Europace Advance Access originally published online on May 14, 2008
Europace 2008 10(7):797-800; doi:10.1093/europace/eun127
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REVIEWS
Update on the pathophysiological basics of cardiac resynchronization therapy
1 Division of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, 6900 Lugano, Switzerland; 2 Department of Physiology, Maastricht University, Maastricht, The Netherlands
Manuscript submitted 21 March 2008. Accepted after revision 22 April 2008.
* Corresponding author. Tel: +41 91 805 3340; fax: +41 91 805 3167. E-mail address: angelo.auricchio{at}cardiocentro.org
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Abstract |
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 Top Abstract IntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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Cardiac resynchronization therapy is an established treatment for patients with severe heart failure and ventricular conduction disturbance. Cardiac resynchronization therapy improves cardiac pump function and clinical status, and reduces morbidity and mortality. This electrical treatment for heart failure has also contributed enormously to the understanding of the pathophysiology of ventricular conduction disturbance. This article highlights the latest findings about the pathophysiology of ventricular conduction disturbance and pacing as well as that of resynchronization, with emphasis on the role of regional mechanical performance in triggering remodeling processes involved and on the selection of patients using mechanical dyssynchrony.
Key Words: Cardiac resynchronization therapy, Heart failure, Physiology, Ventricular activation, Echocardiography
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Introduction |
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TopAbstractIntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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Cardiac resynchronization therapy (CRT) has become an established treatment for patients with severe heart failure and ventricular conduction disturbance (VCD). Cardiac resynchronization therapy improves cardiac pump function and clinical status, and reduces morbidity and mortality. Cardiac resynchronization therapy has also contributed enormously to the understanding of the pathophysiology of VCD. The notion that artificial pacing or intrinsic VCD may elicit cardiac remodelling, is recent,1
–4 as is the knowledge that spontaneous or pacing-induced VCD may increase morbidity and mortality.5,6 Below we will discuss the latest findings about the pathophysiology of VCD and pacing as well as that of resynchronization, with emphasis on the role of regional mechanical performance in triggering remodelling processes involved and on the selection of patients using mechanical dyssynchrony. |
Regional loading and gene expression in ventricular conduction disturbance |
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TopAbstractIntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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Mechanical dyssynchrony, i.e. the disparity in regional contraction timing, is a clear consequence of ventricular pacing and VCD. Early activation leads to early, but unloaded contraction, whereas late-activated regions are being pre-stretched during early systole, which subsequently results in enhanced systolic contraction. The latter results from local activation of the Frank–Starling mechanism. As a result, systolic stress and strain as well as external work are reduced in early-activated regions and increased in late-activated regions.7
The opposing length changes during systole are, most likely, also responsible for the loss of pumping efficiency. i.e. oxygen cost for the myocardium is higher for the same pump work.8 After all, mechanical energy generated by regions, which are shortening, is absorbed by stretched regions rather than resulting into ejection of blood or pressure generation. Because oxygen consumption is tightly coupled to coronary flow volume and patients often have a compromised coronary reserve, dyssynchrony further reduces this coronary reserve,9 thus increasing the risk for ischemic heart disease (Figure 1).
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The differences in stresses and strains within the left ventricular (LV) of patients with dyssynchrony are also the most likely explanation for the regional differences in remodelling processes in asynchronous ventricles (Figure 1).
Studies in the canine heart with left bundle branch block (LBBB) showed that, at the tissue level, LBBB leads to hypertrophy within 2 months, especially in the late-activated LV lateral wall, the region where mechanical work is increased.2 Similar differences in regional wall thickness have been found in patients with LBBB.10 Cardiac resynchronization therapy normalizes the distribution of regional workload in LBBB dogs and leads to disappearance of the regional differences in hypertrophy within 2 months.11 Recent human data are quite consistent with these findings, showing a more homogeneous distribution of wall mass after CRT.12
Remodelling is also expressed at the level of individual genes, characterizing properties of myocytes and/or extracellular matrix. One week of ventricular pacing in the mouse heart resulted in differential expression between LV septal and lateral wall in 18 of the 22 000 genes surveyed.13 Seven of these genes encode for proteins involved with stretch responses, matrix remodelling, stem cell differentiation to myocyte lineage, and Purkinje fibre differentiation.13 A recent study in canine LBBB hearts showed that rapid biventricular pacing reduced interstitial remodelling, TNF-
expression, and apoptosis when compared with rapid atrial pacing.14 In further support of the idea that CRT reverses the various remodelling processes, recent publications on patient studies report favourable changes in the expression of genes regulating contractile function and pathological hypertrophy within a few months after CRT.15,16 After CRT, increased mRNA levels were found for of -myosin heavy chain and for the ratio of -to-β-myosin heavy chain as well as of the ratio between sarcoplasmatic reticulum calcium ATPase 2 and phospholamban. Moreover, expression of brain natriuretic peptide mRNA was reduced. These findings point to a reduction in the expression of the foetal gene programme.
A special interest relates to electrical remodelling in the chronically asynchronous heart. Spragg et al.4 showed that after 4 weeks of LBBB, action potential duration (APD) and refractory period are reduced in the late-activated lateral wall. Somewhat different, but equally interesting data were reported recently by Jeyaraj et al.17 This group showed that 4 weeks of LV pacing in dogs produced a biphasic spatial distribution of APD changes, with APD prolongation in the earliest regions, APD shortening in regions with intermediate activation time, and considerable APD prolongation in the latest activated regions. In addition to the above-mentioned changes in APD, also conduction velocity was shown to be reduced in the late-activated regions.4 Moreover, normal differences in conduction velocity between endocardium and epicardium were reversed in the late-activated lateral LV wall.4 While the total expression of connexin43 was unaltered in LBBB hearts, its subcellular location was redistributed in late-activated myocardium from intercalated discs to lateral myocyte membranes.4 The shortening of the APD in late-activated regions of LBBB hearts compensates, at least partly, for the delay in activation, thus limiting the increase in dispersion of repolarization due to asynchronous activation, as shown in the paced rabbit heart.18 Jeyaraj et al.17 showed in LV paced canine hearts that there is evidence that the electrical remodelling is linked to the difference in mechanical load (‘mechano-electrical feedback’). A similar finding was reported by the group of Rosen, studying ‘cardiac memory’.19 These investigators showed that in isolated rabbit hearts, the larger the T-wave changes were the higher the LV pressure was and were even able to induce the T-wave memory by simply stretching the myocardium locally.
Therefore, the regional differences in mechanic load in dyssynchronous hearts appear to be an important trigger for many differential changes in the heart.
Abnormal calcium handling, decreased gap junction expression and longer conduction time may result in increased arrhythmia susceptibility. Left ventricular chamber hypertrophy, dilatation, and reduced efficiency in the face of reduced coronary reserve lead to increased ischaemia susceptibility, creating a vicious cycle that perpetuates this process into more advanced heart failure and higher risk of sudden cardiac death. As a result, when comparing patients with similar degree of LV dysfunction, those with LBBB, VCD, or right ventricular pacing have a worse overall prognosis.5,6 The reversal of at least several remodelling processes in many CRT patients is presumably the explanation of the favourable impact of CRT on total morbidity and mortality.20 Least clear is the benefit of CRT for sudden cardiac death. Whereas reversal of the aforementioned remodelling processes can be expected to reduce the risk for arrhythmia, some reports suggest that the epicardial LV stimulation may induce arrhythmias, at least in a subset of patients.21
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Patient selection using mechanical dyssynchrony |
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TopAbstractIntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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Based on the important role of abnormal regional mechanical behaviour in dyssynchronous hearts, discussed above, it seems completely logical to use indices of mechanical dyssynchrony for selecting candidates for CRT, in addition or as an alternative to QRS duration. About 55–65% of the CRT patients show significant increase in LV ejection fraction and reduction of both systolic and diastolic volumes, and in 10–15% of these patients even normalization of LV ejection fraction and left ventricular volumes is noted. In contrast, a variable proportion (ranging from 30 to 40%) of seemingly appropriate patients (based upon QRS duration) do not respond to CRT by reverse remodelling, sometimes despite some clinical improvement.
Over recent years, the quest for quantification of mechanical dyssynchrony has yielded many new approaches, most based on ultrasound and advanced tissue Doppler imaging (TDI) methods.22 Recently, however, significant concern has been raised about the use of these echo-based methods for selection of CRT patients. The PROSPECT (Predictors of response to Cardiac Resynchronization Therapy) trial was a prospective, observational study performed in 53 centres and included 426 patients with heart failure and a standard CRT indication. While all echocardiographic measures predicted clinical response and reverse remodelling to some extent, sensitivity and specificity were low. It was concluded that no echo measure of mechanical dyssynchrony could be used to improve the selection of CRT patients.23 The RethinQ (Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS) study included 172 patients with a QRS duration <130 ms and a significant mechanical dyssynchrony, primarily based on TDI measures.24 After 6 months, no significant difference was observed in the change of peak oxygen consumption or cardiac dimensions between the control and CRT arm. Therefore, collectively, these studies showed that in the multicentre setting, assessment of mechanical dyssynchrony does not significantly improve the prediction of clinical and volumetric response to CRT beyond that achieved using QRS duration. These negative findings may be explained by the fact that deformations in dyssynchronous hearts are extremely complex, including large regional differences and multiphasic signals. Moreover, the echocardiographic indices used reflect only part of that complicated deformation pattern. Accordingly, only techniques providing comprehensive and reliable data on deformation can be expected to provide a good estimation of mechanical dyssynchrony. The recently introduced speckle tracking technique25 shows promising results.26
Another explanation for the poor performance of mechanical dyssynchrony measures in the large studies may be that time differences in, for example, onset or peak strain only partially reflect the loss of ventricular pump function. A more comprehensive impression of regional myocardial mechanics may be achieved from indices describing discoordination, i.e. the amount and/or distribution of stretch and shortening within the LV wall. Examples of such indices are the CURE index27 and the recently presented internal stretch fraction (ISF). With respect to the latter index, preliminary data indicate that distinction between CRT responders (defined as reduction in LVESV >15%) and non-responders can be made using ISF, but not using timing differences in onset and peak shortening, as measured by MRI tagging.28 Therefore, in the near future studies need to explore to what extent discoordination and dyssynchrony provide additive information on the prediction of the response of a patient to CRT.
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Conclusions |
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TopAbstractIntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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Ventricular conduction disturbance and mechanical dyssynchrony are an important co-morbidity in heart failure, as these depress LV function and worsen prognosis, independent from other factors, such as infarction and hypertension. Better methods are required for recognizing patients at risk for such poor prognosis, so that CRT is applied in the appropriate patients.
Conflict of interest: A.A. is a consultant for Medtronic and Sorin and has received research grants from Medtronic, Boston Scientific and St Jude Medical. F.W.P. is a consultant for Medtronic and has received research grants from Medtronic, Boston Scientific and EBR Systems Inc.
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References |
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TopAbstractIntroductionRegional loading and gene...Patient selection using...ConclusionsReferences |
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