Cardiac Resynchronization Therapy

Cardiac Resynchronization Therapy

State of the Art Review For the 25

Anniversary of Cardiac Resynchronization Therapy

Valentina Kutyifa ^{1, 2}

1

Clinical Cardiovascular Research Center, Cardiology Division, University of Rochester Medical Center, Rochester, NY, USA, and

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Address reprint requests to:

Valentina Kutyifa, MD, PhD, FHRS, FESC, FACC, Associate Professor of Medicine Clinical Cardiovascular Research Center, University of Rochester Medical Center

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E-mail: Valentina.Kutyifa@heart.rochester.edu or Valentina.Kutyifa@kardio.sote.hu

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FDUGLDFUHV\QFKURQL]DWLRQWKHUDS\&57KDVEHHQVKRZQWRLPSURYHIXQFWLRQDOFDSDFLW\+)V\PSWRPVDQGTXDOLW\RI OLIH6LQFHWKH¿UVWFDVHUHSRUWVZHUHSXEOLVKHGLQWKHUHKDYHEHHQDODUJHQXPEHURIUDQGRPL]HGFRQWUROOHGFOL- QLFDOWULDOVFRQGXFWHGWKDWKDYHSURYHQWKHHႈFDF\RI&57LQGLYHUVH+)SRSXODWLRQVVKRZLQJDVLJQL¿FDQWUHGXFWLRQLQ HF hospitalization and improved survival. CRT has, over the past 25 years, become a guideline-indicated, evidence-ba- VHGGHYLFHWKHUDS\IRUPLOGDQGDGYDQFHG+)SDWLHQWVZLWKVHYHUHO\UHGXFHGOHIWYHQWULFXODUIXQFWLRQDQGDZLGH456 1HYHUWKHOHVVWKHUHDUHDQXPEHURIIDFWRUVQHJDWLQJEHQH¿FLDOUHVSRQVHWR&57DQGPXOWLSOHXQUHVROYHGTXHVWLRQVWR WKLVGD\7KLVUHYLHZDUWLFOHVXPPDUL]HVFXUUHQWDYDLODEOHNQRZOHGJHRQ&57LQ+)SDWLHQWVIURPUDQGRPL]HGFOLQLFDO WULDOVDQGRWKHUUHOHYDQWVWXGLHVGLVFXVVHVLPSRUWDQWGHWHUPLQDQWVRI&57UHVSRQVHDQGSURYLGHVDVHOHFWHGRYHUYLHZ RIXQUHVROYHGTXHVWLRQVZLWKIXWXUHGLUHFWLRQVIRUUHVHDUFK

Keywords:

Cardiac Resynchronization Therapy, Left Ventricular Dyssycnhrony, Clinical Outcomes, Clinical Trials, Future Directions

Mechanism of Cardiac Resynchronization Therapy in the Failing Heart

3DWLHQWV ZLWK +) RIWHQ SUHVHQW ZLWK DQ HOHFWULFDO FRQ- duction delay, resulting in dyssynchronous left ventricu- lar activation, impaired left ventricular systolic function, PLWUDOUHJXUJLWDWLRQDQGDVLJQL¿FDQWO\UHGXFHGFDUGLDF output (1). An electrical conduction delay is manifes- ted either as a left bundle branch block (LBBB), right bundle branch block (RBBB), or as an intraventricular conduction delay (IVCD). Electrical activation of the YHQWULFOHV LQ SDWLHQWV ZLWK /%%% DQG 5%%% KDV EHHQ SUHYLRXVO\GHVFULEHGE\)DQWRQLHWDO3DWLHQWVZLWK LBBB typically have multiple right ventricular (RV) bre- akthrough sites in the septum as compared to RBBB

ZLWK D VLQJOH 59 EUHDNWKURXJK VLWH 7UDQVVHSWDO DFWL- vation time, activation time of the RV, and total activa- WLRQWLPHLVVLJQL¿FDQWO\ORQJHULQ5%%%DVFRPSDUHG WR /%%% ,Q SDWLHQWV ZLWK /%%% RU 5%%% WKHUH LV D VORZ OHIW YHQWULFXODU /9 HOHFWULFDO DFWLYDWLRQ IURP WKH septal or anterior breakthrough sites to the apical and lateral regions. Most typically, the postero-lateral basal region is the latest activated LV area in both LBBB and RBBB, providing the rationale for biventricular pacing ZLWKDQ/9ODWHUDOSRVWHURODWHUDOOHDGLQWKLVSRSXODWLRQ

$OWKRXJKSDWLHQWVZLWK5%%%H[KLELWDPRUHDGYDQFHG conduction tissue disease than LBBB that is often less amenable to CRT.

Cardiac resynchronization therapy (CRT) or biventricu-

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tor system that delivers electrical stimuli to the right atri- um, right ventricle, and left ventricle to synchronize the G\VV\QFKURQRXV/9DFWLYDWLRQLQSDWLHQWVZLWKFRQGXF- tion tissue disease and a severely reduced LV function.

&57ZDVGHYHORSHGWRUHVWRUHWKHSK\VLRORJLFDODWULDO and ventricular contraction in the failing heart and cor- UHFWDWULRYHQWULFXODUG\VV\QFKURQ\DVZHOODVLQWHUYHQW- ricular dyssynchrony and intraventricular dyssynchrony.

Atrioventricular dyssynchrony, or PR-prolongation is RIWHQ REVHUYHG LQ +) SDWLHQWV OLQNHG WR ZRUVH FOLQLFDO outcomes (3). The pathophysiology of a prolonged-PR interval is primarily based on the atrial systole (A) oc- curring early in diastole and therefore, it is superimpo- VHG RQ WKH HDUO\ OHIW YHQWULFXODU ¿OOLQJ SKDVH ( VXE- sequently leading to the fusion of the diastolic E and A ZDYHVVKRUWHQLQJHႇHFWLYHGLDVWROLF/9¿OOLQJWLPHDQG decreasing cardiac output. The early atrial systole un- couples the mitral valve closure from LV systole resul- ting in diastolic pre-systolic mitral regurgitation, dec- UHDVHGSUHORDGDQGGHFUHDVHGIRUZDUGVWURNHYROXPH IXUWKHUZRUVHQLQJ/9IXQFWLRQ)ROORZLQJ&57LPSODQWD- tion, normalization of the PR-interval restores the phy- siologic AV-sequence, eliminating the pathologic E and A fusion, and diastolic pre-systolic mitral regurgitation.

Restoration of interventricular and intraventricular dyssynchrony via synchronized left ventricular (LV) and right ventricular (RV) pacing, or most often, LV pre-ex- citation additionally results in an immediate decrease of intra- and interventricular dyssynchrony, a decrea- se in mitral regurgitation, and an increase in LV cont- ractility (4). Long-term CRT use is linked to a reduction in LV end-diastolic (LVEDV) and LV end-systolic volu- me (LVESV), and improvement in LV ejection fraction (LVEF), described as LV reverse remodeling (5, 6) (Fi-

gure 1). Eliminating LV dyssynchrony, reducing LV vo- lumes, and increasing LVEF is the hallmark of cardiac UHV\QFKURQ]LDWLRQ WKHUDS\ WKDW LV DVVRFLDWHG ZLWK EH- QH¿FLDOFOLQLFDORXWFRPHV(Figure 2).

Randomized Clinical Trials in Cardiac Resynchronization Therapy

There have been a large number of randomized cont- UROOHGFOLQLFDOWULDOVWRDVFHUWDLQWKHVDIHW\DQGHႈFDF\

of CRT or CRT-D to improve quality of life, HF symp- toms, functional capacity, and clinical outcomes. These VWXGLHV DUH VXPPDUL]HG EHORZ LQ Table 1. As it has been evidenced in the early studies enrolling 50-100 SDWLHQWV LPSODQWDWLRQ RI &57 UHVXOWHG LQ D VLJQL¿FDQW improvement in HF symptoms, functional capacity, and TXDOLW\ RI OLIH LQ +) SDWLHQWV ZLWK DGYDQFHG +) V\PS- WRPV 1<+$ FODVV ,,,,9 UHGXFHG /9()” DQG D SURORQJHG 456 GXUDWLRQ 456• PV ± 7KH

¿UVW GRXEOHEOLQG UDQGRPL]HG FRQWUROOHG FRPSDULVRQ RI&57ZDVFRQGXFWHGLQWKH0,5$&/(WULDOHQUROOLQJ SDWLHQWVFRQ¿UPLQJLQDODUJHUFRKRUWRI+)SDWL- HQWV WKDW &57 LPSURYHV 1HZ <RUN +HDUW $VVRFLDWLRQ 1<+$ FODVV TXDOLW\ RI OLIH PLQXWH ZDON WHVW DQG also reduces left ventricular volumes, and improves OHIWYHQWULFXODUHMHFWLRQIUDFWLRQFRXSOHGZLWKLPSURYH- ments in clinical symptoms.

6XEVHTXHQWZHOOGHVLJQHGUDQGRPL]HGFRQWUROOHGODU- ge clinical trials, Cardiac Resynchronization-Heart Fa- ilure (CARE-HF), and Comparison of Medical Therapy, 3DFLQJDQG'H¿EULOODWLRQLQ+HDUW)DLOXUH&203$1,21 KDYHVKRZQIRUWKH¿UVWWLPHWKDW&57DOVRLPSURYHV VXUYLYDOLQSDWLHQWVZLWKDGYDQFHG+)V\PSWRPV1<+$

FIGURE 1. Electrical activation of the left and right ventricle in patients with right bundle branch block and left bundle branch

block (2)

FODVV,,,,9UHGXFHG/9()”DQGDSURORQJHG456 GXUDWLRQ 456• PV $OWRJHWKHU WKHVH VWX- dies provided the basis for current guideline-based in- GLFDWLRQVIRU&57LQDGYDQFHG+)SDWLHQWVZLWK1<+$

Class III or IV (11). Today, tens of thousands of advan- FHG+)SDWLHQWVDUHLPSODQWHGZLWK&57LQ+XQJDU\LQ (XURSHDQGZRUOGZLGH$PHWDDQDO\VLVRI&57WUL- DOVLQDGYDQFHG+)VKRZHGDQRYHUDOOULVNUHGXF- WLRQLQDOOFDXVHPRUWDOLW\DQGDULVNUHGXFWLRQLQ mortality due to progressive HF (13).

)ROORZLQJ WKH VXFFHVV RI &57 LQ DGYDQFHG +) SDWL- ents, subsequent clinical trials focused on broadening WKHLQGLFDWLRQRI&57WRSDWLHQWVZLWKPLOG+)7KH0XO- WLFHQWHU $XWRPDWLF 'H¿EULOODWRU ,PSODQWDWLRQ 7ULDO&DU- diac Resynchronization Therapy (MADIT-CRT), the 5HV\QFKURQL]DWLRQ'H¿EULOODWLRQ LQ $PEXODWRU\ +HDUW Failure Trial (RAFT) and Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction 5(9(56(WULDOVHQUROOHGSDWLHQWVSULPDULO\ZLWKPLOG +)SUHVHQWLQJZLWK1<+$FODVV,DQG,,+)V\PSWRPV 7KHVH VWXGLHV KDYH VKRZQ D VLJQL¿FDQW UH- duction in HF events and improvement in clinical sy- PSWRPVDVZHOODVVLJQL¿FDQW/9UHYHUVHUHPRGHOLQJ 7KH VXEVHTXHQWO\ SXEOLVKHG ORQJWHUP IROORZXS RI 0$',7&57DQG5(9(56(VWXGLHVFRQ¿UPHGVXVWD- LQHGEHQH¿WRI&57LQPLOG+)SDWLHQWVXSWR\HDUV ZLWKUHGXFWLRQLQ+)HYHQWVDQGDVLJQL¿FDQWUHGXFWLRQ in mortality (16, 17).

Modifying Factors of Response to Cardiac Resynchronization Therapy

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als, nearly one third of the patients demonstrate a lack of echocardiographic or clinical response to CRT, they are so-called non-responders. Non-response has been the major focus of CRT research the past 25 years to optimize use, delivery, and care of CRT patients to opti- mize outcomes. Non-response to CRT is multifactorial, including baseline clinical charcteristics linked to unfa- vorable outcomes through CRT delivery, and post-imp- lant factors, such as arrhythmias and CRT program- ming.

Baseline Clinical Characteristics

There have been a number of clinical factors associ- DWHGZLWKSRRUFOLQLFDOUHVSRQVHWR&57LQFOXGLQJGLD- betes, renal dysfunction, and ischemic cardiomyopathy (18). On the contrary, a superior response to CRT is predicted by female sex, non-ischemic etiology of car- GLRP\RSDWK\OHIWEXQGOHEUDQFKEORFNZLGH456DQG a less dilated left ventricle (19). The amount of scar has EHHQ VKRZQ WR QHJDWLYHO\ FRUUHODWH ZLWK RXWFRPHV LQ SDWLHQWV ZLWK &57 DQG ZDUUDQW IXUWKHU LQYHVWLJDWLRQ It is plau sible that advanced scar formation might not be amenable to CRT and on the contrary, might be arrhyth mogenic, especially if LV pacing occurs near a VFDU UHJLRQ DV VKRZQ E\ SUHYLRXV VWXGLHV ,PSRUWDQW JHQGHU GLႇHUHQFHV LQ &57 RXWFRPHV PLJKW EH OLQNHG WRWKHIDFWWKDWZRPHQRIWHQSUHVHQWZLWKQRQLVFKHPLF cardiomyopathy and LBBB, a substrate that is the most responsive to biventricular pacing (20).

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and by the underlying ECG pattern at baseline, befo-

block (2)

UH &57 LPSODQWDWLRQ 7KH ¿UVW ODUJH UDQGRPL]HG WULDOV GHVLJQHG WR HYDOXDWH WKH HႇHFW RI &57 RQ DOOFDXVH mortality, Cardiac Resynchronization-Heart Failure (CARE-HF), and Comparison of Medical Therapy, Pa- FLQJDQG'H¿EULOODWLRQLQ+HDUW)DLOXUH&203$1,21 HQUROOHG RQO\ DQG RI WKHLU SDWLHQWV ZLWK QRQ /%%%UHVSHFWLYHO\7KH5(9(56(VWXG\HQUROOHG RI SDWLHQWV ZLWK QRQ/%%% DQG 0$',7&57 HQUROOHG DOORZLQJ XV ZLWK DQ RSSRUWXQLW\ WR DQDO\]H response by QRS morphology.

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SDWWHUQZHUHVKRZQWRGHULYHOHVVRUQREHQH¿WDQGRXU sub-study from MADIT-CRT suggested potential harm 6XEVHTXHQW VWXGLHV FRQ¿UPHG DQ DVVRFLDWLRQ EHWZHHQ 456 GXUDWLRQ DQG RXWFRPHV LQ WKH 5(9(5- 6(WULDO$VXEDQDO\VLVIURPWKH5$)7WULDOFRQ¿U- PHG D OLQN EHWZHHQ 456 PRUSKRORJ\ 456 GXUDWLRQ DQG RXWFRPHV LQ /%%% DQG QR EHQH¿W LQ QRQ/%%%

SDWLHQWV VLPLODUO\ WR D ODUJH 86 QDWLRQZLGH UH- gistry, the National Cardiovascular Database Registry (NCDR) ICD Registry (25). Based on these observa-

tions, CRT today is a Class I or Class IIa indication for

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The previously conducted and published ECHO-CRT (27) and RethinQ (28) studies assessed CRT indication IRU +) SDWLHQWV ZLWK D QDUURZ 456 FRPSOH[ PV EXWIDLOHGWRGHPRQVWUDWHDEHQH¿W7KHUHIRUH&57LV FXUUHQWO\QRWLQGLFDWHGIRUSDWLHQWVZLWKDQDUURZ456 complex, unless they require frequent ventricular pa- FLQJ!WRWUHDWEUDG\FDUGLDDQLQGLFDWLRQWHVWHGLQ the BLOCK-HF study (29).

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¿OOLQJDQGSRVVLEOHVHULRXVDGYHUVHFOLQLFDOFRQVHTXHQ ces as discussed above (3), and it could potentialy- ly be another important determinant of CRT response.

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TABLE 1. Randomized Past and *Ongoing Controlled Trials of Cardiac Resynchronization Therapy. Abbreviations: 6MWT, 6-min

walk test; CARE-HF, Cardiac Resynchronization-Heart Failure; COMPANION, Comparison of Medical Therapy, Pacing and Defib- rillation in Heart Failure; HF, heart failure; LV, left ventricular; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MADITCRT, Multicenter Automatic Defibrillator Implantation Trial–

Cardiac Resynchronization Therapy; MIRACLE, Multicenter InSync Randomized Clinical Evaluation; MIRACLE ICD, Multicenter InSync Implantable Cardioverter Defibrillator trial; MR, mitral regurgitation; MUSTIC, Multisite Simulation in Cardiomyopathies;

NYHA, New York Heart Association; PATH-CHF, Pacing Therapies in Congestive Heart Failure trial; QOL, quality-of-life score;

RAFT, Resynchronization-Defibrillation for Ambulatory Heart Failure; REVERSE, Resynchronization Reverses Remodeling in Systo- lic Left Ventricular Dysfunction; VO

, volume of oxygen

Clinical Trial Patients (n) Primary end points Secondary end points LVEF (%) QRS (ms)

MUSTIC-SR 58 6MWT NYHA, QOL, Peak VO₂, MR, LV,

Hosp, Mortality “ 174

MUSTIC-AF 64 6MWT NYHA, QOL, Peak VO2, Hosp,

Mortality “ 206

PATH-CHF 2 41 6MWT, peak VO2 NHYA class, QOL,

Hospitalizations “ 175

PATH-CHF-II:

(Europe)

86 6MWT, peak VO2 NHYA class, QOL,

Hospitalizations “ 175

MIRACLE 453 6MWT, NHYA, QOL Peak VO2, LVEF, LVEDD, MR,

Clin Response “ 166

COMPANION 1520 All-cause mortality or hospitalization

All-cause mortality and cardiac mortality

21 159

CARE-HF 814 All-cause mortality NYHA, QOL, LVEF, LVESV,

Hospitalization for heart failure

25 160

REVERSE 610 HF clinical composite score LVESVi “ 153

MADIT-CRT 1820 HF or death LVESV, LVEDV change, multiple

HF events “ 162

RAFT 1798 All-cause mortality or HF

hospitalization

All-cause mortality, cardiac

mortality, HF hospitalization “ 158 RAFT AF* 412 HF hospitalization or death Mortality, HF hosp, QoL, 6MWT, n.a. n.a.

BUDAPEST CRT Upgrade*

360 HF hospitalization, death, or lack of LV remodeling

Mortality, HF hospitalization n.a. n.a.

SDWWHUQ DQG D SURORQJHG 35LQWHUYDO • PV GHULYH DVLJQL¿FDQWFOLQLFDOEHQH¿WIURP&57'DVFRPSDUHG WR,&'ZLWKDULVNUHGXFWLRQLQ+)RUGHDWK DQGDQULVNUHGXFWLRQLQDOOFDXVHPRUWDOLW\1RQ /%%%SDWLHQWVZLWKDQRUPDO35LQWHUYDOPVZHUH KRZHYHUH[SRVHGWRDKDUPIURP&57'ZLWKDPRUH WKDQWZRIROGLQFUHDVHLQPRUWDOLW\ZKHQFRPSDUHGWR ,&'RQO\LQWHUDFWLRQSYDOXH:HVXEVHTX- HQWO\FRQ¿UPHGLQWKH0$',7&57ORQJWHUPIROORZXS VXEVWXG\VXJJHVWLQJDVXVWDLQHGFOLQLFDOEHQH¿WGXULQJ DPHGLDQIROORZXSRI\HDUV$SULRUVWXG\VKR- ZHGVLPLODUDVVRFLDWLRQVIURP&203$1,21ZLWKDSUR- longed PR-interval in more advanced HF patients (32), DQG LQ WKRVH ZLWK D QDUURZ 456 HQUROOHG LQ 5HWKLQ4 +RZHYHU PRUH UHFHQW VWXGLHV FKDOOHQJHG WKHVH

¿QGLQJV XVLQJ GDWD IURP WKH 1&'5 ,&' 5HJLVWU\ KR- ZHYHU WKLV FRKRUW ODFNHG UDQGRPL]DWLRQ )XUWKHU studies are needed in this cohort.

Controversies in CRT and Future Directions

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$9VHTXHQWLDO SDFLQJ LQ +) SDWLHQWV ZLWK D SURORQJHG 35LQWHUYDO LV ZHOO NQRZQ 3UHYLRXVO\ UHSRUWHG FDVH VHULHVRQULJKWYHQWULFXODU59'''SDFLQJZLWKVKRU- WHU$9GHOD\LQ+)SDWLHQWVDQGORZHMHFWLRQIUDFWLRQLQ the 1990’s reported an improvement in HF symptoms ,WKDVEHHQSUHYLRXVO\VKRZQWKDWIUHTXHQWDSLFDO ULJKWYHQWULFXODUSDFLQJKDVGHOHWHULRXVHႇHFWV HVSHFLDOO\ LQ SDWLHQWV ZLWK D GHSUHVVHG OHIW YHQWULFX- lar duntion. In this population, upgrading the pacing or ICD device to CRT could potentially improve outcomes.

7KHUH KDYH EHHQ D IHZ UHWURVSHFWLYH VWXGLHV HYDOXD- WLQJWKHHႇHFWVRI&57XSJUDGHLQSDWLHQWVZLWKIUHTX- HQW59DSLFDOSDFLQJVKRZLQJLPSURYHPHQWVLQUHYHUVH UHPRGHOLQJDQGIXQFWLRQDOFDSDFLW\KRZHYHUQRQHRI WKHVHVWXGLHVZHUHUDQGRPL]HGRUKDGDQDSSURSULDWH control group (38). A large, randomized controlled cli- nical trial, the BUDAPEST CRT Upgrade study is cur- UHQWO\ RQJRLQJ WR SURVSHFWLYHO\ HYDOXDWH WKH HႇHFWV RI CRT upgrade from conventional PM or ICD therapy in SDWLHQWVZLWKLQWHUPLWWHQWRUSHUPDQHQWULJKWYHQWULFXODU (RV) septal/apical pacing, reduced LVEF, and sympto- matic HF. This prospective, randomized, multicentre, LQYHVWLJDWRUVSRQVRUHGFOLQLFDOWULDOZLOOHQUROODWRWDORI VXEMHFWVZLWK/9()”1<+$IXQFWLRQDOFODVV ,,,9DSDFHG456•PVDQG59SDFLQJ•3D- WLHQWVZLOOEHUDQGRPL]HGWR&57'YV,&'LQDUD- WLRDQGWKH\ZLOOEHIROORZHGIRUPRQWKV7KHSULPD- ry composite endpoint is all-cause mortality, or a HF HYHQWRUOHVVWKDQUHGXFWLRQLQ/9HQGV\VWROLFYR- lume at 12 months (Table 2). Secondary endpoints are all-cause mortality, all-cause mortality or HF event, and LV volume reduction at 12 months (https://clinicaltrials.

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8VHRI&57'HÀEULOODWRUYV&573DFHPDNHU ,W KDV EHHQ D ORQJ GHEDWH ZKHWKHU &57 ZLWK D GH¿E- ULOODWRU &57' LV VXSHULRU WR &57 ZLWK D SDFHPDNHU

&573DQGZKRPVKRXOGEHLPSODQWHGZLWKD&57' vs. a CRT-P device. There have been no studies directly FRPSDULQJWKHEHQH¿WRI&57'WR&573LQXQVHOHF- WHGSDWLHQWVLQDUDQGRPL]HGIDVKLRQ3DWLHQWVZLWKQRQ LVFKHPLF FDUGLRP\RSDWK\ WKRVH ZLWK /%%% ZRPHQ DUHDWDVLJQLILFDQWO\ORZHUULVNRIYHQWULFXODUDUUK\W- KPLDV DQG GHULYH VLJQL¿FDQW /9 UHYHUVH UHPRGHOLQJ IURP &57 DOO QHJDWLQJ WKH SRWHQWLDO QHHG DQG EHQH¿W of an added defibrillator (39). In addition, defibrilla- WRUOHDGVDUHDVVRFLDWHGZLWKDKLJKHUULVNRIFRPSOLFD- tions, lead fractures, and infections. Currently, CRT-P XVHLVFRPPRQLQ(XURSHGXHWRWKH¿QDQFLDOFRQVWUD- LQWVRIPDQ\FRXQWULHV2XUYHU\RZQVLQJOHFHQWHU high volume registry data additionally suggested that VHOHFWHG QRQLVFKHPLF SDWLHQWV ZKR ZHUH PRUH RIWHQ ZRPHQ DQG ROGHU GLG QRW KDYH DQ LPSURYHG VXUYLYDO ZLWK &57' DV FRPSDUHG WR &573 )XUWKHU VWX- GLHV DUH FXUUHQWO\ XQGHUZD\ WR SURVSHFWLYHO\ HYDOXDWH outcomes of CRT-D vs. CRT-P in a randomized fashion in both ischemic and non-ischemic patients.

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Several previous studies highlighted the importance of LV lead location for CRT outcomes. Early studies sug- gested that lateral or posterolateral LV lead location LVDVVRFLDWHGZLWKEHWWHURXWFRPHVZKLOHVWXGLHVIURP MADIT-CRT and REVERSE highlighted the importan- ce of avoiding apical LV lead locations to reduce the risk of HF or death (42). A subsequent analysis also suggested that anterior LV lead placement is linked to an increased risk of ventricular arrhythmias and should be avoided (43). Several attempts have been made to individually optimize LV lead placement and target the ODWHVWDFWLYDWHGDUHDLGHQWL¿HGE\LPDJLQJVWXGLHV KRZHYHUGHVSLWHLQLWLDOSURPLVLQJ¿QGLQJVQRQHRI these techniques are currently employed in routine cli- nical practice. A recent study focusing on CRT non-res- ponder non-LBBB patients to optimize lead placement using LV electrical delay measured by Q-LV, also failed to meet its primary end point (https://clinicaltrials.gov/

FWVKRZ1&7 1HZHU WHFKQLFDO DGYDQFH- PHQWVVXFKDVTXDGULSRODU/9OHDGVZLWKPXOWLSRLQWSD- cing, and individually optimized pacing sequences are currently studied to further improve outcomes of CRT non-responders.

2SWLPDO&57SURJUDPPLQJLVDFRUQHUVWRQHRIEHQH¿- FLDO &57 RXWFRPHV ZLWK VHYHUDO VWXGLHV VXJJHVWLQJ that the higher the biventricular pacing percentage is, WKHEHWWHUWKHRXWFRPHV5XZDOGHWDOVKRZHGWKDW

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survival in MADIT-CRT. Prior studies assessing optimal

CRT programming and outcomes using echocardiog-

raphy optimization vs. “out of the box” device settings

YVG\QDPLFRSWLPL]DWLRQWHFKQLTXHVKDYHEHHQKRZH- ver unsuccessful in de novo CRT recipients (47–49), EXWVKRZHGVRPHEHQH¿WVLQ&57QRQUHVSRQGHUV

Atrial Fibrillation

+) SDWLHQWV ZLWK DWULDO ¿EULOODWLRQ KDYH EHHQ VKRZQ WR KDYHDGYHUVHRXWFRPHVZLWKDQLPSODQWHG&57,Q&57 recipients, lack of biventricular pacing and abrogation of the remodeling process are of particular concern. Many UDQGRPL]HG FOLQLFDO WULDOV DOVR H[FOXGHG SDWLHQWV ZLWK SHUVLVWHQWSHUPDQHQW DWULDO ¿EULOODWLRQ VLJQL¿FDQWO\ OLPL- ting our understanding of CRT outcomes in this cohort.

A currently ongoing randomized clinical trial, RAFT-AF KWWSVFOLQLFDOWULDOVJRYFWVKRZ1&7LVHYD- OXDWLQJ WKH UROH RI FDWKHWHU DEODWLRQ ZLWK 39 DQWUDO LVR- lation and LA substrate ablation vs. rate control in CRT recipients, hopefully shedding more lights on treatment RXWFRPHVLQWKLVGLႈFXOWWRWUHDWSDWLHQWSRSXODWLRQ Another prospective, randomized clinical trial of 80 pa- tients, JAVA-CRT is assessing the role of AV-junctional DEODWLRQLQ&57SDWLHQWVZLWKKLJKEXUGHQRIDWULDO¿EULO- lation to improve outcomes (https://clinicaltrials.gov/ct2/

VKRZ1&7

Conclusions

Cardiac resynchronization therapy has evolved as a PDLQVWUHDP WKHUDS\ IRU KHDUW IDLOXUH LQ SDWLHQWV ZLWK mild to advanced heart failure symptoms, severely de- SUHVVHG OHIW YHQWULFXODU HMHFWLRQ IUDFWLRQ DQG D ZLGH QRS. Short- and long-term outcomes have been favo- UDEOH QHYHUWKHOHVV LQÀXHQFHV E\ YDULRXV FOLQLFDO FKD- racteristics, and comorbidities. Tailored LV lead implan- tation or CRT programming does not further improve RXWFRPHVKRZHYHUIXUWKHUVWXGLHVDUHFXUUHQWO\XQGHU- ZD\7KHXWLOLW\RI&57XSJUDGHLQSDWLHQWVZLWKFKURQLF RV apical/septal pacing, rhythm control/AV junctional DEODWLRQ LQ SDWLHQWV ZLWK DWULDO ¿EULOODWLRQ DQG WKH DS- propriate use of CRT-D vs. CRT-P are currently unre- solved issues that need further investigation to optimize outcomes.

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