2002: The Year of Resynchronization

A Review of the Concept of Resynchronization

Patients with congestive heart failure often also exhibit electrical disorder of various forms. The disease process itself, accompanied by its progressive pressure and volume overload in the left ventricle cause diffuse myocardial fibrosis resulting in abnormal intraventricular conduction. This process is probably the culprit of many deleterious electrical disorders noted in patients with progressive congestive heart failure. One notable consequence to slowed conduction is, obviously, the increase preponderance for these patients to develop malignant ventricular tachyarrhythmia. This issue has gained significant attention over the past decade and has been addressed by a multitude of multicenter clinical trials, which have enlightened us with convincing data regarding the complexity of the disorder, the inefficacy of most pharmacologic treatment and the usefulness of device therapy. Interestingly, it was also recognized that device therapy might be useful in the management of the other consequence of conduction delay, namely the mechanical delay that results in cardiac dyssynchrony. Assuming that the slight electrical slowing in the left ventricle in the form of intraventricular conduction delay (IVCD) is the key to progressive deterioration in the patient with dilated cardiomyopathy (regardless of its initial etiology) by way of initiating mechanical dyssynchrony, which in turn increases volume stress in the left ventricle, correction of such delay would not only improve mechanical performance but, hopefully, reverse the electrical-mechanical remodeling process. Such correction can be easily achieved by simultaneously activating the right and left ventricle, the so-called biventricular pacing. In addition to IVCD, many patients with cardiomyopathy are also noted to have moderate first-degree atrioventricular (AV) block. This seemingly mild disorder can further compromise cardiac output as the timing of atrial contraction would superimposed on passive ventricular filling during diastole, thus diminishing total ventricular filling. Therefore, the abnormally long AV timing also needs correction in order to optimize cardiac output. Hence, the artificial pacemaker is an ideal device for providing these patients with ventricular resynchronization and optimized AV delay. Clinical data also showed that the aforementioned conduction abnormalities to be progressive with over 80% of patients developing some degree of conduction delay; and importantly, the changes were noted to have independent prognostic values in terms of mortality.^1-4 One analysis⁵ showed direct correlation between the degree of ventricular conduction delay as measured by QRS duration and mortality (Figure 1). Implementation of CRT Interest in correcting ventricular dyssynchrony with artificial pacing has started in the early 1990s, and initial results were reported ranging from a case report to observational and anecdotal experiences to a prospective but non-randomized study. ^6-10 From those early clinical experiences, it was uniformly believed that left ventricular pacing added hemodynamic benefits. While a few investigators have reported that left ventricular pacing alone would be beneficial, ⁷ the majority of the opinions were to perform synchronous and simultaneous right and left ventricular pacing. The benefits from biventricular pacing were noted in many subjective and objective clinical variables and while the greatest improvement has been primarily subjective, such as the change in quality of life (as measured by various standardized questionnaires) and in New York Heart Association (NYHA) functional class, definite improvements were also noted in measured data, such as cardiac output, left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), 6-minute walk distance, and peak oxygen consumption with exercise.^6,9,11,12 The results of several non-randomized large studies were published in the 1990s, including the InSync (European) trial, showing, among other things, an improvement in NYHA class. The first studies using randomization methods are the PATH-CHF and MUSTIC clinical trials.^12-14 The results from the MUSTIC trial were the first to be published, showing the reproducible benefits from CRT as compared to the control group. Patients were randomized to either CRT or control and crossed-over after 3 months and during both periods, the CRT group was consistently better than the control group in terms of six-minute walk distance and peak oxygen consumption. Other clinical endpoints that are, perhaps, most important to the patients, including quality of life and the hospitalization days. A significant reduction in the number of hospitalization and hospitalization days were noted in the MUSTIC trial. Of interest, the number of hospitalization days decreased in the CRT group for heart failure as well as for all reasons, and this improvement was noted in other studies as well, such as the one published by group in Karolinska Institute.^15,16 In addition to the obvious beneficial effect on patient well being such reduction in hospitalization days may impact positively on cost of health care. Similar endpoints were also used in the three major randomized trials that were recently completed in the U.S., the MIRACLE, Contak-CD, and MIRACLE-ICD trials. The MIRACLE and MIRACLE-ICD trials were similar in design with the main difference being the use of biventricular pacemaker in the MIRACLE trial and biventricular ICD in the MIRACLE-ICD trial. In these trials, patients were randomized into control or CRT arms for six months and then all patients received CRT afterwards. Three variables, improvement in QOL, NYHA functional class, and 6-minute hall walk distance were used as primary endpoints. Significant improvement was noted in all three clinical parameters. Comparison of the results from the three trials is shown in Table 1. There are other clinical variables measured that were not included as primary endpoints. For example, in the MIRACLE trial, ¹⁷ changes in LVEF and left ventricular end-diastolic diameter (LVEDD) were also noted (Figure 3). An important distinction with CRT is in its effect on myocardial oxygen demand. Unlike some pharmacologic therapies, such as with the use of inotropic agent dobutamine, CRT does not increase oxygen demand (Figure 4). This beneficial effect is likely to improve the patient s overall prognosis, including mortality. This latter, important parameter is the main objective of the landmark clinical trial, the COMPANION study, which compares three forms of treatment: 1) optimized medical therapy alone; 2) medical therapy and CRT pacemaker; and 3) medical therapy and CRT ICD. This trial has recently been terminated early by its Data Safety and Monitoring Board (DSMB) after enrolling close to 2,000 patients because the significant difference in mortality was noted amongst the treatment arms. Implantation Techniques Implementation of biventricular pacing requires the additional lead for left ventricular pacing. In the early years of the investigation, epicardial leads were used predominantly.¹² With the observed morbidity with this procedure, alternative techniques were soon implemented. Nowadays, the standard procedure is using coronary sinus lead, ^8,18 although in some cases whereby CS lead could not be installed, epicardial lead insertion remains a viable option. Endocardial left ventricular implantation has also been reported by some investigators, using a transseptal approach. ¹⁹ Special delivery tools have been designed to facilitate CS lead implantation. The standard system involves placement of a guiding sheath into the coronary sinus and through which the CS lead can be advanced into the desired tributary. The main purpose of the guiding sheath is to provide stability and pushability of the CS lead during cannulation of the tributary. While there is still some controversy in terms of the choice of ideal site, it is generally agreed that the posterior or lateral tributary are the best suited sites as they provide access to the free wall of the left ventricle. The middle and anterior cardiac vein lie between the left and right ventricles and are therefore unlikely to provide access to the free wall. The coronary sinus implantation technique can be cumbersome. The reason for this is several folds. First of all, entry into the coronary sinus may not be trivial. The Thebesian valve (Figure 5) that covers the ostium of the coronary sinus can be prominent and prohibit easy access in as much as 10% of cases, based on autopsy report. Such prominent Thebesian valve would result in a superior displacement of the opening to the coronary sinus. This displacement of CS opening also distorts the angle of CS entry, thus the standard CS catheter designed for routine cardiac electrophysiology studies would not easily enter such CS os. In our experience, we encountered prominent Thebesian valve in 6 of our first 100 cases. In such a case, a special guiding sheath may be necessary to assist cannulation, such as shown in Figure 6, where an Amplatz (AL 2 or AL 3) Left coronary sheath was used. In the search of CS os, it would be useful to visualize the low posterior right atrium angiographically. For this reason, it would be wise to choose a catheter with lumen (Figure 6). This type of catheter would also be useful in a more systematic advancement into the coronary sinus proper. In particular, one would need to consider the presence of the Valve of Vieussens (Figure 7), which (based on autopsy data) is present in about 10% of cases. This valve can impede the advancement of CS guiding sheath and is a common cause of CS dissection. Although CS dissection rarely causes hemodynamically significant pericardial effusion, it can prolong CS lead placement and at times CS narrowing or occlusion. The other factor is the variability in the anatomy of the coronary sinus and its tributaries (Figure 8). The posterior vein is missing in as much as 40% of cases (based on review of our first 100 patients). The posterolateral vein is present in almost all cases but its entry is frequently tortuous. The lateral vein is frequently too small for placement at its mid-portion. However, in most cases (about 95% in our series), at least one of these tributaries would be suitable for placement. However, tortuosity may hinder easy entry20 and for this reason, an over-the-wire (OTW) lead would provide some advantage. Otherwise, a stylet driven lead would suffice in most cases. Various tools are now available for CS lead implantation that include specially designed sheaths for coronary sinus cannulation and stylet-driven and over-the-wire pacemaker leads (Figures 9 and 10). The three approved leads for left ventricular pacing ranged from 4 French (Fr) to 6 Fr in diameter. The Medtronic LV Attain 2187 lead is a 6 Fr stylet-driven lead with a curvilinear distal portion designed for entering angulated tributaries and for stabilization. The Medtronic LV Attain 4193 is a 4 Fr body and 5 Fr tip lead that can be placed with either a stylet or over-the-wire method. Its distal portion is also angulated for the same reason (Figure 12). The Guidant EasyTrak lead is a 5 Fr body and tip over-the-wire lead with tines for stabilization. The differences in these leads shape and size offer the operator with some range of options. In addition to the challenges in lead placement, its stabilization can also pose a problem. In general, the smaller leads tend to dislodge easier as its portion outside the coronary sinus (within the right atrium) is more likely to loop or coil upon itself compared to the larger body leads. This problem is more relevant when the coronary sinus opening sits high in the septum (Figure 11).

Choosing The Ideal Candidates for CRT

One final important issue to consider is the identification of the ideal candidates for CRT. While any patient with congestive heart failure and an IVCD is a potential candidate, it is still difficult to predict whether or not such a patient would definitely receive benefit from CRT. Simple parameters such as patient demographic, etiology of cardiomyopathy and even anatomic and electrophysiologic measures such as QRS narrowing (Figure 2) ²¹ and the ability to position the lead into a desirable vein are not helpful in predicting outcome. In a study using echocardiographic data to measure left ventricular wall motion displacement identified a subset of patients with greater benefit from CRT. ²² Patients were classified as having displacement similar to control, a late lateral wall displacement and a late septal wall displacement. Using such categorization, the group with late lateral wall displacement was found to have the greatest benefit (measured by improvement in dP/dtmax). Using similar concept but a simpler method of M-mode echocardiography, some investigators also found that septal-to-lateral wall motion displacement to be predictive of responders to CRT. ²³ The importance of identifying mechanical, rather than electrical resynchronization was also recently analyzed using epicardial mapping and tagged MRI. ²⁴ The study reported that improvement in hemodynamics (dP/dtmax and aortic pulse pressure) were noted with both biventricular and left ventricular pacing while electrical resynchronization was noted only with biventricular. In both studies cited above, both LV and biventricular pacing provided hemodynamic improvement, perhaps underscoring the importance of LV resynchronization rather than biventricular resynchronization. This issue certainly warrants further clinical investigation.

Summary and Future Perspective

During this past year, we have seen a proliferation of CRT procedures. While the procedure can indeed be challenging and time consuming, we have gained significant insight into this form of therapy with respect to both its clinical and technical aspects. In terms of its impact on the EP laboratory and its personnel, CRT is frequently perceived as a non-efficient procedure, requiring a significant amount of time and utilizing extra personnel and resources. However, considering the significant improvement that this form of therapy provides for the refractory heart failure scenario, the effort is well worth. As with all other forms of procedures, experience is key and while the learning curve of this type of procedure may indeed be a steep and long one, once the operator has mastered the procedure, the total average procedure time is typically not any longer than 90-120 minutes. Cardiac electrophysiology labs should encourage its personnel and physicians to continue to perform this procedure as its benefits are frequently quite significant and rewarding to both the physician and patient.