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Assessment and Key Targets for Therapy in the Post-MyocardialInfarction Patient with Left Ventricular Dysfunction

James D. Flaherty, MD,a,* James E. Udelson, MD,b Mihai Gheorghiade, MD,a

Edwin Wu, MD,a and Charles J. Davidson, MDa

In the post-myocardial infarction (MI) patient with coronary artery disease (CAD)and left ventricular dysfunction (LVD), ischemia and adverse remodeling hindermyocardial performance and increase electrical instability. Collectively, the coronaryarteries, myocardium, and conduction system represent the principal pathophysio-logic targets in MI complicated by LVD. Consequently, an accurate assessment ofdisease severity in these targets is essential for the design of an effective therapeuticprogram. This review describes the current modalities for assessing the key patho-physiologic targets in post-MI patients with LVD and the effects of systemic factorson cardiac disease severity. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol

2008;102[suppl]:5G–12G)

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oronary atherosclerosis is the principal cause of isch-mic heart disease, producing atherosclerotic lesions thatevelop over several decades and can ultimately precip-tate myocardial infarction (MI). As coronary artery dis-ase (CAD) progresses, plaque formation can assumelinical significance, especially in lesions that are rich inipids. Although plaques can evolve into stenotic lesionsith a hard fibrous composition, they can also be “vul-erable” without necessarily being obstructive but with aigher likelihood of rupture. When lesions do rupture, thebrupt change in morphology that occurs can lead tohrombus formation and the development of acute isch-mic syndromes, including unstable angina and MI.1

ssessing Coronary Artery Disease

oronary angiography remains the “gold standard” tech-ique for assessing the presence, extent, and severity ofAD and for determining appropriate therapy. Currentmerican College of Cardiology/American Heart Associa-

ion (ACC/AHA) guidelines strongly recommend (class 1)hat coronary angiography be performed in patients withuspected CAD, including post-MI patients who are candi-ates for primary or rescue percutaneous coronary interven-ion.2 Likewise, early angiography with the goal of revas-

aDivision of Cardiology, Department of Medicine, Feinberg School ofedicine, Northwestern University, Chicago, Illinois, USA; and bDivision

f Cardiology, Department of Medicine, Tufts-New England Medical Cen-er, Boston, Massachusetts, USA.

Statement of author disclosure: Please see the Author Disclosuresection at the end of this article.

*Address for reprints: James D. Flaherty, MD, Division of Cardiology,epartment of Medicine, Feinberg School of Medicine, Northwesternniversity, 251 East Huron Street, Galter 8-130, Chicago, Illinois 60611.

cE-mail address: j-flaherty2@md.northwestern.edu.

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.06.005

ularization is also strongly recommended (class 1) inatients with unstable angina/non-ST-segment elevation MInon-STEMI) and any high-risk features, including elevatedardiac biomarkers, ST-segment depression, a reduced leftentricular ejection fraction (LVEF), or signs of heart fail-re (HF).3 Angiography can also identify candidates forevascularization among patients with post-MI left ventric-lar dysfunction (LVD) who present late or have had clin-cally “silent” MI. The technique is especially useful inatients with ongoing angina, ischemia, or HF. Angiogra-hy may also be necessary to identify obvious bypass sur-ery candidates, such as those with LVD and significant leftain CAD.Multislice spiral computed tomographic angiography is a

romising noninvasive imaging modality for the assessmentf CAD. Although it is not as accurate as angiography forharacterizing CAD, partly because of the rapid motion ofhe beating heart and the small dimensions of the coronaryrteries, it could prove to be a useful method for ruling outoronary stenoses in low-risk patients reporting possibleymptoms of ischemia.4

yocardium: Assessing Left Ventricular Dysfunction

eft ventricular function has long been recognized as aajor predictor of both short- and long-term survival afterI. Although LVEF has been the most frequently usedeasure of left ventricular function and a higher LVEF is

ssociated with increased survival, it is not the only factorhat predicts mortality in the post-MI patient with LVD.his was demonstrated in the Oregon Sudden Unex-ected Death Study, where an LVEF of �0.35 was ob-erved in only 30% of cases of sudden cardiac deathSCD) in which left ventricular function had been as-essed within the preceding 2 years.5 This seeming dis-

repancy might exist because although LVEF is primarily

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measure of chronic risk associated with the burden ofyocardial scar, there are a number of transient func-

ional disturbances and electrophysiologic events that canrecipitate a fatal arrhythmia without a lowered LVEF.onditions such as transient ischemia and reperfusion,lectrolyte disturbances, and autonomic fluctuationsould not be detected by an LVEF assessment, but they

ould precede a fatal arrhythmia.6

Several indices have been proposed as alternatives toVEF for predicting risk of SCD in patients with CAD,

ncluding end-systolic volume (ESV) and end-diastolicolume (EDV).7 White and colleagues7 measured ESV,DV, and LVEF 1–2 months post MI in 605 patients,ho were then observed for a mean duration of 78onths. A statistical analysis revealed that ESV was of

reater value for predicting survival than EDV or LVEF.ecause ESV is essentially a measure of left ventricularilation, the investigators concluded that ventricular re-odeling is the major identifiable risk factor for cardiac

eath after MI.7

Many recent trials have addressed the issue of assessinghe prognostic power of different indices of left ventricularunction by studying post-MI patients who have undergoneeperfusion. The Global Utilization of Streptokinase andissue Plasminogen Activator for Occluded Coronary Ar-

eries (GUSTO) angiographic investigators assessed leftentricular function 90 minutes after thrombolysis in pa-ients with acute MI. They found that multiple markers ofeft ventricular function, including LVEF, ESV, and re-ional wall motion, were predictive of 30-day post-MI sur-ival (Figure 1).8 Meanwhile, Bolognese and colleagues9

eported that remodeling assessed by left ventricular dila-ion (�20% increase in EDV) was a good predictor of

igure 1. Indices of left ventricular function 90 minutes after thrombolysin patients who died before 30 days after an acute MI (p � 0.001). ESVI �ith permission from N Engl J Med.8)

-year cardiac mortality in patients with MI who were o

reated with primary percutaneous transluminal coronaryngioplasty (Figure 2).

Ongoing ischemia after MI can be an important thera-eutic target. Recently, it was demonstrated that post-MIatients with silent ischemia randomized to balloon-onlyercutaneous coronary intervention had markedly reducedardiac events and a higher average LVEF through 10 years

ients who survived 30 days after an acute myocardial infarction (MI) andstolic volume index; LVEF � left ventricular ejection fraction. (Reprinted

igure 2. Kaplan-Meier survival curves for cardiac death in patients withnd without left ventricular remodeling at 6 months after primary percu-aneous coronary intervention for acute myocardial infarction (p � 0.005).Reprinted with permission from Circulation.9)

s in patend-sy

f follow-up versus medical management alone.10 In

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7GFlaherty et al/Assessment and Key Targets for Therapy in the Post-MI Patient with LV Dysfunction

ost-MI patients without ongoing ischemia, myocardial vi-bility may be an important therapeutic target. Because leftentricular function can improve significantly in patients withdysfunctional but viable myocardium who undergo coronary

evascularization, viability testing offers a means for predictinghe reversibility of LVD. Viable but dysfunctional myocar-ium may either be “hibernating” or “stunned,” with theormer representing myocardium that has adapted to a chronictate of underperfusion and the latter an adequately perfusedyocardium that is dysfunctional because of active ischemia.11

In a meta-analysis of 24 published studies, Allman et al12

ssessed late survival after revascularization or medicalherapy in patients with CAD and LVD who underwentyocardial viability testing. In patients with myocardial

iability, annual mortality was significantly lower in pa-ients treated with revascularization than it was in the groupeceiving medical treatment alone. In contrast, among pa-ients without myocardial viability, there were no significantifferences in mortality rates between those undergoingevascularization and those receiving medical therapy aloneFigure 3).12

A recent retrospective observational study examined ap-roximately 4,000 patients with HF and CAD, most ofhom (78.2%) had LVD. Patients who underwent revascu-

arization had substantially reduced mortality at 1 year11.8% vs 21.6%; hazard ratio, 0.52; 95% confidence inter-al, 0.47–0.58), which was maintained through 7 years ofollow-up.13

A number of noninvasive imaging methods are used todentify viable myocardium in patients with LVD. Positronmission tomography imaging uses enhanced 18F-fluorode-xyglucose uptake relative to myocardial blood flow as aarker for myocardial viability. Thallium-201 single-pho-

on emission computed tomography imaging assesses mem-rane integrity and myocardial perfusion by measuring up-ake several hours after radioisotope administration. A thirdethod, low-dose dobutamine echocardiography, detects

iability by measuring myocardial contractile reserve dur-ng inotropic stimulation.11

The techniques used to assess myocardial viability caniffer in their accuracy for predicting improvement afterevascularization (Figure 4). Although the combined resultsf 34 studies involving 926 patients showed that positronmission tomography and dobutamine echocardiographyisplayed similar accuracy for predicting improvement inegional left ventricular function after revascularization,hallium single-photon emission computed tomography im-ging showed a lower positive predictive value than thether 2 methods. It did, however, demonstrate a betteregative predictive value.11

A newer method of identifying regions of viable myo-ardium after MI involves the use of contrast-enhancedardiac magnetic resonance imaging (CMR). In animaltudies, hyperenhancement on CMR was found to coincideith both the extent of myocyte necrosis developing days

fter injury and with the extent of scar tissue measured t

eeks later.14 In human studies, the signal intensity ofyperenhanced regions, which correspond to infarcted ar-as, was much higher than it was for normal myocardium,ndicating that CMR can accurately differentiate betweenormal and injured regions of myocardium.15

Kim et al16 used CMR to identify reversible myocardialysfunction before revascularization. Among dysfunctionalyocardial segments, the likelihood of improvement in

egional contractility after revascularization was signifi-antly and inversely related to the transmural extent ofyperenhancement. In addition, the percentage of the leftentricle that was dysfunctional but viable before revascu-arization was strongly correlated with the degree of im-rovement in the global wall motion score and LVEF afterevascularization.16 In a subsequent study, the same groupound a strong correlation between infarct transmurality ataseline, as measured by CMR, and improvement in con-ractile function at 8–12 weeks in post-MI patients whonderwent successful revascularization.17

�-Blockers are known to improve left ventricular func-ion and reduce morbidity and mortality in post-MI patientsith LVD and HF. However, some patients do not respondell to such therapy, which suggests that they have lessiable myocardium. Evidence supporting this hypothesisas obtained in a study using CMR to visualize regions ofyocardial scarring and viability in patients with HF re-

eiving �-blocker therapy. The transmural extent of scar-ing was found to be inversely related to improvement inontractility after 6 months of �-blocker therapy.18

Another predictor of outcome is the degree of microvas-ular obstruction after MI. Obstruction of the microcircula-ion has been associated with both poor recovery of globalnd regional left ventricular function soon after successfuleperfusion19 and with a higher risk for developing HF.20

u et al21 used CMR to visualize regions of significanticrovascular obstruction at the infarct core in patients afterI. After an average follow-up of 16 months, the presence

f microvascular obstruction was found to be predictive oferious cardiovascular complications. Even with the infarctize controlled, the presence of microvascular obstructionemained a prognostic indicator of post-MI complications.21

lectrical Markers of Arrhythmic Risk

ost-MI patients with LVD are at an increased risk of SCD,sually from ventricular tachyarrhythmias. Because electri-al instability is a precursor to fatal arrhythmia, identifyingndices of myocardial electrical activity might help to pre-ict SCD risk.

A number of measures have been theorized to haverognostic value for identifying patients at high risk forCD, especially in the first year after MI. Among sucheasures is the occurrence of ambient arrhythmias, such as

requent premature depolarizations22 and nonsustained ven-

ricular tachycardia.23,24 Although early studies suggested

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8G The American Journal of Cardiology (www.AJConline.org) Vol 102 (5A) September 8, 2008

n association with SCD, a survival benefit has not beenemonstrated for suppression of such arrhythmias.25 In con-rast, spontaneous nonsustained ventricular tachycardia and

igure 3. Annual mortality rates for patients with coronary artery diseaseedical treatment and myocardial viability. (Reprinted with permission fr

igure 4. Predictive value of myocardial viability assessment tools for improABG � coronary artery bypass graft surgery; Echo � echocardiography;mission tomography; PTCA � percutaneous transluminal coronary angioermission from Circulation.11)

low LVEF have been shown to be important predictors of l

mproved survival in post-MI patients with LVD who haveeceived an implantable cardioverter defibrillator (ICD).23

Standard electrocardiographic measures, such as the

t ventricular dysfunction stratified by coronary revascularization (revasc.)m Coll Cardiol.12)

t in regional left ventricular (LV) function after coronary revascularization.18F-fluorodeoxyglucose; MBF � myocardial blood flow; PET � positron

SPECT � single-photon emission computed tomography. (Reprinted with

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9GFlaherty et al/Assessment and Key Targets for Therapy in the Post-MI Patient with LV Dysfunction

osed as markers of arrhythmic risk in post-MI patients. Aonger QRS interval duration on initial electrocardiographyefore reperfusion therapy was associated with an increasen 30-day mortality in patients with MI who were treatedith thrombolysis.26 Similarly, a longer QRS duration ob-

erved on discharge electrocardiography was reported to beredictive of worse 4-year survival after a first MI.27 How-ver, in a study of patients receiving an ICD, QRS durationid not correlate with the occurrence of ventricular arrhyth-ias over a 12-month follow-up period.28 For post-MI pa-

ients who go on to develop symptomatic HF, a prolongedRS duration is an indicator of ventricular dyssynchrony,hich is predictive of a therapeutic response to cardiac

esynchronization therapy.29

Other markers of electrical instability predict fatal arrhyth-ias with varying degrees of success. These include QT dis-

ersion,30–33 microvolt T-wave alternans,34–36 and signal-veraged electrocardiography for detecting microvolt levelignals in the terminal QRS complex.37–39

ystemic Factors Affecting Pathophysiologic Targets

lthough the structural and proarrhythmic consequences of

igure 5. Algorithm for assessing patients with ST-segment elevation myocho � echocardiography; EF � left ventricular ejection fraction. *Higlectrical instability. †Significant ischemia includes moderate-to-severe strereadmill score. (Reprinted with permission from J Am Coll Cardiol.2)

schemia are most important in determining the prognosis in t

ost-MI patients, systemic factors play a significant role, asell. Among these is the neurohormonal activation thatccurs in patients with LVD after MI and several comorbidonditions.

Neurohormonal activation: A complex set of maladap-ive neurohormonal changes occurs in the post-MI patientith LVD. These include activation of the sympatheticervous system (SNS) and the renin-angiotensin-aldoste-one system (RAAS). Neurohormonal activation can causelectrical instability, increasing the risk of ventricular ar-hythmia, and it can induce ventricular remodeling, leadingo a worsening of LVD and the development of HF.

In LVD, a baroreceptor-mediated increase in SNSctivity has a number of consequences, including tachy-ardia, arterial vasoconstriction, and venoconstriction.40

he increased regional and circulating concentrations oforepinephrine that accompany SNS activation can beoxic to cardiac myocytes, an effect that can be reversedy �-blockade.40,41

Another important effect of increased SNS activity isAAS activation.40 The adverse effects of angiotensin make

uppression of its activity an important component of post-MIreatment. Angiotensin II is a potent peripheral vasoconstrictor

infarction (STEMI). Cath � catheterization; ECG � electrocardiography;features include cardiogenic shock and persistent hemodynamic and/orced myocardial perfusion or wall motion abnormalities and/or a high-risk

cardialh-riskss-indu

hat can induce ventricular hypertrophy.42,43 Angiotensin II

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lso stimulates secretion of aldosterone, which causes sodiumetention, further contributing to the development of ventricu-ar hypertrophy.43

Comorbidities: Among comorbid conditions, type 2iabetes mellitus causes significant metabolic, hemody-amic, and neurohormonal changes, which collectivelyncrease cardiovascular risk in the post-MI patient. Insu-in resistance plays a central role through its impact onultiple regulatory pathways. The compensatory hyper-

nsulinemia associated with insulin resistance raiseslood pressure by increasing SNS activity. It also acti-ates RAAS, causing an increase in angiotensin levels.he use of a glucose-insulin infusion followed by anxtended course of subcutaneous insulin has been showno improve long-term survival in patients with diabetesresenting with an acute MI.44

Hyperinsulinemia has also been shown to decrease ad-enal medullary activity, an effect that appears to contributeo dyslipidemia, which is characterized by decreased levelsf high-density lipoprotein and increased levels of triglyc-rides.45–47 Dyslipidemia contributes to CAD progressionnd increases the risk of future coronary events. For exam-le, in men with cardiovascular disease and high total cho-esterol, the risk of death from cardiovascular disease isuch higher than for similarly affected men with normal

erum cholesterol levels.48 A study of middle-aged men,hich was a follow-up to the Primary Prevention Study inöteborg, Sweden, found that 76% of healthy men with low

holesterol and 65% of healthy men with high cholesterolere still alive 16 years after enrollment. By contrast,

mong men with prior MI, 50% of those with low choles-erol were still alive compared with only 21% of those withigh cholesterol.49

Preexisting hypertension in patients with MI is anotheromorbid condition that can negatively affect patientrognoses. Richards et al50 compared patients with MIho had antecedent hypertension with those who did not.lasma neurohormones, which included norepinephrinend the cardiac natriuretic peptides, were significantlyigher in the hypertensive group than in the normotensiveroup days after MI, and these increases were still ap-arent several months later. Patients with hypertensionad larger left ventricular systolic and diastolic volumesnd a lower average LVEF compared with patients whoere normotensive. Finally, the rate of postdischargeortality and the risk of subsequent HF were higher in

atients with hypertension.50

orkup and Management Goals in theost-MI Patient

n algorithm for appropriate workup of the patient withTEMI is presented in Figure 5. A similar scheme can be

sed for a patient with non-STEMI, although there may not t

e the same urgency to achieve immediate reperfusion.etermining the LVEF is crucial to the early assignment of

isk, but information beyond LVEF is also essential forurther elaborating mortality risk and deciding on a thera-eutic strategy. Angiography, electrocardiography, echocar-iography, exercise testing, and viability imaging all maylay a role in a comprehensive assessment.

There are 4 principal goals for management of theost-MI patient with LVD, each associated with �1 thera-eutic options (Table 1). The particular treatment prescribedor an individual patient should be guided by an assessmentf the key pathophysiologic targets: the coronary arteries,he myocardium, and the conduction system.

onclusion

ollectively, the coronary arteries, myocardium and con-uction system represent the principal pathophysiologicalargets in MI complicated by LVD. Systemic factors, suchs neurohormonal activation and comorbid conditions, alsompact prognosis and therapies. An accurate assessment ofisease severity in these targets is essential for the design oftherapeutic program. The therapeutic options available for

reatment of the post-MI patient with LVD are the subject ofubsequent articles in this series.51–54

uthor Disclosures

he authors who contributed to this article have disclosed

able 1oals in the management of post-myocardial infarction with leftentricular dysfunction and recommended therapies

oal Therapy

mprove symptoms Therapies aimed at ischemia and/orcongestion

revent future coronary events(CAD progression)

StatinsAntiplatelet agentsACEIs/ARBsCoronary revascularization (PCI or

CABG)ttenuate progressive pathologicLV remodeling

ACEIs/ARBs�-blockersAldosterone antagonistsCRT

rolong survival by preventingSCD or progression of HF

�-blockersICDCRTLVAD

CEIs � angiotensin-converting enzyme inhibitors; ARBs � angiotensineceptor blockers; CABG � coronary artery bypass graft; CAD � coro-ary artery disease; CRT � cardiac resynchronization therapy; HF � heartailure; ICD � implantable cardioverter defibrillator; LV � left ventricu-ar; LVAD � left ventricular assist device; PCI � percutaneous coronaryntervention; SCD � sudden cardiac death.

he following industry relationships.

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11GFlaherty et al/Assessment and Key Targets for Therapy in the Post-MI Patient with LV Dysfunction

James D. Flaherty, MD, has no financial relationshipso disclose.

James E. Udelson, MD, has served as a member of thedvisory committee for GlaxoSmithKline and Otsuka, re-eived grant/research support from GlaxoSmithKline andolecular Insight, and served as a member of the Speakers’ureau for GlaxoSmithKline.

Mihai Gheorghiade, MD, has served as a member ofhe advisory committee for GlaxoSmithKline, Medtronic,tsuka, PDL, and Sigma Tau.Edwin Wu, MD, has received grant/research support

rom Mallinckrodt.Charles J. Davidson, MD, has served as a member of

he advisory committee for Boston Scientific and GEealthcare; received grant/research support from Abbott,ordis, and GE Healthcare; and served as a member of the

peakers’ bureau for GE Healthcare.

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