Abstract
Electromechanical association in a normal heart results in synchronous regional left ventricular (LV) contraction. Differences in the timing of regional contraction may be associated with the failing human heart. Interest in echocardiographic assessment of synchrony began with applications for pacing therapy, in particular cardiac resynchronization therapy (CRT), also known as biventricular pacing. Current clinical practice is to select heart failure patients with reduced ejection fraction by electrocardiographic criteria of QRS complex widening or left bundle branch block morphology. Although CRT often results in improvement in symptoms, LV reverse remodeling, and prolonging life, one-third to one-half of patients do not appear to benefit and are referred to as nonresponders. It was observed that patients with measurable dyssynchrony at baseline before CRT had a much more favorable response to CRT than patients who lacked baseline dyssynchrony. Interest in measuring regional timing of LV contraction with echocardiographic techniques remains high to gain a better understanding of CRT response and prognosis. Tissue Doppler imaging and, in particular, speckle tracking strain measures have been widely utilized. However, the field advanced to reveal that mechanical dyssynchrony was more complicated than originally thought. A more recent understanding of regional myocardial discoordination has emerged as differences in regional contraction from substrates of electrical delay, contractile heterogeneity, and fibrosis or scar. Defining the strain patterns of contraction and stretch appear promising to help identify the electromechanical substrate that is associated with the most favorable outcome after CRT. This chapter will review the progress in understanding of mechanical dyssynchrony, define the current state of the art, and project potential future clinical applications of assessing cardiac synchrony.
Keywords
cardiac pacing, cardiac resynchronization therapy, heart failure, speckle tracking strain imaging, tissue Doppler echocardiography, ventricular function
Introduction
Electromechanical association in a normal heart results in synchronous regional left ventricular (LV) contraction. Differences in the timing of regional contraction may be associated with the failing human heart. Interest in echocardiographic assessment of synchrony began with applications for pacing therapy, in particular cardiac resynchronization therapy (CRT). CRT, also known as biventricular pacing, was an important advance in treatment of heart failure (HF) patients with reduced ejection fraction (EF) and electrical dispersion recognized by widened electrocardiographic (ECG) QRS complexes. Although CRT often results in improvement in symptoms, LV reverse remodeling, and prolonging life, one-third to one-half of patients do not appear to benefit and are referred to as nonresponders. Several investigators have observed that differences in LV regional timing referred to as dyssynchrony can be measured by a variety of echocardiographic techniques. Interest in measuring regional timing of LV contraction increased with the advent of tissue Doppler imaging (TDI) and speckle tracking strain measures. Many reports have documented that patients with widened QRS complexes have variable degrees of mechanical dyssynchrony at baseline before CRT ( Fig. 25.1 ). It was observed that patients with measurable dyssynchrony at baseline before CRT had a much more favorable response to CRT than patients who lacked baseline dyssynchrony. Accordingly, there was anticipation that measures of timing of regional contraction by echocardiographic methods would play a role in improving patient selection for CRT. However, the field advanced to reveal that mechanical dyssynchrony was more complicated than originally thought, and current clinical guidelines focus exclusively on ECG criteria. This chapter will review the progress in understanding of mechanical dyssynchrony, define the current state of the art, and project potential future clinical applications of assessing cardiac synchrony.
Introduction
Electromechanical association in a normal heart results in synchronous regional left ventricular (LV) contraction. Differences in the timing of regional contraction may be associated with the failing human heart. Interest in echocardiographic assessment of synchrony began with applications for pacing therapy, in particular cardiac resynchronization therapy (CRT). CRT, also known as biventricular pacing, was an important advance in treatment of heart failure (HF) patients with reduced ejection fraction (EF) and electrical dispersion recognized by widened electrocardiographic (ECG) QRS complexes. Although CRT often results in improvement in symptoms, LV reverse remodeling, and prolonging life, one-third to one-half of patients do not appear to benefit and are referred to as nonresponders. Several investigators have observed that differences in LV regional timing referred to as dyssynchrony can be measured by a variety of echocardiographic techniques. Interest in measuring regional timing of LV contraction increased with the advent of tissue Doppler imaging (TDI) and speckle tracking strain measures. Many reports have documented that patients with widened QRS complexes have variable degrees of mechanical dyssynchrony at baseline before CRT ( Fig. 25.1 ). It was observed that patients with measurable dyssynchrony at baseline before CRT had a much more favorable response to CRT than patients who lacked baseline dyssynchrony. Accordingly, there was anticipation that measures of timing of regional contraction by echocardiographic methods would play a role in improving patient selection for CRT. However, the field advanced to reveal that mechanical dyssynchrony was more complicated than originally thought, and current clinical guidelines focus exclusively on ECG criteria. This chapter will review the progress in understanding of mechanical dyssynchrony, define the current state of the art, and project potential future clinical applications of assessing cardiac synchrony.
Echocardiographic Methods to Assess Dyssynchrony
Normal LV mechanical activation results in peak contraction occurring at the same time. 
, using three-dimensional (3D) echocardiographic strain, demonstrate normal contraction. The classic LV dyssynchrony pattern responsive to CRT is observed with a typical left bundle branch block (LBBB) consisting of early contraction of the septum followed by delayed posterior contraction. 
, using 3D echocardiographic strain, demonstrate a typical LBBB contraction pattern. There have been many echocardiographic approaches to define dyssynchrony. The most common methods have been a variety of means to measure regional contractions in the LV. The majority of the literature has focused on methods to measure peak-to-peak regional events representing contraction or the variations in regional contraction, expressed as standard deviation ( Table 25.1 ). A simple approach has been to measure the time difference in peak sepal velocity to peak lateral wall velocity using TDI, including color-coded time to peak velocity ( Fig. 25.2 ). Another tissue-Doppler-based method was to assess the standard deviation in time-to-peak velocities from 12 segments in three standard apical views, introduced by Yu et al. and known as the Yu Index. A more complex method of tissue Doppler cross-correlation was introduced and associated with response to CRT. A simpler approach to dyssynchrony has been the “septal flash” (visual rapid inward and outward septal motion in the preejection period) assessed by routine M-mode or color-tissue Doppler M-mode and used as a marker of CRT response. Speckle tracking methods to assess regional contraction from radial, circumferential, and longitudinal strain have been used frequently and continue to gain in popularity. The original application of speckle tracking strain for dyssynchrony analysis was radial strain from the mid-ventricular short-axis view ( Fig. 25.3 ). The original approach was to measure the time delay in peak-to-peak septal to posterior wall strain at baseline before CRT. CRT patients who had a peak-to-peak radial strain delay greater than 130 ms had a more favorable response to CRT compared to those who did not. The standard deviation in longitudinal strain peaks has been associated with response to CRT. Alternate approaches include measuring delayed LV ejection delay, which is the result of regional dyssynchrony. Both LV preejection time and interventricular mechanical delays have been associated as markers for CRT response. The preejection delay has been defined as an increase in time from onset of QRS complex to onset of LV ejection using pulsed Doppler placed in the LV outflow tract. Interventricular mechanical delay is a related index defined as the time difference in LV preejection time and right ventricular preejection time. More recent approaches have been to evaluate the mechanical contraction pattern associated with electrical delay in radial and longitudinal strain curves. A major advance in understanding has come from computer simulations of the electromechanical substrate responsive to CRT and quantification of these mechanical events as the systolic stretch index (SSI), described in more detail later. A similar approach came from observing a typical LBBB contraction pattern in longitudinal strain curves consisting of early contraction of the septum (before ejection) followed by delayed posterior contraction (after aortic value closure). In addition, more simple visual assessments of apical rocking resulting from early septal shorting followed by late lateral wall contraction was also associated with favorable response to CRT ( 
). Many of the original dyssynchrony approaches have been criticized by the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study, which was an observational study of echocardiographic markers and response to CRT. The results of this study were affected by an overly simplistic interpretation of mechanical dyssynchrony, variability in methods, and lack of a unified echocardiographic approach. There were significant associations of several markers of baseline dyssynchrony with favorable LV reverse remodeling after CRT. However, sensitivity and specificity were considered to be too low, and variability in these measurements considered to be too high to influence patient selection. The current role measures of dyssynchrony remain as markers of prognosis after CRT rather for patient selection. Further work on the potential utility of these measures to influence patient selection for CRT continues to be ongoing.
| Method | Measurement | Marker for CRT response |
|---|---|---|
| Interventricular Mechanical Delay LV outflow track and RV outflow tracks | Time difference between RV preejection and LV preejection | ≥40 ms |
| Tissue Doppler Longitudinal Velocity Apical 4-chamber view (2 sites) | Time from peak septal to peak lateral wall velocity | ≥65 ms |
| Tissue Doppler Yu Index Apical, 4-, 2-, and 3-chamber views (12 sites) | Standard deviation of 12-site peak velocity measures | ≥33 ms |
| Septal Flash Parasternal views: M-mode or color tissue Doppler M-mode | Brief inward and outward motion of the septum early during preejection | Presence or absence |
| Speckle tracking radial strain Mid ventricular short-axis view | Time difference in peak septal to peak posterior wall strain | ≥130 ms |
| Tissue Doppler cross-correlation of myocardial acceleration Apical 4-chamber view | Maximum activation delay from opposing septal and lateral walls | >35 ms |
| Visual Assessment of longitudinal strain pattern of typical left bundle branch Apical 4-chamber view | (1) Early septal peak shortening; (2) early stretching in lateral wall; (3) lateral wall peak shortening after aortic valve closure | All three criteria |
| Apical Rocking Apical 4-chamber view | Visual movement of apex toward septum early during preejection, followed by lateral motion of apex during ejection | Presence or absence |
| Systolic Stretch Index Radial Strain Mid-ventricular short-axis view | Posterolateral prestretch (before aortic valve opening) + Septal systolic stretch (to aortic valve closure) | ≥9.7 % |
New Understanding of Mechanical Dyssynchrony
Enthusiasm for mechanical dyssynchrony to be used for patient selection resulted in two prospective randomized clinical trials of CRT in HF patients with narrow QRS width (<130 ms) selected by echocardiographic mechanical dyssynchrony. The first was the ReThinQ trial which enrolled 172 patients with QRS width less than 130 ms and used tissue Doppler peak-to-peak measures of contraction delay. This trial failed to show any benefit to these patients with LV reverse remodeling at 6 months as the outcome variable. The larger more definitive trial was Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT), which enrolled and randomized 809 reduced EF HF patients with QRS less than 130 ms and either tissue Doppler longitudinal velocity peak-to-peak delay of ≥80 ms or speckle tracking radial strain septal to posterior wall peak-to-peak delay of ≥130 ms. EchoCRT also failed to show benefit in the primary endpoint of HF hospitalization or death. Surprisingly, there was an increase in mortality in EchoCRT patients randomized to CRT-On versus the control group randomized to CRT-Off. These trials brought new insight for peak-to-peak measures of dyssynchrony as markers of contractile heterogeneity that are not associated with favorable response to CRT as in patients with widened QRS complexes. Combining previous studies of dyssynchrony and CRT response with the narrow QRS CRT trials resulted in changing concepts of dyssynchrony and CRT response.
Subsequently, more recent EchoCRT substudy analysis revealed that peak-to-peak echocardiographic dyssynchrony in patients with narrow QRS complexes can be a marker of unfavorable clinical outcome. There were 614 patients in the EchoCRT study (EF ≤35%, QRS <130 ms) who had baseline and 6-month echocardiograms. All patients were required to have baseline dyssynchrony by tissue Doppler longitudinal velocity peak-to-peak delay ≥80 ms or radial strain septal to posterior wall peak-to-peak delay ≥130 ms for randomization in the EchoCRT trial. In this substudy, the measures of tissue Doppler peak-to-peak longitudinal velocity delay and speckle tracking radial strain peak-to-peak septal to posterior wall delay were reassessed at 6-month follow-up. Remarkably, 25% of patients improved either longitudinal or radial dyssynchrony at 6 months, regardless of randomization to CRT-Off or CRT-On. The associated improvement in dyssynchrony was hypothesized to be related to improvements in LV function associated with pharmacological therapy, as 97% of patients in both groups were on beta-blocker therapy and 95% were on angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Using the same predefined criteria for significant dyssynchrony at baseline, as at 6 months, persistent dyssynchrony was associated with a significantly higher primary endpoint of death or HF hospitalization (hazard ratio [HR] = 1.54, 95% confidence interval [CI] 1.03–2.30, P = .03). In particular, persistent dyssynchrony at 6 months was associated with the secondary endpoint of HF hospitalization (HR = 1.66, 95% CI 1.07–2.57, P = .02; Fig. 25.4 ). These observations were similar in patients randomized to CRT-Off as well as CRT-On and were not associated with CRT treatment. Furthermore, HF hospitalizations were also associated with both worsening longitudinal dyssynchrony, defined as an increase in peak-to-peak delay from baseline ≥30 ms (HR = 1.45, 95% CI 1.02–2.05, P = .037), and worsening radial dyssynchrony, defined as an increase in peak-to-peak delay from baseline ≥60 ms (HR = 1.81, 95% CI 1.16–2.81, P = .008). Worsening dyssynchrony was associated with unfavorable clinical outcomes, in particular for HF hospitalizations, in both CRT-Off and CRT-On groups, unrelated to the randomization arm. These findings suggested that echocardiographic dyssynchrony is a new prognostic marker in HF patients with reduced left ventricular ejection fraction (LVEF) and narrow QRS width, Since these associations were similar in CRT-On and CRT-Off groups, these observations suggested that tissue Doppler or radial strain peak-to-peak dyssynchrony may possibly be a marker for unfavorable LV mechanics and myocardial disease severity in patients with narrow QRS width.
