The aim of this study was to evaluate the ability of percutaneous patent foramen ovale (PFO) closure to improve systemic hypoxemia. Although PFO-mediated right-to-left shunt (RTLS) is associated with hypoxemia, the ability of percutaneous closure to ameliorate hypoxemia is unknown. Between 2004 and 2009, 97 patients who underwent PFO closure for systemic hypoxemia and dyspnea that was disproportionate to underlying lung disease were included for evaluation. All patients exhibited PFO-mediated RTLS as determined by agitated saline echocardiography. Procedural success was defined as implantation of a device without major complications and mild or no residual shunt at 6 months. Clinical success was defined as a composite of an improvement in New York Heart Association (NYHA) functional class, reduction of dyspnea symptoms, or decreased oxygen requirement. Procedural success was achieved in 96 of 97 (99%), and clinical success was achieved in 68 of 97 (70%). The presence of any moderate or severe interatrial shunt by agitated saline study (odds ratio [OR] = 4.7; p <0.024), NYHA class at referral (OR = 2.9; p <0.0087), and 10-year increase in age (OR = 1.8; p <0.0017) increased likelihood of clinical success. In contrast, a pulmonary comorbidity (OR = 0.18; p <0.005) and male gender (OR = 0.30; p <0.017) decreased the likelihood of success. In conclusion, based on the largest single-center experience of patients referred for PFO closure for systemic hypoxemia, PFO closure was a mechanically effective procedure with an associated improvement in echocardiographic evidence of RTLS, NYHA functional class, and oxygen requirement.
Patent foramen ovale (PFO) mediated right-to-left shunt (RTLS) is known to be associated with paradoxical embolism, decompression illness, and migraine headache. Although less widely recognized and investigated, hypoxia and associated dyspnea is a potentially prevalent manifestation of PFO-mediated RTLS and promising target for transcatheter closure. Intermittent positional desaturation from platypnea-orthodeoxia syndrome (POS) is the prototype for PFO-driven hypoxia, and percutaneous closure has been shown to ameliorate hypoxia. However, POS is a rare cause of unexplained desaturation. More commonly, PFO RTLS is known to worsen hypoxia in prevalent pulmonary disorders including chronic pulmonary obstructive disease and obstructive sleep apnea, even in the absence of pulmonary hypertension. Accordingly, recent investigations have shown efficacy of transcatheter closure for palliation of hypoxia and associated dyspnea in small cohorts. However, clinical improvement was less evident in chronic respiratory insufficiency patients, raising questions regarding the efficacy of transcatheter closure in this population. We present a 5-year single-center experience in a large cohort of patients with chronic respiratory insufficiency who underwent percutaneous PFO closure for the treatment of dyspnea and hypoxia.
Methods
Using an institutional review board–approved protocol, patients who underwent percutaneous PFO closure at the University of Colorado Hospital for the primary indication of hypoxia between January 1, 2004, and December 31, 2009, were retrospectively reviewed. All subjects provided informed consent.
Initial evaluation of all subjects included saline contrast transthoracic echocardiography performed in the resting state for assessment of possible PFO RTLS. Patients without evidence of resting RTLS underwent provocative testing with Valsalva maneuver, cough, or exercise. Exercise saline contrast echocardiography was peformed before and after maximal exercise using the modified Bruce treadmill protocol with continuous pulse oximetry and electrocardiography while on room air. Exercise was performed to achieve 85% of age-predicted maximum heart rate and was stopped early only if limiting symptoms developed. Echocardiographic images were evaluated by a single reviewer to confirm adequate 4-chamber views and opacification of the right atrium following injection. A positive study was defined as visualization of any saline contrast targets in the left heart within 3 cardiac cycles following right atrial opacification. RTLS severity was characterized semiquantitatively based on the number of bubbles visualized in the right heart (mild: <6 bubbles; moderate: ≥6 and <20 bubbles; severe: ≥20 bubbles) as previously described.
All subjects were assessed for either resting or exertional hypoxemia before referral for possible PFO closure using either a 6-minute walk test or exercise saline contrast echocardiogram. Patients with coexisting pulmonary disease underwent an evaluation that included pulmonary function testing, high-resolution computed tomography of the chest, overnight polysomnography, and nocturnal pulse oximetry.
Right heart catheterization and PFO closure were performed at the University of Colorado Hospital Cardiac and Vascular Center. Intracardiac echocardiography (ICE) was performed during catheterization using an 8Fr Acuson AcuNav catheter (Siemens, San Diego, California) by an experienced interventional cardiologist to visualize the PFO and interatrial septal anatomy. Three-dimensional transesophageal echocardiography was performed only if the anatomic complexity of the PFO tunnel necessitated additional visualization for device deploymment. Agitated saline injection from the femoral vein was used to assess the amount of right-to-left shunting. Right heart catheterization was performed with all ICE studies to determine right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure, and pulmonary vascular resistance using thermodilution-derived cardiac outputs performed in triplicate and averaged.
PFO closure was performed if all the following criteria were present: (1) symptomatic hypoxemia, (2) visualization of a significant RTLS across a PFO via color Doppler or saline contrast at the time of ICE, (3) previous evidence of oxygen desaturation at rest or with exertion, and (4) absence of significant pulmonary hypertension defined as mean pulmonary artery pressure >45 mm Hg and pulmonary vascular resistance >5 Woods units. Following PFO closure, patients were treated with clopidogrel 75 mg daily for 1 month and aspirin 325 mg daily for 6 months. Saline contrast transthoracic echocardiography was performed the day after closure and 1 month later to assess for device position and residual RTLS.
Exercise capacity, supplemental oxygen requirement, symptoms, and New York Heart Association (NYHA) functional class were assessed before and after PFO closure using medical records and telephone interviews when records were not available. For patients receiving supplemental oxygen, NYHA class was determined on symptoms while using oxygen.
At the discretion of the provider, exercise saline contrast echocardiography was performed approximately 6 months after PFO closure to assess for residual shunt and oxygen requirement. To quantify improvement in exercise-induced arterial oxygen desaturation and exercise capacity following PFO closure, patients who underwent exercise saline contrast echocardiography before and after PFO closure were assessed for a change in desaturation magnitude.
Procedural success was defined as implantation of a closure device without a major complication and mild or no residual shunt at 6-month echocardiographic follow-up. Major complications were defined as any of the following: hemorrhage requiring blood transfusion, cerebrovascular event within 1 month, device thrombosis, device embolization, device erosion, new atrial fibrillation, pericardial tamponade, pericardial effusion, cardiac perforation, procedural death, or procedural complication requiring surgical repair.
Patient outcomes were measured using a primary composite end point of improvement in ≥1 NYHA functional class after closure, patient-reported reduction in dyspnea without a change in NYHA class, or a decreased supplemental oxygen requirement. An improvement in ≥1 NYHA functional class after closure was used as a secondary end point for the multivariate analysis.
The Wilcoxon signed-rank test was used to evaluate the difference in NYHA functional class for each patient before and after PFO closure. McNemar’s test was used to evaluate the use of supplemental oxygen before and after PFO closure. A p value <0.05 was chosen as the threshold for statistical significance for all tests. A logistic regression model was used to evaluate the association between improvement in NYHA class and age; male gender; coexisting pulmonary conditions; arterial oxygen desaturation during preprocedure testing; moderate or severe shunt by saline contrast echocardiography with rest, Valsalva, or cough; and NYHA functional class at the time of referral. The effect of each variable was adjusted for all other variables in the model. Statistical analysis was performed by the University of Colorado Denver Research Consortium Laboratory using SAS software version 9.2 (SAS, Cary, North Carolina).
Results
One hundred four patients were evaluated for possible inclusion in this study. Three patients were excluded for having PFO closure performed for emergent indications. Of these patients, 1 underwent PFO closure after right ventricular infarction, a second patient for right ventricular failure and severe RLS following coronary artery bypass grafting, and a third patient with metastatic carcinoid of the tricuspid valve who could not be weaned from mechanical ventilation. Four patients died of noncardiac causes before follow-up could be obtained. Follow-up was obtained in the remaining 97 patients by review of clinical notes and telephone interview when clinical follow-up was not available.
The patients included for review were predominantly NYHA functional class III (54%) and had coexisting pulmonary disease (67%) including chronic pulmonary obstructive disease (20%; Table 1 ). Patients had only borderline elevated right and left heart pressures. There was no evidence of late appearance of saline contrast targets (i.e., appearance after 3 cardiac cycles) during resting echocardiography that would be suggestive of an intrapulmonary RTLS ( Table 2 ). The majority of patients (75 patients, 77%) had evidence of RTLS during resting injection, and most had mild RTLS. Of those 22 patients without RTLS at rest, all had positive RTLS with Valsalva maneuver, cough, or exercise. Aortic root dilation was present in 13 patients (13%), an atrial septal aneurysm was visualized in 38 patients (39%), and a prominent Eustachian valve was demonstrated in 31 patients (32%).
| Variable | N = 99 |
|---|---|
| Age at time of PFO closure (yrs) | 59 ± 15 |
| Males | 49 (47%) |
| Average length of follow-up (d) | 241 ± 319 |
| Any coexisting pulmonary disease | 65 (67%) |
| Chronic obstructive pulmonary disease | 19 (20%) |
| Interstitial lung disease | 15 (16%) |
| Reactive airways disease | 5 (5%) |
| Obstructive sleep apnea | 19 (20%) |
| Pulmonary sarcoidosis | 6 (6%) |
| Oxygen dependent | 41 (42%) |
| Mean pulmonary artery pressure (mm Hg) | 23 ± 7 |
| Mean pulmonary capillary wedge pressure (mm Hg) | 12 ± 5 |
| NYHA class at presentation | |
| I | 7 (7%) |
| II | 34 (35%) |
| III | 52 (54%) |
| IV | 4 (4%) |
| Rest | Valsalva | Cough | Exercise | |
|---|---|---|---|---|
| Total no. studies | 97 | 32 | 24 | 59 |
| No | 22 (23%) | 0 | 1 (4%) | 5 (8%) |
| Mild | 36 (37%) | 11 (34%) | 10 (42%) | 6 (10%) |
| Moderate | 21 (22%) | 14 (44%) | 7 (29%) | 23 (39%) |
| Severe | 18 (19%) | 7 (22%) | 6 (25%) | 25 (42%) |
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