VIEWPOINT AND COMMENTARY
An Epidemic of DyssynchronyBut What Does It Mean?
David A. Kass, MD*
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Manuscript received May 8, 2007;
revised manuscript received July 26, 2007,
accepted September 28, 2007.
* Reprint requests and correspondence: Dr. David A. Kass, Division of Cardiology, Johns Hopkins Medical Institutions, Ross Building, 835, 720 Rutland Avenue, Baltimore, Maryland 21205. (Email: dkass{at}jhmi.edu).
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Abstract
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Cardiac resynchronization therapy (CRT) is used to treat a subset of heart failure patients with discoordinate wall motion. Defining appropriate patients is important, and, although electrical delay (wide QRS) is commonly used, recent data show that measures of mechanical dyssynchrony improve the sensitivity and specificity of predicting responders (including patients with narrow QRS complexes). This has stimulated studies of dyssynchrony per se, and the phenomenon now appears to be very common in virtually all forms of heart failure. However, what all this dyssynchrony means clinically, and how or whether it should be treated by CRT or other means, remains unclear.
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Abbreviations and Acronyms
| | CRT = cardiac resynchronization therapy | | EF = ejection fraction | | HF = heart failure | | LBBB = left bundle branch block | | LV = left ventricular | | RV = right ventricular |
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In the mid 1990s, studies first reported that the simultaneous electrical stimulation of right and left ventricles improved cardiac function in patients with heart failure (HF) and an intrinsic conduction delay (1–3). At first glance, it seemed unlikely that this observation would lead to a clinically significant treatment, yet within the decade cardiac resynchronization therapy (CRT) was developed and confirmed to be beneficial. It soon joined a select group of treatments that improved HF chamber function, symptoms, and mortality (4–6). From the outset, CRT was targeted to a subset of HF patients who had a delay in ventricular activation as manifested by a wide QRS complex. All of the large clinical CRT trials used a QRS >120 ms or longer as a primary entry criteria. However growing evidence that QRS duration poorly predicted acute (7,8) and chronic responses to CRT and that  25% to 30% of seemingly appropriate patients did not experience clinical benefit suggested that other parameters might better identify candidates (9). Mechanical dyssynchrony (i.e., the disparity in regional contraction timing) was proposed as an alternative, and early studies found it better correlated with acute (7) and chronic (10,11) CRT benefit. The latter was particularly important, because both the magnitude of basal dyssynchrony and its reduction by CRT predicted chronic chamber functional improvement (12,13) and enhanced exercise capacity and clinical status (10,11). Furthermore, dyssynchrony was found to be an independent predictor of clinical events and worsened survival in HF patients (14,15). These findings stimulated the search for new and easier ways to quantify mechanical dyssynchrony, and over the past several years such work has yielded many approaches, most based on ultrasound and advanced tissue Doppler imaging methods (16–18).
Given the suspicion that mechanical rather than electrical dyssynchrony would better identify CRT responders, investigators began asking just how prevalent mechanical dyssynchrony was and whether patients suitable for CRT but without QRS widening were being missed. Fueling this interest were early studies of HF patients with mechanical dyssynchrony yet a narrow QRS complex that reported improvements from chronic CRT (19). Questions were next raised as to whether dyssynchrony occurred in patients with HF but a preserved ejection fraction (EF) (i.e., >50%), also termed diastolic HF. Might they benefit from CRT as well? Over the past year, reports have started addressing these questions, and the results seem to suggest that dyssynchrony is extraordinarily common in all forms of HF. Indeed, one might conclude there is almost an epidemic of dyssynchrony, which a majority of HF patients suffer from and for whom CRT could be useful. At the same time, these studies raise important new questions: 1) What is causing the dyssynchrony we observe, and does it all mean the same thing pathophysiologically; 2) is dyssynchrony always clinically relevant or is some of what we see more of a test result; and 3) what should we do about it?
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Dyssynchrony Is Quite Prevalent
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Most of the studies assessing dyssynchrony have focused on dilated HF patients (depressed EF) with either a wide or a narrow QRS complex. The largest database comes from the CARE-HF (Cardiac Resynchronization Heart Failure) study, which reported on 735 New York Heart Association functional class III or class IV HF subjects with a QRS duration of  120 ms, and an EF mean of 25.5% (20). Interventricular dyssynchrony (delay in right vs. left heart ejection based on Doppler flow imaging) was present in 62%. A somewhat higher prevalence (70%) has been reported in studies using tissue Doppler indexes (21,22). In patients with a narrow QRS, the incidence appears to be lower but is still quite substantial, ranging from 30% (21,23,24) in some studies to as much as 50% in others (22). Depending upon how dyssynchrony is defined, however, it can seem present in virtually all HF patients. In a recent study using cardiac magnetic resonance imaging, investigators examined dyssynchrony by the standard deviation of radial motion timing in low EF heart failure patients versus controls (25). Based on having an index >2x normal control values, HF patients (regardless of QRS duration) could be identified with 94% specificity and 100% sensitivity (i.e., all HF patients had at least this amount of dyssynchrony).
More recently, studies have turned to HF patients with a normal-range EF. In this group, wide QRS complexes are rare (11% compared with almost 40% in low-EF HF) (26). In a study of 120 HF narrow-QRS complex patients (half with "diastolic HF," defined as EF 50%, mean pulmonary capillary wedge pressure >12 mm Hg, and/or time constant of LV relaxation >48 ms), Wang et al. (24) found systolic dyssynchrony in 30% to 40% and diastolic dyssynchrony in 60% of both HF groups. Dyssynchrony was assessed by the maximal time difference of peak systolic longitudinal velocity or early filling velocity among different regions in the left ventricle (systolic and diastolic dyssynchrony, respectively). So-called "diastolic dyssynchrony" would appear even more common (by 33%) than systolic dyssynchrony (27), although intriguingly, they rarely seem present in the same patients. For example, in one recent study of preserved-EF HF patients (26), diastolic dyssynchrony and systolic dyssynchrony were observed in 40% of patients, but were coincident in only 15% of these individuals.
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Can We Treat It?
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Even before studies started showing mechanical dyssynchrony to be quite common, investigators began asking whether it identified CRT responders even if they had a narrow QRS complex. Achilli et al. (19) first tested this hypothesis in 14 patients and found beneficial effects of CRT on clinical and echocardiographic parameters similar to those in wide-QRS HF patients. This finding was recently confirmed by Bleeker et al. (28) and Yu et al. (29), reporting collectively on 84 patients with systolic dyssynchrony but a narrow QRS and contrasting the results to a similar-size group of HF patients with a wide QRS. Both found that CRT improved exercise capacity, symptoms, and echocardiographic function regardless of the QRS duration. One caveat is that none of these studies used a true control group or was blinded, because all patients received treatment, and the follow-up period was relatively short (3 to 6 months). Clinical placebo effects, including improved exercise capacity and symptoms from CRT, have been documented (5), and, although this may or may not apply to image-based assessments, bias is difficult to fully exclude when the therapy is known.
These studies targeted patients with "systolic dyssynchrony" and a low EF. In this situation, one can link the 2 behaviors, because studies in animals and humans have shown that systolic dyssynchrony impairs net systolic function. But what about patients where EF is >50% or in those with only diastolic dyssynchrony; would they also respond to CRT? Can you have clinically relevant systolic dyssynchrony with a normal EF? When dyssynchrony is induced by single-site pacing (or left bundle branch block [LBBB]), then cardiac function declines regardless of the initial EF. In a study we performed testing acute RV apical stimulation in subjects with HF due to hypertensive cardiac hypertrophy, pacing-induced dyssynchrony lowered EF from 78% to 65% and dP/dtmax from 1,767 mm Hg/s to 1,522 mm Hg/s (–15%) (30). However, in treating these patients chronically, pacing-induced dyssynchrony (VDD mode) improved cardiac function by helping to prevent cavity obliteration and restoring cardiac reserve and thus improving HF symptoms (31). Some have argued that this syndrome has a component of systolic dysfunction, as indexed by systolic longitudinal tissue Doppler velocities (32), so perhaps one should try to improve it. However, this parameter can reflect chamber geometry and loading and is similarly reduced in hypertensive-hypertrophy patients without HF symptoms (33). Moreover, measurements based on more direct invasive data have found similar (34) or enhanced (35) systolic function in these patients. Therefore, whether a treatment that improved systolic function would help symptoms in this population is unclear. What if you have only diastolic dyssynchrony: Can you pace the heart to fix it? As yet, CRT does not appear to affect diastolic dyssynchrony, at least as it has been clinically defined using tissue Doppler (27). As soon as you apply an electrical stimulation you primarily influence the timing of systole and secondarily that of diastole. It is hard to fathom how pacing could alter timing delays only in early diastole. Biventricular is better than single-site pacing with respect to systolic function but not necessarily better than normal conduction, so one might end up compromising one part of the cycle to target another.
Recent evidence also indicates that the dyssynchrony we are observing can be treated medically, raising further questions about its causes. Diastolic dyssynchrony was found to correlate with prolonged relaxation and elevated estimated mean pulmonary capillary wedge pressure (24), and both changed in tandem with various drug treatments (diuretics, angiotensin-converting enzyme inhibitors, angiotensin type-1 receptor, or calcium-channel blockers) that lowered blood pressure in preserved-EF HF patients (24). Systolic dyssynchrony may also be ameliorable to drug treatment; a recent study of HF patients with a narrow QRS found that carvedilol reduced systolic dyssynchrony (36).
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What Are We Measuring?
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Confronted with so much dyssynchrony, it is appropriate to consider what one is measuring and why it might occur. All of the studies have examined wall motion, either deformation or its velocity, but this does not clarify whether the cause is a delay in electrical activation or the result of heterogeneity of contractile properties in the wall. The former is more easily appreciated as a likely target for an electrical pacemaker therapy such as CRT, whereas for the latter the case is less clear. The left panel of Figure 1
shows a model of how delay in muscle activation of one region relative to another results in dyssynchrony. This would be the classic model with a wide QRS, as generated by an LBBB or single-site pacing. Myocardial activation is modeled by a ventricular time-varying elastance (myocardial stiffening), and one curve (lateral wall) is phase delayed relative to the other. When one wall is stiffer than the other, it stretches the alternate wall, generating dyssynchrony. The difference curve shown in Figure 1 depicts this dyssynchrony which rises during early isovolumic contraction (underlying why dP/dtmax is so sensitive as an index) and peaks at end-systole/early relaxation. The latter explains why systolic dyssynchrony is often assessed at or near aortic valve closure and why postsystolic motion is frequently observed. Electrically phase-advancing one region relative to the other will resolve this problem.
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Figure 1 Schematic of Different Mechanisms for Generating Cardiac Dyssynchrony
Muscle activation is depicted by myocardial elastance (stiffening). In the example with a temporal delay (left panel), both regions of the heart contract with similar force (contractility) but one has a phase delay relative to the other. The vertical difference between curves determines when one area of muscle is stiffer than the other and thus when reciprocal wall contraction and stretch (dyssynchrony) will be observed. This rises early during isovolumic contraction and peaks at end-systole/early diastole. This can be treated by cardiac resynchronization therapy (CRT). The right panel shows an example where the 2 regions of the heart are stimulated at the same time but there is a disparity in contractility, so one territory is stronger the other another. As muscle activation progresses, there will also be dyssynchrony, because the stronger wall pushes out the weaker one, and in early relaxation the weaker wall now appears to contract. This is typical of ischemic heart disease. The vertical difference between curves again identifies the discoordinate wall motion (i.e., dyssynchrony) that would be observed (based on times when maximal regional shortening is observed around the heart, or the variance in its magnitude). However, this dyssynchrony is probably not amenable to a pacing (i.e., CRT) strategy.
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It is a bit difficult to imagine how this behavior can occur without any demonstrable electrical delay (i.e., narrow QRS), if indeed a large portion of the wall is contracting much later than another. One possibility is that right heart activation is so quick that left ventricular dyssynchrony still yields a narrow electrical complex. Alternatively, one might have abnormal excitation-contraction coupling altering the kinetics of force development in one part of the heart compared with another. How often either occurs is unclear. Perhaps a more likely explanation is that the dyssynchrony is not related to electrical timing but more to regional disparities in contractility. For example, what happens if a region of the wall is weaker, perhaps owing to ischemic damage or chronic hypoperfusion, heterogeneity of neural/hormonal stimulation, or fibrosis. This is depicted in the right panel of Figure 1. Here, activation occurs simultaneously, but one part of the wall contracts more strongly than the other. One will again see discoordinate motion as the strong pushes out the weaker wall and the latter contracts in early diastole. However, it is far less clear how altering electrical stimulation will treat this. This condition is more difficult to diagnose, because practical methods to determine regional myocardial contractility remain lacking. However, perhaps by combining mechanical imaging with 3-dimensional electrical analyses (37), one might better reveal the substrate.
Regardless of the precise mechanism, the apparent successes of several smaller tirals of CRT for treating narrow complex QRS HF subjects (19,28,29) supports some benefit. If the problem is simply electrical delay, perhaps having a heart in which the lateral wall contracts late is worse than having it contract sooner. Early contraction could unload the lateral wall so it developed less stress and perhaps less chronic adverse remodeling. These results have been questioned by a larger randomized and controlled trial (RethinQ; Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) (38). This study reported no benefit from CRT on the primary end point (increase in peak oxygen consumption of at least 1.0 ml/kg/min after 6 months) or in the number of HF events requiring intravenous treatment for patients with a QRS interval <120 ms. Differences in how mechanical dyssynchrony was indexed between studies may have played some role, but the latter study importantly included a control group.
The issue raised by the presence or lack of concurrence of systolic and diastolic dyssynchrony in the same patient deserves comment. Some studies have found that everyone with systolic dyssynchrony has it in diastole as well, although diastolic dyssynchrony can also occur alone (24). Others find very little concurrence of the 2 behaviors (26). Figure 2
shows data from the first study to depict the full temporal course of dyssynchrony evolution and resolution in a failing heart with an LBBB. The plot is based on magnetic resonance tagged imaging of a dog with the dyssynchrony index obtained from 3-dimensional circumferential strain maps. Dyssynchrony evolves gradually during systole, peaks near end-systole, and then declines. When induced by a conduction delay (the same findings are obtained with a right ventricular pacemaker), it is impossible to dissociate increased dispersion of strain values or timing during systole (i.e., systolic dyssynchrony) from that during early diastole (diastolic dyssynchrony). As shown in Figure 2, application of CRT affects both and could not likely be targeted to diastole alone. Dissociation of systolic and diastolic behaviors is less surprising if it were due to regional heterogeneity of myocardial function, loading, and so on, that can differentially impact portions of the cardiac cycle. Experimental studies have previously shown that increasing arterial afterload, and particularly imposing this load late in systole, as occurs in older patients with stiffer arteries, results in regional discoordinate motion (39,40). Furthermore, this dyssynchrony correlates with relaxation delay (41). The latter has also been observed in isolated muscle and in hearts with systolic loading imposed (42). Those studies were performed using normal hearts, but load-induced dyssynchrony is probably greater in chronically failing ventricles, because load-induced relaxation delay is also greater. Simply put, the heart is not a homogeneous material nor is it symmetric, so changes in global loading can differentially affect regional loading and thus the timing of local contraction and relaxation as observed by wall motion. The fact that antihypertensive therapy or beta-blockade can improve dyssynchrony in failing hearts speaks to such interactions and mechanisms.
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Figure 2 Measured Time Course of LV Dyssynchrony and its Recovery in an Animal Model of Dilated HF and a LBBB
Dyssynchrony is assessed using 3-dimensional circumferential strains, calculating a vector sum index that not only provides information about the dispersion of strain values during the heart beat but further amplifies this if they are geographically clustered (i.e., the whole lateral wall is late) (45). Dyssynchrony gradually rises to end-systole and then declines, so dyssynchrony during systole and diastole would be observed. Biventricular pacing (cardiac resynchronization therapy) reduces dyssynchrony during both periods. HF = heart failure; LBBB = left bundle branch block; LV = left ventricular.
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Lastly, it is important to comment on the limitations of how dyssynchrony is being assessed. For one, we have now developed sensitive imaging tools, but these are susceptible to user variability of both image acquisition and analysis, and this may limit the reliability of the results. Derivation of these indexes often requires some subjective assessment of which peaks reflect which motion, and this is not always straightforward to interpret. Few, if any, studies have examined repeated assessments of dyssynchrony made by different operators blinded to the prior measurements, with the variance then determined. Cause for concern was highlighted recently by the PROSPECT (Predictors of response to Cardiac Resynchronization Therapy) trial (43) whose preliminary results were reported at the European Cardiology Society Meeting in September, 2007 (44). This multicenter trial of 426 patients receiving CRT involved more than 50 centers throughout Europe, Asia, and North America and examined the reproducibility and predictive value (response to CRT) of many echo and tissue Doppler imaging indexes of dyssynchrony. Each center had received specific training regarding imaging methods—with a clear effort to enhance uniformity of approach, and the data were interpreted by 3 blinded core laboratories, one on each continent. There was marked variability in the analysis derived from the identical images among the core centers, and while some indexes did correlate with CRT response, their sensitivity and specificity was fairly poor. Clearly, more work is needed to achieve an adequately robust and applicable approach to this analysis.
Another factor may be the methods used to quantify dyssynchrony. Most are based on maximal temporal delay or variance of time delays, which do not imply that a substantial contiguous region of the wall is out of synchrony, such as is generated with a single-site pacemaker. Dispersed delays in contractile/relaxation timing due to heterogeneity of a failing heart may contribute to the disease but be no more specific to any pathway or potential therapy than other markers of dysfunction. They would seem unlikely to be benefited by electrical treatment such as CRT. A dyssynchrony index based on peak difference or variance in such delays does not differentiate this situation from one where indeed a whole side of the heart wall contracts late. There are ways, however, that have been described where by a dyssynchrony index is derived that takes this geographic dispersion into account (45). I would propose more of these types of indexes be considered, regardless of the primary measurements employed. Perhaps this may help define what types of dyssynchrony are amenable to what type of treatment.
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Now What?
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Whenever a new methodology evolves that provides a new window into the function of the heart, it can reveal behavior that we have not previously appreciated. To an extent, the initial appearance of Doppler flow imaging revealed a fairly common incidence of mitral regurgitation, and it took some time to clarify what was and what was not clinically meaningful. Whether we are at a similar point with dyssynchrony, which is admittedly not normal but very common in all sorts of HF, remains to be seen. One worry is that we will now develop a new class of CRT nonresponders, patients with apparent mechanical dyssynchrony that is not amenable to CRT. We need to remember that HF is a heterogeneous disease, and, combined with abnormal hormone and loading stimulation, one often sees the wall moving out of synchrony. As we find various forms of dyssynchrony in more and more patients with HF, we should consider the broader pathophysiology to help determine what, if anything, should be done about it in specific patients.
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Footnotes
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Supported by National Health Service (National Heart, Lung, and Blood Institute) grant PO1-HL077180 and the Abraham and Virginia Weiss Professorship. Dr. Kass is a consultant for Boston Scientific (Natick, Massachusetts), a company involved with cardiac resynchronization devices. The content of this Viewpoint in no way presents any intellectual or commercial conflict, because it deals with a question of pathophysiology and its detection by imaging modalities.
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References
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Top
Abstract
Dyssynchrony Is Quite Prevalent