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Ann Thorac Surg 2006;81:207-213
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Hypertensive Pulmonary Vascular Disease in Adults with Secundum or Sinus Venosus Atrial Septal Defect

^a Department of Thoracic and Cardiovascular Surgery, University Hospital, RWTH Aachen University, Aachen
^b Pediatric Cardiac Surgery, University Hospital, RWTH Aachen University, Aachen
^c Institute of Pathology, University Hospital, RWTH Aachen University, Aachen
^d Department of Cardiac Surgery, Ludwigs-Maximilians-University, Munich, Germany

Accepted for publication July 18, 2005.

^_* Address correspondence to Dr Sachweh, Pediatric Cardiac Surgery, University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52057 Aachen, Germany (Email: jsachweh{at}ukaachen.de).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
BACKGROUND: The development of hypertensive pulmonary vascular disease (HPVD) is considered a risk factor in the long-term course of patients with secundum atrial septal defects (ASD). The aim of this study was to assess the prevalence and histologic degree of HPVD and pulmonary hypertension in relation to preoperative clinical and hemodynamic data, intraoperative findings, and operative outcome in adults.

METHODS: Lung biopsies of 75 patients, mean age 44 ± 14 years (18–71 years), with secundum ASD or sinus venosus defect including ten patients with partial anomalous pulmonary venous return were analyzed in accordance with preoperative and intraoperative findings as well as operative outcome. Lung biopsy was performed at the time of defect closure and was classified according to Heath and Edwards.

RESULTS: Structural changes of the pulmonary vasculature were found in 59% of patients; grade 3 and higher changes were present in 19%. There were no statistically significant relations between histologic findings and preoperative clinical and hemodynamic data, intraoperative findings, and operative outcome. The prevalence of moderate (32–50 mm Hg) and severe (> 50 mm Hg) systolic pulmonary hypertension was 27% and 17%, respectively. Increased systolic pulmonary arterial pressure was associated with increased pulmonary vascular resistance (p < 0.000) and patients' age (p = 0.001). Patients with a lower functional capacity had a higher prevalence of pulmonary hypertension (p = 0.011).

CONCLUSIONS: The prevalence of HPVD and pulmonary hypertension in adult patients with secundum ASD or sinus venosus defect is considerable. Preoperative hemodynamic data do not predict the degree of HPVD in lung biopsy. Closure is generally advised to prevent increasing pulmonary arterial pressure and decreasing functional capacity over time.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Secundum atrial septal defect (ASD) is one of the most frequent lesions in the spectrum of congenital heart disease in adulthood. Due to the lack of specific and severe symptoms diagnosis can be missed during childhood. Development of hypertensive pulmonary vascular disease (HPVD) has been considered a risk factor in the long-term course of secundum ASD [1–5]. Although classical reports, especially from the Mayo Clinic [6], indicate an association between secundum ASD and HPVD in adult patients, so far no proof has been given that a secundum ASD bears an inherent risk of HPVD over time. The aim of this retrospective study was to assess the prevalence and histologic degree of HPVD in adults with secundum ASD or sinus venosus defects according to the classification of Heath and Edwards [7, 8] and to compare preoperative clinical and hemodynamic data, intraoperative findings, and operative outcome with pulmonary vascular histology.

	Patients and Methods

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Between November 1981 and October 1999, 75 consecutive adult patients, 47 female: 28 male (1.7:1), mean age 44 ± 14 years (median, 44; 18–71), mean body weight 68 ± 12 kg (median, 68; 45–104), and mean body surface area 1.79 ± 0.20 m² (median, 1.77; 1.45–2.32) underwent closure of secundum ASD (68) or sinus venosus defect (7). In 10 patients (13%) ASD was associated with partial anomalous pulmonary venous return (PAPVR). Patients with ostium primum defect, congenital mitral valve disease, or other congenital or acquired heart disease were excluded. All patients had concomitant lung biopsy from different lung segments except the lingula. None of the patients had taken appetite suppressants or other drugs known to produce pulmonary vascular hypertension [9]. Surgery was done at the University Hospital Aachen, Germany. As the lung biopsies were taken for diagnostic purposes, the patients were consented for this procedure and, thus, no approval of our Institutional Review Board was mandatory.

Clinical and Noninvasive Investigations
Preoperative functional capacity was assessed according to the New York Heart Association. Concomitant pulmonary diseases, electrocardiographic findings, and cardiovascular medication were carefully evaluated.

Invasive Investigations
Cardiac diagnosis was established by catheterization in all patients. Cardiac catheterization preceded surgery by a period of 5.8 ± 6.4 months (median, 4.1 months; 24 days–3.1 years). Intraatrial shunts were detected by oximetry and/or indicator dilution method. Pulmonary and systemic flow indices were calculated by the oximetric principle of Fick using measured or assumed values for oxygen uptake. Pulmonary vascular resistance index (PVRI) was calculated as: PVR (U/m²) = mean pulmonary artery pressure (PAP) / pulmonary flow index; pulmonary arteriolar resistance index (PAR) was calculated as: PAR (U/m²) = (mean PAP - mean left atrial pressure) / pulmonary flow index. Oxygen contents were determined as mixed venous (inferior vena cava weighted to superior vena caval sample 2:1) [10], pulmonary arterial, pulmonary venous (directly or by pulmonary wedge position), and systemic arterial saturation.

Moderate pulmonary hypertension at rest was defined as a systolic PAP of 32–50 mm Hg [11] and severe pulmonary hypertension as PAP of more than 50 mm Hg [10–12]. Relation between PAP, preoperative clinical and hemodynamic findings, as well as intraoperative findings and operative outcome were analyzed.

Surgical Technique
Standard approach for ASD closure was median sternotomy; fifteen (20%) female patients underwent right anterolateral thoracotomy for cosmetic reasons. All operations were performed on extracorporeal circulation, moderate hypothermia (28°–30°), and cardioplegic arrest. Five patients (6.7%) underwent direct and 70 patients (93%) had patch closure of the ASD.

Histologic Investigations
All but two lung biopsies were taken prior to extracorporeal circulation (right lung, 49 [65%]; left lung, 7 [9%]; both lungs in 5 [8%] patients); in 14 (19%) patients the site of the biopsy had not been determined. The biopsies were approximately 1.5 x 1 x 0.5 cm in size and fixed in a state of distention. The biopsies were stained using the conventional hematoxylin and eosin method; additionally, a connective tissue stain (Miller elastic-van Gieson method) was done. A mean of 14 vessels in all fields of a section, ranging from 8 to 24 vessels, were analyzed. These vessels were small muscular pulmonary arteries ranging in diameter from 100 µm to 300 µm. All specimens were classified according to Heath and Edwards [7, 8] by two pathologists independently. There was no different judgement in patients with changes grade 3 or higher. In 5 patients there was a different judgement between grade 1 or grade 2. Final decision was made after discussion of the specimens. According to the histomorphologic findings the patients were assigned to three histologic subgroups:

Group I: no structural changes;

Group II: histomorphologic changes grade 1 (medial hypertrophy, no intimal changes), grade 2 (additional cellular intimal proliferation), and grade 3 (additional mild concentric laminar intimal fibrosis);

Group III: histomorphologic changes grade 3 (additional moderate–severe concentric laminar intimal fibrosis or higher (grade 4: additional plexiform lesions; grade 5: dilatative lesions; grade 6: fibrinoid necrosis, pulmonary arteritis).

Grade 3 histomorphologic changes with mild concentric-laminar intimal fibrosis are considered reversible [13], thus these patients were assigned to group II, whereas patients with more severe intimal fibrosis were assigned to group III. These subgroups were compared with preoperative clinical and hemodynamic findings as well as with the intraoperative measured size of the defect, and operative outcome.

Statistical Analysis
Statistical analysis was done with SPSS Version 11.0 (SPSS Inc, Chicago, IL). Central tendency is expressed by mean and median, and dispersion by standard deviation and range. Normal distribution was ruled out by the Kolmogorov-Smirnov test for most parameters. Consequently, differences among groups were assessed using two-tailed ², Mann-Whitney, and Kruskal-Wallis tests. Correlations were computed using the Spearman rank correlation. All statistical testing was done descriptively and therefore no alpha corrections for multiple testing were performed.

	Results

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Analysis of Lung Histomorphology in Relation to Preoperative and Operative Findings
The distribution of histologic changes of the lung specimens is displayed in Figure 1. Thirty-one patients (41%) were assigned to histologic subgroup I, 30 (40%) to group II, and 14 (19%) to group III. In patients with biopsies from both lungs the results on both sides were equal (no changes in 3 and grade 4 in one) except in one patient (right lung specimen grade 2, left specimen without changes) who was assigned to group II.

View larger version (17K): [in this window] [in a new window]   Fig 1. Pulmonary hypertensive vascular changes of lung biopsies in 75 patients with secundum atrial septal defect or sinus venosus defect.

Pulmonary Histology and Postoperative Course
Mean ventilation time was 1.3 ± 3.5 days (median, 1; 0–30), mean stay on the intensive care unit was 2.3 ± 3.6 days (median, 2: 1–32), and mean hospital stay was 13.6 ± 5.1 days (median, 13; 4–33). There was no significant difference of these parameters among the histologic subgroups (p = 0.542, 0.694, and 0.561).

Analysis of Hemodynamics and Clinical Data
Increasing systolic PAP was found with increasing mean right atrial pressure (RAP) (p = 0.001), right ventricular end-diastolic pressure (p = 0.003), mean left atrial pressure (LAP) (p < 0.000), PVR (p < 0.000), PAR (p < 0.000), and with increasing patient's age (p = 0.001). Systolic PAP was higher in patients with atrial fibrillation (p = 0.043) and in patients with right ventricular conduction delay (p = 0.040).

Systolic PAP was statistically not related to pulmonary blood flow (p = 0.888), magnitude of left-to-right shunt (p = 0.728), size of the interatrial defect (p = 0.203), diagnosis of a sinus venosus defect (p = 0.688), and gender (p = 0.121). An increased size of the defect was associated with an increased magnitude of the left-to-right shunt (p = 0.002). Ventilation time (p = 0.130), intensive care unit stay (p = 0.114), and hospital stay (p = 0.379) were not related to systolic PAP.

Increased PVR correlated with increased mean RAP (p = 0.009), decreased pulmonary blood flow (p < 0.000), and increased mean LAP (p = 0.005); PVR was higher in patients with atrial fibrillation (p = 0.043), but not in patients with a sinus venosus defect (p = 0.102). The correlation of PVR with patient's age could be due to chance (p = 0.094). Patients with atrial fibrillation were older (p = 0.008) and had a higher mean LAP (p = 0.038), but age did not correlate with mean LAP (p = 0.945). With decreasing preoperative functional capacity the patients were older (p = 0.002), had a higher incidence of additional pulmonary disease (p = 0.018), atrial fibrillation (p = 0.003), and a higher incidence of severe pulmonary hypertension (p = 0.011), but had no increasing mean LAP (p = 0.106).

Clinical Course: Mortality
There was one death in a 42-year-old woman with a history of recurrent pulmonary embolism and first catheterization in 1969 at the age of 30 years. A secundum ASD with systolic PAP of 100 mm Hg was diagnosed and a cross-shunt was detected; closure of the defect was not recommended. Functional capacity decreased continuously and the patient developed congestive heart failure. Repeat cardiac catheterization was performed to reassess operability twelve years later. Systolic PAP was 90 mm Hg and PVR was 4.2 U/m², pulmonary-to-systemic flow ratio (Qp:Qs) was 1.3 with a left-to-right shunt of 23% and an additional right-to-left shunt, not quantified. Again, surgical intervention was not recommended, but the patient insisted on operative therapy because of severity of symptoms. In the early 1980s there was not much experience with extensive pulmonary endarterectomy and thus it was not considered in this patient. Weaning from extracorporeal circulation was only possible after complete removal of the ASD patch and under high doses of catecholamines. The patient died of right ventricular failure on the eighth postoperative day. Histopathology of both lungs revealed chronic pulmonary embolism and HPVD grade 4–5.

Complications
Five patients (6.7%) suffered from a new onset of atrial fibrillation postoperatively, but returned to sinus rhythm without electric cardioversion. One patient experienced a transient ischemic attack with complete recovery on the third postoperative day. One patient required rethoracotomy for bleeding and one patient developed pericardial tamponade due to warfarin overdose with subsequent drainage on the 17th postoperative day. One patient developed pneumonia necessitating long-term ventilation.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
A left-to-right shunt in the cardiopulmonary vascular system may lead to pulmonary hypertension depending on the level and size of the communication [8, 12]. Progressive histologic changes of the intima and media of pulmonary arteries and arterioles known as HPVD may develop [7, 8] causing marked luminal narrowing leading to high pulmonary vascular resistance with pulmonary hypertension [4, 7]. In contrast to patients with left-to-right shunts at ventricular or aortopulmonary level [4, 14], in patients with secundum ASD prolonged exposure to increased pulmonary blood flow invariably does not result in HPVD [1] and is still intriguing.

Histologic Findings
We found a considerable number of patients (59%) with structural lung changes of different degrees, including moderate to severe lung changes (grade 3–4) in 19%, indicating that increased pulmonary blood flow leads to changes in pulmonary vasculature in many ASD patients as well. However, lesions may be irregularly distributed so that a single specimen, as taken in the majority of our patients, may not always be representative for the whole lung [15]. This has to be considered a limitation of this study.

Although the number of adult patients with structural lung changes was high, no statistically significant association was found between lung histomorphology and any of the investigated variables; however, this may be related to irregularly distributed histologic changes. In contrast, a correlation between pathomorphology and hemodynamics, predominantly in infants and children with shunts on ventricular level, has been reported in other series using a different morphologic-morphometric approach [16]. Structural changes in secundum ASD may be related to patient's age, because they are a rarity in children and adolescents [3]. However, our results do not confirm this in an adult series. We found a somewhat higher ratio of female patients with a higher grade of HPVD, which has been reported earlier [17]; the reason for this remains unclear.

Hemodynamic Findings
The prevalence of patients with moderate or severe pulmonary hypertension was 27% and was higher than in earlier reports, where the prevalence ranged from 6% to 16% [6, 11, 12, 18]. Although severe pulmonary hypertension was more common in patients with hypertensive pulmonary vascular disease, this finding was not significant, indicating the influence of other factors.

Pulmonary arterial pressure is dependent on pulmonary vascular resistance and pulmonary blood flow. Statistical analysis revealed a strong correlation of pulmonary artery pressure with pulmonary vascular resistance, but not with pulmonary blood flow. Increased pulmonary vascular resistance was associated with decreased left-to-right shunt and decreased pulmonary blood flow. The direction of interatrial flow is influenced by the relative distensibility of the two ventricles [19, 20]. Thus, in the presence of pulmonary hypertension, reduced right ventricular compliance accompanied by right ventricular hypertrophy may decrease the magnitude of left-to-right shunting. In contrast to others, we did not find a correlation between pulmonary arterial pressure and type (sinus venosus versus secundum) [21] or size of the defect [22].

Increased left atrial pressures may indicate postcapillary pulmonary hypertension resulting in an increased pulmonary vascular resistance. In our series left ventricular function was normal in all patients. However, atrial fibrillation was associated with elevated left atrial pressure and age; this may be the cause of increasing clinical symptoms by time in ASD patients [18]. Additionally, our data confirm that pulmonary arterial pressure rises and preoperative functional capacity decreases in ASD patients with age [1, 10, 17, 23].

Clinical Implications
Hypertensive pulmonary vascular disease is considered to influence the natural history and operative mortality of adult patients with secundum ASD [1, 2, 24]. In historical series of the 1960s the expected longevity in ASD patients complicated by pulmonary hypertension was 40 to 50 years of age [3, 12]. Disabling cardiorespiratory symptoms are reported in the majority of older patients with secundum ASD [17]. We also found decreasing functional capacity with increasing age. Left ventricular dysfunction [23], recurrent pulmonary embolism, or repeated pulmonary infections [24] are accused for this condition. Our data did not reveal an association of preoperative functional capacity and left atrial pressure as indicator of an impaired left ventricular function. However, chronic pulmonary embolism played a role in the only hospital death in our series and decreased preoperative functional capacity was associated with the presence of additional pulmonary disease.

Surgical Implications
Generally, closure of secundum ASD is advised, particularly if there is a relevant shunt [25]. There has been some debate about the benefit of closure of secundum ASD in adulthood [19]. About 40 years ago it was suggested that closure of a secundum ASD in patients with pulmonary hypertension and HPVD is unlikely to be beneficial, because the operative mortality was high [1, 3, 12]. In the 1980s, others [6] recommend ASD closure even in patients with PVR up to 15 Um². Currently, additional therapeutic options are available: Extreme postoperative pulmonary hypertension can be treated by inhalation of low dose nitric oxide [26]. The administration of long-term oral prostacyclin has been proven effective to lower pulmonary hypertension in single patients [27]. In the presence of Eisenmenger's syndrome, secundum ASD closure has been combined successfully with single lung transplantation [28]. In patients with chronic pulmonary thromboembolic disease and ASD, defect closure, extensive pulmonary endarterectomy, and inferior vena cava filter placement can be a surgical option with good results in selected cases and experienced institutions [29].

Presently, secundum ASD closure in adults greater than 40 to 50 years of age can be performed with a low operative mortality of 0% to 6% leading to reduced arrhythmias, increased functional capacity, and improved quality of life in long-term follow-up [17, 18, 29] even in physically active patients greater than 70 years of age [30]. Additionally, in aged patients with Qp/Qs greater than 3.0, defect closure is followed by clinical improvement even if pulmonary hypertension or congestive heart failure are associated [31]. In patients greater than 35 years of age operative mortality has been demonstrated to be independent of age or level of pulmonary hypertension [32]. We also did not find an association between operative outcome and pulmonary hypertension or the grade of HPVD, although the only death in our series was related to both.

In summary, histopathologic changes of the pulmonary vasculature according to the Heath and Edwards classification are present in a considerable number of adult patients with secundum ASD. However, neither preoperative clinical and hemodynamic nor postoperative data are evidently related to these structural changes indicating other confounding factors. To strengthen or to disprove this conclusion a study comparing these parameters in patients with multiple biopsies from different lung areas would be meaningful. At present, it is unpredictable which patient with a shunt on atrial level defect will develop HPVD. As the degree of pulmonary hypertension and the decrease of functional capacity are related to age, atrial shunts should be closed in childhood. Currently, ASD closure is performed with low operative mortality and morbidity and, in an increasing number, interventionally [33]. However, care should be taken to identify adult patients with severely elevated pulmonary vascular resistance and/or irreversible pulmonary vascular changes in whom the indication for closure has to be discussed carefully [34].

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
We thank Dr Rolf Weitkunat, Institute for Biometry and Epidemiology, Ludwigs-Maximilians-University, Munich, Germany for the biostatistical work on this paper.

	Footnotes

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^_* Both authors have contributed equally to this paper.

	References

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joerg S. Sachweh Sabine H. Daebritz Bernd Fausten Stefan Jockenhoevel Bruno J. Messmer Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sachweh, J. S. Articles by Messmer, B. J. Search for Related Content PubMed PubMed Citation Articles by Sachweh, J. S. Articles by Messmer, B. J. Related Collections Congenital - acyanotic