Europace Advance Access originally published online on November 6, 2008
Europace 2008 10(12):1370-1374; doi:10.1093/europace/eun296
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Cardiac resynchronization therapy
Relation of mechanical dyssynchrony with underlying cardiac structure and performance in chronic systolic heart failure: implications on clinical response to cardiac resynchronization
1 Section of Heart Failure and Cardiac Transplantation Medicine, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195, USA; 2 Christchurch School of Medicine, Christchurch, New Zealand
Manuscript submitted 28 April 2008. Accepted after revision 9 October 2008.
* Corresponding author. Tel: +1 216 444 2121; fax: +1 216 445 6165. E-mail address: tangw{at}ccf.org
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Abstract |
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Aims: The aim of this study is to describe the relationship between ventricular mechanical dyssynchrony (VMD) and echocardiographic indices of cardiac remodelling.
Methods and results: We evaluated 219 ambulatory patients with chronic systolic heart failure [left ventricular ejection fraction (LVEF) 
35%, New York Heart Association functional classes II–IV] who underwent echocardiographic evaluation. The presence of dyssynchrony was defined by Bader criteria (intra-VMD > 40 ms and/or inter-VMD > 38 ms). In our study cohort, 59% of patients had evidence of dyssynchrony (including 44% with intra-VMD and 38% with inter-VMD, and 20% with both). Inter-VMD correlated with QRS width (r = 0.48, P < 0.0001) better than intra-VMD (r = 0.24, P < 0.001). Higher inter-VMD was associated with less restrictive filling patterns (rank sums P = 0.012) and larger left ventricular end-diastolic dimension (LVEDD, rank sums P = 0.020), but intra-VMD values were similar across diastolic stages and LVEDD tertiles.
Conclusion: In chronic systolic heart failure, evidence of mechanical dyssynchrony is prevalent but the underlying cardiac structure and performance may influence the degree of inter-VMD more so than intra-VMD. Our data suggest that the extent of inter-VMD is directly related to the degree of dilatation of the heart but inversely to diastolic dysfunction.
Key Words: Intra-ventricular mechanical dyssynchrony, Inter-ventricular mechanical dyssynchrony, Cardiac resynchronization therapy, Heart failure
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Introduction |
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In recent years, cardiac resynchronization therapy (CRT) has been widely used in the treatment of patients with chronic heart failure with accompanying evidence of electrical dyssynchrony [New York Heart Association (NYHA) functional classes III–IV, left ventricular ejection fraction (LVEF)
35%, QRS width > 120–130 ms].1
Recent studies have implied that the degree of intra- and inter-ventricular mechanical dyssynchrony (VMD) at baseline may predict reverse of cardiac remodelling.2–5 However, the consistency and reliability of these findings are still being investigated in prospective clinical studies. Different measuring techniques have been proposed, with a broad assumption that the variability of these measures of mechanical dyssynchrony may be independent of the degree of impairment in the underlying cardiac structure and performance. However, the relationship between intra- and inter-VMD with cardiac structure and performance is not characterized. The objective of this study is to examine the prevalence and characteristics of mechanical dyssynchrony as it relates to underlying cardiac structure and performance in an unselected patient population with chronic systolic heart failure likely eligible for CRT.
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Methods |
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Study design and patient population
This is a single-centre, prospective study approved by the Cleveland Clinic Institutional Review Board. We enrolled 219 consecutive patients with stable but symptomatic heart failure between 1 May 2001 and 30 June 2003 with NYHA functional classes II–IV. Eligible patients were 18–75 years of age, with LVEF
35%. Patients were excluded if they had significant valvular diseases, severe aortic stenosis or regurgitation, significant hepatic or renal dysfunction, or were unwilling to provide consent. No patients had received CRT at the time of evaluation. An electrocardiogram was performed at the time of echocardiographic evaluation and the rhythm, QRS duration, and PR interval were measured.
Transthoracic echocardiography
Comprehensive transthoracic echocardiography was performed using commercially available HDI 5000 (Phillips Medical Systems, N.A., Bothell, WA, USA) and Acuson Sequoia (Siemens Medical Solutions USA Inc., Malvern, PA, USA) machines. Two-dimensional gray-scale Doppler imaging was performed in standard parasternal and apical views. Diastolic indexes using pulsed-wave Doppler were acquired and averaged over 10 consecutive beats using sweep speeds of 50 and 100 cm/s. Left ventricular ejection fraction was measured using the Simpson’s biplane method. Patients were grouped according to diastolic stages following previously described echocardiographic criteria.6
Assessment of intra-ventricular mechanical delay
Delay among the lateral, septal, inferior, and anterior left ventricular (LV) walls is measured as the time delay from the onset of QRS to the onset of systolic mechanical contraction using pulsed-wave tissue Doppler imaging (TDI) with the volume sample placed at the mitral valve annulus. Intra-VMD is measured as the maximal wall motion delay difference among the four LV walls. Intra-VMD was considered significant for patients with intra-VMD > 40 ms, which was defined by measuring intra-VMD at the basal wall level.3
Validation of this simplified method of measuring at the mitral valve annulus instead of at the basal wall level was performed in a separate group of 15 subjects. Delays measured from the mitral annulus provides an average of only 7.3 ± 6.4% lower than those measured at the basal wall. Moreover, other authors had already demonstrated excellent concordance between the two measures.5,7 The standard deviation of delay among the four LV walls was also calculated for each patient, and found to have significant correlation with the standard deviation of delay obtained from the basal wall method (r = 0.99).
Assessment of inter-ventricular mechanical delay
The aortic pre-ejection interval (PEI) is measured from the onset of QRS to the onset of flow in the LV outflow tract. The pulmonary PEI is measured from the onset of QRS to the onset of flow in the right ventricular outflow tract. Inter-VMD is calculated as the absolute value of the aortic PEI minus the pulmonary PEI.3 Based on previous studies, an inter-VMD was considered apparent if this difference is >38 ms.3
Statistical analyses
Continuous variables are summarized as mean ± standard deviation. The Wilcoxon rank sums test was used to determine differences among continuous non-parametric VMD variables, whereas the Pearson 
2 test was performed for categorical differences. Intra- and inter-VMD levels are plotted as median and inter-quartile range with whiskers at 10 and 90%, respectively. Univariate correlations of VMD with echocardiographic and clinical indexes were assessed by the Spearman’s correlation coefficient. Cox multivariable analysis was performed to assess the risk of death or hospitalization for increasing dyssynchrony when adjusted for age, NYHA class, and LVEF. The Kruskal–Wallis test (rank sums) was used to compare differences in VMD among subjects grouped according to LV end-diastolic diameter (LVEDD), diastolic stage, and LVEF. All statistical analyses were performed by JMP IN 5.1 (SAS institute, Cary, NC, USA). A P-value of <0.05 was considered significant.
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Results |
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Prevalence of mechanical dyssynchrony
The clinical characteristics of the total patient population studied are shown in Table 1. Of the total of 219 patients evaluated for VMD, 161 had both inter- and intra-VMD analysable; and 51 and 7 patients had only intra- and only inter-VMD analysable, respectively (Figure 1). Lack of analysable VMD was always due to insufficient recording of pre-ejection times and/or pulsed-wave TDI tracings. In this cohort, we found 129 (59%) patients presented with some degree of VMD (44% had intra-VMD > 40 ms, 38% had inter-VMD > 38 ms; and among the 161 with both measures, 18% had both intra- and inter-VMD). In determining intra-VMD, the lateral wall had the longest delay in 34% of patients, followed by the inferior wall in 28%, the septal wall in 20%, and the anterior wall in 18%. Overall, there were no significant differences in age, NYHA class, plasma B-type natriuretic peptide levels, serum creatinine, and mitral regurgitation between those with and those without dyssynchrony. The distributions of intra-VMD and inter-VMD reflecting the narrow QRS (<130 ms, n = 93) and wide QRS (
130 ms, n = 103) cohorts are shown in Figure 2. Intra-observer variability in measurement for tissue Doppler indexes was 5%.
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Relationship of dyssynchrony with electrocardiographic variables
In the total cohort, patients with inter-VMD demonstrated longer QRS width compared with those without inter-VMD (mean QRS width 152 ± 35 vs. 118 ± 31 ms, P < 0.0001). This relationship was consistent within both the LVEF
25% and LVEF > 25% subgroups (r = 0.41, P < 0.001 and r = 0.53, P < 0.0001, respectively). In contrast, the relationship between intra-VMD and QRS duration was less apparent, and correlation was only found within the LVEF > 25% subgroup (r = 0.30, P = 0.004).
Relationship of dyssynchrony with echocardiographic variables
A significantly higher percentage of patients with dyssynchrony had LVEF 25% compared with those without dyssynchrony (61 vs. 41%, P = 0.016). In contrast, patients with inter-VMD > 38 ms were associated with more dilated LVEDD (6.6 ± 1.0 vs. 6.2 ± 0.9 cm, P = 0.016) while no significant relationships between intra-VMD and LV diameters were observed (Figure 3).
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Regarding diastolic indices, an inverse correlation was observed between inter-VMD and diastolic stage (r = –0.22, P = 0.005). Inter-VMD also correlated with isovolumetric relaxation time (r = 0.21, P = 0.009) and mitral E/A ratio (r = –0.19, P = 0.017). These correlations, albeit statistically significant, were not very strong. Nevertheless, it is noteworthy that inter-VMD increased across advancing diastolic stage (rank sums P = 0.020), but not for intra-VMD (rank sums P = 0.419, respectively; Figure 3).
Relationships of dyssynchrony with disease severity
Intra- and inter-VMD were similar across tertiles of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (P= NS for both). Also no relation between mitral regurgitation severity or NYHA class and dyssynchrony was found (P > 0.74 for all). Overall, patients with echocardiographic evidence of dyssynchrony trended towards worse prognosis. However, neither dyssynchrony measures imparted a significant risk of death or hospitalization following adjustment for age, NYHA class, and LVEF in multivariate analysis (Table 2). Furthermore, in multivariate analysis, the presence of dyssynchrony was not an independent predictor of clinical outcomes after adjustment for echocardiographic indices of cardiac geometry and performance in our study cohort.
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Discussion |
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There has been a prevailing concept that the role of CRT is primarily to restore synchrony of systolic functions among or within cardiac chambers, thereby improving cardiac performance. Numerous reports of reverse remodelling and improved function following CRT have supported the hypothesis that dyssynchrony engenders structural degradation and dysfunction. However, most studies have used the presence of a wide QRS or evidence of VMD as sole inclusion criterion for CRT implantation. Our analysis highlights the complex relationships between cardiac structure and performance with the degrees of systolic dyssynchrony in patients with chronic systolic heart failure. We found evidence of echocardiographic VMD in a large proportion of patients with chronic systolic heart failure, and observed greater degrees of inter-VMD linking to broader QRS durations, and larger LV dimensions, but less advanced diastolic dysfunction. Our data suggest that the underlying degree of cardiac remodelling should be taken into consideration regarding patient selection and assessment of responses to CRT.
Our findings of increased inter-VMD in larger LV dimensions are consistent with data regarding the reduction of dyssynchrony after surgical ventricular restoration procedures.8 Usually, LV geometry in patients with chronic dilated cardiomyopathy is associated with a more transverse orientation of apical-septal muscle fibres, and this orientation may result in less efficient contraction and an increase in dyssynchrony.9 Furthermore, with increasing inter-VMD, diastolic filling time and isovolumetric relaxation can be reduced, which can lead to further deterioration of cardiac functions, and enhanced dilatation of the LV.10 Therefore, our data introduce the concept that the route to reach QRS widening may influence the responses to CRT. In other words, patients with significant inter-VMD (often leading to widening QRS) due to progression of cardiac remodelling instead of an underlying primary conduction defect (such as left bundle branch block) may have a different pathophysiological response to CRT.
We also report for the first time the inverse relationship between inter-VMD and diastolic dysfunction. Several studies have shown that responders to CRT have lower E/A ratios, longer deceleration times, lower E/Vp ratios, and higher pulmonary vein S/D ratios (all measures of less advanced diastolic dysfunction) than non-responders before implantation.4,11 Also, patients with more severe restrictive filling patterns are less likely to improve in NYHA class and LV sizes from baseline compared with those with delayed relaxation.12 In stage III (restrictive) diastolic dysfunction, patients often have severe LV fibrosis and highly elevated filling pressures, which may sufficiently restrict diastolic and subsequent systolic motion, such that the electrical–mechanical relationship between the two ventricles can become defective. This can directly result in global hypokinesia and hence shorter inter-VMD,13,14 which is in line with the presence of marked diastolic ventricular interaction in patients with persistently high intra-cavitary pressures.15,16 Increased diastolic ventricular interaction is responsible for the descending limb of the Frank–Starling curve, and will also lead to a leftward shift of the septum. Both effects will reduce left and right ventricular filling and subsequent systolic motion and output, thereby further reducing inter-VMD. Thus, the presence of significant inter-VMD is associated with progressive LV enlargement and less diastolic dysfunction.
This study has a number of limitations that that may influence its interpretation. First, there is no general agreement on the ‘gold standard’ of defining intra- and inter-VMD. Also, recent data have challenged the reproducibility of echocardiographic evaluation as well as the reliability of such decisions based on echocardiographic derivatives of VMD. Clearly, there is a wide range of VMD for each echocardiographic category analysed. In this report, intra-VMD was assessed using pulsed-wave TDI to measure the wall motion at the mitral valve annulus, and not the LV base as reported in many studies. However, we validated our technique in a separate patient cohort with excellent concordance, and this simplified method may facilitate easier adoption in clinical practice because it does not require specialized equipment or software. The limited follow-up echocardiographic data prevents an analysis of functional and structural changes related to the progression of dyssynchrony or potential effects of CRT, and the limited number of recorded events prevents an accurate risk assessment. The lack of three-dimensional echo and/or strain imaging techniques also precludes the analysis of the effects of local myocardial workload and efficiency on dyssynchrony. The number of patients that were implanted with a CRT device could not be retrieved due to logistic limitations. Due to the cross-sectional nature of our study, it is unclear whether dyssynchrony is one of the inciting factors leading to diastolic or systolic dysfunctions, or whether it is a consequence of chronic heart failure. Despite these limitations, our observations are unique in pointing out the potential contribution of underlying cardiac remodelling as a confounding influence on treatment responses. In other words, the lack of ‘response’ may be independent of any benefits derived from CRT. Further studies are needed to distinguish the impact of cardiac geometry and diastolic dysfunction on the reliability of dyssynchrony assessment and their predictive value in long-term responses.
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Conclusion |
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In an unselected cohort of patients with chronic systolic heart failure, echocardiographic evidence of mechanical dyssynchrony is prevalent. However, the underlying ventricular dimension and diastolic performance may influence the degree of dyssynchrony, especially the degree of inter-VMD.
Conflict of interest: R.C.S. and W.H.W.T. are consultants for Medtronic Inc. R.A.G. and A.G.B. are consultants for GE Medical. R.A.G. is a consultant for St Jude Medical. All other authors have no conflicts of interest to declare.
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The original ADEPT study was supported by the 2003 American Society of Echocardiography Outcomes Research Award (R.W.T. as recipient, co-author of this paper), with supplemental funding were provided by Roche Diagnostics (manufacturer of NT-proBNP) Inc. and GlaxoSmithKline Pharmaceuticals Inc.
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