JACC REVIEW TOPIC OF THE WEEK

Mechanical Unloading in Heart FailureNir Uriel, MD, MSC,a,* Gabriel Sayer, MD,a,* Shiva Annamalai, MD,b Navin K. Kapur, MD,b Daniel Burkhoff, MD, PHDc

ABSTRACT

Myocardial injury induces significant changes in ventricular structure and function at both the cellular and anatomic level,

leading to ventricular remodeling and subsequent heart failure. Unloading left ventricular pressure has been studied in

both the short-term and long-term settings, as a means of preventing or reversing cardiac remodeling. In acutemyocardial infarction, cardiac unloading is used to reduce oxygen demand and limit infarct size. Research has demon-

strated the benefits of short-term unloading with mechanical circulatory support devices before reperfusion in the

context of acute myocardial infarction with cardiogenic shock, and a confirmatory trial is ongoing. In chronic heart failure,

ventricular unloading using mechanical circulatory support can reverse many of the cellular and anatomic changes that

accompany ventricular remodeling. Ongoing research is evaluating the ability of left ventricular assist devices to

promote myocardial recovery and remission from clinical heart failure. (J Am Coll Cardiol 2018;72:569–80)

© 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.

A cute myocardial infarction (AMI) remains aleading cause of morbidity and mortality,with >650,000 cases reported in the United

States annually. Over the past 3 decades, early revas-cularization and AMI management have had a signif-icant impact on early mortality, and 30-day survivalfor ST-segment elevation myocardial infarction isnow 95%. However, 1 in 4 patients surviving a firstAMI will develop heart failure (HF) within 1 year,and 75% will develop HF within 5 years from the in-dex event (1). As more people survive the initialAMI, an increasingly heavy burden is placed on ourhealth care system in the form of new HF patients.Additional therapeutic approaches focusing on HFprevention should be developed.

For patients with established HF, either followingmyocardial infarction or in the setting of idiopathiccardiomyopathy, therapies aim to interrupt the cycleof progressive dilation and dysfunction; a processcalled remodeling. Medical therapies, cardiac

resynchronization therapy, and mitral repair/replacement can interrupt this process to a certaindegree, but are insufficient to halt disease progres-sion, and most patients ultimately succumb to HF.Additional therapies that reverse or at least halt dis-ease progression are needed for these patients aswell.

Evidence is mounting concerning the impact of leftventricular (LV) unloading with mechanical circula-tory support on reverse remodeling, and the accom-panying changes at the cellular level. Recent studiesdemonstrated the clinical benefits of LV unloading inacute HF in the setting of AMI. In the short term, LVunloading using mechanical circulatory support aimsto reduce infarct size, limit ventricular remodeling,and prevent the development of the HF syndrome.The physical and molecular mechanisms underlyingthe effects of unloading in the short- and long-termsettings are similar. The purpose of this review is todescribe the anatomic and cellular changes occurring

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.05.038

From the aSection of Cardiology, University of Chicago, Chicago, Illinois; bThe Cardiovascular Center, Tufts Medical Center andTufts University School of Medicine, Boston, Massachusetts; and the cColumbia University Medical Center, and CardiovascularResearch Foundation, New York, New York. *Drs. Uriel and Sayer contributed equally to this work and are joint first authors.Dr. Uriel has received grant support from and has been a consultant to Medtronic and Abbott. Dr. Sayer has been a consultant toMedtronic. Dr. Kapur has received institutional research grants from Abiomed, Boston Scientific, and Abbott; and has been aconsultant to Abiomed, Boston Scientific, Abbott, Maquet, and Medtronic. Dr. Burkhoff has received an unrestricted educationalgrant from Abiomed. Dr. Annamalai has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received February 16, 2018; revised manuscript received May 10, 2018, accepted May 11, 2018.

Listen to this manuscript’saudio summary byJACC Editor-in-ChiefDr. Valentin Fuster.

J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 2 , N O . 5 , 2 0 1 8

ª 2 0 1 8 P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E

A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

during reverse remodeling due to unloadingin the settings of chronic and acute LVdysfunction.

VENTRICULAR REMODELING

Acute or chronic myocardial injury pre-cipitates metabolic derangement, followedby myocyte death. The remaining viablemyocardium responds to cell loss throughmyocyte hypertrophy and development offibrosis in the interstitial space (2,3). Areduction in contractile force activatesneurohormonal compensatory mechanismsaimed at maintaining systemic perfusionsuch as the sympathetic nervous and renin-angiotensin systems. Over time, the LVundergoes structural changes including anincrease in ventricular volume, rightwardshift of the end-diastolic pressure-volumerelationship (EDPVR) and development of amore spherical shape (4–6). These anatomicchanges are accompanied by alterations ingene expression, metabolic substrate prefer-ence and utilization, and the composition ofthe extracellular matrix (7–9). Together,

these structural, biochemical, and molecular changesare termed ventricular remodeling.

ACUTE HEART FAILURE FOLLOWING AMI

Infarct size correlates with mortality and develop-ment of HF (10). The larger the infarct, the higherthe burden on remaining viable myocardium and thegreater the adaptive cardiomyocyte hypertrophy.Myocardial infarction initiates the process of ven-tricular remodeling as described in the precedingtext. Accordingly, limiting myocardial injury is theprimary target of clinical investigations aimed atpreventing HF after an AMI. Two primary ap-proaches have been pursued. The first is to minimizethe overall ischemic time experienced by themyocardium. The adage “time is muscle” suggeststhat the faster an occluded coronary artery can bereperfused and myocardial oxygen supply restored,the smaller the infarct size. This has led to adoptionof a benchmark door-to-balloon time, the time fromarrival to a medical facility to primary reperfusion,of 90 min or less. However, recent reports demon-strate no effect on mortality or post-AMI HFincidence with additional reduction in the door-to-balloon time below 90 min (11). The secondapproach to limit infarct size in AMI has been toemploy interventions and pharmacotherapy toreduce reperfusion injury. These methods have been

reviewed extensively and are founded on solid pre-clinical data, but none have successfully translatedinto routine clinical practice (12).

A key pathophysiological feature that determinesthe extent of necrosis during AMI is the balance be-tween the residual supply of oxygen to the myocar-dium at risk and myocardial metabolic demands.Although the current paradigm—early reperfusiontherapy—focuses on restoring oxygen supply to themyocardium at risk, strategies to reduce myocardialoxygen demand to achieve a more favorable supply–demand ratio as a means of limiting infarct sizehave not been clinically tested. Extensive preclinicaland some clinical evidence suggest that immediatelyreducing the mechanical workload (unloading) of theheart before reperfusion leads to a smaller infarctsize. Short-term cardiac unloading reduces oxygendemand and preconditions myocardium at risk tooppose reperfusion injury, and may limit irreversiblenecrosis, allowing the heart to more fully recoveronce coronary flow is restored. Here, we provide anoverview of the hemodynamic principles and physi-ological mechanisms underlying short- and long-termunloading, and discuss emerging preclinical datasupporting translation of this approach to limitinginfarct size and preventing the development of HF.

SHORT-TERM CARDIAC UNLOADING

Cardiac unloading can be defined as the reduction ofmechanical power expenditure of the ventricle tominimize myocardial oxygen consumption (MVO2)and reduce hemodynamic forces that lead to ven-tricular remodeling and, in MI, to reduce infarct size.

Ventricular hemodynamics, work, power, andenergy demands can be understood within theframework of ventricular pressure-volume analysis(Figure 1) (13). The pressure-volume loop falls withinthe boundaries of the end-systolic pressure-volumerelationship (ESPVR) and EDPVR (Figure 1A). TheESPVR is linear with a slope, Ees, that is considered aload-independent index of ventricular contractility.The EDPVR is nonlinear and characterizes passiveventricular properties (i.e., at a point when all actin-myosin bonds are uncoupled). Ventricular compli-ance (or stiffness, the mathematical reciprocal ofcompliance) is determined by the slope of the EDPVR.Because the EDPVR is nonlinear, ventricular compli-ance decreases as filling pressure increases(Figure 1B). The location of the pressure-volume loopwithin the ESPVR and EDPVR boundaries is deter-mined by the ventricular preload and afterload.

In the setting of AMI (Figure 1C), ventricularcontractility is decreased (decreased slope of the

ABBR EV I A T I ON S

AND ACRONYMS

AMI = acute myocardialinfarction

ATP = adenosine triphosphate

EDPVR = end-diastolicpressure-volume relationship

ESPVR = end-systolicpressure-volume relationship

HF = heart failure

LV = left ventricular

LVAD = left ventricular assistdevice

mPTP = mitochondrialpermeability transition pore

MVO2 = myocardial oxygenconsumption

PE = potential energy

PVA = pressure-volume area

RISK = reperfusion injurysalvage kinases

ROS = reactive oxygen species

SDF1a = stromal derived factor1 alpha

SW = stroke work

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ESPVR) resulting in decreases of stroke volume(width of the loop) and pressure generation (height ofthe loop); the pressure-volume loop shifts rightwardtowards larger volumes (initially along the originalEDPVR) due to the increased filling pressure. Changesin diastolic properties, both active and passive as-pects, play a key role in the pathophysiology in theacute and chronic phases following AMI. With theonset of diminished oxygen supply and onset ofischemia, the rate of relaxation is decreased, andespecially at high heart rates, uncoupling of actin-myosin bonds may be incomplete between contrac-tions (incomplete relaxation) (14). Under suchconditions, the pressure-volume loop may fail to

reach the EDPVR, potentially decreasing ventricularcompliance beyond that due to the increased fillingpressure. Over time, however, with the hypertrophicresponse (elongation and widening) of survivingmyocytes, increased extracellular matrix turnover(caused by the inflammatory response, necrosis, etc.)and increased diastolic wall stress, the EDPVR canshift rightward towards larger volumes, a phenome-non called ventricular remodeling (Figure 1D) (15).Rightward shifts of the EDPVR are also associatedwith further rightward sloping of the ESPVR; thus,remodeling results, not only in chamber enlargement,but also in further reductions of LV contractilitybeyond that caused by loss of myocytes.

FIGURE 1 PV Analysis of LV Hemodynamics During AMI and Following LV Unloading

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(A) The LV pressure-volume (PV) loop is bounded by the end-systolic pressure volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR).Point A represents mitral valve closure and the onset of isovolumic contraction. Point B represents aortic valve opening and the onset of systolic ejection. Point Crepresents aortic valve closure and the onset of isovolumic relaxation. Point D represents mitral valve opening and the onset of the diastolic filling period. (B) TheEDPVR characterizes passive ventricular properties. Ventricular compliance is determined by the slope of EDPVR, and decreases with increased filling pressures. (C)Following acute myocardial infarction, cardiac contractility is reduced, and the ESPVR slope is reduced. The PV loop shows a reduction in pressure generation anddecrease in stroke volume (green loop). (D) Following myocardial injury, ventricular remodeling leads to a rightward shift of the EDPVR, and further downward shiftingof the ESPVR, causing LV enlargement and a decrease in LV contractility (blue loop). (E) Mechanical work of the LV is composed of stroke work (SW) and potentialenergy (PE). The pressure-volume area (PVA) is the sum of the SW and PE, and represents the total mechanical work of the heart per beat. (F) Myocardial oxygenconsumption (MVO2) is composed of basal metabolism, calcium (Ca2þ) cycling, and mechanical work. MVO2 is directly correlated with PVA. AMI ¼ acute myocardialinfarction; LV ¼ left ventricular; DP ¼ change in pressure; DV ¼ change in volume.

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Insights into myocardial energetics are also ob-tained from pressure-volume analysis. There are 2components to the total mechanical work of theheart: stroke work (SW) and potential energy (PE)(Figure 1E). SW is the area inside the pressure-volumeloop and represents the mechanical energy trans-ferred from the myocardium to the blood to propel itthrough the cardiovascular system. PE is the area onthe pressure-volume diagram bounded by the ESPVR,the EDPVR, and the diastolic portion of the pressure-volume loop and is residual energy stored in themyofilaments not released as external energy. Thesum of SW and PE is the total mechanical work of theheart per beat and is referred to as the pressure-volume area (PVA) (PVA ¼ SW þ PE). PVA directlycorrelates with MVO2 (Figure 1F) (16). Three majorprocesses contribute to MVO2: basal metabolism,calcium sequestration by the sarcoplasmic reticulum(SERCA2a adenosine triphosphatase activity), andactin-myosin cross-bridge uncoupling during relaxa-tion by myosin adenosine triphosphatase. Theseprocesses are fueled by adenosine triphosphate (ATP)hydrolysis which is principally generated throughaerobic metabolism and reflected by MVO2 per min-ute. With changes in contractility, heart rate, andloading conditions, calcium cycling and cross-bridging vary significantly, whereas basal meta-bolism is relatively constant. The amount of calciumcycled is linked with myocardial contractility;changes in contractility, therefore, induce changes inoxygen consumption independent of concomitantchanges in workload (i.e., parallel upward anddownward shifts of the MVO2-PVA relationship). Thenumber of actin-myosin bonds created duringcontraction is related to the total mechanical workperformed by the muscle so that the greater the workthe greater the oxygen consumption.

Minimization of the work-related oxygen con-sumption can be achieved by ventricular unloading(defined in the preceding text and detailed furtherlater in the text) by reducing both SW and PE throughreductions of ventricular peak systolic and end-diastolic pressures. Reductions of heart rate andcontractility (when possible) are very effective meansof reducing MVO2.

Heart rate is a critical determinant of oxygen con-sumption because both calcium cycling and me-chanical work occur with each beat. Thus, the oxygenrequired to fuel these processes increases linearlywith increases of heart rate. Accordingly, myocardialoxygen demand can be decreased by reducing heartrate, contractility, and/or total mechanical work. Eachcomponent should be considered when attempting toachieve maximal cardiac unloading.

The forces resulting in ventricular remodeling aresimilar to those that determine MVO2. With ventric-ular remodeling, the ESPVR and EDPVR shift right-ward towards increased volumes. Persistentlyincreased systolic wall stress leads to myocellularhypertrophy and drives apoptosis. Persistentlyelevated diastolic ventricular pressure causes ven-tricular dilation, manifest as rightward shifts of theEDPVR and ESPVR. Ischemic, newly infarcted, andstunned myocardium during acute MI and afterreperfusion therapy are particularly vulnerable toremodeling due to the markedly increased stressesand active cytokines and enzymes (matrix metal-loproteinases) that break down extracellular matrix.Thus, minimization of PVA decreases oxygen demandand limits remodeling.

However, because cardiac output and blood pres-sure are intimately linked with ventricular work,there are limits to which PVA and heart rate can bereduced during AMI without compromising perfusionof vital organs, including the brain, kidneys, liver,and the heart itself. Thus, pharmacotherapies aimedat reducing myocardial work load and minimizingPVA (e.g., beta blockers) are inherently limited asthey run the risk of compromising end-organ perfu-sion due to a reduction in cardiac output. By contrast,a mechanical LV assist device (LVAD) that drawsblood directly from the LV and pumps it to the arterialsystem can uncouple LV pressure and flow generationfrom pressure and flow in the arterial system. In-creases in LVAD flow left-shifts the pressure-volumeloop to lower end-diastolic volumes and pressures,reducing the PVA (Figure 2A). In the time domain(Figures 2B to 2E), progressive increases in LVAD flowreduce peak LV pressure, increase aortic diastolic andmean pressures, and allow for uncoupling of LVpressure generation from aortic pressure. Concomi-tantly, there is an increase in total cardiac output(i.e., the sum of native heart and LVAD flow), therebyshifting oxygen demand/supply balance within theheart, minimizing demand while maximizing supply.

MOLECULAR BIOLOGY OF

UNLOADING IN THE SETTING OF

ISCHEMIA-REPERFUSION INJURY

In 1985, Eugene Braunwald and Robert Kloner (17)described myocardial reperfusion in AMI as a “dou-ble-edged sword” due to the fact that reperfusion ofischemic myocardium also promotes cardiomyocytedeath and microvascular damage through a processreferred to as myocardial ischemia-reperfusioninjury. Since then, multiple studies have definedseveral key mechanisms that drive myocardial

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damage during ischemia and reperfusion (18–22).From the onset of ischemia, mitochondrial oxidativephosphorylation becomes uncoupled and synthesis ofATP is reduced within cardiomyocytes. This loss ofATP generation has 2 effects. First, intracellularcalcium and lactate levels increase, whereas intra-cellular pH decreases. Second, reduced ATP synthesisprovides the substrate for generation of reactiveoxygen species (ROS) that promote a feed-forwardprocess known as ROS-induced ROS-release. The neteffect of increased ROS levels is the opening of a holein the mitochondrial membrane known as the mito-chondrial permeability transition pore (mPTP), whichaccelerates loss of mitochondrial integrity and sub-sequent cardiomyocyte death within the ischemicmyocardium. The magnitude of myocardial damagecorrelates directly with the duration of myocardialischemia, hence the development of the door-to-balloon benchmark. However, reperfusion alsopromotes mPTP opening by triggering an influx ofcalcium, alterations in cellular pH, ROS, andincreasing microcirculatory obstruction.

In 1983, ground-breaking studies using intermit-tent periods of ischemia in a nonischemic myocardialterritory reduced infarct size in an ischemic myocar-dial zone (23). This early preclinical observationintroduced the field of ischemic preconditioning,

whereby episodic myocardial or skeletal muscleischemia reduced myocardial infarct size. Over thenext 20 years, investigators identified that ischemicpreconditioning activates phospho-inositol-3 kinase,Akt, and Erk, which limited formation of the mPTPand reduced myocardial infarct size. Independentof these reperfusion injury salvage kinases (RISK),other investigators identified that activation of thesurvivor activating factor enhancement pathwaymediated by tumor necrosis factor alpha and STAT3also limited ischemia reperfusion injury (24–26). Overthe same time period, a growing body of evidencesupported the cardioprotective role of a circulatingcytokine known as stromal derived factor (SDF)-1a.More recent evidence supports that increasedexpression of SDF-1a promotes Akt-mediated phos-phorylation and inactivation of glycogen synthasekinase 3-beta, which limits mPTP formation andmyocardial infarct size (27–30). On the basis ofthese sentinel studies, multiple investigators haveattempted to target various aspects of the RISK,survivor activating factor enhancement, and SDF-1asignaling pathways using pharmacological andischemic conditioning approaches without clearbenefit.

In parallel to the growing body of published reportsexploring biological mechanisms of cardioprotection,

FIGURE 2 Hemodynamic Changes During LV Unloading by Mechanical Circulatory Support

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(A)During acutemyocardial infarction or in chronic heart failure, the PV loop shifts to the right along the EDPVR, resulting in elevated end-diastolic pressures (black loop).With LV unloading by a continuous-flow left ventricular assist device (LVAD), the isovolumic contraction and relaxation periods are lost, and the PV loop assumes atriangular shape. Increases in LVAD support result in progressive leftward shifting of the PV loop to lower points on the EDPVR curve, with a reduction in LV volume (LVV).(B to E) Increases in LVAD flow result in uncoupling of LV pressure (LVP) and aortic pressure (AoP). LPM ¼ liters per minute; other abbreviations as in Figure 1.

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multiple investigators in the late 1980s were begin-ning to identify that reducing myocardial wall stressand oxygen consumption using mechanical pumpscould also reduce infarct size. Various approachesemployed counterpulsation pumps, extracorporealcentrifugal flow pumps, and large transvalvular axialflow pumps. These investigators identified that earlyand effective LV unloading reduced MVO2, whichcorrelated directly with reduced infarct size. Howev-er, few of these studies explored the impact of LVunloading on myocardial biology. In 2003, Meynset al. (31) identified a reduced myocardial lactateextraction ratio in sheep unloaded with a trans-valvular axial flow pump before reperfusion, sug-gesting a potential beneficial impact on myocardialmetabolism. In 2005, Achour et al. (32) identified thatischemia and reperfusion increased contraction bandnecrosis, mitochondrial calcium deposits, and mito-chondrial swelling. By contrast, activation of atransvalvular axial flow pump before, not after,reperfusion was associated with normal mitochon-drial integrity and cardiomyocyte ultrastructure. Forthe next decade, there were no further advances inthe field of LV unloading and myocardial biology.

In 2015, Kapur et al. (33) employed a contemporarytransvalvular axial flow pump and identified that firstmechanically unloading the LV and delaying reper-fusion reduced infarct size in a swine model of AMI.These authors further identified that LV unloadingactivated the RISK pathway within the infarct zoneand increased myocardial levels of SDF-1a and itsdownstream effector glycogen synthase kinase3-beta. This study was the first to link LV unloadingdirectly to the ischemic conditioning biology firstintroduced in the 1980s. More recently, using agenomic approach, the same authors reported that LVunloading and delayed reperfusion, known as pri-mary unloading, triggers a global shift in geneexpression that primarily involves preserved cellularrespiration and mitochondrial integrity (34). Theseobservations are consistent with the findings ofAchour et al. (32) and suggest that the field ofmechanobiology and cardioprotection remain largelyunexplored and future investigation may identifynovel approaches to limit ischemia-reperfusioninjury.

TRANSLATING SHORT-TERM UNLOADING

TO A CLINICAL THERAPY

Dating back to the 1970s, ex vivo and in vivo experi-mental models of AMI demonstrated that unloadingbefore, during, or after an index ischemic eventpositively affects cardiac function post-infarction

(35–38). However, unloading the ventricle in theclinical setting was previously infeasible from atechnological perspective. The development ofpercutaneous ventricular assist devices in the early2000s allowed for clinically relevant investigationsinto the effect of unloading on infarct size. With thisbackground in mind, Kapur et al. (39) hypothesizedthat first reducing myocardial oxygen demand bylimiting LV PVA (primary unloading), followed bycoronary reperfusion would decrease myocardialinfarct size compared with reperfusion alone (primaryreperfusion). Activation of a percutaneous left atrial-to-femoral artery bypass pump (TandemHeart, Car-diac Assist, Pittsburgh, Pennsylvania) in a swinemodel of anterior myocardial infarction reduced LVPVA and, despite delaying coronary reperfusion,reduced myocardial infarct size by over 40% (39).Primary unloading (initiating mechanical support andreducing LV myocardial oxygen demand first whilemaintaining systemic perfusion) slows myocardialinjury, enabling coronary reperfusion while reducingreperfusion injury. The reproducibility of primaryunloading has been established in several labora-tories worldwide using swine, canine, and bovineAMI models and a less invasive transvalvular axial-flow catheter (Impella CP, Abiomed, Danvers, Mas-sachusetts), which decreased LV wall stress, activateda myocardial protection program involving up-regulation of the cardioprotective RISK pathway,and limited myocardial infarct size (33,40–42).

Clinical findings have mimicked these preclinicaldevelopments. In the USpella registry, among 154consecutive patients with AMI complicated bycardiogenic shock, mechanical circulatory supportwith the Impella device before coronary reperfusionwas associated with higher in-hospital and 30-daysurvival (43). In a separate registry study of 287consecutive patients with AMI complicated bycardiogenic shock, Basir et al. (44) demonstrated thatinitiation of Impella support before percutaneouscoronary intervention and before the administrationof vasopressors or inotropes was independentlyassociated with increased survival to dischargecompared with patients receiving late mechanicalsupport. It is important to remember that noneof these studies were randomized. Furthermore,in-hospital survival was higher among patientssupported within 60 min before reperfusion,compared with those supported later in the course oftreatment (45). Interestingly, intra-aortic balloonpump counterpulsation without any delay to coronaryreperfusion in the CRISP-AMI (CounterpulsationReduces Infarct Size Pre-PCI for AMI) trial failed toreduce infarct size (46), which may have been due

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to both the lesser hemodynamic effects of theintra-aortic balloon pump compared with Impellaas well as the minimal period of unloading beforerevascularization.

Contemporary AMI management includes firstrestoring myocardial oxygen supply (reperfusion)then attempting to pharmacologically reducemyocardial oxygen demand. The concept of primaryunloading in ST-segment elevation myocardial in-farctions alters the sequence of therapy by firstsignificantly reducing myocardial oxygen demand(unloading) while maintaining systemic perfusion,and then restoring myocardial oxygen supply (reper-fusion). The Food and Drug Administration hasrecently granted approval to initiate a safety andfeasibility human trial of primary unloading in pa-tients presenting with ST-segment elevationmyocardial infarction (Door To Unloading withIMPELLA CP System in Acute Myocardial Infarction

[DTU]; NCT03000270) as a first step before con-ducting a large-scale pivotal efficacy trial.

REVERSE REMODELING AND MYOCARDIAL

RECOVERY IN LONG-TERM HF

Long-term HF represents a challenge that is differentthan what is encountered in AMI, because the ven-tricular remodeling has already occurred, and as such,the goal is to reverse the remodeling process. Reverseremodeling is defined as the return of the ventricularsize and shape, genotype, metabolism, and myocar-dial function towards normal. Normalization ofcellular and intracellular myocardial properties isrequired to achieve improved myocardial functionand, ultimately, myocardial recovery. Neurohormonalblockade serve as the mainstay therapy to achievethose goals. The primary objective of medical therapyis to: 1) unload excess pressure to which the LV is

FIGURE 3 Changes in Ventricular Size and Shape During LVAD Speed Adjustment

Figures were obtained from surface analysis of 3-dimensional echocardiographic images acquired during LVAD ramp studies. The HeartMate II(HM II) LVAD is shown on the left, HVAD LVAD is shown in the middle, and Heartmate 3 (HM 3) LVAD is shown on the right. In the top row,changes in LV size and shape are depicted with the lowest speeds represented by a gray net, and highest speeds represented in solid color. Inthe bottom row, changes in right ventricular size and shape are depicted with lowest speeds represented in red, and the highest speedsrepresented by a gray net. RPM ¼ revolutions per minute; RV ¼ right ventricle; other abbreviations as in Figures 1 and 2.

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CENTRAL ILLUSTRATION Following Acute Myocardial Infarction, There Is a Decrease inContractility and a Rightward Shift of the Pressure-Volume Loop

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exposed, by reducing preload volume (i.e., diuresis);2) reduction in afterload utilizing vasodilator medi-cations; and 3) promote restoration of beta-responsiveness and improve ventricular contractility(beta-blocker therapy). Animal models demonstratedthat angiotensin-converting enzyme inhibitors ach-ieved marked reductions in LV pressures, accompa-nied by a decrease in LV mass and volume (47,48).Similar unloading properties have been demonstratedin human studies, and the benefits of angiotensin-converting enzyme inhibitors have been repeatedlydemonstrated in randomized, clinical trials (49–51).Reverse remodeling was also shown with adminis-tration of beta-blockers and aldosterone blockers(52–54). Cardiac resynchronization therapy inducesfurther reverse remodeling by achieving electricaloptimization of myocardial contraction. However, themost dramatic reverse remodeling has been reportedwith LVADs. LVADs remove blood from the LV,providing direct mechanical unloading of the heartwhile also restoring systemic perfusion (Figure 2). Thehemodynamic effects of LVADs include reduction inthe LV end-diastolic pressure and volume, elimina-tion of the isovolumic contraction and relaxationperiods, and significant reduction in the energeticrequirements of the heart (55). Unloading was moreprofound with the first-generation pulsatile-flowLVADs than the current continuous-flow LVADs;however, the hemodynamic benefits of earlier LVADswere overshadowed by their adverse effect profile andlimited durability (56).

Reverse remodeling induced by the LVAD isdependent on the operating speed of the LVAD andthe flow generated in response to the pressuregradient between the LVAD inflow cannula and theascending aorta. Each device has a unique relation-ship between flow and pressure, as represented bydevice-specific pressure-flow (H/Q) curves. Short-term changes in LV shape can be demonstrated bychanging the LVAD operating speed (ramp study). Aspreviously shown, increases in LVAD speed at fixedintervals result in progressive linear decreases in LVsize as assessed by 2-dimensional echocardiography,or transition from a spherical to a conical shape with

significant reduction in LV volumes as shown by 3-dimensional echocardiography (57–59) (Figure 3).Furthermore, the reverse remodeling process is de-vice specific. Intrathoracic devices, such as theHeartWare HVAD (Medtronic, Minneapolis, Minne-sota) and the HeartMate 3 (Abbott, Abbott Park, Illi-nois) compress the LV apex, bringing it closer to thebase of the heart. As a result, the heart remains morespherical, with volumetric changes occurring globallythroughout the LV. By contrast, intra-abdominal de-vices, such as the HeartMate II (Abbott), pull the LVapex downward, resulting in a more conical shapewith the most pronounced changes in size at the baseof the heart. Regardless of the form of reverseremodeling that occurs, hemodynamic changes arecomparable for the 2 device types, indicating equiv-alent degrees of pressure unloading (60). Significantreductions in LV volumes have been demonstrated asearly as 30 days post-implantation, and are accom-panied by marked reductions in LV mass as well assustained improvement in LV ejection fraction (61).

Unloading LV pressure reduces neurohormonalactivation and improves the responsiveness of ß-adrenergic receptors (62–64). The addition of standardHF pharmacotherapy to LVAD support augments thesuppression of neurohormonal activity, further pro-moting a reversal of LV structural changes (65). How-ever, since the initial studies on reverse remodelingand myocardial unloading following LVAD, there wereconcerns that complete normalization of both theanatomic shape and function alongwith reversal of themolecular changes could not be achieved. Margulieset al. (7) studied the transcriptional adaptations in 199failing and LVAD-supported hearts. The authors re-ported that over 3,000 genes exhibit dysregulation inHF. Among these dysregulated genes, a relativelysmall number exhibit a pattern of normalization, par-tial recovery, or overshoot after LVAD support. Theauthors concluded that mechanical unloading withLVAD does not normalize the dysregulated genes inthe failing myocardium and more likely results in theexpression of a new gene expression profile (7). On thecellular level, Diakos et al. (66) reported a decrease incardiomyocyte size after LVAD unloading, without any

CENTRAL ILLUSTRATION Continued

Primary reperfusion increases cardiac output, but does not relieve the increase in left ventricular (LV) pressure and wall stress, resulting ininfarct expansion and adverse ventricular remodeling. Primary unloading reduces LV pressure, wall stress, and myocardial oxygen con-sumption, preventing infarct expansion and decreasing subsequent ventricular remodeling. In the chronically remodeled heart, implantationof a durable left ventricular assist device results in a leftward shift of the pressure-volume loop, which promotes reverse remodeling, and insome cases, myocardial recovery. MI ¼ myocardial infarction; MIS ¼ myocardial infarct size.

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sign of atrophy. From this small study of 44 patients,the authors concluded that LVAD unloading is suffi-cient to induce cardiomyocyte normalization. How-ever, the extracellular changes were not consistentacross different reports. In their original report on 15patients, the Utah group reported: 1) 33% increase incapillary density; 2) 36% decrease in microvascularlumen area; 3) endothelial cell activation; and 4) sig-nificant increase in interstitial and total collagen con-tent (67). On the other hand, a recent paper by Farriset al. (68) failed to show any differences in myocardialfibrosis and/or capillary density following mechanicalunloading. Interestingly, the authors reported areduction of fibroblast-specific collagen expression.The final answer on the extracellular changes occur-ring following LVAD support is still not clear.

From the metabolic standpoint, LVAD implanta-tion induces only partial normalization in amino acidutilization. Specifically, the failing myocardiumdemonstrates a decrease in glucose utilization.Following mechanical unloading, there is an increaseof glycolysis; however, there is not a significantchange in oxidative metabolism. Furthermore, citricacid cycle abnormalities persist despite mechanicalunloading with LVAD therapy (69).

The concerns about partial normalization raised bythe above reports were further supported by Topkaraet al. (70). In this seminal study, the authors reportedthe genetic and epigenetic changes during the failingand recovery phases in a transgenic mouse model.They found that suppression of the transgene wasassociated with a reversal of cardiac hypertrophy andimproved cardiac myocyte contractile function.Those changes occurred concurrently with improvedLV contractility and reverse LV remodeling. However,the normalization of LV structure and function wasaccompanied by only partial normalization (w60%) ofgene expression.

Although the recovery of myocardial function isoften sustained, cellular studies of both animal andhuman tissue have shown a persistence of abnor-malities in genetic expression and properties of theextracellular matrix, indicating that reversal of theHF phenotype is not always matched by a reversal ofthe genotypic, metabolic, and molecular changes thataccompany ventricular remodeling (7,70).

TRANSLATING LONG-TERM UNLOADING

TO A CLINICAL THERAPY

Many studies have evaluated the effect of long-termunloading, utilizing LVAD therapy, on myocardial

recovery and the rate of LVAD explantation (71). TheHarefield group, Birks et al. (72), pioneered the studyof myocardial recovery in LVAD patients, demon-strating that device explantation can be achieved in73% of selected patients with the combination ofmedical therapy, clenbuterol, and a pulsatile-flowLVAD. The same group demonstrated similar resultswith the HeartMate II continuous-flow LVAD (73).However, a study in the United States failed toreplicate these studies, and was discontinued due tolack of efficacy. Investigators continued to evaluatethe rate of myocardial recovery in large datasets andeventually identified a patient profile that is associ-ated with myocardial recovery in response to long-term unloading (74,75). Young age, nonischemicetiology of HF, LV size <6.5 cm, creatinine #1.2 g/dl,lack of implantable defibrillator, and a short durationof HF before LVAD implantation were associated withhigher incidence of LVAD explantation for recovery. Ascoring system was developed that predicts thechance of myocardial recovery in response to long-term unloading in LVAD patients. The results of themuch-anticipated RESTAGE-HF (Remission FromStage D Heart Failure; NCT01774656) study, evalu-ating the rate of LVAD explantation among patientswith a good profile for myocardial recovery, wererecently presented, and found that 36% of the pa-tients enrolled underwent LVAD explantation, withsustainable remission from the HF syndrome (76).This study highlights the importance of activelyattempting to achieve myocardial recovery throughaggressive medical management and systematicallylooking for evidence of recovery during LVAD sup-port. Importantly, the LV should be evaluated in areloaded state (i.e., during minimal degrees of LVADsupport) to fully assess function, although it remainsdebatable whether it is important to slowly recondi-tion the heart through gradually increased loadingover time (77).

CONCLUSIONS

Cardiac unloading reduces mechanical powerexpenditure of the LV, minimizing MVO2 andreducing ventricular remodeling (Central Illustration).Unloading can be achieved both in AMI and chronicHF. There is a significant body of evidencedemonstrating that initiation of cardiac unloadingleads to anatomic, cellular, molecular, and geneticchanges in both the short- and long-term setting.Current studies are focusing on the clinical appli-cations of early unloading in the setting of

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myocardial infarction as a tool to reduce infarct size(DTU trial), and late unloading to achieve partial orcomplete myocardial recovery in chronic HF to testthe degree to which partial or complete myocardialrecovery can be achieved in patients with chronicHF (RESTAGE-HF study).

ADDRESS FOR CORRESPONDENCE: Dr. Nir Uriel,Section of Cardiology, University of Chicago, 5841 SouthMarylandAvenue, Chicago, Illinois 60637. E-mail: nuriel@medicine.bsd.uchicago.edu. Twitter: @NirUrielMD,@UChicago, @TuftsMedicalCtr, @ColumbiaMed.

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KEY WORDS acute myocardial infarction,hemodynamics, LVAD, mechanical circulatorysupport, remodeling

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