Cardiac Resynchronization Therapy: An Established Pacing Therapy for Heart Failure and Mechanical Dyssynchrony

Heart failure is a very prevalent disease in the general population, but more so in the elderly. It has a very high morbidity and mortality and it is a growing public health problem. Half of the patients with heart failure have a reduced left ventricular ejection fraction and fewer have a left bundle branch block, which is our currently best selection criterion to identify electrical and mechanical dyssynchrony. When these patients are severely symptomatic despite adequate medical treatment of their heart failure, implantation of a biventricular pacemaker can resynchronize the ventricles and induce a reverse remodelling of the left ventricle and marked symptomatic improvement.

The idea of cardiac resynchronization therapy (CRT), most likely came out of a variety of animal studies performed in the late 1980s and early 1990s. From 1995 - 1997 there were many observational studies that confirmed the initial value of cardiac resynchronization. From 1998 - 1999 we had available randomized studies, placebo controlled, to determine exercise capacity, NYHA, quality of life, and from 2000 we had randomized studies to determine hospitalizations and mortality.

All randomized trials have confirmed a significant alleviation of symptoms and increase in exercise capacity: mean NYHA class decreased by 0.5-0.8 points, distance in 6 min walk test increased by a mean of 20% and peak oxygen consumption during exercise increased by 10-15%. Later, a meta analysis in 2003 found a 30% reduction of hospitalizations for the management of congestive heart failure (CHF), attributable to CRT. Lately, the study COMPANION: CRT with/out implantable cardiac defibrillator (ICD) lowered the combined end point of mortality and re-hospitalization by 35-40% and in the CARE-HF, CRT lowered the proportion of hospitalization for CHF by 52% and unplanned hospitalizations for major cardiovascular events by 39%. CRT reverses left ventricular (LV) remodelling, decreases LV end systolic and end diastolic volumes (By 15%), and increases LV ejection fraction (EF) (By 6%). The REVERSE study has confirmed this aspect. It is often said that about onethird of patients who appear to warrant CRT will not benefit from the therapy. The definition of failure to respond, however, needs to be considered carefully. The failure to implant an effectively functioning system, a poor lead position or failure of pacing stimuli may explain some non responders. Patients whose condition worsened with CRT might have done much worse without CRT, or worsen due to intercurrent illness. In summary there is a large number of patients studied in randomized clinical trials that demonstrate that CRT improves quality of life, exercise capacity, functional capacity, improves cardiac function and structure and, in addition, CRT reduces the risk of mortality.

Despite single center studies have suggested that mechanical markers of LV synchrony could predict outcome after CRT, these results have not been reproduced in the multicentric setting and indeed, failure of this markers as predictors of CRT response has been shown. This paradox underscores the limited reproducibility and variability of the currently proposed dyssynchrony analysis techniques. The echocardiographic techniques for the study of dyssynchrony will be discussed in this chapter, pointing out the evidence supporting the use of each method as well as their limitations.

Since the first application of cardiac resynchronization therapy (CRT) in 1994, an important body of information has been delivered from many randomized trials including a large number of patients. Most of these trials have showed strong evidence to support the use of CRT to improve heart failure symptoms, quality of life, left ventricular ejection fraction, exercise capacity and survival. As a result, current guidelines recommend the use of CRT as a Class I indication in patients with NYHA classes III or IV, LVEF less than 35%, QRS duration greater than120 ms, LV end-diastolic diameter > 55 mm and, sinus rhythm. However, a lack of information exists regarding other scenarios such as patients in NYHA classes II, patients with a narrow QRS complex, patients with normal ejection fraction or patients with baseline rhythms other than sinus rhythm such as those in atrial fibrillation or pacing dependent. The following chapter is dedicated to the indications for CRT therapy recommended on current clinical guidelines from the American and European Societies reviewing the clinical evidence supporting these indications.

This chapter addresses one of the most controversial aspects of cardiac resynchronization, the need of incorporating defibrillation (ICD) capabilities into resynchronization devices (CRT). As will be described, apart from other more or less marginal arguments, the issue is basically one of cost, since the price of a CRT-ICD is more than three times that of a CRT alone system (CRT-PM). This is a theme that is familiar to electrophysiologists used to debate about the efficiency (or the cost-efficiency) of ICD in primary prevention in the field of resynchronization. Although it is generally accepted that ICD implantation is indicated in patients who have suffered from ventricular fibrillation / tachycardia (class I, evidence level A or B) [1-5], and despite a growing number of clinical trials and its inclusion into the latest guidelines as class I [5], ICD utilization still is a subject of controversy that has extended to CRT.

Clearly, we are not in possession of a clear and final answer to this question. Moreover, all arguments are based on the assumption of current costs and the performance of currently available stratifiers. In this chapter, we will describe the most relevant evidence regarding: 1) scientific findings on the reduction of mortality with CRT-ICD; 2) the impact on quality of life associated with CRT and ICD; 3) available cost efficiency analyses; and finally 4) the current situation concerning the indications for the defibrillator, as recognized in guidelines, and future perspectives.

Despite the fact that there is no consensus on the clinical impact of optimizing cardiac resynchronization devices, echocardiography is currently the most used method to optimize the programming of the device in the absence of other well validated methodology. On the other hand, while the role of cardiac imaging in the selection of candidates for cardiac resynchronization therapy remains controversial, it is well established that imaging is essential to establish an objective evidence of response to the therapy. In the present chapter, the role of cardiac imaging in optimizing the programming of CRT devices as well as of the usefulness in the follow-up of patients treated with CRT will be discussed.

Cardiac resynchronization therapy is a well-recognized treatment option in patients with advanced heart failure, left ventricular dysfunction and dyssynchrony. This mode of therapy improves symptoms, quality of life, and mortality. The devices used are designed to specifically pace the left ventricle, and for this reason they have a number of unique programming issues that will be discussed in the present chapter. The complexity of CRT devices and the need for careful management of severe heart failure patients emphasize the need for a multidisciplinary team. The efficacy of CRT is based on monitoring the function of the devices by means of assessment of the clinical status of the patient, electrocardiographic follow-up and interrogation of the device. The present chapter offers an in-depth review of the different electrocardiographic patterns than can be obtained in CRT patients.

Randomized clinical trials have shown important clinical benefits from cardiac resynchronization therapy, in addition to those obtained with optimal medical treatment, in the advanced heart failure population. However, the criteria for inclusion in these trials are restrictive and only a small proportion of heart failure patients are candidates. The logical next step is to expand this therapy and its possible benefits to heart failure patients in less advanced stages of the disease, with narrow QRS and in atrial fibrillation. In this chapter we review the available findings on the use of this therapy in these subsets of patients.

The beneficial effects of cardiac resynchronization therapy (CRT) on symptoms, hospitalizations and mortality are well established in patients with left ventricular systolic dysfunction and QRS. 120 ms. Majority of studies about CRT have included patients with left bundle branch block (LBBB). However, in some subgroups of patients with heart failure and electrical disorders such as right bundle branch block (RBBB) or induced LBBB by permanent pacing, the benefit of CRT remains uncertain.

Right ventricle apex (RVA) pacing cause electrical and mechanical dyssynchrony, which could worsen the left ventricular ejection fraction and remodel left ventricle. Some trials, as DAVID or MOST, have suggested a possible harmful role of RVA pacing. In patients with left ventricular dysfunction and need of pacing, CRT could be considered as an alternative. Several trials, as HOBIPACE and RD-CHF, support CRT in patients with left ventricular disfunction who need pacing. Therefore, current clinical practice guidelines recommend the use of CRT in heart failure patients with depressed systolic function who need permanent pacing.

In other hand, RBBB also causes electrical disorders like interventricular and intraleft ventricular dyssynchrony. And this has been identified as a predictor of HF worsening. CRT might also have some hemodynamic benefits in patients with RBBB and intraleft ventricular dyssynchrony. Nowadays, recommendations for CRT in the guidelines do not specify QRS morphology although emphasize that there is not yet sufficient evidence to provide specific recommendations for patients with RBBB.

Multisite ventricular pacing, including left ventricular pacing, is associated with hemodynamic, echocardiographic and clinical benefits in patients with congestive heart failure (CHF) and left ventricular dysfunction undergoing cardiac resynchronization therapy (CRT). The clinical outcome of CRT using left univentricular pacing (LVp) is essentially comparable to other CRT pacing modalities (sequential or simultaneous biventricular pacing, BiVp), although BiVp appears to be associated with a greater improvement of the left ventricular performance. Biventricular pacing, unlike LVp, is also associated with a greater reduction in the QRS complex duration, which has been described as a predictor of good outcome in CRT patients. Sequential BiVp appears to be superior to simultaneous BiVp, although the clinical impact of these two CRT pacing modalities is essentially equal in the long-term follow-up. Left univentricular pacing is limited by the increasing indication of devices allowing for antitachycardia/defibrillation therapy in CRT patients, for which a right ventricular lead is needed. However, this pacing modality might be indicated in a selected CHF population with important comorbilities, difficult venous access for the lead implantation and/or unfavorable life time expectancy.