Role of Apoptosis inAdverse VentricularRemodeling

Antonio Abbate, MD, PhD, FESCa,*,Jagat Narula, MD, PhD, FRCP(Edin)b

KEYWORDS

� Apoptosis � Heart failure � Ventricular remodeling� Caspase

Heart failure is a progressive disease. Thesubstrate for symptomatic heart failure may existlong before the symptoms occur. Stage B heartfailure refers to a condition in which the heart isstructurally abnormal (such as after an acutemyocardial infarction [AMI]), yet the clinical symp-toms and signs of heart failure may not bepresent.1,2 Unlike stage B, stage A refers to clinicalconditions that predispose to heart failure but inwhich the heart is considered to be structurallynormal. In stage C, structural heart disease isassociated with symptoms of heart failure, andthe disease is progressed to a point in which heartfailure is considered refractory to conventionalmedical therapy in stage D. The classification ofheart failure in stages A to D reflects very wellthe progressive nature of the disease.1 Theprogressive changes in cardiac structure andfunction are referred to as adverse cardiac remod-eling, a process in which heart chamber dilatationand wall thinning occur in association with systolicand diastolic dysfunction.1,2

Stage B heart failure therefore represents a tran-sition between normal heart function and lack ofsymptoms (stage A) and abnormal heart struc-ture/function and presence of heart failure symp-toms (stage C). Independent of the etiologycausing stage B heart failure, cardiac remodelingis characterized by changes in the size andnumber of cardiomyocytes; more specifically, incell death (apoptosis) and hypertrophy of surviving

a VCU Pauley Heart Center, Virginia Commonwealth UnRichmond, VA, 23298, USAb Cardiovascular Imaging Program, Zena and Michael AHenry R. Kravis Center for Cardiovascular Health, Mount* Corresponding author.E-mail address: abbatea@yahoo.com

Heart Failure Clin 8 (2012) 79–86doi:10.1016/j.hfc.2011.08.0101551-7136/12/$ – see front matter � 2012 Elsevier Inc. All

cells (compensatory hypertrophy), as well as inqualitative changes in the type of cells, witha progressive increase in fibroblasts andmyofibro-blasts and an increase in extracellular matrix.3 Inthis article, the authors review the role of apoptosis(or programmed cell death) in determining theevolution of symptomatic heart failure and particu-larly the adverse remodeling in the aftermathof AMI.

Myocardial dysfunction in the border zoneextends to involve contiguous normal myocardiumleading to a dilated cardiomyopathy in the weeksfollowing AMI.3–6 The border zone remodels asa small area circumferential to the infarct that isnormally perfused but displays abnormal contrac-tility and leads to increased circumferential stressand further involvement of adjacent normallycontractile myocardial areas. The events occurringin the border zone are histopathologicallycharacterized by patchy interstitial fibrosis andmyofibrillarlytic or myocytolytic (vacuolized) cardi-omyocytes, reflective of autophagy. The increasedwall stress indeed alters the myocardium atbiochemical and molecular levels that ultimatelylead to loss of previously functional myocardiumby nonischemic cell loss predominantly by theprocess of apoptosis (Fig. 1). The extent of remod-eled myocardium is variable among patients and,in severe cases, may produce a gradually expand-ing dysfunction out of proportion to the initialischemic insult.6

iversity, VCU Medical Center, 1200 East Broad Street,

. Wiener Cardiovascular Institute, Marie-Josee andSinai School of Medicine, New York, NY, USA

rights reserved. heartfailure.th

eclinics.com

Fig. 1. (A) Geometrical changes in the infarct zone (red), the border zone (blue), and remote myocardium (green)over 8 weeks after AMI. (B, C) Changes in perfusion, contraction, and expansion (vs baseline) in the infarct area,border zone, and remote myocardium 8 weeks after experimental AMI in sheep. After AMI, the border zonebecomes dysfunctional despite normal perfusion and expands parallel to the infarct area, extending to involvealso the previously normocontracting myocardium. (Data from Jackson BM, Gorman JH, Moainie SL,et al. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Coll Cardiol2002;40:1160–7.)

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BIOCHEMICAL AND MOLECULARALTERATIONS OF THE REMODELEDMYOCARDIUM

Numerous studies have focused on the remodeledmyocardium in the border zone after AMI. The initialobservations from lightmicroscopydescribed find-ings of patchy interstitial fibrosis and cardiomyo-cytes filled with cytoplasmic vacuoles, and theseverity of fibrosis and vacuolization predictedthe severity of the cardiomyopathy.6,7 The vacuol-ized cardiomyocytes have been described as de-generated, myofibrillarlytic, or cytolytic and wereconsidered a prelude to cell death.6–9 The vacuoleswere further characterized by autophagosomes.Autophagy (self-eating) is now considered a cellsurvival program, a highly regulated process bywhich the cell uses cytoplasmic structures, whichmay be injured during stress, to provide fuel forthe energy demand of the cell and substrates forcell repair andalso allows for compartmentalizationof injured mitochondria, which would otherwise

have promoted cell death (mitophagy).10 Myofibril-larlyticmyocytes are therefore also called autopha-gic. Formation of autophagosomes and fusionwith lysosomes is a physiologic process that isexaggerated in the remodeled myocardium.The formation of autophagosomes is, however,random, whereas, in response to cell injury, ubiqui-nation occurs as the initial step wherein stressedor abnormal proteins are bound to ubiquitinand destined to degradation in the proteasomes.Although autophagy is generally protective, exces-sive proteolysis and excessive storage of ubiquiti-nated protein complexes lead to impaired cellularfunctions, primarily impaired contractility.11 Furtherprogression of cytolysis leads to blockade ofprotein synthesis and leads to the inability to savethe injured cell, at which point cell death isinevitable via a unique form of autophagic celldeath (or ubiquitin-related autophagic death).11

Numerous studies have shown that ubiquitin-containing vacuolization and cell death arecommon in the border zones of recent infarcts.11,12

Role of Apoptosis in Adverse Ventricular Remodeling 81

CASPASE 3: THE LINK BETWEENDEGENERATION AND CELL DEATH

The mechanisms by which the functional proteo-lytic process in the injured cell fails leading to path-ologic proteolysis and death are not completelyunderstood. Caspase 3 has been consistentlyshown to be upregulated and activated in theremodeled myocardium.12–16 Caspase 3 is anexecutor cysteine protease primarily involved inapoptotic cell death. Caspase 3 on one hand hasbeen also shown to inhibit the proteasome leadingto intracellular accumulation of ubiquitin conju-gates, and, on the other hand, it induces cleavageof troponin I and other proteins in the sarcomere,leading to loss of the functional contractile appa-ratus. Caspase 3 is thought to mediate ischemicmyocardial stunning.16,17

Activation of caspase 3 occurs through 2distinct but not mutually exclusive pathways:caspase 8–mediated death receptor–dependentpathway and caspase 9–mediated mitochondrialpathway.3 Although both pathways are activatedin the remodeled myocardium, activation of themitochondrial pathway seems to be predominant.Stressed cardiomyocytes consistently showelevated bax/bcl-2 ratios, known to regulate mito-chondrial membrane permeability and decreasedlevels of mitochondrial cytochrome c, whichimpairs energy production, with consequentlyincreased levels of cytoplasmic cytochrome cleading to activation of caspase 9. Caspase 9 acti-vates caspase 3, which initiates the death programand ultimately leads to DNA fragmentation andcell condensation. The presence of activated cas-pase 3, DNA fragmentation, and cell condensationdefines apoptosis (or apoptotic cell death) anddifferentiates it from other modalities of cell death,although overlap forms often occur.18

APOPTOSIS

Initially described in embryonic development andcancer, apoptosis has been rapidly found tohave broad implications for tissue kinetics inhealth and disease.18,19

The interest in cardiac apoptosis is rather recentdating to the mid-1990s when the initial studiesshowed an increased rate of apoptosis in thehearts explanted from patients undergoing hearttransplantation for end-stage heart failure.13 Theidentification of a signaling cascade leading tocell death allows the definition of the molecularmechanisms and novel therapeutic strategies.

Transition toward stage C heart failure is charac-terized by a progressive decline in the number ofcardiomyocytes in the heart,20 later identified as

cell death due to apoptosis.21 Being an organwith low proliferation and turnover, if any,apoptosis was considered not to occur in the so-called postmitotic organs such as the heart.This assumption was not entirely appropriate.The initial studies of apoptosis in heart failurewere substantially validated, and the conceptthat cell loss (by apoptosis) occurred in theheart, increases with age, and contributed tothe development of cardiomyopathy becamecommonplace.

The observations in advanced heart failure,however, did not allow determining whetherapoptosis was a consequence of heart failure orits cause. Subsequent studies showed thatapoptosis occurs in many, if not all, stage B heartfailure conditions that are prone to the develop-ment of heart failure, suggesting a causative roleof apoptosis.3,22–29 The cause-effect link wasfurther validated by the use of experimentalmodels in which the rate of apoptosis could bemodulated.24

In the border zone of recent infarcts (remodeledmyocardium), cardiomyocytes seem to be highlysusceptible to proapoptotic insults and henceprone to apoptosis. Numerous studies have re-ported a marked increase in the rate of apoptosisin the border zone (by several folds) for severaldays to weeks after AMI and a gradual increasein apoptosis in the remote myocardium in the leftand right ventricles.14,25–27 The rate of apoptosisin the heart during the healing phases of AMIseems to be predictive of the severity of theadverse remodeling and the occurrence of heartfailure. The greater the apoptosis in the borderzone or in the remote myocardium, the worse theremodeling in both human and animal experi-mental studies.3

Although postmortem studies are not probativeof a causal relationship, several studies have asso-ciated increased apoptosis with a pattern of moreadverse cardiac remodeling progressing fromuncomplicated AMI or compensated concentrichypertrophy to eccentric hypertrophy and toend-stage stages characterized by marked dilata-tion and thin walls.25 In the most severe formsof adverse remodeling after AMI, dilatation ofthe right ventricle is also present (biventricularremodeling).27,28

The presence of a patent infarct-related arteryindicating reperfusion is associated with a morefavorable remodeling pattern and reducedapoptosis.29 Neurohormonal blockers that preventadverse remodeling, such as angiotensin-converting enzyme inhibitors and b-adrenergicblockers, also inhibit apoptosis after AMI.3 Genet-ically modified animal models prone to apoptosis

Abbate & Narula82

were shown to be prone also to heart failureand death, whereas animal models resistant toapoptosis were protected.3

Similar to ischemic cardiomyopathy, othercardiomyopathies, such as chronic pressure over-load, volume overload, doxorubicin induced, andothers, are also characterized by increased rateof apoptosis contributing to the transition betweenthe compensated and decompensated stages ofthe disease.

APOPTOSIS INTERRUPTUS AND REMODELEDMYOCARDIUM

The release of cytochrome c and activation of cas-pase 3 lead to increased incidence of apoptosisand progressive loss of cellular componentsand gradual increase in interstitial fibrosis. Manystudies show that the degree of cell death byapoptosis or autophagic cell death and the degreeof fibrosis predict the lack of functional recoveryof hibernating myocardium after revasculariza-tion.30–33 Activation of caspase 3, however, doesnot necessarily equate to cell death.34,35 Thefinding of caspase 3 activation in cardiomyocytesis far more common than the finding of apoptoticcell death, and the presence of activated caspase3 does not impede complete functional recovery ofhibernating myocardium after revascularization.11

Fig. 2. In heart failure, the myocardium expresses proapopbetween death and survival. Apoptosis interruptus referapoptotic phenotype. Caspase 3 activation occurs in the aations secondary to caspase 3 activation lead to exposure

Such findings led to the concept of apoptosisinterruptus.36 This expression relates to theevidence of activation of the apoptotic cascade(namely caspase 3) in the absence of trueapoptotic phenotype35,36 and suggests that acti-vation of the cascade does not necessarilyaccomplish cell death but denotes a relativelylarge area of myocardium at jeopardy in a fragilebalance (Fig. 2).35,36 This concept goes hand inhand with the concept of programmed cellsurvival. The injured or stressed cell responds bysimultaneously activating a death pathway anda repair pathway; the balance or unbalance ofthese 2 pathways determines the outcome of thecell. Mitochondrial apoptosis pathways and theunfolded protein response are involved in thissurvival balance (see Fig. 2). Parallel to partial acti-vation of inducer of apoptosis, such as bid andcaspase 8, and the release of cytochrome c frommitochondria, caspase 9 and caspase 3 are alsocleaved in heart failure, yet concomitant increasein inhibitors of apoptosis, such as XIAP, subduethe activation of caspase 3.35 Survivin, an essen-tial cellular antiapoptotic mechanism in controlof the upstream initiation of mitochondrial-dependent apoptosis, is upregulated in the re-modeled myocardium and promotes cell survivalunder stress.37 Cellular stress is intimately relatedto stress of endoplasmic reticulum and the

totic and antiapoptotic mediators in a delicate balances to activation of the apoptotic cascade without thebsence of DNA fragmentation. Cell membrane alter-of PS, which is recognized by annexin V.

Fig. 3. A delicate balance exists between death andsurvival in the border zone after AMI (remodeledmyocardium). Stretch and other form of injuries acti-vate the apoptotic cascade, which eventually leadsto cell death. Parallel to a cell death program, auto-phagy and natural inhibitors of apoptosis delayexecution of cell death and prolong cell survival.

Role of Apoptosis in Adverse Ventricular Remodeling 83

unfolded protein response, and failure toeliminate misfolded proteins leads to apoptoticcell death.11,12 After AMI, endoplasmic reticulumstress occurs, yet upregulation of members ofthe unfolded protein response, such as proteindisulfide isomerase, protects the cell from dying.38

This survival instinct in the remodeled myocardiumexemplifies as to why cardiomyocytes are

Fig. 4. Potential targets of antiapoptotic interventions inAmin MS, et al. Acute myocardial infarction and hear2006;38:1837; with permission.)

deserving of the supreme status of terminallydifferentiated cells (Fig. 3).39

The clinical implications of such observation areobvious, and it is likely that the strategies inhibitingcell death and/or promoting cell survival couldhelp halt the progression of cardiomyopathy andprevent heart failure.

The recognition of the existence of a portion ofthe heart that is at jeopardy has generated theidea of rescuing the myocardium at risk. Most ofthe initial studies were focused on revasculariza-tion of ischemic myocardium, especially wherethere was evidence of hypoperfused hypocontrac-tile myocardium (hibernating myocardium).11 Therecent multicenter Surgical Treatment for IschemicHeart Failure trial has equated the benefits ofmedical therapy to that of revascularization andhas emphasized the need to further strengthenmedical therapy.40 Based on the experimentalevidence that the myocardium at risk in the borderzone is often normally perfused yet hypocontrac-tile and prone to apoptosis, it would be prudentthat even revascularization is also abundantly sup-ported by aggressive medical therapy.6

APOPTOSIS-TARGETED INTERVENTIONSIN HEART FAILURE

The observation that the activation of theapoptotic cascade and the actual rate of apoptoticcardiomyocytes correlate with prognosis and thatapoptosis can be inhibited using pharmacologicinhibitors has led to a large number of studies ad-dressing whether inhibition of apoptosis halts theprogression of the cardiomyopathy.3,41 Given the

heart disease. (Modified from Abbate A, Bussani R,t failure: role of apoptosis. Int J Biochem Cell Biol

Fig. 5. Caspase 3 activation induces cell membrane alterations that lead to exposure of PS, which is recognized byannexin V. Annexin V scans have been performed in patients with nonischemic cardiomyopathy. Patients withannexin V uptake in the myocardium (white arrows) (approximately 50%, either patchy [as in patient #1] ordiffuse [as in patient #2]) had further reduction in left ventricular systolic function compared with those withno myocardial uptake (as in patient #3). (Modified from Kietselaer BL, Reutelingsperger CP, Boersma HH, et al.Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure. J Nucl Med2007;48:564; with permission.)

Abbate & Narula84

complexity of the apoptotic cascade, althoughmultiple targets exist, only few may be viable interms of targeted efficacy (Fig. 4). Treatmentapproaches vary from elimination of the triggers(ie, relief of ischemia and neurohormonal blockadeand ventricular unloading with ventricularassist devices) to more focused inhibition ofthe apoptotic signaling. Although nonspecificapoptotic inhibitors have shown to be clinicallyeffective (ie, angiotensin-converting enzyme inhib-itors, b-adrenergic blockers, aldosterone antago-nists), it remains unclear whether the benefit ofsuch agents is through reduction of apoptosis.Animal studies with caspase inhibitors have shownpromising results,42,43 but clinical trials with tar-geted apoptotic inhibitors in heart disease arelacking.

MOLECULAR IMAGING OF CARDIACAPOPTOSIS

Most of the clinical studies on myocardialapoptosis are limited by the design being mostlycross-sectional. This is likely related to the chal-lenges of detecting cell death in vivo because ofthe need of invasive procedure such asmyocardialbiopsies. The molecular imaging methods todetect apoptosis may offer means for adjunctivediagnostic or prognostic information. Proof ofconcept clinical studies has shown that annexinV–targeted nuclear scans identify cells in whichthe apoptotic cascade is activated. Caspase 3leads to membrane abnormalities and redistribu-tion of phosphatidylserine (PS) to the cell surface,

which is recognized by annexin V imaging. Annex-in V uptake shows diffuse or patchy uptake inpatients with heart failure.32,43 An abnormal an-nexin V study in patients with decompensatedheart failure predicted further worsening of leftventricular systolic function over time (Fig. 5).32 Ithas been proposed that annexin V uptake repre-sents the magnitude of caspase 3 activity andprovides a noninvasive portal to identify thebalance between proapoptotic and antiapoptoticfactors in heart failure. However, whether annexinV imaging can guide management of patientsremains to be tested.

SUMMARY

Apoptosis is a key feature in the progression ofheart disease. Stage B heart failure is character-ized by a structurally abnormal heart in which theremodeled myocardium is prone to apoptosis.Elimination of the proapoptotic stimuli or inhibitionof the apoptotic cascade could presumablyrescue the myocardium and halt the progressionof adverse remodeling and heart failure.

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