NONPHARMACOLOGIC THERAPY: SURGERY, VENTRICULAR ASSIST DEVICES, BIVENTRICULAR PACING, AND EXERCISE (AK HASAN, SECTION EDITOR)

Recent Advances in the Optimization of CardiacResynchronization Therapy

Satish Chandraprakasam & Gina G. Mentzer

# Springer Science+Business Media New York 2014

Abstract Heart failure (HF) continues to grow and affectmore than five million people in the USA. One of the leadingdevice therapies in HF is cardiac resynchronization therapy(CRT) which has been studied for over 20 years. Recentadvancements in lead placement, lead technology, patientselection, and CRT optimization by electrical maneuvers andimaging modalities have improved outcomes in morbidity,hospitalization reductions and mortalities in those who haveresponded CRT therapy. This review article is intended todiscuss the mechanisms and benefits of CRT, clinical trials,and guidelines for CRT along with a focus on recent updatesfrom the past 3 to 5 years and glimpse into future directions.

Keywords CRT . Cardiac resynchronization . LBBB .

RBBB . IVCD . 120ms . 150ms . ICD . Dyssynchrony .

Heart failure . Echocardiography guided CRToptimization

Introduction

The burden of chronic heart failure is growing at rapid pacewith estimation of over five million suffering from heart failure(HF) in the USA alone. Of these, approximately half havesystolic heart failure with ejection fraction less than 40 % andof those, approximately 30 % have a QRS duration greaterthan 120 ms [1, 2]. This condition still carries very high

mortality rates despite guideline-directed medical therapy(GDMT), partly from electrical dyssynchrony stemming froma delayed activation of the left free wall and septal stretch.Implantable cardioverter defibrillator (ICD) and cardiacresynchronization therapy (CRT) have now becomeestablished therapies in patients with chronic heart failurerefractory to GDMT [3]. GDMT for chronic heart failureinclude beta blockers, angiotensin-converting enzyme inhibi-tors, angiotensin receptor blockers, and aldosterone antago-nists which have demonstrated their efficacy in clinical trials.More interesting, drugs that improve the long-term prognosis(e.g., beta-blockers) may even worsen them initially, anddrugs that improve function and symptoms initially (e.g.,dobutamine and milrinone) can actually worsen the long-term prognosis. The number of patients with refractory heartfailure and functionally debilitating symptoms requiring ven-tricular assist devices (VAD) and transplantation are on therise. But, these options are not without their limitations—availability, cost, and complications. So when patients ceaseto respond adequately to GDMT, one of the options in ourarmamentarium is CRT. Several landmark clinical trials haveshown CRT to improve symptoms, exercise capacity, reducehospitalizations, and promote reverse remodeling thereby im-proving left ventricular function and decrease mortality. Sinceits introduction in 1994, the indications for CRT have grownand will continue to expand. Despite the tremendous impactthat it has made since it was commercially approved by the USFDA in 2001, several challenges still remain in identifying theideal recipient for this therapy, predicting CRT response, andoptimizing CRT therapy in non-responders. The field ofresynchronization therapy has evolved over the past two de-cades to smarter devices with capabilities for remote hemo-dynamic monitoring and novel pacing algorithms. In addition,our understanding of the pathophysiology of chronic heartfailure, mechanisms of CRT response, and novel lead place-ment techniques have made the delivery of CRT more effec-tive [4]. This review article is intended to discuss the mecha-nisms and benefits of CRT, clinical trials, and guidelines for

This article is part of the Topical Collection on NonpharmacologicTherapy: Surgery, Ventricular Assist Devices, Biventricular Pacing, andExercise

S. ChandraprakasamThe Cardiac Center of Creighton University, 3006 Webster Street,Omaha, NE 68131, USAe-mail: SatishChandraprakasam@creighton.edu

G. G. Mentzer (*)Nebraska Heart Institute and Nebraska Heart Hospital, 7440 South91st Street, Lincoln, NE 68526, USAe-mail: gmentzer@neheart.com

Curr Heart Fail RepDOI 10.1007/s11897-014-0234-4

CRT along with a focus on recent updates from the past 3 to5 years and glimpse into future directions.

Pathophysiology for Cardiac Resynchronization Therapy

It is very clear that CRT therapy has improved the quality oflife of those living with chronic heart failure as well as reducedthe morbidity and mortality. But, what has been less clear iswhy CRT is not successful in every single patient, implyingthe notion that its beneficial effects are just beyondreestablishing ventricular synchrony [5]. This requires theunderstanding of effects of CRTat various levels—molecular,genetic, acute hemodynamic responses, and chronicremodeling.

CRT effects at the molecular level have been demonstratedin animal models. Changes in phosphorylation status andmyofilament Ca2+ sensitivity have been implicated in heartfailure progression. Kirk et al. showed that glycogen synthasekinase-3β (GSK-3β) was deactivated in heart failure due todyssynchrony and reactivated by CRT. Studies have demon-strated that CRT improves calcium responsiveness of myofil-aments through GSK-3β reactivation and suggest beneficialeffects from biventricular pacing of the failing heart identify-ing molecular targets for heart failure therapy—myofilamentCa2+ sensitizers and activators of GSK-3 β [6•{Aiba T, 2012#183}]. This notion has been strengthened by another studythat demonstrated remodeling of the transverse tubular system(t-system) and the spatial association of ryanodine receptor(RyR) clusters in a canine model [7]. Progressive left ventric-ular dysfunction has been blamed on certain genetic polymor-phism involving renin-angiotensin-aldosterone system(RAAS)—specifically involving a gene involved in the aldo-sterone signaling pathway (NR3C2 gene polymorphism)identified by TaqMan assays [8]. Similarly, gene polymor-phisms of the beta adrenergic receptors (Beta-2 Gln27GluARs gene polymorphism) have been identified, the underly-ing theme being that these polymorphisms may influencecardiac remodeling and impact response to CRT [9].

Mechanical Dyssynchrony

It is hypothesized that stretching of an activated cardiomyo-cyte causes delayed force redevelopment. Speckle trackingechocardiography has showed mechanical dyssynchrony(MD) in left bundle branch block (LBBB) which is relatedto a pattern of early septal contraction, associated with poste-rior–lateral stretch followed by posterior–lateral contraction,associated with septal stretch, which delays the timing of peaksegmental shortening. This reduces myocardial efficiency be-cause work performed by one segment is wasted by stretchingother segments, resulting in inefficient work during segmentallengthening and dysregulation of regional work distribution,

especially in the septum. Following CRT, wasted work ratioand heterogeneous distribution of work can be rebalanced byaltering the pattern of electrical activation [10].

Biochemical Effects of CRT

Proinflammatory cytokines such as interleukin (IL)-6, tumornecrosis factor (TNF)-alpha, matrix metalloproteinases(MMPs), and their tissue inhibitors (TIMPs) play a role in leftventricular (LV) structural remodeling. Increased levels ofthese proinflammatory markers in heart failure were indepen-dently associated with a poor prognosis. CRT response wasassociated with a decrease of transforming growth factor(TGF)-β1, IL-6, and TNF-α, and positive extracellular matrixremodeling was associated with decreasing levels of MMP-2and increasing TIMP-2 [11, 12]. Another study by Rubaj et al.demonstrated that highly sensitive C-reactive protein (hs-CRP), neopterin, and brain natriuretic peptide (BNP) werenoted to increase even with short periods of CRT interruption[13].

Role of Ventricular Interactions

The correction of mechanical asynchrony and the recruitmentof right ventricular (RV) myocardial fibers induced by leftventricular (LV) stimulation can explain the positive hemody-namic results despite the absence of correction of electricaldyssynchrony in LV pacing. There appears to be an interactionbetween LVand RV during both phases of the cardiac cycles.LV dysfunction leads to impaired RV systolic and diastolicfunction as evidenced by increased RV diastolic pressures.The role of RV contraction in CRT is debatable as somestudies have demonstrated that CRT optimization improvedcardiac output by increasing RV contractility while other haveshowed that the RV dP/dtmax (maximal rate of ventricularpressure rise, i.e., contractility) failed to identify the optimalventriculo-ventricular (VV) interval when compared with LVdP/dtmax [14, 15].

Hemodynamic Effects of CRT

CRT-pacing increased the percent change in maximal rate ofLV dP/dtmax, decreased electrical dyssynchrony, and increasedtotal ventricular myofibril work. These findings provided thenovel insight that, through ventricular interaction, the RVmyocardium importantly contributes to the improvement inLV pump function induced by cardiac resynchronization ther-apy [16]. Early after CRT, central and peripheral arterialbiomechanics improved as illustrated by a decrease in arterialelastance and aortic impedance and increase in arterial disten-sibility and LV end-systolic elastance [17]. Dyssynchronouschronic heart failure may also attenuate normal coronaryblood flow, determined by a backward-traveling

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decompression (suction) wave in diastole, due to regionalrelaxation and contraction overlap. It is hypothesized thatCRT improves coronary blood flow by augmenting the suc-tion wave in diastole thereby increasing the LV dP/dtmax [18•].

Clinical Benefits/Outcomes of CRT

In patients with prolonged QRS (≥120 ms), there is a delaybetween onset of LV and RV contraction (interventriculardyssynchrony), especially in those with LBBB. This isreflected by a decrease in EF and cardiac output mechanicsthat cause symptoms of HF. By visualization, there is obviousmechanical interventricular dyssynchrony and alterations inventricular dependence as well as atrial–ventriculardyssynchrony. Unfortunately, this can result in worsening ofmitral regurgitation (MR) with progressive ventricular andatrial dilatation. Furthermore, as described, it causes decreasedcardiac perfusion and therefore subsequent arrhythmias thatcould be life threatening. CRT-induced improvement of LVdyssynchrony was associated with significant reduction ofventricular arrhythmias in patients with LBBB [19]. Thoughmost patients requiring CRT have co-existing mechanical andelectrical dyssynchrony, it is argued that improvement inmechanical dyssynchrony is responsible for survival benefit[20]. The favorable clinical outcomes are mediated by positivestructural alterations or reverse remodeling associated withsignificant reduction in septal and posterior wall thickness,LV mass along with LV volume changes (decrease in end-systolic volume >15 % from baseline), and improvement inleft atrium (LA) volumes. In HF patients, increased baselineLA volume (LA volume index (LAVI) >34 ml/m2) has beenconsidered a poor prognostic factor with reverse remodelingof LA occurring independent of LV remodeling [21]. Im-provement in NHYA class symptoms, exercise capacity, qual-ity of life (QOL), LV ejection fraction (at least 5 % increasefrom baseline), functional mitral regurgitation, pulmonaryartery pressures, and lung function tests are the beneficialfunctional outcomes [22]. This has been validated in severalobservational and randomized controlled trials. Several scor-ing systems have been used to predict who derive the clinicalbenefits of CRT. The Seattle Heart Failure Model (SHFM) is amultifactor risk assessment score for patients with heart fail-ure, which has been validated in several cohorts to predictoutcomes and mortality risks. Limitation of SHFM was thatthe mortality risk was underestimated in patients with HFtreated with CRT. In contrast, a simple and novel scoringsystem byKhatib et al. showed that EAARN (ejection fraction(EF), age, atrial fibrillation (AF), renal dysfunction, NewYorkHeart Association (NYHA) class IV) was a good predictor ofmortality in CRT patients as it is derived from the specificgroup of HF patients treated with CRT and hence allows forstratification of CRT patients as each additional predictorincreased the mortality [23•]. Some clinical trials have

suggested that there could be gender differences in clinicaloutcomes with women outperforming men in a patient withmild HF, although the mechanism is unclear. It is theorizedthat women demonstrated greater degrees of biventricularpacing and enhanced response to atrioventricular optimization(AVO) augmenting CRT response [24]. But, the real worlddata from IMPROVE HF registry suggest that therapiesshould be offered to all eligible patients with heart failure,without modification based on sex [25].

Hyper Responders or Super Responders with CardiacResynchronization Therapy

Goldenberg et al. reported seven predictors of echocardio-graphic CRT response (defined as percent reduction in LVend-diastolic volume after 1 year of CRT) in theMADIT-CRTtrial (NYHA class I to II), which included female sex, non-ischemic origin, LBBB, QRS >150 ms, prior hospitalizationfor HF, LV end-diastolic volume (LVEDV)>125 ml/m2, andLA volume <40 ml/m2. The study proposed a 0- to 14-pointresponse score based on these seven factors, with a riskreduction of HF or death with CRT of 69, 36, and 33 % forthe upper (>9 points), third, and second quartiles, respectively,without significant risk reduction in the first quartile (<4points) [26]. Hsu et al. reported the predictors of CRT super-responders (highest quartile of LVEF change after CRT im-plant) in asymptomatic NYHA class I to II HF after 6 monthsof CRT, which included female sex, lack of prior myocardialinfarction, QRS duration >150 ms, LBBB, body mass index<30 kg/m2, and smaller LAvolume index [27•]. Lead positioncan play a critical role in determining response to CRTamongthe non-clinical risk predictors. Studies have compared therelative position of LV lead (apical vs lateral vs posterior vslateral), number of leads (BiV vs Triple V), versus approach toLV lead placement (conventional coronary sinus lead place-ment vs epicardial placement vs endocardial LV lead place-ment) [28, 29]. Initial data suggests that posterior or lateral LVlead position and triple V pacing with dual LV leads may besuperior in terms of reducing risk of ventricular arrhythmiasand that endocardial LV lead placement may have severaladvantages including maintaining the endo to epicardial de-polarization sequence.

Independent, randomized, prospective studies (TARGETand STARTER) have demonstrated that targeting LV leadplacement to sites of latest LV mechanical activation as de-fined by speckle tracking echocardiography is a most prom-ising method to improve clinical outcome after CRT. Othershave studied the utility of pre and intraprocedural magneticresonance imaging to guide CRT therapy. Pacing at the site oftransmural LV scar is a well-documented risk factor for CRTnon responders. Cardiac magnetic resonance imaging (MRI)can precisely determine intraventricular dyssynchrony andscar extent [30].

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Trials in Cardiac Resynchronization Therapy

Randomized controlled trials (RCTs) have validated the use ofCRT in patients with NYHA class III or IV symptoms, LVEF≤35 %, and QRS duration ≥120 to 140 ms to reduce symp-toms, reduce hospitalizations, and improve survival. Bothsymptomatic and mortality benefit were clearly demonstratedby several RCTs published prior to 2003 presented by Abra-ham et al [31].

Since then, the indications for CRT have expanded basedon evidence from more RCTs (Table 1). ResynchronizationReverses Remodeling in Systolic left Ventricular Dysfunction(REVERSE), Multicenter Automatic Defibrillator Implanta-tion Trial-Cardiac Resynchronization Therapy (MADIT-CRT)and Resynchronization for Ambulatory Heart Failure Trial(RAFT) have investigated the effectiveness of CRT in HFpatients with a wide QRS complex and NYHA class I–II(mild or HF symptoms). CRT benefit shown in these studiesis consistent with those from older studies performed in pa-tients with more severe HF symptoms.

REVERSE

This trial demonstrated that CRT improves LV structure andfunction and clinical outcomes in NYHA functional class Iand II HF with prolonged QRS. Six hundred ten patients withNYHA class I or II heart failure with a QRS >120 ms and aLVEF <40 % received a CRT device ±defibrillator and wererandomly assigned to active CRT (CRT-ON; n=419) or con-trol (CRT-OFF; n=191) for 12 months. The primary end pointHF clinical composite response, which compared only the

percent worsened, indicated 16 % worsened in CRT-ON com-pared with 21 % in CRT-OFF (p=0.10). Patients assigned toCRT-ON experienced a greater improvement in LV end-systolic volume (LV-ESV) index (p<0.0001) and other mea-sures of LV remodeling. Time-to-first HF hospitalization wassignificantly delayed in CRT-ON (p=0.03) [32].

MADIT CRT

This is the largest trial in patients with mild HF which dem-onstrated a beneficial impact of CRT on HF events and re-modeling in patients with NYHA class I or II symptoms. In1820, patients with an LVEF ≤30 %, QRS duration ≥130 ms,and NYHA class I (15 %) or II (85 %) HF were randomlyassigned to CRT-D or ICD alone. The study included patientswith ischemic (55 %) or non-ischemic (45 %) cardiomyopa-thy. At follow-up of 29 months, CRT-D produced a decreasein the primary end point (death from any cause or nonfatalheart failure events) as compared to ICD alone (17 vs 25 %),the benefit driven by a 41 % reduction in HF events. Thisbenefit was observed primarily in patients with QRS duration>150 ms. The trial also identified predictors of CRT response.In ischemic heart disease, in addition to prolonged QRSduration of >150 ms, systolic blood pressure <115 mmHg orLBBB were predictors of CRT response, whereas in non-ischemic cardiomyopathy, female gender, diabetes mellitus,or LBBB were identified as predictors. Also, patients withRBBB or intraventricular conduction disturbances did notbenefit from CRT-D. During long-term follow-up of thiscohort, the mortality rate was also lower among patients withLBBB randomly assigned to CRT-D [33••].

Table 1 Expansion of CRT indications from randomized controlled trials to include NYHA I–II, LVEF <40 %, QRS >120 ms, and chronic RV pacingsecondary to AV block [32, 33••, 34••, 35, 36••]

Study Design Patients Results

REVERSE Prospective, randomized,double-blind trial

610 patients with NYHA class I/II QRS>120,LVEF<40 %, randomly assigned to activeCRTor control for 12 months

Greater improvement in LV end-systolicvolume index and other measures of LVremodeling. Time-to-first HF hospitalizationwas significantly delayed INCRT-ONgroupat 12 months

MADITCRT

Prospective, multicenter,randomized, 3:2 ratio toCRT-D or only ICD

1820 patients with LVEF ≤30 %, QRS ≥130 ms,and NYHA class I/II assigned to CRT-D or ICDalone. Ischemic (55 %) or non-ischemic (45 %)

Significant decrease in death from any cause ornonfatal heart-failure events in CRT-D at2.4 years, primarily in patients with QRS>150 ms

RAFT Prospective, multicenter, double-blind, randomized, controlledtrial

1798 patients with NYHA class II/III,LVEF<30 %, QRS >120 ms to ICD alone or CRT-D

Greater reduction in death and hospitalizationfor heart failure at 40 months with increasein adverse events

BLOCKHF Prospective, multicenter,randomized, double-blind trial

691 patients with pacing indication for highdegree AV block; NYHA class I, II, or III;LVEF 50 % or less

Reduction in death from all cause, HFhospitalization, LV ESVat 37 months

PACE prospective, double-blind,multicenter, randomized trial

177 patients implanted with CRT randomized toBiV pacing or RVapical pacing only

LVEF significantly lower in RV pacingwhereas LV ESV was significantly lower inBiV pacing at 12 months

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RAFT

This landmark trial confirmed the efficacy of CRT in patientswith mild or moderate HF. Close to 1800 patients with anLVEF ≤30, QRS ≥120 ms (or paced QRS ≥200 ms), andNYHA class II and III HF who were randomly assigned toCRT-D or ICD alone. Patients with CRT-D had a greaterdecrease in the primary outcome of death from any cause orhospitalization compared to ICD alone. Again, the benefit wasobserved primarily in patients with a QRS duration ≥150 msin this trial as well. This study also included a significantnumber of patients with permanent atrial fibrillation (AF) thatfailed to demonstrate an improvement in clinical or surrogateoutcome despite a trend for reduction of HF hospitalizations.Negative outcome from this trial has been attributed to sub-optimal delivery of CRTwith only one third of patients having>95 % BiV pacing. Permanent AF is present in 25 to 30 % ofCRTcandidates which remains a limitation for optimized CRT[34••].

Newer Indications for CRT in Patients with PacemakerIndications

Approximately eight to 15 % of patients with HF have pace-makers implanted for symptomatic bradycardia. Such patientshave a dyssynchronous contraction caused by RV pacingwhich leads to increased risk of mortality. Biventricular pac-ing for AV block to prevent cardiac desynchronization(PACE) and Biventricular versus RV Pacing in patients withLeft Ventricular dysfunction and AV Block (BLOCK-HF)trials demonstrated the efficacy of BiV pacing in thesepatients.

PACE

Studies have also determined the clinical impact of BiVpacing in pacemaker candidates with normal LVEF. In theprospective, double-blind, multicenter PACE trial, 177 pa-tients implanted with BiV pacemaker were randomly assignedto receive biventricular pacing (89 patients) or RV apicalpacing (88 patients). After 1 year, mean LVEF was signifi-cantly lower in RV pacing group with an absolute differenceof 7.4 percentage points compared to BiV pacing, whereasLV-ESV was significantly lower in the biventricular-pacinggroup [35].

BLOCK HF

In this trial, all 691 patients with high-degree atrioventricular(AV) block, NYHA class I to III HF, and LVEF ≤50 % had aCRT device implanted and then were randomly assigned in adouble-blind fashion to single-chamber RVapical only or BiVpacing. At 37 months, the primary outcome (combination of

all-cause mortality, urgent HF visit requiring intravenous ther-apy, or 15 % or more increase in LV-ESV index) was signif-icantly less likely to have occurred in the BiV pacing group.This change was mainly driven by the reduction in LV-ESV.This trial was built on evidence from Dual Chamber and VVIImplantable Defibrillator (DAVID) and MOde Selection Trial(MOST) that had already shown that RV pacing was associ-ated with unfavorable LV dysfunction and outcomes [36••].

Guidelines in Cardiac Resynchronization Therapy 2008,2012

Before device therapy can be implemented, GDMTwith betablockers, ace-inhibitors and aldosterone antagonists must beachieved [37]. Currently, the guidelines require failed GDMT,LVEF ≤35 %, sinus rhythm and QRS duration ≥150 ms as aclass I indication for CRT implantation. Since 2010, guide-lines have expanded to include patients with mild symptomssuch as found in NYHA class I or II, with LBBB and QRS≥150 ms and NYHA II–IV with LBBB with QRS ≥120–149 ms. Those with NYHA III and ambulatory NYHA classIV, an indication is for LBBB QRS ≥120 ms, non-LBBB, andQRS ≥120–149 ms. According to the most recent guidelines,those with NYHA class II with non-LBBB and QRS ≥120–149 ms are not indicated to have CRT.

In order for CRT to be optimized, it is recommended thatgreater-than 95 % ventricular pacing occurs. In patients withrhythm issues such as atrial fibrillation and chronic ventriculararrhythmias, this previously posed an issue. Now, with ad-vanced technology, those with rate-controlled atrial fibrillationand LVEF ≤35% regardless of functional class are consideredas a class IIa recommendation. Another class IIa recommen-dation is for CRT to be implemented in those with LVEF≤35 % with ventricular pacing over 40 % of the time aschronic RV pacing has shown to worsen LV function overtime certain subset populations.

Lastly, in NYHA class I patients, there have been advance-ments in earlier implementation for CRT. These are class IIBrecommendations to implement CRT in those with severecardiomyopathy as LVEF ≤30 % due to ischemia, LBBB,and QRS duration ≥150 ms, in patients with LVEF ≤35 %with non-LBBB pattern and QRS ≥120–149 ms and NYHAIII/IVas well as for those with LVEF ≤35 %, in sinus rhythmwith non-LBBB pattern but QRS ≥150 ms and NYHA class IIsymptoms.

It is not recommend to place CRT in a patient whose lifeexpectancy is poor (i.e., less than 1 year) and in those whohave mild symptoms (NYHA I/II) with non-LBBB patternand QRS <150ms. Other indications for CRTaccording to the2012 guidelines from the ACC/AHA/HRS are as follows inTables 2 and 3 [38].

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Improving/Predicting CRT Response

Optimal LV Lead Placement—Imaging Guided CoronarySinus Placement

Placement of the LV lead to the latest sites of contraction andaway from the scar confers the best response to CRT. A studydone by Khan et al. with 220 patients scheduled for CRTunderwent baseline echocardiographic speckle-tracking 2-di-mensional radial strain imaging and were then randomized 1:1into two groups. In group 1 (targeted left ventricular lead place-ment to guide cardiac resynchronization therapy (TARGET)), theLV lead was positioned at the latest site of peak contraction withan amplitude of >10 % to signify freedom from scar. In group 2(control), patients underwent standard unguided CRT. Patientswere classified by the relationship of the LV lead to the optimalsite as concordant (at optimal site), adjacent (within 1 segment),or remote (≥2 segments away). In the TARGET group, therewere a greater proportion of responders at 6months (70 vs. 55%,p=0.031), giving an absolute difference in the primary end pointof 15 % (95 % confidence interval 2 to 28 %). Compared withcontrols, TARGET patients had a higher clinical response (83 vs.65 %, p=0.003) and lower rates of the combined end point (log-rank test, p=0.031) [39•].

In addition to speckle tracking, cardiac magnetic resonance(CMR) can be used to guide LV lead placement to avoid scar

tissue at the site of LV pacing. CMR targets were defined asthree latest activated segments and had <50 % scar. The studydemonstrated that CMR-guided lead placement led to im-provements in both acute hemodynamic response (AHR) aswell as chronic response defined as decrease in LV ESV at6 months <15 % [40].

LV Lead Placement—Alternative Approaches to CoronarySinus LV Pacing

Coronary sinus LV lead placement by conventionalendovascular approach versus robotic-assisted surgical epicar-dial LV lead placement for CRT in patients with HF showedno significant differences. Surgical approaches are still a via-ble alternative when a transvenous procedure has failed or isnot technically feasible [41].

Despite the excellent results and absence of significantcomplications demonstrated thus far in the literature, the lackof a simple, straightforward, and standard technique limits itswidespread utilization of endocardial stimulation of the leftventricle for cardiac resynchronization therapy. The Jurdhamprocedure is a technique for inserting the left ventricle leadthrough a femoral transseptal sheath to the pectoral implantsite. A snared 85-cm standard active fixation endocardialpacing lead is implanted on the left ventricle endocardiumthrough a femoral transseptal sheath with subsequent

Table 2 Indications for CRT according to class of recommendation and level of evidence (LOE) from the ACC/AHA/HRS 2012 guidelines [38]

LOE A LOE B LOE C

Class I NYHA III and ambulatory NYHA IVLVEF≤35 %Sinus rhythmQRS≥150 msLBBB

NYHA IILVEF≤35 %Sinus rhythmQRS≥150 msLBBB

Class IIa NYHA III and ambulatory NYHA IVLVEF≤35 %Sinus rhythmQRS≥150 msNon-LBBB morphology

NYHA II ambulatory NYHA IVLVEF≤35 %Sinus rhythmQRS 120–149 msNYHA III and ambulatory NYHA IVLVEF≤35 %Atrial fibrillationRequires ventricular pacingor after AV nodal ablationor pharmacological rate willallow near 100 % pacing

NYHA III and ambulatory NYHA IVLVEF <35 %Indication for conventionalpacing and anticipatedsignificant (>40 %)ventricular pacing

Class IIb NYHA III and ambulatory NYHA IVLVEF≤30 %Sinus rhythmQRS 120–149 msNon-LBBB morphologyNYHA IILVEF≤35 %Sinus rhythmQRS≥150 msNon-LBBB morphology

NYHA ILVEF≤30 %Sinus rhythmQRS≥150 msLBBBIschemic cause

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mobilization of the proximal end of the lead to the prepectoralarea via the snare. During short-term follow-up, there has beenan excellent clinical response without significant complica-tions [42].

Lastly, Burger et al. demonstrated that there was no signif-icant difference between the different concepts of lead implan-tation with epicardial LV lead implantation [43].

Updates in Cardiac Resynchronization Devices

Pacing Algorithm

RESPOND CRT is an active clinical trial evaluating a novelSonR algorithm that can automatically optimize atrioventric-ular (AV) and interventricular (VV) intervals each week usingan accelerometer to measure change in the SonR signal, in

patients with NYHA class III or ambulatory IVHF eligible fora CRT-D device. Enrolled patients are randomized in a 2:1ratio to either SonR CRT optimization or to a control armemploying echocardiographic optimization. All patients arefollowed for at least 24 months in a double-blinded fashion.The primary effectiveness end point is evaluated for non-inferiority, with a nested test of superiority, based on theproportion of responders (defined as alive, free from HF-related events, with improvements in NYHA class or im-provement in Kansas City Cardiomyopathy Questionnairequality of life score) at 12 months. The two primary safetyend points are acute and chronic SonR lead-related complica-tion rates, respectively. Secondary end points include propor-tion of patients free from death or HF hospitalization, propor-tion of patient with worsened NYHA class, and lead electricalperformance, assessed at 12 months. The RESPOND CRTtrial will also examine associated reverse remodeling at 1 year[44].

Table 3 Indications for CRT categorized by NYHA functional class further delineated by class of recommendation and level of evidence (LOE) fromthe ACC/AHA/HRS 2012 guidelines [38]

Functional class Indication Indication Indication Indication

NYHA I Class IIb; LOE CNYHA ILVEF≤30 %Sinus rhythmQRS≥150 msLBBBIschemic cause

NYHA II Class I; LOE BNYHA IILVEF≤35 %Sinus rhythmQRS≥150 msLBBB

Class IIa; LOE BNYHA II ambulatory NYHA IVLVEF≤35 %Sinus rhythmQRS 120–149 msLBBB

Class IIb; LOE BNYHA IILVEF≤35 %Sinus rhythmQRS≥150 msNon-LBBBmorphology

NYHA III/IV Class I; LOE ANYHA III and ambulatoryNYHA IV

LVEF≤35 %Sinus rhythmQRS≥150 msLBBB

Class IIa; LOE ANYHA III and ambulatory NYHA IVLVEF≤35 %Sinus rhythmQRS≥150 msNon-LBBB morphologyClass IIa; LOE BNYHA III and ambulatory NYHA IVLVEF≤35 %Atrial fibrillationRequires ventricular pacing or after AV nodalablation or pharmacological rate will allownear 100 % pacing

Class IIa, LOE CNYHA III and ambulatory NYHA IVIndication for conventional pacing and anticipatedsignificant (>40 %) ventricular pacing

Class IIb; LOE BNYHA III and ambulatoryNYHA IV

LVEF≤30 %Sinus rhythmQRS 120–149 msNon-LBBB morphology

Any class HFSA class IIb; LOE CNo NYHA class,Chronic ventricular pacing,Reduced LVEF

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Cardiac Contractility Modulation

Cardiac contractility modulation (CCM) is a new device-based therapy shown to augment the strength of left ventric-ular contraction independent of myocardial oxygen consump-tion in animal models as well as human studies. It is applicablein patients with advanced systolic HF with normal QRSduration and therefore who are not suitable for cardiacresynchronization therapy (CRT). It involves applying electri-cal signals during the absolute refractory period of the myo-cardial action potential. Left ventricular (LV) reverse remod-eling was reported in patients treated with CCM or CRT. In anobservational study of 56 patients, CCM exhibited a similarLV reverse remodeling response to CRT for patients with amildly prolonged QRS, though the effect was less strongwhen compared to CRT for patients with a very wide QRS[45•].

The mechanism underlying CCM is an alteration of myo-cardial calcium handling leading to a shift of abnormallyexpressed genes towards normal function and positively af-fecting pathways involving proteins that regulate calciumcycling and myocardial contraction. Clinical benefits ofCCM include improvement in exercise tolerance, as measuredby peak VO2 and quality of life, assessed by the MinnesotaLiving with Heart Failure Questionnaire. Although the deviceis currently available for the treatment of HF in Europe,approval in the USA is pending additional testing currentlyunderway using a protocol approved by the US FDA [46].

Vagus Nerve Stimulation and Role of Autonomic Regulationin Heart Failure

The Autonomic Neural Regulation Therapy to Enhance Myo-cardial Function in Heart Failure (ANTHEM-HF) study hasbeen designed to address several key clinical questions aboutthe role of autonomic regulation therapy (ART) in patientswith LV dysfunction and chronic symptomatic heart failure.ANTHEM-HF should provide additional and valuable infor-mation regarding the safety and the relationship between thesite and intensity of ART and its salutary effects on HF inpatients with overall poor prognosis despite being on neuro-hormonal blocking agents and CRT [47].

Concept of Dynamic LV Dyssynchrony

Contrary to our belief, LV dyssynchrony (LVD) may not astable phenomenon. Variables such as inducible ischemia,exercise, and drug administration may significantly alter thepresence and the magnitude of LVD, which could per semodulate response to treatment for HF. Dynamic changes inLV synchronicity during stress testing occur independently ofinducible ischemia and irrespective of QRS width and varysubstantially from patient to patient. The dynamic increase in

LVD can influence the severity of exercise-induced changes inmitral regurgitation and limit stroke volume adaptation duringexercise. But, it is not clear if this phenomenon can affect theoutcome in CRT patients. In the setting of CRT, the assess-ment of dynamic LVDmight help patient selection, predict themagnitude of response, and optimize pacing delivery duringexercise. Further longitudinal studies are required to confirmthe value of assessing dynamic LVD [48].

Lead Technology and Dual-Site LV Leads

LV leads have emerged with multiple stimulation sites tofurther optimize synchrony and LV function. Therefore, thestimulation site can be altered to improve QRS duration orecho-guided synchrony with clinical follow-up. Newer LVleads have multiple sites and configurations for stimulationselection for optimization. Furthermore, devices have ex-plored the placement of two LV leads in different coronarysinus branches to optimize mechanical and electricalsynchrony.

Leadless Endocardial LV Implantation

With the advent of leadless pacemakers for RV pacing(Nanostim–St Jude and Micra–Medtronic) already showingpromise, similar technology has been tried for LV pacing inCRT. The study titled Wireless Stimulation Endocardially forCRT (WiSE-CRT) is evaluating the safety and feasibility inspecific subsets of patients with CRT-eligible HF. Advantagesare numerous and include the following: lower capture thresh-olds, reduced phrenic nerve stimulation, stability of an activefixation endocardial receiver electrode, choice of the site ofLV stimulation, less arrhythmogenic, improved ventricularresynchronization, increase in dP/dtmax and alleviate or sup-press the thromboembolic complications and interaction withmitral valve, and free of worry about lead-related complica-tions, including lead infections or fractures [49].

Remote Monitoring of Intracardiac Devices and Reductionin HF Readmission Rates

Remote follow-up using intracardiac devices for early detec-tion of fluid overload monitors thoracic impedance and pre-dicts stroke volume to predict hospitalization due to acute HF[50–52]. Intrathoracic impedance and intravascular fluid sta-tus have an inverse relation which can notify the provider ofimpending exacerbations, dehydration, and bleeding events.Weights, blood pressures, and pulse rates can also be trans-mitted for provider review.

The diagnostic data from cardiac resynchronization therapydefibrillator (CRT-D) devices can identify outpatient HF pa-tients at risk of future HF events. In a retrospective analysis offour studies, patients with CRT-D devices with a HF

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admission, the 30-day post discharge follow-up data wereanalyzed. The evaluation of the device diagnostic data forimpedance, atrial fibrillation, ventricular heart rate duringatrial fibrillation, loss of CRT-D pacing, night heart rate, andheart rate variability was used to create a combined score.After adjusting for confounding variables, it was determinedthat daily impedance, high atrial fibrillation burden with poorrate control (>90 beats/min), or reduced CRT-D pacing (80beats/min) were significant univariate predictors of 30-day HFreadmission. Patients in the “high”-risk group for the com-bined diagnostic had a significantly greater risk (hazard ratio25.4, 95 % confidence interval 3.6 to 179.0, p=0.001) com-pared to the “low”-risk group for 30-day readmission for HF[53•].

Non-responders

What Is Defined as CRT Response?

There is a lot of variability in definition of CRT responders.However, the widely accepted criteria for response to CRT at6 months after implantation included clinical, biochemical,and echocardiographic parameters. Clinical criteria included aclinical composite score (CCS), combining all-cause mortali-ty, HF hospitalization, NYHA class, and patient global assess-ment, and was defined as improved if a patient was alive withimprovement in both NYHA class and patient global assess-ment, with no hospital admissions for HF. Such patients wereclassified as responders and those not fulfilling these criteria,non-responders. Other indicators of CRT response at follow-up included the following: improvement in NYHA class,increase in total 6MWT distance, and reduction in MinnesotaLiving with Heart Failure Questionnaire (MLHFQ) score.Biochemical indicators for CRT response included a fall inthe level of NT-proBNP, and imaging criteria was a reductionin LV end-diastolic diameter (LVEDD, measured from theparasternal long axis view) or an increase in LVEF (biplane)or decrease in end-systolic volume, as evaluated by echocar-diography [54].

Characteristics of Normal Responders

As mentioned earlier, clinical and imaging characteristics ofsuper responders have been described by Hsu et al [27•]. CRTresponders typically have electrocardiography predictors in-cluding a QRS duration ≥150 ms and LBBB; echocardio-graphic predictors including interventricular (≥40 ms differ-ence between LV and RV preejection intervals) or intraven-tricular mechanical dyssynchrony (≥65 ms delay betweentime to peak systolic velocity of the basal septal and basallateral LV segments) were used to predict CRT response.

Cardiac magnetic resonance (CMR) predicted respondershad a composite of septal-lateral LV wall delay ≥65 ms andthe absence of transmural late gadolinium enhancement(LGE) within the anteroseptum or inferolateral wall

Characteristics with Suboptimal CRT Response

Approximately 30 % of CRT candidates are non-responders[31]. Advanced age, male sex, severe mitral regurgitation,atrial fibrillation, ischemic cardiomyopathy, NYHA ambula-tory class IV HF, chronic renal failure, diabetes mellitus, QRS<150, RBBB, and increased levels of brain natriuretic peptidehave been associated with poorer outcomes after CRT withdefibrillator implantation.

Echocardiographic Predictors of Dssynchrony

Echocardiogram has been widely used to identify mechanicaldyssynchrony and optimize CRT. Several modalities includeM-mode, pulsed tissue Doppler, color-coded tissue Doppler,strain imaging, speckle tracking, and more recently 3D echo-cardiography to identify AV, VV, and intraventriculardyssynchrony as seen in Table 4. AV and VV optimizationaims to improve LV hemodynamics by maximizing LV fillingtime and decreasing LV mechanical dssynchrony. However,there is conflicting data about the role of VVoptimization inpredicting CRT responders. Most widely used intraventriculardyssynchrony parameter is the color-coded tissue Dopplerimaging. Strain imaging to predict CRT response is alsolimited by its dependency on angle of insonation, an inherentlimitation of Doppler techniques. This has been overcome byspeckle tracking echocardiography and direct volumetric 3Dindices such as systolic dyssynchrony index (SDI) [55–57].

CRT Failure

Suboptimal BiV Pacing

In real world practice, about 40 % of patients on CRT have<98 % BiV pacing. Atrial arrhythmias such as atrial tachycar-dia and atrial fibrillation (AT/AF) are likely to be accountedfor the largest portion of CRT loss in all patients with <98 %CRT pacing; however, its contribution diminishes as theamount of CRT pacing approached 98% or greater. Prematureventricular contractions (PVC) contributed to loss of CRTpacing as overall pacing percentages approached 98 %. But,the overall largest contributor to more sustained loss of CRTpacing (i.e., ventricular sensed episodes (VSE) containing atleast 10 consecutive beats without CRT) was inappropriateprogramming of sensed or paced atrioventricular (SAV/PAV)intervals and lack of using rate adaptive AV (RAAV) pacing.

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These concerns can be alleviated by treating the AT/AF/PVCby ablation or AAD and adjustment of PAVand SAV intervalsand using RAAV pacing [59].

Indications for CRT in Special Populations

CRT in CKD

Badheka et al. performed a post hoc analysis addressing theimpact of renal dysfunction on survival in a secondary pre-vention population from the Antiarrhythmics Versus Implant-able Defibrillators (AVID) trial (n=1016), a large multicenterrandomized controlled trial designed to evaluate the role ofICDs versus conventional antiarrhythmic therapy in a second-ary prevention population. Patients were assumed to haverenal disease if they had glomerulonephritis, chronic kidneyinfections, acute tubular necrosis, renal insufficiency, orchronic renal failure. The AVID trial had 41 patients withrenal disease in the ICD arm. Renal disease was an indepen-dent predictor of all-cause mortality, and ICDswere protectivefor secondary prevention of cardiac (but not all-cause) mor-tality in patients with renal disease. This analysis concludedthat cardiac mortality and not all-cause mortality would be amore appropriate end point in evaluating ICD use for second-ary prevention of cardiac mortality in patients with renaldisease [60]. Despite small numbers in the subgroup analysis,this trial demonstrated a trend towards benefit of ICD utiliza-tion in this cohort.

CRT in Elderly

As the field of CRT advances, together with shifting demo-graphics and expanded indications for implantation, there is a

need for practitioners caring for older adults to understandabout the use of CRT specifically in the geriatric population.The mean age of patients included in most of the landmarktrials validating the use of CRT in HF were <70 years (COM-PANION 65±11, CARE-HF 67 (60–73), MIRACLE 63.9±10.7, MIRACLE-ICD 66.6±11.3). Unfortunately, elderly HFpatients >75 years, octogenarians, or patients with more se-vere co-morbidities have been largely underrepresented orexcluded in CRT trials. However, observational and registrydata have confirmed the efficacy of CRT in terms of clinicaland functional parameters, reverse remodeling, and even car-diac mortality in elderly patients over 75–80 years [61, 62].The risk of complications from LV lead implantation is notany worse than younger patients. But, most importantly, inelderly patients with several co-morbidities, the choice ofimplanting a device has to consider not only the potentialbenefit of the device but also the life expectancy, end-of-lifecare experiences, and cost-effectiveness.

Limitations of Cardiac Resynchronization Therapy

The surface EKG demonstration the QRS duration remainsthe cornerstone for indications for CRT. Unfortunately, thereare many who may benefit from CRT therapy but do not meetthe guideline-derived indications and there are nearly 30 %that do not respond to CRT despite guidelines inclusions.Clearly, more clinical trials are needed to assess CRT benefitsand indications.

Studies have shown that there are other predictors of poorventricular remodeling and improved clinical outcomes innarrow QRS HF patients. However, ECHO-CRT and Lesser-Earth failed to show improvement and in fact, both studieswere prematurely stopped as CRT did not reduce the rate ofdeath or hospitalization for HF and may actually worsen

Table 4 Summary of studies that demonstrated optimal echocardiographic parameters to improve CRT response. Table adapted from Klein et al 2011[58]

Author No Measurement Echocardiographic Technique Cut off value

Pitzalis et al 20 Septal-to-posterior wall motion delay M-mode ≥130 ms

Diaz-Infante et al. 67 Septal-to-posterior wall motion delay M-mode ≥130 ms

Penicka et al 49 Sum of LV and VV dyssynchrony (pulsed-wave systolic velocities) Pulsed-wave TDI >102 ms

Bax et al. 85 Delay in peak systolic velocities (four segments: basal septum, lateral,anterior, and inferior walls)

Color-coded TDI ≥65 ms

Yu et al. 56 Standard deviation of time to peak systolic velocities (12 LV segments) Color-coded TDI ≥31.4 ms

Dohi et al. 38 Delay in peak radial strain (septal-to-posterior wall) TDI-derived strain ≥130 ms

Delgado et al. 161 Delay in peak radial strain (anteroseptal-to-posterior wall) 2-dimensional radial strainspeckle tracking

≥130 ms

Marsan et al. 57 Systolic dyssynchrony index: standard deviation of time to minimumvolume (16 LV segments)

Real-time 3D echocardiography ≥6.4 %

Van de Veire et al. 60 Standard deviation of time to peak systolic velocities (12 LV segments) Triplane Tissue synchronizationindex (TSI)

>33 ms

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electrical dyssynchrony and be harmful by increasing mortal-ity in patients with narrow QRS [63••, 64].

The ideal position of the LV lead for CRT is still underdebate as to the area of maximal mechanical dyssynchronyversus the region with maximal electrical delay. Furthermore,native venous anatomy limits the “ideal” placement in pa-tients; therefore, advancements in imaging, placement ap-proach, lead design, and surgical techniques continue to beexplored.

Summary and Conclusions

HF remains one of the top five diseases and growing popula-tions in the USA. CRT has surfaced as one of the leadingdevice therapies in HF and has improved the lives of manysuffering with HF with indications that meet guideline provenbenefits. Advancements have made the therapy more apt inimproving symptoms, reducing hospitalizations, and decreas-ing mortality in those with HF. With advancements in diseaseunderstanding and technology as well as demonstration ofbenefits from more randomized, clinical trials, CRT will re-main a long-standing therapy in HF and continue to expand.

Acknowledgments We would like to thank Dr Priya Vejayan MD andMs Judi (Creighton Health sciences library) for their assistance in thepreparation of this manuscript.

Compliance with Ethics Guidelines

Conflict of Interest Satish Chandraprakasam and Gina G. Mentzerdeclare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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