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Dr. Victoria Delgado
Dr. Victoria Delgado, EACVI Board member, Scientific Documents Committee
Cardiac Resynchronization Therapy (CRT) is an established therapy for heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF), wide QRS - preferably left bundle branch block (LBBB) morphology and >150 ms duration - and who remain symptomatic (New York Heart Association (NYHA) class III-IV) despite optimal medical treatment. It has shown to be beneficial in terms of reducing morbidity and mortality and an extensive number of single-center and multicenter randomized clinical trials – the first of which were conducted in the early 1990s - have shown that CRT improves heart failure symptoms and left ventricular (LV) function and induces a significant reduction in LV volumes and mitral regurgitation.
When compared to other heart failure medical treatments, CRT is a long-term effective therapy. As a result of its sustained beneficial effect, it is not surprising that the European Society of Cardiology guidelines consider CRT a class I indication for patients with drug-refractory heart failure symptoms, LV ejection fraction <35%, and wide QRS complex (>120 ms). However, there are some issues which remain controversial and need ongoing research such as the selection of patients, the definition of response, efficacy of this therapy in patients with non- LBBB QRS morphology and intermediate duration (120-140 ms) and whether CRT optimization should be based on imaging or on electrocardiogram (ECG) or not be done at all.
Despite its beneficial effects, CRT still has a 30% non-response rate based on current inclusion criteria, which suggests inadequate specificity when patients are selected for CRT. Although the inclusion criteria for CRT implantation (New York Heart Association functional class III-IV heart failure symptoms despite optimized medical therapy, LV ejection fraction < 35%, and QRS duration >120) have not been significantly modified, other parameters might be helpful in assessing which patients are most likely to benefit from CRT and thus improve the selection process. These parameters are measurement of LV dyssynchrony, detection of the presence and extent of myocardial scar tissue, and assessment of the site of latest mechanical activation (positioning of the LV lead, targeted to the latest activated segment or just in posterolateral regions avoiding the LV apex).
Furthermore, it can be disputed what the definition of response is: either an improvement in symptoms or an improvement in LV systolic function and reserve remodeling. And perhaps improvement in survival would be a clear response, too. It has been shown that patients with QRS duration >140ms and patients with LBBB configuration show higher CRT response rates compared with patients with narrower QRS duration or with non-LBBB morphology. Non-invasive imaging techniques have proposed several parameters to characterize LV mechanical dyssynchrony. It has been demonstrated that LV mechanical dyssynchrony is an independent determinant of long-term survival, and therefore, the evaluation of this parameter in candidates for CRT seems clinically relevant.
Research has been done in 3D imaging modalities which are able to provide more robust and accurate parameters of LV mechanical dyssynchrony to predict CRT response and long-term survival. However, CRT response is not exclusively determined by LV mechanical dyssynchrony. There are other pathophysiological factors of importance, such as extent and location of myocardial scar and LV lead position which have been associated with response to CRT.
Current 3D imaging modalities, including echocardiography, magnetic resonance imaging (MRI) and nuclear imaging, provide comprehensive and robust information on the main determinants of CRT response: LV mechanical dyssynchrony and site of latest mechanical activation, extent and location of myocardial scar, and venous anatomy.
It can be questioned if imaging helps the efficacy of CRT in patients with non-LBBB QRS morphology and with intermediate duration (120-140 ms) as they do not seem to benefit from a reduction in all-cause mortality and heart failure hospitalizations such as patients with complete LBBB morphology. In patients who do not respond to CRT, optimization of device settings has been proposed in order to improve LV systolic function and symptoms. However, landmark trials have not consistently demonstrated a significant impact on the outcomes of patients who undergo CRT optimization versus patients in whom the settings of the device are not optimized. Of note, the trials included heterogeneous populations with patients who already showed a benefit to CRT and in whom optimization of the device may be unnecessary. Trials including patients who do not benefit from CRT would have been more appropriate to answer the question on the role of CRT optimization. Another discussion point is whether CRT optimization should be based on imaging or on ECG or perhaps not be done at all.
As it is thus clear that the current criteria for patient selection for CRT are not optimal, it will be worth looking into the role of personalized medicine in which all pathophysiological determinants of response to CRT are integrated and evaluated. This approach may prove to be helpful in further improving outcomes for patients. For instance, patients with significant LV dyssynchrony, no or minimal myocardial scar tissue (especially in the LV segments which are targeted by the LV lead) and with an LV lead placed at the site of latest activation are likely to benefit from CRT. However, the opposite is true for patients with more synchronous LV contraction, extensive myocardial scar (or transmural scar in the segments where the LV lead is positioned) or an LV lead position far from the site of latest activation (LV lead mismatch); they will most likely not benefit from CRT.
There is reason to believe that the implantation of the LV lead according to an integrative evaluation of LV dyssynchrony, site of latest activation and location and extent of myocardial scar is associated with increased rates of response and improved long-term survival. The selection of the appropriate imaging technique to evaluate these parameters will depend on the availability and expertise of the center and the presence/absence of specific characteristics of the patients. Taking all the above into account, echocardiography will remain the first choice imaging technique for the evaluation of patients eligible for CRT. The current echocardiographic technologies permit accurate assessment of LV dyssynchrony and identification of the site of latest mechanical activation and these data can be combined with the venous anatomy and the presence, transmural extent and location of scar tissue obtained with MRI or computed tomography. The potential of specific imaging software allowing for segmentation of MRI data displaying the cardiac veins in relation to the location of transmural scar has recently been demonstrated. It is without doubt that future studies will determine the precise role of non-invasive imaging in the selection of patients who are candidates for CRT.
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