Author + information
- Received September 21, 2011
- Revision received December 19, 2011
- Accepted January 5, 2012
- Published online April 1, 2012.
- ↵⁎Reprint requests and correspondence:
Dr. Richard A. Krasuski, Desk J2-4, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195
Objectives This study was designed to assess the prevalence of provoked exercise desaturation (PED) in patients with patent foramen ovale (PFO) referred for cardiovascular evaluation and to evaluate the impact of PFO closure.
Background Platypnea orthodeoxia syndrome is a rare, mechanistically obscure consequence of PFO that results in oxygen desaturation during postural changes. In our clinical experience, however, it is far less common than desaturation during exercise.
Methods This was a single-center prospective study of 50 patients with newly diagnosed PFO. Each patient underwent standardized assessment for arterial oxygen saturation with pulse oximetry during postural changes and stair climbing exercise. Provoked exercise desaturation was defined as a desaturation of at least 8% from baseline to <90%. All patients who underwent closure were reevaluated 3 months after the procedure. Those with baseline PED were similarly reassessed for desaturation at follow-up.
Results Mean age of the cohort was 46 ± 17 years, 74% were female, 30% had migraines, and 48% had experienced a cerebrovascular event. Seventeen patients (34%) demonstrated PED. Provoked exercise desaturation patients seemed demographically similar to non-PED patients. Ten PED patients underwent PFO closure (2 surgical, and 8 percutaneous). Drop in oxygen saturation was improved by an average of 10.1 ± 4.2% after closure (p < 0.001), and New York Heart Association functional class improved by a median of 1.5 classes (interquartile range: 0.75 to 2.00, p = 0.008).
Conclusions One-third of patients referred for assessment of PFO experience oxygen desaturation during stair exercise. Closure of PFO seems to ameliorate this phenomenon and improve functional status.
Platypnea orthodeoxia syndrome (POS) is traditionally defined as dyspnea or hypoxemia observed when moving from a recumbent to an upright or seated position (1,2). Although there are several potential causes for this phenomenon, POS is classically described as resulting from right-to-left shunting through a patent foramen ovale (PFO) (3,4). The precise mechanism of shunting through a PFO despite normal intracardiac pressures, however, remains obscure (5). Under physiological conditions the left atrial pressure is typically 5 to 8 mm Hg higher than the right atrial pressure (6). Logically this pressure gradient should prevent right-to-left shunting and would thereby preclude the mixing of deoxygenated blood with the systemic circulation in the presence of a PFO. However, specific circumstances, such as rigorous exertion might sufficiently increase venous return to briefly overcome the pressure difference, thereby initiating a transient shunt (5). Certainly this so-called “provoked exercise desaturation” (PED) would allow for right-to-left shunting in a manner similar to but technically distinct from POS. This mechanism of desaturation would agree with the findings that: 1) desaturations caused by PFO can reflect an inducible arterial desaturation and not a permanent shunt (7); and 2) these desaturations are a rarely observed phenomenon (1), even though PFO is present in up to 25% of the population (8).
In addition to the ambiguities surrounding the definition and mechanism of shunting through a PFO, the question of how to manage this enigmatic finding remains. Although many patients undergo closure of PFO for oxygen desaturation or dyspnea (9), the utility of this intervention has never been evaluated in a prospective manner. Furthermore, recently presented data from the CLOSURE I trial (A Prospective, Multicenter, Randomized, Controlled Trial to Evaluate the Safety and Efficacy of the STARFlex Septal Closure System vs. Best Medical Therapy in Patients with Stroke or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale) (10) have given more weight to conservative management over intervention when weighing the potential risks and benefits of PFO closure. In light of these complexities, we sought to examine the prevalence of PED in a population of patients referred for cardiovascular recommendations with regard to PFO management and investigate the impact of PFO closure on those patients exhibiting PED.
A diverse cohort of consecutive patients undergoing consultation for newly diagnosed PFO in an adult congenital heart clinic was prospectively enrolled between August 2009 and December 2010. The diagnosis of PFO was confirmed in each patient by transthoracic and/or transesophageal echocardiogram with agitated saline contrast and color Doppler imaging. As part of their initial workup each patient underwent standardized assessment of their arterial oxygen saturation. Saturations were measured with an OxiMax pulse oximeter (Nellcor OxiMax, Pleasanton, California), in a seated position, standing, while ambulating, and during ascent and decent of 4 flights of stairs. We defined PED as those patients experiencing a sustained arterial desaturation during assessment of at least 8% to a value ≤90%. The decision to undergo PFO closure was not controlled by the study protocol and was left to the discretion of both the clinician and the patient.
All patients who underwent percutaneous PFO closure were re-evaluated in the office 3 months after the procedure. Persistence of an atrial level shunt was assessed by transthoracic echocardiography with agitated saline contrast and color Doppler at that time. Patients who demonstrated PED during original assessment were re-evaluated for arterial desaturation during exercise with the same technique used during initial assessment. New York Heart Association (NYHA) functional class was assessed and recorded at each visit with a very detailed review of systems.
Data are presented as mean ± SD for continuous variables and as a percentage for discrete variables. Comparison of dichotomous variables was performed with the Pearson chi-square test or Fisher exact test where appropriate. Comparisons of continuous variables between groups were performed with 2-sided t tests. Comparisons of individual patient outcomes before and after PFO closure were performed with matched pair analysis with Wilcoxon matched-pairs signed-ranks test or paired t test where appropriate. For all tests a p value <0.05 was considered statistically significant. Data were analyzed and compiled with JMP 9.0 software (SAS Institute, Inc., Cary, North Carolina).
During the 17-month period a total of 50 patients with PFO were enrolled into the study. The baseline demographic data of our cohort are listed in Table 1: 34% of patients had an atrial septal aneurysm, 30% had experienced migraine headaches, and 48% had suffered a transient ischemic attack or stroke with confirmatory imaging. Twenty-two patients (44%) were referred specifically due to concern for paradoxical embolism, 6 patients (12%) were referred for POS, and 22 (44%) were referred for evaluation of an incidentally found PFO. During the assessment of arterial oxygen saturations, 17 patients experienced a desaturation of at least 8% to value <90%, thereby meeting the criteria for PED. The patients with PED were not demographically distinct from those without PED. Of the 17 patients identified to have PED, 13 underwent PFO closure, and 10 of these patients completed follow-up. The drop in oxygen saturation during exercise 3 months after closure improved by an average of 10.1 ± 4.2% (p < 0.001) (Fig. 1). Similarly, NYHA functional class improved by a median of 1.5 classes (interquartile range: 0.75 to 2.00, p = 0.008). The individual patient data are shown in Table 2.
Only 6 patients were referred for PFO evaluation primarily due to arterial oxygen desaturation, and 4 of these patients demonstrated PED when tested. Interestingly, 13 cases of PED were noted in patients with no documented history of oxygen desaturation. Twenty-one patients in the entire cohort underwent subsequent closure of their PFO: 13 who demonstrated PED, and 8 who did not. Two patients elected to undergo surgical closure of their PFO, and 19 underwent percutaneous closure. Of those receiving percutaneous PFO closure, 16 were closed with the Helex device (Gore Medical, Flagstaff, Arizona), 1 was closed with the Starflex device (NMT Medical, Boston, Massachusetts), 1 was closed with the CardioSeal (NMT Medical, Boston, Massachusetts), and 1 was closed with the Amplatzer cribiform device (AGA Medical, Plymouth, Minnesota). Five patients were noted to have minor residual shunting on postprocedure echocardiographic examination (1 post-Amplatzer cribiform device, and 4 post-Helex device). Of these 5 patients, 3 had initially demonstrated PED, and 2 of these patients had completed follow-up. The presence of a residual shunt did not seem to impact on the efficacy of PFO closure in ameliorating PED.
This prospective, single-center study used standardized methods to determine the prevalence of provoked exercise desaturation in a diverse patient cohort referred for evaluation of a newly recognized PFO. Although platypnea orthodeoxia syndrome is considered a rare phenomenon (3,4,6), we identified a relatively high proportion of patients (33%) who met the criteria for PED. This proportion should likely not be applied to the general population of patients with PFO, because it represents a cohort that was referred for cardiovascular evaluation and consideration of PFO closure and therefore is more likely to feature symptomatic PFO. The greater implication, however, is that arterial desaturation through a PFO is a particularly challenging diagnosis that is likely underdiagnosed in the general population (11). Given that there is no consensus mechanism for right-to-left shunting at normal cardiac pressures and that POS commonly presents without postural changes (6), there might be a substantial number of patients who experience PED or platypnea-type physiology that go undiagnosed due to the inability to meet traditional criteria or the inadequacy of current testing.
Nonetheless, PFO closure leads to resolution of arterial oxygen desaturation and significant improvement in functional capacity in PED patients. Although assessment of NYHA functional class is subjective and might be subject to placebo effect, the improvement in arterial desaturation seems to be a common phenomenon and not just limited to a few patients. Prior studies have retrospectively examined the effect of PFO closure in POS patients and have shown dramatic improvements in standing oxygen saturation (12–14). However, these investigations limited their cohort to patients experiencing postural orthodeoxia. Our inclusion of patients with exertional desaturations might have selected a less restricted cohort that might be more reflective of the diverse presentations resulting from shunt through a PFO.
We were also able to demonstrate symptomatic improvement with PFO closure in all patients with PED who underwent closure. There was a significant improvement in NYHA functional class after PFO closure by an average of 1.3 ± 0.8 classes (p < 0.001). This is consistent with the Guérin et al. (4) retrospective multicenter study performing transcatheter PFO closure in 78 patients with POS, which reported NYHA functional class improvement from grade 2.7 ± 0.7 to 1 ± 1 after PFO closure.
These findings are the first to validate the important mechanistic role that PFO plays in the pathophysiology of the transient desaturation observed in patients during stair exercise and suggest that PFO closure might be an effective strategy for improving arterial desaturation and functional status in patients with PED. Our employment of a standardized assessment of arterial desaturation (including postural changes and standardized exertion) is likely to have helped us identify a larger group of patients with POS-type physiology than would have been recognized with a more routine assessment. These findings suggest that right-to-left shunting through a PFO is an underdiagnosed phenomenon and implies that patients with poor functional class might suffer from unrecognized shunting and might benefit from PFO closure. Furthermore, our method of assessing arterial desaturation is simple to implement and should become part of the routine assessment of PFO patients, particularly considering that there is no a priori way to determine which patients will desaturate. Although the recent results of the CLOSURE-I trial (10) have cast doubt upon the field of percutaneous PFO closure, our findings along with the established safety of percutaneous PFO closure in POS (3,4) emphasize the continued utility of intervention in a properly selected patient population.
Drs. Devendra and Rane have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Krasuski has received speaker fees from Actelion and Roche (modest); is an advisory board member of Actelion, Gilead, and Ventripoint (modest); and has received research funding from Actelion.
- Abbreviations and Acronyms
- New York Heart Association
- provoked exercise desaturation
- patent foramen ovale
- platypnea orthodeoxia syndrome
- Received September 21, 2011.
- Revision received December 19, 2011.
- Accepted January 5, 2012.
- American College of Cardiology Foundation