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Click here to read this article as a CME activity
Ann Thorac Surg 2007;84:900-906
© 2007 The Society of Thoracic Surgeons
a Divisions of Cardiovascular Surgery and Cardiology, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
b Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada
Accepted for publication March 20, 2007.
* Address correspondence to Dr McCrindle, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada (Email: brian.mccrindle{at}sickkids.ca).
Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
| Pediatric cardiac surgery:
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Abstract |
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Methods: Record review of all children (n = 313) diagnosed with subaortic stenosis was conducted between 1975 and 1998 at our institution. Cox proportional hazard models determined the prevalence and associated factors for initial subaortic resection. Mixed models of serially obtained echocardiographic data (n = 933) established longitudinal LV gradient trends and identified factors associated with more rapid LV gradient progression.
Results: Median age at presentation was 8 months. Freedom from initial subaortic resection was 40% at 16 years from diagnosis. Earlier progression to subaortic resection was associated with patient characteristics at presentation, including a higher initial LV gradient (p < 0.001), larger aortic annulus z-score (p = 0.005), smaller body surface area (p < 0.001), and smaller mitral annulus z-score (p = 0.003). Initial resection was also associated with a faster rate of LV gradient progression (p = 0.003). Factors determining the increased rate of LV gradient progression included an initial LV gradient greater than 30 mm Hg (p < 0.001), initial aortic valve thickening (p = 0.003), and attachment of subaortic stenosis to the mitral valve (p = 0.003). Worse aortic regurgitation grade with time was also associated with an initial LV gradient greater than 30 mm Hg (p < 0.001).
Conclusions: Subaortic resection should be delayed until the LV gradient exceeds 30 mm Hg because most children with an initial LV gradient less than 30 mm Hg have quiescent disease.
Discrete subaortic stenosis (SAS) is generally accepted to be a progressive disease, with obstruction of the left ventricular outflow tract (LVOT) by subvalvular fibromuscular tissue [1–5]. Progressive subaortic obstruction may also lead to aortic valve damage, resulting in aortic regurgitation. However, clinically important progression is not universal, and factors determining at-risk substrates are unclear [4]. Routine echocardiographic evaluation has identified earlier more asymptomatic patients with SAS, and many have advocated earlier intervention aimed at preventing damage to the aortic valve and reducing recurrences. However, the efficacy of early surgery is controversial because of the variable outcomes in patients undergoing early surgical intervention coupled with a high postoperative prevalence of both recurrent stenosis and aortic regurgitation even after successful relief of subaortic obstruction [1, 3, 6]. Additionally, there is some debate about what constitutes "early" intervention. Our group [2] has previously shown that preoperative mean systolic gradient across the left ventricular outflow tract (LV gradient) greater than 30 mm Hg provides a reasonable threshold for intervention in children with discrete SAS, yet further confirmatory data regarding the utility of this threshold in optimizing outcomes are unknown.
Our primary objective was therefore to determine the prevalence of intervention and associated risk factors in children diagnosed with SAS. Our secondary objective was to investigate whether a protocol adopted in 1994 of early subaortic resection at a preoperative LV gradient greater than 30 mm Hg was supported by time-event and longitudinal outcome data.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Serial transthoracic echocardiograms (n = 933) were analyzed from 238 of the 313 subjects for whom reports were available. The median number of studies per subject was 3 (range, 1 to 14 per subject), and occurred during an interval of 2 years before subaortic resection and up to 19 years after repair. Aortic and mitral valve sizes, as well as left ventricular dimensions, were converted into z-scores using regression equations based on previously published nomograms [7, 8]. Rate of LV mean gradient difference was calculated as follows:
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) indicates the mean gradient at subsequent (nth) times.
Surgical Technique
Our techniques for subaortic resection (fibrous ridge resection, myotomy, subaortic fibrous resection, and myectomy) have been previously described [2]. Briefly, an oblique aortotomy extending down to the noncoronary sinus was made, and the aortic valve leaflets were inspected and retracted. The subaortic ridge was identified, elevated with traction sutures, and circumferentially excised. When indicated, part of the adjacent muscular septum was incised (myotomy) or excised (myectomy), with the most medial aspect of the myectomy limited by the mid aspect of the right coronary cusp [2]. All patients had either fibrous ridge resection with or without concomitant myomectomy.
Data Analysis
Data are given as frequency, median with range, or mean ± standard deviation, as appropriate, with the number of nonmissing values indicated. All data analyses were performed using Statistical Analysis System software (version 9.1; Statistical Analysis System Institute, Inc, Cary, NC). Informative imputation, when possible, was used to determine missing patient variables such as age or weight, either based on nomograms or other information available in the medical record. Mean imputation was used otherwise, with missing value flags created and forced into all models in which the imputed variable was used. Time-related freedom from initial intervention was analyzed by the Kaplan–Meier method for the entire cohort and among those patients (n = 238) for whom echocardiographic data were available. Risk factors for initial operation and subsequent reoperation among the latter 238 patients were sought using Cox proportional hazards regression. Serial echocardiographic assessments of mean LV gradient and semiquantitative aortic regurgitation grade were modeled, and risk factors were sought by using general linear mixed and ordinal regression models as previously reported [9, 10]. Univariate exploratory plots were generated initially to determine the longitudinal relationship (linear, quadratic, cubic, and so forth) between each potential predictor and outcome. Factors were then entered using a stepwise selection algorithm, with interaction terms added in a hierarchical manner. Candidate covariance structures were tested explicitly, with the final matrix selected based on variograms and minimization of the information criteria (AIC and BIC) generated from PROC MIXED. For the mixed and ordinal models, time zero was taken to be the date of initial subaortic stenosis diagnosis. Preoperative values (as time-independent covariables) and the rate of change for time-dependent continuous variables (eg, gradient and ventricular dimensions) were used as potential predictors in all models.
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Results |
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Factors Associated With Initial Subaortic Resection
There were 238 children with echocardiographic data available for analysis, among whom 109 underwent initial subaortic resection (Table 2). Important differences existed among those children with echocardiographic data compared with those in whom such data were unavailable. Specifically, those with echocardiographic data available were younger at the time of presentation (median, 2.3 years versus 3.4 years; p = 0.04), born later (1990s versus 1980s; p < 0.001), and less likely to undergo initial intervention (46% versus 67%; p = 0.002), compared with those without echocardiographic data. Freedom from initial operation for these 238 children was 60% at 5 years and 49% at 15 years from diagnosis of SAS (Fig 3). Initial subaortic resection was associated with patient demographic and anatomic characteristics at presentation, including a higher initial LV gradient (p < 0.001), larger aortic annulus z-score (p = 0.005), and longer left ventricular ejection time (p < 0.001), as well as smaller body surface area (p < 0.001) and smaller mitral annulus z-score (p = 0.003). Initial resection was also associated with a faster rate of LV gradient progression (p = 0.003) before intervention compared with those (n = 129) who did not have surgery.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Overall freedom from initial intervention was 54% at 5 years from initial diagnosis. Our freedom from subsequent reoperation, 75% at 15 years, compares favorably with other large series [3, 11, 12], especially considering the younger age and long duration of follow-up of our current cohort. Brauner and colleagues [3], using a threshold value for the LV peak gradient of 40 mm Hg, reported a 65% freedom from a composite end point (recurrence and reoperation) at 10 years in their series of 83 patients. Serraf and colleagues [13] reported 85% freedom from reoperation using, as a general guideline, a peak LV gradient of 50 mm Hg. However, their median age at initial resection was 10 years, and they identified younger age to be a risk factor for reoperation by univariate analysis.
We found that initial subaortic resection was related to higher initial LV mean gradient, faster mean gradient progression, larger aortic annulus z-score, smaller mitral annulus z-score, smaller body surface area, and longer left ventricular ejection time. The association between smaller body surface area and initial subaortic resection is multifactorial. Smaller body surface area at presentation is likely a surrogate for younger age, which has been shown by Brauner and colleagues [3] to be associated with recurrence. The association between intervention and smaller indexed mitral valve size may reflect a bias toward earlier operative intervention in children with more severe or tandem left-sided obstruction. Finally, children operated on earlier after initial diagnosis have a protracted at-risk interval that may have relevance, as our study and others [2, 3, 6, 13] have documented the positive association between duration of follow-up and LV gradient progression.
Higher initial LV gradient was linearly related to initial subaortic resection. However, we also found that children with accelerated gradient progression were associated with an increased risk of initial resection. A reciprocal finding from our longitudinal data demonstrates that disease progression is not inevitable in patients with discrete SAS. There exists a subset of patients whose obstruction will remain stable for years (if not indefinitely), and these patients can reliably be differentiated by an initial gradient less than 30 mm Hg coupled with longitudinal echocardiographic follow-up.
We found, in agreement with prior reports by others [2, 3, 5, 6] that aortic regurgitation is progressive and correlated with higher LV mean gradient. The majority of patients, though, remained with mild or moderate aortic regurgitation grade throughout the study interval, with severe aortic regurgitation developing in less than 1% of our patients. Importantly, our threshold value of 30 mm Hg was also a useful predictor of more severe regurgitation grade with time. Prior results from our institution by Coleman and colleagues [2] also indicated that subaortic resection at a preoperative mean LV gradient less than 30 mm Hg reduced the prevalence of subsequent aortic regurgitation, although it did not confer a reduced risk of recurrence. Therefore, in developing definitive criteria and timing for subaortic resection, the degree of LVOT obstruction as opposed to the grade of regurgitation should be used as the former predicts the latter, especially in more simple forms of discrete SAS in which the propensity to severe aortic regurgitation is low.
We were unable to demonstrate a direct reduction in the incidence of reoperation with early subaortic resection less than the threshold value. However, it is plausible that our study was underpowered to establish such a correlation, as only 19 of the 23 children who underwent reoperation had echocardiographic data available for analysis. One could also argue that the comparatively small number of reoperative events during 15 years offers indirect evidence supporting our current policy. Neither the report by Brauner and associates [3], using a preoperative threshold of 40 mm Hg peak LV gradient, nor the previous report from our institution [2], using a threshold 30 mm Hg mean gradient, was able to demonstrate an association between the threshold value and reoperative risk after adjustment for other confounders. However, irrespective of the identification of a definitive cutoff point regarding reoperation, our study and others [3, 13] demonstrated that a higher gradient after initial resection predicts recurrence. It is probable that a single number will be inadequate to predict the risk of recurrence or progression of aortic regurgitation given the morphologic heterogeneity of recurrent SAS, the increased likelihood of aortic valvular dysfunction at reoperation, and the variable outcome of initial resection.
The results of different surgical techniques have been reviewed elsewhere [12–15], with no clear benefit consistently identified with one technique compared with others. Similarly, we did not find any impact of operative strategy on echocardiographic progression of disease (either LVOT obstruction or aortic regurgitation), or on the prevalence of reoperation. However, the present study has limited power to detect differences based on procedure type because the vast majority of patients underwent subaortic fibrous resection and concomitant myectomy, with only 5 patients having isolated fibrous ridge resection. This trend reflects our institutional bias toward fibrous ridge resection and myectomy based on earlier results that demonstrated a reduction in reoperation prevalence for recurrent SAS from 83% to 45% in patients who had more aggressive resection [2]. Additionally, the exclusion of more complex forms of SAS in the present study limited variation in operative approach.
Limitations
Our study is a retrospective review from a single institution without standardized echocardiographic review. Few patients underwent reoperation despite the length of time circumscribed by our study. Aortic regurgitation was qualitatively described rather than quantitatively measured using jet width indexed to annulus size, and therefore less precise and more subjective. Missing data, information regarding outcome, and selection bias therefore represent potential sources of bias, especially considering that echocardiographic data were unavailable in some patients. Criteria for initial subaortic resection and reoperation were recommended at a threshold value, yet decision to proceed with operation was ultimately left to the discretion of the attending surgeon or cardiologist. Furthermore, operative strategy may have varied, and there have been new techniques introduced during the study period not available to patients treated earlier.
Conclusions
On the basis of our data, intervention to ameliorate SAS should be delayed until the LV gradient exceeds 30 mm Hg because the majority of children with minimal gradients remain stable with no progression of either stenosis or aortic valve damage. Surgical resection should be offered when the LV mean gradient reaches 30 mm Hg to prevent progression of subaortic obstruction and the development of important aortic regurgitation.
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Discussion |
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I’ll quickly ask you a question while people are coming up to the microphone. What is the role of aortic valve insufficiency at the time of diagnosis when you consider that as part of your decision tree for whether or not to recommend an operation?
DR KARAMLOU: I think that is a very good point. I think in general our institution in 1982 started operating on patients at a lower gradient, and then this was further refined based on the study by Coleman et al., which was published in JACC (Journal of the American College of Cardiology) in 1994. Using the lower gradient threshold meant that there were not many patients with greater than mild AI (aortic insufficiency). However, in general, patients who have important aortic regurgitation, those patients would be more likely to undergo a resection.
Another reason why I sort of glossed over the AI criteria is that most of the patients, as you probably noted, in our series are much younger. So again very few of our patients actually had moderate or severe aortic insufficiency at their initial presentation, though the degree of AI is progressive over time. So we have not really in any rigorous analytic sense used aortic regurgitation as a defining criterion for operative intervention.
And I think the last point I will make is that there is a significant correlation, if you look at a simple correlational analysis, between worse regurgitation and increasing left ventricular mean gradient with an r of 0.23 and a significant p value. So, using mean gradient, one can actually infer information about the degree of AI, and so mean gradient is a more powerful predictive tool than degree of AI.
DR MUHAMMAD A. MUMTAZ (Cleveland, OH): Just a short question. I notice there were 4 deaths in the patients that you did not operate on. Could you elaborate a little bit on those, and were they a gradient less than 30?
DR KARAMLOU: That is a great point. Unfortunately, in four of these, we do not have any echocardiographic data. Obviously, one of the limitations in the study that patients operated on or diagnosed in an earlier era were the patients who we did not have echo data on, and the majority of those deaths occurred early in our experience.
So I do not have a lot of data. I know that 1 patient died of a cardiac arrhythmia 3 years after the initial diagnosis. And the patient who died who had an intervention died in the perioperative period of refractory heart failure.
DR MUMTAZ: So in your data, is there any patient who had a gradient of less than 30 and died? We follow exactly the same guidelines as you published, so I am just curious to know, are there patients that you identified that had a less than 30 gradient and they died?
DR KARAMLOU: No. The patient who died after initial intervention had a gradient over 30.
DR GERHARD ZIEMER (Tuebingen, Germany): While the data you present can be only as good as you find them, you may be more precise as far as the term fibromuscular resection is used. To me, the term is quite fishy. It just says somebody resected whatever was there. I mean, the anatomy allows that the fibrous part can be really peeled off, and some suggest that this may be all you need to do.
But this is not a fibromuscular resection. It is a fibrous peel-off, and after that you decide whether a myectomy is done also. So maybe you will recall in a subset of reports that you may find this approach? I personally always add a myectomy to a fibrous peel-off. It never, however, is a fibromuscular resection.
DR KARAMLOU: You have brought up another good point. There is certainly no uniform nomenclature. We struggled with this because in an earlier era, we were referring to a lot of these as a membranectomy where you can just take off if there is a very sort of thin membrane.
And then our initial operative strategy, again based on Coleman’s paper, we had a reduction in SAS recurrence of 83% to 45% when we actually did a muscle resection, a myectomy at the time, rather than an isolated myotomy or just doing a membranectomy. So, because treatment changed from myotomy to a more aggressive fibromuscular myectomy as a result of this paper, we do not really have the data to look at the question of whether outcomes differed based on approach.
DR ZIEMER: Well, I would prefer the term fibrous resection plus or minus myectomy and not put it together.
DR KARAMLOU: Good point.
DR BACKER: Can I please poll the audience? How many people resect muscle routinely when they perform a standard subaortic membrane resection?
(A show of many hands.)
And how many people just do a membranectomy?
(A show of only one hand.)
You’re the only one. Sorry, Ralph.
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