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From bench to practice: cardiac resynchronisation therapy - from the basics to the outcome

Session presentations
Non-Invasive Imaging

Frits W Prinzen: The physiological basis of CRT
This speaker distinguished between guidelines indication for CRT such as QRS >120 ms, NYHA II-III heart failure and with a question mark for the usefulness of mechanical dyssynchrony versus physiological background LBBB with or without heart failure and discoordination rather than dyssynchrony. Discoordination better reflects the mechanical dyssynchrony caused by LBBB or prolongation of QRS.

Substudies of MADIT CRT show that CRT only helps in LBBB; morphology is neutral in RBBB and even has a negative effect in indeterminate QRS prolongation called IVCD. In experimental models, the concept of CRT reverses the abnormalities of contraction of induced LBBB.

CRT is an electrical therapy with an immediate effect on timing of contractility which results in increase in blood pressure and sets off the process of reverse remodeling. If CRT is turned off this effect is immediately lost as well as the reverse remodelling process. Prinzen also stressed that hemodynamic measures can predict benefit of CRT, i.e. baseline LV dP/dt ( > 650) was recently shown to predict survival by CRT, whereas increment LV dP/dt CRT was not.

He stressed that reverse remodelling is a long process which can be observed acutely but develops in full over time, at least over 2 years. In animal models, induced CRT causes hypertrophy of both the lateral and the septal wall accompanied by an increase in LV chamber size. 

In dog models, dilated cardiomyopathy causes regional differences in gene expression in the anterior and lateral wall. Importantly, CRT reverses gene expression both regarding hypertrophy and fibrosis; for example, captase in animal models both in septal and lateral walls. He discussed whether a delay in septal to lateral wall reflecting dyssynchrony is the best way to describe physiopathologic mechanism or whether septal rebound stretch reflecting discoordination is a more adequate description. There is a relationship between septal rebound stretch and septal work which is positively influenced by CRT. This measure of mechanical dyssynchrony has been predictive of significant reverse remodelling in a study of 62 patients and in another study of 101 patients treated with CRT was an independent predictor of morbidity and mortality.

My opinion: there is emerging evidence as to the important pathophysiological mechanisms of CRT from hemodynamic response to CRT, to how LBBB affects septal and lateral strain and how this may be overcome by CRT. Reverse remodelling, one of the key mechanisms of action, is linked to alterations of gene expression for both fibrosis and hypertrophy, which may highlight the comprehensive effects of myocardial contractility and metabolism present in responders to CRT. Even though mechanical dyssynchrony criteria are not in guidelines as a selection criteria for CRT, Prinzen highlighted some single centre studies that show incremental value in predicting response to CRT by the use of septal rebound stretch reflecting discoordination

Paul A Grayburn:  How to assess mechanical dyssynchrony

This presenter stressed the value of initial and easy to measure signs of mechanical dyssynchrony (MD) such as diastolic filling time/RR interval (should be > 50 and judged as abnormal when < 40) as well as Aortic and pulmonary pre-ejection intervals. Septal to lateral wall motion delay has clear difficulties. Newer ways to assess MD is speckle tracking, which is not angle dependant and therefore more reproducible and can be measured as radial, global strain, time to peak strain, Tissue Doppler standard deviations (SD) of 6, 12 or 18 segments. A new measure, strain delay index, can be calculated and has been shown to predict reverse remodeling. In MADIT CRT, studying CRTD vs ICD alone in mild heart failure, global strain rate was a better predictor of response in terms of heart failure-related hospitalisations or death than tissue Doppler SD 12 indicating that strain or speckle tracking are emerging methods to predict response to CRT.

My Opinion: There is numerous ways to measure MD and none has been shown to be significantly better than others. Older simple MD criteria still apply but Speckle tracking techniques are more reproducible and have been show to predict response to CRT e.g. in the MADIT CRT trial. This is tested in the ongoing randomised controlled trial, the Echo/CRT trial of patients with heart failure, QRS <130 ms 

Christophe Leclercq. Which parameters can predict improvement?
Some clinical parameters are linked to enhanced response to CRT, as judged by the RCTs in moderate or mild heart failure. There is no indication that older patients should be excluded from therapy. Both materials comparing the effects of CRT in patients >80 yrs of age compared to < 80 yrs of age showed the same benefit as well as the > 70 yrs of age or 70 yrs of age performed in the CARE HF study. Renal impairment may be an underemphasised but important underlying disease condition for predicting the effect of CRT. Bommels et al recently showed that pts with GFR < 60 ml/min did worse with CRT than those with higher GFR.

Importantly, and easy to overlook, a multidisciplinary approach to optimise device and medical therapy after CRT implantation by Altman et al showed that pts that were optimised had significantly better survival than those who did not.

Importantly, NYHA class IV patients do not derive a benefit from CRT or CRT-D as evidenced in the COMPANION trial. In concordance, a recent publication highlighted that patients who still have a relatively high functional capacity with 6 min walk distance of > 400 m before CRT do better than those who manage less. Poor RV function is also indicative of worse response to CRT.

LBBB patients do better than non-LBBB patients as seen in both in MADIT CRT and REVERSE, as well as the COMPANION trials.

An early drop in biomarkers such as BNP or BT proBNP by CRT is indicative of reverse remodeling and linked to response to CRT.

Substudies from several large RCT in mild and moderate heart failure indicate that patients with ischemic etiology experience less magnitude of reverse remodeling than pts with dilated cardiomyopathy, but still derive the same clinical benefit. Overall, they are sicker and have higher morbidity and mortality rates than non/ischemics patients. But in one recent study by Adelstein, if patients with scars were removed from those with ischemic cardiomyopathy, the benefit in morbidity/mortality rate equals that in non ischemic patients. Thus a number of parameters can predict response.

My opinion: A lot of important predictors of response and non response were highlighted in this insightful talk.
Female gender, LBBB, not having undergone myocardial infarction and QRS > 150 ms are amongst them.

Jose Ramon Gonzalez Juanatey: Which outcomes to select
This speaker emphasised the importance of reverse remodeling as a key mechanism for CRT response. In contrast to previous speakers, he indicated that CRT response was more marked in low GFR and made a parallel to betablocker response, which was also greater in pts with reduced GFR compared to normal renal function. BNP is important for diagnosis, prognosis and for guiding therapy and reductions related to the reverse remodeling process. There are also recent scores of response and superresponse to CRT in which measures of reverse remodelling, such as left atrial volume > 40 ml and left ventricular end systolic volume are strong parts of the predictive scores. Furthermore, the speaker stressed that the magnitude of reverse remodeling achieved by CRT is greater than what is achieved by betablockers and ACEI and ivabradine.

My opinion: These results indicate that use on clinical parameters but also echo-parameters can better predict which patients will derive benefit from CRT and by follow up of some of these measures such as reverse remodeling and BNP will be able to judge who is responding to therapy and take further actions in the non-responders.




From bench to practice: cardiac resynchronisation therapy - from the basics to the outcome

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.