Summary
Adults with congenital heart lesions constitute a rapidly growing group of patients with cardiovascular disease. This nascent demographic phenomenon is creating major issues concerning the optimal management of these patients, in whom sudden death and progressive heart failure are predominant causes of death. Ventricular dyssynchrony appears to be very common in this population and can appear early in the history of the disease. Recently, cardiac resynchronization therapy (CRT) has emerged as a potential treatment option for patients with congenital heart disease (CHD). In this paper, we review the clinical evidence for the role of CRT in a number of different groups of patients with congenital heart lesions. In particular, we focus on whether there is a plausible mechanistic role for CRT and, if so, whether this results in acute and longer-term beneficial effects. We conclude that CRT shows promise as a potential treatment option for patients with CHD and ventricular impairment, but larger clinical outcome studies are required before definitive guidance can be issued.
Résumé
Les pathologies cardiaques congénitales de l’adulte représentent une nouvelle population de patients qui ne cesse de croître et qui pose des problèmes spécifiques pour leur prise en charge. La mort subite et l’installation progressive de l’insuffisance cardiaque chez ces patients jeunes représente un des challenges majeur en termes de surveillance et de thérapeutique. L’asynchronisme est fréquent dans ces groupes de patients et apparaît souvent très précocement dans l’enfance. La stimulation cardiaque de resynchronisation, sur le modèle de l’insuffisance cardiaque gauche avec bloc de branche gauche, est proposée depuis quelques années chez les enfants ou les adultes congénitaux qui souffrent d’insuffisance cardiaque. Les premiers travaux ont décrit l’effet positif immédiat de la resynchronisation en post chirurgie de cardiopathie congénitale sur des tableaux de dysfonction ventriculaire gauche. Les effets a plus long terme sont limités a quelques cas isolés de patients inclus dans de rares études mono- ou multicentriques portant sur la resynchronisation dans les cardiopathies congénitales. Les informations que l’on peut tirer de ces études sont convergentes et suggèrent toutes une amélioration clinique et échographique de la resynchronisation chez ces patients avec cependant des différences en fonction du groupe anatomique et fonctionnel de chacun : dysfonction ventriculaire avec bloc de branche droit, ventricule droit systémique ou ventricule unique. Dans cette revue nous étudions pour chaque groupe de cardiopathie le rôle de l’asynchronisme et ses implications sur le développement de l’insuffisance cardiaque, voire des arythmies ventriculaires et rapportons les diverses expériences et application de resynchronisation publiées dans ces populations.
Introduction
Cardiac resynchronization therapy (CRT) has been shown to be a useful therapy for adult patients with chronic left ventricular (LV) failure due to idiopathic or ischaemic dilated cardiomyopathy and electromechanical dyssynchrony. It has been shown to improve exercise tolerance, heart failure symptoms, and survival . In both European and North American guidelines, CRT is a class I (level of evidence A) therapy for patients with an LV ejection fraction less or equal to 35% and QRS ≥ 120 ms who remain symptomatic (New York Heart Association [NYHA] functional class III–IV) despite optimal medical treatment.
At the same time, the evidence is mounting that conventional dual-chamber pacing might have detrimental effects . Several trials have shown that right ventricular (RV) apical pacing has deleterious effects on LV function, most likely due to the induction of LV dyssynchrony . RV pacing has also been shown to have adverse effects on LV cellular structure, ventricular geometry, and systolic and diastolic function, all of which lead to an adverse haemodynamic response .
In contrast to the vast experience with biventricular stimulation gathered in adults with acquired LVdysfunction , the safety and efficacy of CRT in patients with congenital heart disease (CHD) and RV dysfunction has not been fully established. Evidence is limited to case reports, retrospective analyses of heterogeneous populations, and small crossover trials conducted in the immediate postoperative period . Although preliminary results are encouraging, the applications of CRT in patients with CHD, and the mechanisms by which it might be therapeutic, remain unclear.
In this article, we review the indications and technical aspects for implantation of CRT devices in patients with CHD. We evaluate the various short- and intermediate-term results and discuss future directions of biventricular resynchronization in patients with CHD.
Is there a clinical need for cardiac resynchronization therapy (CRT) in congenital heart disease (CHD)?
CHD is the most prevalent major birth defect, and currently affects more than 1% of children . As a result of major improvements in surgical techniques, postoperative care, and medical management in recent years, the population of adults with repaired CHD, particularly patients with complex lesions , is increasing. The growth of this population is linear and the mortality rate, at least in the early adult years, is relatively low . However, this nascent demographic phenomenon is creating major issues concerning the optimal management of adults with CHD .
Surgery is undoubtedly the cornerstone of treatment for the majority of patients with CHD. Good short- and mid-term results are, however, tempered by later complications, including the development of ventricular dysfunction and sudden death. The prevention of ventricular impairment and ventricular arrhythmias has now become one of the most important challenges we face in the management of grown-up congenital heart (GUCH) patients. RV dysfunction is an object of growing interest, although currently, the therapeutic options remain limited. Even if surgical repair has apparently restored normal architecture, it is likely that subtle and persistent abnormalities of cardiac or extracardiac structure and function persist. Additionally, the natural history of the underlying condition and/or the development of complications may all lead to the development of heart failure and/or arrhythmias even after many years.
Cardiac electromechanical dyssynchrony decreases regional loading, contractile work, myocardial blood flow, and oxygen consumption in the early-activated anterior myocardium, whereas these parameters are increased in the late-activated lateral left ventricle. Asymmetrical contraction resulting from an intraventricular conduction delay is now well identified as an independent predictor of mortality in patients with heart failure due to acquired cardiopathy. In GUCH patients, electromechanical dyssynchrony is becoming more frequent in asymptomatic patients, either progressively or early after surgery. A relationship between electrical and mechanical dysfunction, as well as a link between myocardialremodelling, rhythm disturbances, and electromechanical dyssynchrony, probably exists. The results from a small number of studies published thus far have been encouraging. They indicate that patients presenting with CHD have an anatomic substrate that is amenable to cardiac pacing therapy; and have also shown positive effects with both biventricular and RV pacing . However, it is important to highlight that the specific treatment approach is very much dependent on the underlying condition being treated. Patients with CHD are a heterogeneous population with a variety of different lesions responsible for their symptoms, such as tetralogy of Fallot (TOF), single ventricle, and systemic right ventricle. In the next part of this manuscript, we review the current evidence for the use of CRT in each of these groups.
Right ventricular (RV) impairment in surgically corrected tetralogy of Fallot (TOF)
The majority of patients with ischaemic or dilated cardiomyopathy, LV systolic dysfunction, and asynchrony have left bundle branch block (LBBB) morphologies . In this setting, CRT improves haemodynamics and bioenergetics . Right bundle branch block (RBBB) is almost invariably present on the electrocardiogram after surgical repair of TOF. The prognostic importance of a wide QRS is clear, as is the high correlation between QRS duration and the risk of developing ventricular arrhythmias . While failure of the right heart is multifactorial, caused by the combined effects of pressure and volume overloads, and of myocardial lesions inflicted during and after surgery, the haemodynamic consequences of this electrical anomaly might play an important role in the long-term clinical outcomes of these patients. Sudden death and progressive heart failure, the most common causes of death in this population , may be promoted by the remodelling induced by mechanical dyssynchrony, which therefore may be a desirable therapeutic target .
RV dysfunction has been associated with a prominent RV mechanical delay in a porcine model that emulated some of the mechanical and electrophysiological abnormalities observed in TOF . Biventricular stimulation significantly improved the function of both ventricles, measured using invasive haemodynamic studies and echocardiography. In contrast, RV stimulation from three separate sites has been found to confer no functional benefit over intrinsic conduction . While this model reproduced, albeit imperfectly, the anatomical and electrophysiological abnormalities observed in patients suffering from TOF, it is noteworthy that RV dysfunction was alleviated by cardiac stimulation.
Lumens et al. have observed favourable effects with stimulation of the RV free wall in a computer model of pulmonary hypertension associated with RV dysfunction . This suggests that, in the presence of pulmonary arterial hypertension, stimulation of the RV free wall can: alleviate the heavy overload imposed on that wall; equalize the load conditions and amplitudes of segmental contraction; and increase RV contractility.
Acute effects of cardiac stimulation
The immediate haemodynamic effects of RV or biventricular stimulation in adults presenting with TOF, RV dysfunction, and a wide QRS have been examined in two studies . In the study by Dubin et al., seven patients (six suffering from TOF) who presented with isolated RV dysfunction and RBBB underwent haemodynamic investigation . Transvenous pacing catheters were positioned in the right atrium and ventricle. The atrioventricular (AV) interval was programmed to 90% of the PR interval. A number of different RV pacing sites were tested, including the apex, outflow tract, and septum. Overall, sequential AV pacing improved cardiac output and RV dP/dt and decreased QRS duration when compared to atrial pacing alone and normal sinus rhythm . The site that optimized QRS duration did not correlate with the one yielding optimal RV function. There was, however, a strong relationship between the degree of QRS improvement and the observed increase in cardiac output.
In our study of eight adults who presented with repaired TOF, RV and LV dP/dt max were measured invasively during: spontaneous rhythm; RV apical stimulation; and biventricular stimulation . The AV delay was programmed at 70% of spontaneous to allow complete capture of both ventricles. The mean LV ejection fraction was significantly lower than in a control population. Single RV stimulation increased RV dP/dt max , but did not increase LV dP/dt max , whereas biventricular stimulation increased the contractility of both ventricles. These acute studies suggest that RV pacing may be beneficial in patients with heart failure and RBBB, which is contrary to RV pacing for bradycardia in the presence of normal ventricular function. Conversely, biventricular stimulation seems preferable in presence of concomitant LV dysfunction.
Acute postoperative setting
In the acute postoperative setting, the failing ventricle has traditionally been managed by inotropic support. With most inotropic agents, contractility is enhanced at the expense of increasing myocardial oxygen consumption and energy store depletion . In contrast, in patients with dilated cardiomyopathy and LBBB, CRT may improve cardiac function while modestly diminishing myocardial energy demand . Following complex congenital heart surgery, both AV block and intraventricular conduction delay are not uncommon.
Initial experience with CRT in CHD has focused on the acute postoperative setting. The immediate postoperative effects of CRT were initially studied in mixed populations of patients presenting with CHD, which included patients with TOF . One case report described a 6-month-old infant with TOF and atresia of the left pulmonary artery in whom acute epicardial CRT led to improved LV function and successful weaning from extracorporeal circulation . In all the reports, atrial synchronized RV stimulation with optimized AV delays was performed, using temporary RV wires placed during the operation. Ventricular stimulation immediately increased systemic blood pressure, enabled a decrease in inotropic support and volume replacement, and stabilized haemodynamic function during the first postoperative 48 hours, after which stimulation could be uneventfully discontinued.
Long-term ventricular pacing
Interpretation of long-term clinical results of CRT in TOF patients is problematic due to the absence of dedicated studies. The only available data are from case reports or studies of CRT in patients suffering from CHD, where statistical analyses did not distinguish TOF patients from patients with other types of CHD. The first case report describing the application of CRT in a TOF patient was in an infant who developed complete AV block and had a permanent RV pacing lead implanted at the time of surgery . The patient subsequently developed left heart failure and a markedly depressed LV ejection fraction. The addition of an LV lead was followed by a clear clinical improvement and his LV ejection fraction returned to normal. As well as the positive effect of CRT in TOF, this report highlighted the importance of adapting the stimulation mode to the individual patient characteristics, and supports the use of biventricular stimulation in the presence of concomitant LV dysfunction due to RV pacing. Cecchin et al. implanted CRT devices into six patients with TOF or a variant of the disease , while the study by Dubin et al. included 11 such patients . CRT appeared to provide clinical benefit in these patients. Additionally, there was a suggestion that the TOF patients derived a greater treatment benefit from CRT than patients with other congenital heart lesions, such as a systemic right ventricle.
Summary
Patients with surgically corrected TOF presenting with RV failure with RBBB potentially have a substrate that is suitable for treatment with cardiac pacing. Little clinical data currently exists, but acute haemodynamic studies have shown improvements with RV pacing, and the small number of patients receiving CRT devices appear to have gained clinical benefit. Further clinical studies are required before CRT can be recommended in evidence-based clinical guidelines, however, it does show promise in this group of patients.
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