Do we understand who benefits from resynchronisation therapy?

Ole A Breithardta,*, Piet Clausb and George R Sutherlandb

a Department of Cardiology, University Hospital Aachen, D-52057 Aachen, Germany
b Department of Cardiology, University Hospital Gasthuisberg, Catholic University Leuven, Belgium

* Corresponding author. Tel.: +49-2418089301; fax: +49-2418082414
E-mail address: olebreithardt{at}gmx.de

This editorial refers to "Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration"1 by S. Ghio et al. on page 571

Interest in ventricular dyssynchrony in heart failure patients has been renewed recently by the introduction of cardiac resynchronisation therapy (CRT). CRT is currently accepted as an adjunct to the medical treatment of symptomatic heart failure in patients with severe left ventricular systolic dysfunction and ECG manifestations of ventricular conduction delay.1 It aims to reduce the electrical conduction delay by pre-excitation of late-activated regions with left- or biventricular pacing to restore a more synchronous contraction pattern. Although this strategy has been proven to be effective at group level in large clinical trials, it is clear that up to 30% of such patients do not benefit from CRT. Part of the explanation for the failure of patient response may lie in the current suboptimal criteria used for patient selection. The clinically important question is to identify ventricular segments with delayed onset of contraction (active force development), as this represents regional function that can potentially be recruited by changing the sequence of electrical activation.

There is growing evidence that in patients with left bundle-branch block (LBBB), the timing and extent of mechanical dyssynchrony are poorly related to QRS duration and that assessment of mechanical dyssynchrony may help to better identify responders.2–4 The study of Ghio et al.5 reported in this issue highlights the poor predictive value of QRS duration for the identification of mechanical dyssynchrony. Moreover, it has been suggested, somewhat provocatively, that even patients with a normal QRS duration might benefit from CRT, provided that a correctable mechanical dyssynchrony can be identified.6 However, there remain many unsolved issues and methodological problems in the current criteria used for patient selection.

There is debate on which type of dyssynchrony is more important for the success of CRT: interventricular (delay between right and left ventricular contraction), intraventricular (within left ventricular walls), or both? Verbeek et al.7 examined this problem in animal experiments and demonstrated the haemodynamic importance of correcting intraventricular delays as opposed to correcting interventricular delays. Ghio et al.5 found a high prevalence of both inter- and intraventricular dyssynchrony, but only a moderate correlation between interventricular dyssynchrony by conventional Doppler and QRS duration. This correlation improved slightly after excluding patients with high pulmonary artery pressure, which may delay pulmonary valve opening. However, they failed to demonstrate any impact of dyssynchrony on patients' outcome. This issue was studied by Bader et al.8 who found intraventricular dyssynchrony to be of prognostic relevance, but not interventricular dyssynchrony.

The question remains – what are the best methods for identifying intraventricular mechanical dyssynchrony and determining the success of resynchronisation? The ideal imaging technique would be cost-efficient, widely available, easy to interpret, reproducible, and would allow the accurate identification of clinically important abnormalities in the timing of the onset of regional ventricular active force development. In addition, the technique should have a high enough sampling rate to resolve the mechanical events that must be detected. The normal left ventricle is both electrically and mechanically slightly asynchronous. Normal electrical dispersion (60–80 ms) within the left ventricle can result in delays of up to 40 ms between the earliest onset of systolic deformation in the apical septum compared to the later onset of activation in LV free walls.

Echocardiography, with its high temporal resolution, is the technique that may best fulfil the above criteria. Myocardial velocity imaging techniques (to evaluate either regional systolic velocity or deformation profiles) have been used to resolve the complexities in myocardial motion in heart failure. However, it remains unclear what degree of dyssynchrony is sufficiently abnormal to warrant CRT and how should such delays be detected? Regional longitudinal velocity profiles are temporally resolved and can be obtained from all ventricular segments. Yet systolic velocity profiles do not necessarily represent regional contractile function (contractility). The new ultrasound techniques of regional strain rate/strain estimation quantify parameters of regional deformation that are more closely related to local contractile function and are independent of overall heart motion. They should prove to be the optimal approach to evaluating recruitable function in asynchronous ventricles but are difficult to apply to dilated ventricles with thin walls because of current limitations in technology.

Some investigators have measured time-to-onset of regional systolic motion,5,8 while others have measured time-to-peak systolic motion2 or focused on postsystolic events.9 Intuitively, the earlier a systolic parameter is measured, the less it is affected by either segment interaction or loading conditions. Thus, the approach taken by Ghio et al.,5 the measurement of time-to-onset of systolic motion, would seem to be a more appropriate parameter of dyssynchrony than time-to-peak systolic velocity. The latter shows some variability, even in healthy individuals, and may be difficult to identify due to a systolic velocity plateau. Velocity-based parameters are also more affected by tethering effects, as has been demonstrated in a direct comparison of velocity data with the sequence of myocardial deformation obtained by strain/strain-rate imaging (SRI),4 which showed that the sequence of septal–lateral motion does not always correlate to the sequence of deformation obtained by SRI.

Sogaard et al.9 observed that CRT may reduce postsystolic shortening (PSS, so-called "delayed longitudinal contraction"). In LBBB, the presence of PSS may be due to delayed segment activation with delayed onset of contraction, thus indicating recruitable function by resynchronisation. However, PSS does not necessarily represent late contraction: in ischaemia, the presence of PSS with a concomitant reduction in end-systolic strain is a passive phenomenon due to segment interaction and does not represent recruitable function. The trick to identifying suitable candidates for CRT is to distinguish between the two situations, because resynchronising ischaemic segments in dilated ventricles with marked PSS will have no important functional effect.10 PSS can also be a normal finding when it is less than 10% of systolic shortening.

In summary, echocardiography is an indispensable tool in the assessment and management of patients with heart failure. Recent evidence suggests that the identification of left ventricular mechanical dyssynchrony is of prognostic value and has important implications for the selection of therapy. It remains unclear if there is an added benefit to identifying coexisting marked interventricular dyssynchrony prior to CRT. Moreover, the role of interatrial dyssynchrony has yet to be understood. However, the use of the various echo modalities requires sound knowledge of the pathophysiology of dyssynchrony and of the benefits and limitations of each ultrasound technique. Patient selection for CRT should be based on the combination of QRS duration, as a rough marker of potential mechanical dyssynchrony, and an echocardiographic study to determine its presence, but the optimal ultrasound technique has not yet been established. Thus, large, controlled randomised trials will be required to prove the clinical efficacy of an ultrasound-based approach in improving on current guidelines.

Footnotes

1 10.1016/j.ehj.2003.09.030 Back

References

  1. Gregoratos G, Abrams J, Epstein AE et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J. Am. Coll. Cardiol. 2002;40(9):1703–1719.[CrossRef][Medline]
  2. Yu CM, Fung WH, Lin H et al. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am. J. Cardiol. 2002;91(6):684–688.[CrossRef]
  3. Sogaard P, Egeblad H, Pedersen AK et al. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation. 2002;106(16):2078–2084.[Abstract/Free Full Text]
  4. Breithardt OA, Stellbrink C, Herbots L et al. Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle-branch block. J. Am. Coll. Cardiol. 2003;42(3):486–494.[CrossRef][Medline]
  5. Ghio S, Constantin C, Klersy C et al. Interventricular and intraventricular dyssynchrony are common in patients with heart failure, regardless of QRS duration. Eur Heart J. 2004;25:571–781.[Abstract/Free Full Text]
  6. Achilli A, Sassara M, Ficili S et al. Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and "narrow" QRS. J. Am. Coll. Cardiol. 2003;42(12):2117–2124.[CrossRef][Medline]
  7. Verbeek XA, Vernooy K, Peschar M et al. Quantification of interventricular asynchrony during LBBB and ventricular pacing. Am. J. Physiol. Heart Circ. Physiol. 2002;283(4):H1370–H1378.[Abstract/Free Full Text]
  8. Bader H, Garrigue S, 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(2):248–256.[CrossRef][Medline]
  9. Sogaard P, Egeblad H, Kim W et al. Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J. Am. Coll. Cardiol. 2002;40(4):723–730.[CrossRef][Medline]
  10. Claus P, Bijnens B, Breithardt OA et al. Why ischemic hearts respond less to cardiac resynchronisation therapy. A modeling study. In: Magnin IE, Montagnat J, Clarysse P et al., editors. Functional imaging and modeling of the heart. 2003. p. 287–94.

Related articles in EHJ:

Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration
Stefano Ghio, Cristina Constantin, Catherine Klersy, Alessandra Serio, Alessandra Fontana, Carlo Campana, and Luigi Tavazzi
EHJ 2004 25: 571-578. [Abstract] [Full Text]