Impact of Mitral Stenosis and Aortic Atresia on Survival in Hypoplastic Left Heart Syndrome

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1 ORIGINAL ARTICLES: Impact of Mitral Stenosis and Aortic Atresia on Survival in Hypoplastic Left Heart Syndrome Jenifer A. Glatz, MD, Raymond T. Fedderly, MD, Nancy S. Ghanayem, MD, and James S. Tweddell, MD Division of Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin Background. Aortic atresia has been implicated as a Results. Of the 72 patients, 36 had AA-MA, 17 had risk factor for decreased survival after stage 1 palliation. AS-MS, and 19 had AA-MS. The stage 1 hospital survival Prior studies evaluating the association of anatomic subtypes and mortality report conflicting results. Our objec- AS-MS, and 79% for AA-MS p ( 0.05). Interstage mor- was 92% for the entire cohort, 97% for AA-MA, 94% for tive was to determine if mitral valve patency with aortictality was 8% (6 of 72) overall, but was 21% (4 of 19) for atresia is associated with increased mortality in hypoplastic left heart syndrome (HLHS). AS/MS. Overall survival to date was 79% for the entire AA-MS versus 6% (2 of 36) for AA-MA and 0% for Methods. All patients (n 72) with classic HLHS born cohort but was 58% for AA-MS, 86% for AA/MA, and between August 1996 and May 2002, who underwent 88% for AA-MS p ( 0.015). Aortic atresia alone was not stage I Norwood palliation, had presenting echocardiograms reviewed for patency of the mitral and aortic Conclusions. In patients with HLHS, aortic atresia associated with increased mortality p ( 0.2). valves. The cohort was divided into three groups: aorticwas associated with increased mortality only in the atresia-mitral atresia (AA-MA), aortic stenosis-mitral stenosis (AS-MS), and aortic atresia-mitral stenosis (AA- dence of death was observed primarily during the presence of a patent mitral valve. The highest inci- MS). Analysis included analysis of variance techniques interstage period. for continuous variables and the 2-tailed Fisher exact test for categoric variables. Survival analysis was performed using the Kaplan-Meier method with log-rank testing. (Ann Thorac Surg 2008;85: ) 2008 by The Society of Thoracic Surgeons Hypoplastic left heart syndrome (HLHS) refers to a perfusion, arrhythmias, obstruction to pulmonary blood spectrum of cardiac malformations consisting of flow, and residual lesions such as neoaortic arch obstruction [7 9]. Studies evaluating the impact of anatomic underdevelopment of left sided structures, including the mitral valve, left ventricle, and the aorta, subsequently subtype and ascending aortic size on mortality in HLHS leading to the inability of the left heart to maintainhave produced conflicting results [3 5, 7, 10 16]. The adequate systemic perfusion 1]. [ At the most severe end majority of these studies focused on aortic atresia (AA) in of this spectrum is atresia of the mitral and aortic valves isolation as a risk factor for overall mortality. We undertook this study to evaluate the impact of anatomic sub- with an essentially nonexistent left ventricle. Two other subtypes, mitral stenosis with aortic valve stenosis and type, specifically aortic atresia-mitral stenosis (AA-MS), mitral stenosis with aortic atresia, are associated with lefton mortality in our population of patients with HLHS. ventricular hypoplasia and a discrete left ventricular We hypothesized that AA only in the presence of a patent cavity [2]. Without intervention, HLHS is uniformly fatal mitral valve places the infant at greater risk for sudden [1]. However, the introduction of the Norwood procedure death. in 1983 and modifications in perioperative management strategies have resulted in nearly 90% early survival for this lesion [3, 4]. Material and Methods Despite improved early survival after stage 1 palliation Study Design (S1P), patients with HLHS continue to have high risk circulation until the time of the stage 2 cavopulmonarywe conducted a retrospective review of all patients born anastomosis. Death during the interstage period accounts for 4% to 16% of mortality in HLHS [3 8]. Sug- defined as right ventricle dependent circulation associ- between August 1996 and May 2002 with classic HLHS, gested mechanisms for cause of death during this periodated with atresia or severe hypoplasia of the aortic valve, include right ventricular dysfunction, impaired coronary Accepted for publication Feb 6, Address correspondence to Dr Fedderly, Children s Hospital of Wisconsin, Division of Cardiology, 9000 W Wisconsin Ave, Milwaukee, WI 53226; rfedderly@chw.org. who underwent a stage 1 Norwood palliation with placement of an aortopulmonary shunt at the Children s Hospital of Wisconsin. Two independent reviewers evaluated all initial postnatal transthoracic echocardiograms for the size of the ascending aorta and patency of the aortic and mitral valves based on the presence of ante by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 2058 GLATZ ET AL Ann Thorac Surg MITRAL STENOSIS-AORTIC ATRESIA SURVIVAL 2008;85: grade or retrograde flow as demonstrated on color flow Doppler analysis. Ascending aortic size was measured from the parasternal long axis view as the internal diameter of the proximal ascending aorta above the sinotubular junction. The patients were then divided into three groups based on the patency of the aortic and mitral valve. Specifically, these three groups included aortic atresia-mitral atresia (AA-MA), aortic stenosismitral stenosis (AS-MS), and AA-MS. A chart review was performed to identify patient characteristics including birth weight, gestational age, gender, surgical history, and age at most recent follow-up. Interstage mortality was defined as a death after hospital discharge from a S1P but prior to stage 2 palliation (S2P). Available medical records, including autopsy reports, were reviewed to determine cause of death if applicable. Transthoracic echocardiograms were also evaluated for right ventricular function at the following time points: pre and post S1P, prior to S2P, prior to stage three Fontan completion (S3P), and the most recent available follow-up study. Right ventricular function was graded qualitatively by visual inspection from apical and parasternal short axis images as poor (1) for severe dyskinesis and minimal right ventricular shortening, fair (2) for mild to moderate hypokinesis or mild to moderate wall motion abnormalities, and good (3) for normal right ventricular shortening with no evidence of hypokinesis or wall motion abnormalities. Survival status and patient follow-up data through March of 2007 was obtained through the primary cardiologist or the cardiac database at the Children s Hospital of Wisconsin. This study was approved by the Institutional Review Board at the Children s Hospital of Wisconsin and parental consent was waived. Table 1. Patient Characteristics for Each of the Three Anatomic Subtypes: Data for Continuous Variables are Reported as Mean Standard Deviation Characteristics AA-MA AS-MS AA-MS Female gender N 13 (36%) N 5 (28%) N 5 (28%) Male gender N 23 (64%) N 12 (70%) N 14 (74%) Age (days) S1P Wt (kg) S1P a AAo diameter b Age (days) S2P Wt (kg) S2P a AA-MA AS-MS, p b AS/MS AA/MA and AA/MS, p AA-MA aortic atresia-mitral atresia; AA-MS aortic atresia-mitral stenosis; AS-MS aortic stenosis-mitral stenosis; AAo ascending aortic; N number; S1(2)P stage 1 (2) palliation. Table 2. Right Ventricular Function Assessed by Transthoracic Echocardiogram With a Qualitative Analysis Performed at Five Different Time Periods; 1 Poor Function, 2 Fair Function, and 3 Good Function Time Periods AA/MA AS/MS AA/MS Pre-stage Post-stage 1 a Pre-stage Pre-Stage Most recent study a AA/MA AS/MS and AA/MS, p AA-MA aortic atresia-mitral atresia; AA-MS aortic atresia-mitral stenosis; AS-MS aortic stenosis-mitral stenosis. Patient Population From August 1996 to May 2002, 72 infants were born with classic HLHS and subsequently underwent a stage 1 Norwood palliation. Patients with HLHS variants such as double outlet right ventricle or an unbalanced atrioventricular canal defect were excluded from the study. Patients with a single left ventricle and aortic arch obstruction undergoing a S1P were also excluded. The AA-MA group consisted of 36 patients, AS-MS had 17 patients, and AA-MS had 19 patients. Follow-up was obtained for all patients with a follow-up duration of 5 to 10.5 years (mean, 7.3 years). Surgical Technique During the study period, the standard staged surgical management for HLHS at our institution included an aortopulmonary anastomosis, patch aortic arch reconstruction using pulmonary homograft, atria septal resection and innominate to pulmonary artery shunt at S1P, a cavopulmonary anastomosis at S2P, and a Fontan completion with fenestration at S3P. Details of surgical technique and perioperative management strategies during this time period are well-described in prior publications [4, 17]. Statistical Analysis Statistical analysis was completed using SPSS Version 15.0 (SPSS Inc., Chicago, IL). Analysis of continuous variables was performed with analysis of variance techniques and analysis of categoric variables was completed with a 2-tailed Fisher exact test. Continuous variables analyzed included ascending aortic size, age and weight at S1P and S2P, and right ventricular function at the previously mentioned time points. Survival analysis was performed using Kaplan-Meier methods with log-rank comparison of cumulative survival by group. Data are reported as mean standard deviation for continuous variables and count with percent for categoric variables. Differences were considered statistically significant when p was less than Median values are included when appropriate. Results Patient Characteristics Patient characteristics for each anatomic subgroup are shown in Table 1. All 72 patients underwent S1P as previously described: 36 with AA-MA; 17 with AS-MS; and 19 with AA-MS. Eighty-five percent (61 of 72) of the initial cohort progressed to S2P: 33 of 36 (92%) with

3 Ann Thorac Surg GLATZ ET AL 2008;85: MITRAL STENOSIS-AORTIC ATRESIA SURVIVAL 2059 Table 3. Summary of Age, Timing, Cause of Death, and Autopsy Findings, if Available, for the Fifteen Patients Who Died Group Age (days)/timing of Death Cause of Death Autopsy AA-MA 24/S1P RV dysfunction after S1P AA-MA 56/ISP Sudden cardiac arrest AA-MA 68/ISP Sudden cardiac arrest/shunt clot AA-MA 193/post S2P Enterovirus infection causing cardiovascular collapse AA-MA 1182/post S3P Sudden cardiac arrest AS-MS 68/S1P Sudden cardiac arrest Cerebral and pulmonary infarct AS-MS 224/post S2P RV dysfunction, sepsis AA-MS 15/S1P Sudden cardiac arrest Pulmonary embolus AA-MS 34/S1P Sudden cardiac arrest Multiple emboli with RV infarct AA-MS 45/S1P RV dysfunction, sepsis AA-MS 55/S1P RV dysfunction, sepsis, cardiac arrest AA-MS 56/ISP RV dysfunction, sudden cardiac arrest AA-MS 61/ISP RV dysfunction, cardiac arrest Cardiac failure, pulmonary edema AA-MS 114/ISP Sudden cardiac arrest Shunt clot AA-MS 114/ISP Sudden cardiac arrest AA-MA aortic atresia-mitral atresia; AA-MS aortic atresia-mitral stenosis; AS-MS aortic stenosis-mitral stenosis; ISP interstage period; RV right ventricular; S1P death during hospitalization for stage 1 palliation; post-s2p and S3P death after discharge from stage 2 and stage 3 palliation, respectively. AA-MA; 16 of 17 (94%) with AS-MS; and 12 of 19 (63%) with AA-MS. The S3P was performed in 55 of 72 patients: 30 of 36 (83%) with AA-MA; 14 of 17 (83%) with AS-MS; and 11 of 19 (58%) with AA-MS. Two patients, both AA-MA, required heart transplantations; one prior to S3P and one after S3P. Fig 1. Bar-graph depicting 30-day survival, survival to stage 2 palliation (S2P), and survival to date for each anatomic subtype. (AA-MA [e] aortic atresia-mitral atresia; AA-MS [p] aortic atresia-mitral stenosis; AS-MS [ ] aortic stenosis-mitral stenosis.) Of the 72 patients, 49 (68%) were male and 23 (32%) were female. For the cohort, mean birth weight was kilograms and the mean age at S1P was 6 4 days (median of 5 days). The average ascending aortic diameter was millimeters. Shunt size ranged from 3.0 to 4.5 mm in diameter with the majority of patients (64%) receiving a 3.5-mm shunt. Average initial hospital length of stay was days (median of 29 days). At S2P, the mean weight was kilograms and the mean age was days. The mean age of S3P was months. Gender, mean age, and weight at S1P and S2P and the mean ascending aortic diameter for each group are depicted in Table 1. Mean weight at S1P was significantly greater in the AS-MS group (p 0.04). The ascending aortic size was also significantly greater for the AS-MS group when compared with the other two groups (p ). The mean age at the S1P and the mean age and weight at the S2P were similar between groups. The average length of stay for all stages and mean age of S3P were not significantly different between the groups. Right Ventricular Function Table 2 depicts the qualitative assessment of right ventricular (RV) function for each of the three subtypes at various time points including pre- and post-s1p Norwood, pre-s2p cavopulmonary anastomosis, pre-s3p Fontan completion, and the most recent available study. As shown, RV function was significantly better after S1P for the AA-MA group when compared with the other groups (p 0.038). There was no significant difference among groups at the other evaluated time points. However, RV function was significantly worse after S1P and prior to S3P in those patients who died compared with those that survived (p and 0.02, respectively). The pre-s1p and pre-s2p RV function was not associated with increased mortality. In addition, those who died had

4 2060 GLATZ ET AL Ann Thorac Surg MITRAL STENOSIS-AORTIC ATRESIA SURVIVAL 2008;85: Fig 2. Kaplan-Meier survival curve of cumulative survival for each anatomic subtype. (AA-MA aortic atresia-mitral atresia; AA-MS aortic atresia-mitral stenosis; AS-MS aortic stenosis-mitral stenosis.) significantly worse RV function at their most recent study than those who survived (p 0.002). The RV dysfunction was a risk factor for mortality by univariate analysis, but this risk was independent of subtype. Survival Table 3 lists the individual patient deaths, anatomic subtype, age of death, timing relative to staged palliation, cause of death, and autopsy findings, if available. The 30-day postoperative survival for this cohort was 96%, and for the specific subtypes was 97% in AA-MA, 100% in AS-MS, and 89% in AA-MS (p 0.7) (Fig 1). An additional three patients who survived beyond 30 days after S1P died prior to hospital discharge. No patients died within 30 days of S1P after hospital discharge. Hospital survival was 92% overall; 97% for AA-MA, 94% for AS-MS, and 79% for AA-MS (p 0.05). The AS-MS patient who died during the S1P hospitalization had a delayed presentation and diagnosis at one month of age. Six patients died during the interstage period after S1P discharge. One of these patients presented in shock with a shunt thrombosis and underwent an emergent S2P to restore pulmonary flow. Support was withdrawn shortly after surgery due to complications caused by necrotizing enterocolitis. Interstage mortality was 8% (6 of 72) overall, but was 21% (4 of 19) for AA-MS versus 6% (2 of 36) for AA-MA. No interstage deaths occurred in the AS-MS group. Survival through S2P by anatomic subgroup was only 58% (11 of 19) for AA-MS compared with 92% for AA-MA (33 of 36) and 94% (16 of 17) for AS-MS (p 0.023). Two patients died after discharge following S2P, and one patient died after discharge following S3P. Overall survival for the cohort was 79% (57 of 72) and by anatomic subgroup was 58% (11 of 19) in AA-MS compared with 86% (31 of 36) in AA-MA and 88% (15 of 17) in AS-MS (p 0.015) (Fig 2). Aortic atresia or smaller ascending aortic diameter alone were not risk factors for mortality (p 0.3 and 0.36, respectively). An autopsy was performed in only five patients. Cause of death in four of these patients was due to thromboembolic events. No specific coronary abnormalities were noted. Comment In 1982, O Connor and colleagues [18] published their report of ventriculocoronary connections in patients with HLHS. In this study, they evaluated 12 autopsy specimens and noted that those with a patent inflow but an obstructed outflow had an increased rate of coronary abnormalities compared with other HLHS subtypes. The abnormalities included multiple ventriculocoronary arterial connections, thick walled coronaries, prominent endocardial fibroelastosis, and focal calcification with scarring of the myocardium. They speculated that these changes were due to increased intracavitary pressure created by this anatomic subtype. Similarly, Sauer and colleagues [19] evaluated the subepicardial coronary arteries in autopsy specimens with either AA-MA or AA-MS. They found that those with AA-MS had a higher prevalence of coronary artery abnormalities, including tortuosity, fibroelastic thickening, and fragmentation of the intima and duplication of the internal elastic lamina. In addition, Baffa and colleagues [20] evaluated 151 specimens with

5 Ann Thorac Surg GLATZ ET AL 2008;85: MITRAL STENOSIS-AORTIC ATRESIA SURVIVAL 2061 HLHS and again found an increased incidence of coronary cameral fistulae and tortuous coronaries in those with AA-MS. As a result of these findings, several studies have sought to determine if these abnormalities of the coronary vasculature are a risk factor for mortality in HLHS, specifically for sudden death. It has been hypothesized that these coronary abnormalities place the RV at risk for ischemia and therefore RV dysfunction, which has been considered to be a potential risk factor for sudden death [6, 8, 9]. In the previously mentioned study by Baffa and colleagues [20], these abnormalities were not associated with an alteration in RV perfusion. However, Sugiyama and colleagues [21] studied the relationship between RV function and left ventricular morphology from angiographic and pathologic perspectives and found that those with the AA-MS subtype had significantly lower RV end-diastolic volumes and increased hypokinesis of the RV posterior wall and the interventricular septum compared with the AA-MA subtype. Again, those with mitral stenosis had more frequent findings of myocardial necrosis, calcification, and interstitial fibrosis of the left ventricle. Despite the potential for increased morbidity and mortality, the AA-MS subtype has not consistently been found to be a risk factor for death. Most studies have focused exclusively on the aortic valve, either the presence of aortic atresia or the size of the ascending aorta. Although several studies have found that an atretic or smaller ascending aorta did not increase mortality (3, 10, 15), several others have found a statistically significant difference [4, 12, 14]. Gaynor and colleagues [13] reported that by univariate analysis aortic atresia was not a risk factor for operative mortality, but was a significant risk factor for survival at one year of age. This risk was not found to be consistent by multivariate analysis, suggesting that other factors may have contributed to the increase in mortality. In 1994, Jonas and colleagues [10] reviewed their experience with survival of patients from 1983 to 1991 with HLHS after operative reconstruction based on anatomic subtype. They found that those with the AA-MS subtype had a trend toward increased inhospital mortality (p 0.06), but that those with the AA-MA subtype had worse late survival. Those with the AS-MS subtype had the best reported survival with 76% three-year survival. The following year, Forbess and colleagues [14] published their ten-year experience with palliative surgery for HLHS and reported that those with AS-MS again had the best operative survival and survival to S2P. On the other hand Mahle and colleagues [5, 7], in their 15-year review of reconstructive surgery for HLHS, did not find that anatomic subtype was a risk factor mortality or unexpected death. In this study, we conducted a six-year review of all 72 patients with HLHS who underwent palliative surgery at the Children s Hospital of Wisconsin and found that presence of the anatomic subtype AA-MS was a significant risk factor for mortality, primarily during the interstage period. Aortic atresia or size of the ascending aorta alone were not risk factors for mortality suggesting that aortic atresia is only a risk factor in the face of a patent mitral valve. The primary cause of demise in these patients was sudden cardiac arrest and right ventricular dysfunction. Unfortunately, a comprehensive autopsy was only performed on five patients so no conclusions could be made in regard to cause of death and anatomic subtype. Interestingly though, the primary fatal event for four of these patients was thromboembolic in nature. Several factors may be responsible for the increased mortality in the AA-MS subtype. As previously described, coronary abnormalities including thickening of the intima and ventriculocoronary connections are more prevalent in this subtype. The presence of these abnormalities may predispose this subtype to ischemia and therefore ventricular dysfunction, and the potential for fatal arrhythmias. Due to the retrospective nature of this study, the presence of these abnormalities in those that did not survive could not be determined. Although prior studies have not yet verified this association, case reports of sudden death with AA-MS due to coronary abnormalities have been published [22, 23]. The increased risk for these patients during the period post-s1p but prior to S2P may be due to the difference in coronary perfusion with flow after S1P occurring primarily in systole with diastolic run-off to the aortopulmonary shunt and that after S2P being continuous in diastole [24]. Another factor that has been suggested as a risk factor for increased mortality, particularly during the interstage period, is RV dysfunction [6, 8, 9, 15, 16]. In this study, we found that those patients who died had significantly worse right ventricular function after S1P than those who survived. However, there was no significant difference in RV function between anatomic subtypes. Alterations in ventricular interactions and reduction in the RV volumes due to a noncompliant, thick left ventricular mass in AA-MS patients has also been suggested as a potential etiology for increased mortality in this subtype, although this was not further analyzed in this study [21]. Future studies, including a more quantitative analysis of RV function, may aid in the evaluation of the impact of RV function on mortality in these patients. In an effort to reduce the interstage mortality in our patients with HLHS, our institution has introduced a home surveillance program for early identification of physiologic variances that may be associated with interstage death [17, 25]. This monitoring program, which involves daily home pulse oximetry and weight checks, was initiated in September of 2000, midway through this study, and since its introduction there were no additional interstage deaths during our study period. This finding suggests that vigilant monitoring of this high risk group may be an effective way to reduce mortality. Limitations of this study include its retrospective nature, the subjective analysis of RV function, and the lack of confirmation of coronary anatomy, ventriculocoronary connections, and pathologic cause of death by autopsy. Future studies are clearly warranted to delineate the exact etiology of this higher mortality in the AA-MS subtype. We speculate that the Sano modification of stage 1 palliation [26] may be of benefit to the AA-MS subtype patients by limiting the diastolic runoff into the

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