BIVENTRICULAR PACING FOR HEART FAILURE

0733-8651/01 $15.00

HEART FAILURE

+ .OO

BIVENTRICULAR PACING FOR HEART FAILURE Stephen V. Pavia, MD, and Bruce L. Wilkoff, MD

Congestive heart failure (CHF) is a common, debilitating, and usually lethal condition responsible for an enormous proportion of the cost of health care, in the form of hospital days, patient lifestyle interruption, and medication burden. The morbidity and mortality improvement shown with angiotensinconverting enzyme (ACE) inhibitor and Pblocker medical therapy in very large trials is so impressive that failure to prescribe these drugs in the absence of a contraindication now borders on medical negligence. Advances in heart transplantation management make this a real alternative for many patients. Despite the clearly documented advantage of medical therapy, however, the prognosis overall remains dismal, and donor organs remain scarce. Given this gloomy backdrop, alternative strategies, including pacing for management of CHF, are being sought zealously; however, the authors believe it to be extremely important that the potential effectiveness of any alternative heart failure management strategy should be compared, ultimately, to no end point other than proven medical therapy. HISTORY OF DUAL CHAMBER PACING IN HEART FAILURE

The concept of pacing as a therapy for heart failure is not new. In 1990, Hochleitner et

alE reported clinical improvement allowing cardiac ionotropic therapy withdrawal after implantation of physiologic dual-chamber pacemaker programmed to a short atrioventricular (AV) delay. A follow-up studyz4from the same group was published in 1992, showing continued clinical improvement in patients who survived; however, a high rate of sudden, presumed cardiac death was noted. In 1992, Brecker et als reported symptomatic and echocardiographic improvements with physiologic pacing in 12 cardiomyopathy patients, without conventional pacing indications. All of these patients had shortened ventricular filling times owing to AV valve regurgitation, and most had abnormal transmitral valve inflow Doppler recordings at echocardiography. At a programmed short AV interval, breathlessness, cardiac output, exercise duration, and maximum oxygen consumption all improved compared with a longer, either programmed or spontaneous, AV delay. Not all reports proved encouraging, however. In 1995, Linde et a133 reported disappointing results of physiologic pacing in cardiomyopathy patients despite acute optimization of the programmed AV delay. Although an acute improvement in stroke volume and cardiac output was noted, it was not sustained to 3 and 6 months. Gold et all6also

From the Section of Cardiac Pacing and Electrophysiology, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio

CARDIOLOGY CLINICS VOLUME 19 * NUMBER 4 NOVEMBER 2001

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PAVIA & WILKOFF

found no acute improvement in hemodynamic, clinical, or echocardiographic variables in patients with VDD pacing at various AV delays. Longer follow up in a randomized cross-over design (VDD pacing with an AV delay of 100 msec or a backup mode of W I pacing at 40 beats per minute [bpm]) revealed no significant differences in ejection fraction (EF) or New York Heart Association (NYHA) functional class. Nishimura et a137found that in severe left ventricular (LV) dysfunction there were differences in response to AV sequential pacing based on resultant minimization of the presystolic AV valve regurgitation, which was mostly related a prolonged baseline PR interval. Specifically, patients with PR intervals greater than 200 msec had significant improvements with respect to cardiac output, LV end-diastolic pressure, diastolic filling time, and diastolic mitral regurgitation during AV sequential pacing at an optimized AV delay. Obviously, the improvement noted was limited to a select group of patients with heart failure. Furthermore, in the patients with a normal baseline PR interval, measured cardiac output decreased with pacing, without a noted change in the diastolic filling time. A similar negative theme was demonstrated by Sack et a1.4O They could not identify any variable that consistently predicted a beneficial response to AV sequential pacing, other than assessing the acute hemodynamic effect of pacing for each individual patient. It is possible that the potential detrimental effect of pacing-induced broadening of the ECG QRS complex duration in severe ventricular disease may be overcome by the beneficial effect of increased ventricular filling time in a select group of patients with heart failure; however, all of these studies were small, and they often varied in LVEF, functional class, cardiomyopathy etiology, pacing indications, PR and QRS duration, and follow-up parameters and duration. Importantly, a potential placebo effect was not always accounted for. Consequently,' in the absence of controlled, randomized studies that link acute to longterm benefit, it is difficult to advocate dualchamber pacing as a general therapy for heart failure. Individual testing of patients appears to be the only way to distinguish those who may benefit from AV resynchronization

achieved through right-sided AV sequential pacing. This is an extremely cumbersome and invasive technique, and acute improvement does not always extrapolate to continued improvement during longer periods of followup. As a consequence, interest has now shifted to LV-based, mainly biventricular (concomitant right ventricular [RV] and LV) pacing. The valuable lessons learned from optimization of the AV delay from these early studies have been used as an important supplementary facet in the total resynchronization strategy. ELECTROMECHANICAL CARDIAC DYSYNCHRONY

The association of asynchronous ventricular contraction with ventricular dysfunction has been recognized for many years. Initially, it was described by W i g g e r ~in~ ~1926, confirmation being obtained using kinetocardiograms by Harrison*I in 1965, and subsequently, the correlation of asynchrony with clinical CHF was shown by Herman et a P in 1967. More recently, the presence of left bundle branch block (LBBB) was shown to correlate with decreased LV function. In a study by Bramlet et a1,7 patients with no evidence of structural or coronary heart disease who developed rate-dependent LBBB with exercise showed an abrupt decrease in LV function in comparison with a mean increase in LV function in an exercising control group. Furthermore, radionuclide angiographic wallmotion analysis revealed that the development of LBBB coincided with the development of asynchronous LV contraction. Grines et all9 confirmed that altered ventricular activation secondary to LBBB resulted in delayed LV contraction with consequent decline in LVEF and abnormal interventricular septa1 motion. These studies all support the notion that intraventricular asynchrony is certainly associated with LV systolic dysfunction. This particular study by Grines et all9 extended this notion by demonstrating that LBBB also caused RV-LV asynchrony, also implicating interventricular asynchrony as a potential mechanism. In the same study, this mechanistic explanation was further confounded by

BIVENTRICULAR PACING FOR HEART FAILURE

the association of LBBB with decreased diastolic filling times, manipulation of which is often explained more simply by AV a s p chrony. Finally Xiao et a151 revealed that a prolonged QRS duration was associated with reduced peak dP/dt, prolonged overall duration of the pressure pulse, and time to peak dP/dt. If the QRS duration could be reduced, cardiac function may improve. This can be achieved with certain specific pacing configurations. THE MECHANICS OF RESYNCHRONIZATION THERAPY

The term cardiac resynchronization pacing therapy implies potential improvement at many different levels. In any given patient with CHF, cardiac asynchrony may occur in differing degrees at, firstly, an AV level, secondly, at an intraventricular level, and thirdly, at an interventricular level. Transthoracic echocardiography may be used to assess changes in certain cardiac hemodynamic parameters. Pulsed-wave Doppler transmitral flow patterns assessing atrial contribution to LV filling, and Doppler velocity time integral (VTI) across the aortic valve as a surrogate measurement of cardiac output, are easily obtained noninvasively. In this way, the efficacy of multisite pacing configurations on hemodynamic improvement in heart failure can be assessed. Device programming adjustments then can be tailored to the individual patient with heart failure in an attempt to optimize the therapeutic response to multisite pacing. Atrioventricular Synchrony

Individual patient echocardiographic optimization of programmed AV delay is performed often, particularly using the mitral inflow Doppler information. This is in an attempt to prolong the diastolic filling duration so the end of the atrial contribution to LV filling coincides with complete mitral valve closure. Ventricular pacing will pre-excite the ventricle previous to otherwise spontaneous activation and uncouple the superimposed E and A wave echocardiographic Doppler mi-

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tral inflow recordings, often found at baseline in these patients with CHF. By shortening the AV delay in this way, the timing of the E wave is advanced compared with the stationary A wave, and therefore the two separate. Diastolic filling can be prolonged maximally until the time of mitral valve closure, and the end of the A wave from the following cardiac cycle. At this point, the maximum diastolic filling prolongation has been achieved. If further shortening of the AV delay is attempted, truncation of the end of the A wave will occur and cardiac output may be effected adversely by this separate mechanism. If the AV delay is overly prolonged, the time between the end of A wave and mitral valve closure is not used for LV filling and is effectively wasted. This retardation of the timing of the E wave allows the E and A wave to remain fused, and, consequently, cardiac AV asynchrony is perpetuated. Certain formulas exist to calculate the optimal AV delay used when programming a resynchronization pacemaker. One of these is the method described by Ritter et al.39Figure 1in an example of variability of cardiac output in the same patient with cardiomyopathy with the device programmed to different AV delays.37One possible associated beneficial mechanism, diastolic mitral regurgitation elimination, is also illustrated in Figure 1. lnterventricular Synchrony

The consequences of electromechanical interventricular conduction delay include LV isovolumetric contraction and relaxation time prolongation, mitral regurgitation worsening, and shortening of LV filling time with consequently diminished cardiac An approach to therapy is available. Specifically, the onset of the ECG QRS complex to the onset of aortic ejection flow is termed the LV preejection interval. If the QRS duration is prolonged, this interval will prolong. In doing so, the timing of the next echocardiographic Doppler mitral inflow E wave becomes superimposed on the stationary A wave, causing a single summation wave similar to the situation described with nonoptimized AV delay. The AV delay is adjusted in an attempt to

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Figure 1. Hemodynamic atrioventricular (AV) delay optimization with DDD pacing. Simultaneous mitral valve inflow velocity curves and left atrial (LA) left ventricular (LV) pressure tracings. Leff, Atrial pacing with intrinsic conduction to the ventricle is shown. The LV pressure tracing increases to above LA pressure in mid diastole (arrow), with consequent diastolic mitral regurgitation and an associated shortening in the time available for left ventricular filling. This situation achieves the cardiac output (CO) shown. Center, AV synchronous pacing with a short programmed AV delay (60 msec) advances the ventricular contraction by pacing in the ventricle. Consequently, mitral inflow E and A wave components become superimposed with an adverse effect on the measured CO. Rigbf, At a programmed AV delay individually optimized to 180 msec, diastolic LV filling occurs throughout diastole and the previously superimposed mitral inflow E and A waves appropriately separate. The consequent beneficial effect on CO is obvious. E = early mitral inflow Doppler component; A = atrial contribution mitral inflow. (Modified from Nishimura RA, Wayes DL, Holmes DR Jr, et al: Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricle dysfunction: An acute Doppler and catheterization hemodynamic study. J Am Coll Cardial 25:281-288, 1995; with permission.)

overcome this asynchrony, using the mitral inflow E and A waves, so as to optimize LV filling; however, this duration is often not optimal for the filling of the right ventricle. If both ventricles are paced in a biventricular configuration, this problem may be minimized. In this way, biventricular pacing therapy addresses the issue of interventricular asynchrony by reducing the LV pre-ejection interval.1°

lntraventricular Synchrony

When addressing intraventricular asynchrony, the therapeutic aim is to abolish the overlap of systole and diastole. In this way, ventricular contraction does not continue through into the ventricular filling phase, which is marked by the beginning of the next echocardiographic mitral inflow E wave. If it did, the required isovolumetric relaxation phase effectively would be abolished, and contraction would then extend beyond the completion of aortic ejection-a situation

highly detrimental to forward cardiac output. Theoretically, this may be minimized by early capture of the LV, specifically, biventricular pacing or LV pacing alone. BENEFICIAL EFFECT OF MULTlSlTE PACING IN CARDIOMYOPATHY

The initial pioneering work with multisite pacing therapy in patients with refractory heart failure was encouraging and paved the way for larger trials. Ongoing, randomized trials continue, and the results are eagerly awaited. Based on early, small, positive trials in this field, however, enthusiasm for this new therapy has been embraced zealously despite the incomplete evidence from large, controlled, ongoing trials of biventricular pacing. In 1996, Cazeau et all' showed that biventricular pacing improved NYHA functional class and cardiac index. In 1998, Leclercq et a131studied the acute hemodynamic response to biventricular pacing in patients with se-

BIVENTRICULAR PACING FOR HEART FAILURE

verely symptomatic heart failure with intraventricular conduction delay. Results were compared to AAI and RV DDD pacing, the individual patients functioning as their own controls. Cardiac index improved and pulmonary capillary wedge pressure decreased significantly with the biventricular pacing configuration. Kass et alZ7confirmed this finding in 1999 and suggested further that left ventricular pacing alone could out-perform biventricular pacing, with both of these configurations being significantly better than RV midseptum and RV apex VDD pacing. This too was an acute hemodynamic study that included dP/dt max, pulse pressure measurements and pressure-volume loops to assess stroke work and end-systolic volumes. These and other observational, short-term trials fueled the impetus to pursue this revolutionary concept in heart failure therapy. Recently completed trials in the field include two prospective trials without control groups, that is, the European and Canadian InSync Study17 and the PATH-CHF (Pacing Therapies for Congestive Heart Failure) trial5 and one prospective, randomized case controlled trial in the form of MUSTIC (Multisite Stimulation in Cardiomyopathy).lZIt is im-

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portant to note that these trials, and the ongoing trials of biventricular pacing in heart failure, exclude patients with a conventional pacing indication or nonsinus rhythm. Preliminary results of the European and Canadian InSync Study were reported by Gras et all7 in 1998 (Table 1). The trial was conducted without a control group. Essentially it was a study exploring the safety and efficacy of biventricular pacing therapy in patients with refractory heart failure with encouraging results. The PATH-CHF trial (Pacing Therapies for Congestive Heart Failure) was reported by Auricchio et al.5 This was a randomized, single-blind crossover trial of pacing therapy. At the time of discharge, patients were assigned randomly to either atriobiventricular pacing or to the best atriouniventricular pacing (either right or left ventricle based on the results of an acute hemodynamic study performed under general anesthesia during device implantation). After 4 weeks of pacing, the devices were switched to no pacing for 4 weeks in all patients. The patients were then paced again for 4 weeks, in the opposite AV mode to which they had been assigned in the first 4 weeks of the study. All patients were then

Table 1. COMPLETED TRIALS OF MULTlSlTE PACING THERAPY IN CONGESTIVE HEART FAILURE ~

~~

Trial

Inclusion

InSync” (pacemaker)

NYHA 11-IV QRS >150 msec LVEDD >60 mm Stable medication

PATH-CHF5 (pacemaker)

NYHA 111-IV QRS >120 msec PR >150 msec Optimal medications

~

Endpoints

Patients

Follow-Up

Results

QOL 6-Minute walk NYHA class 12-Lead ECG Echocardiography

68 (81 enrolled)

12 mo

Peak Vo2 6-Minute walk NYHA class QOL Hospitalizations LVEF

53 (27 reported)

12 mo

Improved NYHA class, QOL, and 6-minute walk distance; decreased QRS duration and echocardiographic interventricular mechanical delay Improved 6-minute walk distance, QOL, LVEF, and HR variability

58

6 mo

co

MUSTIC’2 (pacemaker)

“HA QOL

=

NYHA I11 QRS >150 msec LVEF <35% LVEDD >60 mm Sinus rhythm

Filling patterns 6-Minute walk QOL Peak VO, CHF admissions Death/ transplant / LVAD Patient preference

Improved 6-minute walk distance, peak Vo,; decreased hospitalization

= New York Heart Association; LVEDD = left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; quality of life; ECG = electrocardiogram; CO = cardiac output; CHF = congestive heart failure.

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PAVIA & WILKOFF

placed in the best chronic pacing mode and followed every other month for a year after the initial 12-week protocol. The results of the acute hemodynamic effects of pacing in 27 of the total of 53 patients showed that biventricular and LV pacing increased LV + d P / dtmax and pulse pressure more than RV pacing, and LV pacing increased both parameters more than biventricular pacing4 The longerterm and very favorable results of clinical parameters have been reported2,41 and are summarized in Table 1. The trials discussed above all included class 111-IV patients with heart failure with depressed LVEF; however, there also were significant differences in the baseline characteristics of these study populations. The PATH-CHF patients compared with the InSync patients were younger, had a shorter required QRS complex duration, and included a larger proportion of females with a noncoronary etiology for cardiomyopathy being more prevalent. Another important difference was the use of P-blocker therapy. In PATH-CHF, 60% as compared to only 18% of the patients in InSync were prescribed a Pblocker. When comparing the results of these and ongoing trials, these are very important considerations. The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial results represent the first published randomized data for biventricular pacemakers.12In this trial, patients were randomized to a single-blind crossover of biventricular pacing or no pacing for 3 months, followed by a crossover to the opposite mode for 3 months. Preliminary findings are presented in Table 1. In addition, over 85% of patients in MUSTIC preferred the biventricular pacing configuration compared with 4% preferring no pacing. The remaining 10% of the enrolled patients had no preference.12 The diagnosis and gradation of the severity of heart requires the clinical acumen of an experienced physician combined with complementary invasive and often cumbersome hemodynamic' measurements. Serum norepinephrine (NE) level measurement has been proposed as a surrogate to evaluate heart failure severity, because it parallels sympathetic nervous system activity. Saxon et a142evaluated a sub-study from the VIGOR-CHF trial

and showed a progressive, significant reduction in NE levels from baseline (to almost 60%) after biventricular pacing had been operational for 4 months. This seems to be yet another parameter that has been shown to improve when biventricular pacing is used in the patient with heart failure. BIVENTRICULAR PACING WITH DEFIBRILLATOR CAPABILITY

Patients with heart failure have a significantly shortened life expectancy, which may be due to end-stage heart failure or sudden death. Overall mortality increases with worsened functional class and impairment of LVEF; however, as functional class deteriorates, the contribution of sudden death to overall mortality decreases.47In addition, sudden cardiac death in patients with heart failure should not be presumed automatically to be owing to ventricular tachyarrhythmia. Pulmonary embolism and acute coronary syndrome along with bradyarrhythmia are possibilities. Despite these questions, 30% to 50% of all patients with heart failure will die suddenly, and at least 30% of these will be as a result of ventricular tachyarrhythmia." For this reason, the addition of defibrillation capability must be considered in this population. The efficiency of performing electrophysiological study to assess ventricular arrhythmia inducibility in all patients being considered for biventricular pacing has been Considered. Up to 35% of patients with cardiomyopathy with potential biventricular pacing indications had inducible ventricular a r r h ~ t h m i a . ~ ~ This raises the question as to whether defibrillation capability should be considered routinely in this patient group, particularly if they are to receive a device implant of some type anyway. Further study is required. The corollary to this question was studied by Stellbrink et al.45They found that if current implantable cardioverter defibrillator (ICD) implant selection criteria were used, 7.3% of the patients with ICDs could be considered candidates for biventricular pacing. Pending the results of ongoing, multicenter trials of ICD therapy, if the criteria for ICD implantation

BIVENTRICULAR PACING FOR HEART FAILURE

were to be extended to include NYHA class I1 patients with EF less than or equal to 30%, then that proportion would increase to 12.5%. Left ventricular EF and the surface ECG QRS duration43in patients with heart failure have been shown to independently predict survival, and biventricular pacing without defibrillation has been shown to improve LVEF and narrow the QRS duration in some studies. Hence, biventricular pacing may in itself be considered a possible mechanism to decrease mortality, particularly given the added capability to treat potentially lifethreatening bradyarrhythmia. To this end, biventricular pacing has been found to diminish the requirement for appropriate ICD therapies, raising the possibility that this form of therapy may not only improve symptoms but may also effect the natural history of heart failure with respect to sudden cardiac death.z3 Whether mortality is reduced by biventricular pacing, mortality in biventricular pacing patients remains high despite improvement in acute hemodynamics and mid-term symptom progress. Follow-up of a total of 153 patients paced in a biventricular configuration for 10 to 15 months revealed a 20% to 36% death rate, of which 33% to 47% was sudden death.l**30 Obviously, arrhythmia secondary to LV dysfunction and associated heart failure is of paramount concern, and, given the proven efficacy of ICD therapy in preventing sudden death in a coronary population at least, defibrillation capability continues to appear most attractive. Furthermore, the potential for the development of proarrhythmia with biventricular pacing devices exists. It is possible that pacing in the left ventricle may contribute directly to arrhythmia development in a population already at increased risk for sudden death; however, the converse may be true. Pacing delivered at an LV site closer to a culprit ventricular tachycardia circuit may increase the efficacy antitachycardia pacing (ATP) therapy, and multisite simultaneous pacing may decrease dispersion of refractoriness in the ventricle, making ventricular arrhythmia less frequent. These potential mechanisms may offset some of the potential proarrhythmic effects. Large clinical trials of

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biventricular ICD therapy are ongoing and are discussed later.20, 35, 42 ONGOING TRIALS OF BIVENTRICULAR PACING THERAPY

The VIGOR CHF is a prospective, randomized study in which patients with symptomatic heart failure and QRS greater than or equal to 120 msec undergo VDD biventricular pacing or no pacing (ODO) after a 2-week period of no pacing. After 6 weeks, the OD0 group is also converted to VDD pacing until 18 weeks have elapsed. At that time, the optimal pacing mode for each patient is continued. This is a blinded study to assess placebo effect, and patients serve as their own controls. Further study details are outlined in Table 2. The VENTAK CHF is an ICD trial with biventricular pacing capability and includes a patient population similar to the VIGOR CHF trial, with LVEF less than or equal to 35%. The LV lead is placed via a mini-thoracotomy. A conventional indication for ICD implantation is required. This blinded trial compares biventricular pacing with OD0 for 3 months, after which the patients crossover to the opposite randomization option. Again, the patients are serving as their own controls. The defibrillation function is constantly active. Further details are outlined in Table 2. The MIRACLE (Multicenter InSync Randomized Clinical E ~ a l u a t i o n )differs ~~ from the previously reported InSync study in that it is a blinded study with a control group. Patients will be randomized to 6 months of biventricular pacing or to ODO. After 6 months, all patients will be programmed to biventricular pacing. Further details are outlined in Table 2. The InSync ICD is a blinded, prospective, randomized, multicenter trial in whch all patients receive an InSync ICD system. The biventricular pacing function will be randomized to either on or off for the first 6 months, after which all patients will be paced in a biventricular configuration. The tachyarrhythmia therapy function will be active at all times. Further details are outlined in Table 2.

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PAVIA & WILKOFF

Table 2. ONGOING TRIALS OF MULTlSlTE PACEMAKER AND IMPLANTABLE CARDIOVERTER DEFIBRILLATOR IN CONGESTIVE HEART FAILURE Trial

NYHA 11-111-IV QRS >120 msec

VENTAK-CHF42 (ICD)

NYHA 11-111-IV QRS >120 msec LVEF <35% Thoracotomy LV lead NYHA 111-IV LVEF <35% QRS >130 msec

MIRACLE34 (Pacemaker)

~ n s p 1c ~ ~ (ICD) 3 5

NYHA 111-IV LVEF <35% QRS >130 msec No previous ICD

COMPANIONZo (Pacemaker + ICD)

NYHA 111-IV QRS >120 msec PR >150 msec LVEF <35% No conventional ICD indication

NYHA

=

Endpoints

Inclusion

VIGOR-CHF42 (Pacemaker)

Peak VoZ 6-Minute walk QOL Echocardiography Plasma NE level Peak VoZ QOL BiV ATP or defibrillation efficacy or safety QOL NYHA class 6-Minute walk LVEF Peak VoZ Echocardiography Neurohormone and cytokine levels NYHA class QOL 6-Minute walk Echocardiography Plasma neurohormone levels Peak Vo2 Patient survival NYHA class I1 patient response ATP therapy efficacy with BiV pacing Combined all-cause mortality and hospitalization All-cause mortality Cardiac morbidity Exercise performance peak Vo,

New York Heart Association; LVEF = left ventricular ejection fraction; QOL NE = norepinephrine.

=

quality of life; BiV = biventricular; ATP

= antitachycardia pacing;

The COMPANION Trial (Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure)*O has 3 separate, unblinded randomization limbs including (1) optimal medical therapy (20% of those enrolled), (2) optimal medical therapy and biventricular pacing (40%), and (3) optimal medical therapy, biventricular pacing, and defibrillation (40%). Further details are outlined in Table 2.

TECHNICAL ASPECTS OF BIVENTRICULAR PACING DELIVERY

To pace the left ventricle, the basis of biventricular pacing, new approaches compared with conventional dual-chamber pacing techniques are required.

Successful Access to the Epicardial Left Ventricular Surface

The most invasive technique is to place epicardial leads via thoracotomy or thoracoscopy. This requires anesthesia and entails a higher risk than a transvenous approach but, until recently, was the norm before the advent of relatively successful transvenous lead systems. With this approach, the cardiac veins, which are entered via the coronary sinus (CS), provide an epicardial conduit allowing pacing the LV free wall via the transvenous route. Fluoroscopic guidance is required. Success is variable and appears dependent on the individual anatomy of the CS and cardiac veins, lead technology, and operator experience. Daubert et all3 compared standard, unipolar leads, and leads specifically designed for use in the CS. Successful transvenous CS/cardiac vein lead implantation was achieved in 75.4%

BIVENTRICULAR PACING FOR HEART FAILURE

of patients enrolled. Dedicated CS leads performed better than standard leads with respect to success of initial implantation (81.8% versus 53.3%),with 97% of the leads retaining adequate function at 10 plus or minus 8 months follow up. Cardiac Vein Anatomy

The anatomy of the CS and cardiac veins visualized at selective venography is subject to wide individual ~ariabi1ity.l~ Venography is performed after cannulation of the CS with a long sheath, and previous attempted placement of the LV lead. The great cardiac vein and the middle cardiac vein appear to be almost always present; however, the angle of take off of the ostium of the CS from the right atrial septa1 approach is variable and may preclude cannulation. The presence, number, location, size, angulation, and tortuosity of the left posterior cardiac veins are extremely variable. These important aspects cannot be predicted previous to cannulation and the injection of contrast, and, consequently, individual cardiac anatomy has obvious implications for the outcome of CS lead placement attempts.

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Left Ventricular Lead Design

In an attempt to improve the success of CS lead implantation, novel lead systems have been developed. In general, the newer leads are lower profile, with some degree of preformed curve. Many different leads are currently under investigation in randomized clinical trials. Most CS leads followed the same conventional central-stylet technology, with individualized curves being fashioned to negotiate the variable cardiac vein anatomy. Borrowing the technology of angioplasty colleagues, however, an over-the-wire lead deployment system has been developed (EASYTRAK [Guidant Corporation, St. Paul, MN]), and the results of its use r e p ~ r t e dDeploy.~ ment in the cardiac vein is rapid (approximately 12 min), although in about 10% of cases, the procedure still is not successful. Overall, the success rate for implantation of 17, 38 left-sided leads ranges from 75% to 89'/0.~~, Other Endovascular Approaches

Alternative means of endocardia1 access to LV pacing lead placement, other than the transvenous CS approach, have been consid-

Figure 2. Coronary sinus (CS) venography. Retrograde coronary venous system contrast injections performed using an occlusive balloon system for the CS ostium. Possible lead placement target sites are revealed with this procedure. A, Right anterior oblique (RAO) view. B, The inflated balloon is seen clearly at the coronary sinus ostium in the left anterior oblique (LAO) view.

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PAVIA & WILKOFF

ered. These include transseptal and transarterial routes. Reports of inadvertent transeptal puncture in an attempt to place a conventional RV pacing lead have resulted in neurological complication at follow-up44,48; however, these patients were not prescribed anticoagulation therapy. Jais et alZ6performed transseptal pacing when an attempt at CS cannulation failed. This proved successful without neurological complication in the presence of anticoagulation therapy but was technically difficult. Subsequently, Leclercq et a132used transseptal catheterization in three patients, requiring less than 30 additional minutes to place the LV lead. On anticoagulation, clinical improvement was noted without neurological complication at 6 months in this small series. Obviously, the transeptal approach for placement of LV pacing leads has not been studied adequately.

Optimal Left Ventricular Pacing Site and Pacing Configuration

Once access to the cardiac veins is established, the optimal position of LV pacing leads is not yet known with certainty. Presumably, the specific regional dysfunction pattern may be one determinant of the optimal pacing site.

Ongoing studies continue in an attempt to determine this target site. Preliminary findings from the PATH-CHF trial suggest that increases in pulse pressures and dP/dtmax were most impressive at the midlateral epicardial pacing sites compared with other regions of the left ventricle? Consequently, the posterolateral cardiac vein branches currently are targeted (Fig. 3); however, this is not always possible to achieve. Sometimes, only an anterior site can be attained. In this situation, it is important to be aware that in up to 30% of patients, pacing from the anterior cardiac vein will significantly worsen baseline + dP/dt rather than improve it. Currently, this potential deterioration cannot be predicted without acute, individual case hemodynamic testing. Usually, a LBBB pattern is present in patients undergoing a biventricular pacing implantation attempt. With a coronary cause for the underlying cardiomyopathy, an LBBB pattern would be a rarity with a posterolateral infarction. Therefore, this pacing site almost always should be viable and adequate for pacing. In the unusual case of a true lateral infarction patient who qualified for biventricular pacing, an anterior placement of the cardiac vein lead may be acceptable. Otherwise, anterior placement is to be discouraged. The concept of LV-based pacing using LV

+

Figure 3. Biventricular (BiV) pacing configuration lead placement. The final lead positions are shown in RAO (A) and LAO (4 views. The right atrial (RA) and RV leads are also shown. The LV unipolar lead has been placed via the coronary sinus into a postero-lateral,mid-to-basalcoronary vein branch.

BIVENTRICULAR PACING FOR HEART FAILURE

lead pacing configuration alone, without biventricular configuration, has been addressed, somewhat observationally, in two studies. Initially, Blanc et a1,6 in 1997, and Kass et al,27in 1999, showed that LV singlesite pacing was equal or superior to biventricular pacing when patients with LBBB surface ECG conduction abnormality were compared. It is possible that single-site LV pacing may not resynchronize the right and left interventricular contraction, as the LV is now initially depolarized earliest. As suggested by Kass et al,27however, pragmatically, myocardial conduction emanating from the LV pacing site is significantly slower than via the conducting right bundle in this LBBB group, so that the end result may be that interventricular contractile synchrony remains. This concept does not take into account the differential degrees of myocardial hypertrophy, which would impact on conduction time, particularly as the LV pacing site is epicardial, compared with the traditional endocardia1 RV pacing site. To this end, a device with a programmable interventricular delay may become an important issue as more information is collected. Furthermore, particularly in atrial fibrillation and high-grade heart block patients, where LV-RV timing relation is not controlled, biventricular pacing may be superior to singlesite LV pacing. This requires further study. A cardiac vein pacing site may be complicated by concurrent pacing of the diaphragm. This should always be excluded once a pacing site is chosen. This may compromise the final positioning of the pacing lead. In the future, given the many limitations of the current transvenous LV lead implantation technique and the previously used alternative surgical epicardial approach, consideration may be given to a percutaneous epicardial approach now being used for some radiofrequency ablation procedures indicated when conventional endovascular approaches have failed. OTHER ISSUES CONCERNING PACING THERAPY FOR HEART FAILURE

Currently, the application of biventricular pacing has been extensively limited by re-

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search protocols. It is quite feasible that patients excluded from these studies may, in the future, be shown to benefit from this new technology. For example, patients with atrial fibrillation and patients with conventional indications for pacing will need to be considered specifically, because these groups have been excluded from studies thus far. Consequently, many patients with heart failure who potentially may benefit from this therapy have been excluded from trials. Given the enthusiasm for biventricular pacing fueled by currently completed trails, however, often these patients receive this novel therapy, using conventional approved, noninvestigational devices and lead systems in a nonevidence-based manner. In general, this practice is to be discouraged. A specific problem, for example, has been the implantation of nonstudy protocol, conventional approved ICDs in a biventricular pacing configuration via adapters to accommodate the extra coronary lead. In this way, ventricular signal double counting in the nonpaced mode is possible given the temporal separation of the RV and LV sensed signals, and consequently, inappropriate shocks may be delivered when the shock zone detection rate becomes satisfied. Patient discomfort and dissatisfaction with this situation are maximized, despite this therapy still being supposedly an investigative one. Many other potential unknowns concerning this new technology exist. The feasibility of safe and efficacious CS lead extraction must be considered. Any implantation of a device has a low, albeit definite, infection rate. The success of percutaneous endovascular extraction techniques have not yet encompassed this lead configuration and the possibility exists that an open-heart procedure may be required to remove such leads. The massive number of open heart procedures now undertaken provides an ideal opportunity for surgical implantation of an LV epicardial lead, while the chest is open, with transvenous right atrial and RV leads and pulse generator being implanted at a later date. Patients could be screened before heart surgery and selected based on functional class, prolonged QRS duration and LV systolic dysfunction. A randomized, prospective

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study using this approach has not been performed. Because conduction system abnormalities may be a late or even terminal manifestation of dysyn~hrony,~~ earlier intervention with biventricular pacing may be appropriate, thereby encompassing an even larger segment of the patient population, with CHF. At times, it is not possible to attain efficacious biventricular pacing because of implant technical difficulties or suboptimal patient characteristics. A promising new pacing therapy for heart failure is under investigation currently, with preliminary animal study results available. Cardiac contractility modulation (CCM) uses nonexcitatory, subthreshold, diastolic electrical stimulation to modulate cardiac contractility by augmenting sarcoplasmic reticulum calcium flux. Trials of this therapy are currently in an infancy stage but preliminary, as yet unpublished, acute animal study data appear promising (Fig. 4). Finally, the potential benefit of the ability to program specific, optimized interventricular delay, in combination with the conventional

AV delay optimization, has yet to be tested clinically, and consequently, this potentially useful programming option is not currently available in biventricular pacing devices. CURRENT RECOMMENDATIONS FOR BIVENTRICULAR PACING

The immense impact of heart failure on morbidity and mortality, along with the current disappointing results of conventional therapy, make the concept of a new and effective therapy for heart failure extremely attractive; however, multisite pacing is an invasive and expensive procedure and clearly is not indicated in every patient with heart failure. The challenge remains to identify those patients who will benefit, based on a minimally invasive selection criteria. Most trials have used symptomatic heart failure, a reduced LVEF and the baseline, surface 12-lead ECG as the method of patient selection. The ideal characteristics appear to be LBBB pattern with a prolonged PR interval.

LVP dP/dt (mm Hghec)

Sinus

DDD

BiV

BiV + CCM

BiV - CCM

Figure 4. Cardiac contractility modulation (CCM) therapy. Results of acute hemodynamic monitoring during different pacing configurations, including CCM. RA, RV, and CS leads were placed percutaneously into a normal heart, open chest pig. Note the improvement in cardiac contractility as measured by dP/dt and LV systolic pressure (LVP) with BiV pacing. A further improvement is seen when both modalities are engaged simultaneously (BiV + CCM). This complementary effect is lost when the CCM contribution is discontinued (BiV - CCM). The onset of each pacing mode starts with each respective arrow and continues to the next arrow. The patient is in sinus rhythm unit1 the DDD pacing arrow starts. DDD = Atrial synchronous RV pacing. (From Dresing TJ, Natale A: Congestive heart failure treatment: The pacing approach. Heart Fail Rev 6:15-25, 2001; with permission.)

BIVENTRICULAR PACING FOR HEART FAILURE

This baseline ECG pattern may not be the best method, however. According to a report from Alonso et al,' functional class and peak VO, improvement correlated not with baseline ECG QRS duration but with the degree of QRS shortening when the biventricular pacing configuration was employed, independent of the baseline measurements. By definition, a tool that could assess accurately and quantitatively Ventricular mechanical dyssynchrony would seem to be the gold standard in evaluating the efficacy of any resynchronization therapy. To this end, Nelson et a136used tagged MR imaging and showed the degree of baseline mechanical dyssynchrony is the best predictor of response to biventricular pacing. In an attempt to correlate this method with a more readily available investigative parameters, the combination of a baseline ECG QRS duration of greater than 155 msec and a baseline +dP/dtmax less than or equal to 700 mm Hg per sec consistently predicted a positive response to biventricular pacing. Nelson et a13'j also confirmed, along with the current body of evidence, that improvement with biventricular pacing is most often predicted by the presence of LBBB pattern on the surface ECG. The right bundle branch block (RBBB) patients were seen to improve with standard RV apical pacing in this study; however, a contrasting result was reported recently by Kerwin et a1.28When the response to biventricular pacing was assessed by phase scintigraphic nuclear imaging analysis, improved synchronization and cardiac performance were observed in patients with baseline RBBB and nonspecific intraventricular conduction delay and in the patients with LBBB. This improvement was not associated with shortening of the QRS duration as it has been in other studies. Finally, in a study by Breithardt et a1,9 the chronic response to biventricular pacing was not always predicted by an acute hemodynamic response demonstrated at implant. This preliminary study showed that very dilated hearts, based on end-diastolic volumes previous to implantation, showed impressive acute hemodynamic benefit but did not respond to longer-term pacing. This correlated with a concerning increase in heart size over

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the study period. This raises the question as to whether there exists a stage in the progression of a cardiomyopathic process when the degree of cardiac enlargement would preclude benefit from biventricular pacing consideration. SUMMARY

The completed trials of biventricular pacing in congestive cardiac failure are impressively encouraging as a novel therapy for the symptoms of a most devastating disease. The actual delivery of the LV pacing hardware and final patient selection criteria require further refinement, as it is clear that not all patients with heart failure respond favorably. What is clear is that all patients should be prescribed maximally tolerated, proven medical therapy before assessment as to the feasibility of biventricular pacing therapy. This should be the case until potentially proven otherwise in newly planned trials designed to assess the comparative efficacy of both approaches. It is difficult to see that the two approaches should be anything but complementary in their benefit. The expense and potential complication associated with any invasive procedure needs to be considered, however, and it would seem reasonable that all of these patients should be receiving maximally tolerated medical therapy before and after the implantation of a device. Finally, the effect of this therapy on mortality needs to be assessed and, consequently, the requirement for defibrillation capability considered in this population of patients with a known high incidence of sudden death. References Alonso C, Leclercq C, Victor F, et al: Electrocardiographic predictive factors of long-term clinical improvement with multisite biventricular pacing in advanced heart failure. Am J Cardiol84:1417-1421,1999 Auricchio A, on behalf of the PATH-CHF investigators: Optimal cardiac resynchronization decreases heart rate and increases heart rate variability in heart failure patients with conduction delay. Pacing Clin Electrophysiol 23:602, 2000 Auricchio A, Klein H, Tockman B, et al: Transvenous biventricular pacing for heart failure: Can the obstacles be overcome? Am J Cardiol 83:136P142D, 1999

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4. Auricchio A, Stellbrink C, Block M, et al: Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure: The Pacing Therapies for Congestive Heart Failure Study Group: The Guidant Congestive Heart Failure Research Group. Circulation 99:29933001, 1999 5. Auricchio A, Stellbrink C, Sack S, et al: The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: Rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 83:130D-l35D, 1999 6. Blanc J, Etienne Y, Gillard M, et al: Evaluation of different ventricular pacing sites in patients with severe heart failure: Results of acute hemodynamic study. Circulation 96:3273-3277, 1997 7. Bramlet DA, Morris KG, Coleman RE, et al: Effect of rate-dependent left bundle branch block on global and regional left ventricular function. Circulation 671059-1065, 1983 8. Brecker SJ, Xiao HB, Sparrow J, et a1 Effects of dualchamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 340:1308-1312, 1992 9. Breithardt 0, Stellbrink C Diem B, et al: Chronic multisite pacing leads to reduced ventricular volumes in selected patients with congestive heart failure [abstract]. Eur Heart J 20:3, 1999 10. Cazeau S, Lazarus A, Ritter P, et a1 Biventricular pacing decreases interventricular but not intraventricular asynchrony in multi-site paced patients for congestive heart failure [abstract]. Pacing Clin Electrophysiol 21:792, 1998 11. Cazeau S, Ritter P, Lazarus A, et al: Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol 19:1748-1757, 1996 12. Cazeau S, Leclercq C, Lavergne T, et al: Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344873-880,2001 13. Daubert JC, Ritter P, Le Breton H, et a1 Permanent left ventricular pacing with transvenous leads inserted into the coronary veins. Pacing Clin Electrophysiol 21:239-245, 1998 14. Gaita F, Bocchiardo M, Porciani M, et al: Should stimulation therapy for congestive heart failure be combined with defibrillation backup? Am J Cardiol 86(s~ppl):165K-l68K,2000 15. Gilard M, Mansourati J, Etienne Y, et al: Angiographic anatomy of the coronary sinus and its tributaries. Pacing Clin Electrophysiol 21:2280-2284, 1998 16. Gold MR, Feliciano Z, Gottlieb SS, et al: Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: A randomized study. J Am Coll Cardiol26:967-973, 1995 17. Gras D, Mabo P, Tang T, et al: Multisite pacing as a supplemental treatment of congestive heart failure: Preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol21:2249-2255, 1998 18. Gras D, MaboP, Tang T, et al: Multisite pacing as a supplemental ,treatment of congestive heart failure: Preliminary results of the Medtronic Insync Study. Pacing Clin Electrophysiol 21:2249-2255,1998 19. Grines CL, Bashore TM, Boudoulas H, et a1 Functional abnormalities in isolated left bundle branch block The effect of interventricular asynchrony. Circulation 792345453, 1989 20. Guidant Product Information 1999: Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study guidelines. St. Paul, MN, Guidant

21. Harrison T Some unanswered questions concerning enlargement and failure of heart. Am Heart J 69:lOO115, 1965 22. Herman MV, Heinle RA, Klein MD, et al: Localized disorders in myocardial contraction: Asynergy and its role in congestive heart failure. N Engl J Med 277222-232, 1967 23. Higgins S, Yong P, Scheck D, et al: Biventricular pacing diminishes the need for implantable cardibvertgr defibrillator therapy. J Am College Cardiol 36:82&827,2000 24. Hochleitner M, Hortnagl H, Fridrich L, et al: Longterm efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 70:1320-1325, 1992 25. Hochleitner M, Hortnagl H, Ng CK, et al: Usefulness of physiologic dual-chamber pacing in drug-resistant idibpathic ailated cardiomyopa&y. Am'J Cardiol 66:198-202. 1990 26. Jais P, Douard H, Shah DC, et al: Endocardia1biventricular pacing [see comments]. Pacing Clin Electrophysiol 21:2128-2131, 1998 27. Kass DA, Chen CH, Curry C, et al: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99:1567-1573,1999 et al: Ven28. Kenvin WF, Botvinick EH, OConnell JW, tricular contraction abnormalities in dilated cardiomyopathy: Effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 35:1221-1227,2000 29. Lam C, Rose M, Jaeger F, et al: Wide QRS duration predicts inducibility of sustained ventricular arrhythmia [abstract]. Circulation 102(suppl 11):11475, 2000 30. Leclerq C, Cazeau S, Alonso C, et al: Multisite biventricular pacing in heart failure: current status of the French Pilot Study [abstract]. Pacing Clin Electrophysiol 22:733, 1999 31. Leclercq C, Cazeau S, Le Breton H, et al: Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 321825-1831, 1998 32. Leclercq F, Hager FX, Macia JC, et al: Left ventricular lead insertion using a modified transseptal catheterization technique: A totally endocardia1 approach for permanent biventricular pacing in end-stage heart iailure [see comments]. Facing Clin ElectrGphysiol 22:1570-1575, 1999 33. Linde C, Gadler F, Edner M, et al: Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 75:919-923, 1995 34. Medtronic MIRACLE Trial: Multicenter InSyncm RAndomized CLinical Evaluation Investigational Plan. Medtronic, Minneapolis, MN, 1998 35. Medtronic InSyncm ICD Trial Investigational Plan, Insync@ ICD Clinical Study Evaluating Cardiac Resynchronization Therapy for Heart Failure Patients with ICD Indications. Medtronic, Minneapolis, MN, 1999 36. Nelson GS, Curry CW, Wyman BT, et al: Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation 101:2703-2709,2000 37. Nishimura RA. Haves DL. Holmes DR lr, et al: Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: An acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol25:281-288, 1995 I

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Address reprint requests to Bruce L. Wilkoff, MD Section of Cardiac Pacing and Electrophysiology Department of Cardiology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 e-mail: [email protected])