New directions in pacemaker therapy among children and adult patients with congenital heart disease

In the field of pediatric/congenital cardiology, three concepts have arisen over the past few years. First, is the somewhat intuitive notion that children are not little adults; second, structural congenital heart disease (CHD) is not the same as acquired heart disease; and third, repaired CHD does not mean a normal heart. In these regards, application of the vast amount of information and extensive multicenter collaborative reports obtained from pacing studies in internal medicine cardiology do not necessarily apply to children or adults with any of the multiple forms of structural CHD. Unfortunately, perhaps on the simple logistical issue of patient and physician numbers, there are far fewer pacing studies in CHD than coronary or other forms of acquired heart disease patients. Nevertheless, the past 20 years have seen an increase in information related to pacemaker therapy in the young. Also, perhaps as a somewhat ironic twist, although internal medicine studies might not apply to CHD, the reverse is quite different. Pacing and pacing lead studies in children and young adults with CHD definitely do apply to older patients. This will be increasingly noticeable in the future as more children with CHD attain adulthood. At the time of writing, there are now more patients over the age of 21 years with CHD than under. And that number will continue to increase, requiring continuous re-evaluation of present pacing guidelines and practices.

Initial applications: staying alive

The advent of cardiac bypass and the pump oxygenator in the 1950s permitted open congenital heart surgeries involving septal defects. Unfortunately, as a result of these reparative procedures, sinus and atrioventricular (AV) nodal, as well as distal His–Purkinje conduction systems, were often directly or indirectly damaged, resulting in brady- or tachy-arrhythmias. The original large external pacemakers in use at the time, which were not suitable for children, soon evolved into the more identifiable implantable devices of today, although their dimensions more closely resembled that of an ice hockey puck. Both transvenous and epicardial leads were utilized. Initial pediatric and CHD experiences were often associated with multiple complications, including infection, erosion and exit block, in which myocardial fibrosis at the immediate lead insertion site increased the need for more current to stimulate the surrounding viable tissue. Often that energy requirement exceeded the output of the pulse generator. Generator replacements as frequently as 14 months in children were not uncommon [1]. Nevertheless, pacemakers maintained basic heart rates and prevented postoperative morbidities due to surgical heart block and interest in them continued.

The early modern era: lead & generator design

By the 1980s multiple changes in lead and generator design technologies emerged, associated with an increasing interest in cardiac function. Improvements in pacemaker programmability lead to a new key term, ‘physiologic pacing’. Initially, this concept was associated with newer pacemaker engineering capabilities permitting variations in paced ventricular rate in response to sensed atrial signals permitting dual-chamber AV synchrony or simply atrial/ventricular rate increases in response to body motion, temperature, chest wall impedance, pH or QT intervals.

However, ‘physiologic’ was a misnomer as only rate increases were involved. Eventually, this concept evolved into a more scientific study of cardiac hemodynamic responses of cardiac pacing, not simply paced rate. Merely increasing the rate was soon recognized as not optimal for all patients [2]. The era of investigations of quality not quantity of life with pacing emerged.

From the earliest implants, lead design technology often dictated where leads were to be positioned to permit stability and prevent dislodgement. For epicardial implants that was typically dictated by the surgical exposure, essentially the right ventricular free wall. Since the earliest transvenous leads were devoid of fixation capabilities, the most stable implants could be achieved in the right atrial appendage and ventricular apex. Ventricular pacing, typically, was easily identified by a left bundle/superior axis QRS morphology. However, dating to the 1920s, studies demonstrated real physiologic benefits of cardiac stimulation as close to the normal His–Purkinje system as possible. Canine studies showed adverse histopathologic changes associated with apical pacing and a comparable clinical study in children with congenital AV block demonstrated similar adverse cellular responses of chronic apical pacing [3,4]. However, technological improvements in lead design were first required before any advances in lead position could be accomplished.

Improved lead and electrode design technology with better fixation and less tissue inflammation were applied with patient benefit. Less electrode–tissue interface inflammation lead to less need for increased energy which, in turn, lead to smaller batteries and generators. Chronic epi- and endocardial lead performances were excellent, even in small children. Lack of local inflammation, better fixation and reliable conductor coils and insulation permitted feasibility studies into alternate sites for lead placement.

Into the 21st Century: alternate site, His bundle & resynchronization pacing

With an increasing store of knowledge evolving from both animal and clinical studies, adverse effects of pacing from the atrial appendage and ventricular apex, with their associated altered hemodynamic responses, became apparent [5,6]. With lead design improvements, the next concept was that of ‘alternate site pacing’. Assuming that the appendage and apex were ‘standard’ lead implant sites, any other implant site was termed ‘alternate’. These included atrial septal (Bachmann’s bundle), coronary sinus, outflow tract, septal and His bundle/para-His. Alternate epicardial sites included left ventricular base and apex. Multiple studies of these implant sites were reported in adult patients with some terminology confusion. Experiences in children were more limited. However, it has become apparent that all patients are different and the most optimal implant site is patient-specific. In essence there is no universal ‘sweet spot’ that provides the best paced myocardial contractility to all patients. The recent introduction of a flexible delivery catheter to permit lead implant at almost any preselected location appears very promising, especially in children and patients with adverse congenital heart anatomy. Currently there are multiple studies to evaluate the potential of this new delivery system, especially among patients with congenital heart defects.

The first report of precise His bundle lead implant and pacing was performed in immature canines from both epi- and endocardial approaches utilizing custom design leads [7,8]. However, although there have been some attempts at pacing from this site in older patients, concerns for lead stability and thresholds have limited its application, especially in younger patients. However, it is quite plausible that with continuing improvements in electrode lead design, this application may have more appeal, especially for patients with proximal conduction system problems, such as congenital AV block [9].

It is now well recognized that normalization of the electrical QRS does not necessarily equate to normalization of mechanical contractility. In patients with existing myocardial dysfunction, or ventricular ‘dyssynchronization’, combining both right and left ventricular stimulation simultaneously (cardiac ‘resynchronization’ therapy [CRT]) may be beneficial in some patients based on established guidelines of heart failure, ejection fraction and QRS duration. In deference to internal medicine experiences, the incidence of ischemic heart disease is very low among children and young adults with CHD. As a result, there have been no randomized multicenter studies among pediatric/congenital heart groups. However, CRT pacing applications to children and young CHD patients does exist. Following several small initial studies, larger compilation reports have been published [10]. The first involved 103 patients (mean age 12.8 years) from 22 institutions and the second comprised of 65 patients (mean age 14.8 years) from 11 countries. In both, clinical benefits of CRT were observed with ‘responder rates’ of 89 and 87% of patients, respectively [11,12]. Of even more importance was that 23% of patients were removed from heart transplant consideration following CRT pacing. This potential for positive myocellular remodeling among younger CHD patients may be the most significant contribution of CRT to date. Since a repaired congenital heart is never normal, many patients will eventually experience ventricular deterioration solely on the basis of altered structural anatomy, such as seen with single ventricle, transposition of the great arteries and tetralogy of Fallot. CRT may become a needed ‘bridge to transplant’, improving patient quality and quantity of life while effectively postponing transplant. Newer experiences with alternate atrial pacing sites also indicate that higher septal or atrial superior vena cava locations may offer the most optimal mechanical effects of atrial pacing [13].

Adult congenital heart, intracardiac devices & beyond

The incidence of congenital heart defects in the general population is approximately 1%. That number is increased among some patients with CHD, who attain adulthood and have children. At the time of writing, there are more adults than children with structural CHD and this patient population will continue to age with increasing numbers joining. Depending on the CHD itself or as a result of previous surgical repair, both sinus and AV node dysfunction can be anticipated. Owing to altered anatomy and the current practice of interventional catheterization implants in lieu of surgery (septal closure devices and systemic venous or intracardiac stents), the future will reveal more challenges for pacemaker implant and evaluation of myocardial function [14]. In some patients, there will be no venous access to intracardiac chambers necessitating alternative approaches to epicardial lead implant. Finally, intravascular stents placed to open narrowed venous channels interact with pacing leads placed through them. This results in a cellular response of neointimal proliferation and eventual restenosis, causing new vascular problems and potentially complicating lead removal [15]. Fetal pacing, although attempted, is not currently a valid pacing application. The potential application of genetic engineering of the conduction system or creation of cellular bridges and formation new AV nodal tissue in lieu of mechanical devices appears intriguing but has yet to be fully evaluated.

Conclusion

In the past 30 years, pacemaker technical designs and clinical applications have advanced steadily and rapidly, providing patients with improved quality and quantity of life. Downsizing of pulse generators and small diameter leads permit their application to nearly all patients regardless of size or congenital heart anatomy. Improved pacing leads and their delivery permit implant at nearly any location. The real challenges for the future will be to continue to apply optimal pacing therapy among the growing population of patients with structural congenital heart defects that promote and permit normal cardiac mechanical activity, prevent adverse cellular responses and correct intrinsically abnormal contractile function.