Dilated Cardiomyopathy in Children With Isolated Congenital Complete Atrioventricular Block
Article ID: CJ-16-0284
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Article ID: CJ-16-0284
Isolated congenital complete atrioventricular block (CCAVB), also known as congenital heart block (CHB), is a rare life-threatening bradyarrhythmia with a prevalence of 1 per 15,000–20,000 live-born infants.1 Although most cases of isolated CCAVB develop in association with maternal autoantibodies (ie, anti-SSA (Ro) and anti-SSB (La)), as a manifestation of neonatal lupus (NL), the exact mechanism of CCAVB remains elusive. A major issue is why only 1–2% of autoimmune-positive pregnancies result in CCAVB. This means maternal autoantibodies are not sufficient for the development of CCAVB, suggesting the involvement of some other factors, such as genetic susceptibility or maternal microchimerism of the fetus. The precise mechanism of the binding of placentally transferred maternal autoantibodies with intracellular proteins (Ro52 and Ro60) also remains to be investigated. Some researchers proposed a mechanism in which maternal anti-Ro60 antibodies first bind to apoptotic cells (which normally appear in the developing fetal heart), and then anti-Ro52 antibodies bind to the necrotic cells, inducing inflammation and fibrosis in the developing conduction system.2 The 3rd question is why the primary site of cardiac injury is usually confined to the atrioventricular (AV) node. For this question, clinical observations have demonstrated cardiac manifestations other than CCAVB, including dilated cardiomyopathy (DCM), endocardial fibroelastosis (EFE), valve insufficiency and arrhythmias, as sequels in some cases of NL (Table 1).3 Clinically, DCM is one of the important factors that determine the prognosis of infants with CCAVB. Although pathological studies demonstrated antibodies, complements, and signs of inflammation or fibrosis throughout the myocardium, suggesting the importance of the same molecular mechanisms involved in CCAVB in the development of DCM,2 there is an increasing number of reports demonstrating that chronic right ventricular (RV) single-site pacing can cause left ventricular (LV) dysfunction and DCM through ventricular dyssynchrony. From this point of view, the article by Tsujii et al4 in this issue of the Journal deals with an essential issue in the management of CCAVB children. This editorial will focus on the development of DCM after pacemaker implantation (PMI) in children with CCAVB.
| Congenital complete AV block (CCAVB) (irreversible) |
| 1st degree AV block (may be reversible) |
| 2nd degree AV block (may be reversible) |
| Dilated cardiomyopathy |
| (from autoimmune injury and/or chronic RV pacing) |
| (can occur in the absence of CCAVB) |
| Endocardial fibroelastosis (EFE) |
| Sinus bradycardia or sick sinus syndrome |
| (possibly from autoimmune injury to ICaL, ICaT) |
| QT prolongation |
| AV valve insufficiency |
| (from chordal rupture) |
AV, atrioventricular; RV, right ventricular.
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Prevalence of DCM in Patients With CCAVBThe advent of small high-performance pacemakers has reduced the mortality rate of infants with CCAVB. However, DCM was then recognized as a life-threatening sequel of NL. Tsujii et al4 report in their retrospective study that DCM (and/or fatal heart failure) developed in 8 of 32 (25%) patients who underwent PMI but in none of 6 patients who did not. The data from larger studies were similar; Levesque et al5 reported that postnatal DCM was present or developed in 35 cases of 186 (18.8%) children after a median follow-up of 7 years. Among the 35 cases, 9 (26%) had PMI and 14 (40%) died. Izmirly et al6 studied 325 children with cardiac NL and identified 40 cardiac-related deaths, with 37 from cardiomyopathy (DCM, EFE, or fetal hydrops). However, PMI was not associated with mortality in all study subjects or in live-born babies. In a multicenter study by Eliasson et al,7 impaired LV function or DCM was observed in 17 (12%) of 141 cases. LV dysfunction at follow-up was associated with abnormal LV function before PMI. These results implicate the abovementioned autoimmune mechanism in the development of DCM, although PMI is definitely related to DCM development in a considerable number of patients with CCAVB and the possibility should always be considered, as recommended.4
Mechanisms of DCM Development by RV PacingRecently, evidence for implication of RV single-site pacing in the development of DCM in children with CCAVB has been reported.4–8 This relationship is supported by the fact that DCM may develop after PMI in patients with originally normal LV function. In CCAVB, most of the pacemaker recipients are small children whose typical abnormality is bradycardia because of CCAVB usually associated with healthy myocardium, and ventricular pacing is beneficial to directly increase heart rate. The epicardial side of the RV free wall is easy to approach, and has long been chosen for most small children, without recognition of the possibility of LV systolic dysfunction induced by permanent RV pacing.
Abnormal electrical activation pattern and the consequent mechanical dyssynchrony of the ventricles have been proposed as the most significant contributors to LV dysfunction.9 The LV portion close to the RV pacing site contracts at low chamber pressure and stretches the opposing non-contracting wall. The delayed activated portion contracts with increased force through the Frank-Starling mechanism produced by this stretching, and at high wall stress as the early-activated region is in a period of systolic stiffening. This stretching and contraction of opposing LV walls leads to redistribution of myocardial mechanical work and perfusion, wasted energy, as well as inefficient global pump function caused by mechanical dyssynchrony. Other proposed mechanisms include changes in LV myocardial remodeling, and alterations in myocardial protein expression because of changes in regional hypertrophy and blood flow.9
Pacemaker UpgradeDevelopment of significant LV dysfunction or DCM in a child with CCAVB after permanent RV pacing is a marker of poor prognosis,4–8 and additional interventions should be considered. The literature describes encouraging results of apparent improvement or resolution of LV dysfunction/heart failure after upgrading the pacemaker to the CRT system or changing the pacing site to the LV,8,10–16 although some report poor outcome (examples of such cases in which individual data are available are listed in Table 2). CRT might be ideal for restoration of ventricular synchrony, but the device is large to implant in a small child and the majority of children’s hospitals in Japan do not meet the institutional criteria for CRT use.14 Vanagt et al11 presented a 2-year-old girl with CCAVB and heart failure under permanent RV single-site pacing, who showed recovery of normal LV function shortly after changing the pacing site to the LV apex. They stated that LV single-site pacing was practical, compared with CRT, and sufficient to restore LV function, suggesting the importance of pacing site rather than atrioventricular sequence. Acute positive effects of temporary termination of RV pacing on LV function were also demonstrated in other studies.11,17 Results of LV pacing as an initial PMI instead of conventional RV pacing for 10 neonates or infants with CCAVB have been published recently,18 showing normal and synchronous LV function in most patients at 12-month follow-up. The benefits of biventricular pacing have also been reported in patients with CCAVB who developed congestive heart failure or DCM after RV pacing.10,15 Actually, strategies using LV single-site pacing or CRT have been increasingly applied worldwide, even in infants, with favorable results. However, there are currently no guidelines for selection of patients or timing for revision of pacing site or upgrading of pacing mode or devices. Definite parameters to detect LV dyssynchrony have not been established either.
| Case no. |
Author | Year | Original pacing site (age) |
Revised PM site/mode (age) |
Before PM revision |
After PM revision, clinical outcome |
|---|---|---|---|---|---|---|
| 1 | Moak et al10 | 2006 | RV (0.2 years) | CRT (6 years) | LVEF 30% | LVEF 59% |
| 2 | Moak et al10 | 2006 | RV (3 years) | CRT (15.5 years) | LVEF 20% | LVEF 60% |
| 3 | Moak et al10 | 2006 | RV (5.5 years) | CRT (17 years) | LVEF 12% | LVEF 66% |
| 4 | Vanagt et al11 | 2007 | RV free wall (1 day) | LV apex (2 years) | LVSF 20% | LVSF 36% |
| 5 | Kurosaki et al12 | 2008 | RV (5 days) | LV (5 years) | – | Alive (for 10.5 years), LVSF 38%, CTR 54%, BNP 17 pg/ml |
| 6 | Kurosaki et al12 | 2008 | RV (10 days) | CRT (4 years) | – | Alive (for 4.3 years), LVSF 20%, CTR 54%, BNP 23 pg/ml |
| 7 | Kurosaki et al12 | 2008 | RV (1 day) | LV | – | Alive (for 11.2 years), LVSF 31%, CTR 55%, BNP 56 pg/ml |
| 8 | Kurosaki et al12 | 2008 | RV (5 days) | CRT-P (6 months) | – | Died (7 months) from DCM |
| 9 | Gebauer et al8 | 2009 | RV free wall (neonatal) | CRT (3.4 years) | NYHA class IV, LVSF 30% |
Deterioration, LVSF 10% |
| 10 | Matsuhisa et al13 | 2014 | RV lateral (0.2 years) | LV apex (3.8 years) | LVSF 24%, BNP 18.2 pg/ml |
LVSF 41%, BNP 10.2 pg/ml |
| 11 | Matsuhisa et al13 | 2014 | LV base (1.2 years) | LV apex (4.7 years) | LVSF 14%, BNP 327 pg/ml |
LVSF 48%, BNP 21.1 pg/ml |
| 12 | Horigome et al15 | 2014 | RV (neonatal) | CRT-P (16 months) | CTR 70%, BNP 6,520 pg/ml |
CTR 55%, BNP 28 pg/ml |
| 13 | Ellesøe et al16 | 2014 | RV outflow (31 days) | CRT-P (16 months) | LVSF 10% | LVSF 33% |
| 14 | Tsujii et al4 | 2016 | RV inflow | LV apex | – | Alive (for 7 years), NYHA class I |
| 15 | Tsujii et al4 | 2016 | RV apex | CRT | – | Alive (for 8 years), NYHA class I |
Most cases showed improvement or resolution of LV dysfunction/heart failure after upgrading pacemakers to CRT system or changing the pacing site to LV, though some showed poor outcome. Only cases with cited individual data are included. BNP, B-type natriuretic peptide; CCAVB, congenital complete atrioventricular block; CRT, cardiac resynchronization therapy; CRT-P, CRT with a biventricular pacemaker; CTR, cardiothoracic ratio; DCM, dilated cardiomyopathy; LV, left ventricular; LVEF, LV ejection fraction; LVSF, LV shortening fraction; NYHA, New York Heart Association; PM, pacemaker. Other abbreviation as in Table 1.
Development of DCM in CCAVB children is frequently associated with pre-PMI LV dysfunction possibly caused by an autoimmune mechanism. However, it can occur after chronic RV single-site pacing, even in patients with completely normal echocardiography before PMI. Tailored follow-up of patients at risk and accurate monitoring of LV function before and after PMI are mandatory for detection of deterioration of LV dysfunction at an early stage.
