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Mechanical Dyssynchrony in Congestive Heart Failure
Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 51, No. 1, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.08.052
Mechanical Dyssynchrony in Congestive Heart Failure Diagnostic and Therapeutic Implications Sherif F. Nagueh, MD Houston, Texas Myocardial imaging has been successfully applied to the evaluation of patients with heart failure, particularly identifying candidates who are likely to respond to cardiac resynchronization therapy (CRT). Recent studies have shown the benefits of CRT in heart failure patients with depressed ejection fraction (EF) and a narrow QRS complex, albeit in a small number of patients, and without a placebo arm. In addition, few reports have noted the presence of pathophysiologically relevant mechanical dyssynchrony in patients with heart failure and normal EF. Collectively, these data support the need for a better understanding of cardiac function/dysfunction and its treatment in these patient groups. (J Am Coll Cardiol 2008;51:18–22) © 2008 by the American College of Cardiology Foundation
Electrical dyssynchrony leads to mechanical dyssynchrony. This relation explains in part the presence of left ventricular (LV) dysfunction in a number of patients with congestive heart failure. It also accounts for the favorable effects of cardiac resynchronization therapy (CRT), with respect to reverse LV remodeling, improved LV function, and, therefore, exercise tolerance and clinical outcome in this population. The QRS duration is currently used as a surrogate for electromechanical dyssynchrony. However, there are ample data showing the limitations of using the QRS duration as a surrogate for mechanical dyssynchrony. Excluding patients with a left bundle branch block, a wide QRS duration does not necessarily identify responders to CRT. In particular, the 20% to 30% CRT failure rate despite a wide QRS complex (1) and the low accuracy of this measurement in identifying CRT responders (2) expose the need for a more accurate and clinically applicable direct measurement of mechanical dyssynchrony that is amenable to improvement/correction by CRT. Myocardial imaging has proven extremely valuable in that regard. This commentary addresses the opinions expressed in the previous Viewpoint (3), which primarily revolve on imaging methods for the diagnosis of mechanical dyssynchrony, and whether this diagnosis, per se, should lead to a recommendation for CRT. This is a timely topic, and the plethora of available methods creates the need for a thoughtful and comprehensive analysis of the literature. As will be noted below, my views agree with some, but not all, of the expressed opinions in the Viewpoint (3). In my comment, I will answer 4 key questions, namely the definition of mechanical systolic dyssynchrony; its pathophysiological consequences and clinical implications in patients
From The Methodist DeBakey Heart Center, The Methodist Hospital, Houston, Texas. Dr. Nagueh has served as a consultant for St. Jude Medical and has received lecture fees from speaking at the invitation of Medtronic. Manuscript received August 15, 2007; accepted August 22, 2007.
with heart failure and depressed EF; its pathophysiological consequences and clinical implications in patients with heart failure and normal EF; and the clinical application of the aforementioned data. Definition of Mechanical Dyssynchrony Intraventricular systolic dyssynchrony refers to differences in the timing of contraction between the different myocardial segments. It is important to distinguish dyssynchrony from dyssynergy (“contractile disparity” on the right side of Fig. 1 of the Viewpoint article by Kass [3]), as well as define what constitutes clinically significant dyssynchrony. Dyssynergy refers to differences in function (e.g., peak systolic velocity or strain), but not major differences in timing. Figure 1 shows examples of dyssynchrony and dyssynergy. The application of myocardial imaging is centered on the diagnosis of dyssynchrony, and not dyssynergy. Normality can be defined as it pertains to function per se, as well as from a statistical perspective. There are minor differences in regional function in normal hearts, both for amplitude and timing of contraction. Thus, pathophysiologically relevant dyssynchrony should not be diagnosed unless a certain threshold is met. This threshold is identified as one that is associated with a significant degree of LV dysfunction/clinical events, and present in ⬍5% of the normal population (both functional and statistical components needed). Notwithstanding this definition, dyssynchrony is not an all-or-none phenomenon, but exists as a continuous variable with different grades of severity. It also follows that studies (4) selecting lower cutoff values will report a high prevalence of dyssynchrony, as highlighted in the selected reference (in addition, 80% of the patients in reference 4 had coronary artery disease with a severely depressed ejection fraction [EF], who likely had multiple regional wall motion abnormalities, and thus the very high prevalence of dyssynchrony).
Nagueh Mechanical Dyssynchrony in CHF
JACC Vol. 51, No. 1, 2008 January 1/8, 2008:18–22
There are a number of myocardial imaging techniques that have been utilized to identify dyssynchrony, including M-mode, 2-dimensional, and 3-dimensional echocardiography. However, most of the available literature has used tissue Doppler, either as color (including tissue synchronization imaging), or pulse wave tissue Doppler. More recently, the role of speckle tracking was evaluated. Likewise, there are a number of analytic approaches, including time to onset/peak systolic ejection velocity, displacement mapping, and deformation measurements. Furthermore, it is possible to acquire signals in the longitudinal and cross-sectional planes, and not only at rest, but also with exercise. The relative merits of these techniques and analyses are beyond the scope of this comment, and the reader is referred to a more comprehensive review of this topic (5). The 2 most commonly adopted approaches are the opposite wall delay (measured by comparing time to peak systolic contraction between opposite walls by color tissue Doppler imaging), and the standard deviation of the time to peak systolic velocity in a 12-segment model, or the Yu index (5). Statistically, the presence of significant time delay (⬎60 to 65 ms between opposite walls, or a Yu index ⬎33 ms) is associated with a clinically significant degree of LV dysfunction, and occurs in ⬍5% of the normal population, satisfying both components of the definition (5).
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patients with QRS duration ⬍120 Abbreviations and Acronyms ms, to 89% in those with QRS duration ⬎150 ms (6). However, CRT ⴝ cardiac this does not mean that all these resynchronization therapy cases can benefit from CRT as will DHF ⴝ diastolic heart be discussed in later text. failure With respect to clinical releEF ⴝ ejection fraction vance of dyssynchrony indexes, LV ⴝ left numerous studies by many laboraventricle/ventricular tories (5) have convincingly shown RV ⴝ right that the presence of mechanical ventricle/ventricular dyssynchrony in patients with a prolonged QRS duration identifies the clinical and echocardiographic “responders” to CRT. In these patients, the improvement in mechanical dyssynchrony is tied to an increase in LV systolic function (using invasive and noninvasive measurements), a reduction in the severity of mitral regurgitation, reverse LV remodeling, and in some cases improvement in LV filling dynamics. Therefore, myocardial imaging has the potential (still to be realized) to facilitate “individualized” therapy in this large segment of patients with heart failure. I will next address studies in patients with a normal QRS duration. Narrow QRS
Dyssynchrony in Patients With Systolic Heart Failure The prevalence of dyssynchrony varies based on the methodology, the severity of LV dysfunction, QRS duration, and loading conditions. Therefore, a single value is not representative of the whole spectrum. The prevalence is higher in studies including patients with larger ventricles, coronary artery disease, lower EF, and a wide QRS. It ranges from 27% in
Figure 1
As noted in the preceding text, intraventricular dyssynchrony is not uncommon in heart failure patients with a narrow QRS complex. In that regard, 2 recent studies were published comparing the effects of CRT in this group of patients with the effects of CRT on those having a wide QRS complex (7,8). Importantly, the authors of one of these studies (7) declared that all echocardiographic measurements were performed without knowledge of the patients’ clinical status. Collectively,
Examples of Dyssynchrony and Dyssynergy
(Left) An example of dyssynchrony from a patient with depressed ejection fraction. Lateral systolic velocity (blue) occurs 76 ms after septal systolic velocity (yellow). (Right) An example of dyssynergy. Notice the simultaneous occurrence of peak systolic velocities in these 2 opposite walls, despite a notable difference in the velocity amplitude. In both panels, yellow arrows indicate time intervals to peak systolic velocities.
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Nagueh Mechanical Dyssynchrony in CHF
these 2 reports included 84 patients with a narrow QRS complex and showed that CRT results in similar benefits irrespective of the QRS duration, which showed no significant correlation with the time delay measured by tissue Doppler. The benefits included improvements in New York Heart Association functional class, 6-min walking distance, reverse LV remodeling, and an increase in EF. In one study, CRT was withheld for 4 weeks and resulted in loss of the CRT benefits on LV function (8). Both studies have the important limitation of lacking a randomized design with a placebo group, which is a valid concern when considering changes in patients’ symptomatology. However, “placebo treatment” does not result in reverse LV remodeling and improvement in EF, as shown in the randomized MIRACLE (Multicenter InSync Randomized Clinical Evaluation) echocardiographic substudy, where the analysis was performed without reference to images or measurements from other visits (9). Furthermore, it is LV reverse remodeling that better predicts survival after CRT (10). In addition, as shown in one of the two studies, LV functional improvement is pacing dependent (8). In conclusion, while the existing studies are not sufficient to recommend CRT in this population, they certainly show the need for additional studies, using a randomized design, and powered to address clinically relevant end points. Dyssynchrony in Patients With Diastolic Heart Failure (DHF) Unlike patients with depressed EF, there are very few studies (11–13) that examined this population, and the true prevalence of the problem in patients with heart failure and normal EF awaits large epidemiologic studies. Nevertheless, the existing
Figure 2
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literature not only supports its presence, but also its adverse effects on cardiac function (Figure 2 and the Online Video show an example from a patient with DHF). In this population, dyssynchrony was defined based on age-matched normal control groups. Specifically, dyssynchrony was observed in 0% to 2% of the control group (11,12). Therefore, a rigorous statistical standard was applied. It is important to emphasize that the cutoff used to define dyssynchrony was not based on the attempt to identify heart failure patients, but the reverse was true (i.e., the normal values in the control group were used to define the prevalence of the problem in the patient groups). As to the effect of dyssynchrony on cardiac function, our group has noted consistent evidence of depressed LV systolic properties, and not only longitudinal systolic velocities, in the group with DHF and systolic dyssynchrony. Specifically, LV stroke work, slope of stroke work versus end-diastolic volume, EF, ratio of LV end-systolic pressure to end-systolic volume, and the ratio of mid-wall fractional shortening to circumferential wall stress (11) were all significantly lower in the group with systolic dyssnchrony. Furthermore, this group (DHF patients with systolic dyssynchrony) had the worst LV diastolic function measurements (11). Therefore, these findings support the conclusion that systolic dyssynchrony as defined in the preceding text has pathophysiologically relevant consequences in patients with DHF, despite a “normal EF,” albeit a significantly lower EF (50s range) in comparison with DHF patients without systolic dyssynchrony. Is it possible that inducing further dyssynchrony in this group would lead to clinical improvement? While there are no data to directly answer this question, our current understanding would not lead us to believe so, given the well-documented adverse effects of right ventricular (RV) apical pacing on
Systolic Dyssynchrony and Mitral Annulus Velocities From a Patient With Heart Failure and Normal EF
(Top) An example of systolic dyssynchrony from a patient with heart failure and normal ejection fraction (EF). Posterolateral systolic velocity (yellow) occurs 110 ms after anteroseptal systolic velocity (blue). (Lower left) Myocardial velocities at septal annulus. (Lower right) Myocardial velocities at lateral annulus. Notice the reduced systolic (Sa) and early diastolic (Ea) velocities and the markedly reduced Ea/Aa ratio at both sites. Aa ⫽ myocardial late diastolic velocity.
JACC Vol. 51, No. 1, 2008 January 1/8, 2008:18–22
cardiac function, including decreasing the EF to values ⬍50%, and further impairing LV diastolic function (14). In fact, one study (15) showed that RV apical pacing increases the risk of heart failure hospitalizations and atrial fibrillation (even when atrioventricular synchrony is maintained) in patients with a normal QRS duration and a median EF of 55% (similar to the group with systolic dyssynchrony studied by Wang et al. [11]). Furthermore, the results of a recent randomized multicenter trial that are pertinent to this discussion were published (16). In this study in 1,065 patients with sinus node disease and normal EF (mean 58 ⫾ 10%), the effect of minimal RV pacing (which reduces the duration of dyssynchrony caused by RV pacing) on clinical events was compared with conventional dual-chamber pacing (99% of ventricular beats were RV paced). The study noted that minimal RV pacing, and therefore fewer periods of pacing-induced dyssynchrony (only 9% of ventricular beats were paced), results in a significantly lower incidence of persistent atrial fibrillation, ablation procedures, and heart failure hospitalizations (16). In light of the preceding text, one has to seriously question whether further dyssynchrony is a good treatment strategy in these patients. The argument in the Viewpoint (3) about the beneficial effects of RV pacing (study with 9 patients) in patients with EF ⬎70% is not applicable to DHF patients with systolic dyssynchrony, and EF in the 50s range. Diastolic Dyssynchrony For this topic, my views are mostly similar to those expressed in the Viewpoint (3), and are herein summarized. Diastolic dyssynchrony is common in patients with heart failure, and appears to have an important contribution to their hemodynamic and clinical status (11). As we and others have shown (11,17), loading conditions have a strong influence on dyssynchrony. However, aside from load, LV hypertrophy has a strong association with dyssynchrony. These observations support the recommendation for the need to achieve adequate control of hypertension in patients with DHF, preferably with medications that can also result in regression of LV hypertrophy and interstitial fibrosis. At this time, it is unknown how CRT affects diastolic dyssynchrony in this population, but, as previously discussed (11), CRT may not be a viable treatment modality for diastolic dyssynchrony, given the multiple pathophysiological mechanisms that contribute to it, and that may not be favorably affected by CRT. Clinical Application of Myocardial Imaging to CRT There are 2 points to address here. The first deals with the perception that imaging detects abnormalities that are not clinically significant, much similar to trace regurgitant lesions by color Doppler. Trace regurgitation occurs in normal hearts and has no impact on cardiac function, or survival. As detailed in the previous paragraphs, and conceded in part in the previous Viewpoint (3), significant mechanical dyssynchrony does not occur in normal hearts, has serious adverse effects on cardiac function, and provides important outcome data, which
Nagueh Mechanical Dyssynchrony in CHF
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are independent of many other variables (including QRS duration) in patients with prolonged QRS (18), as well as those with a normal QRS duration (19). Therefore, there are striking differences when one considers what trace regurgitation represents, and what mechanical dyssynchrony (as defined in this comment) by myocardial imaging means. The second point is how to use the imaging data clinically. I will indicate up front that many cases with mechanical dyssynchrony are not candidates for CRT, and that imaging data should not be the sole determinant of who should, or should not, receive CRT. Dyssynchrony occurs for several reasons, including electrical delay, myocardial ischemia and infarction, and abnormal loading conditions. To identify the cases that can potentially benefit from CRT, it is essential to perform the echocardiographic study after medical therapy— which reduces afterload— has been optimized. This recommendation is in line with the approved indications for CRT, where patients are not considered candidates until medical therapy has been optimized (beta-blockers, angiotensinconverting enzyme inhibitors/angiotensin receptor blockers, spironolactone, and nitrates ⫹ hydralazine in African Americans), and is supported by recent reports showing the effects of cardiac medications on dyssynchrony measurements (11,17). Second, a comprehensive echocardiographic evaluation by experienced personnel is needed. Sonographers and physicians who perform and interpret these studies need to have adequate training (attendance of few courses without adequate demonstration of competence is not sufficient), and maintain competence by doing/interpreting a reasonable number of studies each year. Aside from image acquisition, the analysis can be very challenging when one considers the small signal amplitudes, the myriad of abnormal conduction patterns that exist, and the confounding variables of regional dysfunction because of previous myocardial infarction. The recently announced results of the PROSPECT (Predictors of Response to Cardiac Re-Synchronization Therapy) trial highlight the challenges that can be present in these exams and their interpretation, which were pointed out in the Viewpoint (3) (no disagreement here). However, rather than abandoning a sound and logical approach to “individualized” therapy, the PROSPECT trial should fuel the search for more robust methods with higher specificity to diagnose dyssynchrony, which at this time should not be considered as a routine test that can be performed in any clinical laboratory. From an analysis perspective, each of the single indexes has its limitations. For an example, an increased Yu index may be present because of mid/apical akinesis/dyskinesis, but without a significant systolic time delay between the basal segments. Likewise, a systolic time delay between basal segments may be due to the presence of a myocardial scar. In both scenarios, the specificity of mechanical dyssynchrony for the prediction of reverse remodeling is low (20). However, one can entertain approaches that include more than one index, for example the opposite wall delay and the Yu index together. The rationale for such an approach stems from identifying both the location of delayed contraction and the global impact it has on dyssyn-
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Nagueh Mechanical Dyssynchrony in CHF
chrony. Alternatively, the combination of longitudinal and radial dyssynchrony could be utilized, and a recent study (21) has shown that method to be highly promising. A clinically useful echocardiographic evaluation should identify the presence of regional dysfunction and scar tissue (diagnosed by reduced wall thickness and increased brightness, but additional imaging modalities may be needed when in doubt). It is also advantageous to note the site with the latest activation before lead implantation. The results may dissuade from the procedure altogether, for example in the setting of septal, as opposed to free wall delay, as CRT (with lead implantation aimed at earlier activation of LV free wall) in this setting is not necessarily helpful. Alternatively, the echocardiographic findings can confirm the presence of latest contraction at a site that is amenable to improvement by CRT, to the extent that this is technically feasible. Conclusions Myocardial imaging offers unique insights into the evaluation of mechanical dyssynchrony in heart failure patients. The arguments about the high prevalence and “imperfect technique” are valid points to discuss. However, myocardial imaging can play a critical role in selected groups, and is here to stay. While the technique is not perfect, we are moving towards a better understanding of its advantages and limitations, with promising ongoing developments. Recently, the RethinQ (Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) study was published looking at CRT in 172 patients with heart failure (EF ⱕ35%), and a narrow QRS complex, but with mechanical dyssynchrony, with the majority of patients (96%) enrolled based on the opposite wall delay method by color tissue Doppler imaging (22). In this randomized double-blind study, CRT did not result in a significant change in peak oxygen consumption (primary end point), Minnesota Living With Heart Failure score, 6-min walk, and LV volumes/EF at 6 months. The potential reasons for these results include problems with the echocardiographic methods used to identify patients, issues with lead placement as it relates to the site with latest contraction and scar tissue, and the actual possibility that dyssynchrony in this population is not due to a conduction delay that can be corrected by CRT (as stated in the Viewpoint by Kass [3]). Pending analysis aimed at dissecting these possibilities, and additional studies, caution is warranted for considering CRT in this population. Reprint requests and correspondence: Dr. Sherif F. Nagueh, Methodist DeBakey Heart Center, 6550 Fannin, SM-677, Houston, Texas 77030. E-mail: [email protected].
JACC Vol. 51, No. 1, 2008 January 1/8, 2008:18–22 2. Molhoek SG, Bax JJ, Van Erven L, et al. QRS duration and shortening to predict clinical response to cardiac resynchronization therapy in patients with end-stage heart failure. Pacing Clin Electrophysiol 2004;27:308 –13. 3. Kass DA. An epidemic of dyssynchrony: but what does it mean? J Am Coll Cardiol 2008;51:12–7. 4. Chalil S, Stegemann B, Muhyaldeen S, et al. Intraventricular dyssynchrony predicts mortality and morbidity after cardiac resynchronization therapy: a study using cardiovascular magnetic resonance tissue synchronization imaging. J Am Coll Cardiol 2007;50:243–52. 5. Bax JJ, Abraham T, Barold SS, et al. Cardiac resynchronization therapy: part 1—issues before device implantation. J Am Coll Cardiol 2005;46:2153– 67. 6. Hawkins NM, Petrie MC, MacDonald MR, Hogg KJ, McMurray JJ. Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur Heart J 2006;27:1270 – 81. 7. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol 2006;48:2243–50. 8. Yu CM, Chan YS, Zhang Q, et al. Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting systolic asynchrony by echocardiography. J Am Coll Cardiol 2006;48:2251–7. 9. St. John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–90. 10. Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580 – 6. 11. Wang J, Kurrelmeyer KM, Torre-Amione G, Nagueh SF. Systolic and diastolic dyssynchrony in patients with diastolic heart failure and the effect of medical therapy. J Am Coll Cardiol 2007;49:88 –96. 12. Yu CM, Zhang Q, Yip GW, et al. Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition. J Am Coll Cardiol 2007;49:97–105. 13. Wang YC, Hwang JJ, Lai LP, et al. Coexistence and exercise exacerbation of intra-left ventricular contractile dyssynchrony in hypertensive patients with diastolic heart failure. Am Heart J 2007;154:278 – 84. 14. Tse HF, Yu C, Wong KK, et al. Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation. J Am Coll Cardiol 2002;40:1451– 8. 15. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–7. 16. Sweeney MO, Bank AJ, Nsah E, et al. Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) trial. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007;357:1000 – 8. 17. Takemoto Y, Hozumi T, Sugioka K, et al. Beta-blocker therapy induces ventricular resynchronization in dilated cardiomyopathy with narrow QRS complex. J Am Coll Cardiol 2007;49:778 – 83. 18. Bader H, Garrigue G, Lafitte S, et al. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol 2004;43:248 –56. 19. Cho GY, Song JK, Park WJ, et al. Mechanical dyssynchrony assessed by tissue Doppler imaging is a powerful predictor of mortality in congestive heart failure with normal QRS duration. J Am Coll Cardiol 2005;46:2237– 43. 20. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006;113:969 –76. 21. Gorcsan J 3rd, Tanabe M, Bleeker GB, et al. Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy. J Am Coll Cardiol 2007;50:1476 – 83. 22. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357:2461–71.
REFERENCES APPENDIX
1. Kass DA. Predicting cardiac resynchronization response by QRS duration: the long and short of it. J Am Coll Cardiol 2003;42:2125–7.
For an accompanying video, please see the online version of this article.
Vol. 51, No. 1, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.08.052
Mechanical Dyssynchrony in Congestive Heart Failure Diagnostic and Therapeutic Implications Sherif F. Nagueh, MD Houston, Texas Myocardial imaging has been successfully applied to the evaluation of patients with heart failure, particularly identifying candidates who are likely to respond to cardiac resynchronization therapy (CRT). Recent studies have shown the benefits of CRT in heart failure patients with depressed ejection fraction (EF) and a narrow QRS complex, albeit in a small number of patients, and without a placebo arm. In addition, few reports have noted the presence of pathophysiologically relevant mechanical dyssynchrony in patients with heart failure and normal EF. Collectively, these data support the need for a better understanding of cardiac function/dysfunction and its treatment in these patient groups. (J Am Coll Cardiol 2008;51:18–22) © 2008 by the American College of Cardiology Foundation
Electrical dyssynchrony leads to mechanical dyssynchrony. This relation explains in part the presence of left ventricular (LV) dysfunction in a number of patients with congestive heart failure. It also accounts for the favorable effects of cardiac resynchronization therapy (CRT), with respect to reverse LV remodeling, improved LV function, and, therefore, exercise tolerance and clinical outcome in this population. The QRS duration is currently used as a surrogate for electromechanical dyssynchrony. However, there are ample data showing the limitations of using the QRS duration as a surrogate for mechanical dyssynchrony. Excluding patients with a left bundle branch block, a wide QRS duration does not necessarily identify responders to CRT. In particular, the 20% to 30% CRT failure rate despite a wide QRS complex (1) and the low accuracy of this measurement in identifying CRT responders (2) expose the need for a more accurate and clinically applicable direct measurement of mechanical dyssynchrony that is amenable to improvement/correction by CRT. Myocardial imaging has proven extremely valuable in that regard. This commentary addresses the opinions expressed in the previous Viewpoint (3), which primarily revolve on imaging methods for the diagnosis of mechanical dyssynchrony, and whether this diagnosis, per se, should lead to a recommendation for CRT. This is a timely topic, and the plethora of available methods creates the need for a thoughtful and comprehensive analysis of the literature. As will be noted below, my views agree with some, but not all, of the expressed opinions in the Viewpoint (3). In my comment, I will answer 4 key questions, namely the definition of mechanical systolic dyssynchrony; its pathophysiological consequences and clinical implications in patients
From The Methodist DeBakey Heart Center, The Methodist Hospital, Houston, Texas. Dr. Nagueh has served as a consultant for St. Jude Medical and has received lecture fees from speaking at the invitation of Medtronic. Manuscript received August 15, 2007; accepted August 22, 2007.
with heart failure and depressed EF; its pathophysiological consequences and clinical implications in patients with heart failure and normal EF; and the clinical application of the aforementioned data. Definition of Mechanical Dyssynchrony Intraventricular systolic dyssynchrony refers to differences in the timing of contraction between the different myocardial segments. It is important to distinguish dyssynchrony from dyssynergy (“contractile disparity” on the right side of Fig. 1 of the Viewpoint article by Kass [3]), as well as define what constitutes clinically significant dyssynchrony. Dyssynergy refers to differences in function (e.g., peak systolic velocity or strain), but not major differences in timing. Figure 1 shows examples of dyssynchrony and dyssynergy. The application of myocardial imaging is centered on the diagnosis of dyssynchrony, and not dyssynergy. Normality can be defined as it pertains to function per se, as well as from a statistical perspective. There are minor differences in regional function in normal hearts, both for amplitude and timing of contraction. Thus, pathophysiologically relevant dyssynchrony should not be diagnosed unless a certain threshold is met. This threshold is identified as one that is associated with a significant degree of LV dysfunction/clinical events, and present in ⬍5% of the normal population (both functional and statistical components needed). Notwithstanding this definition, dyssynchrony is not an all-or-none phenomenon, but exists as a continuous variable with different grades of severity. It also follows that studies (4) selecting lower cutoff values will report a high prevalence of dyssynchrony, as highlighted in the selected reference (in addition, 80% of the patients in reference 4 had coronary artery disease with a severely depressed ejection fraction [EF], who likely had multiple regional wall motion abnormalities, and thus the very high prevalence of dyssynchrony).
Nagueh Mechanical Dyssynchrony in CHF
JACC Vol. 51, No. 1, 2008 January 1/8, 2008:18–22
There are a number of myocardial imaging techniques that have been utilized to identify dyssynchrony, including M-mode, 2-dimensional, and 3-dimensional echocardiography. However, most of the available literature has used tissue Doppler, either as color (including tissue synchronization imaging), or pulse wave tissue Doppler. More recently, the role of speckle tracking was evaluated. Likewise, there are a number of analytic approaches, including time to onset/peak systolic ejection velocity, displacement mapping, and deformation measurements. Furthermore, it is possible to acquire signals in the longitudinal and cross-sectional planes, and not only at rest, but also with exercise. The relative merits of these techniques and analyses are beyond the scope of this comment, and the reader is referred to a more comprehensive review of this topic (5). The 2 most commonly adopted approaches are the opposite wall delay (measured by comparing time to peak systolic contraction between opposite walls by color tissue Doppler imaging), and the standard deviation of the time to peak systolic velocity in a 12-segment model, or the Yu index (5). Statistically, the presence of significant time delay (⬎60 to 65 ms between opposite walls, or a Yu index ⬎33 ms) is associated with a clinically significant degree of LV dysfunction, and occurs in ⬍5% of the normal population, satisfying both components of the definition (5).
19
patients with QRS duration ⬍120 Abbreviations and Acronyms ms, to 89% in those with QRS duration ⬎150 ms (6). However, CRT ⴝ cardiac this does not mean that all these resynchronization therapy cases can benefit from CRT as will DHF ⴝ diastolic heart be discussed in later text. failure With respect to clinical releEF ⴝ ejection fraction vance of dyssynchrony indexes, LV ⴝ left numerous studies by many laboraventricle/ventricular tories (5) have convincingly shown RV ⴝ right that the presence of mechanical ventricle/ventricular dyssynchrony in patients with a prolonged QRS duration identifies the clinical and echocardiographic “responders” to CRT. In these patients, the improvement in mechanical dyssynchrony is tied to an increase in LV systolic function (using invasive and noninvasive measurements), a reduction in the severity of mitral regurgitation, reverse LV remodeling, and in some cases improvement in LV filling dynamics. Therefore, myocardial imaging has the potential (still to be realized) to facilitate “individualized” therapy in this large segment of patients with heart failure. I will next address studies in patients with a normal QRS duration. Narrow QRS
Dyssynchrony in Patients With Systolic Heart Failure The prevalence of dyssynchrony varies based on the methodology, the severity of LV dysfunction, QRS duration, and loading conditions. Therefore, a single value is not representative of the whole spectrum. The prevalence is higher in studies including patients with larger ventricles, coronary artery disease, lower EF, and a wide QRS. It ranges from 27% in
Figure 1
As noted in the preceding text, intraventricular dyssynchrony is not uncommon in heart failure patients with a narrow QRS complex. In that regard, 2 recent studies were published comparing the effects of CRT in this group of patients with the effects of CRT on those having a wide QRS complex (7,8). Importantly, the authors of one of these studies (7) declared that all echocardiographic measurements were performed without knowledge of the patients’ clinical status. Collectively,
Examples of Dyssynchrony and Dyssynergy
(Left) An example of dyssynchrony from a patient with depressed ejection fraction. Lateral systolic velocity (blue) occurs 76 ms after septal systolic velocity (yellow). (Right) An example of dyssynergy. Notice the simultaneous occurrence of peak systolic velocities in these 2 opposite walls, despite a notable difference in the velocity amplitude. In both panels, yellow arrows indicate time intervals to peak systolic velocities.
20
Nagueh Mechanical Dyssynchrony in CHF
these 2 reports included 84 patients with a narrow QRS complex and showed that CRT results in similar benefits irrespective of the QRS duration, which showed no significant correlation with the time delay measured by tissue Doppler. The benefits included improvements in New York Heart Association functional class, 6-min walking distance, reverse LV remodeling, and an increase in EF. In one study, CRT was withheld for 4 weeks and resulted in loss of the CRT benefits on LV function (8). Both studies have the important limitation of lacking a randomized design with a placebo group, which is a valid concern when considering changes in patients’ symptomatology. However, “placebo treatment” does not result in reverse LV remodeling and improvement in EF, as shown in the randomized MIRACLE (Multicenter InSync Randomized Clinical Evaluation) echocardiographic substudy, where the analysis was performed without reference to images or measurements from other visits (9). Furthermore, it is LV reverse remodeling that better predicts survival after CRT (10). In addition, as shown in one of the two studies, LV functional improvement is pacing dependent (8). In conclusion, while the existing studies are not sufficient to recommend CRT in this population, they certainly show the need for additional studies, using a randomized design, and powered to address clinically relevant end points. Dyssynchrony in Patients With Diastolic Heart Failure (DHF) Unlike patients with depressed EF, there are very few studies (11–13) that examined this population, and the true prevalence of the problem in patients with heart failure and normal EF awaits large epidemiologic studies. Nevertheless, the existing
Figure 2
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literature not only supports its presence, but also its adverse effects on cardiac function (Figure 2 and the Online Video show an example from a patient with DHF). In this population, dyssynchrony was defined based on age-matched normal control groups. Specifically, dyssynchrony was observed in 0% to 2% of the control group (11,12). Therefore, a rigorous statistical standard was applied. It is important to emphasize that the cutoff used to define dyssynchrony was not based on the attempt to identify heart failure patients, but the reverse was true (i.e., the normal values in the control group were used to define the prevalence of the problem in the patient groups). As to the effect of dyssynchrony on cardiac function, our group has noted consistent evidence of depressed LV systolic properties, and not only longitudinal systolic velocities, in the group with DHF and systolic dyssynchrony. Specifically, LV stroke work, slope of stroke work versus end-diastolic volume, EF, ratio of LV end-systolic pressure to end-systolic volume, and the ratio of mid-wall fractional shortening to circumferential wall stress (11) were all significantly lower in the group with systolic dyssnchrony. Furthermore, this group (DHF patients with systolic dyssynchrony) had the worst LV diastolic function measurements (11). Therefore, these findings support the conclusion that systolic dyssynchrony as defined in the preceding text has pathophysiologically relevant consequences in patients with DHF, despite a “normal EF,” albeit a significantly lower EF (50s range) in comparison with DHF patients without systolic dyssynchrony. Is it possible that inducing further dyssynchrony in this group would lead to clinical improvement? While there are no data to directly answer this question, our current understanding would not lead us to believe so, given the well-documented adverse effects of right ventricular (RV) apical pacing on
Systolic Dyssynchrony and Mitral Annulus Velocities From a Patient With Heart Failure and Normal EF
(Top) An example of systolic dyssynchrony from a patient with heart failure and normal ejection fraction (EF). Posterolateral systolic velocity (yellow) occurs 110 ms after anteroseptal systolic velocity (blue). (Lower left) Myocardial velocities at septal annulus. (Lower right) Myocardial velocities at lateral annulus. Notice the reduced systolic (Sa) and early diastolic (Ea) velocities and the markedly reduced Ea/Aa ratio at both sites. Aa ⫽ myocardial late diastolic velocity.
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cardiac function, including decreasing the EF to values ⬍50%, and further impairing LV diastolic function (14). In fact, one study (15) showed that RV apical pacing increases the risk of heart failure hospitalizations and atrial fibrillation (even when atrioventricular synchrony is maintained) in patients with a normal QRS duration and a median EF of 55% (similar to the group with systolic dyssynchrony studied by Wang et al. [11]). Furthermore, the results of a recent randomized multicenter trial that are pertinent to this discussion were published (16). In this study in 1,065 patients with sinus node disease and normal EF (mean 58 ⫾ 10%), the effect of minimal RV pacing (which reduces the duration of dyssynchrony caused by RV pacing) on clinical events was compared with conventional dual-chamber pacing (99% of ventricular beats were RV paced). The study noted that minimal RV pacing, and therefore fewer periods of pacing-induced dyssynchrony (only 9% of ventricular beats were paced), results in a significantly lower incidence of persistent atrial fibrillation, ablation procedures, and heart failure hospitalizations (16). In light of the preceding text, one has to seriously question whether further dyssynchrony is a good treatment strategy in these patients. The argument in the Viewpoint (3) about the beneficial effects of RV pacing (study with 9 patients) in patients with EF ⬎70% is not applicable to DHF patients with systolic dyssynchrony, and EF in the 50s range. Diastolic Dyssynchrony For this topic, my views are mostly similar to those expressed in the Viewpoint (3), and are herein summarized. Diastolic dyssynchrony is common in patients with heart failure, and appears to have an important contribution to their hemodynamic and clinical status (11). As we and others have shown (11,17), loading conditions have a strong influence on dyssynchrony. However, aside from load, LV hypertrophy has a strong association with dyssynchrony. These observations support the recommendation for the need to achieve adequate control of hypertension in patients with DHF, preferably with medications that can also result in regression of LV hypertrophy and interstitial fibrosis. At this time, it is unknown how CRT affects diastolic dyssynchrony in this population, but, as previously discussed (11), CRT may not be a viable treatment modality for diastolic dyssynchrony, given the multiple pathophysiological mechanisms that contribute to it, and that may not be favorably affected by CRT. Clinical Application of Myocardial Imaging to CRT There are 2 points to address here. The first deals with the perception that imaging detects abnormalities that are not clinically significant, much similar to trace regurgitant lesions by color Doppler. Trace regurgitation occurs in normal hearts and has no impact on cardiac function, or survival. As detailed in the previous paragraphs, and conceded in part in the previous Viewpoint (3), significant mechanical dyssynchrony does not occur in normal hearts, has serious adverse effects on cardiac function, and provides important outcome data, which
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are independent of many other variables (including QRS duration) in patients with prolonged QRS (18), as well as those with a normal QRS duration (19). Therefore, there are striking differences when one considers what trace regurgitation represents, and what mechanical dyssynchrony (as defined in this comment) by myocardial imaging means. The second point is how to use the imaging data clinically. I will indicate up front that many cases with mechanical dyssynchrony are not candidates for CRT, and that imaging data should not be the sole determinant of who should, or should not, receive CRT. Dyssynchrony occurs for several reasons, including electrical delay, myocardial ischemia and infarction, and abnormal loading conditions. To identify the cases that can potentially benefit from CRT, it is essential to perform the echocardiographic study after medical therapy— which reduces afterload— has been optimized. This recommendation is in line with the approved indications for CRT, where patients are not considered candidates until medical therapy has been optimized (beta-blockers, angiotensinconverting enzyme inhibitors/angiotensin receptor blockers, spironolactone, and nitrates ⫹ hydralazine in African Americans), and is supported by recent reports showing the effects of cardiac medications on dyssynchrony measurements (11,17). Second, a comprehensive echocardiographic evaluation by experienced personnel is needed. Sonographers and physicians who perform and interpret these studies need to have adequate training (attendance of few courses without adequate demonstration of competence is not sufficient), and maintain competence by doing/interpreting a reasonable number of studies each year. Aside from image acquisition, the analysis can be very challenging when one considers the small signal amplitudes, the myriad of abnormal conduction patterns that exist, and the confounding variables of regional dysfunction because of previous myocardial infarction. The recently announced results of the PROSPECT (Predictors of Response to Cardiac Re-Synchronization Therapy) trial highlight the challenges that can be present in these exams and their interpretation, which were pointed out in the Viewpoint (3) (no disagreement here). However, rather than abandoning a sound and logical approach to “individualized” therapy, the PROSPECT trial should fuel the search for more robust methods with higher specificity to diagnose dyssynchrony, which at this time should not be considered as a routine test that can be performed in any clinical laboratory. From an analysis perspective, each of the single indexes has its limitations. For an example, an increased Yu index may be present because of mid/apical akinesis/dyskinesis, but without a significant systolic time delay between the basal segments. Likewise, a systolic time delay between basal segments may be due to the presence of a myocardial scar. In both scenarios, the specificity of mechanical dyssynchrony for the prediction of reverse remodeling is low (20). However, one can entertain approaches that include more than one index, for example the opposite wall delay and the Yu index together. The rationale for such an approach stems from identifying both the location of delayed contraction and the global impact it has on dyssyn-
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chrony. Alternatively, the combination of longitudinal and radial dyssynchrony could be utilized, and a recent study (21) has shown that method to be highly promising. A clinically useful echocardiographic evaluation should identify the presence of regional dysfunction and scar tissue (diagnosed by reduced wall thickness and increased brightness, but additional imaging modalities may be needed when in doubt). It is also advantageous to note the site with the latest activation before lead implantation. The results may dissuade from the procedure altogether, for example in the setting of septal, as opposed to free wall delay, as CRT (with lead implantation aimed at earlier activation of LV free wall) in this setting is not necessarily helpful. Alternatively, the echocardiographic findings can confirm the presence of latest contraction at a site that is amenable to improvement by CRT, to the extent that this is technically feasible. Conclusions Myocardial imaging offers unique insights into the evaluation of mechanical dyssynchrony in heart failure patients. The arguments about the high prevalence and “imperfect technique” are valid points to discuss. However, myocardial imaging can play a critical role in selected groups, and is here to stay. While the technique is not perfect, we are moving towards a better understanding of its advantages and limitations, with promising ongoing developments. Recently, the RethinQ (Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) study was published looking at CRT in 172 patients with heart failure (EF ⱕ35%), and a narrow QRS complex, but with mechanical dyssynchrony, with the majority of patients (96%) enrolled based on the opposite wall delay method by color tissue Doppler imaging (22). In this randomized double-blind study, CRT did not result in a significant change in peak oxygen consumption (primary end point), Minnesota Living With Heart Failure score, 6-min walk, and LV volumes/EF at 6 months. The potential reasons for these results include problems with the echocardiographic methods used to identify patients, issues with lead placement as it relates to the site with latest contraction and scar tissue, and the actual possibility that dyssynchrony in this population is not due to a conduction delay that can be corrected by CRT (as stated in the Viewpoint by Kass [3]). Pending analysis aimed at dissecting these possibilities, and additional studies, caution is warranted for considering CRT in this population. Reprint requests and correspondence: Dr. Sherif F. Nagueh, Methodist DeBakey Heart Center, 6550 Fannin, SM-677, Houston, Texas 77030. E-mail: [email protected].
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REFERENCES APPENDIX
1. Kass DA. Predicting cardiac resynchronization response by QRS duration: the long and short of it. J Am Coll Cardiol 2003;42:2125–7.
For an accompanying video, please see the online version of this article.