Pediatr Cardiol DOI 10.1007/s00246-015-1142-4
ORIGINAL ARTICLE
Left Ventricular Dysfunction Following Neonatal Pulmonary Valve Balloon Dilation for Pulmonary Atresia or Critical Pulmonary Stenosis Christina Ronai1,2 • Rahul H. Rathod1,2 • Audrey C. Marshall1,2 • Rebecca Oduor1,2 Kimberlee Gauvreau1,2 • Steven D. Colan1,2 • David W. Brown1,2
•
Received: 25 November 2014 / Accepted: 4 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary valve (PV) balloon dilation (BD) is the primary therapy for infants born with critical pulmonary stenosis (PS) or membranous pulmonary atresia with intact ventricular septum (PAIVS). We observed left ventricular (LV) dysfunction in patients following BD and sought to determine its incidence, clinical course and associated risk factors. Clinical, echocardiographic and catheterization data for all patients who underwent neonatal (\2 weeks age) PV BD for critical PS or PAIVS between January 2000 and February 2014 were retrospectively analyzed (n = 129). Post-procedure LV dysfunction was defined as ejection fraction (EF)\54 %. Median age at PV BD was 1 day. Most (71 %) patients had critical PS. Median PV diameter pre-BD was 6.0 mm with PV z-scores -4.1 to 0.9, median LV EF pre-BD was 58 %. Post-BD LV dysfunction developed in 45 patients (35 %); 15 patients had LV EF B40 %. Median time to normalization of LV EF was 10 days (range 2–72). In univariate analysis, diagnosis (critical PS or PAIVS), right ventricle to LV pressure ratio pre-BD, acute procedural complication and post-BD inotropic support were not associated with postBD LV dysfunction. In multivariable analysis, the predictors of post-procedure LV dysfunction were lower PV z-score (OR 1.81, p 0.04), tricuspid regurgitation preBD C moderate (OR 3.73, p 0.008) and larger right ventricular apical area (OR 1.99, p 0.04). LV dysfunction postneonatal PV BD develops in a significant number of & Christina Ronai [email protected] 1
Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
2
Department of Pediatrics, Harvard Medical School, Boston, MA, USA
patients (35 %) and can be severe, but resolves. The risk of developing LV dysfunction post-PV BD is highest in patients with larger right ventricles. Keywords Catheterization Valvuloplasty Pulmonary valve Congenital heart disease
Introduction Pulmonary valve (PV) balloon dilation (BD) constitutes primary therapy for infants born with critical pulmonary stenosis (PS) and has been pursued in many centers for treatment of membranous pulmonary atresia with intact ventricular septum (PAIVS) [3, 18]. Follow-up studies of patients having undergone PV perforation and/or BD have shown high rates of initial success and modest need for reintervention [4, 7, 10, 13, 15, 18]. Studies have also demonstrated successful growth of both the right ventricle (RV) and PV after BD [6, 11, 17]. However, in the setting of acute gradient reduction post-PV BD and freedom from prostaglandin dependence, we have observed a number of patients develop significant left ventricular (LV) dysfunction, some severe in degree. Since first described as a method of intervention by Kan in 1982, there has been no focused examination of this complication following transcatheter relief of RV outflow tract obstruction. LV dysfunction prior to relief of neonatal RV outflow obstruction has been described in the literature [16]. In addition, regional LV dysfunction has been described in patients with mild coronary abnormalities; however, global LV dysfunction following neonatal PV perforation or balloon dilation for critical PS or membranous PAIVS has not been described or characterized [5]. We sought to determine the incidence of LV dysfunction, associated risk
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factors and subsequent outcomes in a large cohort of patients who underwent transcatheter RV decompression.
Methods Patients Patients with the diagnosis of either critical PS (requiring prostaglandin infusion) or membranous PAIVS who underwent catheter-based intervention on the PV from January 1, 2000 to February 14, 2014 were ascertained from the computer databases in the Department of Cardiology. Patients C2 weeks of age at intervention, and those with RV-dependent coronary circulation by angiography, were excluded from the study. Demographic and clinical variables including subsequent procedures were collected from the medical records of the 129 infants who met inclusion criteria through to the time of discharge from the hospital. Catheterization The technical details of PV BD for critical PS as well as radiofrequency perforation and balloon dilation of membranous PAIVS have been described previously [3, 4]. Our general approach is to use serially larger balloons, typically with a balloon diameter/pulmonary valve annulus ratio of \1.2. Data were collected retrospectively from reports produced at the time of the catheterization, including saturation and pressure data, balloon and annulus dimensions, number of BD performed and pre- or postcatheterization use of inotropes were included in the analysis. In addition, pre- and post-BD ratio of RV pressure to aortic or LV pressure was calculated. Echocardiography All patients had a pre-catheterization echocardiogram performed and at least one post-catheterization echocardiogram performed within 14 days of the procedure. For those with multiple post-catheterization echocardiograms prior to discharge, the study with the lowest LV ejection fraction was recorded. We defined LV dysfunction as an ejection fraction \54 %. Variables and z-scores collected for analysis from pre-procedure echocardiograms included PV annulus dimension, main pulmonary artery dimension, tricuspid valve annulus, tricuspid valve area, RV diastolic apical area from four-chamber view [1], LV end-diastolic and end-systolic dimensions (2D measurements), and LV end-diastolic and end-systolic volumes (using the 5/6*Area*length algorithm) [14] and ejection fraction. Z-scores were calculated as previously described [2]. In addition, the presence of antegrade pulmonary blood flow
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and estimated RV pressure by tricuspid regurgitation jet velocity, if present, was collected. Qualitative grading of tricuspid and pulmonary regurgitation from the original signed report was also documented. From the post-catheterization studies, LV end-diastolic and end-systolic dimensions, LV ejection fraction, the presence of a patent ductus arteriosus, RV pressure by tricuspid regurgitation jet and degree of pulmonary and tricuspid regurgitation were collected. If LV dysfunction was present, subsequent echocardiograms were reviewed and the date when left ventricular function returned to normal (ejection fraction [55 %) was documented. Any missing data elements from the original reports (e.g., valve annulus measurements, ejection fraction) were measured on all patients with digital images available. Statistical Analysis The primary outcome variable was LV dysfunction postPV BD as defined as a LV ejection fraction \54 % on the post-catheterization echocardiogram. Continuous variables are summarized as either mean ± standard deviation or median (range) and compared between groups using the unpaired t test or Wilcoxon’s rank sum test. Categorical variables are displayed as number (percent) and compared using Fisher’s exact test. Multivariable analysis for the outcome LV dysfunction was performed using logistic regression; variables with p B 0.10 in univariate analysis were considered for inclusion, but p \ 0.05 was required for retention in the final model. Odds ratios and 95 % confidence intervals are presented. Discrimination of the model was assessed using the area under the receiver–operator characteristic curve. This retrospective study was performed according to a protocol approved by the Committee for Clinical Investigation at Boston Children’s Hospital. The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Results Patients Between January 1, 2000 and February 14, 2014, 129 patients B2 weeks of age underwent PV BD for critical PS or membranous PAIVS. Demographic and clinical data are shown in Table 1. Median age at catheterization was 1 day; ninety-one (71 %) of the patients had critical PS, and 38 (29 %) had membranous PAIVS. A prenatal diagnosis of the patient’s congenital heart disease was made in 42 % (54). Two patients in the study died during the initial
Pediatr Cardiol Table 1 Patient characteristics (n = 129)
Number (%) or median (range) Pulmonary atresia intact ventricular septum
38 (29 %)
Critical pulmonary stenosis
91 (71 %)
Male
69 (53 %)
Age at catheterization (days)
1 (0–12)
Weight (kg)
3.2 (1.5–4.7)
BSA
0.21 (0.13–0.28)
Premature*
15 (12 %)
Prenatal diagnosis
54 (42 %)
Pre-catheterization echocardiogram LV EF(%) n = 100
58 (46–73)
2
RV apical area (cm ) (n = 98)
2.25 (0.7–4.38)
LV EDV z-score
0.6 (-5.2 to 3.3)
Pre-catheterization pressors
19 (15 %)
Post-catheterization pressors
31 (24 %)
Pre-dilation RVp (mm Hg) PV annulus/balloon ratio
103 (33–170) 1.19 (0.70–2.00)
Post-dilation RVp (mm Hg)
52 (26–114)
Post-catheterization echocardiogram LV EF (%) (n = 100)
55 (12–75)
LV EF \44 % (n = 100)
25 (25 %)
LV EDV z-score
0.3 (-2.5 to 3.3)
Outcomes Time to normalization (days) (n = 25)
10 (2–72)
Post-catheterization LV dysfunction
45 (35 %)
Mortality
2 (2 %)
Surgery prior to discharge
31 (24 %)
Surgery ever
45 (35 %)
Length of stay (days)
12 (1–117)
Discharge medications
25 (19 %)
BSA body surface area, LV left ventricle, EF ejection fraction, RV right ventricle, EDV end-diastolic volume, RVp right ventricular pressure * Defined as gestational age \36 weeks
hospitalization; one had undergone fetal PV dilation and subsequently developed multi-system organ failure, and the other was a 30-week premature infant who developed sepsis after surgery for placement of a Blalock-Taussig shunt. Post-PV BD, no patients were found to have RVdependent coronary circulation. Forty-five patients (35 %) developed LV dysfunction after PV BD with moderate or severe LV dysfunction (ejection fraction \40 %) in 15 (12 %) patients. Prior to undergoing PV BD, the median LV ejection fraction for the entire group was 58 % (range 46–73 %). Of the eight patients (6.2 %) with ejection fractions \54 % prior to PV BD, four had post-PV BD LV dysfunction and four had normal LV function post-PV BD. Precatheterization echocardiograms showed the median PV diameter to be 6 mm (3.5–10 mm) with z-score -1.8
(-4.1 to 0.9). RV diastolic apical area from four-chamber view was measured in 98 of the patients with a median area of 2.25 cm2 (0.70–4.38 cm2). Moderate-to-severe tricuspid regurgitation was present in 53 % (68) of patients. Eightyfive patients (66 %) had antegrade pulmonary blood flow prior to their cardiac catheterization, 86 % had no or trivial pulmonary regurgitation initially. Median LV end-diastolic volume z-score pre-dilation was 0.6 (-5.2 to 3.3). Procedural Data Catheterization data for the 129 patients demonstrated that median RV pressure (pre-intervention) was 103 mmHg (33–170 mm Hg), with an RV to aortic pressure ratio of 1.70 (0.49–2.93). The median PV annulus to balloon ratio was 1.19 (0.70–2.00). Post-PV dilation the median RV to
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Pediatr Cardiol
aortic pressure ratio was 0.85 (0.39–1.75). Acute procedural complications, all of which were right ventricular outflow tract wire perforations, occurred in seven patients (5.5 %), and all were managed medically.
Diagnosis and ejection fraction 80
EF (%)
60
20
S C rit ic al P
PA IV S
S al P rit ic C
Fig. 2 Relationship between diagnosis and pre- and post-cardiac catheterization ejection fraction (EF)
(-2.1 ± 0.9 vs. -1.6 ± 1.0, p = 0.002) (Figs. 3, 4). Additionally, the presence of more than moderate tricuspid regurgitation pre-cardiac catheterization was associated with developing post-catheterization LV dysfunction. The proportion of patients with greater than moderate tricuspid regurgitation post-cardiac catheterization was larger in the patients who developed left ventricular dysfunction (51 vs. 26 %, p = 0.006). In addition, there was no difference in LV end-diastolic volume z-scores in the LV dysfunction and no dysfunction patients either pre- or post-cardiac catheterization (Table 2). Post-PV BD having greater than moderate pulmonary regurgitation was not associated with LV dysfunction. Lower RV pressure pre-catheterization was associated with the development of LV dysfunction (93 vs.
RV apical area and LV dysfunction p=0.002
RV apical area (cm2)
0.8 0.6
4 3 2 1 0
dy
40
60
80
LV
20
Days to normalization (EF
o
0
N
0.0
54%)
Fig. 1 Time course to normalization of left ventricular ejection fraction (EF)
123
dy sf
sf
un
0.2
un ct
ct
io
io
n
n
0.4
LV
Fraction of subjects with abnormal EF
5
1.0
po st ca th
po st ca th
pr e
ca th
ca th
0
pr e
Post-intervention echocardiograms showed 94 (73 %) patients still had a patent ductus arteriosus, 42 % (54) had greater than moderate pulmonary regurgitation, and 34 % had greater than moderate tricuspid regurgitation. Median RV pressure (calculated from the tricuspid regurgitation jet velocity) was 40 mm Hg (20–80) in 77 patients. 24 % (37) of patients underwent surgery prior to discharge (all were Blalock-Taussig shunts except one who underwent aortic coarctation repair). Of the 37 patients who underwent surgery, 24 % (9) had post-PV BD LV dysfunction prior to surgery. Twenty-five patients went home on cardiac medications which included furosemide, propranolol, captopril and spironolactone. Median time course to normalization of LV ejection fraction was 10 days (range 2–72 days) in those with serial echocardiographic followup (Fig. 1). Comparison of the patients with post-intervention LV dysfunction and those with no dysfunction showed no difference between diagnoses (critical PS vs. membranous PAIVS, Fig. 2), age at catheterization, weight or prematurity. In addition, only two of the seven patients with right ventricular outflow tract perforations developed LV dysfunction. In univariate analysis, factors associated with developing LV dysfunction post-cardiac catheterization intervention included a larger RV apical area (2.65 vs. 2.15 cm2, p = 0.002), larger tricuspid valve area z-score (1.70 ± 3.18 vs. 0.38 ± 2.18, p = 0.02), and smaller PV z-score
40
PA IV S
Post-PV BD
Fig. 3 Relationship between right ventricular (RV) apical area and the presence of left ventricular (LV) dysfunction post-cardiac catheterization
Pediatr Cardiol
Pulmonary Valve z-score and LV dysfunction
PV z-score
2
p=0.002
0 -2 -4
N o
LV
LV
dy sf un ct io n
dy sf un ct io n
-6
Fig. 4 Relationship between pulmonary valve (PV) z-score and left ventricular (LV) dysfunction
106 mmHg, p = 0.02) (Table 3). In addition, post-PV BD, a lower RV pressure as measured by tricuspid regurgitation jet was associated with post-catheterization LV dysfunction (36 mmHg ± 10 vs. 44 mmHg ± 14, p = 0.004). Residual patent ductus arteriosus post-PV BD was not associated with the development of LV dysfunction. In multivariable analysis (n = 98), the statistically significant predictors of LV dysfunction were smaller PV z-score, increased RV apical area and greater than moderate tricuspid regurgitation pre-cardiac catheterization (Table 4) with area under the ROC curve (C-statistic) = 0.77. Further analysis of patients with LV ejection fraction \40 % (moderate-to-severe LV dysfunction) (n = 15 patients) in univariate analysis continued to demonstrate that larger tricuspid valve z-score (0.98 vs. -0.76, p = 0.02), greater than moderate tricuspid regurgitation precatheterization and larger RV apical area (2.94 vs. 2.25 p = 0.02) were associated with development of post-PV
Table 2 Comparison echocardiogram data by outcome LV dysfunction (n = 129) Post-cath LV dysfunction (n = 45)
No post-cath LV dysfunction (n = 84)
p value
Pre-catheterization echo Diagnosis
0.69
PAIVS
12 (27 %)
12 (27 %)
Critical pulmonary stenosis
33 (73 %)
58 (69 %)
LV EF (%) (n = 41, 59)
59 ± 6
60 ± 5
LV EF \54 % (n = 41, 59)
4 (10 %)
4 (7 %)
0.26 0.71
LV EDV z-score (n = 39, 57)
0.4 ± 1.7
0.5 ± 1.1
0.61
RV apical area (n = 40, 58)
2.65 ± 0.84
2.15 ± 0.69
0.002
PV diameter (mm)
5.7 ± 1.0
6.3 ± 1.3
0.002
PV z-score
-2.1 ± 0.9
-1.6 ± 1.0
0.002
TV AP (mm) (n = 42, 67)
10.6 ± 2.8
9.2 ± 2.0
0.009
TV AP z-score (n = 42, 67)
0.14 ± 2.14
-0.85 ± 1.34
0.009
TV area z-score (n = 44, 82) RVp TR Jet (mm Hg) (n = 34, 59)
1.70 ± 3.18 94 ± 25
0.38 ± 2.18 104 ± 25
0.02 0.07 \0.001
Degree of TR C moderate (pre-cath)
34 (76 %)
35 (42 %)
Degree of TR severe (pre-cath)
12 (27 %)
4 (5 %)
0.001
LV EF (%) (n = 41, 59)
41 ± 9
58 ± 4
\0.001
LV EDV z-score (n = 40, 53)
0.5 ± 1.6
0.3 ± 1.1
0.37
RVp TR jet (mm Hg) (n = 31, 46)
36 ± 10
44 ± 14
0.004
PDA present
29 (64 %)
65 (77 %)
0.24
Degree of PR C moderate
24 (53 %)
29 (37 %)
0.09
Degree of Cmoderate TR
23 (51 %)
21 (26 %)
0.006
Degree of severe TR
6 (13 %)
1 (1 %)
0.008
Post-catheterization echo
Values shown are number (%), median (range) or mean ± SD PAIVS pulmonary atresia intact ventricular septum, Cath cardiac catheterization, LV left ventricle, EF ejection fraction, RV right ventricle, PV pulmonary valve, TV tricuspid valve, AP anterior-posterior, EDV end-diastolic volume, RVp right ventricular pressure, TR tricuspid regurgitation, PR pulmonary regurgitation, PDA patent ductus arteriosus
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Pediatr Cardiol Table 3 Comparison catheterization data by outcome LV dysfunction (n = 129) Catheterization data
Post-cath LV dysfunction (n = 45)
No post-cath LV dysfunction (n = 84)
p value
Pre-cath pressors
11 (24 %)
8 (10 %)
0.04
Pre-dilation MV saturation (%) (n = 43, 81)
61 ± 12
67 ± 10
0.01
Pre-dilation aortic saturation (%) (n = 43, 83)
87 ± 7
90 ± 7
0.02 0.02
Pre-dilation RVp (mm Hg)
93 ± 29
106 ± 25
Pre-dilation RV–LV/Ao (n = 45, 83)
1.58 ± 0.50
1.74 ± 0.51
0.10
PV annulus/balloon ratio
1.27 ± 0.21
1.19 ± 0.21
0.04 0.54
Post-dilation RVp (mm Hg)
54 ± 14
56 ± 16
Post-dilation RV–LV/Ao (n = 44, 83)
0.86 ± 0.21
0.86 ± 0.27
0.86
Post-dilation aortic saturation (%) (n = 29, 58)
88 ± 6
92 ± 8
0.02
Post-cath pressors
13 (29 %)
18 (21 %)
0.39
Values represent number (%), median (range), or mean ± SD MV mixed venous, RVp right ventricular pressure, RV right ventricle, LV left ventricle
Table 4 Multivariable analysis: factors associated with LV dysfunction (n = 98)
Odds ratio
95 % CI
p value
PV z-score (;1)
1.81
(1.02, 3.24)
0.04
Degree of TR pre-cath Cmoderate
3.73
(1.41, 9.84)
0.008
RV apical area (:1)
1.99
(1.04, 3.80)
0.04
Area under ROC 0.767
Values represent number (%), median (range), or mean ± SD Ao aortic, Cath cardiac catheterization, LV left ventricle, MV mitral valve, PV pulmonary valve, TR tricuspid regurgitation, RV right ventricle, RVp right ventricular pressure
BD LV dysfunction. In multivariate analysis, the statistically significant predictors of Cmoderate LV dysfunction (ejection fraction \40 %) were larger tricuspid valve z-score, and increased RV apical area, with area under the ROC curve = 0.764.
Discussion We examined our experience with neonates who had undergone balloon dilation of PV for either critical PS or PAIVS and determined the incidence of post-dilation LV dysfunction which had been noted anecdotally. To our knowledge, the development of LV dysfunction post-balloon dilation of the PV has not previously been described. Prior to this study, neonates with LV dysfunction would get serial echocardiograms, often remain inpatient while waiting for the LV function to improve and be started on afterload reduction. In this study, we show that LV dysfunction develops in 35 % of patients after balloon dilation of the PV in the neonatal period and was moderate to severe in 12 %. Additionally, in all patients with serial echocardiographic follow-up, this LV dysfunction resolved
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completely and in a relatively short period of time; the median time to resolution was 10 days. The underlying pathophysiological mechanisms leading to this phenomenon are not entirely clear. One hypothesis is that the LV dysfunction could be related to the sudden, dramatic alteration in interventricular interaction following relief of RV outflow tract obstruction; this change in interventricular interaction is predicted to increase in proportion to the size of the right ventricle. An alternative hypothesis is that closure of the ductus arteriosus postcatheterization in the setting of prostaglandins being discontinued may acutely change the loading conditions of the LV, resulting in the appearance of LV systolic dysfunction. A third hypothesis implicates acute changes in coronary perfusion post-cardiac catheterization, since relief of RV hypertension could cause a transient coronary steal phenomenon post-BD, leading to relative LV ischemia. Given the relatively high incidence of LV dysfunction in this large cohort, we were able to do an analysis to determine risk factors associated with developing dysfunction. Factors associated with developing LV dysfunction postballoon dilation of the PV included greater RV apical area, tricuspid valve annular dimensions and tricuspid valve
Pediatr Cardiol
area, all consistent with larger RVs. This would support the hypothesis that there is increased potential for adverse ventricular–ventricular interactions in those patients with larger RVs, since a larger right ventricle shares a greater septal area with the LV and is able to exert a more dramatic influence on septal motion. In addition, these RVs tend to have more tricuspid regurgitation prior to PV BD, as well as being at lower pressure both pre- and post-PV BD. Finally, the short period of time required for recovery of left ventricular function is consistent with a temporary alteration in ventricular–ventricular interaction. In addition, this dysfunction manifests as global LV dysfunction and not segmental, suggesting that coronary ischemia is likely not the mechanism for the depressed function. Procedural ischemia is also not consistent with the observation that dysfunction was not always seen immediately post-BD, it was often seen on the echocardiogram performed 24 h after the catheterization to assess the status of the ductus arteriosus. Finally, the end-diastolic volumes of the LV postPV BD were not significantly different between the two groups, indicating that the onset of LV dysfunction was unlikely to be secondary to an acute change in volume loading of the LV. Our study also supports the findings of previous studies [9] that have reported that patients with PAIVS and larger RV’s are less likely to require surgery to augment pulmonary blood flow, since only three of the nine patients that had LV dysfunction (with larger RV’s) and required surgery were patients with PAIVS. Multiple prior studies looking at the short- and longterm outcomes after PV balloon dilation in the neonatal period consistently neglect evaluation of the LV [8]. Our observations raise the question of whether patients with acute post-procedural LV dysfunction are at increased risk of some later adverse outcome relative to those who never experienced LV dysfunction [12]. Future studies are needed to identify mechanisms for the development of left ventricular dysfunction in this population. Strain analysis of the LV in these patients both pre- and post-PV BD may be useful in better defining the adverse ventricular–ventricular interaction that occurs post-PV BD in the patients with larger RVs. This study has several limitations that stem primarily from the retrospective study design. Most importantly, echocardiographic surveillance for LV dysfunction postPV BD was not systematically performed at standard intervals, and follow-up echocardiogram intervals for those patients with LV dysfunction varied according to practitioner preference. Accordingly, the time course to normalization of LV function should be considered an estimate. Additionally, digital images were not available for additional measurements for patients born prior to 2004.
Conclusions After neonatal PV dilation for critical PS or PAIVS, a significant proportion of patients develop left ventricular dysfunction. Risk factors for left ventricular dysfunction after pulmonary balloon dilation include smaller PV annulus, increased RV apical area and larger TV size. While further study is necessary, this may be related to increased potential for ventricular–ventricular interaction in those with larger RVs. Conflict of interest
No conflicts to disclose.
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ORIGINAL ARTICLE
Left Ventricular Dysfunction Following Neonatal Pulmonary Valve Balloon Dilation for Pulmonary Atresia or Critical Pulmonary Stenosis Christina Ronai1,2 • Rahul H. Rathod1,2 • Audrey C. Marshall1,2 • Rebecca Oduor1,2 Kimberlee Gauvreau1,2 • Steven D. Colan1,2 • David W. Brown1,2
•
Received: 25 November 2014 / Accepted: 4 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary valve (PV) balloon dilation (BD) is the primary therapy for infants born with critical pulmonary stenosis (PS) or membranous pulmonary atresia with intact ventricular septum (PAIVS). We observed left ventricular (LV) dysfunction in patients following BD and sought to determine its incidence, clinical course and associated risk factors. Clinical, echocardiographic and catheterization data for all patients who underwent neonatal (\2 weeks age) PV BD for critical PS or PAIVS between January 2000 and February 2014 were retrospectively analyzed (n = 129). Post-procedure LV dysfunction was defined as ejection fraction (EF)\54 %. Median age at PV BD was 1 day. Most (71 %) patients had critical PS. Median PV diameter pre-BD was 6.0 mm with PV z-scores -4.1 to 0.9, median LV EF pre-BD was 58 %. Post-BD LV dysfunction developed in 45 patients (35 %); 15 patients had LV EF B40 %. Median time to normalization of LV EF was 10 days (range 2–72). In univariate analysis, diagnosis (critical PS or PAIVS), right ventricle to LV pressure ratio pre-BD, acute procedural complication and post-BD inotropic support were not associated with postBD LV dysfunction. In multivariable analysis, the predictors of post-procedure LV dysfunction were lower PV z-score (OR 1.81, p 0.04), tricuspid regurgitation preBD C moderate (OR 3.73, p 0.008) and larger right ventricular apical area (OR 1.99, p 0.04). LV dysfunction postneonatal PV BD develops in a significant number of & Christina Ronai [email protected] 1
Department of Cardiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
2
Department of Pediatrics, Harvard Medical School, Boston, MA, USA
patients (35 %) and can be severe, but resolves. The risk of developing LV dysfunction post-PV BD is highest in patients with larger right ventricles. Keywords Catheterization Valvuloplasty Pulmonary valve Congenital heart disease
Introduction Pulmonary valve (PV) balloon dilation (BD) constitutes primary therapy for infants born with critical pulmonary stenosis (PS) and has been pursued in many centers for treatment of membranous pulmonary atresia with intact ventricular septum (PAIVS) [3, 18]. Follow-up studies of patients having undergone PV perforation and/or BD have shown high rates of initial success and modest need for reintervention [4, 7, 10, 13, 15, 18]. Studies have also demonstrated successful growth of both the right ventricle (RV) and PV after BD [6, 11, 17]. However, in the setting of acute gradient reduction post-PV BD and freedom from prostaglandin dependence, we have observed a number of patients develop significant left ventricular (LV) dysfunction, some severe in degree. Since first described as a method of intervention by Kan in 1982, there has been no focused examination of this complication following transcatheter relief of RV outflow tract obstruction. LV dysfunction prior to relief of neonatal RV outflow obstruction has been described in the literature [16]. In addition, regional LV dysfunction has been described in patients with mild coronary abnormalities; however, global LV dysfunction following neonatal PV perforation or balloon dilation for critical PS or membranous PAIVS has not been described or characterized [5]. We sought to determine the incidence of LV dysfunction, associated risk
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factors and subsequent outcomes in a large cohort of patients who underwent transcatheter RV decompression.
Methods Patients Patients with the diagnosis of either critical PS (requiring prostaglandin infusion) or membranous PAIVS who underwent catheter-based intervention on the PV from January 1, 2000 to February 14, 2014 were ascertained from the computer databases in the Department of Cardiology. Patients C2 weeks of age at intervention, and those with RV-dependent coronary circulation by angiography, were excluded from the study. Demographic and clinical variables including subsequent procedures were collected from the medical records of the 129 infants who met inclusion criteria through to the time of discharge from the hospital. Catheterization The technical details of PV BD for critical PS as well as radiofrequency perforation and balloon dilation of membranous PAIVS have been described previously [3, 4]. Our general approach is to use serially larger balloons, typically with a balloon diameter/pulmonary valve annulus ratio of \1.2. Data were collected retrospectively from reports produced at the time of the catheterization, including saturation and pressure data, balloon and annulus dimensions, number of BD performed and pre- or postcatheterization use of inotropes were included in the analysis. In addition, pre- and post-BD ratio of RV pressure to aortic or LV pressure was calculated. Echocardiography All patients had a pre-catheterization echocardiogram performed and at least one post-catheterization echocardiogram performed within 14 days of the procedure. For those with multiple post-catheterization echocardiograms prior to discharge, the study with the lowest LV ejection fraction was recorded. We defined LV dysfunction as an ejection fraction \54 %. Variables and z-scores collected for analysis from pre-procedure echocardiograms included PV annulus dimension, main pulmonary artery dimension, tricuspid valve annulus, tricuspid valve area, RV diastolic apical area from four-chamber view [1], LV end-diastolic and end-systolic dimensions (2D measurements), and LV end-diastolic and end-systolic volumes (using the 5/6*Area*length algorithm) [14] and ejection fraction. Z-scores were calculated as previously described [2]. In addition, the presence of antegrade pulmonary blood flow
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and estimated RV pressure by tricuspid regurgitation jet velocity, if present, was collected. Qualitative grading of tricuspid and pulmonary regurgitation from the original signed report was also documented. From the post-catheterization studies, LV end-diastolic and end-systolic dimensions, LV ejection fraction, the presence of a patent ductus arteriosus, RV pressure by tricuspid regurgitation jet and degree of pulmonary and tricuspid regurgitation were collected. If LV dysfunction was present, subsequent echocardiograms were reviewed and the date when left ventricular function returned to normal (ejection fraction [55 %) was documented. Any missing data elements from the original reports (e.g., valve annulus measurements, ejection fraction) were measured on all patients with digital images available. Statistical Analysis The primary outcome variable was LV dysfunction postPV BD as defined as a LV ejection fraction \54 % on the post-catheterization echocardiogram. Continuous variables are summarized as either mean ± standard deviation or median (range) and compared between groups using the unpaired t test or Wilcoxon’s rank sum test. Categorical variables are displayed as number (percent) and compared using Fisher’s exact test. Multivariable analysis for the outcome LV dysfunction was performed using logistic regression; variables with p B 0.10 in univariate analysis were considered for inclusion, but p \ 0.05 was required for retention in the final model. Odds ratios and 95 % confidence intervals are presented. Discrimination of the model was assessed using the area under the receiver–operator characteristic curve. This retrospective study was performed according to a protocol approved by the Committee for Clinical Investigation at Boston Children’s Hospital. The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Results Patients Between January 1, 2000 and February 14, 2014, 129 patients B2 weeks of age underwent PV BD for critical PS or membranous PAIVS. Demographic and clinical data are shown in Table 1. Median age at catheterization was 1 day; ninety-one (71 %) of the patients had critical PS, and 38 (29 %) had membranous PAIVS. A prenatal diagnosis of the patient’s congenital heart disease was made in 42 % (54). Two patients in the study died during the initial
Pediatr Cardiol Table 1 Patient characteristics (n = 129)
Number (%) or median (range) Pulmonary atresia intact ventricular septum
38 (29 %)
Critical pulmonary stenosis
91 (71 %)
Male
69 (53 %)
Age at catheterization (days)
1 (0–12)
Weight (kg)
3.2 (1.5–4.7)
BSA
0.21 (0.13–0.28)
Premature*
15 (12 %)
Prenatal diagnosis
54 (42 %)
Pre-catheterization echocardiogram LV EF(%) n = 100
58 (46–73)
2
RV apical area (cm ) (n = 98)
2.25 (0.7–4.38)
LV EDV z-score
0.6 (-5.2 to 3.3)
Pre-catheterization pressors
19 (15 %)
Post-catheterization pressors
31 (24 %)
Pre-dilation RVp (mm Hg) PV annulus/balloon ratio
103 (33–170) 1.19 (0.70–2.00)
Post-dilation RVp (mm Hg)
52 (26–114)
Post-catheterization echocardiogram LV EF (%) (n = 100)
55 (12–75)
LV EF \44 % (n = 100)
25 (25 %)
LV EDV z-score
0.3 (-2.5 to 3.3)
Outcomes Time to normalization (days) (n = 25)
10 (2–72)
Post-catheterization LV dysfunction
45 (35 %)
Mortality
2 (2 %)
Surgery prior to discharge
31 (24 %)
Surgery ever
45 (35 %)
Length of stay (days)
12 (1–117)
Discharge medications
25 (19 %)
BSA body surface area, LV left ventricle, EF ejection fraction, RV right ventricle, EDV end-diastolic volume, RVp right ventricular pressure * Defined as gestational age \36 weeks
hospitalization; one had undergone fetal PV dilation and subsequently developed multi-system organ failure, and the other was a 30-week premature infant who developed sepsis after surgery for placement of a Blalock-Taussig shunt. Post-PV BD, no patients were found to have RVdependent coronary circulation. Forty-five patients (35 %) developed LV dysfunction after PV BD with moderate or severe LV dysfunction (ejection fraction \40 %) in 15 (12 %) patients. Prior to undergoing PV BD, the median LV ejection fraction for the entire group was 58 % (range 46–73 %). Of the eight patients (6.2 %) with ejection fractions \54 % prior to PV BD, four had post-PV BD LV dysfunction and four had normal LV function post-PV BD. Precatheterization echocardiograms showed the median PV diameter to be 6 mm (3.5–10 mm) with z-score -1.8
(-4.1 to 0.9). RV diastolic apical area from four-chamber view was measured in 98 of the patients with a median area of 2.25 cm2 (0.70–4.38 cm2). Moderate-to-severe tricuspid regurgitation was present in 53 % (68) of patients. Eightyfive patients (66 %) had antegrade pulmonary blood flow prior to their cardiac catheterization, 86 % had no or trivial pulmonary regurgitation initially. Median LV end-diastolic volume z-score pre-dilation was 0.6 (-5.2 to 3.3). Procedural Data Catheterization data for the 129 patients demonstrated that median RV pressure (pre-intervention) was 103 mmHg (33–170 mm Hg), with an RV to aortic pressure ratio of 1.70 (0.49–2.93). The median PV annulus to balloon ratio was 1.19 (0.70–2.00). Post-PV dilation the median RV to
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Pediatr Cardiol
aortic pressure ratio was 0.85 (0.39–1.75). Acute procedural complications, all of which were right ventricular outflow tract wire perforations, occurred in seven patients (5.5 %), and all were managed medically.
Diagnosis and ejection fraction 80
EF (%)
60
20
S C rit ic al P
PA IV S
S al P rit ic C
Fig. 2 Relationship between diagnosis and pre- and post-cardiac catheterization ejection fraction (EF)
(-2.1 ± 0.9 vs. -1.6 ± 1.0, p = 0.002) (Figs. 3, 4). Additionally, the presence of more than moderate tricuspid regurgitation pre-cardiac catheterization was associated with developing post-catheterization LV dysfunction. The proportion of patients with greater than moderate tricuspid regurgitation post-cardiac catheterization was larger in the patients who developed left ventricular dysfunction (51 vs. 26 %, p = 0.006). In addition, there was no difference in LV end-diastolic volume z-scores in the LV dysfunction and no dysfunction patients either pre- or post-cardiac catheterization (Table 2). Post-PV BD having greater than moderate pulmonary regurgitation was not associated with LV dysfunction. Lower RV pressure pre-catheterization was associated with the development of LV dysfunction (93 vs.
RV apical area and LV dysfunction p=0.002
RV apical area (cm2)
0.8 0.6
4 3 2 1 0
dy
40
60
80
LV
20
Days to normalization (EF
o
0
N
0.0
54%)
Fig. 1 Time course to normalization of left ventricular ejection fraction (EF)
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dy sf
sf
un
0.2
un ct
ct
io
io
n
n
0.4
LV
Fraction of subjects with abnormal EF
5
1.0
po st ca th
po st ca th
pr e
ca th
ca th
0
pr e
Post-intervention echocardiograms showed 94 (73 %) patients still had a patent ductus arteriosus, 42 % (54) had greater than moderate pulmonary regurgitation, and 34 % had greater than moderate tricuspid regurgitation. Median RV pressure (calculated from the tricuspid regurgitation jet velocity) was 40 mm Hg (20–80) in 77 patients. 24 % (37) of patients underwent surgery prior to discharge (all were Blalock-Taussig shunts except one who underwent aortic coarctation repair). Of the 37 patients who underwent surgery, 24 % (9) had post-PV BD LV dysfunction prior to surgery. Twenty-five patients went home on cardiac medications which included furosemide, propranolol, captopril and spironolactone. Median time course to normalization of LV ejection fraction was 10 days (range 2–72 days) in those with serial echocardiographic followup (Fig. 1). Comparison of the patients with post-intervention LV dysfunction and those with no dysfunction showed no difference between diagnoses (critical PS vs. membranous PAIVS, Fig. 2), age at catheterization, weight or prematurity. In addition, only two of the seven patients with right ventricular outflow tract perforations developed LV dysfunction. In univariate analysis, factors associated with developing LV dysfunction post-cardiac catheterization intervention included a larger RV apical area (2.65 vs. 2.15 cm2, p = 0.002), larger tricuspid valve area z-score (1.70 ± 3.18 vs. 0.38 ± 2.18, p = 0.02), and smaller PV z-score
40
PA IV S
Post-PV BD
Fig. 3 Relationship between right ventricular (RV) apical area and the presence of left ventricular (LV) dysfunction post-cardiac catheterization
Pediatr Cardiol
Pulmonary Valve z-score and LV dysfunction
PV z-score
2
p=0.002
0 -2 -4
N o
LV
LV
dy sf un ct io n
dy sf un ct io n
-6
Fig. 4 Relationship between pulmonary valve (PV) z-score and left ventricular (LV) dysfunction
106 mmHg, p = 0.02) (Table 3). In addition, post-PV BD, a lower RV pressure as measured by tricuspid regurgitation jet was associated with post-catheterization LV dysfunction (36 mmHg ± 10 vs. 44 mmHg ± 14, p = 0.004). Residual patent ductus arteriosus post-PV BD was not associated with the development of LV dysfunction. In multivariable analysis (n = 98), the statistically significant predictors of LV dysfunction were smaller PV z-score, increased RV apical area and greater than moderate tricuspid regurgitation pre-cardiac catheterization (Table 4) with area under the ROC curve (C-statistic) = 0.77. Further analysis of patients with LV ejection fraction \40 % (moderate-to-severe LV dysfunction) (n = 15 patients) in univariate analysis continued to demonstrate that larger tricuspid valve z-score (0.98 vs. -0.76, p = 0.02), greater than moderate tricuspid regurgitation precatheterization and larger RV apical area (2.94 vs. 2.25 p = 0.02) were associated with development of post-PV
Table 2 Comparison echocardiogram data by outcome LV dysfunction (n = 129) Post-cath LV dysfunction (n = 45)
No post-cath LV dysfunction (n = 84)
p value
Pre-catheterization echo Diagnosis
0.69
PAIVS
12 (27 %)
12 (27 %)
Critical pulmonary stenosis
33 (73 %)
58 (69 %)
LV EF (%) (n = 41, 59)
59 ± 6
60 ± 5
LV EF \54 % (n = 41, 59)
4 (10 %)
4 (7 %)
0.26 0.71
LV EDV z-score (n = 39, 57)
0.4 ± 1.7
0.5 ± 1.1
0.61
RV apical area (n = 40, 58)
2.65 ± 0.84
2.15 ± 0.69
0.002
PV diameter (mm)
5.7 ± 1.0
6.3 ± 1.3
0.002
PV z-score
-2.1 ± 0.9
-1.6 ± 1.0
0.002
TV AP (mm) (n = 42, 67)
10.6 ± 2.8
9.2 ± 2.0
0.009
TV AP z-score (n = 42, 67)
0.14 ± 2.14
-0.85 ± 1.34
0.009
TV area z-score (n = 44, 82) RVp TR Jet (mm Hg) (n = 34, 59)
1.70 ± 3.18 94 ± 25
0.38 ± 2.18 104 ± 25
0.02 0.07 \0.001
Degree of TR C moderate (pre-cath)
34 (76 %)
35 (42 %)
Degree of TR severe (pre-cath)
12 (27 %)
4 (5 %)
0.001
LV EF (%) (n = 41, 59)
41 ± 9
58 ± 4
\0.001
LV EDV z-score (n = 40, 53)
0.5 ± 1.6
0.3 ± 1.1
0.37
RVp TR jet (mm Hg) (n = 31, 46)
36 ± 10
44 ± 14
0.004
PDA present
29 (64 %)
65 (77 %)
0.24
Degree of PR C moderate
24 (53 %)
29 (37 %)
0.09
Degree of Cmoderate TR
23 (51 %)
21 (26 %)
0.006
Degree of severe TR
6 (13 %)
1 (1 %)
0.008
Post-catheterization echo
Values shown are number (%), median (range) or mean ± SD PAIVS pulmonary atresia intact ventricular septum, Cath cardiac catheterization, LV left ventricle, EF ejection fraction, RV right ventricle, PV pulmonary valve, TV tricuspid valve, AP anterior-posterior, EDV end-diastolic volume, RVp right ventricular pressure, TR tricuspid regurgitation, PR pulmonary regurgitation, PDA patent ductus arteriosus
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Pediatr Cardiol Table 3 Comparison catheterization data by outcome LV dysfunction (n = 129) Catheterization data
Post-cath LV dysfunction (n = 45)
No post-cath LV dysfunction (n = 84)
p value
Pre-cath pressors
11 (24 %)
8 (10 %)
0.04
Pre-dilation MV saturation (%) (n = 43, 81)
61 ± 12
67 ± 10
0.01
Pre-dilation aortic saturation (%) (n = 43, 83)
87 ± 7
90 ± 7
0.02 0.02
Pre-dilation RVp (mm Hg)
93 ± 29
106 ± 25
Pre-dilation RV–LV/Ao (n = 45, 83)
1.58 ± 0.50
1.74 ± 0.51
0.10
PV annulus/balloon ratio
1.27 ± 0.21
1.19 ± 0.21
0.04 0.54
Post-dilation RVp (mm Hg)
54 ± 14
56 ± 16
Post-dilation RV–LV/Ao (n = 44, 83)
0.86 ± 0.21
0.86 ± 0.27
0.86
Post-dilation aortic saturation (%) (n = 29, 58)
88 ± 6
92 ± 8
0.02
Post-cath pressors
13 (29 %)
18 (21 %)
0.39
Values represent number (%), median (range), or mean ± SD MV mixed venous, RVp right ventricular pressure, RV right ventricle, LV left ventricle
Table 4 Multivariable analysis: factors associated with LV dysfunction (n = 98)
Odds ratio
95 % CI
p value
PV z-score (;1)
1.81
(1.02, 3.24)
0.04
Degree of TR pre-cath Cmoderate
3.73
(1.41, 9.84)
0.008
RV apical area (:1)
1.99
(1.04, 3.80)
0.04
Area under ROC 0.767
Values represent number (%), median (range), or mean ± SD Ao aortic, Cath cardiac catheterization, LV left ventricle, MV mitral valve, PV pulmonary valve, TR tricuspid regurgitation, RV right ventricle, RVp right ventricular pressure
BD LV dysfunction. In multivariate analysis, the statistically significant predictors of Cmoderate LV dysfunction (ejection fraction \40 %) were larger tricuspid valve z-score, and increased RV apical area, with area under the ROC curve = 0.764.
Discussion We examined our experience with neonates who had undergone balloon dilation of PV for either critical PS or PAIVS and determined the incidence of post-dilation LV dysfunction which had been noted anecdotally. To our knowledge, the development of LV dysfunction post-balloon dilation of the PV has not previously been described. Prior to this study, neonates with LV dysfunction would get serial echocardiograms, often remain inpatient while waiting for the LV function to improve and be started on afterload reduction. In this study, we show that LV dysfunction develops in 35 % of patients after balloon dilation of the PV in the neonatal period and was moderate to severe in 12 %. Additionally, in all patients with serial echocardiographic follow-up, this LV dysfunction resolved
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completely and in a relatively short period of time; the median time to resolution was 10 days. The underlying pathophysiological mechanisms leading to this phenomenon are not entirely clear. One hypothesis is that the LV dysfunction could be related to the sudden, dramatic alteration in interventricular interaction following relief of RV outflow tract obstruction; this change in interventricular interaction is predicted to increase in proportion to the size of the right ventricle. An alternative hypothesis is that closure of the ductus arteriosus postcatheterization in the setting of prostaglandins being discontinued may acutely change the loading conditions of the LV, resulting in the appearance of LV systolic dysfunction. A third hypothesis implicates acute changes in coronary perfusion post-cardiac catheterization, since relief of RV hypertension could cause a transient coronary steal phenomenon post-BD, leading to relative LV ischemia. Given the relatively high incidence of LV dysfunction in this large cohort, we were able to do an analysis to determine risk factors associated with developing dysfunction. Factors associated with developing LV dysfunction postballoon dilation of the PV included greater RV apical area, tricuspid valve annular dimensions and tricuspid valve
Pediatr Cardiol
area, all consistent with larger RVs. This would support the hypothesis that there is increased potential for adverse ventricular–ventricular interactions in those patients with larger RVs, since a larger right ventricle shares a greater septal area with the LV and is able to exert a more dramatic influence on septal motion. In addition, these RVs tend to have more tricuspid regurgitation prior to PV BD, as well as being at lower pressure both pre- and post-PV BD. Finally, the short period of time required for recovery of left ventricular function is consistent with a temporary alteration in ventricular–ventricular interaction. In addition, this dysfunction manifests as global LV dysfunction and not segmental, suggesting that coronary ischemia is likely not the mechanism for the depressed function. Procedural ischemia is also not consistent with the observation that dysfunction was not always seen immediately post-BD, it was often seen on the echocardiogram performed 24 h after the catheterization to assess the status of the ductus arteriosus. Finally, the end-diastolic volumes of the LV postPV BD were not significantly different between the two groups, indicating that the onset of LV dysfunction was unlikely to be secondary to an acute change in volume loading of the LV. Our study also supports the findings of previous studies [9] that have reported that patients with PAIVS and larger RV’s are less likely to require surgery to augment pulmonary blood flow, since only three of the nine patients that had LV dysfunction (with larger RV’s) and required surgery were patients with PAIVS. Multiple prior studies looking at the short- and longterm outcomes after PV balloon dilation in the neonatal period consistently neglect evaluation of the LV [8]. Our observations raise the question of whether patients with acute post-procedural LV dysfunction are at increased risk of some later adverse outcome relative to those who never experienced LV dysfunction [12]. Future studies are needed to identify mechanisms for the development of left ventricular dysfunction in this population. Strain analysis of the LV in these patients both pre- and post-PV BD may be useful in better defining the adverse ventricular–ventricular interaction that occurs post-PV BD in the patients with larger RVs. This study has several limitations that stem primarily from the retrospective study design. Most importantly, echocardiographic surveillance for LV dysfunction postPV BD was not systematically performed at standard intervals, and follow-up echocardiogram intervals for those patients with LV dysfunction varied according to practitioner preference. Accordingly, the time course to normalization of LV function should be considered an estimate. Additionally, digital images were not available for additional measurements for patients born prior to 2004.
Conclusions After neonatal PV dilation for critical PS or PAIVS, a significant proportion of patients develop left ventricular dysfunction. Risk factors for left ventricular dysfunction after pulmonary balloon dilation include smaller PV annulus, increased RV apical area and larger TV size. While further study is necessary, this may be related to increased potential for ventricular–ventricular interaction in those with larger RVs. Conflict of interest
No conflicts to disclose.
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