Cardiac Resynchronization Therapy

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J Am Coll Cardiol. 2004 Dec 7;44(11):2157-65.
Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing.
Bordachar P, Lafitte S, Reuter S, Sanders P, Jais P, Haissaguerre M, Roudaut R, Garrigue S, Clementy J.
Hospital Cardiologique du Haut Leveque, Pessac, France.
J Am Coll Cardiol. 2004 Dec 7;44(11):2157-65.

OBJECTIVES: We sought to evaluate the relationship between hemodynamic and ventricular dyssynchrony parameters in patients undergoing simultaneous and sequential biventricular pacing (BVP). BACKGROUND: Various echocardiographic parameters of ventricular dyssynchrony have been proposed to screen and optimize BVP therapy. METHODS: Forty-one patients with heart failure undergoing BVP implantation were studied. Echocardiography coupled with tissue tracking and pulsed Doppler tissue imaging (DTI) was performed before and after BVP implantation and after three months of optimized BVP. Indexes of inter- or intraventricular dyssynchrony were correlated with hemodynamic changes during simultaneous and sequential BVP (10 intervals of right ventricular [RV] or left ventricular [LV] pre-excitation). RESULTS: Variations in intra-LV delay(peak), intra-LV delay(onset), and index of LV dyssynchrony measured by pulsed DTI were highly correlated with those of cardiac output (r = -0.67, r = -0.64, and r = -0.67, respectively; p < 0.001) and mitral regurgitation (r = 0.68, r = 0.63, and r = 0.68, respectively; p < 0.001), whereas variations in the extent of myocardium displaying delayed longitudinal contraction (r = -0.48 and r = 0.51, respectively; p < 0.05) and the variations in septal-to-posterior wall motion delay (r = -0.41, p < 0.05 and r = 0.24, p = NS, respectively) were less correlated. The changes in interventricular dyssynchrony were not significantly correlated (p = NS). Compared with simultaneous BVP, individually optimized sequential BVP significantly increased cardiac output (p < 0.01), decreased mitral regurgitation (p < 0.05), and improved all parameters of intra-LV dyssynchrony (p < 0.01). At three months, a significant reverse mechanical LV remodeling was observed with significantly decreased LV volumes (p < 0.01) associated with an increased LV ejection fraction (p = 0.035). CONCLUSIONS: Specific echocardiographic measurements of ventricular dyssynchrony are highly correlated with hemodynamic changes and may be a useful adjunct in the selection and optimization of BVP. Individually optimized sequential BVP provided a significant early hemodynamic improvement compared with simultaneous BVP.

Biventricular pacing and left ventricular pacing in heart failure: similar hemodynamic improvement despite marked electromechanical differences.
Bordachar P, Lafitte S, Reuter S, Garrigue S, Sanders P, Roudaut R, Jais P, Haissaguerre M, Clementy J.
Hospital Cardiologique du Haut Leveque, Pessac, France.
J Cardiovasc Electrophysiol. 2004 Dec;15(12):1342-7.

INTRODUCTION: We conducted an acute echocardiographic study comparing hemodynamic and ventricular dyssynchrony parameters during left ventricular pacing (LVP) and biventricular pacing (BVP). We sought to clarify the mechanisms responsible for similar hemodynamic improvement despite differences in electrical activation. METHODS AND RESULTS: Thirty-three patients underwent echocardiography prior to implantation with a multisite pacing device (spontaneous rhythm [SR]) and 2 days after implantation (BVP and LVP). Interventricular dyssynchrony (pulsed-wave Doppler), extent of myocardium displaying delayed longitudinal contraction (%DLC; tissue tracking), and index of LV dyssynchrony (pulsed-wave tissue Doppler imaging) were assessed. Compared to SR, BVP and LVP caused similar significant improvement of cardiac output (LVP: 3.2 +/- 0.5, BVP: 3.1 +/- 0.7, SR: 2.3 +/- 0.6 L/min; P < 0.01) and mitral regurgitation (LVP: 25.1 +/- 10, BVP: 24.7 +/- 11, baseline: 37.9 +/- 14% jet area/left atria area; P < 0.01). LVP resulted in a smaller index of LV dyssynchrony than BVP (29 +/- 10 vs 34 +/- 14; P < 0.05). However, LVP exhibited a longer aortic preejection delay (220 +/- 34 vs 186 +/- 28 msec; P < 0.01), longer LV electromechanical delays (244.5 +/- 39 vs 209.5 +/- 47 msec; P < 0.05), greater interventricular dyssynchrony (56.6 +/- 18 vs 31.4 +/- 18; P < 0.01), and higher%DLC (40.1 +/- 08 vs 30.3 +/- 09; P < 0.05), leading to shorter LV filling time (387 +/- 54 vs 348 +/- 44 msec; P < 0.05) compared to BVP. CONCLUSION: Although LVP and BVP provide similar hemodynamic improvement, LVP results in more homogeneous but substantially delayed LV contraction, leading to shortened filling time and less reduction in postsystolic contraction. These data may influence the choice of individual optimal pacing configuration.

Relation between abnormal ventricular impulse conduction and heart failure.
Vernooy K, Verbeek XA, Peschar M, Prinzen FW.
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
J Interv Cardiol. 2003 Dec;16(6):557-62.

Ventricular pacing and left bundle branch block (LBBB) are two of the most common causes of asynchronous electrical activation of the ventricles. The sequence of activation is an important determinant of cardiac pump function. The sequence of activation during LBBB and during pacing at the conventional pacing site, the RV apex, is similar. In this article the literature on the effect of RV pacing and LBBB on regional and global LV pump function, on long-term adaptations (remodeling) and on their possible contribution to the development of heart failure is discussed. Evidence is increasing that asynchronous electrical activation contributes significantly to the development of heart failure.

A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping.
Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade LE, Gorcsan J 3rd.
University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA.
J Am Coll Cardiol. 2004 Oct 19;44(8):1619-25.

OBJECTIVES: We tested the hypothesis that an immediate reduction in mitral regurgitation (MR) after cardiac resynchronization therapy (CRT) results from improved coordinated timing of the papillary muscle insertion sites, using the novel approach of mechanical activation strain mapping. BACKGROUND: Heart failure patients with left bundle branch block often benefit acutely from CRT; however, the role and mechanism of reduction of MR are unclear. METHODS: Twenty-six consecutive patients undergoing CRT with at least mild MR were studied (ejection fraction 24 +/- 6%; QRS duration 168 +/- 30 ms). Echocardiographic Doppler and strain imaging was performed immediately before and the day after CRT, as well as in 10 normal control subjects. Mechanical activation sequence maps were constructed using longitudinal strain from 12 basal and mid-LV sites, with color coding of time-to-peak strain. RESULTS: Mitral regurgitation by the volumetric method consistently decreased after CRT: regurgitant volume from 40 +/- 20 ml to 24 +/- 17 ml and regurgitant fraction from 40 +/- 12% to 25 +/- 14% (both: p < 0.001 vs. baseline). Normal controls had uniform segmental time-to-peak strain, with a difference of only 12 +/- 8 ms between all segments. In contrast, CRT patients at baseline had a 106 +/- 74 ms time delay between papillary muscle insertion sites (p < 0.001 vs. normal). This interpapillary muscle time delay shortened after CRT to 39 +/- 43 ms (p < 0.001 vs. baseline) and was significantly correlated with reductions in mitral regurgitant fraction (r = 0.77, p < 0.001). CONCLUSIONS: Cardiac resynchronization therapy significantly and immediately reduced MR. Improved coordinated timing of mechanical activation of papillary muscle insertion sites appears to be a mechanistic contributor to immediate MR reduction by CRT.

What is Cardiac Resynchronization Therapy?
Barold SS
Am J Med. 2001;111:224-232

Cardiac resynchronization refers to pacing techniques that change the degree of atrial and ventricular electromechanical asynchrony in patients with major atrial and ventricular conduction disorders. Atrial and ventricular resynchronization is usually accomplished by pacing from more than one site in an electrical chamber--atrium or ventricle--and occasionally by stimulation at a single unconventional site. Resynchronization produces beneficial hemodynamic and antiarrhythmic effects by providing a more physiologic pattern of depolarization. Atrial resynchronization may prevent atrial fibrillation in selected patients with underlying bradycardia or interatrial block. Its antiarrhythmic effect in the absence of bradycardia is unclear. Ventricular resynchronization is of far greater clinical value than atrial resynchronization. Biventricular (or single-chamber left ventricular) pacing is beneficial for patients with congestive heart failure, severe left ventricular systolic dysfunction, dilated cardiomyopathy (either ischemic or idiopathic), and a major left-sided intraventricular conduction disorder, such as left bundle branch block. The change in electrical activation from resynchronization, which has no positive inotropic effect as such, is translated into mechanical improvement with a more coordinated left ventricular contraction. Several recent randomized trials and a number of observational studies have demonstrated the long-term effectiveness of ventricular resynchronization in the above group of patients. The high incidence of sudden death among these patients has encouraged ongoing clinical trials to evaluate the benefit of a system that combines biventricular pacing and cardioversion-defibrillation into a single implantable device.

Biventricular Pacing Therapy for Congestive Heart Failure: A Review of the Literature
Conti JB
Cardiol Rev. 2001;9:217-226

Biventricular pacing is a new therapy for patients with congestive heart failure and mechanical dyssynchrony. Its therapeutic intent is to activate both ventricles simultaneously, thus improving the mechanical efficiency of the ventricles. Preliminary evidence indicates improvement in hemodynamics, quality of life, and exercise capacity in patients in sinus rhythm as well as in patients with atrial fibrillation. An improvement in diastolic filling, a decrease in mitral regurgitation, and more efficient systolic ejection are proposed as the mechanisms behind these benefits. In addition, some evidence indicates that the frequency of ventricular arrhythmias is decreased. All clinicians involved in the management of patients with congestive heart failure eagerly await the results of ongoing trials. The results of these trials will define which patients are eligible for this therapy, which patients will derive the most benefit from it, and its effect on morbidity and mortality.

Left Ventricular and Biventricular Pacing in Congestive Heart Failure
Gerber TC, Nishimura RA, Holmes DR Jr, Lloyd MA, Zehr KJ, Tajik AJ, Hayes DL
Mayo Clin Proc. 2001;76:803-812

Dual-chamber pacing improved hemodynamics acutely in a subset of patients with left ventricular (LV) dysfunction but conveyed no long-term symptomatic benefit in most. More recently, LV pacing and biventricular (multisite) pacing have been used to improve systolic contractility by altering the electrical and mechanical ventricular activation sequence in patients with severe congestive heart failure (CHF) and intraventricular conduction delay or left bundle branch block (LBBB). Intraventricular conduction delay and LBBB cause dyssynchronous right ventricular and LV contraction and worsen LV dysfunction in cardiomyopathies. Both LV and biventricular cardiac pacing are thought to improve cardiac function in this situation by effecting a more coordinated and efficient ventricular contraction. Short-term hemodynamic studies have shown improvement in LV systolic function, which seems more pronounced with monoventricular LV pacing than with biventricular pacing. Recent clinical studies in limited numbers of patients suggest long-term clinical benefit of biventricular pacing in patients with severe CHF symptoms. Continuing and future studies will demonstrate whether and in which patients LV and biventricular pacing are permanently effective and equivalent and which pacing site within the LV produces the most beneficial hemodynamic results.

How Many People With Heart Failure Are Appropriate for Biventricular Resynchronization?
Farwell D, Patel NR, Hall A, Ralph S, Sulke AN
Eur Heart J. 2000;21:1246-1250

Aims: Increasing evidence exists suggesting that biventricular pacing improves outcome and symptoms in severe heart failure if various selection criteria are fulfilled. It is unsure how many people might benefit from this therapy. Our aim was to provide such data. Methods And Results: Over one calendar year all patients admitted to a large U.K. District General Hospital, that were classified with a diagnosis of heart failure, were audited. The selection criteria were; (1) severe heart failure (NYHA class III or IV), (2) heart failure due to a dilated cardiomyopathy, (3) QRS duration greater than 120 ms or (4) the presence of a bundle branch block pattern. Subjects were divided into those in sinus rhythm to determine those who would be suitable for atrially synchronized biventricular pacing and those with an abnormally long PR interval (>210 ms) who might additionally benefit from improved atrioventricular synchrony. 1042 patients were coded with heart failure. 721 fulfilled diagnostic criteria and were studied. 202 (28%) had severe heart failure, 178 (25%) had a QRS of at least 120 ms, 437 (61%) had an ischaemic cardiomyopathy, 176 (24%) an idiopathic cardiomyopathy and 433 (60%) were in sinus rhythm. Overall mortality at the time of census was 29%. 43 patients were suitable for biventricular pacing with a further 29 atrial patients fibrillation who might benefit from biventricular pacing alone. Conclusion: Using our criteria, approximately 10% of an unselected group of heart failure admitted to a typical U.K. district general hospital over a calendar year would be appropriate for biventricular pacing. This represents a large number of patients who might derive benefit from this new therapy.

Resynchronization Pacing is a Useful Adjunct to the Management of Acute Heart Failure After Surgery for Congenital Heart Defects
Janousek J, Vojtovic P, Hucin B, et al
Am J Cardiol. 2001;88:145-152

The acute hemodynamic effect of atrioventricular (AV) and inter/intraventricular (IV) resynchronization accomplished by temporary pacing using multiple epicardial pacing wires was evaluated in 20 children (aged 3.4 months to 14.0 years) after surgery for congenital heart defects fulfilling the following criteria: (1) presence of AV and/or IV conduction delay, and (2) need for inotropic support. AV resynchronization (n = 13) was achieved by AV delay optimization during atrial synchronous right ventricular outflow tract pacing. IV resynchronization (n = 14) was accomplished by atrial synchronous pacing from the right ventricular lateral wall in 7 patients with right bundle branch block and normal AV conduction and by atrial synchronous multisite ventricular pacing in another 7 patients with previously performed AV resynchronization. Compared with baseline values, AV resynchronization resulted in an increase in arterial systolic, mean, and pulse pressures by 7.2 +/- 8.3% (p <0.01), 8.6 +/- 8.1% (p <0.005), and 6.9 +/- 13.5% (p = NS), respectively. IV resynchronization used either alone or added to previously performed AV resynchronization led to a pressure increase of 7.0 +/-4.7%, 5.9 +/- 4.7%, and 9.4 +/- 7.8%, respectively (p <0.001 for all). The combined effect of AV and IV resynchronization resulted in a systolic, mean, and pulse pressure increase of 10.2 +/- 5.0% (range 4.0 to 19.1), 8.6 +/- 5.4% (range 0.8 to 14.8), and 15.2 +/-8.5% (range 6.1 to 33.3), respectively (p <0.001 for all). The increase in systolic arterial pressure after IV resynchronization was positively correlated with the initial QRS duration (r = 0.62, p <0.05) and extent of QRS shortening (r = 0.66, p <0.05). In conclusion, resynchronization pacing led to a significant increase in arterial blood pressure and was a useful adjunct to the treatment of acute postoperative heart failure in patients with AV and/or IV conduction delay.

Clinical Trials

Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure
James B. Young, MD; William T. Abraham, MD; Andrew L. Smith, MD; Angel R. Leon, MD; Randy Lieberman, MD; Bruce Wilkoff, MD; Robert C. Canby, MD; John S. Schroeder, MD; L. Bing Liem, DO; Shelley Hall, MD; Kevin Wheelan, MD; for The Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators
JAMA. 2003;289:2685-2694.

Context Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown.
Objective To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management.
Design, Setting, and Participants Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment.
Interventions Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on).
Main Outcome Measures The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared.
Results At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (17.5 [21 to 14] vs 11.0 [16 to 7], P = .02) and functional class (1 [1 to 1] vs 0 [1 to 0], P = .007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P = .36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (0.1 to 0.8) in controls (P = .04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired.
Conclusions Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.

Rationale and Design of a Randomized Clinical Trial to Assess the Safety and Efficacy of Cardiac Resynchronization Therapy in Patients With Advanced Heart Failure: The Multicenter In Sync Randomized Clinical Evaluation (MIRACLE)
Abraham WT
J Card Fail. 2000;6:369-380

Up to 50% of patients with chronic systolic heart failure have interventricular conduction delays, such as left bundle branch block, that result in abnormal electrical depolarization of the heart. Prolonged QRS duration results in abnormal interventricular septal wall motion, decreased contractility, reduced diastolic filling time, and prolonged duration of mitral regurgitation, which places the failing heart at a significant mechanical disadvantage. Prolonged QRS duration has been associated with poor outcome in heart failure patients. Atrial-synchronized, biventricular pacing or cardiac resynchronization therapy optimizes atrial-ventricular delay, narrows QRS duration, and seems promising in the management of advanced heart failure patients. Initial studies show improved quality of life and functional capacity compared with baseline or with no pacing. These studies, however, were either uncontrolled or poorly controlled, unblinded or only single-blinded, and enrolled small numbers of patients. The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) is a large, prospective, randomized, double-blind, controlled trial designed to more definitively evaluate the clinical efficacy and safety of cardiac resynchronization for heart failure. The study is being completed in 3 phases (an initial pilot phase, a pivotal phase, and an expansion phase), enrolling 500 patients with New York Heart Association (NYHA) class III and IV systolic heart failure and QRS durations of 130 ms or more. Prospectively defined primary end points for the pivotal phase include evaluation of safety (implant success rate, freedom from stimulator- and ventricular-lead-related complications) and effects on functional status (quality of life, NYHA class, 6-minute hall walk distance) at 6 months. A variety of secondary end points will further define the efficacy and mechanism(s) of action of cardiac resynchronization in heart failure. The pivotal phase of MIRACLE will conclude in January 2001.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
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.
Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
N Engl J Med. 2004 May 20;350(21):2140-50.

BACKGROUND: We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. METHODS: A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause. RESULTS: As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker-defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker-defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker-defibrillator reduced the risk by 36 percent (P=0.003). CONCLUSIONS: In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.

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