Outcome and Growth Potential of Left Heart Structures After Neonatal Intervention for Aortic Valve Stenosis

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provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 50, No. 25, 2007 © 2007 by the American College of Cardiology Foundation ISSN 0735-1097/07/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2007.07.082

Congenital Heart Disease

Outcome and Growth Potential of Left Heart Structures After Neonatal Intervention for Aortic Valve Stenosis

Ra K. Han, MD, FRCPC,* Rebecca C. Gurofsky, BSC,* Kyong-Jin Lee, MD, FRCPC,* Anne I. Dipchand, MD, FRCPC,* William G. Williams, MD, FRCSC,† Jeffrey F. Smallhorn, MD, FRCPC,* Brian W. McCrindle, MD, MPH, FRCPC* Toronto, Ontario, Canada

Objectives The purpose of this study was to determine trends of growth of left heart structures after intervention for neonatal aortic valve stenosis.

Background The growth potential of left heart structures in neonatal aortic valve stenosis after relief of obstruction might inﬂuence risk for subsequent outcomes.

Methods From 1994 to 2004, 53 patients underwent neonatal (Յ30 days old) balloon aortic valve dilation. Factors associated with time-related outcomes (death, reintervention, aortic valve replacement) and longitudinal changes in normalized left heart dimensions were sought.

Results The median age at intervention was 3.5 days (range 1 to 30 days). During a median follow-up of 3.2 years rang- ing up to 10.9 years, there were 31 reinterventions on the aortic valve in 21 (40%) patients and 7 deaths (13%). The presence of moderate or severe left ventricular (LV) endocardial fibroelastosis was the only independent predictor for time-related mortality (hazard ratio 22.1; p ϭ 0.004), and a smaller initial aortic valve annulus z-score was a significant independent predictor for aortic valve replacement (hazard ratio 0.63 per 1-U change; p ϭ 0.007). Aortic valve annulus, aortic sinus, and LV dimension z-scores significantly increased over time, whereas mitral valve z-scores remained below normal. The structure’s initial z-score and concomitant size of other left heart structures were significant independent factors associated with subsequent z-scores.

Conclusions There is potential catch-up growth of the aortic valve and LV over time for neonates after intervention for aortic valve stenosis. However, the continued hypoplasia of the mitral valve warrants further consideration in the long- term management of these patients. (J Am Coll Cardiol 2007;50:2406–14) © 2007 by the American College of Cardiology Foundation

Aortic valve stenosis in neonates is associated with varying deﬁcits in functional status, and need for further interven- degrees of hypoplasia of left heart structures. Fetal echocar- tions. However, the pattern of growth in left heart structures diographic studies have demonstrated the progressive devel- after the relief of left-sided obstruction is unclear, even in opment of hypoplasia of left heart structures related to the absence of hypoplasia. A recent study demonstrated left-sided obstructive lesions (1,2). This hypoplasia adds to potential catch-up growth of the aortic valve and left increased morbidity and mortality for this patient popula- ventricle (LV) in those with smaller left heart structures (5). tion (3). In severe cases, the hypoplasia of left heart However, growth was not the focus of this study, the data structures associated with neonatal aortic valve stenosis provided were descriptive and limited to the aortic valve necessitates univentricular palliation or transplantation (4). annulus and left ventricular end-diastolic (LVED) dimen- In less severe cases, ongoing or progressive hypoplasia or sion, and multivariable longitudinal data analysis for trends growth failure might contribute to subsequent morbidity, and associated factors was not performed. Hence, we sought to determine the trends in longitudinal changes in left heart dimensions and aortic insufﬁciency and determine factors From the *Division of Cardiology, Department of Pediatrics, and the †Division of associated with clinical outcomes and growth of left heart Cardiovascular Surgery, Department of Surgery, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. structures for patients with neonatal balloon aortic valve Manuscript received July 5, 2007; accepted July 25, 2007. dilation. JACC Vol. 50, No. 25, 2007 Han et al. 2407 December 18/25, 2007:2406–14 Left Heart Growth in Aortic Valve Stenosis

Methods z-scores over time and demo- Abbreviations graphic characteristics, echocar- and Acronyms Patient population. Patients with a diagnosis of aortic diography measurements at pre- Congenital Heart ؍ valve stenosis who underwent neonatal aortic valve dilation CHSS sentation, and at follow-up and at Յ30 days of age at the Hospital for Sick Children in Surgeons Society the degree of aortic and mitral confidence interval ؍ Toronto, Ontario, Canada, from January 1994 to December CI valve stenosis and insufficiency left ؍ were identified from the cardiac catheterization data- LV 2004 were initially tested in a stepwise base. All patients had situs solitus, levocardia, concordant ventricle/ventricular regression model (p Ͻ 0.25 to left ventricular ؍ atrioventricular and ventriculoarterial connections, a left LVED enter); backward selection was aortic arch, and normal venous connections. Patients with end-diastolic used to obtain a final multivari- parameter estimates ؍ initial univentricular palliation were excluded. Patients un- PE able model. Results from these derwent initial percutaneous transcatheter balloon dilation models are given as parameter of the aortic valve with previously described techniques (6). estimates (PE) with standard error that correspond to the Patient demographic characteristics, clinical status before average increase in outcome measure for each increase of 1 intervention and at last follow-up, procedural characteristics measurement unit (or otherwise indicated) in predictor and hemodynamic status, and outcomes were abstracted measurement. All data analyses were performed with SAS from patient records. The study was approved by our statistical software (version 9.1, SAS Institute Inc., Cary, institutional Research Ethics Board, and patient confiden- North Carolina). tiality was maintained. Anatomic measurements. Initial pre-procedural and follow-up post-procedural echocardiograms and echocar- Results diographic reports were reviewed. Measurements of left Patient characteristics. Between January 1994 and De- heart structures were performed offline with electronic cember 2004, 53 patients underwent neonatal balloon aortic calipers and included the standard published (4) morpho- valve dilation. Fetal diagnosis of isolated aortic valve steno- logic and functional characteristics. Measurements were sis was made in 6 (11%) patients. The majority (81%) of normalized for body surface area as z-scores on the basis of patients were male. There were 2 (4%) pre-term neonates published normative data (7). Published normative data was born at 34 and 35 weeks’ gestational age. used rather than institution-specific normative values to The median age at presentation was 2 days (range 0 to 30 facilitate comparison with different institutions. Degree of days). Median weight was 3.4 kg (range 2.0 to 4.5 kg), aortic valve insufficiency was assessed both qualitatively with median length was 50 cm (range 44 to 57 cm), and median a global assessment based on aortic insufficiency jet width body surface area was 0.22 m2 (range 0.16 to 0.26 m2). ratio, LV dilation and function, and diastolic flow reversal in Although 26 (49%) patients presented with a fetal diagnosis the descending aorta and quantitatively with aortic insuffi- or an asymptomatic murmur, 27 (51%) presented with ciency jet width to aortic valve annulus ratio in diastole symptoms of low cardiac output or heart failure. Before the measured offline by a single reviewer. The initial pre- initial intervention, prostaglandin E1 infusion was initiated procedural echocardiographic measurements were used to in 33 (62%) patients, 26 (49%) were mechanically ventilated determine the Congenital Heart Surgeons Society (CHSS) for symptoms or for hospital transfer, and 15 (28%) received score with the published regression equation for critical inotropic medications. aortic stenosis (4) and the Rhodes score (3). Anatomic data. Initial anatomic features on echocardio- Data analysis. Data are presented as frequencies, means gram before the initial intervention are listed in Table 1. with standard deviations (SDs), or median with minimum Decreased LV systolic function (ejection fraction Ͻ55%) and maximum, as appropriate. Time-related survival, time was noted in 25 (47%) patients. Table 2 lists the z-scores of to reintervention, and time to aortic valve replacement were left heart structures at presentation. The initial mitral valve modeled with nonparametric Kaplan-Meier estimates. Fac- dimensions, LV dimension and length, aortic valve annulus, tors associated with these outcomes were sought from aortic root at the sinus, and sinotubular junction were demographic characteristics, medical status at presentation, generally smaller than normal, whereas the ascending aorta and echocardiography measurements with Cox proportion- was larger than normal. The median CHSS score was 0 ate hazard regression. Variables were initially included in a (range Ϫ46 to 55). Only 28 (53%) patients had a negative stepwise model (p Ͻ 0.05 to enter), and those selected were CHSS score, which predicts a survival benefit with biven- included in a multivariable model through backward selec- tricular repair, whereas 25 (47%) patients had a positive tion to obtain a final model for each event. CHSS score indicating that they would have had better Changes in the z-scores of left heart structure dimen- predicted survival with univentricular palliation rather than sions over time after initial intervention but before a biventricular repair. The median Rhodes score was 0.28 reintervention were modeled with linear regression ad- (range Ϫ0.98 to 1.39). With a score of ϽϪ0.35 being justed for repeated measures through an autoregressive predictive of death after a 2-ventricle repair, the Rhodes covariance structure. Associations between changes in score predicted death in 8 (15%) patients. Patients in the 2408 Han et al. JACC Vol. 50, No. 25, 2007 Left Heart Growth in Aortic Valve Stenosis December 18/25, 2007:2406–14

AnatomyEchocardiogram From the at Initial Presentation Anatomy From the Initial Table 1 Echocardiogram at Presentation

Structure n (%) Patent foramen ovale or atrial septal defect 50 (94) Apex-forming left ventricle 51 (95) Grade of endocardial fibroelastosis (CHSS grade [4]) None 26 (49) Mild (papillary muscle only) 13 (25) Moderate (papillary muscle and endocardium) 8 (15) Severe (extensive) 6 (11) Aortic valve morphology Trileaflet 17 (32) Bicuspid 12 (23) Functionally bicuspid 19 (36) Unicuspid 5 (9) Dysplastic 44 (83) Transverse aortic arch hypoplasia 3 (6) Longitudinal Trends in Aortic Valve Patent ductus arteriosus 34 (64) Figure 1 Insufficiency to Aortic Valve Annulus Jet Width Ratio n ϭ 53. CHSS ϭ Congenital Heart Surgeons Society. Individual trends from initial intervention until reintervention, death, or last follow-up. more recent era (years 2000 to 2004) had more favorable median CHSS and Rhodes scores at Ϫ2 and 0.15, respec- Ϯ tively, compared with patients in the earlier era (years 1994 peak-to-peak gradient of 59 27 mm Hg. After the to 1999) whose median CHSS and Rhodes scores were 6 procedure, the mean LV and aortic systolic pressures by Ϯ and Ϫ1.80, respectively. However, this difference was not pullback or simultaneous recording measured 78 16 mm Ϯ statistically significant. Hg and 61 15 mm Hg, respectively, giving a mean Ϯ Procedural characteristics. The median age at initial in- peak-to-peak gradient of 17 10 mm Hg. The overall Ϯ tervention was 3.5 days (range 1 to 30 days). The median mean reduction in peak-to-peak gradient was 69 20%. aortic valve annulus size by angiography and echocardio- Aortic valve insufficiency. Follow-up echocardiograms gram was 6.8 mm (range 4.5 to 8.6 mm). The median size demonstrated aortic valve insufficiency in the majority of of the largest balloon used was 7 mm (range 5 to 8 mm), patients. Although 9 (19%) patients did not have any aortic giving a median maximum balloon-to-annulus ratio of 1.0 valve insufficiency immediately after intervention, there was (range 0.9 to 1.3). The approach used for balloon dilation qualitatively trivial-to-mild insufficiency in 24 (50%), mod- was antegrade in 40 (75%) and retrograde in 13 (25%) erate in 14 (29%), and severe in 1 (2%) patient. The mean patients. aortic valve insufficiency to aortic valve annulus jet width Ϯ Hemodynamic status. Before initial balloon aortic valve ratio measured 33 15%. However, there was no signifi- dilation, the mean LV and aorta systolic pressures by cant change in the degree of aortic valve insufficiency over pullback or simultaneous recording measured 115 Ϯ 27 mm time (Fig. 1), as analyzed with general linear modeling for Hg and 57 Ϯ 11 mm Hg, respectively, giving a mean longitudinal data. Z-Scores of Left Heart Structures at Presentation Clinical outcomes. There were 7 (13%) early deaths dur- Table 2 Z-Scores of Left Heart Structures at Presentation ing the initial hospital stay with no late deaths. Hence, survival was 86% at 1 year (95% confidence interval [CI] Structure Z-Score Values (Mean ؎ SD) 76% to 96%), which was unchanged at 5 years and 10 years Mitral valve after intervention (Fig. 2). The causes of death were: severe AP dimension Ϫ1.18 Ϯ 1.49 aortic valve regurgitation with poor LV function in 4 Ϫ Ϯ Lateral dimension 0.62 1.57 patients, 2 of whom underwent surgical reintervention with LV urgent Ross-Konno procedures before death, and 1 patient LVED dimension (M-mode) Ϫ1.00 Ϯ 3.00 LV endocardial length Ϫ0.23 Ϯ 1.38 each who had residual aortic valve stenosis and underwent Aortic valve reintervention with the Ross-Konno procedure followed by Annulus Ϫ2.83 Ϯ 2.33 aortic valve replacement with homograft before death; poor Sinus Ϫ1.23 Ϯ 1.91 ventricular function with high end-diastolic pressure and no Sinotubular junction Ϫ0.92 Ϯ 1.92 residual aortic valve stenosis resulting in multiorgan failure; Aortic arch and fatal intracranial hemorrhage during thrombolytic ther- Ascending aorta 0.92 Ϯ 1.82 apy for arterial thrombosis. n ϭ 53. The median duration of follow-up was 3.2 years (range 5 AP ϭ anteroposterior; LV ϭ left ventricular; LVED ϭ left ventricular end-diastolic. days to 10.9 years). There were 31 subsequent reinterven- JACC Vol. 50, No. 25, 2007 Han et al. 2409 December 18/25, 2007:2406–14 Left Heart Growth in Aortic Valve Stenosis

Figure 2 Kaplan-Meier Curve Depicting Survival Over Time Figure 4 Kaplan-Meier Curve Depicting Freedom From Reintervention Over Time The solid line represents the Kaplan-Meier estimates, and the dashed lines represent 95% confidence intervals. The solid line represents the Kaplan-Meier estimates, and the dashed lines represent 95% confidence intervals. tions in 21 (40%) patients during the follow-up period, as shown in Figure 3. The indications for reintervention were Factors associated with clinical outcomes. Factors associated with time-related mortality, reintervention, and aor- aortic valve stenosis for 20 procedures, aortic valve regurgi- tic valve replacement are shown in Table 3. tation for 8 procedures, and combined aortic valve stenosis Patients who died had a mean CHSS score of 31 Ϯ 20 and regurgitation for 3 procedures. The median age at the and a mean Rhodes score of Ϫ0.24 Ϯ 0.43, compared with first reintervention was 0.7 years (range 1 day to 7.6 years). the patients who survived, who had a mean CHSS score of The time-related freedom from reintervention was 68% at 1 Ϫ2 Ϯ 19 and a mean Rhodes score of 0.31 Ϯ 0.56. year (95% CI 52% to 79%), 56% at 5 years (95% CI 39% to However, moderate or severe LV endocardial fibroelastosis 66%), and 33% at 10 years (95% CI 12% to 55%) (Fig. 4). was the only significant independent factor associated with There were 11 aortic valve replacement procedures in 10 time-related mortality from multivariable analysis, and after (19%) patients at a median age of 0.6 years (range 1 day to controlling for this variable, no other variable was significant. 9.0 years). The indications for aortic valve replacement were Trends in longitudinal change in left heart dimen- aortic valve stenosis for 3 procedures, aortic valve regurgi- sions. Follow-up echocardiograms after initial intervention tation for 6 procedures, and combined aortic valve stenosis were available for 48 patients for review. The length of time and regurgitation for 2 procedures. All 3 patients who underwent aortic valve replacement in the neonatal period died before hospital discharge. The freedom from aortic valve replacement was 87% at 1 year (95% CI 81% to 93%), 75% at 5 years (95% CI 61% to 89%), and 59% at 10 years (95% CI 36% to 81%) (Fig. 5).

Figure 5 Kaplan-Meier Curve Depicting Freedom From Aortic Valve Replacement Over Time

The solid line represents the Kaplan Meier estimates, Figure 3 Flowchart of Patient Outcomes and the dashed lines represent 95% conﬁdence intervals. 2410 Han et al. JACC Vol. 50, No. 25, 2007 Left Heart Growth in Aortic Valve Stenosis December 18/25, 2007:2406–14

Signiﬁcant Predictors for Time-Related Outcomes Table 3 Signiﬁcant Predictors for Time-Related Outcomes

Univariate Analysis Multivariate Analysis Variable Parameter Estimate ؎ SE p Value, Hazard Ratio p Value, Hazard Ratio Mortality Presence of moderate or severe LV EFE 3.11 Ϯ 1.08 0.004, 22.1 0.004, 22.3 Decreased ejection fraction by M-mode Ϫ0.03 Ϯ 0.02 0.08, 0.97 Lower initial aortic valve annulus z-score Ϫ0.50 Ϯ 0.18 0.006, 0.61 Lower initial aortic sinus z-score Ϫ0.65 Ϯ 0.20 0.002, 0.52 Lower initial ascending aorta z-score Ϫ0.45 Ϯ 0.23 0.05, 0.64 Lower initial LV length z-score Ϫ0.65 Ϯ 0.31 0.04, 0.52 Higher CHSS score (4) (favors single ventricle palliation) 0.07 Ϯ 0.02 0.001, 1.07 Lower Rhodes score (predicts mortality after biventricular repair) Ϫ1.61 Ϯ 0.77 0.04, 0.20 Younger age at initial intervention (per yr) Ϫ0.82 Ϯ 0.40 0.04, 0.44 Higher balloon/annulus ratio (per 0.1 increase) 0.57 Ϯ 0.25 0.03, 1.77 Reintervention Lower initial aortic valve annulus z-score Ϫ0.25 Ϯ 0.11 0.03, 0.78 Lower % change in gradient across aortic valve with initial intervention Ϫ0.29 Ϯ 0.10 0.006, 0.76 0.006, 0.76 (per 10% change) Aortic valve replacement Presence of moderate or severe LV EFE 1.58 Ϯ 0.72 0.03, 4.84 Presence of unicuspid aortic valve 1.61 Ϯ 0.71 0.03, 5.01 Lower initial aortic valve annulus z-score Ϫ0.46 Ϯ 0.17 0.007, 0.63 0.007, 0.63 n ϭ 53. CHSS ϭ Congenital Heart Surgeons Society; EFE ϭ endocardial fibroelastosis; LV ϭ left ventricular. from initial intervention to an end-state (i.e., death, rein- follow-up were a larger initial aortic valve annulus z-score tervention, or last follow-up) ranged from 4 days to 9.8 (PE 0.33 Ϯ 0.07, p Ͻ 0.001), a larger aortic sinus z-score years. There was a median of 2 echocardiograms/patient during follow-up (PE 0.49 Ϯ 0.07, p Ͻ 0.001), and longer (range 1 to 14) from this time period. The z-scores of time from initial intervention (PE 0.10 Ϯ 0.03/year, p ϭ measurements of left heart structures after the initial inter- 0.005). Independent factors associated with a larger aortic vention until an end-state was reached were plotted over sinus z-score during follow-up were a larger initial aortic time for each individual patient, and a fitted line represent- sinus z-score (PE 0.31 Ϯ 0.10, p ϭ 0.005) and a lower ing the overall trend of all patients was derived. The trends CHSS score (favoring a biventricular repair, Ϫ0.02 Ϯ 0.01, in longitudinal change in left heart dimension are shown in p Ͻ 0.05) as well as a larger LVED diameter z-score (PE Figure 6. 0.10 Ϯ 0.05, p ϭ 0.04) and a larger aortic valve annulus Aortic valve annulus, aortic sinus, and LVED diameter Ϯ Ͻ Ͻ z-score (PE 0.39 0.06, p 0.001) during follow-up and z-scores were significantly associated with time (p 0.001), longer time from initial intervention (PE 0.15 Ϯ 0.03/year, with a rapid increase during the first year after initial interven- p Ͻ 0.001). tion followed by a plateau or slowing in the rate of increase. There was no significant trend of change with time in the LV. Independent factors significantly associated with a z-score of LV endocardial length. The mitral valve lateral larger LV endocardial length z-score during follow-up were dimensions were also significantly related to time (p Ͻ 0.05). a larger initial LV endocardial length z-score (PE 0.30 Ϯ However, the mitral valve dimension z-scores decreased in the 0.07, p ϭ 0.001), a larger mitral valve lateral dimension first year after intervention before becoming fairly constant z-score during follow-up (PE 0.20 Ϯ 0.06, p ϭ 0.001), and below normal, although remaining within 2 SDs of predicted a higher echocardiographic peak instantaneous LV outflow normal and without clinically important gradients. tract gradient during follow-up (PE 0.01 Ϯ 0.003, p ϭ Independent factors associated with z-scores of left heart 0.04). Independent factors associated with a larger LVED structures during follow-up. AORTIC VALVE. Indepen- diameter z-score during follow-up were a larger initial dent factors associated with z-scores of left heart structures LVED diameter z-score (PE 0.23 Ϯ 0.08, p ϭ 0.006), a larger during follow-up were determined with general linear mod- mitral valve lateral dimension z-score during follow-up (PE eling for repeated measures, and factors that influenced time 0.31 Ϯ 0.09, p ϭ 0.001), a larger aortic sinus z-score during trends (interactions) were also sought. Results are reported follow-up (PE 0.23 Ϯ 0.09, p ϭ 0.008), and a longer time as PE from the multivariable model, which represent the from initial intervention (PE 0.12 Ϯ 0.05/year, p ϭ 0.02). amount by which a unit change in the factor influences the z-score during follow-up, adjusted for all other factors MITRAL VALVE. Independent factors associated with a significant in the model. Independent factors significantly larger anteroposterior dimension z-score during follow-up associated with a larger aortic annulus z-score during were a larger initial mitral valve anteroposterior dimension JACC Vol. 50, No. 25, 2007 Han et al. 2411 December 18/25, 2007:2406–14 Left Heart Growth in Aortic Valve Stenosis

Figure 6 Longitudinal Trends for Left Heart Structures After Initial Intervention to Reintervention, Death, or Last Follow-Up

The solid dark lines represent overall trends from regression modeling, the dotted lines represent 2 SDs from the predicted trends, and the light lines indicate measurements for individual patients over time. There was no significant interaction between left ventricular endocardial length z-score and time, and thus a time trend line is not provided. AP ϭ anteroposterior. z-score (PE 0.15 Ϯ 0.07, p Ͻ 0.05), a larger LVED those with lower initial z-scores demonstrated greater po- diameter z-score during follow-up (PE 0.26 Ϯ 0.05, p Ͻ tential catch-up growth in the first year, as illustrated in 0.001), and less time from initial intervention (PE Ϫ0.09 Ϯ Figure 7. 0.03/year, p ϭ 0.001). Independent factors associated with Age at initial intervention, gender, antenatal diagnosis, a larger lateral dimension z-score during follow-up were a Rhodes score, mitral or aortic valve morphology, and larger LV endocardial length z-score (PE 0.25 Ϯ 0.09, p ϭ severity of endocardial fibroelastosis were not found to be 0.004), a larger LVED diameter z-score during follow-up significantly associated with longitudinal change in any of (PE 0.20 Ϯ 0.05, p Ͻ 0.001), and less time from initial the left heart dimensions. The degree of aortic valve intervention (PE Ϫ0.09 Ϯ 0.03/year, p ϭ 0.001). insufficiency immediately after initial intervention and at There was significant interaction between the initial follow-up by qualitative assessment or quantitative jet width z-scores and the trend of change with time. Patients with ratio was also not significantly associated with longitudinal lower initial z-scores had lower z-scores during follow-up change in left heart dimension. Although LVED dimension compared with those with higher initial z-scores. However, z-scores exceeded predicted normal values during follow- 2412 Han et al. JACC Vol. 50, No. 25, 2007 Left Heart Growth in Aortic Valve Stenosis December 18/25, 2007:2406–14

Figure 7 Predicted Z-Scores of Left Heart Structures After Initial Intervention Stratiﬁed by Initial Z-Score in Quartiles

AP ϭ anteroposterior. up, the degree of LV dilation was similar regardless of the highlight the important impact of associated left heart degree of aortic valve insufficiency immediately after inter- hypoplasia and endocardial fibroelastosis on survival after vention, as illustrated in Figure 8. biventricular repair. These anatomic factors also contribute to the high rate of reintervention and aortic valve replace- Discussion ment in this patient population. Growth of left heart structures. There is an early phase in Hypoplasia of left heart structures associated with neonatal aortic valve stenosis contributes importantly to increased the first year after initial intervention where there are rapid morbidity and mortality in this patient population. We increases in aortic valve and LV diameter z-scores. This is examined a contemporary group of patients undergoing consistent with previous studies of neonates with coarcta- neonatal intervention for aortic valve stenosis and evaluated tion of the aorta or aortic valve stenosis and hypoplastic LV time-related clinical outcomes and longitudinal trends in (5,9–12). This might be affected by changes in the geometry left heart dimensions and factors associated with these of the LV after the relief of obstruction but might also outcomes and measurements over time. reflect volume load in the presence of aortic valve regurgi- Outcomes. Neonatal intervention for aortic valve stenosis tation. In fact, we found that LVED dimension z-scores is associated with considerable morbidity and mortality exceeded normal predicted values in the first year after (6,8). Associated hypoplasia of left heart structures is a initial intervention, although we could not find an associa- well-established risk factor for mortality (3,4) in this pop- tion with the degree of aortic valve stenosis. After the initial ulation. Consistent with previous studies, our findings period of catch-up growth or dilation in the first year, JACC Vol. 50, No. 25, 2007 Han et al. 2413 December 18/25, 2007:2406–14 Left Heart Growth in Aortic Valve Stenosis

(5) have found that patients with post-dilation aortic valve insufficiency had a more rapid increase in LVED z-scores and higher LVED z-scores in follow-up. In contrast, the peak instantaneous gradient across the LV outflow tract was a significant independent predictor for higher LV length and aortic valve annulus z-scores in our study. This then raises the question as to how residual lesions, either regurgitation or stenosis, influence the growth of heart structures. This potential for growth of left heart structures might have implications for patients with aortic valve stenosis and “borderline left ventricles.” Although the left heart appears small and inadequate on initial assessment, there might be immediate expansion or growth after the relief of obstruction and change in loading conditions, followed by potential catch-up growth sufficient to support the systemic circulation. Many studies have attempted to define the lower limits of LV hypoplasia that are adequate to support a systemic circulation (3,15), but these lower limits continue to be challenged (16,17). The patterns in longitudinal changes in left heart structures might suggest that if patients survive the potentially difficult early post-intervention period, they might have sufficient dilation or growth to support a Figure 8 Predicted Trends in LV Dimensions Stratified by Initial Grade of Aortic Valve Insufficiency biventricular circulation. However, the cost of achieving a biventricular circulation must be weighed against the po- Trends since initial intervention. LV ϭ left tentially higher early mortality and reintervention rates that ventricular; LVED ϭ left ventricular end-diastolic. might make single ventricle palliation preferable in selected cases. however, the aortic valve and LV seem to have a normal rate Controversy still remains as to whether fetal intervention of growth, resulting in a plateau in the mean z-scores near for aortic valve stenosis would allow for sufficient catch-up or above normal. growth and hence prevention or reversal of the development In contrast, the mitral valve dimension z-score in our of hypoplastic left syndrome in utero. Tworetzky et al. (18) study decreased in the first year after initial intervention and presented their early results for balloon dilation of severe remained below normal thereafter although within 2 SDs of aortic stenosis in the fetus and found that there was an predicted normal. There were no interventions in our series increase in mitral valve, aortic valve, and ascending aorta for mitral valve stenosis during the intermediate follow-up diameters as well as LV length, for the fetuses that had a period; hence, the functional impact and long-term impli- successful intervention compared with those that did not. cations of this continued mitral valve hypoplasia remain Although still in the early stages of development and unclear. application, the potential catch-up growth in the neonatal The highest rate of growth in heart structures occurs in and fetal hearts after the relief of obstruction presents a the first year of life (13) and might represent a time for hopeful area for intervention and prevention. potential catch-up growth. Humpl et al. (14) in their study The limitations of this study include its retrospective of pulmonary atresia and intact ventricular septum found design, with the lack of clear pre-defined indications for that the growth of hypoplastic right heart structures was reintervention or aortic valve replacement, and the variable proportional to the initial values. This was also our finding, length and frequency of monitoring, including patients with higher initial z-scores being predictive of higher undergoing part of their follow-up assessments outside of z-scores during follow-up. This implies that patients with our institution. Hence, patients requiring reintervention and normal or near normal size structure maintain their normal- aortic valve replacement might be over-represented in our ity during follow-up. There was also size concordance sample, because these patients would be more likely to between different left heart structures, so that if a patient continue their follow-up assessments at our tertiary care had a higher z-score for one left heart structure, they were institution. In addition, with our contemporary patient more likely to have higher z-scores for the other left heart population, we have intermediate follow-up data available, structures as well. Although the degree of aortic valve but further long-term longitudinal research is required insufficiency by both qualitative and quantitative assessment particularly as it relates to any potential areas of concern, was not statistically significantly associated with higher such as the implications for the continued hypoplasia of the LVED z-scores over time in our study, McElhinney et al. mitral valve. 2414 Han et al. JACC Vol. 50, No. 25, 2007 Left Heart Growth in Aortic Valve Stenosis December 18/25, 2007:2406–14

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