Physiology of Cardiac Pacing and Resynchronization

Electrical Activation during Sinus Rhythm

The cardiac action potential originates from the sinus node, located in the high right atrium (RA) ( Fig. 7-1 ). Its cells depolarize spontaneously and initiate the spontaneous depolarization of action potentials at a regular rate from the sinus node. This rate depends on various conditions, such as atrial stretch and sympathetic activation but is usually between 60 and 100 beats per minute (bpm) at rest. Myocytes are electrically coupled to each other through gap junctions. These structures consist of connexin molecules and allow direct intercellular communication. Gap junctions do not have a preferential direction of conduction, but because the action potential starts in the sinus node, it spreads from there through the atria. There is evidence for specialized conduction pathways in the atrium, but their (patho-) physiologic relevance is still disputed.

In the human heart, spread of the action potential through the atria takes approximately 100 msec, during which period the impulse also reaches the atrioventricular (AV) node (see Fig 7-1 ). In the normal heart, the AV node is the only electrical connection between the atria and ventricles because a fibrous ring (anulus fibrosus) is present between the remaining parts of the atria and ventricles. The AV nodal tissue conducts the electrical impulses very slowly; indeed, it takes approximately 80 msec for these impulses to travel from the atrial side to the ventricular side of the AV node. This delay between atrial activation and ventricular activation has functional importance, because it allows ventricular filling. Like everywhere else in the heart, conduction in the AV node has no preferential direction. Consequently, impulses can also be conducted retrogradely through the AV node, a condition that can occur when the ventricles are electrically stimulated.

From the AV node, the electrical impulse reaches the His bundle, the first part of the specialized conduction system of the ventricles called the Purkinje system. Within this system, the electrical impulse is conducted approximately four times faster (3 to 4 m/sec) than in the working myocardium (0.3 to 1 m/sec). This difference is due to the fact that Purkinje cells are longer and have a higher content of gap junctions.

The intraventricular conduction system can be regarded as a trifascicular conduction system consisting of the right bundle branch (RBB) and two divisions of the left bundle branch (LBB). The RBB proceeds subendocardially along the right side of the interventricular septum until it terminates in the Purkinje plexuses of the right ventricle (RV); the LBB also has a short subendocardial route.

It seems that the bifascicular vision of structure of the LBB is oversimplified. The general picture that now emerges is that the left ventricular (LV) Purkinje network is composed of three main, widely interconnected parts, the anterior subdivision, the posterior subdivision, and a centroseptal subdivision of the left main bundle. This third medial or centroseptal division supplies the midseptal area of the LV and arises from the LBB, from its anterior or posterior subdivision, or both. The fascicles continue in a network of subendocardially located Purkinje fibers. In the LV, the Purkinje fibers form a network in the lower third of the septum and free wall, which also covers the papillary muscles. In humans, the bundles are present only underneath the endocardium, whereas species like ox, sheep, and goat have networks of Purkinje fibers across the entire ventricular wall.

It is important to note that the His bundle as well as the RBB and LBB and their major tributaries are electrically isolated from the adjacent myocardium. The only sites where the Purkinje system and the normal working myocardium are electrically coupled are the Purkinje-myocardial junctions. The exits of the Purkinje system are located in the subendocardium of the anterolateral wall of the RV and the inferolateral LV wall (see Fig. 7-1 ). This area of exit corresponds with the area of the ventricular muscle that is activated earliest. The distribution of the Purkinje-myocardial junctions is spatially inhomogeneous, and the junctions themselves have varying degrees of electrical coupling.

Endocardial activation of the RV starts near the insertion of the anterior papillary muscle 10 msec after onset of LV activation ( Fig. 7-2 ). After activation of the more apical regions, the activation of the ventricular working myocardium occurs predominantly from apex to base, both in the septum and in the LV and RV free wall. Further depolarization occurs centrifugally from endocardium to epicardium as well as tangentially. The earliest epicardial breakthrough occurs in the pretrabecular area in the RV, from which there is an overall radial spread toward the apex and base. The last part of the RV that becomes activated is the AV sulcus and pulmonary conus. Overall, the posterobasal area of the LV or an area more lateral is the last part of the heart to be depolarized (see Fig. 7-2 ).

The time between arrival of the impulse in the His bundle and the first ventricular muscle activation is approximately 20 msec, whereas total ventricular activation lasts 60 to 80 msec, corresponding to a QRS duration of 70 to 80 msec. These numbers illustrate the important role of the Purkinje fiber system in the synchronization of myocardial activity. This role is due to the system's unique propagation properties and its geometrically widespread distribution. During normal excitation, fast propagation over long fibers, together with wide distribution of Purkinje-myocardial junctions, induce a high degree of coordination between distant regions of the myocardium.

Electromechanical Coupling

As in many other muscle cells, electrical activation leads to contraction in cardiac myocytes, a process referred to as excitation-contraction (E-C) coupling. In cardiac E-C coupling, the calcium ion (Ca ²⁺ ) plays a central role ( Fig. 7-3 ). The contraction-relaxation cycle starts when depolarization leads to entry of Ca ²⁺ into the cell via voltage-dependent L-type Ca ²⁺ channels. This Ca ²⁺ entry triggers a much larger amount of Ca ²⁺ to be released from the sarcoplasmic reticulum (Ca ²⁺ -induced Ca ²⁺ release). These processes increase intracellular Ca ²⁺ from approximately 10 ⁻⁷ M to 2 × 10 ⁻⁶ M. This high calcium concentration catalyzes the interaction between myosin and actin filaments, leading to contraction. After repolarization, relaxation occurs as Ca ²⁺ dissociates from the contractile apparatus and is taken up again by the sarcoplasmic reticulum through the action of sarcoplasmic reticular Ca ²⁺ adenosine triphosphatase (SERCA). Intracellular Ca ²⁺ homeostasis is also maintained through action of the sodium-calcium (Na ⁺ Ca ²⁺ ) exchanger (NCX). Normally, this exchanger removes Ca ²⁺ from the cell (forward mode). Figure 7-3 also shows that the intracellular Ca ²⁺ concentration rises rapidly after the upstroke of the action potential but that there is some delay between the Ca ²⁺ increase and the development of force. This delay is the main determinant of the delay between electrical and mechanical activation.

The electromechanical delay, that is, the delay between the depolarization and the onset of force development, amounts to approximately 30 msec. On a global basis this delay can be observed as the delay between the R wave of the electrocardiogram (ECG) and the rise in LV pressure ( Fig. 7-4 ). Electromechanical coupling in failing hearts is different from that in normal hearts. A prominent feature of heart failure is that the relation between SERCA and the NCX changes. Often SERCA is downregulated and/or the NCX is upregulated in the heart failure state. On the one hand, the reduced SERCA activity leads to less Ca ²⁺ loading of the sarcoplasmic reticulum, resulting in less Ca ²⁺ release during the subsequent activation and so a weaker contraction (systolic dysfunction). On the other hand, during diastole, Ca ²⁺ removal from the cytosol is slower and incomplete, leading to a slower relaxation and greater diastolic stiffness (diastolic dysfunction). The upregulation of the NCX and the elevated intracellular Na ⁺ concentrations in failing myocardium may compensate for the SERCA downregulation. The high Na ⁺ concentration facilitates the NCX to work in the “reverse mode,” that is, to remove intracellular Na ⁺ and exchange it for extracellular Ca ²⁺ . This additional Ca ²⁺ influx enhances systolic function at least to some extent. Because the SERCA pump is much faster in pumping calcium than the NCX, insufficiencies in contraction and relaxation in failing hearts are most pronounced at higher heart rates. These changes result in decreasing contractile force with increasing heart rate, leading to a negative force-frequency relation. The changes in the failing myocardium lead to the altered expression of other proteins involved in E-C coupling as well as shifts in isoforms of various contractile proteins. Because of the tight coupling between excitation and contraction, atrial activation is followed by atrial contraction, and ventricular activation by ventricular contraction. Consequently, atrial contraction precedes ventricular contraction, as illustrated in Figure 7-4 . The atrial contraction adds roughly 20% to the volume of the ventricles. This “atrial kick” increases the length of ventricular muscle cells and of their sarcomeres. The sarcomere length is an important determinant of myocardial contractile force. Over the entire physiologic range of sarcomere lengths (1.6 to 2.4 µm), the longer the sarcomeres are, the greater the contractile force. This effect, known as the Frank-Starling relation (Starling's law of the heart), is characterized by more active force development at a given submaximal Ca ²⁺ concentration at longer sarcomere length (“length-dependent activation”). Despite intense research efforts, the mechanistic basis of the Frank-Starling relationship remains unclear. Potential mechanisms involve myofibrillar lattice spacing, function of the giant myofibril titin, cooperative activation of myosin heads, and strain between and within half sarcomeres.

Ventricular contraction starts after ventricular depolarization. After a short isovolumic contraction phase, the aortic valve opens, starting the ejection phase. The velocity of emptying of the ventricle is highest in the first half of the ejection phase due to a higher pressure gradient between the LV and the aorta. In the second half of the ejection phase, LV pressure actually falls below aortic pressure, but the aortic valve stays open because of the inertia of the flowing blood. With increasingly negative LV-aortic pressure gradients, the aortic valve closes and the isovolumic relaxation phase starts, ending with the opening of the mitral valve. Because of the filling of the atrium during ventricular systole, atrial pressure is relatively high. This event, in combination with the rapid fall in LV pressure, causes a positive AV pressure gradient during the early filling phase. Thus rapid acceleration of blood occurs, contributing to most of the LV filling in the early diastolic phase. This event is also reflected by the large Ei wave on mitral valve Doppler recordings in healthy hearts ( Fig. 7-5 ).

Atrial contraction, after the P wave on the ECG, produces a surge of blood into the ventricle at the end of diastole, causing the final filling of the ventricle. Reversal of the pressure gradient across the mitral valve, due to atrial relaxation and ventricular contraction, pulls the valve cusps in apposition, facilitating closure of the valve. Therefore coupling and proper timing of atrial and ventricular contractions are important determinants of ventricular pump function. The loss of atrial systole diminishes effective LV stroke volume. The influence of the difference pacing modes on atrial contribution and pump function in different categories of patients are discussed later in the chapter.

Although both Frank-Starling and force-frequency relations are properties of the myocardium itself, which can regulate cardiac function to an important extent, extrinsic factors also modulate cardiac performance. Many of these factors are related to the autonomic nervous and hormonal systems. The afferent parts of these systems can be divided into low-pressure and high-pressure domains. Low-pressure sensors are present in the atria and pulmonary circulation. Stimulation, from increased pressures and stretch, leads to parasympathetic stimulation and sympathetic withdrawal. Moreover, atrial stretch induces release of atrial natriuretic factor (ANF). This 28-amino acid polypeptide is a potent arterial and venous vasodilator that raises urine production. Effectively, the low-pressure sensors monitor the filling status of the circulation. However, erroneous readings may occur during inadequate AV synchronization, leading to elevated atrial pressures. Stimulation of the reflexes and ANF production are involved in the so-called pacemaker syndrome (see later).

The high-pressure sensors consist predominantly of the baroreceptors in the arterial system. These sensors feed back to the brainstem through afferent neurons in the vagal and glossopharyngeal nerves. Stimulation of these receptors through a decrease in blood pressure induces sympathetic stimulation and parasympathetic withdrawal. Although reduced parasympathetic activation is the most important factor leading to the increase in heart rate during hypotension, the greater sympathetic stimulation induces arterial and venous vasoconstriction and increases myocardial contractility.

Other pressure sensors are found in the juxtaglomerular apparatus in the kidneys. Their stimulation leads to greater production of renin, angiotensin, and aldosterone, resulting in vasoconstriction as well as water and salt retention. These systems are effective in maintaining equilibrium in blood pressure and cardiac output during short-term variations. However, sustained neurohumoral stimulation is an important factor in the long-term development of hypertrophy and the rise in filling pressure.

Importance of Interatrial and Intra-Atrial Synchrony

Usually cardiac pacing utilizes pacing of the RA. The RA lead is commonly positioned in the RA appendage. This wave of ectopic activation in the RA bypasses the faster atrial conduction pathways, leading to a slower activation of the RA and later activation of the LA, the latter (LA) with delays up to 200 msec. Such delays can disturb the left-sided atrioventricular contraction sequence with subsequent increase in LA pressures, pulmonary edema and pathophysiologic responses, sometimes referred to as pseudo-pacemaker syndrome.

In order to avoid these adverse effects some studies have been performed aiming at more physiologic atrial pacing sites, such as the atrial septum. However, because, like for the ventricles, pacing at any site other than the sinus node bypasses the fast atrial conduction pathways, atrial activation is abnormal. Atrial septal pacing creates a left-to-right atrial activation, as opposed to the right-to-left activation during RA appendage pacing, thus influencing the AV delay.

Importance of Atrioventricular Synchronization

Basically, the role of the atrial contraction is to help maintain a laminar flow of blood from the venous system to the ventricles; this role is tightly integrated with the movement of the ventricles to create a smooth motion of blood across the system. To perform its role, the atrium changes its function from that of a conduit during early filling to that of a booster pump during atrial systole, to that of a reservoir during ventricular systole. These changes are closely related to longitudinal displacement of the anulus of the mitral and tricuspid valves along the long axis of the heart. Indeed, the anulus is displaced toward the apex of the ventricles during systole and toward the atria during diastole, thus significantly contributing to the smooth movement of blood from the atria to the ventricles. This displacement keeps the overall volume of the heart nearly constant during systole and diastole.

An optimally timed atrial contraction maximizes LV filling and thereby its output by virtue of the Frank-Starling relation. Too early atrial contraction (as in the case of long P-Q times and dual-chamber pacing with long AV intervals) causes a loss of the booster pump function of the atrium. Moreover, early atrial contraction may initiate early mitral valve closure, thereby limiting ventricular diastolic filling time.

This observation can be explained by the importance of three factors collaborating to achieve optimal closure of the AV valves. First, the ending of transvalvular flow at the end of the atrial contraction makes the valvular leaflets approach one another. Second, the annulus of the AV valve contracts, and so do the papillary muscles that hold the leaflets. Simultaneously, at the start of the ventricular contraction, ventricular pressure rises above atrial pressure, and the valves close. When these factors are misaligned, an opportunity for diastolic and systolic mitral regurgitation is created.

In the early years of pacing, the electrical stimulus was selectively applied to the ventricle (ventricular single-chamber pacing). With ventricular pacing, the contraction of atria and ventricles is uncoupled, leading to an atrial contribution to LV filling that varies from beat to beat. This also results in large beat-to-beat variations in stroke volume, systolic pressure, and other hemodynamic variables. The introduction of sequential AV pacing resulted in more regular heart beats and improved hemodynamics. With advances in pacemaker technology, appreciation of the importance of maintaining AV synchrony has improved.

A summary of the main consequences of an optimal AV timing can be seen in Figure 7-6 . Because filling time is limited, especially at high heart rates, the atrial contribution to stroke volume is more prominent at high than at low heart rates.

Disturbances of Interventricular and Intraventricular Synchrony by Right Ventricular Pacing and Left Bundle Branch Block

The normal, physiologic, and almost synchronous ventricular electrical activation is lost in diseases affecting the ventricular conduction system, such as conduction block in the LBB or RBB and the presence of an accessory pathway bypassing the AV node, as in the Wolff-Parkinson-White syndrome. Additionally, ectopic impulse generation, occurring during ventricular pacing and extrasystoles, leads to abnormal impulse conduction. Under all of these circumstances, the impulse is conducted primarily through the slowly conducting working myocardium rather than rapidly through the specialized conduction system. As a consequence, under conditions of abnormal activation, the time required for activation of the entire ventricular muscle, expressed as QRS duration, may be more than twice as long as that during normal ventricular activation.

The extent and sequence of electrical dyssynchrony during abnormal conduction are determined by at least four myocardial properties, as follows:

• 1.

  Conduction through the myocardium is up to four times slower than conduction through the Purkinje system.

• 2.

  Conduction is approximately two times faster along the muscle fibers than perpendicular to them. Therefore in a particular layer, the wavefront around a pacing site has an elliptical shape, especially in the epicardial and midmyocardial layers.

• 3.

  Impulses originating from the working myocardium rarely reenter into parts of the rapid conduction system. Early researchers had believed that such reentry was ubiquitous and that the amount of reentry was the main determinant of the total dyssynchrony of ventricular activation. However, later studies indicated that, although parts of the intact rapid conduction system are often present, ectopically generated impulses appear to couple poorly to the rapidly conducting specialized conduction system. Myerburg and colleagues elegantly showed that impulses coming from the normal myocardium can enter the Purkinje system only at the apical part of this system (presumably the Purkinje-myocardial junctions; see Fig. 7-1 ). This finding implies that the impulse often has traveled already for some time before reaching Purkinje-myocardial junctions. Also, in order to reach remote zones, the impulse has to travel retrogradely through one branch of the system all the way to the proximal part and then descend to another part. Therefore in most cases, the sequence of activation during ventricular pacing is governed by slow conduction through the normal myocardium, away from the pacing site.

• 4.

  Most endocardial fibers, even though not part of the Purkinje system, conduct impulses faster than the fibers in the rest of the LV wall. Moreover, the endocardial circumference is smaller than its epicardial counterpart. Therefore total time required for electrical activation is shorter for LV endocardial pacing than for LV epicardial pacing.

Detailed studies on the three-dimensional spread of activation during ventricular pacing in canine hearts have been conducted since the 1960s. The sequence of electrical activation in left bundle branch block (LBBB) is similar to that during RV apex pacing. This sequence can be derived from the QRS configuration on the surface ECG and from endocardial activation maps in experimental LBBB and RV pacing. The similarity has led to the use of AV sequential RV apex pacing as a model for “experimental LBBB.” More detailed mapping studies, however, showed that activation patterns differ between RV apex pacing and LBBB, with activation in RV apex pacing being more dyssynchronous due to extremely late LV basal activation.

Until the early 2000s, information on impulse conduction in patients with LBBB was limited to the data reported by Vassallo and associates. These investigators mapped LV endocardial activation during RV apex pacing and in LBBB at a limited number of endocardial sites, showing that activation starts at the RV endocardium in both conditions. The first noticeable activation at the LV endocardium after right-to-left conduction of the impulse occurs at a single breakthrough site, which in nearly all patients is the LV breakthrough time, 50 to 70 msec after the earliest RV activation. The impulse is conducted from the septum toward the distal free wall in a gradual manner, the site of latest activation generally being the inferoposterior wall. More recently, this finding has been confirmed using high resolution endocardial mapping systems ( Fig. 7-7 ). Even more recent is the development of noninvasive mapping techniques that are based on solving the inverse problem of calculation of epicardial cardiac activation times from multiple body surface electrodes, examples of which are shown later in this chapter. All together, these studies showed significant heterogeneity in the activation pattern; that difference may be largely due to differences in the origin of LBBB—either proximal conduction block or uniform but slow conduction through the LBB. In approximately one third of patients with heart failure and typical LBBB QRS morphology, transseptal activation time (i.e., the time between the earliest RV and LV septal breakthrough point) is bimodally distributed and has a large range in both groups of patients with transseptal conduction times ≤40 msec and >40 msec. This indicates a large heterogeneity in the RV to LV activation time. In experimental LBBB, transseptal conduction is slower than conduction across the LV free wall, a difference that even increases upon development of (tachypacing-induced) heart failure. Furthermore, in patients with LBBB, the total LV endocardial activation time widely ranges from 60 to 160 msec. Etiology does not seem to have a major impact on the total endocardial activation time. Of note, the sum of transseptal and total endocardial activation time does not account for the maximum duration of the QRS; QRS duration is 20 to 60 msec longer, probably because of LV endocardial to epicardial conduction time ( Fig 7-7 ). These data also show that QRS duration provides a reasonable, but not perfect estimate of total electrical activation time.

Patients with LBBB show a very peculiar spread of ventricular activation. In two thirds of patients with LBBB, a functional line of block is present, resulting in a U -shaped electrical activation wavefront. The activation front propagates first around the inferior wall and then spreads onto the lateral and basal wall. The location and length of the line of block are highly variable and are related to the site and time of LV breakthrough. In patients with significant prolongation of the QRS duration (>150 msec), the line of block is consistently located in an anterior position. In contrast, in patients with QRS duration ranging between 120 and 150 msec, the line of block is usually shorter and located either anteriorly, laterally, or posteriorly ( Video 7-1 ).

Abnormal Contraction Patterns during Left Bundle Branch Block and Right Ventricular Pacing

Given the tight relationship between excitation and contraction in the myocardium, it is not surprising that an abnormal electrical activation pattern also leads to dyssynchronous contraction. Regions where the impulse arrives first also start to contract first. During LBBB or RV pacing, local contraction patterns differ not only in the onset of contraction but also, and more importantly, in the pattern of contraction. These contraction patterns imply that opposing regions of the ventricular wall are out of phase and that energy generated by one region is dissipated in opposite regions leading to “wasting” of myocardial work. In patients with LBBB or RV pacing, the early-contracting region is most typically the septum. The earliest-contracting fibers can shorten rapidly by up to 10% just during the isovolumic contraction phase; this occurs because the remaining muscle fibers are still in a relaxed state ( Video 7-2 ). This rapid early shortening is followed by an additional but modest systolic shortening, eventually followed by systolic stretch (due to delayed mechanical contraction of other regions—the lateral wall), and premature relaxation ( Fig. 7-8 ; see Video 7-2 ). In late-activated regions, in contrast, the fibers are stretched in the early systolic phase (by as much as 15%) as a consequence of contraction of the early-activated region. Doubling of net systolic shortening and delayed relaxation occur in late-activated regions (see Fig. 7-8 and Video 7-2 ). The discoordination between early and late activated regions leads to lower output and efficiency of the heart as a pump.

The cause of the regional differences in contraction pattern is most likely related to the local differences in myocardial fiber length during the early systolic phase. This idea is supported by studies using two isolated papillary muscles in series in which dyssynchronous stimulation caused a downward shift in the force-velocity relation in the earlier-activated muscle and an upward shift in the later-activated one. Furthermore, during ventricular pacing, regional systolic fiber shortening increases with greater isovolumic stretch. Similarly, a close correlation exists between the time of local electrical activation and the extent of systolic fiber shortening. Therefore the regional differences in contraction pattern during ventricular pacing are most likely caused by regional differences in effective preload and local differences in the contraction force triggered by the Frank-Starling relation.

On M-mode echocardiography, abnormal contraction patterns during RV pacing and LBBB show characteristics like septal flash (early systolic leftward motion ) and paradoxical septal motion (late systolic rightward motion ). These motions are the net result of different forces: the dyssynchrony between RV and LV, which produces dynamic alterations in transseptal pressure differences, presystolic shortening of septal muscle fibers and late systolic LV lateral wall contraction, stretching the septal muscle. Abnormal septal motion results in a diminished contribution of the interventricular septum to LV ejection. This has been measured in experimental LBBB using MRI tagging and in patients with LBBB using speckle tracking. The septal regions, even in absence of detectable scar, showed the lowest amount of systolic strain within LV ( Fig. 7-9 ); in contrast, the lateral wall shows the highest regional strain. This finding demonstrates that LBBB determines a unique and unequal LV strain distribution, which may be corrected by CRT.

Energetic Aspects of Dyssynchrony

The aforementioned local differences in wall motion and deformation reflect regional differences in myocardial work. This relationship was demonstrated by construction of local fiber stress-fiber strain diagrams and calculation of local external and total mechanical work (see Fig. 7-9 ). In regions close to the pacing site (or in the septum in patients with LBBB), shortening occurs at low pressure, whereas these areas are transiently being stretched at higher ventricular pressures. As a consequence, the stress-strain loops have a figure-eight-like shape with a low net area, indicating the absence of external work. In regions remote from the pacing site (or in the lateral wall in patients with LBBB), the loops are wide, and external work can be up to twice that during synchronous ventricular activation ( Fig. 7-10 ). Total myocardial work (sum of external work and potential energy) in LBBB and with RV pacing is reduced by 50% in early-activated regions and is increased by 50% in late-activated regions in comparison with atrial pacing. Russell et al recently described a method for noninvasive estimation of the abnormal work distribution, using data from arm-cuff blood pressure, valve opening and closing times, and myocardial strain.

Several studies reported that ventricular pacing and LBBB are associated with regional differences in myocardial blood flow, glucose uptake, and oxygen consumption. During RV apex pacing and LBBB, low values are found in the septum, the early-activated part of the LV. In comparison with normal activation, myocardial blood flow and oxygen consumption are 30% lower in early-activated regions and 30% higher in late-activated regions. In patients who are paced in the RV false positive perfusion defects may occur because of this redistribution. There is a controversy regarding the cause of the reduced septal blood flow and glucose uptake in LBBB and RV apex pacing. Various observations in animal experiments, such as close correlations among local myocardial oxygen consumption, work, and blood flow, suggest that the lower blood flow is a physiologic adaptation to the lower demand. However, at higher heart rates, the dyssynchronous contraction pattern may also impede myocardial perfusion. Also, the coronary reserve may be limited in patients, hampering sufficient physiologic adaptations.

The nonuniform contraction patterns translate into a lower efficiency of conversion of metabolic energy into mechanical pump function. This was observed in isolated, isovolumically beating hearts as well as in anesthetized open-chest, closed-chest, and conscious dogs. Mills et al also showed that efficiency remained low after 4 months of RV pacing. In all these preparations RV apex pacing reduced mechanical output, whereas myocardial oxygen consumption was unchanged or even increased in comparison with atrial pacing; thus efficiency dropped by 20% to 30% in these studies. The opposite change was found when ventricular activation in patients with preexisting dyssynchrony due to LBBB-like activation was improved by biventricular (BiV) or LV pacing alone. In these patients, BiV pacing improved LV dP/dt _max (maximal rate of rise of LV pressure) without increasing myocardial oxygen consumption, indicating improved efficiency. This higher efficiency can be understood from the decrease in wasted work: work done by some contracting wall segments that is being wasted by stretching other segments.

Efficiency of conversion of metabolic energy to pumping energy is of particular interest in patients with compromised coronary circulation, because higher oxygen consumption over longer periods (as in during β-agonist therapy) leads to higher mortality.

Effect of Dyssynchronous Activation on Systolic and Diastolic Pump Function

Both RV pacing and LBBB reduce systolic and diastolic function. These effects are independent of changes in preload and afterload. This conclusion can be reached on the basis of results from studies using preparations in which preload and afterload were controlled, as well as those in which preload- and afterload-independent indices of ventricular function were determined ( Figs. 7-11 and 7-12 ). The negative mechanical effect of dyssynchronous activation has been observed under various loading conditions, exercise, and in patients with and without coronary artery disease or impaired LV function ( Fig. 7-13 ). LBBB was shown to impair regional and global cardiac pump function in patients and animals, even in the absence of other cardiovascular diseases. Therefore it appears that under all circumstances, dyssynchrony is an important, independent determinant of cardiac pump function.

LV dP/dt _max , the maximum rate of rise of LV pressure, is very sensitive to changes in ventricular activation sequence (see Fig. 7-13 ). Thus, although this parameter is also preload-dependent, LV dP/dt _max appears to be an appropriate marker of dyssynchrony-induced changes in LV global contractile function and its correction by any pacing technique. Additionally, ventricular relaxation is slower during ventricular pacing, as expressed by a less negative LV dP/dt _min and a longer Tau. The detrimental effect of pacing on relaxation is more pronounced in patients with impaired ventricular function ( Fig. 7-14 ). Parameters of auxotonic relaxation (rate of segment lengthening or LV volume increase) are also lower during ventricular pacing than during sinus rhythm, but the difference is less pronounced than for the isovolumic relaxation parameters.

As a consequence of the slower contraction and relaxation, isovolumic contraction and relaxation phases last longer, thus leaving less time for ventricular filling and ejection. Therefore it is not surprising that cardiac output and systolic arterial and LV pressures are also affected by dyssynchronous activation. In general, stroke volume is affected more than systolic LV pressure, presumably because baroreflex regulatory mechanisms partly compensate for the decrease in blood pressure. This idea is supported by the finding of higher catecholamine levels and greater systemic vascular resistance during ventricular pacing. With regard to the changes in stroke volume, it is important to note that RV apex pacing and LBBB can induce mitral regurgitation, as has been demonstrated in animals and patients. The immediate cause of this mitral valve regurgitation is most likely a combination of papillary muscle desynchronization, increased papillary muscle tethering forces, and decreased transmitral pressure gradient.

In addition to reduced stroke volume at unchanged preload, ejection fraction is usually found to be depressed during ventricular pacing as well as in LBBB. Similarly, ventricular pacing can increase pulmonary wedge pressure. The negative inotropic effect of ventricular pacing under various loading conditions is clearly illustrated by a rightward shift of the LV function curve, that is, the relationship between cardiac output and mean atrial pressure (see Fig. 7-11 ). Later studies showed a rightward shift of the end-systolic pressure-volume (P-V) relation (see Fig. 7-12 ), thus suggesting that for each end-systolic pressure, the LV must operate at a larger LV volume.

Effects of Acute and Chronic Dyssynchrony