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The physiological underpinning for cardiac resynchroni-zation therapy (CRT) began with Carl Wiggers in 1925.

He showed that when contraction of the heart was induced by direct cardiac electric stimulation, the early phase of contrac-tion of the heart was slowed and myocardial tension developed more gradually.1 Wiggers explained these findings by differ-ences in the order of excitation of the ventricle. Subsequent studies by a number of investigators highlighted the fact that a left bundle-branch block conduction pattern was associated with dyssynchronous contraction that exacerbated left ven-tricular systolic dysfunction. Few people appreciate the fact that Dr Morton Mower, who was involved in the development of the implantable cardioverter defibrillator,2,3 also developed the patent for cardiac resynchronization therapy in 19904 that was assigned to CPI/Guidant and subsequently licensed to Medtronic.

In 1994, Cazeau et al5 reported 1 patient with widened QRS and advanced heart failure who achieved dramatic improve-ment with biventricular pacing. Various short-term animal and clinical hemodynamic studies showed significant improve-ment in cardiac function when both right and left ventricles of a diseased heart with conduction disturbance were preexcited (biventricular pacing),6 and similar findings were observed recently with univentricular left ventricular stimulation in the compromised heart with conduction block.7 Central to all these studies was that dyssynchronous contraction associ-ated with disturbed left ventricular conduction improved with direct left ventricular pacing.

A series of large randomized trials, including COMPANION,8 CARE-HF,9 MADIT-CRT,10 and RAFT,11 have documented the safety and efficacy of biventricular car-diac reynchronization pacing in patients with various degrees of severity of heart failure. All the studies involved patients with wide QRS complexes, with the best results observed in those with left bundle-branch block. Cardiac guideline recom-mendations followed in 2008,12 with a recent update in 201213 emphasizing the importance of wide QRS and left ventricular conduction disturbance as the best substrate for CRT efficacy.

The article by Thibault et al14 in Circulation involves a small randomized trial of CRT in patients with heart failure

and narrow QRS (<120 ms) using exercise duration at 1 year as the primary end point. The Thibault trial was designed in 2002 and initiated in 2003, and it appears to be based on an observational study reported in 2003 by Achilli et al.15 The Achilli study enrolled patients with refractory heart failure (HF) and incomplete left bundle-branch block (narrow QRS) together with echocardiographic evidence of interventricular and intraventricular asynchrony. There were 38 patients with QRS >120 ms and 14 patients had a narrow QRS <120 ms. The CRT benefit was similar in patients with wide or narrow QRS. It should be emphasized that the authors put the word narrow in quotes (“narrow”) in the title and throughout the article when referring to QRS <120 ms because many of the patients had QRS durations <100 ms. The authors concluded that “cardiac resynchronization therapy may be helpful in patients with echocardiographic evidence of interventricular and intraventricular asynchrony and incomplete left bundle-branch block”.15

It is surprising that Thibault et al.14 initiated their study based on limited findings in the literature, and their study did not include echocardiographic evidence of dyssynchrony. The average QRS duration was 104+9 ms, with many of the enrolled patients with QRS <100 ms. There were 12 enrolling centers, and the study ran for 8 years from 2003 to 2011 with a total enrollment of only 85 patients in the study. That means that, on average, each center enrolled <1 patient per center per year. It is surprising that the Data and Safety Monitoring Board waited 8 years to terminate the study because of futility and safety concerns.

After Thibault et al initiated their study but before publication in Circulation, there were several reports of variable CRT efficiacy in heart failure patients with narrow QRS complexes. In a small observational study by Bleeker et al16 involving 66 studied patients with low ejection fraction and left ventricular dyssynchrony on tissue doppler imagaing, the 33 patients with QRS <120 ms had left ventricular reverse remodeling with CRT comparable with the 33 patients with QRS complex >120 ms. A larger randomized trial by Beshai et al17 involved 172 patients with the primary end point an increase in peak oxygen consumption of at least 1.0 mL per kilogram of body weight per minute during cardiopulmonary exercise testing at 6 months after randomization. The CRT-treated patients did not improve peak oxygen consumption when compared with the nontreated control group. The results of this randomized study were not very encouraging that CRT would be beneficial in patients with narrow QRS complexes.

What have we learned from the large MADIT-CRT trial regarding CRT efficacy and QRS duration? CRT was sig-nificantly more effective when the QRS duration was >150 ms than in the 130 to 149 ms range,10 and female patients

(Circulation. 2013;127:1093-1094.)© 2013 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.orgDOI: 10.1161/CIRCULATIONAHA.113.001363

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

From the University of Rochester Medical Center, Rochester, NY.Correspondence to Arthur J. Moss, MD, Professor of Medicine

(Cardiology), Heart Research Follow-Up Program, University of Rochester Medical Center, 265 Crittenden Blvd, CU 420653, Rochester, NY 14642-0653. E-mail heartajm@heart.rochester.edu

Narrow QRS Is Not the Right Substrate for Cardiac Resynchronization Therapy

Arthur J. Moss, MD

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1094 Circulation March 12, 2013

were the only ones who achieved significant CRT benefit with QRS of 130 to 149 ms.18 Heart failure patients with left bundle-branch block conduction obtained excellent benefit from CRT, and there was no appreciable benefit from CRT in patients with right bundle-branch block or intraventricular conduction delay.19

It is quite clear that CRT does not achieve a favorable result in patients with QRS durations <120 ms. On the other hand, mechanical left ventricular dyssynchrony, an impor-tant myocardial substrate for effective CRT, is exacerbated by abnormal excitation of the left ventricle with a wide QRS duration, especially when a left bundle branch conduction disturbance is present. Although many factors influence the cardiac responsiveness to CRT (lead position, type of cardio-myopathy [ischemic versus nonischemic], extent and severity of the myocardial damage, and sex), wide QRS complex and left bundle-branch block are excellent electric biomarkers for identification of heart failure patients who are likely to benefit from resynchronization therapy.

DisclosuresDr Moss reports a research grant from Boston Scientific to the University of Rochester, of which he is a principal investigator.

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cial surface stimulation. Am J Physiol 1925;73:346–378. 2. Mirowski M, Mower MM, Langer A, Heilman MS, Schreibman J. A

chronically implanted system for automatic defibrillation in active con-scious dogs: experimental model for treatment of sudden death from ven-tricular fibrillation. Circulation. 1978;58:90–94.

3. Mirowski M, Reid PR, Mower MM, Watkins L, Gott VL, Schauble JF, Langer A, Heilman MS, Kolenik SA, Fischell RE, Weisfeldt ML. Termi-nation of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med. 1980;303:322–324.

4. Mower MM. Method and apparatus for treating hemodynamic dysfunc-tion. Patent issued May 29,1990.

5. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, Mundler O, Daubert JC, Mugica J. Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol. 1994;17(11 Pt 2):1974–1979.

6. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circula-tion. 1999;99:1567–1573.

7. Thibault B, Ducharme A, Harel F, White M, O’Meara E, Guertin MC, Lavoie J, Frasure-Smith N, Dubuc M, Guerra P, Macle L, Rivard L, Roy D, Talajic M, Khairy P. Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex >/=120 millisec-onds. Circulation. 2011;124:2874–2881.

8. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart fail-ure. N Engl J Med. 2004;350:2140–2150.

9. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549.

10. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA III, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiac-resynchro-nization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361:1329–1338.

11. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010;363:2385–2395.

12. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, III, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC, Jr., Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Riegel B, Tarkington LG, Yancy CW. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices): Developed in collaboration with the american association for thoracic surgery and society of thoracic surgeons. Circula-tion. 2008;117:e350–408.

13. Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA, III, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guide-lines and the Heart Rhythm Society. Circulation. 2013 Jan 22;127:e283–352. doi: 10.1161/CIR.0b013e318276ce9b. Epub 2012 Dec 19.

14. Thibault B, Harel F, Ducharme A, White M, Ellenbogen K, Frasure-Smith N, Roy D. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: the Evaluation of Resynchroni-zation Therapy for Heart Failure (LESSER-EARTH) trial. Circulation. 2013;127:873–881.

15. Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C, De Spirito S, Guerra R, Patruno N, Serra F. Long-term effectiveness of cardiac resyn-chronization therapy in patients with refractory heart failure and “narrow” QRS. J Am Coll Cardiol. 2003;42:2117–2124.

16. Bleeker GB, Holman ER, Steendijk P, Boersma E, van der Wall EE, Schalij MJ, Bax JJ. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol. 2006;48:2243–2250.

17. Beshai JF, Grimm RA, Nagueh SF, Baker JH II, Beau SL, Greenberg SM, Pires LA, Tchou PJ; RethinQ Study Investigators. Cardiac-resynchroniza-tion therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007;357:2461–2471.

18. Arshad A, Moss AJ, Foster E, Padeletti L, Barsheshet A, Goldenberg I, Greenberg H, Hall WJ, McNitt S, Zareba W, Solomon S, Steinberg JS; MADIT-CRT Executive Committee. Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchroniza-tion Therapy) trial. J Am Coll Cardiol. 2011;57:813–820.

19. Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M, Cannom D, Daubert JP, Eldar M, Gold MR, Goldberger JJ, Goldenberg I, Lichstein E, Pitschner H, Rashtian M, Solomon S, Viskin S, Wang P, Moss AJ; MADIT-CRT Investigators. Effectiveness of Cardiac Resyn-chronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation. 2011;123:1061–1072.

KEY WORDS: Editorials ■ cardiac resynchronization therapy