© 2008 European Society of Cardiology
Mechanical dyssynchrony in CRT patients: Still searching for the Holy Grail!
Division of Cardiology, Fondazione Cardiocentro Ticino Lugano, Switzerland
* Corresponding author. Division of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, 6900 Lugano, Switzerland. Tel.: +41 91 805 3340; fax: +41 91 805 3167. E-mail address: angelo.auricchio{at}cardiocentro.org (A. Auricchio).
Received January 22, 2008; Mechanical dyssynchrony, i.e. the disparity in regional contraction timing, has been proposed as an alternative to QRS duration for selecting the most optimal candidates for Cardiac Resynchronization Therapy (CRT). Indeed, about 30% of seemingly appropriate patients based upon QRS duration do not experience clinical benefit. Furthermore, mechanical dyssynchrony has been found to be an independent predictor of clinical events and worsened survival in HF patients [1,2]. Given the suspicion that mechanical rather than electrical dyssynchrony could be better for identifying heart failure patients as candidates for CRT, investigators started looking for new and easier ways to quantify mechanical dyssynchrony. Over recent years, such work has yielded many new approaches, most based on ultrasound and advanced tissue Doppler imaging (TDI) methods [3]. However, significant concern about the use of TDI methods for selection of CRT patients was recently highlighted by the PROSPECT (Predictors of response to Cardiac Resynchronization Therapy) trial [4]. The PROSPECT study examined the reproducibility and predictive value (response to CRT) of many echo and TDI indexes of dyssynchrony. Despite specific training in imaging methods in nearly all 50 centres participating in the study to enhance the uniformity of the methodology, and the fact that the data were interpreted by 3 blinded core laboratories, there was marked variability in the analysis of identical images between the core centres. While some indexes did correlate with CRT response, their sensitivity and specificity was fairly poor. As more work is needed to achieve an adequately robust and applicable approach to dyssynchrony assessment, investigators have started to look into alternatives to TDI-based indexes.
In this issue of the European Journal of Heart Failure, Cazeau et al. [5] and De Boeck et al. [6] report on different approaches which individually may be considered as reasonable alternatives to TDI-derived parameters for quantifying mechanical dyssynchrony in CRT candidates, and are therefore welcomed. Moreover, the authors discuss the inherent shortcomings of the TDI technique and poorly defined conventions about acquisition and measurement methodology. We acknowledge that sensitive imaging tools have been developed but these are susceptible to user variability of both image acquisition and analysis, and this may limit the reliability of the results. Derivation of these indexes often requires some subjective assessment of which peaks reflect which motion, and this is not always straightforward to interpret. In addition, range of normality has been evaluated for time-to-peak TDI and real-time 3D echocardiography, but has not been confirmed by independent investigators, in a large cohort and in a real-life scenario. Moreover, control groups and normal range of normality has not yet been defined for the vast majority of parameters measuring mechanical dyssynchrony; obviously, this has major clinical implications for patient screening purposes. Another related but important question is whether in the same healthy person, different echocardiography methods agree with each other. At the present time, only one study has evaluated the degree of concordance between standard echocardiography parameters and TDI, concluding that agreement was poor [7]. Finally, few if any studies have examined repeated assessments of dyssynchrony made by different operators blinded to the other measurements, with the variance then determined.
We congratulate Cazeau and the DESIRE investigators, because they have evaluated a new CRT population, i.e. heart failure patients with narrow QRS duration [5]. Other investigators have also recently started to look into different heart failure patient populations for implementing CRT. All have been particularly intrigued to find significant mechanical dyssynchrony even in patients with normal QRS duration. Early studies of HF patients with mechanical dyssynchrony and narrow QRS complex reported improvements with chronic CRT. Achilli et al. [8] first tested this hypothesis in 14 patients and found beneficial effects of CRT on clinical and echocardiographic parameters similar to those in wide-QRS HF patients. This finding was recently confirmed by other study groups. Both Bleeker et al. [9] and Yu et al. [10] found that CRT improved exercise capacity, symptoms, and echocardiographic function regardless of the QRS duration. In contrast to other studies, including the RethinQ (Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) trial [11], Cazeau et al. [5] propose a different, yet simpler, analysis of atrioventricular, interventricular and in particular, intraventricular dyssynchrony (not based on advanced TDI techniques). Patients were defined as having mechanical dyssynchrony if at least one or more criteria at any level (atrioventricular, interventricular and left intraventricular delay) was found. All echo recordings were centrally analyzed by physicians experienced in both cardiac pacing and echo assessment. A minority of patients included in the DESIRE study (27 out of 60 patients, 45%) had any evidence of atrioventricular (left ventricular filling time <40% of the cardiac cycle), interventricular (interventricular delay >40 ms), or intraventricular (left ventricular pre-ejection time >140 ms or diastolic contraction of LV free wall) dyssynchrony, or a combination of one or more of these criteria at the baseline evaluation. Intraventricular dyssynchrony is usually considered more relevant than interventricular dyssynchrony for achieving good results with CRT, the former being present in about 19 patients (32%). Thus, one would expect that a significant proportion of patients would not benefit from CRT. Surprisingly enough, 33 of these 60 patients were clinically improved at short term follow-up; a higher proportion of patients with mechanical dyssynchrony (19 of 27 patients, 70%) showed clinical benefit compared to 14 out of 33 patients (42%) who did not show any mechanical dyssynchrony at baseline evaluation. Putting these results in the context of other uncontrolled trials of similar size in narrow QRS patients, we noticed that the proportion of responders to CRT was of the same order of magnitude. Thus, simple or advanced echocardiographic screening methods have limited applicability to patients with narrow QRS duration and their sensitivity and specificity in predicting responders to CRT is modest or moderate.
There are a few further caveats which should be considered before widely applying the diagnostic criteria proposed by Cazeau et al. [5] in patients with narrow QRS complex. The study by Cazeau et al. [5] did not use a true control group or was not blinded, because all patients received treatment, and the follow-up period was relatively short (3 to 6 months). This limitation equally applies to all previous studies including patients with narrow QRS. Clinical placebo effects, including improved exercise capacity and symptoms from CRT, have been documented [12], and, although this may or may not apply to image-based assessments, bias is difficult to fully exclude when the therapy is known. Moreover, the recently published results of the RethinQ study [12] are also very relevant to our discussion. The RethinQ trial looked at CRT in 172 patients with heart failure (EF <35%), and a narrow QRS complex, but with mechanical dyssynchrony, with the majority of patients (96%) enrolled based on the opposite wall delay method by colour tissue Doppler imaging [12]. In this randomised 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-minute walk, and LV volumes/EF at 6 months. These findings contradict previously published small, uncontrolled studies and clearly indicate that when translating results from small non-randomised trials to large controlled prospective trials, results might differ considerably. Moreover, the potential reasons for the RethinQ results, which obviously could also apply to the DESIRE study, might include problems 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.
The results of the DESIRE trial support the findings by De Boeck et al. [6]. De Boeck et al. [6] are to be congratulated because their study is very thorough and precise, and sheds additional light on the reasons why TDI parameters have failed to accurately and consistently predict reverse remodelling with CRT. The study by De Boeck et al. [6] is a single centre, prospective observational trial. The study included 46 typical CRT candidates. In addition to TDI parameters, the investigators evaluated mechanical dyssynchrony using 2D strain, a visual assessment of the ventricular motion, and measured BNP plasma levels. The end-point was prediction of significant ventricular reverse remodelling, i.e. change in left ventricular end-systolic volume of at least 15% of baseline volume. Intriguingly enough the most simple echocardiographic valuation, visual asynchrony scoring, was a better predictor than any TDI-derived measurement. This might indicate that experienced investigators are able to capture small, yet relevant wall motion abnormalities which are correctable by CRT. According to De Boeck et al. [6] longitudinal strain evaluation appeared a robust predictor of volume response to CRT; this parameter performed better than TDI-derived septal to lateral delays of peak velocities and the standard deviation. Although from a conceptual point of view this may be also true, a large prospective randomised trial is needed to confirm this approach.
In conclusion, both the DESIRE trial [5] and the study by De Boeck at al. [6] show that the extraordinary complexity of asynchrony makes it unlikely that any single asynchrony parameter will be able to reliably predict response to CRT, no matter how it is defined. A multi-imaging modality approach is most likely required which however will undoubtedly lead to a significant increase in the use of both human and financial resources. Given the uncertainty about which imaging modality is the gold standard for measuring mechanical dyssynchrony (Magnetic Resonance Imaging, Cardiac Computer Tomography, advanced echocardiographic techniques, etc.), the cost-benefit of this extra work and whether it is worth doing, are unknown. Indeed, we should probably admit that CRT, like any other pharmacological and non-pharmacological therapy for heart failure cannot achieve reasonable results in some patients, just because they are "beyond repair".
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