Exercise in Chronically Paced Children
Exercise in Chronically Paced Children
The purpose of this study is to evaluate the exercise capacity of patients with complete
 heart block who are chronically being paced from the right ventricle. Also, we hope to
 correlate the level of uncoordinated contraction with the patients exercise capacity. We will
 enroll patients with complete heart block as diagnosed by standard electrocardiographic means
 and now have a permanent pacemaker. All patients we approach for this study will receive an
 echocardiogram to assess their heart function. As part of the echocardiogram, they will also
 receive a Tissue Synchronization Imaging (TSI) evaluation to assess the level of
 uncoordinated contraction they have. The patients will then be subjected to a cardiac
 exercise stress test which will involve them running on a treadmill until they cannot
 continue while data is collected regarding their heart's response to exercise. All portions
 of the study are noninvasive, which means they work from probes and monitors outside the
 body.
In third degree, or complete atrioventricular (AV) block, atrial electrical impulses fail to
 conduct to the ventricles. Congenital complete AV block (CCAVB) has an incidence of 1 in
 15,000 to 1 in 25,000 live births and has a strong association with maternal antibodies.
 Patients with isolated CCAVB range from completely asymptomatic to experiencing syncope,
 exercise intolerance or congestive heart failure. A portion of the symptoms attributable to
 CCAVB are secondary to the inability to increase heart rate, and hence cardiac output, in
 response to varying physiologic demands. For symptomatic patients, the mainstay of therapy
 has been cardiac pacing. Dual chamber pacing, with atrial sensing and ventricular pacing,
 allows for restoration of physiologic heart rates and response to exercise or increased
 metabolic demands. Resumption of AV synchrony allows for more efficient ventricular filling.
 Overall, pacing in patients with CCAVB would be expected to result in improved cardiac
 function and exercise tolerance.

 The traditional ventricular site for pacing in patients with CCAVB has been the right
 ventricular apex (RVA). This results in interventricular dyssynchrony as pacing first
 stimulates the right ventricle, rather than the typical midline ventricular activation
 pattern seen in patients with intact AV node conduction. Mounting evidence shows that long
 term RV pacing results in morphologic changes to the LV with resultant compromised
 performance. Further studies have shown that chronic RV pacing diminishes exercise capacity
 in patients with heart failure as well as asymptomatic adults. There have been studies, by
 our group in particular, that have documented ventricular changes in the paced pediatric
 patient. No published study has examined the possible deleterious effects of RV pacing on
 exercise capacity in children. We, therefore, propose to do a detailed evaluation of exercise
 performance, as measured by exercise duration, maximal heart rate, oxygen uptake and
 ventilatory response, in asymptomatic chronically RV paced children and young adults.

 Specific Aim 1: To describe the effects of dyssynchronous ventricular activation on exercise
 performance in children requiring long term RV pacing

 Hypothesis 1: Long term dyssynchronous electromechanical activation, secondary to right
 ventricular apical pacing, has deleterious effects on the exercise capacity of asymptomatic
 pediatric patients.

 Specific Aim 2: To correlate changes in exercise performance with tissue Doppler indices of
 mechanical dyssynchrony.

 Hypothesis 2: Tissue Doppler is a sensitive means of evaluating dyssynchrony in chronically
 paced patients.

 Background and Significance The goal of pacemaker therapy for CCAVB is to restore, as closely
 as can be approximated, physiologic rates and activation. Standard dual chamber pacing allows
 for sinus node participation in cardiac conduction. As a result, a more physiologic
 chronotropic response to exercise and AV conduction could be achieved. Indeed, prior studies
 concluded that dual chambered pacing resulted in increased exercise performance and improved
 perception of general well being as compared to ventricular demand pacing [1-3]. There is,
 however, increasing evidence that long term RVA pacing leads to detrimental effects on
 cardiac function secondary to the non-physiologic ventricular activation sequence. Animal
 studies have revealed regional left ventricular changes in perfusion, function and
 innervation in chronically RVA paced subjects as well as asymmetric hypertrophy of the LV
 wall [4,5]. Examinations of patients with inter/intraventricular dyssynchrony reveal a loss
 of coordination of ventricular contraction and relaxation. When the RV is the initial site of
 activation, portions of the LV are prematurely activated resulting in early segmental
 contraction at a low pressure with dissipation of energy and no resultant ejection, while the
 areas that activate later do so at higher stress and effect a paradoxical stretch on earlier
 contracted areas [6]. These factors lead to decreased efficiency and diminished systolic
 function. Ventricular dyssynchrony impairs LV pressure generation, diastolic filling and
 stroke volume, as well as, increasing wall stress [7]. Tissue Doppler echocardiography has
 recently proven to be a valuable tool in assessing and verifying regional wall motion
 abnormalities and aberrant LV activation by its ability to determine peak systolic velocity
 of different myocardial regions, degree of myocardial deformation and distinguish between
 active systolic contraction and passive displacement [8,6].

 Recognizing the less-than-optimal long term functional and hemodynamic effects of RVA pacing,
 prior investigators have attempted to utilize alternative RV pacing sites with variable
 success in improving LV function [9,10]. Most evidence, however, indicates that dyssynchrony
 results in maladaptive ventricular remodeling compromised function and decreased exercise
 capacity [11,12]. Evaluation of patients with dilated cardiomyopathy and conduction delay has
 yielded ample evidence of the deleterious effects of dysscynchronous ventricular activation.
 Conversely, the positive response to the restoration of ventricular synchrony via
 bi-ventricular pacing has further highlighted the negative effects of ventricular
 dyysynchrony. In this subset of patients, acute biventricular pacing, as compared to RV
 pacing, demonstrated increases in systolic function and ejection fraction, along with
 decreased mitral insufficiency and LV volumes [13]. Resynchronization positively influences
 reverse remodeling with significant reductions in LV end systolic and LV end diastolic
 volumes and left atrial size - changes that appear permanent [7]. Resynchronization has also
 been implicated in improved exercise capability, peak oxygen uptake and improved quality of
 life measures [14].

 With established evidence of maladaptive changes to cardiac morphology and function, plus
 emerging evidence of adversely effected exercise capacity in adults with chronic RVA pacing,
 it is necessary to investigate the possible aberrancy in exercise capacity in the RVA paced
 pediatric population.

 Patient Population

 Patients between 10 and 21 years of age seen at Children's Healthcare of Atlanta and Sibley
 Heart Center satisfying the following criteria:

 -  Structurally normal heart

 -  Congenital complete heart block

 -  Dual chamber, right ventricular apex paced

 -  Normal function via traditional transthoracic echocardiography

 -  Absence of preexisting condition that precludes patient from exercise All participating
 subjects and their parents (if applicable) will be required to sign an informed consent
 prior to any study procedure. Patients with repaired or palliated congenital heart
 disease will be excluded from the study. We anticipate enrolling 30 patients for this
 study.

 Research Design and Methods

 Design:

 The proposed study will be a single center, prospective, pilot examination of exercise
 capacity in pediatric patients requiring right ventricular apical pacing. We will assess the
 effects of chronic ventricular dyssynchrony on exercise duration, oxygen uptake and
 ventilatory response to exercise. All subjects will be extracted from active patients of the
 Children's Healthcare of Atlanta/ Sibley Heart Center pacemaker clinic, being followed for
 CCAVB and dual chamber RVA pacing. All participants will be required to sign an informed
 consent prior to a procedures. Patients with palliated or corrected congenital heart disease
 will be excluded.

 Procedures:

 1. Echocardiographic Assessment: all participants will receive a standard 2-dimensional
 M-mode and Doppler evaluation. We will assess cardiac function using left ventricular
 shortening fraction and ejection fractions. Tissue Doppler imaging will be utilized to
 evaluate ventricular synchrony.

 2. Exercise Testing: Using a modified Bruce treadmill protocol, with staged increases in
 belt speed and incline, the subject's duration of exercise, work, oxygen uptake, maximal
 heart rate, blood pressure and ventilatory responses will be measured. The procedure
 will take place at the exercise laboratory at Children's Healthcare of Atlanta at
 Egleston, utilizing the customary staff. There will be physician attendance for all
 procedures. Analysis of the exercise results will be conducted by an attending pediatric
 cardiologist.

 3. Clinical Assessment: Clinical evaluation will be performed during routine pacemaker
 clinic visit, during treadmill exercise testing and at subsequent routine pacemaker
 clinic visits. The information gained from this study will not be used for individual
 care.

 Study Regimens After eligibility is established and baseline assessment completed, consenting
 patients will undergo exercise treadmill testing. Using established CHOA protocols, max heart
 rate, oxygen uptake, blood pressure and ventilatory changes will be measured during the test.
 Subjects will then return to their usual and customary cardiac follow up schedule.

 MANAGEMENT OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

 1. Monitoring of Adverse Events (AEs) and Serious Adverse Events (SAEs) is an important
 aspect of data collection in this study. Families will be questioned about possible AEs
 follow up survey and asked to notify clinical staff of any AE, illness, medical procedure or
 hospitalization. The duration after the completion of all study procedures for which AE's
 will be recorded will be one month. One month will be a sufficient time to capture all
 possible AE's given that most potential AE's would occur in the immediate testing period. An
 adverse event case report form (CRF) will be created to capture any medical symptoms
 experienced since the exercise test to solicit unexpected AEs. For any adverse experience
 reported during the study, the nature, duration, intensity and any remedial action will be
 recorded. Serious AEs (life-threatening, requiring hospitalization) will be reported to the
 IRB within 48 hours of notification. The Research Coordinator in conjunction with the
 Principal Investigator will collect the adverse experiences from the medical record/subject.
 The Principal Investigator will determine the seriousness of each adverse event.

 Statistical Considerations We anticipate analyzing the obtained data utilizing analysis of
 covariance (ANCOVA). The independent variable will be the group assignment (healthy vs paced
 patients) and the co-variable being added to the model is age.

 Ethics and Patient Safety This study will be conducted in accordance with the ethical
 principals that have their base in the Declaration of Helsinki and will be conducted with
 Good Clinical Practice (GCP) and applicable regulatory requirements. This study will be
 conducted in compliance with the protocol. The protocol, any amendments and the subject
 informed consent will receive Institutional Review Board (IRB) approval prior to initiation.
 During the conduct of the study, all adverse events will be reported to the IRB during the
 renewal period however, adverse events classified as serious (SAEs) will be reported within
 24 hour of knowing of the occurrence to the IRB.

 Freely given written informed consent including patient authorization per HIPAA guidelines
 will be obtained from every subject, parent or legal guardian prior to the initiation of any
 study procedures. A copy of all consent documents will be provided to the parent or legal
 guardian. The rights, safety and well-being of the trial subjects are the most important
 considerations and will prevail over interests of science and society.
Inclusion Criteria:

 -  between 10 and 21 years of age

 -  structurally normal heart

 -  congenital complete heart block

 -  dual chamber pacemaker, right ventricular apex paced

 -  normal function via traditional transthoracic echocardiography

 Exclusion Criteria:

 -  preexisting condition that precludes patient from exercise

 -  no informed consent