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Cardiac Resynchronization Therapy—Evolving Strategies to Enhance Response

although a surrogate for ventricular dyssynchrony, is not predictive of acute and long-term response to CRT. The imprecision in the ability of surface QRS to predict response is explained by the complexity and multiple levels of electrical and mechanical dyssynchrony in the myopathic heart. This dyssynchrony can exist at numerous levels and can be inter-atrial, atrio-ventricular, inter-ventricular, intra-ventricular, or intramural. 6 Most studies have emphasized the importance of intra-Abstract Cardiac resynchronization therapy (CRT) has gained widespread acceptance as a safe and effective therapeutic strategy for congestive heart failure (CHF) refractory to optimal medical therapy. The use of implantable devices has substantially altered the natural history of systolic heart failure. These devices exert their physiological impact through ventricular remodeling, associated with a reduction in left ventricular (LV) volumes and an improvement in ejection fraction (EF). Several prospective randomized studies have shown that this in turn translates into long-term clinical benefits such as improved quality of life, increased functional capacity, and reduction in hospitalization for heart failure and overall mortality. Despite these obvious benefits, there remain more than a few unresolved concerns, the most important being that up to one-third of patients treated with CRT do not derive any detectable benefit. There are several determinants of successful delivery and response to CRT, including selecting the appropriate patient, patient-specific optimal LV pacing lead placement, and appropriate post-implant device care and follow-up. This article highlights the importance of collectively working on all of these aspects of CRT to enhance and maximize response.

To further complicate matters, we now know that there is considerable inconsistency in the clinical response between patients with left bundle branch block (LBBB) and non-LBBB morphology. Characteristically, LBBB is linked with a U-shaped activation pattern that courses the apex with delayed activation of the lateral and postero-lateral portion of the LV. 9 This spread of electrical activity parallels the mechanical activation, and constitutes the basic reasoning behind the conventional LV lead implantation strategy of targeting the lateral wall. Even in a pure LBBB, there remains a high level of heterogeneity in the LV activation pattern, accompanied by a wide variance in the line of functional block. 10 Recent work has suggested that within patients with a non-LBBB morphology, a non-specific intra-ventricular conduction defect (IVCD) subset has a poorer outcome, while those with right bundle branch block (RBBB) fare even worse. 11 Also noteworthy is that patients with an RBBB have a 3. 5 13,14 There remains, however, a lack of standardization in accepted measures, as well as several limitations to this technology. TDI is still predominantly a 2D technique and the need for high frame rates required by this technique limits resolution and image quality. Also, on account of its angle dependence, TDI allows only specific views of the cardiac anatomy. Strain-rate imaging constitutes one of the newer echocardiographic imaging strategies, and is being prospectively evaluated as part of several ongoing studies. Also, of late, realtime 3D ultrasound, which allows for simultaneous imaging of all of the cardiac segments in a cardiac cycle with new segmental wall volume techniques, may provide a better understanding of the extent of cardiac dyssynchrony during the same cardiac cycle (see Figure 1).
Since most of the imaging modalities provide complementary information regarding cardiac structure (e.g. fluoroscopy for coronary venous anatomy) and function (e.g. echocardiography for mechanical dyssynchrony), combining some of these technologies may help improve the diagnosis and facilitate the planning of treatment and delivery of pacing therapy in patients receiving CRT (see Figure 2). 15,16 Data from small retrospective studies have shown that pacing over the site with maximal discordance and avoiding a region of scar may result in a better outcome. 17,18 Current use of intra-procedural echo to demonstrate the most delayed segment to guide LV lead placement is cumbersome and technically challenging. Hence, pre-procedural evaluation of mechanical dyssynchrony and intra-procedural integration with venous mapping may be a useful strategy, but still needs to be effectively developed and tested prospectively. 15 Single imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) have the potential to provide both anatomical and functional information, thereby obviating the need for image-integration strategies. Multidetector CT (MDCT) has the potential to provide important information pertinent to: the coronary venous anatomy, i.e. distribution of tributaries, patency, and luminal size of the coronary veins; LV contractile function; localization of scar; mechanical dyssynchrony; and integrated information regarding the relationship of the venous branch with the segment of dyssynchrony and/or scar. 19,20 MRI is actively being evaluated for its ability to more precisely quantify dyssynchrony and better select patients. Currently, work at the MRI level is also focusing on the development of novel methods to characterize myocardial fiber architecture and ultrastructure and 3D

Implantation Strategies
So far, the approach for lead positioning has been rather simplistic and has been typically directed at placement of the lead along the lateral wall of the LV. Data from small retrospective studies have shown that pacing over the site with maximal discordance may have better reverse remodeling and an improved clinical outcome. In all of these studies, the assessment of the lead-segment relationship was a retrospective assumption without true image integration. Nevertheless, these and other studies have shown that reversal of mechanical dyssynchrony and improved remodeling of the heart is the primary underlying mechanism for improvement with CRT.
The importance of venous angiography during LV lead implantation cannot be overemphasized. As our understanding of CRT has evolved, it has become clear that a venous map helps us individualize our approach by selecting the most suitable lead for the appropriate branch anatomy (see Figure 3). Also important is the need for a segmental shown that pacing from a site with more delayed electrical activation, as assessed by an LV lead electrical delay greater than half the width of the baseline QRS (LVLED >50%), is associated with a beneficial acute hemodynamic response (measured as percentage change in dP/dt) and an improved long-term outcome (see Figure 4). 24 Recent work has also suggested that site-specific pacing over the segments with dyssynchrony may be associated with a better clinical outcome. 18 Another important aspect of LV lead placement relates to physical separation between the two pacing electrodes. 25 However, there is still no conclusive study delineating whether the best lead implantation approach is targeting the most electrically delayed segment, lead

Follow-up Strategies
A new genre of ambulatory heart failure patients with implanted devices has resulted from the high prevalence of heart failure and increasing patient population eligible for device therapy. This is a frail group of patients needing care from their primary cardiologist, electrophysiologist, and heart failure specialist, often with additional input from an imaging (echocardiography) specialist (see Figure 5). Most centers lack a form of structured cross-talk between the cardiac sub-specialties and often several weeks may pass between individual sub-specialty evaluations, resulting in disjointed and often sub-optimal medical care. Current postdevice-implant care is deficient on many fronts, namely consideration of device diagnostic information and utilization of such data to titrate medications, enhance device response in patients, and, more importantly, enable early identification and treatment of non-responders.
There is a certain level of reticence when it comes to proactively optimizing the atrio-ventricular and inter-ventricular timings of these devices to maximize the stroke volume. Several studies have now demonstrated that device optimization facilitates functional improvement and increases the extent of reverse remodeling. [28][29][30][31] Non-responsive patients usually come to attention via a heart failure exacerbation or a hospitalization, and one of the goals of an integrated healthcare delivery program is to detect problems early, with proactive modification of the drug regimen or device settings to prevent acute disease decompensation. Having all the disciplines work together can facilitate better patient selection, CRT device optimization, and careful titration of medical therapy in the postimplantation period. A multidisciplinary clinic provides an ideal structure for consultation between different specialties to allow these data to be used more efficiently in the care of these patients. Although it appears intuitive that this multispecialty model would translate into better patient care, the impact of such integrated services still needs to be prospectively assessed.
CRT devices record and provide detailed information pertinent to patient activity, heart rate, autonomic activity, and transthoracic impedance, and in the near future they will also provide realtime hemodynamic data. 32 The recent advent of remote monitoring of these devices has enabled the realtime automatic transmission of ambulatory information regarding heart rate, physical activity, development of incipient pulmonary edema (transthoracic impedance measure), etc., via the Internet. Although this may result in a risk of information overload, it provides the opportunity to enhance the quality of patient care and identify non-responders well before they actually decompensate. Also, ongoing work to enhance sensor technology has enabled over-the-web transmission of other

Conclusion
Although CRT has had a large impact on the field of heart failure, its complete potential has not been realized. Over the next few years, our understanding of ventricular mechanical dyssynchrony along with substrate-and pacing-site-specific response will improve, enabling wider As the population eligible for device therapy rapidly expands, the need to be more cognizant of its cost-effectiveness and to refine the selection criteria will become more important. In order to maximize the level of response derived from device therapy, we have to make certain that we not only select the appropriate patient but also