Multivessel myocardialinfarction: a window to futuretreatments of myocardialinfarctionPhilip D Houck,1 Walter J Linz2

INTRODUCTIONDuring the last 50 years, the treatment ofmyocardial infarction has evolved. Moni-toring of arrhythmias,1 defibrillation ofthe detected arrhythmias and the eventualimplantation of defibrillators havedecreased the risk of sudden death.2

Anticoagulation, antiplatelets and throm-bolytics attacked the initiating event ofthrombosis within the artery.3e8 Thisevent, easily accepted today, requiredvisualisation of the thrombus in livepatients, since the clot was often absent inpathological examination.9e12 A great dealof effort has been spent in refiningantithrombotic drugs and the develop-ment of protocols that would reducethrombosis with the least risk of bleeding.The observation of clot in a vessel enabledcardiology to decrease the mortality ofmyocardial infarction from 50% to lessthan 5%. Although many agents havebeen added to the patient to reducethrombosis, there has never beena consideration to remove offendingagents from the patient.

A new paradigm in the aetiology ofmyocardial infarction has been growing inour clinical trials. This new concept is therole of inflammation.13e15 Inflammationof blood vessels is one explanation for theonset of the clinical syndrome. Coronaryatherosclerosis is present in 75% of indi-viduals over the age of 21. This fact hasbeen known since the Korean War.16 17

Inflammation weakens the lipid-filledplaque wall. The thinned plaque ruptures,exposing the blood vessel to thrombogenicfactors, and attracts clumping platelets to

initiate clots. Inflammation occurs ina smaller percentage of individualsexplaining why acute events are lessfrequent than the prevalence of disease.18

Inflammation can be helpful by signallingfor repair progenitors, but may alsoimpede the healing of the myocardium bydestroying the progenitor cells ordisrupting differentiation that wouldreplace the damaged myocardium.Inflammation of the vessel wall is moredifficult to visualise than clots, butappears to the initiating culprit prior toa thrombosis. Recent studies demonstratethat attacking inflammation can bea preventive strategy.19 Many of ourtherapies that have been shown todecrease mortality after myocardialinfarction also have anti-inflammatoryproperties.An unusual case of inflamed coronary

blood vessel may point to a new approachin the treatment of myocardial infarction.The case, still considered an unknownclinical event, is thought to representa primary inflammation of the coronaryarteries. A recent pregnancy in the case isthought to be the aetiology of theinflammation that somehow targeted theheart vessels as a foreign invader. It hassimilar findings to acute myocardialinfarction with chest pain, EKG findingsof acute myocardial infarction, ischaemicventricular fibrillation cardiac arrest,enzyme rise and wall motion abnormali-ties. It is different from acute myocardialinfarction in that it involved all threecoronary distributions. This case will beused to illustrate successful removal ofinflammatory cytokines and coagulants.Additional anti-inflammatory therapieswill be presented that may prepare theinfracted heart for recovery.

INFLAMMATORY MYOCARDIALINFARCTIONThe patient is a 31-year-old femaleapproximately 12 weeks postpartum. Shepresented to her primary care physician

with the complaint of chest discomfort,radiation to the left shoulder whichoccurred while eating. The rest of the dayshe had recurrence with eating, but thenext day she had discomfort not associ-ated with eating and not relieved withantiacid. These events prompted a visit tothe emergency room. Past medical historywas remarkable for G2 P2 by C-section12 weeks prior, previous obesity statuspost gastric bypass surgery with a 45 kgweight loss and pregnancy-inducedhypertension. Her medications consistedof Propanolol LA 80 mg daily, Ibuprofen800 mg twice daily, Ortho Tri-Cyclen anda multivitamin. She had no known drugallergies and no significant family history.The physical examination (postventricularfibrillation arrest) was normal with theexception of S4.In the Emergency Room, the patient

initially was triaged to non-cardiac chestpain and was in the process of being given0.5 mg of Dilaudid when the monitordisplayed ventricular fibrillation (figure 1).Post defibrillation, her pain resolved, andshe spontaneously converted to sinusrhythm with normalised ST segments(figures 2, 3). Echocardiogram at thebedside demonstrated posterior-lateralhypokinesis with left ventricular hyper-trophy. The assessment at that time wasischaemic ventricular fibrillation. Theaetiology of the ischaemia could besecondary to ruptured atheroscleroticplaque or coronary artery spasm. Thepatient was then treated with intravenouslidocaine, heparin, IIb IIIa inhibitors andintravenous nitroglycerine. She remainedpain-free overnight on this therapy andwent to cardiac catheterisation the nextday.Coronary angiography was performed

on intravenous nitroglycerine and is bestdescribed as severe pruning of her coro-nary tree in all three distributions withTIMI flow being worse in the circumflexdistribution (figures 4, 5). The appearancewas consistent with transplant vasculop-athy. No intervention was possible, andthe patient was assigned medical therapy.She promptly demonstrated acute injurypattern during the anticoagulation-freeperiod of sheath removal.The differential diagnosis includes

typical coronary disease, but this is unlikelydue to the acute onset with an angiogramdemonstrating diffuse native disease in anindividual who had recently carried a full-term pregnancy. Some form of coronaryvasculitis seemed more plausible, butassociated symptoms were lacking. Theonly other vascular distribution that may

1Division of Cardiology, Department of Medicine, Scott &White Healthcare, Temple, Texas, Texas A&M HealthScience Center College of Medicine, College Station,Texas, USA; 2Department of Pathology, Scott & WhiteHealthcare, Temple, Texas, Texas A&M Health ScienceCenter College of Medicine, College Station, Texas, USA

Correspondence to Dr Philip D Houck, Division ofCardiology, 2401 S 31st Street, Temple, TX 76508, USA;phouck@swmail.sw.org

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have been clinically implicated was themesenteric vessels manifested by painwitheating. The differential as listed by Walleret al includes tuberculosis, polyarteritisnodosa, giant cell arteritis, rheumatic fever,systemic lupus erythematosus, thrombo-angitis obliterans, Wegner granulomatosis,

salmonella, leprosy, Kawasaki disease,Takayasu disease, typhus, infective endo-carditis, rheumatoid arthritis, ankylosingspondylitis and syphilis.20 The patient hadno other associated finding, and 4 years offollow-up has not revealed any diagnosislisted.

In a flurry of calls to transplant centres,there were rumoured cases of postpartumsevere coronary disease that may havebeen similar to transplant coronaryvasculitis. The literature review for docu-mentation of these cases was howeverempty. It was felt that pregnancy andfetal cells stimulated the immune systemto react in an adverse manner. A similarprocess occurs in transplant vasculopathywhere the vessels are foreign and attackedby the immune system. Plasmaphaeresishas been reported to be beneficial intreatment of transplant vasculopathywhich the angiogram most resembled.This reasoning prompted the additionaltherapies of immune suppression andplasmaphaeresis.The hospital course over the next

several days continued to demonstrateEKG changes and recurrent pain withinfarct pattern in all three distributions(figures 6e9) and troponin rise (figure 10).The dips in the troponin graph representthe affect of plasmaphaeresis. Echocar-diograms demonstrated a decline in leftventricular function. She was treatedwith standard therapy for myocardialinfarction: aspirin, clopidigrel, warfarin,proton-pump inhibitor, b blockers, ACEI,Spironolactone, Amiodarone and aninternal defibrillator. Additional non-standard therapy was initiated on the dayof her catheterisation, day 2.Since vasculitis was the working diag-

nosis, plasmaphaeresis was initiated: days2, 3, 4, 7, out patient for 3 weeks, intrave-nous immunoglobulin between plasma-phaeresis 3 and 4, and steroids. Her steroidswere tapered after being boosted during onereadmission for recurrent pain and minorinjury, andplasmaphaeresis completed. Sheremained on warfarin for apical aneurysmfor 3 months. Six months after her admis-sion, a CT angiogram was performed thatdemonstrated healing of her vasculitis.Plavix was discontinued at this time. Herleft ventricular function was normal. Sheremained on aspirin, b blocker, ACE inhib-itor and statin. She has remained wellwithout heart failure or angina for the last4 years. No other collagen vascular orvasculitic symptoms have occurred.

REVIEW OF ANTI-INFLAMMATORYTHERAPIESInflammation and immunity is a funda-mental law of biology. Self needs to beprotected from the environment. It isa complex process that has evolvedmultiple pathways with multiple checksand balances. Regeneration and replace-ment of senescent cells utilises this system

Figure 1 R on T ventricular fibrillation.

Figure 2 Postventricular fibrillation conversion to atrial fibrillation.

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to process the dying cells. Inflammationutilises cellular components (endothelium,T cells, B cells, dendritic cells, leucocytes,eosinophils, basophils, monocytes, macro-phages, mast cells, plasma cells andplatelets), humeral elements (immuno-globulin IgG, IgM, IgA, IgE, naturalantibodies and immune antibodies) andsignalling proteins (compliment cascade,tumour necrosis factor, intercellular adhe-sion molecule, monocyte chemoattractantprotein, bradykinin, histamine, interleukin,platelet-activating factor, prostaglandins,leucotrienes, selectins (L, E, P) and otherctyokines. Reactive oxygen speciesproduced through inflammatory pathwaysare deadly molecules that can cause direct

injury.21 The inflammatory pathways aremore complicated than the coagulationpathways and have proven to be farmore difficult to target in therapeutics.Inflammatory and coagulation pathwaysare intertwined with inflammation,resulting in thrombosis and anticoagulationreducing inflammation. Trials targetinga single pathway such as anti-CD 18 totarget the complement cascade havedemonstrated promise in animal experi-ments but have fallen short in humans.22

Many of the pathways have self regula-tion, so disturbing one pathway mayenhance other pathways. The inflamma-tory pathways are also instrumental inrepair and regeneration. Senescent cells

are labelled by natural autoantibodies andreprocessed by macrophages. Disruptionof one pathway may have deleteriouseffects when other pathways compensatefor the disruption. The review thatfollows is certainly not inclusive of allmechanisms involved in treatment ofmyocardial infarction inflammation butreflects the rationale in this case. Thiscase illustrates that multiple attacks onthe inflammatory system including thecytokines, cellular and humeral pathwaysmay be necessary to achieve success. Itwould suggest that removal of cytokinesand procoagulants is a safe and effectivewindow to new therapies of myocardialinfarction.

PLASMAPHAERESISTherapeutic plasmaphaeresis results in thenon-selective removal of proteins andother soluble constituents from theplasma portion of whole blood. The rela-tive reduction of any given plasma frac-tion after a one-volume plasma exchangewith albumin as replacement is a functionof the relative distribution of that fractionbetween the intravascular and extravas-cular compartment, the rate of equilibra-tion between the compartments and therate of synthesis of the constituent afterremoval. As an example, for a large proteinsuch as fibrinogen located primarily in theintravascular space, approximately 60%will be removed after a one-volumeexchange. The percentage decrease forsmaller proteins such as clotting factorsranges from 25% to 50%. Any constituentin the plasma fraction will be at leasttransiently reduced. In this case, Hs-CRPwas reduced to zero with the firstexchange.For approximately four decades, the

principle of non-selective removal of odious

Figure 3 Spontaneous conversion from atrial fibrillation to normal sinus rhythm.

Figure 4 Left coronary artery two views.

Figure 5 Right coronary artery.

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plasma proteins and substances by thera-peutic plasmaphaeresis has been utilisedto treat a variety of conditions.23e25

Examples include removal of the IgGplasma fraction to treat such diseases asGoodpastures syndrome, myasthyeniagravis and GuillaineBarré. Removal ofthe IgM plasma fraction treats coldagglutinin disease and cryoglobulinemia.Removal of the lipid fraction treats

primary hypercholesterolaemia. Finally,removal of an aberrant phytanic acidmetabolite treats Refsum disease. It isnow increasingly recognised that thera-peutic plasmaphaeresis also has an effecton immunomodulation and affects therheological properties of blood by makingit less viscous.26 In the cardiac transplantstudy, nine patientswith 3e7-year survivalperiods after heart transplantations

underwent plasmaphaeresis twice a yearwith 2100e2700 ml of plasma removed. Inthis group with transplant vasculopathy,there was a significant improvement in thecoronary perfusion of the myocardiumby radionuclide scintigraphy of themyocardium and coronary angiography.27

Plasmaphaeresis can be performedthrough central access of the femoral orjugular vein or even the antecubital vein.Preload sensitive patients may be managedby albumin infusion during the initiationof plasmaphaeresis. During plasmaexchange, the extracorporeal volume ofmost circuits is approximately 200 ml ofwhole blood.Plasmaphaeresis, in this case, is unique

in the treatment of myocardial infarction.Instead of adding things to the patient toprevent further thrombosis, inflammationand clotting factors are removed. It is thefastest method of reducing inflammationand a shotgun approach in that multipleconstituents in the inflammatorypathway can be removed. Plasmaphaeresismay reboot the immune system when ithas gone astray.

INTRAVENOUS IMMUNOGLOBULINThe source of intravenous immunoglob-ulin comes from as many as 10 000 blooddonors. The half life of an administrationof immunoglobulin is 3 weeks. It is usedas replacement therapy in immunodefi-cient states and is used in autoimmuneconditions such as myasthenia gravis, idio-pathic thrombocytopaenia purpura, Guil-lian-Barre, Kawasaki coronary vasculitisand transplant rejection.28 The mecha-nism of action in these autoimmuneconditions is not well understood, andthe actions are multiple. Immunoglobu-lins act on B cells and can control theirproliferation, production of antibodiesand cytokines. Immunoglobulins can actdirectly on autoantibodies and disruptfeedback loops and prevent activation ofT cells. These interactions can halt ordelay apoptosis, and neutralise inflam-mation. Removing autoantibodies tomyocardial cells that had been targetedfor destruction may allow these cells torecover.

STEROIDSCorticosteroids, since 1976, have beenconsidered deleterious in the treatment ofacute myocardial infarction.29 30 Initialanimal experiments in dogs demonstratedinfarct reduction.31 The controversy iscertainly not resolved and is fuelled byanimal models not reflecting the humancondition, the studies performed in non-

Figure 6 Posterior lateral injury.

Figure 7 Inferior lateral injury.

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reperfused arteries and not having theability to measure infarct recovery overan extended length of time. Corticoste-roids have multiple actions and areresponsible for white cell infiltration,and inhibit formation of thromboxane,prostaglandins, and leucotrienes.32 Theyare a dominate factor in inflammation.Steroids can cause apoptosis of haemato-poietic cells and protect other glandular

cells.33 Glucocorticoids have a directactivation of endothelial nitric oxidesynthase.34 Steroids likely have a role inmyocardial recovery. Trials with steroidsusually have low numbers; however, meta-analysis of these trials is favourable.35

Preventive data exist in the populationof COPD patients who take inhaled andoral steroids. These individuals appearedto be protected.36 Trials performed in the

reperfusion era need to be separatedfrom those performed prior to reperfu-sion to determine if the adverse healingin myocardial infarction may be offsetby increased regeneration.

ANTIPLATELETS: ASPIRIN, CLOPIDIGRIL,INTRAVENOUS IIB IIIA INHIBITORSThese agents have been accepted into thetreatment of acute coronary syndromesbecause of their antithrombotic proper-ties. The first of these drugs, aspirin,was invented by Felix Hoffman in 1897to relieve his father ’s arthritis pain. Theanti-inflammatory mechanisms of thesedrugs are complex. They include anti-platelet effects, which modify the reactionof leucocytes, monocytes and endothe-lium. Inflammatory mediators such asP-selectin, CD40L, NF-kB, CRP, platelet-activating factor, platelet factor 4,thrombospondin and platelet-derivedgrowth factor are produced by plateletsand have a profound affect upon inflam-mation.37 Both aspirin and Clopidigril38 39

have had clinical benefits when adminis-tered to high-risk patients who have beenstratified by inflammatory markers suchas HS-CRP. Bare metal stents require dualplatelet therapy for at least 1 month tolessen the thrombogenic potential untilnormal endothelium covers the metalstruts. However, these patients still derivebenefit from this therapy a year later,far longer than their risk of thrombosisfrom the stent. Therefore, the platelet istargeted as a therapeutic goal for bothantithrombosis and anti-inflammation.

HEPARINHeparin has long been established as anantithrombotic and has been used inmyocardial infarction and acute coronarysyndromes for over 50 years. It also hasanti-inflammatory properties by blockingadhesion receptors of P-selectin and

Figure 8 Anterior and inferior injury.

Figure 9 Anterior injury.

Figure 10 Graph of troponin.

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L-selectin.40 By accomplishing this task,leucocyte movement into tissues isblocked with a reduction in inflammation.

WAFARINThe anticoagulant warfarin acts onvitamin k to reduce coagulation factors. Ithas been shown in rat inflammationmodels that warfarin decreased inflamma-tion. One mechanism is inhibition of signaltransduction.41 Another method demon-strated that the by-products of coagulationsuch as the D-dimer were proinflammatory.In a study of patients with atrial fibrilla-tion, they were able to show a reduction inD-dimer and subsequent reduction in CRPand IL-6.42

ACE-INHIBITORS, ANGIOTENSINRECEPTOR BLOCKERS AND b blockersBy inhibiting the effects of angiotensin II,ACE-inhibitors and angiotensin receptorblockers mediate inflammation. Angio-tensin II is proinflammatory and exertsthose effects through an NF-kB dependentpathway. During drug therapy, Hs-CRP,IL-6 and TNF-a have been shown tobe reduced. Both b blockers and ACE-inhibitors exert effects through prosta-glandin-dependent vasodilation and haveanti-inflammatory affects through thispathway.43

STATINSThe JUPITER trial has reinforced theimportance of reducing inflammation toprevent primary events.19 Statins weredeveloped to lower cholesterol but theirinteraction with the endothelium hasgiven them pleotrophic properties whichinclude a reduction in inflammation,improvement in endothelial function andan improvement in repair by increasingcirculating progenitor cells. The benefitsof statin have been seen in reducingoperative risk, survival of systemicinflammation from sepsis, bone fracture,and have a very early affect on reducingmorbidity from myocardial infarctionand angioplasty.43e46 The mechanism ofanti-inflammation includes a reduction ofadherence molecules, and thus therecruitment of mononuclear cells into thevessel walls. Cytokines and proteinsinvolved in inflammation are alsoreduced, and these include the COX-2.

HYPOTHERMIAHypothermia was not utilised in this casebut is included as an inflammatorytherapy. Cooling the body after ventric-ular fibrillation cardiac arrest has survival

benefit, improved central nervous systemfunction and improved cardiac function.Cooling the body slows chemical reactionand in particular slows the inflammatoryresponse associated with apoptosis.47

EXERCISE/CARDIAC REHABILITATIONExercise continues to be underutiliseddespite multiple studies proving goodoutcomes. Heberden in 1772 firstdescribed the exercise of sawing wood asa benefit in the control of angina, whichhe also described. Exercise lowers Hs-CRP,increases circulating stem cells, improvesendothelial function and has additionalbenefits in improving lipid profile, bloodpressure, diabetes and obesity. There is nopopulation that has not demonstratedbenefit from exercise. The improvement inall of these areas is difficult to determine,since the benefits cross many risk factors.The probable common pathway is theincrease in progenitor cells that will affectthe other risk factors.

CONCLUSIONThe lack of a textbook diagnosis in thepresented case allows speculation as tothe aetiology and the response totherapy. The patient’s given diagnosiswas coronary vasculitis secondary toimmunological sensitisation during thepregnancy. The only clinical identifiedmanifestation of vasculitis was found inthe coronary tree. The mesenteric vesselswere also possibly involved due to thesymptoms of abdominal angina. Coro-nary spasm was an early consideration inthis patient. She did not respond tonitrate therapy, and her clinical coursewas not consistent with coronary spasm.Using the presumed diagnosis of animmunological reaction to the coronaryvessels, multiple therapies for vasculitiswere initiated. The clinical responseincluded improvement in the electrocar-diogram, echocardiogram and coronariesdemonstrated by 6-month imaging of thecoronary arteries by CT angiography.Acute myocardial infarction has many ofthe same features with both isolatedand multiple localised areas of inflam-mation that eventually leads to an acuteevent.48 49 After the infarction, thenecrotic myocardium also becomesinflammatory and impedes healing. Newtherapies that attempt to regenerate theheart with progenitor cells will need todeal with those barriers to healing. Plas-maphaeresis, in this case, is unique inthe treatment of myocardial infarction.Instead of adding things to the patient toprevent further thrombosis, inflamma-

tion and clotting factors are removed.This technique of removing inflamma-tory milieu from the body may be thenecessary step to allow regeneration ofthe damaged organ. Successful therapiesof myocardial infarction (ASA, heparin,wafarin, antiplatelets, plavix, b blockers,ACE inhibitors, hypothermia and cardiacrehabilitation) are all anti-inflammatorytherapies. This case suggests thata more robust study of inflammation inaetiology and recovery of myocardialinfarction should be studied as intenselyas antithrombotics.50e52

Competing interests None.

Patient consent Obtained.

Provenance and peer review Not commissioned;externally peer reviewed.

Heart Asia 2010:82e88.doi:10.1136/ha.2009.001545

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