Atrial Asynchrony

The right atrium (RA) and the left atrium (LA) are activated nearly simultaneously (within 50 to 80 ms) during sinus rhythm. Significant interatrial conduction delays can occur in myopathic atria and during RA pacing. Delayed LA contraction disrupts left-sided atrioventricular (AV) synchrony and may cause atrial transport block.

Atrioventricular Asynchrony

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

AV conduction delay displaces atrial contraction earlier in diastole. Atrial contraction occurs during ventricular filling and shortens diastolic filling time. 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 LV, which reduces ventricular volume and contractile force. Diastolic mitral regurgitation (MR) occurs when elevated LV end-diastolic pressure exceeds LA pressure. Partial closure of the mitral valve may also occur, further shortening diastolic filling time. This situation is corrected by proper timing of ventricular contraction with pacing. Atrial fibrillation (AF) causes atrial and AV desynchronization.

Ventricular Asynchrony

Normal LV electrical activation is rapid and homogeneous with minimal temporal dispersion. This elicits synchronous mechanical activation and ventricular contraction. The resulting coordinated myocardial segment activation maximizes ventricular pump function. Wiggers established the linkage between pacing-induced alterations in ventricular conduction and pump function with two seminal observations in 1925: (1) Stimulation at virtually any ventricular site disturbs the natural pattern of activation and contraction because the evoked electrical wavefront propagates slowly through ventricular myocardium rather than through the Purkinje system; and (2) altered ventricular activation causes an immediate reduction in pump function.¹

Optimal interventricular and intraventricular synchrony is more important than AV synchrony for ventricular pump function. Left bundle branch block (LBBB) induces delays in transseptal and intraventricular conduction. Interventricular asynchrony refers to a sequential RV-LV activation delay. In LBBB earliest ventricular depolarization is recorded over the anterior RV surface and generally is latest at the posterolateral basal LV. Interventricular asynchrony can be quantified by the time delay between the upslopes of LV and RV systolic pressure, as well as the time delay between opening of the pulmonic and aortic valves. This disruption to ventricular interdependence is a determinant of paradoxical septal motion. Presumably the reduction in ventricular septal contribution to LV ejection is an important factor in the reduction of pump function during LBBB.

Delayed intraventricular activation is the most important determinant of reduced pump function in LBBB. Electrical activation starts in the interventricular septum, and the posterolateral LV wall is activated >100 ms later. Such considerable intraventricular delay during LBBB is due to slow spread of the depolarization wavefront through the working myocardium rather than through the Purkinje system. LBBB is a complex electrical disease that results from LV conduction delay at multiple anatomical levels; it may be anatomically fixed or functional and is exhibited differently according to substrate characterization (ischemic vs. nonischemic cardiomyopathy). High-resolution endocardial and epicardial mapping studies have revealed that LV activation during LBBB, despite a similar surface electrocardiographic appearance, is heterogeneous. At least three patterns of delayed LV activation have been characterized: (1) transseptal delay with or without LV endocardial delay, (2) normal transseptal conduction with slow conduction velocities in peri-infarct regions or globally slow in nonischemic disease, and (3) slow U-shaped activation around a line of functional block on the anterior wall.2–4 Generally, QRS duration (QRSd) of 120 to 150 ms indicates delay confined specifically to the specialized conduction system, whereas QRSd >150 ms usually indicates additional conduction delay in diseased myocardium. Nominally, the posterolateral basal LV is the latest activated region.

The pattern of LV activation is also influenced by the location and size of lines of fixed or functional conduction block. Fixed conduction block is due to replacement of normal myocardium by scar. The physiological basis for functional conduction blocks has not been elucidated but could relate to stretch, heart rate, and spontaneous diastolic depolarization. Anterior locations of the line of functional block are characterized by a U-shaped LV activation pattern,³ more prolonged QRSd (>150 ms), and greater time to LV breakthrough.³ Late activation of the posterolateral basal LV occurred by wavefront propagation around the line of block using the apical or inferior LV walls. Lateral locations of the lines of block are characterized by less prolonged QRSd (<150 ms) and shorter time to LV breakthrough. Pacing maneuvers shift either line of block, indicating their functional nature.³ Noninvasive mapping of epicardial activation using body surface potentials demonstrates that electrical activation patterns in LBBB are highly heterogeneous and unpredictable.⁴ Lines of conduction block do not correlate with regions of wall motion abnormality or scarring. Some lines of block arose only during pacing and were site dependent (functional), whereas other lines of block could not be manipulated with pacing maneuvers, indicating that these were due to slow or absent conduction (fixed). Latest activation most often occurred in the posterolateral wall but was also observed in the anterior and inferior walls in some patients.

Effects of Asynchrony on LV Mechanics and Structure

Regions that are activated early also start to contract early. In LBBB earliest and latest sites of segmental LV activation correlate well with time to peak systolic velocity by Doppler and strain by tagged magnetic resonance imaging (MRI), providing evidence that ventricular conduction delay is responsible for mechanical asynchrony. The effect is dramatic because the various regions differ not only in the time of onset of contraction but also in the pattern of contraction (Figure 118-1). Contraction of early-activated myocardium is energetically inefficient because LV pressure is low and ejection has not begun. Instead, stretching of not as yet activated remote regions 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 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 undergo systolic paradoxical stretch. This reciprocated stretching of regions within the LV wall causes a less effective and energetically efficient contraction.

Hemodynamic consequences of the asynchronous LV contraction include reductions in contractility and relaxation. These changes occur immediately upon induction of LBBB.⁵ Loss of pump function is indicated by decreases in stroke volume and stroke work and slower rates of rise of LV pressure (Figure 118-2). Moreover, the LV end-systolic pressure-volume relationship shifts rightward, indicating that the LV operates at a larger volume to recruit the Frank-Starling mechanism. Premature relaxation in early-activated regions and delayed contraction in others also cause abnormal relaxation, expressed as a slower rate of fall of LV pressure. These changes lead to prolongation of isovolumetic contraction and relaxation times, which is characteristic of asynchronous hearts. Prolongation of isovolumetic times occurs mainly at the expense of diastolic filling time, leading to reduced preload.

Redistribution of the mechanical load within the ventricular wall also leads to reduction of regional myocardial perfusion and oxygen consumption in the septum.⁶ These defects express regional differences in myocardial workload, are reversible, and are noted after biventricular pacing.⁶ Chronic asynchronous LV activation results in regional and global structural changes indicated by asymmetric hypertrophy, increased end-diastolic volume, and reduced ejection fraction (Figure 118-3),⁶ as well as locally different molecular abnormalities including reductions in sarcoplasmic reticulum calcium–adenosine triphosphatase (ATPase) and phospholamban.

Similar to the situation after myocardial infarction, acute loss of pump function initiates compensatory responses (Figure 118-4). Some of these responses, after a certain time or a certain degree of asynchrony, may lead to further impairment of pump function and clinical heart failure. Various triggers for these “remodeling” processes have been identified. As is the case for other conditions of hemodynamic overload, LBBB leads to stimulation of the sympathetic system, resulting in elevated myocardial catecholamine levels and activation of the renin-angiotensin-aldosterone system. Regional differences in stretch and mechanical load heterogeneity are most likely important stimuli for remodeling processes.

Mechanistic Basis for Development of Asynchronous Heart Failure Due to Ventricular Conduction Delay

Multiple factors may contribute to heart failure associated with ventricular asynchrony. At least three candidate factors are readily identified: (1) reduced pump function due to asynchronous contraction, (2) adverse remodeling due to long-term asynchrony, (3) left-sided AV desynchronization, and (4) functional mitral regurgitation (fMR). The first three factors have already been discussed. With regard to the fourth factor, fMR frequently accompanies asynchronous HF and has multiple mechanisms. If it is assumed that the anterior mitral leaflet is structurally normal, the immediate cause of fMR is delayed activation of the LV posterior “apparatus” due to ventricular conduction delay. 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 reducing contractility (closing forces) and increasing papillary muscle tethering forces. The latter mechanical effect is strongly dependent on alterations in ventricular shape as tethering forces that act on the mitral leaflets are higher in dilated, more spherical ventricles. Ventricular dilatation and increased chamber sphericity increase the distance from the papillary muscles to the enlarged mitral annulus, as well as between each other, restricting leaflet motion and increasing the force needed for effective mitral valve closure.