Uncoupling at the Atrial Level

The right atrium and left atrium are activated nearly simultaneously (within 50-80 milliseconds) during sinus rhythm. Preferential sites of interatrial conduction exist at the posterior-superior interatrial septum (Bachmann’s bundle region), fossa ovalis, and coronary sinus ostium.^1,2 Significant interatrial conduction delays (up to 200 msec or greater) can occur in myopathic atria. Similar conduction delays can be also be induced, or exacerbated, by right atrial (RA) pacing. Delayed left atrial (LA) contraction can disrupt optimal left-sided atrioventricular (AV) coupling. Severe atrial decoupling and delayed LA contraction reverses the left-sided AV contraction sequence, resulting in atrial transport block.³ This causes increased LA pressures, retrograde flow in the pulmonary veins, and counterphysiologic neurohormonal responses termed pseudo–pacemaker syndrome.^4–6

Uncoupling at the Atrioventricular Level

Optimal AV coupling contributes to ventricular pump function through Starling’s law. The normal intrinsic atrioventricular interval (iAVI) results in atrial contraction just before the preejection (isovolumetric) period of ventricular contraction that maximizes left ventricular (LV) filling (LV end-diastolic pressure, or preload) and cardiac output. Appropriately timed AV coupling maintains a low mean atrial pressure, increases LV filling time, maximizes preload and pump function (Starling mechanism), and positions the mitral valve for closure during the isovolumetric phase of ventricular systole (Fig. 31-1).

Figure 31-1 Schematic representation of optimal atrioventricular (AV) coupling.

Atrial contraction (A) occurs just before isovolumetric contraction (ic); ir, isovolumetric relaxation. Passive diastolic left ventricular (LV) filling (E) is unimpeded, and total diastolic filling time (E + A) is maximized. Left atrial pressure (blue line) remains low during diastole, LV pressure (orange line) is high during ejection.

Delayed AV coupling resulting from AV conduction delay displaces atrial contraction earlier in diastole (Fig. 31-2). Atrial contraction occurs during ventricular filling, which shortens diastolic filling time, and in extreme situations, occurs immediately after or coincident with the preceding ventricular contraction. This situation is aggravated by ventricular conduction delay, which increases ventricular ejection time and delays diastolic filling, increasing the probability of collision with atrial contraction. Atrial contraction before completion of venous return reduces preload stretching of the left ventricle, which reduces ventricular volume and contractile force. Delayed AV coupling reduces diastolic filling time and may result in diastolic mitral regurgitation when elevated LV end-diastolic pressure exceeds LA pressure. Partial closure of the mitral valve may also occur, further shortening diastolic filling time.

Figure 31-2 Schematic of hemodynamic effects of AV decoupling on LV pump function.

Same arrangement as in Figure 31-1. Atrial contraction truncates passive diastolic filling (E-A fusion). A late diastolic left ventricular–left atrial (LV-LA) pressure gradient before mitral valve closure results in diastolic mitral regurgitation. LV filling is reduced and pump function declines (reduced LV pressure during ejection).

Delayed AV coupling may be worsened or induced by atrial pacing. This is a consequence of atrial capture latency, increased atrial conduction time resulting from altered activation, and increased AV nodal conduction time from altered atrial input. These effects of atrial pacing are enhanced by increased heart rates during atrial pacing and autonomic changes during sleep.⁷

Severe AV decoupling coexists with ventriculoatrial (VA) coupling. In extreme conditions LA contraction occurs immediately after, within, or preceding the LV contraction, causing reversal of the left-sided AV contraction sequence,³ which initiates counterphysiologic circulatory and neurohumoral reflexes. These derangements (pseudo–pacemaker syndrome) have been rarely described during marked first-degree AV block and atrial pacing.⁴ The identical pathophysiology occurs during AV synchronous ventricular pacing when LV contraction timing is too early, resulting in LA transport block (Fig. 31-3). This situation is corrected by proper timing of ventricular contraction with pacing (see Atrioventricular Optimization).

Figure 31-3 Hemodynamic effects of short A-V interval on LV pump function.

Same arrangement as in Figures 31-1 and 31-2. Ventricular contraction triggered by premature pacing stimulus (arrow) truncates atrial emptying (atrial transport block). Atrial pressure increases, LV filling decreases, and pump function declines (reduced LV pressure during ejection).

Atrial fibrillation disrupts atrial coupling (atrial desynchronization) and eliminates AV coupling (AV uncoupling).

Effects of Asynchrony on Left Ventricular Mechanics and Structure

Regions that are activated early also start to contract early. Accordingly, in RVA pacing and LBBB, earliest and latest sites of segmental LV activation correlate well with time to peak systolic velocity by Doppler imaging¹⁹ and strain by tagged magnetic resonance imaging (MRI),^9,26–28 providing evidence that ventricular conduction delay is responsible for heterogeneous mechanical performance (asynchrony). The mechanical effect of asynchronous electrical activation is dramatic, because the various regions differ not only in the time of onset of contraction, but also in the pattern of contraction (Fig. 31-4). Contraction of early-activated myocardium is energetically inefficient because LV pressure is low and ejection has not begun. Instead, stretching of remote regions not yet activated absorbs the energy generated by the early-activated regions. This stretching further delays shortening of these late activation regions and increases their force of local contraction by virtue of the Frank-Starling mechanism (locally enhanced preload). Vigorous late systolic contraction at delayed sites occurs against high LV cavity pressures (locally enhanced afterload) and imposes loading on the earlier activated regions, which now undergo systolic paradoxical stretch.²⁹ This reciprocated stretching of regions within the LV wall causes a less effective and energetically efficient contraction.³⁰

Figure 31-4 Effects of synchronous (left panel) and asynchronous (right panel) ventricular activation on LV and aortic pressure (A), regional strain (B), ventricular conduction (C), electrocardiographic tracings), RV and LV pressure signals (D), and pressure-volume loops (E). Asynchronous contraction causes reduction in ejection time and slows rates of rise and fall of LV pressure and aortic pressure and increases duration of isovolumetric contraction (ic) and relaxation (ir) (A). Onset of LV shortening (strain) is regionally delayed (negative deflection of curve) (B). Asynchronous electromechanical activation induces increased QRSd (C) and interventricular/intraventricular activation times (D), which instantaneously reduce stroke volume, stroke work, dP/dt_max, and dP/dt_min, indicating an acute reduction in pump function (E).

(Modified from Sweeney MO, Prinzen FW: Ventricular pump function and pacing: physiological and clinical integration. Circ Arrhythmia Electrophysiol 1:127-139, 2008.)

The hemodynamic consequences of the asynchronous LV contraction are reductions in contractility and relaxation. These changes occur immediately on initiating RVA pacing in humans and animals,^11,31 and induction of LBBB in animals¹² (see Fig. 31-4). The loss of pump function is indicated by decreases in stroke volume, stroke work, and slower rate of rise of LV pressure (Fig. 31-5). Moreover, the LV end-systolic pressure-volume relationship shifts rightward, indicating that the left ventricle operates at a larger volume in order to recruit the Frank-Starling mechanism.¹¹ Premature relaxation in early-activated regions, and delayed contraction in others also causes abnormal relaxation,¹¹ as expressed as slower rate of fall of LV pressure, increase in the relaxation time constant tau, and decrease of E-wave velocity amplitude on Doppler echocardiograms.³² These changes also lead to prolongation of the isovolumetric contraction and relaxation times, which are characteristic for asynchronous hearts.³³ The prolongation of the isovolumetric times occurs mainly at the expense of the diastolic filling time, leading to reduced preload.

Figure 31-5 Left bundle branch block (LBBB)–induced asynchrony causes immediate reduction in LV contractility.

A, Left ventricular (LV) endocardial activation maps. Inner circle represents LV apex and outer circle represents LV base. S, A, L, and P indicate the septum, anterior, lateral, and posterior walls, respectively. Arrows indicate activation delay vectors, the amplitude of which reflects the degree of intraventricular asynchrony (intra VA). B, Surface electrocardiogram (ECG) tracings, where QRS duration indicates total ventricular asynchrony (total VA). C, Right ventricular (RV) and LV pressure signals normalized to reveal pressure differences (interventricular asynchrony, inter VA). D, Pressure-volume (PV) loops. Loop area is stroke work, loop width is stroke volume.

During normal ventricular conduction (top row, pre-LBBB) intraVA and interVA are minimized, QRSd is normal and LV contractility is greater (larger PV loop). After induction of LBBB (bottom row, post-LBBB), intra VA, inter VA, and total VA are increased, which immediately reduces LV pump function (smaller PV loop indicating declines in stroke work, stroke volume, and LV pressure generation).

(Modified from Vernooy K et al: Left bundle branch block induces ventricular remodeling and functional septal hypoperfusion. Eur Heart J 26:91-98, 2005.)

The redistribution of the mechanical load within the ventricular wall also leads to reduction of regional myocardial perfusion and oxygen consumption near the RVA pacing site^30,34,35 and in the septum during LBBB.^36,37 Such perfusion defects and wall motion abnormalities have been demonstrated in up to 70% of patients with angiographically normal coronary arteries exposed to chronic RVA pacing.^38–41 These defects are reversible on cessation of RVA pacing^39,41 and after biventricular pacing.^36,37,42 Accordingly, such perfusion “deficits” do not necessarily indicate coronary heart disease, because they may simply express the regional differences in myocardial workload.

Similar to the situation after myocardial infarction, acute loss of pump function initiates compensatory responses (Figs. 31-6 and 31-7). Some of these responses, after a certain time and or degree of asynchrony, may result in further impairment of pump function and clinical heart failure. There are various triggers for these “remodeling” processes. As for other conditions of hemodynamic overload, RVA pacing and LBBB lead to stimulation of the sympathetic system, resulting in elevated myocardial catecholamine levels,⁴³ and activation of the renin-angiotensin-aldosterone system. Regional differences in stretch and mechanical load heterogeneity are most likely important stimuli for remodeling processes. Chronic asynchronous LV activation results in regional and global structural changes indicated by asymmetric hypertrophy, increased end-diastolic volume, and reduced ejection fraction^36,44 (see Fig. 31-6), as well as locally different molecular abnormalities, including reductions in sarcoplasmic reticulum calcium-ATPase and phospholamban.⁴⁵ Even stronger regional differences in gene expression are found in failing hearts with conduction abnormalities.⁴⁶ Dystrophic calcifications, disorganized mitochondria, and myofibrillar cellular disarray⁴⁷ have been described with RVA pacing, especially in immature hearts.

Figure 31-6 Left bundle branch block (LBBB).

*P, 0.05 compared to baseline. †Significant change over time by ANOVA. A, Effects of induced LBBB on electromechanics. Dashed lines on surface electrocardiogram (ECG) indicate earliest and latest left ventricular (LV) endocardial activation times. Bull’s-eye plots indicate septal (S), posterior (P), lateral (L), and anterior (A) LV wall, where outer ring indicates LV base and inner ring indicates LV apex. Activation is color-coded where lighter shades indicate later activation times. During normal ventricular conduction (Baseline), QRSd is narrow and LV electromechanical activation is simultaneous throughout. During LBBB, QRS is prolonged and LV electrical and mechanical activation is delayed with lateral wall latest. B-D, Change in LV end-diastolic volume (increase), LV septal-lateral wall mass ratio (decrease, indicating asymmetrical hypertrophy), and ejection fraction (decrease) after 16 weeks of LBBB in a canine model. The purple and red lines in B and D indicate the time course for two individual dogs that were most and least sensitive to the adverse electromechanical effects of LBBB.

(Modified from Vernooy K et al: Left bundle branch block induces ventricular remodeling and functional septal hypoperfusion. Eur Heart J 26:91-98, 2005.)

Figure 31-7 Mechanisms of ventricular remodeling and progressive reduction in pump function during mechanical dyssynchrony induced by ventricular conduction delay (LBBB, RVA pacing). For details, see text.

(Modified from Sweeney MO, Prinzen FW: Ventricular pump function and pacing: physiological and clinical integration. Circ Arrhythmia Electrophysiol 1:127-139, 2008).

Early signs of cellular and molecular adaptation to disturbed ventricular activation are manifest as reduction in ejection fraction (EF) within the first week of RVA pacing. In patients with normal EF, Nahlawi et al.³¹ showed an immediate drop in EF of about 7%, followed by another 7% drop during the subsequent week. Suppression of RVA pacing returned EF to baseline values, but only after several days.⁴⁸ Also, ventricular repolarization abnormalities have been observed within hours of RVA pacing. Alterations in potassium and calcium channels likely play a role in these phenomena.

Mechanistic Basis for Development of Asynchronous Heart Failure Caused by Ventricular Conduction Delay

As mentioned, synchronous activation consistently leads to acute and long-term adverse effects on cardiac pump function, which create a vicious cycle of deterioration. Accordingly, the pacing-induced ventricular conduction delay has been linked to increased risks of atrial fibrillation, heart failure, ventricular tachyarrhythmia, and death in large, randomized clinical trials of pacemakers and ICDs.^49–56 Similar risks have been reported for LBBB and cardiac morbidity and mortality.⁵⁷

Multiple factors may contribute to heart failure associated with ventricular asynchrony. At least three candidate factors are readily identified: (1) reduced pump function caused by asynchronous contraction (dyssynchrony), (2) adverse remodeling caused by long-term dyssynchrony, (3) left-sided AV desynchronization, and (4) functional mitral regurgitation (fMR). The first three factors are discussed earlier. The fMR frequently accompanies pacing-induced or spontaneous asynchronous heart failure and has multiple mechanisms.^24,25,58,59 Assuming the anterior mitral leaflet is structurally normal, the immediate cause of fMR is delayed activation of the LV posterior “apparatus” caused by ventricular conduction delay.^25,60 This apparatus consists of the posterior leaflet and annulus, the LV summit it sits on, the chordae, the papillary muscles, and the LV wall from which they emanate. Rapid activation of the posterior apparatus requires normal ventricular conduction.

Early closure of the mitral valve is arguably the most important accomplishment of the entire conduction system because it facilitates Starling’s law; that is, it permits isovolumetric systole to occur when the ventricle is as full as it can be given the filling conditions. Delayed ventricular conduction prevents mitral valve coaptation and induces fMR during isovolumetric contraction. Ventricular conduction delay instantaneously reduces the transmitral pressure gradient (systolic LV pressure–LA pressure difference) or mitral valve closing force, by reducing contractility (↓LV dP/dt). Chronically, volumetric remodeling contributes to fMR by further reductions in contractility (closing forces) and increasing papillary muscle tethering forces^59,61,62 (Fig. 31-8). Tethering strongly depends on alterations in ventricular shape because the tethering forces that act on the mitral leaflets are higher in dilated, more spherical ventricles. Ventricular dilation and increased chamber sphericity increase the distance between the papillary muscles to the enlarged mitral annulus as well as to each other, restricting leaflet motion and increasing the force needed for effective mitral valve closure. Under these conditions, the mitral regurgitant orifice area will be largely determined by the phasic changes in transmitral pressure.

Figure 31-8 Effects of augmented mitral valve leaflet tethering in dilated cardiomyopathy.

Functional mitral regurgitation (fMR) results from an imbalance between the closing and tethering forces that act on the mitral leaflets. When the mitral valve is tethered, mitral regurgitant orifice area is largely determined by phasic changes in transmitral pressure (TMP). Reductions in LV pump function (↓dP/dt) results in decreased rate of LV (and thus transmitral) pressure, which will increase MR severity because of the impaired closing force.

(Modified from Otsuji Y, et al: Restricted diastolic opening of the mitral leaflets in patients with left ventricular dysfunction: evidence for increased valve tethering. J Am Coll Cardiol 32:398-404, 1998.)

There is some intriguing evidence that LBBB may be the primary cause of DCM in some patients. Progressive LV enlargement after the emergence of LBBB unaccompanied by any other explanation has been documented in case series.⁶³ Furthermore, complete recovery of ventricular function shortly after initiation of biventricular pacing in “hyperresponders” suggests that LBBB may be a primary and reversible trigger of DCM in some patients.^64,65

Several studies also showed that LBBB is associated with increased mortality, with greater impact in sicker patient populations. The relative risk associated with the presence of LBBB varied between 1.5 and 2.0, even after adjustment for covariates.⁵⁷ The only study rejecting the association of LBBB with increased mortality drew this conclusion after adjustments for LV EF as a covariable.⁶⁶ However, the conclusion that LBBB is not an independent predictor of mortality after the adjustment for EF can be understood because LBBB directly reduces EF because of its acute and chronic effect on LV pump function (see earlier).

Improved Atrioventricular Mechanics from Optimal AV Resynchronization

When LV contraction timing is delayed, even when AV conduction times are normal, the hemodynamic consequences are similar to a prolonged AV interval, as shown in Figure 31-2. Left-sided AV decoupling, due to LV conduction delay and/or AV conduction delay, is corrected with LV pacing. Optimal AV timing improves LV pump function, but the primary mechanism of improved ventricular mechanics during CRT is reduction in ventricular conduction delay. AV timing considerations during CRT are considered in detail later.

Improved Ventricular Mechanics from Reduced Ventricular Conduction Delay

Reduction of intraventricular delay during atrial-synchronous LV or biventricular pacing has an immediate positive effect on ventricular mechanics and is the dominant therapy effect of CRT. Instantaneous improvement in pump function is indicated by increases in LV +dP/dt_max, stroke volume, stroke work, arterial pulse pressure and peak systolic pressure,^67,68 and reduced end-systolic volume (Fig. 31-9). Moreover, unlike the inotropic effects of dobutamine, systolic augmentation with ventricular resynchronization increases efficiency of conversion of myocardial oxygen consumption to mechanical work.⁶⁹ This positive contractile response demonstrates a modestly positive correlation with increasing baseline QRSd^67–69 and is strongly correlated with baseline mechanical dyssynchrony.^69,70 Conversely, neither improved contractility nor reverse volumetric remodeling requires QRS narrowing during LV or biventricular pacing.^68,71,72 However, unlike the inotropic effects of dobutamine, systolic augmentation with ventricular resynchronization does not increase detrimental myocardial oxygen consumption. These acute improvements in ventricular mechanics are maintained chronically and are accompanied by reverse volumetric remodeling of the LV (see later).⁷³ Abrupt discontinuation of LV pacing results in immediate reduction in indices of improved contractility and regression of reverse remodeling over several weeks,^73,74 as well as recurrence of fMR.²⁵

Figure 31-9 Pressure-volume loops during LBBB and LV pacing.

Correction of regional mechanical delay results in immediate reduction in left ventricular (LV) volumes (leftward shift of pressure-volume relationship) and increases in stroke work (larger loop), stroke volume (width of loop), and dP/dt_max. CRT, Cardiac resynchronization therapy.

(Modified from Verbeek XA, Vernooy K, Peschar M: Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block. J Am Coll Cardiol 42:558-567, 2003.)

Maximally effective ventricular resynchronization occurs at the midpoint of the interventricular (V-V) interval (Fig. 31-10), which is the conduction time from RV to LV pacing site during native activation. A single optimum AV delay will achieve maximally effective ventricular resynchronization by advancing LV activation sufficiently to minimize the V-V interval. The AV delay and the V-V interval have an interactive relationship. The effect of AV delay on acute hemodynamic response to CRT is best understood in terms of the effect on ventricular resynchronization during biventricular (BiV) or left univentricular pacing (Fig. 31-11). During LBBB, the right ventricle is activated by right bundle branch conduction (RBBc) before the left ventricle, and the time difference between RV and LV activation is the interventricular conduction delay.¹³ BiV pacing at short atrioventricular delay (AVD) results in complete replacement of intrinsic activation, allowing complete control of chamber timing with sequential ventricular stimulation. Intermediate AVDs result in fusion among RBBc, RV paced activation, and LV paced activation. Long AVDs result in “pure” fusion between RBBc and LV paced activation since LV preexcitation is still possible because of interventricular conduction delay.^13,75,76 Modification of the AVD alone can therefore achieve (1) BiV paced fusion, (2) BiV paced fusion with sequential ventricular stimulation (LV first), and (3) “pure” RBBc-LV pacing fusion. Therefore, LV preexcitation is possible across a range of AVDs because LV time is delayed relative to RV time. RV pacing is not necessary to achieve fusion, and AVD can be used to time the relative prematurity of LV preexcitation. At very short AVDs, this requires sequential VV timing. At very long AVDs, this occurs spontaneously because of the native V-V interval.

Figure 31-10 Relationship between intraVA and interVA under various LV pacing conditions.

At long atrioventricular delay (AVD), ventricular conduction delay persists (large intraVA and interVA). At very short AVD, large intraVA and interVA persist because complete reversal of LV activation has occurred. At the optimal AVD, intraVA is minimized and interVA resides at the midpoint of the interVA during either extreme condition, which yields the maximum improvement in pump function.

(Modified from Verbeek XA, Vernooy K, Peschar M: Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block. J Am Coll Cardiol 42:558-567, 2003; and Vernooy K, et al: Calculation of effective VV interval facilitates optimization of AV delay and VV interval in cardiac resynchronization therapy. Heart Rhythm 4:75-82, 2006.)

Figure 31-11 Top, Interaction between atrioventricular delay (AVD) and V-V interval to determine LV activation fusion. T-RV is time to intrinsic RV activation (RA sense to RV sense, or P-R interval). During short AVD pacing (AVD < T-RV), biventricular pacing completely replaces native activation (surrogate fusion), and relative timing of ventricular activation is determined by sequential ventricular stimulation (RV first, simultaneous, LV first). When AVD = T-RV, RV pacing occurs simultaneously with intrinsic conduction, resulting in a combination of RV pacing and intrinsic conduction, whereas left ventricle is still activated earlier than would have occurred due to LBBB. When AVD > T-RV, LV-only pacing occurs with true fusion of native and paced activation. Bottom, Epicardial isochrone maps are shown during LV-only pacing at increasing pacemaker A-V intervals (pAVIs). Activation times relative to QRS onset are color-coded with red earliest and blue latest; framed numbers indicate earliest and latest activated sites. Asterisk, LV stimulation site. Black lines indicate line/region of conduction block, which influences activation wavefront propagation (see Fig. 31-77). A, pAVI = 0 msec. Note sequential ventricular activation (LV→RV): LV is activated earliest, and latest activation occurs at posterobasal right ventricle. B to C, Progressive fusion of paced LV activation with intrinsic LV activation via RBB as pAVI is increased from 65 to 86 msec. Note also progressively early RV activation from RBB conduction. D, Maximum ventricular activation wavefront fusion at pAVI = 173 msec. Note right and left ventricles are simultaneously activated (Esyn, electrical synchrony, = −18 msec).

(Modified from Jia P et al: Electrocardiographic imaging of cardiac resynchronization therapy in heart failure: observation of variable electrophysiologic responses. Heart Rhythm 3:296-310, 2006.)

Early acute hemodynamic studies demonstrated that the relationship between AVD and LV dP/dt_max in patients with an acute improvement in contractile response to simultaneous BiV pacing is positive and unimodal, with a peak effect at approximately 50% of the native P-R interval, resulting in complete replacement of native ventricular conduction with paced activation^67,68,77 (Fig. 31-12). This dose-response relationship between AVD and acute contractile response shown is interpreted as follows. The magnitude of the acute contractile response depends on the magnitude of baseline asynchrony (ventricular conduction delay, QRSd) and the AVD, which titrates how much intrinsic ventricular activation is replaced by pacing activation. Patients with greater ventricular conduction delay (QRS >150 msec) benefit from near-complete replacement of intrinsic activation with BiV or LV pacing (i.e., short AVDs). Patients with less ventricular conduction delay (QRS <150 msec) benefit from limited replacement of intrinsic activation (e.g., long AVDs). Typically, programmed short AVDs of 100 to 120 msec, although near-optimal for some patients, may result in decreased contractile function in patients with less baseline asynchrony (e.g., QRS <150 msec) because even BiV pacing induces asynchrony.⁹ LV dP/dt_max increased 15% to 45% across a narrow range of AVDs and declined at very short AVDs (truncated filling times) or very long AVDs (inadequate correction of LV conduction delay). This maximum improvement in pump function (LV +dP/dt_max and stroke volume) occurs at minimal intraventricular asynchrony and unchanged LV end-diastolic pressure (preload).¹³ This indicates that the acute contractile response is explained by ventricular resynchronization, not by better filling, and that the dose of resynchronization is titrated by the AVD.

Figure 31-12 Interaction between atrioventricular delay (AVD), magnitude of LV conduction delay, and acute improvement in contractility during CRT.

Mean (±SEM) change in LV dP/dt_max when BiV pacing at various AVDs in patients with QRS duration greater than 150 msec (diamonds) or 120 to 150 msec (triangles). The AVDs tested were fixed percentages of the intrinsic A-V interval (iAVI) determined individually for each patient. Acute hemodynamic responders (type I) demonstrate improvement across a broad range of AVDs, whereas hemodynamic nonresponders (type II) may worsen because of very short AVDs.

(Modified from Auricchio A et al: Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 99:2993-3001, 1999.)

The best ventricular resynchronization occurs when the wavefronts from the RV pacing site (or originating from RBBc) and the LV pacing site collide halfway.⁷⁸ Experimental evidence suggests that optimal hemodynamic effect can be achieved using LV pacing at certain AVDs as well as using simultaneous and sequential BiV pacing because fusion of electrical wavefronts can be achieved by either approach^13,79 (see Fig. 31-10). Although this and other experimental studies show a clear mechanism of action for optimizing the interaction between AV and VV timing, confusion surrounds this area, and a clinical advantage of patient-specific timing optimization has not been convincingly demonstrated in clinical trials^80–82 (see later).

Reverse Volumetric Left Ventricular Remodeling

Mechanical resynchronization reduces mechanical load heterogeneity throughout the left ventricle. Sustained improvement in ventricular mechanics results in regression of adverse LV remodeling, termed reverse remodeling. This is indicated by reductions in LV volumes and mass, reduced mitral orifice size, regression of asymmetric hypertrophy, and increased EF.^73,83–90 The magnitude of the reduction in end-systolic volume ranges between 10% and 30%,^83,87,91,92 which is equivalent or greater than the effects of beta-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors. These hemodynamic effects are chronically sustained assuming LV pacing is continuously maintained.⁷³ Although improvement in New York Heart Association (NYHA) functional class, quality of life, and 6-minute walk tests may be confounded by placebo effects and reporting bias, reverse remodeling is a completely objective measure. More importantly, it appears to be related to better survival.^92,93

Evidence of greater baseline electromechanical asynchrony and acute mechanical resynchronization appears to be necessary for reverse remodeling to occur, and the greater the reduction in asynchrony, the higher the probability of remodeling.^72,90,94 Likewise, absence of electromechanical resynchronization acutely eliminates the possibility of chronic reverse remodeling.^72,90 In canine hearts with induced LBBB, 8 weeks of CRT was sufficient to reverse almost completely the about 25% LV cavity dilation and asymmetric LV hypertrophy induced by dyssynchrony to pre-LBBB baseline values.⁴² This observation has been replicated in clinical studies where in some cases, reverse remodeling results in complete normalization of LV volumes and EF.⁶⁴ This suggests that ventricular conduction delay may be the primary cause of DCM in some patients,^63–65 as it was to a more moderate degree in the LBBB dogs.

Reduction in Functional Mitral Regurgitation

In many patients, CRT reduces fMR, which likely accounts for immediate reduction in symptoms in advance of possible reverse volumetric remodeling. This can be attributed to the following complex factors:

Figure 31-13 One mechanism for acute reduction in severity of functional mitral regurgitation during CRT.

Schematic representation of the relationship between the increase in transmitral pressure (TMP) and the decrease in effective mitral valve regurgitant orifice area (EROA). Top, Left bundle branch block (LBBB). Left ventricular (LV) contractility is low, indicated by a slow rate of rise and delayed peak in LV pressure. This results in delayed and reduced TMP such that EROA remains large throughout systole. Bottom, Cardiac resynchronization therapy (CRT). Acute improvement in contractility, indicated by rapid rate of rise and early peak of LV pressure, results in higher TMP earlier in systole, which reduces EROA. Shaded area represents the time in systole during which EROA is below 50% of its initial value. Reduction in regurgitant V wave preserves TMP.

(Modified from Breithardt OA, et al: Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 203:765-770, 2003.)

Figure 31-14 Effect of earlier delivery of posterior apparatus on functional mitral regurgitation (fMR).

Echocardiographic strain images from the four-chamber view and two-chamber view (top), with corresponding time-strain plots from sites adjacent to papillary muscles before and after CRT (bottom). Baseline plots demonstrate delayed peak strain occurring in the anterolateral papillary muscle site compared with the posteromedial papillary muscle site. CRT results in time alignment of peak strain at papillary muscles (top). Time to peak systolic strain is color-coded, with lines representing isochrones of mechanical activation times at 50-msec intervals. The X indicates sites of lead placement, and the arrow indicates the direction of the propagating mechanical activation. Time to peak strain of sites adjacent to anterolateral (AL P) and posteromedial (PM P) papillary muscles are shown. A decrease in interpapillary muscle time delay was associated with decreased fMR.

(Modified from Kanzaki H, et al: A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. J Am Coll Cardiol 44:1619-1625, 2004.)

Factors 1 to 3 are acute effects and unrelated to geometrical changes (reverse remodeling). Factors 2 to 4 are the primary determinants of reduction in fMR and are directly related to reduction in ventricular conduction delay. It is not well understood what part of the benefit of CRT is caused by reduction in fMR versus resynchronization of contraction directly, because few studies quantitatively measure regurgitant flow.

Improved Heart Rate Profile

Ventricular resynchronization favorably modifies autonomic balance, as evidenced by reduced mean heart rate and increased heart rate variability, which correlate with improved functional capacity, reverse remodeling, and reduced mortality.⁹⁵

Leads and Electrodes: Non–Independently Programmable Ventricular Polarity Configurations

Transvenous and epicardial LV pacing leads may be either unipolar or bipolar, although the former dominates current applications. Multiple ventricular pacing polarity configurations are therefore possible. Because programmed polarity settings are common to both ventricular leads, and the type (bipolar or unipolar) of these leads may not be the same, the following considerations apply.

In a dual-bipolar configuration, both lead tips are the active electrodes (cathodes) and the rings are the common (nonstimulating) anode. However, the type of ventricular leads implanted defines the pacing/sensing vector (Figs. 31-15 and 31-16). With two unipolar leads, the bipolar setting results in no pacing or sensing. If both leads are bipolar, both rings act as the common electrode. If one lead is bipolar (RV) and the other lead is unipolar (typically LV), the ring on the bipolar lead acts as the common electrode (nonstimulating anode). This configuration results in shared-ring bipolar pacing and sensing. This hybrid bipolar/unipolar stimulation configuration (“dual cathodal”) is employed in most contemporary CRT pacing systems.

Figure 31-15 Biventricular pacing configurations.

(From Barold SS, Stroobandt RX, Sinnaeve AF: Cardiac pacemakers step by step: an illustrated guide. Malden, Mass, 2004, Blackwell.)

Figure 31-16 Leads and electrodes for biventricular pacing.

(From Barold SS, Stroobandt RX, Sinnaeve AF: Cardiac pacemakers step by step: an illustrated guide. Malden, Mass, 2004, Blackwell.)

In a dual-unipolar configuration, the lead tips are the active electrodes; the noninsulated device case is the common electrode. This polarity configuration is infrequently used in CRT pacing systems and is not feasible in CRT-D systems because of the concerns regarding ventricular oversensing associated with the unipolar pacing stimulus.

Pulse Generators

Conventional dual-chamber pulse generators or specially designed multisite pacing pulse generators may be used for CRT applications (Fig. 31-17). A conventional dual-chamber pulse generator is well suited for CRT in patients with permanent atrial fibrillation. In this situation, the ventricular port is used for the RV lead and the atrial port is used for the LV lead. This permits programming of independent outputs and ventricular-ventricular timing by manipulation of the AV delay. The programming mode can be either DDD/R or DVI/R (see later). A conventional dual-chamber pulse generator can also be used for atrial-synchronous BiV pacing. The single ventricular output must be divided to provide simultaneous stimulation of the RV and LV (dual cathodal system with parallel outputs). This is achieved with a Y adapter and results in simultaneous RV and LV sensing, which may result in ventricular double-counting and loss of CRT, or pacemaker inhibition in the case of LV lead dislodgment into the coronary sinus with sensing of atrial activity.⁹⁶

Figure 31-17 Pulse generators for biventricular pacing.

(From Barold SS, Stroobandt RX, Sinnaeve AF: Cardiac pacemakers step by step: an illustrated guide. Malden, Mass, 2004, Blackwell.)

First-generation multisite pacing pulse generators similarly provide a single ventricular output for simultaneous RV and LV stimulation. However, two separate ventricular channels internally connect in parallel. This connection is made for both the lead tip and ring connections and eliminates the need for a Y adapter. This configuration still provides simultaneous RV and LV sensing with associated limitations.

Second-generation multisite pacing pulse generators have independent ventricular ports. Each ventricular lead therefore has separate sensing and output circuits. This arrangement permits optimal programming of outputs and time delay between RV and LV stimulation for each patient. It also eliminates the potential complications of BiV sensing.

Pacing Modes

It is axiomatic that for maximal delivery of CRT, ventricular pacing must be continuous.

The DDD mode (atrial and ventricular pacing/sensing) guarantees AV synchrony by synchronizing ventricular pacing to all atrial events, except during episodes of atrial tachycardia or atrial fibrillation. However, DDD mode increases the probability of atrial pacing (depending on programmed lower rate limit) that may alter the left-sided AV timing relationship because of interatrial conduction time and atrial pacing latency.

The VDD mode (atrial sensing only, ventricular pacing and sensing) guarantees the absence of atrial pacing and synchronizes all atrial events to ventricular pacing at the programmed AV delay. However, if the sinus rate is below the lower programmed rate limit, AV synchrony is lost because the VDD mode is operationally VVI (ventricular-only sensing and pacing).

Although conventional dual-chamber pacing systems are not designed for BiV pacing and generally do not allow programming of an AV delay of zero, or near zero, they are being increasingly used with their shortest AV delay (0-30 msec) for CRT in patients with permanent atrial fibrillation. The advantages include programming flexibility, elimination of the Y adapter (required for conventional VVIR devices), protection against far-field sensing of atrial activity (an inherent risk of dual cathodal devices with simultaneous sensing from both ventricles), and cost. When a conventional dual-chamber pacemaker is used for CRT, the LV lead is usually connected to the atrial port and the RV lead to the ventricular port. This provides LV stimulation before RV activation (LV preexcitation) and protection against ventricular asystole related to oversensing of far-field atrial activity, when the LV lead is dislodged toward the AV groove.

The DVIR mode is ideally suited for this application. The DVIR mode (committed atrial pacing, ventricular pacing and sensing) behaves similar to the VVIR mode, except that there are always two closely coupled independent ventricular stimuli, thereby facilitating comprehensive evaluation of RV and LV pacing and sensing performance. The DVIR mode also provides absolute protection against far-field sensing of atrial activity in case of LV lead dislodgment, because no sensing occurs on the “atrial” (LV) lead in the DVIR mode.

Determining LV and RV Capture: Importance of Electrocardiography

The 12-lead electrocardiogram (ECG) is essential to ascertain RV and LV capture during follow-up of CRT systems without separately programmable ventricular outputs. It is recognized that at least six distinct 12-lead ventricular activation patterns may be seen during threshold determination: (1) intrinsic rhythm during loss of RV and LV capture or pacing inhibition (native QRS), (2) isolated RV stimulation, (3) isolated LV stimulation, (4) BiV stimulation with complete replacement of native ventricular activation by paced activation, (5) BiV stimulation with fusion between native activation (RBB conduction) and paced activation, and (6) BiV stimulation with anodal capture. Further, fusion between paced and native activation may result in a wide range of unique global activation patterns on the 12-lead ECG (see later).

Ventricular pacing thresholds should ideally be performed independently and in the VVI mode at a rate exceeding the prevailing ventricular rate so as to obtain continuous ventricular capture uncontaminated by fusion with native activation. Alternately, thresholds can be performed in the VDD or DDD mode at very short AV delays (e.g., 50% of P-R interval) to ensure full ventricular capture without fusion. In older devices without separately programmable ventricular outputs, RV and LV capture can only be determined by ECG analysis during common ventricular voltage decrement. In this situation it is advisable to initiate threshold determinations at maximum output (voltage and pulse duration) because a significant differential often exists in capture thresholds between RV (lower) and LV (higher). Knowledgeable analysis of the ventricular activation sequence using the 12-lead surface ECG reliably establishes univentricular capture.

Monochamber RV apical (RVA) pacing generates right (R) → left (L) activation in the frontal plane and anterior (A) → posterior (P) activation in the horizontal plane, resembling LBBB activation (Fig. 31-18). Consequently, mean QRS frontal plane axis is usually left superior and is infrequently right superior. Pacing from the midsuperior RV septum also generates right (R) → left (L) activation in the frontal plane and anterior (A) → posterior (P) activation in the horizontal plane, but the mean QRS frontal plane axis is typically left inferior. Monochamber LV pacing produces a variety of activation sequences depending on stimulation site and conduction blocks. A few generalizations are possible. Posterior wall stimulation usually generates an L → R, P → A activation, and mean QRS frontal plane axis is usually right superior, less often right inferior. A detailed discussion of ventricular activation sequences during monochamber LV and BiV pacing is provided later. Figure 31-19 shows a typical example of ventricular activation during monochamber RVA versus monochamber LV capture threshold determination.

Figure 31-18 Mean frontal plane QRS axis during various conditions of ventricular pacing.

(From Barold SS, Stroobandt RX, Sinnaeve AF: Cardiac pacemakers step by step: an illustrated guide. Malden, Mass, 2004, Blackwell.)

Figure 31-19 Typical ventricular activation sequences during monochamber RV and LV pacing threshold determination.

Top, Right ventricular (RV) apex pacing. Activation is R → L, A → P; frontal plane axis is left superior. Bottom, Left ventricular (LV) posterior wall pacing. Activation is L → R, P → A; frontal plane axis is right superior.

The majority of current CRT-P/CRT-D systems use either dual cathodal or dedicated bipolar pacing configuration. Anodal capture refers to the situation when myocardial capture occurs at the RV anode in a dual cathodal arrangement. This could theoretically occur in isolation with the LV cathode, but most often occurs with both RV and LV cathodes, and is referred to as “triple-site” pacing, an unfortunate misnomer; a more accurate descriptor would be “capture at three sites during biventricular pacing.” Anodal capture is more common at high-voltage outputs and with true bipolar RV leads because of the small surface area and higher current density of the ring electrode, as opposed to the larger surface area and lower current density of the coil electrode in integrated bipolar leads.

Anodal capture results in a distinct change in activation pattern compared to BiV pacing that can only be appreciated on the 12-lead ECG (Fig. 31-20). The change in QRS morphology related to loss of anodal capture as voltage output is decremented during a temporary threshold test using a single ECG lead may be misinterpreted as loss of LV capture and may result in erroneous overestimation of the LV threshold.

Figure 31-20 Effect of anodal capture on ventricular activation sequence during simultaneous biventricular (BiV) pacing.

Same patient as in Figure 31-19. RV apex and LV posterior wall capture thresholds are less than 1 V. Top, Simultaneous BiV pacing when LV output is 5 V (5 times > threshold) resulting in anodal capture. Bottom, Simultaneous BiV pacing when LV output is 2 V and no anodal capture. Note change in activation sequence. During high-LV-output BiV pacing, anodal capture is indicated by attenuation of monophasic R wave in V1 and loss of R (QS) in V2 (horizontal plane) and attenuation of QS in lead I and aVL (frontal plane). QRS duration is shorter. During lower-output BiV pacing, loss of anodal capture is indicated by dominant QS in I, aVL, and dominant R (V1) and RS (V2). QRS duration is longer.

The physiologic consequences of anodal capture are uncertain. One study demonstrated that anodal capture might be advantageous during CRT by counteracting the regional activation delay located at the inferior wall of the left ventricle and improving regional measures of intraventricular dyssynchrony.⁹⁷

Automatic Adjustment of Left Ventricular Pacing Output

Left ventricular capture management (LVCM) provides automatic adjustment of LV pacing output voltage based on periodic assessment of LV capture (Medtronic). As with all automatic threshold adjusting protocols, the intent of LVCM is to deliver continuous LV pacing at the minimum output of voltage that yields 100% capture. The primary purpose of LVCM is battery conservation. This is clinically relevant because LV voltage thresholds are typically higher than RV thresholds, rendering a single voltage output for both sites inefficient. An ancillary value is the possibility of overcoming phrenic stimulation when the voltage differential between phrenic nerve capture (higher) and LV capture (lower) is sufficiently differentiated. In this situation, LV output voltage can be automatically “capped” beneath the phrenic nerve capture voltage without compromising LV capture. Provision of long-term threshold behavior as a dedicated diagnostic measure might reduce follow-up time by eliminating the need for in-office real-time determinations, and is particularly useful during remote surveillance.

When LVCM is enabled, the device automatically monitors the pacing amplitude threshold at periodic intervals, nominally 01:00 am daily. The minimum amplitude that consistently results in ventricular capture (threshold) is stored and reported. If LVCM is programmed to “adaptive,” LV output voltage is automatically reprogrammed toward a selectable maximum output voltage defined by the desired “maximum amplitude safety margin” and reported. Alternately, if LVCM is programmed to “monitor,” LV output is not adjusted, although data regarding threshold determinations are recorded.

Operating Details

Unlike automatic RV pacing threshold adjusting algorithms in conventional pacemakers, LVCM does not use the evoked response to determine ventricular capture. Rather, LVCM determines LV capture by recording RV sensed events in response to LV monochamber pacing. This requires timing methods to ascertain whether RV sensed events during monochamber LV pacing are caused by native AV conduction, ventricular premature beats, electromagnetic interference (EMI), or other extraneous conditions. RV sensed events outside the “expected” timing window for native AV conduction, or loss of RV sensing during monochamber LV pacing, is used to indicate loss of LV capture (e.g., threshold voltage).

The LVCM operation consists of four stages: (1) ventricular rate and stability check, (2) LV-RV conduction check, (3) AV conduction check, and (4) LV pacing threshold search (LVPTS). The order of these stages is not arbitrary. Ventricular rhythm must be stable (<200 msec R-R interval variability) and rate less than about 90 beats per minute (bpm) for 12 cycles. The reason for this is the need to ensure stable AV conduction timing and LV-RV conduction timing during atrial-synchronous monochamber LV pacing in tracking modes and/or 100% overdrive ventricular pacing during atrial fibrillation (nontracking modes).

The LV (paced) → RV (sensed) conduction time is determined during cycles of up to eight (atrial synchronous) monoventricular pacing sequences (Fig. 31-21). To enhance accurate measurement of unidirectional ventricular conduction time, this test is initiated approximately 15 bpm above the ventricular rate measured during the rate and stability check. In dual-chamber modes, the pacemaker atrioventricular interval (pAVI) is shortened to 30 msec. These two adjustments are intended to guarantee complete replacement of AV and VV conduction with paced activation. Additionally, the blanking period on the RV sense amplifier is minimized to enhance RV sensing. LV-RV conduction is performed with LV output at the prevailing programmed setting. If RV sensing does not occur in response to a LV-only test stimulus, a backup BV pacing stimulus with LV at maximum amplitude occurs on the following cycle, and LV output remains at maximum amplitude except for single-test cycles.

Figure 31-21 Left ventricular capture management (LVCM) operation.

Top, Surface ECG, event markers, right ventricular electrogram (RV EGM). Successful LV-RV and AV conduction checks. During overdrive atrial pacing and LV monochamber pacing, the LV-RV interval is 180 msec (left). During AV conduction check (right) PAV is set to 180 msec + 80 msec (260 msec). Note that this example was obtained from a prototype RAMware download; in the market-released application, the PAV would be set to 180 + 60 (240 msec); see text for details. Absence of intrinsic AV conduction within this timing window is confirmed, satisfying the condition for LV Pacing Threshold Search (LVPTS). Bottom, Surface ECG, event markers for LVPTS. The expected LV-RV conduction time is 180 msec, which sets the capture detection window 150 to 200 msec (30 msec earlier—20 msec later than the expected LV-RV conduction time) from the LV test pace. The first LV test pace (0.5V/0.9 msec) is ineffectual; loss of LV capture is indicated by emergence of native AV conduction (conduction time = 300 msec). The second LV test pace (1.0V/0.9 msec) is effective with LV-RV conduction time 180 msec, satisfying the capture detection window.

(Modified from Crossley GH, et al: Automated left ventricular capture management. Pacing Clin Electrophysiol 30:1190-1200, 2007.)

Atrioventricular conduction time is determined during overdrive (atrial pacing) simultaneous BiV pacing at a long pAVI sufficient to yield BiV sensing. This pAVI is set to 30 msec (nominal during LV-RV conduction check) + measured LV-RV conduction time + 30 msec. If no VS events during atrial pacing are seen during this time window, LVPTS can proceed. If any VS events occur within this time window, the test aborts. The difference between LV → RV and AV conduction time must therefore be consistently greater than about 60 msec to proceed with LV capture threshold determination. If the time difference between LV → RV and AV conduction is similar (e.g., <60 msec), loss of capture during LV monochamber pacing cannot be differentiated from native AV conduction. Anticipated increases in AVIs during overdrive atrial pacing increases the probability that AV conduction times will be sufficiently longer than LV-RV times. If AV conduction is absent (heart block), LVPTS proceeds. The AV conduction test is not performed in nontracking modes.

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