B. PEZZULICH, P. GRECOLUCCHINA
Cardiac resynchronisation therapy (CRT) is a non-pharmacological treat- ment for patients with severe congestive heart failure (CHF) due to systolic dysfunction who also present an intraventricular conduction abnormality and a QRS duration greater than 120 ms [1]. CRT has been shown to improve functional status, quality of life, and exercise tolerance and to decrease hospitalisation frequency in these patients: recent results of the MUSTIC [2] and MIRACLE [3] trials are consistent in showing an improve- ment in NYHA class, quality of life scores, and distance covered during a 6- min walking test. A decrease in dynamic mitral regurgitation, increase in left ventricular ejection fraction, and reverse remodelling effect on the left ven- tricle has also been noted. The COMPANION study has recently demonstrat- ed that CRT provides significantly better results regarding a combined end- point of mortality and heart failure hospitalisation [4].
Consequently, CRT has been included in the current American Heart Association/American College of Cardiology/North American Society of Pacing and Electrophysiology guidelines for the implantation of permanent pacemakers as a therapeutic option for patients with systolic heart failure, NYHA class ≥ 3, QRS duration ≥ 130 ms, left ventricular end-diastolic diameter ≥ 55 mm and ejection fraction < 35% [5]. According to these cri- teria, between 13% and 35% of patients with heart failure would be eligible for CRT [6, 7]. However, a growing body of evidence seems to suggest that a larger proportion of heart failure patients could benefit of CRT. Some of the
‘new’ indications for CRT are discussed in this paper.
Cardiology Department San Luigi Gonzaga Hospital, Turin, Italy
CRT in Patients with a Narrow QRS (≤ 130 ms)
Most of the work done in these years in the field of CRT has focused on the deleterious effects of a wide QRS, especially with LBBB morphology, and narrowing of the QRS complex was considered a major target. This approach has several pitfalls, namely it remains unclear whether a classical LBBB mor- phology is required or not, and what is the ‘right’ duration of QRS, which in different studies has ranged from 120 to more than 150 ms [2–4]. Moreover it became clear that atrio-left-ventricular pacing, often associated with a widening of QRS duration, can yield comparably positive clinical results. In recent years it has been appreciated that mechanical cardiac dyssynchrony has to be the target of CRT [8], and that the electrical phenomenon of QRS widening is just a marker of this condition [9]. To define ventricular dyssyn- chrony by the threshold QRS > 150 ms is easy but, while it is true that the larger the QRS, the more likely the dyssynchrony, many patients with mechanical dyssynchrony and narrow QRS can be misdiagnosed and not scheduled for CRT. In a study based on tissue Doppler analysis of regional longitudinal left ventricular function in normal subjects as opposed to patients with CHF and QRS > 140 ms, Faber et al. found that two-thirds of the CHF patients had intra-left-ventricular dyssynchrony with the lateral wall moving last, while in the other one-third the opposite was found. Of note, 12% of these patients had no detectable dyssynchrony, despite a large QRS [10]. Yu et al. found left ventricular systolic mechanical dyssynchrony to be common in patients with a narrow QRS complex, ranging from 51% to 69% [11]. These findings suggest that left ventricular dyssynchrony does not parallel the degree of conduction disturbance, and that different types of mechanical dyssynchrony may have similar ECG patterns.
A more recent study has suggested that, while patients with QRS > 150 ms have an almost immediate benefit, patients with QRS between 120 and 150 ms also showed an improvement in functional class and in exercise per- formance after 6 months.
Considering the limitations of conventional EKG, echocardiographic parameters are investigated in the ongoing CARE-HF study in which ventric- ular dyssynchrony is assessed in patients with QRS < 150 ms by considering (1) a prolonged aortic pre-ejection delay (> 140 ms), (2) an increased mechanical interventricular delay (> 40 ms), and (3) a left ventricular seg- mental post-systolic contraction [12].
It must be remembered that at present it is unclear which of these para- meters [involving Tissue Doppler Imaging (TDI), strain, strain rate] provides optimal information on prospective identification of responders to CRT.
Furthermore, it is becoming clear that various forms of dyssynchrony can be present, and it is unclear which form contributes most to heart failure.
Moreover, the underlying aetiology of heart failure can be important, as fre- quently scar tissue shows the latest activity, and it is unknown whether pac- ing of non-viable tissue results in clinical improvement.
CRT in Right Bundle Branch Block
The most frequent intraventricular conduction delay in heart failure patients is left bundle branch block; little is known about right bundle branch block.
In 12 patients studied by Garrigue et al. with NYHA class II–III disease, ejec- tion fraction 24%, and right bundle branch block (QRS average 189 ms) biventricular pacing resulted in a sustained increase in aortic time velocity integral, a significant decrease in mitral regurgitation, and a significant decrease in left ventricular end-diastolic diameter after 1 year [13]. In our experience five patients with dilated cardiomyopathy, NYHA class III, right bundle branch block, mean QRS duration 160 ms, showed sustained and sig- nificant improvement in functional class and in exercise capacity in car- diopulmonary testing. All of them at baseline showed significant ventricular dyssynchrony at TDI.
It may be speculated that biventricular pacing may be useful in patients with heart failure, right bundle branch block, and ventricular dyssynchrony, but this issue remains unproven.
CRT in Conventional Pacemaker Therapy
Right ventricular apical pacing may result in significant haemodynamic deterioration. An adverse effect of long-term ventricular pacing has been documented in patients with normal systolic and diastolic left ventricular function before pacemaker implantation [14]. In the Mode Selection Trial, which studied 1339 patients, percentages for normal ejection fraction, NYHA class I or II disease, baseline QRS duration < 120 ms, and hospitalisation for heart failure paralleled the percentage of right ventricular pacing. Patients paced in DDD less than 10% of the time had a 2% incidence of hospitalisa- tion for heart failure, while patients paced for more than 90% of the time had a 12% incidence of hospitalisation. For patients paced with VVIR mode, hospitalisations for heart failure increased from 7% (for < 10% pacing) to 16% (for > 90% pacing) [15].
In the DAVID ICD trial, pacing in DDD-R mode with lower rate 70 bpm increased the relative risk of death or heart failure hospitalisation by 1.6 [16]. In terms of quality of life and exercise capacity, the PAVE study has recently shown biventricular pacing to be superior to conventional pacing after atrioventricular nodal ablation for atrial fibrillation.
Thus, for patients requiring conventional pacing, it may be speculated that right septal pacing or biventricular pacing may result in a lower inci- dence of heart failure during long-term follow-up. The BIOPACE study is addressing this issue in a randomised multicentre study [17].
It must be remembered that all trials were performed using lower rate 40 bpm or VDD mode, and whether atrial-biventricular pacing is equally effec- tive remains unproven.
Prophylactic Effect of CRT in LBBB
Intraventricular conduction delay has been identified as a major negative prognostic indicator in patients with heart failure. In more than 5500 patients from the Italian Network of Congestive Heart Failure, mortality and hospitalisation due to heart failure after 1 year in patients with LBBB was 1.5-fold that in patients with a narrow QRS complex [18].
Acting through several mechanisms, including redistribution of regional ventricular loading, reduction or abolition of mitral regurgitation, reduction of sympathetic activity, increase of parasympathetic activity, and others, CRT also induces reverse remodelling of the failing left ventricle. Hence, the left ventricle gets smaller and contractility is improved after a period of CRT.
Moreover, functional mitral regurgitation is reduced acutely and chronically during CRT. The effects of CRT on reverse ventricular remodelling have been consistently demonstrated in all randomised prospective controlled studies and in smaller mechanistic studies [19].
Recent data from Multicenter InSync Randomised Clinical Evaluation (MIRACLE) study have shown that reverse remodelling during CRT can also take place in patients not receiving beta-blocking agents. This effect of reverse remodelling, which has been demonstrated in all major cohorts, may be partly due to a decrease in mitral regurgitation and improved myocardial energetics as shown in acute and in chronically paced patients [20].
Moreover, recent data from the COMPANION study showed that patients assigned to optimal medical therapy had progressive reduction of systolic blood pressure, consistent with progression of the underlying disease, whereas patients assigned to CRT did not [21].
Reversing the natural course of the disease is an exciting promise, but a word of caution is necessary. Inadequate patient selection, lead selection, or device programming may impair survival or quality of life. Long follow-up periods are required to prove the hypothesis that early CRT influences dis- ease progression and improves long-term survival.
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