Author + information
- Received January 14, 2010
- Revision received June 18, 2010
- Accepted June 21, 2010
- Published online November 30, 2010.
- David W. Brown, MD* (, )
- Amy E. Dipilato, BA,
- Erin C. Chong, BA,
- Kimberlee Gauvreau, ScD,
- Doff B. McElhinney, MD,
- Steven D. Colan, MD and
- James E. Lock, MD
- ↵*Reprint requests and correspondence:
Dr. David W. Brown, Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115
Objectives The aims of this study were to determine the incidence and risk factors of sudden unexpected death (SUD) after balloon aortic valvuloplasty (BAVP) for congenital aortic stenosis (AS) and to assess the effect of exercise restriction.
Background Exercise restriction is recommended for some patients with congenital AS because of a perceived increased risk for SUD. Little is known about the incidence of SUD in those with treated AS or the efficacy of exercise restriction in preventing SUD.
Methods A review was conducted of 528 patients who underwent BAVP for congenital AS at Children's Hospital Boston from 1984 to 2008. Exercise restriction status was ascertained for those ≥4 years of age, censored at aortic valve replacement or transplantation.
Results Median subsequent follow-up was 12.0 years (range 0 to 24.8 years), for a total of 6,344 patient-years of follow-up. There were 63 deaths, with SUD in 6 patients, 5 of which occurred at ≤18 months of age. For patients ≥4 years of age at most recent follow-up with no histories of pulmonary hypertension (n = 422), median follow-up after BAVP was 14.6 years, for 6,019 patient-years of follow-up. Exercise restriction was prescribed in 183 patients (43%; 2,541 patient-years) and no restriction in 220 (52%; 2,691 patient-years); there were insufficient data in 19 patients. There were 17 deaths in this cohort of 422 patients, with 1 SUD (the patient, who was exercise restricted, died during sleep), for an incidence of 0.18/1,000 patient-years (95% confidence interval: 0.01 of 1,000 to 1.01 of 1,000).
Conclusions SUD is extremely rare after BAVP for congenital AS. No beneficial effect of the recommendation for exercise restriction was observed in this longitudinal cohort with 6,000 patient-years of follow-up.
Since first reported 25 years ago (1), balloon aortic valvuloplasty (BAVP) has gradually become the preferred treatment for newborns, children, and young adults with congenital aortic stenosis (AS) at most centers (2–8). Although this treatment is usually effective for acutely relieving left ventricular outflow obstruction, a number of studies of short-term and midterm outcomes of BAVP for congenital AS have demonstrated subsequent progressive aortic valve disease in some patients, both stenosis and regurgitation (3,5–7,9). Long-term outcomes are less well characterized but suggest a steady long-term hazard for aortic valve replacement (AVR) (8–10).
Sudden unexpected death (SUD) has been documented rarely in both symptomatic and asymptomatic patients with severe congenital AS (11,12). Large case series and registries of athletes who died suddenly have included small numbers of patients with congenital AS (13,14). Consensus expert panel recommendations have thus been developed that restrict patients with congenital AS from strenuous exercise and competitive sports to varying degrees, such as the 36th Bethesda Conference (15), with similar recommendations endorsed by national organizations, including the American Heart Association and American College of Cardiology (16). In brief, these recommendations restrict asymptomatic patients with moderate AS (defined as a maximal instantaneous Doppler gradient of 40 to 70 mm Hg) from some types of competitive sports, and those with severe AS (maximal instantaneous Doppler gradient >70 mm Hg) from all competitive athletics. Patients with treated AS are restricted from competitive sports on the basis of subsequent residual gradients after intervention by the same criteria.
Few long-term studies, however, have been performed in patients with congenital AS, and the data on which these recommendations are based are largely from case reports and series. In the Second Natural History Study of Congenital Heart Defects, SUD occurred in 25 of 462 patients with congenital AS followed for an average of more than 15 years; however, the majority of these patients had undergone surgical valvotomy (11). The true incidence and risk factors for SUD in patients treated with modern transcatheter techniques are unknown. There is little evidence that exercise increases the risk for SUD in patients with treated congenital AS, and such recommendations are at odds with the known beneficial effects of regular exercise in maintaining cardiovascular health (17). Highly divergent views among physicians at our institution about the appropriateness of exercise and competitive sports restriction in patients followed noninvasively with known congenital AS have thus resulted in significant practice variation. We sought to determine the incidence and risk factors for SUD in a large cohort of patients who underwent BAVP for congenital AS over a 24-year period and to determine if a beneficial effect of exercise restriction in preventing SUD could be demonstrated.
Patients with congenital valvular AS who underwent transcatheter BAVP at Children's Hospital Boston from December 1984 through January 2009 were ascertained from the computer database of the Department of Cardiology. Patients who were converted to a functionally univentricular circulation within 30 days of catheterization were excluded. Patients who underwent prior surgical or transcatheter aortic valve intervention before referral to our center were included, as were those with associated congenital cardiovascular anomalies; patent ductus arteriosus in newborns, patent foramen ovale, and atrial septal defects not treated surgically were not considered “associated cardiovascular anomalies.” Indications for catheterization and valve dilation were not standardized and may have varied according to patient age, clinical status, era, referring physician, and interventional cardiologist. General guidelines for intervention considered symptomatic status, AS gradient, ventricular function, and the presence and severity of associated anomalies. From 1985, BAVP was the preferred therapy for congenital AS at our center, and surgical aortic valvotomy would have been performed almost exclusively in patients with coexisting anomalies requiring open-heart surgery, or after unsuccessful balloon dilation. The technical details of BAVP have been described previously (2,3,5).
Cross-sectional follow-up was obtained by June 2009. Patients not followed longitudinally at our center were contacted by mail and subsequent telephone call detailing the study. Exercise restriction status was considered relevant for patients ≥4 years of age at most recent follow-up and was ascertained by review of clinical records and/or verified by direct inquiry. Because of complex clinical variation in the nature and degree of restriction from exercise, we simplified our analysis by considering patients “restricted” if their cardiologist had placed any restrictions on exercise or competitive sports participation. Patients with histories of pulmonary hypertension, which was defined as mean pulmonary artery pressure ≥30 mm Hg at an age >30 days, were also excluded from the exercise restriction portion of the analysis, because this represents a known risk factor for sudden death and separate indication for exercise restriction. Most recent follow-up echocardiographic data were collected (before AVR if applicable), and maximal instantaneous AS gradient by Doppler was categorized according to the cutoffs recommended in the Bethesda guidelines: mild, <40 mm Hg; moderate, 40 to 70 mm Hg; and severe, >70 mm Hg (15).
Patients were considered lost to follow-up if there was no available contact information and no known clinical follow-up for >4 years. For these patients (n = 48), vital status and cause of death (if deceased) were ascertained by query of both the Social Security Death Index (maintained by the Social Security Administration) and the National Death Index, a large database maintained by the U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, and the National Center for Health Statistics.
The primary outcome was SUD in patients with biventricular circulation after BAVP. Secondary outcomes included cardiovascular death and all-cause mortality. Kaplan-Meier analysis with log-rank testing and Cox proportional hazards regression were performed to assess the relationship between predictor variables and time to event, with the start time set at the initial BAVP procedure. Variables significant at the 0.10 level by the log-rank test were considered for inclusion in the multivariate Cox model; a forward selection procedure was used. Variables significant at the 0.05 level on the basis of a likelihood ratio test were retained in the final model. Patients were censored at time of first use of AVR or heart transplantation. Comparisons between patients with and without exercise restriction were performed using the Wilcoxon rank sum test for continuous variables and the Fisher exact test for categorical variables.
This retrospective study was performed according to a protocol approved by the Committee for Clinical Investigation at Children's Hospital Boston.
Between December 1984 and January 2008, 563 patients with congenital AS underwent BAVP at Children's Hospital Boston. Thirty-five of these patients were excluded from the present study because they were converted to functionally univentricular circulation during the same hospitalization, either as part of a planned strategy of left-heart rehabilitation or because of circulatory insufficiency after aortic valve dilation. The remaining 528 patients constituted the study cohort. Demographic and diagnostic details of these 528 patients are summarized in Table 1.The median age at BAVP was 1.9 years, and most patients (75%) were ≤10 years of age. The majority had isolated valvular AS (n = 334 [63%]), and most (n = 384 [73%]) had no other cardiac interventions before BAVP.
Most patients (n = 447 [85%]) had pre-intervention peak AS gradients ≥50 mm Hg at catheterization. The peak AS gradient decreased significantly after balloon dilation (median acute decrease, 35 mm Hg; p < 0.001 by Wilcoxon signed rank test). Pre- and post-intervention aortic valve hemodynamic variables are summarized in Table 2.Moderate or worse AR was present in 14% of the cohort by angiography acutely after BAVP. Approximately 100 of these 528 patients were included in a previous report that evaluated factors associated with anatomic suitability for biventricular repair in newborns with AS (18).
The median duration of vital status follow-up was 12.0 years (range 0.1 to 24.8 years), for a total of 6,344 patient-years of follow-up (Table 3).Among 488 patients who underwent balloon dilation before 2006, clinical follow-up data were available for at least 2 years or until the time of death in all but 6. Among more recent patients, none met our definition of loss to follow-up, although in 6, the most recent follow-up was <2 months after dilation. During follow-up, repeat BAVP was performed in 117 patients (22%), for a total of 149 repeat procedures. AVR (including the Ross procedure) was subsequently performed in 116 (22%). Further analyses of patient and procedural variables associated with long-term valve function and reintervention after BAVP are the subject of another study and were not further investigated for the purposes of this report.
Among 422 patients ≥4 years of age at most recent follow-up and without pulmonary hypertension, median follow-up after BAVP was 14.6 years, for total 6,019 patient-years of follow-up (Table 3). Exercise restriction was able to be defined from medical records and/or patient inquiry in 403 patients (not available in 19), with 183 (43%) exercise restricted and 220 (52%) not restricted. No cases of “crossover” from exercise restricted to unrestricted, or vice versa, were noted. Cumulative follow-up in the 2 groups was similar: 2,541 patient-years for exercise-restricted patients versus 2,691 patient-years for those unrestricted.
Exercise-restricted and unrestricted patients did not differ with regard to baseline demographics, anatomic features, or peri-BAVP hemodynamic status (Table 4).The median duration of follow-up was longer in the exercise-restricted group (14.4 years vs. 12.1 years), although as noted previously, the cumulative patient-years of follow-up were similar. The proportion of patients who had undergone repeat BAVP before cross-sectional follow-up was similar in both groups (24%), although more had undergone AVR in the restricted group (33%) than the unrestricted group (20%). Measures of aortic valve function by echocardiography at most recent follow-up showed a modestly but not significantly higher AS gradient in those restricted from exercise (median maximal instantaneous gradient, 44 mm Hg vs. 41 mm Hg; p = 0.60). In both restricted and unrestricted patients, the distribution of AS gradients was skewed, but most patients had moderate or severe AS in both groups (Fig. 1). The proportion of patients with severe AS (maximal instantaneous Doppler gradient ≥70 mm Hg) was not significantly different between exercise-restricted and unrestricted patients (11% vs. 9%, p = 0.73). The proportion of patients with moderate or worse aortic regurgitation was similar in both groups.
Sixty-three of 528 patients died during follow-up, with death from cardiovascular causes in 50 patients. Twenty of these occurred within 1 month of BAVP. Survival over time was 95 ± 1% at 5 years, 93 ± 1% at 10 years, and 88 ± 2% at 20 years by Kaplan-Meier analysis, with a steep early hazard for death, followed by a steady hazard (Fig. 2). Among patients ≥4 years of age at most recent follow-up (n = 423), there were 20 total deaths, 17 of which occurred in patients in whom exercise restriction status could be ascertained (Table 4, Figs. 3and 4).
The causes of death for the whole cohort included congestive heart failure (primarily infants with circulatory failure after BAVP; n = 27), operative complications during or after aortic or mitral valve surgery (n = 9), pneumonia or sepsis (n = 4), accidental death (n = 3), acute catheterization complications (n = 2), and drug overdose (n = 2); a complete list is provided in Table 5.Five patients underwent heart or heart-lung transplantation, 4 of whom subsequently died. Among patients with diagnoses of pulmonary hypertension, 46% died during follow-up, compared with 6.7% of those without this diagnosis.
In multivariate analysis, age <30 days at BAVP (hazard ratio [HR]: 5.7; 95% confidence interval [CI]: 3.2 to 10.1; p < 0.001), presence of multiple left-sided obstructive lesions (HR: 11.9; 95% CI: 5.9 to 24.4; p < 0.001), and BAVP during the first decade of experience (HR: 5.9; 95% CI: 2.3 to 15.1; p < 0.001) were the only pre-procedural or acute post-procedural predictors of subsequent cardiovascular death.
Of the 63 deaths in the entire cohort, 6 were considered SUD (Table 6).Five of these patients died at ≤18 months of age and 3 at <2 months of age. Only 1 SUD occurred in the group ≥4 years of age at most recent follow-up, a 28-year-old asymptomatic patient who was restricted from competitive sports, who died suddenly during sleep. Thus, the minimal incidence of SUD in the cohort ≥4 years of age was 18 of 100,000 patient-years (95% CI: 1 of 100,000 to 101 of 100,000). Although patient follow-up for the purpose of SUD was censored at time of AVR or transplantation by study design, SUD did not occur in any patients censored for this reason.
In this long-term observational cohort of 528 patients who underwent BAVP for congenital AS, we found an extremely low rate of SUD; there were only 6 cases in more than 6,300 patient-years of follow-up. Although the small number of patients with SUD precluded formal statistical analysis for associated variables, SUD was more common in the young, with 5 of 6 cases occurring in infants ≤18 months of age and 3 of the 6 cases in those ≤45 days of age. Patients with neonatal AS requiring BAVP early in life may thus be at higher risk than older children for SUD, a finding that has not been reported to date and may have implications for clinical follow-up.
Among patients ≥4 years of age at most recent follow-up, in whom exercise restriction could reasonably be postulated to have a beneficial or protective effect, we found only a single occurrence of SUD in more than 6,000 patient-years of follow-up. Cumulative patient-years of follow-up were roughly similar in the group of patients restricted in any fashion from exercise and those unrestricted (2,541 patient-years vs. 2,691 patient-years), and we could find no differences between these groups in baseline characteristics (such as age at initial BAVP, frequency of associated cardiovascular anomalies, or pre-intervention AS gradient), or acute procedural results (post-intervention AS gradient, degree of AR). There were no obvious differences in subsequent outcomes, with 24% of patients in both groups requiring repeat BAVP and similar number requiring heart transplantation (1 patient in both groups). Although the median AS gradient by most recent echocardiogram was slightly higher in the exercise-restricted group (44 mm Hg vs. 41 mm Hg), and although the exercise-restricted group was more skewed toward higher gradients, as shown in Figure 1, the majority of patients in both groups would be classified as having moderate or greater AS by the Bethesda guidelines. A similar proportion in both groups had moderate or worse aortic regurgitation by most recent echocardiogram. There were more AVR procedures in the restricted group (33% vs. 20%), although given the known steady risk for AVR in this population (8–10), this may be at least partially explained by a longer median follow-up time in the exercise-restricted group (14.4 years vs. 12.1 years). Thus, within the constraints of this retrospective study, although some differences between the 2 groups, such as AS gradient at most recent follow-up, exist, the decision to restrict patients from exercise or sports participation did not appear to be determined by clinical factors alone but in large part by the practice pattern of the treating cardiologist, presumably informed by his or her interpretation of national guidelines such as the Bethesda Conference (15). The issue of how patients followed such recommendations could not be ascertained by this study design. Despite a large number of patient-years of follow-up, we did not observe a beneficial effect of the recommendation for exercise restriction in preventing SUD.
This study included only patients with congenital AS who had undergone BAVP. Patients with congenital AS who underwent surgical valvotomy as primary treatment of their disease, or with AS not severe enough to require intervention, were not included. At our center, surgical valvotomy was primarily used in an earlier treatment era, before the advent of BAVP in the mid-1980s, and since that time has been used nearly exclusively for patients undergoing surgical repair of other significant congenital heart lesions, which may modify the subsequent natural history, or for BAVP treatment failures. Patients with congenital AS who did not undergo BAVP during the study period were primarily those with milder forms of the disease, and they were not included in this report for a number of reasons, including the known inaccuracy of noninvasive Doppler determinations of the severity of AS in children (19) as well as the presumed lower risk for SUD in those with mild disease as informed by previous natural history studies (11). As congenital valvular AS often worsens over time, the number of patients followed at our center with significant AS in which BAVP was not undertaken over the 24-year time period of this study was relatively small. Our study focused on a group with severe enough AS by invasive measurement to require BAVP, which represents a population with the most severe disease and presumably the highest risk for SUD.
Case series (12) and large cohort studies (11) have suggested that patients with symptoms and the highest AS gradients are at higher risk for SUD. Although such retrospective data have been used to inform national guidelines regarding exercise restriction and restriction from competitive athletics (15,16), patients with severe, symptomatic, untreated AS are rarely encountered clinically in the current era. This study of patients with congenital AS managed with more contemporary BAVP techniques would indicate that the absolute risk for SUD is extremely low, with a reasonably long cohort follow-up in both exercise restricted and unrestricted patients. In contrast, there has been mounting evidence that regular exercise offers a number of health benefits, including improved survival and lower risk for cardiovascular events (17) in normal patients and improved functional capacity and quality of life even in patients with severe congenital heart disease (20–22). Rhodes et al. (23) found a significant positive impact of regular exercise on behavior, emotional state, and well-being in patients with severe congenital heart disease. Although the intent of competitive sports restriction is not to preclude regular exercise for the maintenance of cardiovascular fitness, patients may interpret such restriction as an indication that vigorous exercise may be detrimental to their health, which might have unintended negative consequences that surpass any positive benefit. The full impact of restriction from competitive athletics on patients, including long-term cardiovascular risk factors (such as sedentary life-style and body mass index), exercise capacity, and psychological well-being, has not been well studied to date but deserves further evaluation, particularly in light of the lack of a clear beneficial effect on SUD.
Overall, the risk for cardiovascular death after BAVP was not associated with acute post-procedural hemodynamic status. However, there were some significant predictors of subsequent cardiovascular death, most notably the presence of multiple left-heart obstructions (HR: 11.9), a subset of patients with congenital AS known to have significant associated mortality (24–26). Many of these patients also had pulmonary hypertension, which was also associated with mortality in this study; 46% of patients diagnosed with pulmonary hypertension at some point during follow-up died, compared with 6% in patients without this diagnosis. Patients undergoing BAVP during the first decade of experience had a higher risk for cardiovascular death than those treated in subsequent years. Patients undergoing BAVP as neonates also had a higher risk for cardiovascular death (HR: 5.7), often early after BAVP, which may be a marker of more severe or progressive disease.
One of the primary limitations of this study is that the rarity of SUD in patients of exercising age managed with BAVP precluded insight into 1 of our central clinical questions: does exercise restriction prevent SUD in patients with congenital AS? Other limitations to this study are the retrospective study design and extended enrollment period, logistic considerations that may limit the applicability of our findings. Similarly, although general clinical guidelines for intervention were followed, criteria for referral for catheterization or BAVP were not standardized, and practice likely varied over time and among practitioners. Hemodynamic variables likely changed over time in some patients, but we did not attempt to account for the potential time variance in AS or aortic regurgitation. As a retrospective evaluation, the clinical decision making that informed restricting or not restricting a given patient from competitive sports or exercise was often not available, only the prescription itself; we also did not verify the actual activity levels of the patients. Other clinical information that might factor into the decision to restrict from exercise, such as electrocardiographic changes, were not available in many patients and thus were not included in the analysis. Furthermore, the complex variation in types and levels of exercise restriction, including changes in restriction status, precluded a more complex analysis of the data. Also, many of the patients in this cohort were primarily followed elsewhere, and inquiry of the National Death Index and Social Security Death Index was required to ascertain vital status in some patients; although these are highly sensitive tools for ascertaining deaths and causes of death in most studies (27), it is possible that a small number of deaths were either missed or misclassified. However, given the rarity of SUD in this study, most of the methodological limitations noted likely had little impact on our primary conclusions.
SUD is extremely rare after BAVP for congenital AS. Infants may be at somewhat higher risk for SUD after BAVP. No beneficial effect of the recommendation for exercise restriction was observed in this longitudinal cohort with 6,000 patient-years of follow-up. Current guidelines that restrict some patients with congenital AS from sports participation may overestimate the beneficial impact this practice has in preventing SUD.
This study was supported by the Higgins Family Fundand the Dunlevie Family Fund. All authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- aortic stenosis
- aortic valve replacement
- balloon aortic valvuloplasty
- confidence interval
- hazard ratio
- sudden unexpected death
- Received January 14, 2010.
- Revision received June 18, 2010.
- Accepted June 21, 2010.
- American College of Cardiology Foundation
- Sholler G.F.,
- Keane J.F.,
- Perry S.B.,
- Sanders S.P.,
- Lock J.E.
- Moore P.,
- Egito E.,
- Mowrey H.,
- Perry S.B.,
- Lock J.E.,
- Keane J.F.
- Egito E.S.,
- Moore P.,
- O'Sullivan J.,
- et al.
- Reich O.,
- Tax P.,
- Marek J.,
- et al.
- Fratz S.,
- Gildein H.P.,
- Balling G.,
- et al.
- Doyle E.F.,
- Arumugham P.,
- Lara E.,
- Rutkowski M.R.,
- Kiely B.
- Maron B.J.,
- Doerer J.J.,
- Haas T.S.,
- Tierney D.M.,
- Mueller F.O.
- Graham T.P.,
- Driscoll D.J.,
- Gersony W.M.,
- Newburger J.W.,
- Rocchini A.,
- Towbin J.A.
- Maron B.J.,
- Thompson P.D.,
- Ackerman M.J.,
- et al.
- Colan S.D.,
- McElhinney D.B.,
- Crawford E.C.,
- Keane J.F.,
- Lock J.E.
- Rhodes J.,
- Curran T.J.,
- Camil L.,
- et al.