L with CRP levels 10 mg/L. Higher CRP was implicated in RR of 4.2 for in-hospital death and a RR of 4.07 for death within 20 months (Muller et al 2002) It was reported that preoperative elevated hsCRP (>3vs<3 mg/L) was

associated with an increased risk of recurrent ischemia at 1 to 6 years after coronary artery bypass grafting (Milazzo et al 1999) hsCRP is also predictive of cardiovascular events in symptomatic patients of angiographically determined significant stenosis who are treated medically Absolute risk of death or MI was found in patients with the lowest CAD scores (those with normal angiograms). and the highest hsCRP levels exceeded the risk for patients with highest CAD

27

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 inflammatory system 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) .

28

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

29

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. If

elevation 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 4 C for 60 day s,(Kebler A et al 1994) at 70 C 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<3 mg/L: adjusted RR, 8.0) but was unrelated to mortality from noncardiovascular causes (Tice et al 2003)

5b.3.3.Population Distribution of hsCRP Ranges of less than 1, 1 to 3, and greater 3 mg/L, correspond to tertiles of the CRP distribution in healthy adults, which classifiy of individuals into low-,

30

moderate-, and high-risk groups for primary cardiovascular prevention (Ridker et al 2003& Pearson et al 2003 ), Individuals with the lowest hsCRP levels (<0.5 mg/L) are at very low cardiovascular risk, whereas those with long-term marked elevations of hsCRP (>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 percentile for 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

31

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 metaanalytic 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,

32

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 having elevated 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 <149

mg/dL but hsCRP 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

33

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

34

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 the use of aspirin and lipid-lowering therapies. In the future, novel anti-

inflammatory therapies that directly target the vascular endothelium may become available.

35

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

36

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 <80mm of Hg for >5min) were taken into account .Fortunately no such complications

occured in any of the patients Successful PCI was judged by <20% residual stenosis of target lesions (after stenting) ,TIMI 3 distal coronary blood flow at the end of the procedure ref and absence of complications like emergency coronary artery bypass surgery and acute myocardial infarction (by immediate post PCI ECG).

37

6.6 Laboratory analysis

Blood sample were taken before and after CRP,CKMBM & TnT

the PCI for estimation of

hs

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 <1mg/L, intermediate 1-3, high >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 analyzer

manufactured by Roche).Lab data of SJH suggests value of <0.01 g/L as normal & between 0.01 & 0.05 g/L may be suggestive of myocardial definite myocardial injury

injury.Values >0.05 g/L is suggestive of

(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).

38

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 <0.05 is considered significant.

39

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) & 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 radial approach. Left anterior descending was the most commonly treated artery (47.4 %) followed by right coronary (36.8%) and left circumflex (34.2%).Single vessel 1 (2.6%) had silent

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) .

40

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(p<0.05). 60.5% individuals had hsCRP values in the 3rd tertile (>3mg/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 & 75th percentile showed significantly higher values post PCI (median 0.015 vs 0.01 g/L p<0.001).19 (50%) patients developed some increase in their TnT value post PCI.Among them 11(29%) developed significant rise of TnT 0.06. CKMBM values were found to be higher in all three interquartile ranges after PCI (median 4.45 vs 2.90 p<0.001).76.3% of subjects had an increase in the CKMBM values after PCI (though 15.8% showed decline & 7.9% showed a tie).18.4% of pre PCI CKMBM values were >4 g/L whereas 60.5% corresponding post PCI value was above this limit.No prePCI value was above 8 g/L but 18.4% of the post PCI value was above the cutoff. Pre PCI hsCRP level did not have a significant correlation with post PCI TnT (corr coefficient -0.074/p NS) or post PCI CKMBM (corr coefficient 0.036/p NS).Similar relation was observed between difference (post-pre PCI) of hsCRP with .TnT ,CKMBM. However the difference of (post-pre PCI) TnT &CKMBM showed statistically significant moderate positive correlation (corr coefficient 0.52/p <0.001) Route of PCI did not have a significant influence on the hsCRP difference (p =0.74) TnT difference (p=0.08) and CKMBM difference (p=0.29) There was no correlation of age with hsCRP difference (corr coefficient 0.26/p NS) CKMBM diff (corr coeff -.023/p NS) TnT diff (corr coeff .115/p NS).Similar trend was observed with clinical background (angina status) Predilatation and stent deployment parameters (inflation time and pressure stent number and length) did not show any significant correlation with difference of hsCRP, TnT &CKMBM.Direct stenting vs stenting following predilatation and single vs multivessel also did not influence hsCRP, TnT &CKMBM

41

Of the ongoing medications calcium channel blockers significantly influenced CKMBM difference (p<0.05) and oral nitrates influenced hsCRP difference (p<0.01). Estimated influence of other medications were insignificant.

Tables
Table 1: Showing age distribution of the study population

Age range 40-49 50-59 60-69 70-79 >80 Total

Number 5 7 10 13 3 38

Percentage 13.2 18.4 26.3 34.2 7.9 100

Table 2: Showing sex distribution of the study population Sex Male Female Total Frequency 33 5 38 Percent 86.8 13.2 100

Table 3: Showing clinical background of study population:

Clinical Background ST Number Percentage 6 15.8

MI

UA

Stable

Silent

Angina ischaemia NST 2 5.3 Primary pCABG pPTCA 11 28.9 5 13.2 1 2.6 12 31.6 1 2.6

42

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

Risk factor Dyslipidaemia Hypertension Family history Current smoking Diabetes Mellitus

Frequency 18 17 13 11 04

Percentage 47.4 44.7 34.2 28.9 10.4

Table 5: Showing the number of number of risk factors per individual patient Number of risk factors 0 1 2 3 4 Total Frequency 6 11 10 10 1 38 Percentage 15.8 28.9 26.3 26.3 2.6 100

Table 6 : Showing the ongoing cardiac medications at the time of PCI Medication Aspirin Clopidogrel Statin Beta-blocker ACEI/ARB Heparin (low molecular ) Nitrate (oral) Calcium blocker Alpha-blocker Nicorandil Frequency 38 38 37 30 19 11 09 07 03 03 Percentage 100 100 97.4 78.9 50.0 28.9 23.7 18.4 07.9 07.9

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Table 7:Showing the the route of PCI.

Route Femoral Radial Total

Frequency 24 14 38

Percentage 63.2 36.8 100

Table 8: Showing the target arteries of PCI

Artery Left main (protected) Left anterior descending Left circumflex Right coronary Graft vessel

Frequency 02 18 13 14 02

Percentage 5.3 47.4 34.2 36.8 5.3

Table 9 Showing single & multivessel intervention Number Single vessel Multivessel Others (left main/graft) 25 09 04 Percentage 65.8 23.7 10.5

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

Lesion type A B A & B in same patient Total

Frequency 07 23 08 38

Percentage 18.4 60.5 21.1 100

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Table 11: Showing the PCI strategy in the study population

PCI Strategy Direct stenting Predilatation & stenting Total

Frequency 11 27 38

Percentage 28,9 71.1 100

Table 12: Showing balloon preditatation parameters of the 27 subjects

Parameter Infation number Pressure (atm) Time (seconds)

Minimum 01 08 10

Maximum 13 22 206

Median 03 13 48.0

Table 13: Showing the types of stents deployed

Type of stent Sirolimus eluting (Cypher) Paclitaxel eluting (Taxus) Bare metal (Driver) Total

Numbers deployed 42 27 06 75

Percentage 56.0 36.0 8.0 100

Table 14: Showing different parameters for stent deployment population

in study

Parameter Number Length(mm) Pressure(atm) Time (secs)

Minimum 01 08 12 10

Maximum 05 33 18 98

Median 02 19.8 16 39

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Table 15: Showing trend of TnT before and after PCI(numbers in parenthesis indicate percentage) TnT(g/L) <0.06 0.06 Pre PCI 38(100) 0(0) Post PCI 27(71) 11(28)

Table 16: Shows trend of CKMBM before and after PCI(numbers in parenthesis indicate percentage) CKMBM(g/L) >4 >8 Pre PCI 7(18.4) 0(0) Post PCI 23(60.5) 07(18.4)

Table :17 Shows trend of hsCRP distribution before and after PCI in the study population hsCRP tertile Pre PCI Number 1(<1mg/L) 2(1-3 mg/L) 3(>3 mg/L) 9 6 23 Percentage 23.7 15.8 60.5 Post PCI Number 7 6 25 Percentage 18.4 15.8 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. Parameter Minimum
Maximum

Percentlles 25th 50th(median) 3.61 4.58 0.01 0.015 2.90 4.45 75th 8.00 8.11 0.01 0.073 3.50 6.78

P value

(pre PCI)hsCRP (post PCI)hsCRP (pre PCI) TnT (post PCI) TnT (pre PCI) CKMBM (post PCI) CKMBM

0.21 0.44 0.01 0.01 1.60 2.40

47.2 39.2 0.03 1.82 5.20 24.20

1.06 1.52 0.01 0.01 2.40 3.20

<.05

<.001

<.001

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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) hsCRP difference TnT difference CKMBM difference 18.71 23.32 22.00 Femoral (Mean rank) 19.96 17.27 18.04 Z value -0.33 -1.73 -1.06 p value 0.74(NS) 0.08(NS) 0.29(NS)

Table 20 :showing correlation of age with difference of hsCRP,TnT,CKMBM Difference in hsCRP Corr coef P value Corr coef P value Age 0.26 NS 0.16 NS -0.023 NS Corr coef P value Difference in TnT Difference in CKMBM

Table 21: showing background influence of unstable angina(17 pts) and stable angina (12 pts) on difference of hsCRP,TnT,CKMBM Diff hsCRP Chi-square P value 0.7 0.79 Diff TnT 0.09 0.77 Diff CKMBM 0.008 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 Multivessel intervention Mann Whitney U P value Direct vs stenting after predilatation Mann Whitney U P value 134.0 0.66 140.0 0.80 142.5 0.85 147.5 0.64 124.5 0.21 151.0 0.72 Diff hsCRP Diff TnT Diff CKMBM

47

Table 23: Showing correlation

of predilatation & stent

parameters with

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

hsCRP difference Corr coef P value

CKMBM difference Corr coef P value

TnT difference Corr coef P value

Predilatation Time(secs) Predilatation Pressure Stentinflation time (secs) Stentinflation Pressure Stent number Stent Length

0.117

NS

0.284

NS

0.235

NS

-0.043

NS

0.027

NS

0.042

NS

0.082

NS

0.127

NS

0.094

NS

-0.051

NS

0.048

NS

0.04

NS

0.119

NS

0.218

NS

0.103

NS

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 Correlation coefficient Pre PCI hsCRP -0.074 NS P value Post PCI CKMBM Correlation coefficient 0.036 NS P value

48

Table 25 :Showing correlation of difference (post PCI and pre PCI) of hsCRP, TnT & CKMBM. (by Spearman rho)

CKMBM difference Cor coefficient hsCRP diff TnT difference 0.139 0.52* 0.41 <0.001** P value

TnT difference Cor coefficient 0.117 0.48 P value

Table 26 Showing the influence of common ongoing medications on difference (post PCI and pre PCI) of hsCRP, TnT & CKMBM. Beta blocker Mann Whitney U P value Calcium blocker Mann Whitney U P value ACEI/ARB Mann Whitney U P value Heparin(LMW) Mann Whitney U P value Nitrate Mann Whitney U P value 54.5 0.009 98.0 0.23 87.0 0.14 144.5 0.90 107.5 0.16 131.5 0.58 179.0 0.96 177.0 0.91 117.5 0.06 77.0 0.24 78.5 0.23 53.5 0.04 Diff hsCRP 119.0 0.97 Diff TnT 106.5 0.61 Diff CKMBM 115.5 0.87

49

8 DISCUSSION
The present study evaluated the presence of preexisting systemic inflammatory state (estimated by hsCRP) correlation with in patients undergoing elective PCI and its

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 al in 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 more aggressive 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.

50

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 (no reference 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 als series. 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 al in 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 <0.05).Median hsCRP in Saleh et als series was 1.83 mg/L which much lower than the present study. There was statistically significant increase in median value of TnT after PCI in this study.(p<0.001). 28% patients developed TnT values 0.06 g/L after PCI (indicating significant myocardial injury.) This figure was 21% as reported by

51

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.(p<0.001).18.4% of post PCI CKMBM values were >8 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 obvervation was 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 rho 0.52/p <0.001)In another study by Saadeddin et al in 2000 it is reported that both TnT & CKMB was raised following PCI but TnT increase was more sensitive. In the present study no significant correlation was observed between difference of hsCRP TnT & CKMBM (post minus pre PCI) and various procedural

parameters (predilatation time & pressure,stent inflation time & pressure ,stent number & length). In the study of Saadeddin et al total time of inflation

significantly influenced post PCI troponin I value (p=0.008).Stent implantation compared to plain balloon angioplasty accounted for increased rise of TnT in Saleh et als series (p=0.03).But no comparison in this aspect is possible as all the patient in the present study received stent implantation.In Saadeddin et als series side branch occlusion is another factor influencing post PCI troponin rise.(p=0.015).This aspect was again not comparable as no patient developed side branch occlusion in the present study. Beta blocker therapy has not influenced difference of hsCRP TnT & CKMBM (post minus pre PCI) in present study.Sharma et al in 2000 reported that oral beta blocker prior to PCI reduces post PCI CKMB elavation.However another

52

study (Ellis et al 2002) reported that patients on oral beta blockers at the time of PCI had better long term survival but not lower incidence of PCM.There was no influence of ACE inhibitor & calcium blocker on the difference of hsCRP TnT & CKMBM (except the statistically significant influence of calcium blocker on CKMBM p=0.04) This observation is supported by Herrmann J 2005. Influence of aspirin, clopidogrel & statin could not be evaluated as nearly all the subjects received these medications.

53

9 CONCLUSION
1. Significant systemic inflammatory state (evaluated by hsCRP) was present in a large number of stable patients undergoing elective

PCI.Performance of PCI causes significant worsening of inflammation. 2. Both the specific cardiac biomarker (TnT & CKMBM) values were

significantly increased after PCI. 3. Change in TnT & CKMBM values was not influenced by by the systemic inflammatory state 4. Balloon dilatation and stent parameters did not influence the change in hsCRP TnT & CKMBM values.Same applies to most of ongoing

medications,

54

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