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Europace Advance Access originally published online on December 7, 2007
Europace 2008 10(1):63-68; doi:10.1093/europace/eum262
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

CARDIAC RESYNCHRONISATION THERAPY

Mechanical dyssynchrony by 3D echo correlates with acute haemodynamic response to biventricular pacing in heart failure patients

J. van Dijk1,2,*, P. Knaapen1, I.K. Russel3, T. Hendriks1, C.P. Allaart1, C.C. de Cock1 and O. Kamp1,2

1 Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; 2 Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands; 3 Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands

Manuscript submitted 18 August 2007. Accepted after revision 7 November 2007.

* Corresponding author. Tel: +31 20 444 2244; fax: +31 20 444 2446.E-mail address: jeroen.vandijk{at}vumc.nl


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Funding
 References
 
Aims: One-third of dilated cardiomyopathy patients receiving a biventricular pacing-device do not respond to this form of therapy. Therefore, the utility of mechanical dyssynchrony by real-time 3D echocardiography (RT3DE) for predicting systolic response to biventricular pacing, of which maximal rate of pressure rise (dP/dtmax) served as the gold-standard, was evaluated.

Methods and results: Seventeen consecutive heart failure patients (aged 64 ± 10 years, 8 male, 6 ischaemic cardiomyopathy, mean QRS duration 136 ± 32 ms) underwent RT3DE and biventricular pacing. Post-processing software provided data of global left ventricular (LV) function and the systolic dyssynchrony index of 17 LV segments (SDI17, %) for mechanical dyssynchrony. During biventricular pacing, percentual change in dP/dtmax compared to the non-pacing mode, {Delta}dP/dtmax was measured invasively with conductance catheters. LV ejection fraction was 31 ± 10%, SDI17 was 10.2 ± 4.2% and percentual {Delta}dP/dtmax during biventricular pacing was 14.5 ± 12.4. A significant correlation (r = 0.729, P = 0.001) was found between SDI17 and percentual {Delta}dP/dtmax, and between QRS duration and percentual {Delta}dP/dtmax (r = 0.721, P = 0.001).

Conclusion: The present study suggests that mechanical dyssynchrony measured by RT3DE shows a good correlation with invasively determined acute haemodynamic response to biventricular pacing in patients with symptomatic dilated cardiomyopathy. Future studies are needed to further define the clinical utility of RT3DE in identifying patients who are most likely to respond to cardiac resynchronization therapy.

Key Words: Real-time 3D echocardiography, Acute haemodynamic response, Cardiac resynchronization therapy, Heart failure


   Introduction
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 Abstract
 Introduction
Methods
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 References
 
Cardiac resynchronization therapy by means of biventricular pacing has emerged as a valuable treatment strategy in drug-refractory heart failure patients with dilated cardiomyopathy, resulting in a significant decrease in morbidity and mortality.1Go,2Go However, approximately one-third of patients receiving a biventricular pacing-device, do not respond to this form of therapy.2Go,3Go A disparity between electrical and mechanical dyssynchrony most likely contributes to this high non-responder rate.4Go Several echo-guided parameters, including M-Mode echocardiography,5Go pulsed-wave Doppler,6Go and tissue Doppler imaging (TDI),7Go have shown to be useful for the assessment of mechanical dyssynchrony, and thereby facilitate the identification of patients who are likely to respond to biventricular pacing. However, the previous imaging techniques highlight potential limitations and support further efforts to develop non-invasive synchrony measures based on circumferential deformation.

Real-time 3D echocardiography (RT3DE) is a promising imaging technique which allows for fast and accurate quantification of left ventricular (LV) function and mechanical dyssynchrony.8Go–13Go Therefore, RT3DE could potentially be of similar use in optimizing the selection of eligible candidates for biventricular pacing. However, data pertaining the value of RT3DE for this purpose are scarce.

Accordingly, the present study was conducted to evaluate the utility of RT3DE measured mechanical dyssynchrony for predicting systolic response to biventricular pacing. Maximal rate of pressure rise (dP/dtmax) served as the gold standard for the assessment of systolic response.14Go–16Go We hypothesized that mechanical dyssynchrony assessed by RT3DE correlates well with invasively measured acute haemodynamic response to biventricular pacing.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Funding
 References
 
Study population
Seventeen consecutive heart failure patients with ischaemic or non-ischaemic dilated cardiomyopathy were enrolled in the study according to the following criteria: New York Heart Association (NYHA) functional class III–IV and an impaired LV ejection fraction (EF) <35%. A good acoustic window and sinus rhythm was required. Electrical conduction delay reflected by the QRS-duration was disregarded as an inclusion criterion given the prevalence of mechanical dyssynchrony in patients with a small QRS-complex and vice versa.17Go Chronic medications were unchanged (digoxin, beta-blocker, ACE-inhibitor/AII-antagonist and diuretics). The local ethical committee approved the study protocol.

Transthoracic RT3DE
All patients were examined using a Sonos 7500 or iE33 echo machine (Philips Medical Systems, Eindhoven, The Netherlands). Both echo machines were equipped with a matrix transducer. Transthoracic apical acquisitions were made during a 5–7 s breath-hold. Care was taken to include the entire LV volume within the pyramid-shaped 3D scan-volume. Specially designed software (Research-Arena 1.2.2TM 4D LV-Analysis, TomTec Imaging Systems, Munich, Germany) was used for quantification of global LV function and mechanical dyssynchrony. In apical long-axis planes of the LV, endocardial contours were semi-automatically detected during the complete cardiac cycle. On the basis of these contours, a LV cast as shown in Figure 1 was created. A global volume-time curve was generated and end-systolic volume (ESV), end-diastolic volume (EDV), and EF were obtained. The LV cast was divided into 16 pie-shaped subsegments, pointing towards a non-fixed central line of gravity between the apex and centre of mitral valve, and one additional apical segment. The segments correspond to the LV 17-segment model as described by the American Society of Echocardiography.18Go For each segment, a regional volume-time curve was generated, see Figure 2. The systolic dyssynchrony index (SDI17), based on the standard deviation of mean time-to-minimal-volume of 17 LV segments, starting from the R-top of the ECG was calculated.8Go To allow comparisons of different patients, time was calculated as percentage of the RR-interval.


Figure 1
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  		Figure 1 Real-time 3D echo (RT3DE) based end-diastolic left ventricular cast. Using post-processing software, the left ventricular cast can be divided in sub-volumes indicated by the lines on the left ventricular cast surface.

 


Figure 2
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  		Figure 2 Volume-time curves of the subsegments of the left ventricular cast of a heart failure patient. The standard deviation of mean time-to-minimal volume of the sub-segments was used for quantification of mechanical dyssynchrony (SDI17).

 
Evaluation of acute haemodynamic response
After the RT3DE exam, patients were scheduled for the biventricular pacing procedure. Via the femoral approach, under fluoroscopy, an 8-French guiding catheter (Cordis, USA) was introduced for access of the coronary sinus. A balloon-occlusive venogram of the coronary sinus and its tributaries was performed. A 0.014-inch pacing-wire, suitable for unipolar pacing (Biotronik, Berlin, Germany) was inserted in the postero-lateral branch of the coronary sinus. In addition, bipolar pacing catheters (Biotronik, Berlin, Germany) were positioned in the right atrial appendage and right ventricular (RV) apex. During simultaneous biventricular pacing, dP/dtmax was measured with a LV conductance catheter (CD Leycom, Zoetermeer, the Netherlands) and compared to the non-pacing mode. The atrioventricular delay was fixed at 100 ms providing the absence of fusion beats of patients underlying rhythm and pacemaker rhythm. During pacing, the percentual increase in dP/dtmax compared to the non-pacing mode at baseline ({Delta}dP/dtmax, %) was registered and used for further analysis. Other parameters that were measured during registration of the acute haemodynamic response were heart rate, LV EF, LV end-diastolic pressure, and LV end-systolic pressure.

Statistical analysis
Data were analyzed using standard statistical software (SPSS for Windows version 9.0, SPSS Inc., Chicago, USA) and presented as mean ± SD. Pearson’s correlation was used for measuring correlations. A value of P < 0.05 was considered as statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Funding
 References
 
Seventeen consecutive patients were included. Baseline characteristics are listed in Table 1, all patients were symptomatic (NYHA III) despite an optimized medical regime. Mechanical dyssynchrony SDI17 was 10.2 ± 4.2%. During temporary biventricular pacing, the LV lead was initially placed in the posterior part of the coronary sinus, which in most patients (76%) resulted in the highest increase of {Delta}dP/dtmax. However, results of pacing in the anterior part of the coronary sinus were also measured and resulted in the highest increase in {Delta}dP/dtmax in a minor group of patients (24%). Invasively measured haemodynamic data at baseline and the highest increase during biventricular pacing, in posterior or anterior part of the coronary sinus, are described in Table 2.


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  		Table 1 Baseline patient characteristics

 


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  		Table 2 Haemodynamic responses to biventricular pacing

 
Mean percentual increase in {Delta}dP/dtmax, during biventricular pacing compared to baseline, was 14.5 ± 12.4%. A significant correlation was observed between SDI17 and percentual {Delta}dP/dtmax during biventricular pacing (r = 0.729, P = 0.001), see Figure 3A. A similar significant correlation was found for the percentual {Delta}dP/dtmax and QRS width (r = 0.721, P = 0.001), see Figure 3B. Furthermore, QRS duration and SDI17 showed a significant correlation (r = 0.653, P = 0.004), see Figure 3C.


Figure 3
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  		Figure 3 (A) Correlation between systolic dyssynchrony index of 17 LV segments (SDI17) and percentual {Delta}dP/dtmax during biventricular pacing. (B) Correlation between QRS duration and percentual {Delta}dP/dtmax during biventricular pacing. (C) Correlation between QRS duration and SDI17.

 
Acute haemodynamic response in ischaemic vs. non-ischaemic cardiomyopathy
The study population consisted of seven patients with an ischaemic cardiomyopathy (64 ± 11 years, 5 male) and 10 patients with a non-ischaemic, idiopathic dilated cardiomyopathy (age 64 ± 15 years, 3 male). With a LV EF 33 ± 8% vs. 30 ± 11% (P = 0.595), LV EDV 134 ± 45 vs. 164 ± 74 mL (P = 0.375), QRS-duration 120 ± 28 vs. 147 ± 39 ms (P = 0.083) and SDI17 8.3 ± 3.6 vs. 11.2 ± 4.2% (P = 0.155) for non-ischaemic vs. ischaemic cardiomyopathy patients, respectively, no significant differences could be observed. A significant difference in {Delta}dP/dtmax was observed between ischaemic and non-ischaemic cardiomyopathy patients, 6.4 ± 8.6 and 20.2 ± 11.9% (P = 0.013), respectively. In ischaemic cardiomyopathy patients, no significant correlation between {Delta}dP/dtmax and SDI17 could be observed (r = 0.406, P = 0.366), whereas in non-ischaemic cardiomyopathy patients, a significant correlation could be observed between {Delta}dP/dtmax and SDI17 (r = 0.805, P = 0.005), see Figure 4.


Figure 4
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  		Figure 4 Correlation between systolic dyssynchrony index of 17 LV segments (SDI17) and percentual {Delta}dP/dtmax during biventricular pacing in non-ischaemic cardiomyopathy patients.

 
RT3DE segmental analysis of LV systolic contraction
As described earlier, RT3DE analysis revealed regional LV time-volume curves. Of each patient, the segments that showed minimal volume before and after global LV end-systole were scored. A variety of contraction patterns was observed: (i) delayed contraction of septal segments, without segments contracting before global end-systole (35%), (ii) delayed contraction of lateral segments, without segments contracting before global end-systole (12%), (iii) septal–anterior contraction pattern (12%), (iv) delayed contraction of inferior segments, without segments contracting before global end-systole (6%), (v) anterior–septal contraction pattern (6%), (vi) inferior–septal contraction pattern (6%), lateral–septal contraction pattern (6%), (vii) lateral–inferior contraction pattern (6%), (viii) septal–inferior contraction pattern (6%) or (ix) lateral–anterior contraction pattern (6%).

Discussion
The present study was conducted to evaluate whether RT3DE measured mechanical dyssynchrony, SDI17, correlated with invasively measured {Delta}dP/dtmax during biventricular pacing. Indeed, SDI17 showed a significant correlation with percentual {Delta}dP/dtmax. Subanalysis of ischaemic cardiomyopathy patients vs. non-ischaemic cardiomyopathy patients, demonstrated a significant higher increase of {Delta}dP/dtmax in non-ischaemic cardiomyopathy patients and a significant correlation between {Delta}dP/dtmax and SDI17 compared to ischaemic cardiomyopathy patients. Segmental analysis of contraction patterns showed classical septal–lateral delay, however, a substantial number of patients showed a delayed contraction of septal segments and other contraction patterns. Most patients showed highest increase in {Delta}dP/dtmax, while biventricular paced with LV lead in the posterior coronary sinus, however, some patients showed highest increase of {Delta}dP/dtmax with LV lead in the anterior coronary sinus. Although the study should be considered a pilot, the results suggest that RT3DE is a valuable tool for assessment of the magnitude of LV mechanical dyssynchrony in end-stage heart failure patients. This is reflected by the fact that SDI17 was significantly greater (10.8 ± 4.5%) than recently published SDI17.8Go,11Go Using this approach, the parameter percentual {Delta}dP/dtmax is, more than any other parameter, an adequate parameter for evaluating acute haemodynamic response to biventricular pacing, as it is considered a substitute for global LV contractile function and has demonstrated to be highly correlated to the degree of synchronous contraction among the LV walls.1Go,19Go In this respect, RT3DE, like other echo-guided parameters for the assessment of LV mechanical dyssynchrony, may facilitate the identification of heart failure patients who are likely to respond to cardiac resynchronization therapy. Moreover, the 3D coverage of the LV may prove to be superior to the single or 2D based imaging techniques. Direct head-to-head comparative studies between these different methods of mechanical dyssynchrony assessment are currently lacking and warrant further investigation.

There are, however, some important issues that hamper the interpretation of the current data. First, patients were included regardless of QRS width as it has recently been demonstrated that the absence of electrical conductance delay does not exclude the presence of LV mechanical dyssynchrony, and a minority of these patients may respond beneficially to cardiac resynchronization therapy.17Go This liberal inclusion approach, however, has led to a wide range of studied QRS durations that has facilitated the observed significant correlations between SDI17 and percentual {Delta}dP/dtmax, which otherwise may have remained obscured when only patients were included with electrical conduction delay. Consequently, a likewise good correlation was found between QRS width and percentual {Delta}dP/dtmax and, more importantly, RT3DE did not appear to more accurately predict the magnitude of LV systolic response improvement in comparison to QRS duration. However, this study focused on mechanical dyssynchrony assessed by RT3DE and its correlation with invasively measured acute haemodynamic response to biventricular pacing, therefore, the relation of invasively measured acute haemodynamic response and QRS duration was not a main topic in this study. Several studies that used TDI for assessment of mechanical dyssynchrony did not observe a correlation between QRS duration and mechanical dyssynchrony, in contrast to what was observed in the present study. This might be explained by the fact that TDI is influenced by angle dependency during acquisition and complexity during post-processing analysis. Furthermore, the use of high-frame rate during TDI imaging acquisition provides detailed temporal resolution of myocardial contraction, however, a very high-temporal resolution might result in oversensitivity of detection of mechanical dyssynchrony.

Second, acute haemodynamic responses were monitored in the present study and information about a long-term response is lacking and could have strengthened the results. On the other hand, previous studies have shown a good agreement between a favourable acute haemodynamic response and long-term follow-up response to biventricular pacing.20Go,21Go

Limitations
The number of studied patients in this pilot study was small and results should therefore be interpreted with caution. In addition, the small patient population prohibited the definition of a cutoff value for SDI17 in order to predict a response to biventricular pacing. Clearly, more studies in a larger number of patients are warranted.

Also, the effects of chronic medication as beta-blockers and digitalis, despite the fact that doses remained unchanged, might have hampered the conduction of the electrical signals during biventricular pacing and thereby being of influence at the measured results. Finally, the biventricular pacing protocol consisted of simultaneously biventricular pacing, one might imagine that sequential biventricular pacing, theoretically, might have led to further improvement of acute haemodynamic response.

Conclusions
The present study suggests that mechanical dyssynchrony measured by RT3DE shows a good correlation with invasively determined acute haemodynamic response to biventricular pacing in patients with symptomatic, primarily idiopathic dilated cardiomyopathy. Future studies are needed to further define the clinical utility of RT3DE in identifying patients who are most likely to respond to cardiac resynchronization therapy.


   Funding
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 Abstract
 Introduction
 Methods
 Results
 Funding
References
 
IKR is supported by ZonMW, grant number (945-05-016).

Conflict of interest: none declared.


   References
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 Abstract
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 Methods
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 Funding
 References
 
[1] Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M, et al. Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation (2000) 101:2703–9.[Abstract/Free Full Text]

[2] Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JW, Garrigue S, et al. Cardiac resynchronization therapy: part 1–issues before device implantation. J Am Coll Cardiol (2005) 46:2153–67. 20.[Abstract/Free Full Text]

[3] Yu CM, Abraham WT, Bax J, Chung E, Fedewa M, Ghio S, et al. Predictors of response to cardiac resynchronization therapy (PROSPECT)–study design. Am Heart J (2005) 149:600–5.[CrossRef][Web of Science][Medline]

[4] 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.[Abstract/Free Full Text]

[5] Pitzalis MV, Iacoviello M, Romito R, Guida P, De Tommasi E, Luzzi G, et al. Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy. J Am Coll Cardiol (2005) 45:65–9.[Abstract/Free Full Text]

[6] Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, et al. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation (2004) 110:66–73.[Abstract/Free Full Text]

[7] Yu CM, Zhang Q, Fung JW, Chan HC, Chan YS, Yip GW, et al. A novel tool to assess systolic asynchrony and identify responders of cardiac resynchronization therapy by tissue synchronization imaging. J Am Coll Cardiol (2005) 45:677–84.[Abstract/Free Full Text]

[8] Kapetanakis S, Kearney MT, Siva A, Gall N, Cooklin M, Monaghan MJ. Real-time three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation (2005) 112:992–1000.[Abstract/Free Full Text]

[9] Mannaerts HF, Van Der Heide JA, Kamp O, Papavassiliu T, Marcus JT, Beek A, et al. Quantification of left ventricular volumes and ejection fraction using freehand transthoracic three-dimensional echocardiography: comparison with magnetic resonance imaging. J Am Soc Echocardiogr (2003) 16:101–9.[CrossRef][Web of Science][Medline]

[10] Monaghan MJ. Role of real time 3D echocardiography in evaluating the left ventricle. Heart (2006) 92:131–6.[Free Full Text]

[11] van Dijk J, Dijkmans PA, Gotte MJ, Spreeuwenberg MD, Visser CA, Kamp O. Evaluation of global left ventricular function and mechanical dyssynchrony in patients with an asymptomatic left bundle branch block: a real-time 3D echocardiography study. Eur J Echocardiogr (2007) epub.

[12] Zhang Q, Fung JW, Auricchio A, Chan JY, Kum LC, Wu LW, et al. Differential change in left ventricular mass and regional wall thickness after cardiac resynchronization therapy for heart failure. Eur Heart J (2006) 27:1423–30.[Abstract/Free Full Text]

[13] Van Der Heide JA, Mannaerts HF, Spruijt HJ, van Campen LM, de Cock C, Visser CA, et al. Noninvasive mapping of left ventricular electromechanical asynchrony by three-dimensional echocardiography and semi-automatic contour detection. Am J Cardiol (2004) 94:1449–53.[CrossRef][Web of Science][Medline]

[14] Mansourati J, Etienne Y, Gilard M, Valls-Bertault V, Boschat J, Benditt DG, et al. Left ventricular-based pacing in patients with chronic heart failure: comparison of acute hemodynamic benefits according to underlying heart disease. Eur J Heart Fail (2000) 2:195–9.[CrossRef][Web of Science][Medline]

[15] Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation (1999) 99:1567–73.[Abstract/Free Full Text]

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[18] Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr (1989) 2:358–67.[Medline]

[19] Breithardt OA, Stellbrink C, Kramer AP, Sinha AM, Franke A, Salo R, et al. Echocardiographic quantification of left ventricular asynchrony predicts an acute hemodynamic benefit of cardiac resynchronization therapy. J Am Coll Cardiol (2002) 40:536–45.[Abstract/Free Full Text]

[20] van Campen CM, Visser FC, de Cock CC, Vos HS, Kamp O, Visser CA. Comparison of the haemodynamics of different pacing sites in patients undergoing resynchronisation treatment: need for individualisation of lead localisation. Heart (2006) 92:1795–800.[Abstract/Free Full Text]

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