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J Am Coll Cardiol, 2007; 49:797-802, doi:10.1016/j.jacc.2006.08.063 (Published online 6 February 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: PATENT FORAMEN AND STROKE

Patent Foramen Ovale and the Risk of Ischemic Stroke in a Multiethnic Population

Marco R. Di Tullio, MD*,1,*, Ralph L. Sacco, MD{dagger},{ddagger}, Robert R. Sciacca, EngScD*, Zhezhen Jin, PhD§ and Shunichi Homma, MD, FACC*,2

* Department of Medicine, Columbia University Medical Center, New York, New York
{dagger} Department of Neurology, Columbia University Medical Center, New York, New York
{ddagger} Department of Epidemiology and Public Health at the Sergievsky Center, Columbia University Medical Center, New York, New York
§ Department of Biostatistics, Columbia University Medical Center, New York, New York.

Manuscript received June 27, 2006; revised manuscript received August 11, 2006, accepted August 14, 2006.

* Reprint requests and correspondence: Dr. Marco R. Di Tullio, Professor of Clinical Medicine, Columbia University Medical Center, PH3-342, 622 West 168th Street, New York, New York 10032. (Email: md42{at}columbia.edu).

This study was presented in part at the 2003 American Heart Association Stroke International Conference, Phoenix, Arizona.


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to assess the risk of ischemic stroke from a patent foramen ovale (PFO) in the multiethnic prospective cohort of northern Manhattan.

BACKGROUND: Patent foramen ovale has been associated with increased risk of ischemic stroke, mainly in case-control studies. The actual PFO-related stroke risk in the general population is unclear.

METHODS: The presence of PFO was assessed at baseline by using transthoracic 2-dimensional echocardiography with contrast injection in 1,100 stroke-free subjects older than 39 years of age (mean age 68.7 ± 10.0 years) from the Northern Manhattan Study (NOMAS). The presence of atrial septal aneurysm (ASA) also was recorded. Subjects were followed annually for outcomes. We assessed PFO/ASA-related stroke risk after adjusting for established stroke risk factors.

RESULTS: We detected PFO in 164 subjects (14.9%); ASA was present in 27 subjects (2.5%) and associated with PFO in 19 subjects. During a mean follow-up of 79.7 ± 28.0 months, an ischemic stroke occurred in 68 subjects (6.2%). After adjustment for demographics and risk factors, PFO was not found to be significantly associated with stroke (hazard ratio 1.64, 95% confidence interval [CI] 0.87 to 3.09). The same trend was observed in all age, gender, and race-ethnic subgroups. The coexistence of PFO and ASA did not increase the stroke risk (adjusted hazard ratio 1.25, 95% CI 0.17 to 9.24). Isolated ASA was associated with elevated stroke incidence (2 of 8, or 25%; adjusted hazard ratio 3.66, 95% CI 0.88 to 15.30).

CONCLUSIONS: Patent foramen ovale, alone or together with ASA, was not associated with an increased stroke risk in this multiethnic cohort. The independent role of ASA needs further assessment in appositely designed and powered studies.

Abbreviations and Acronyms
  ASA = atrial septal aneurysm
  CI = confidence interval
  PFO = patent foramen ovale
  TEE = transesophageal echocardiography

In recent years, the presence of a patent foramen ovale (PFO) has been shown to be associated with an increased risk of ischemic stroke (1–4). The association has been predominantly shown in younger patients with unexplained (cryptogenic) stroke but also has been suggested in older patients (4). The increased stroke risk, mainly demonstrated by case-control studies, has led to the application of different strategies to prevent recurrent events. Medical treatment using antiplatelet agents or systemic anticoagulation (5–7), open heart surgery (8–10), and transcatheter PFO closure (11–16) have all been shown to be effective in reducing the risk of recurrent events in stroke patients with a PFO. However, the risk of first ischemic stroke associated with a PFO in prospective population-based cohorts is not well established. Such information is of crucial importance, given the high prevalence of PFO in the population (approximately 25%) (17,18). Therefore, the purpose of the present study was to evaluate prospectively the risk of ischemic stroke associated with the presence of a PFO in the multiethnic cohort of northern Manhattan. The role of an associated atrial septal aneurysm (ASA), which has also been associated with stroke risk (19,20), was also evaluated.


   Methods
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Results
 Discussion
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The study cohort was derived from the NOMAS (Northern Manhattan Study), an epidemiological study that evaluates the incidence, risk factors, and clinical outcome of stroke in the multiethnic population of northern Manhattan. The study design and other methodological details regarding NOMAS have been described previously (21). In brief, community subjects from northern Manhattan were eligible if they: 1) had never been diagnosed with a stroke, 2) were older than 39 years of age, and 3) resided in northern Manhattan for at least 3 months in a household with a telephone. Stroke-free subjects were identified by random digit dialing using dual-frame sampling to identify both published and unpublished telephone numbers. Of the prospective study participants that were contacted telephonically, 90% agreed to come in for an in-person visit. Of those, 75% agreed to be enrolled in NOMAS and undergo the echocardiographic testing.

From May 24, 1993, through November 11, 1999, 1,148 stroke-free subjects underwent transthoracic echocardiography with contrast injection as part of NOMAS. Echocardiographic contrast study was technically inadequate in 47 subjects (4.1%). No follow-up information could be obtained in 1 additional subject. Therefore, this article reports on results obtained in 1,100 subjects.

All study subjects provided informed consent. The study was approved by the Institutional Review Board of Columbia University Medical Center.

Diagnostic evaluation.   Data were collected through interview, review of the medical records, physical and neurological examination by the study physicians, in-person measurements, and fasting blood specimen drawing. Routine laboratory tests included complete blood counts, coagulation studies, serum electrolytes, liver function tests, glucose, and cholesterol determination. Arterial hypertension was defined as the presence of a positive history or antihypertensive treatment, or blood pressure values >140/90 mm Hg during the interview. Hypercholesterolemia was defined as a total serum cholesterol >240 mg/dl or the presence of appropriate drug treatment. Diabetes mellitus was defined on the basis of abnormal fasting glucose >125 mg/dl, positive history, or the presence of oral or insulin treatment. Coronary artery disease included a history of myocardial infarction or typical angina or the patient’s reporting of a positive diagnostic test (stress test, coronary angiography) and/or drug treatment. The presence of atrial fibrillation was classified by history (current or past electrocardiography [ECG] or Holter provided by the patient) and also included the results of an ECG done at the time of enrollment.

Echocardiographic evaluation.   Transthoracic 2-dimensional echocardiography was performed in all study subjects according to the recommendations of the American Society of Echocardiography. Saline contrast injection (aerated saline solution) was used for PFO detection (1–3), and Valsalva maneuver and coughing were used to increase sensitivity (22). A PFO was considered to be present if any microbubble was seen in the left-sided cardiac chambers within 3 cardiac cycles from maximum right atrial opacification (1–3). An ASA was defined as more than a 10-mm protrusion beyond the plane of the septum into the left or right atrium (23).

Follow-up and outcome evaluation.   All subjects were followed annually by telephone. The proportion of subjects who had a follow-up point at 5 years from baseline was 98% (1,078 of 1,100). Any vascular event or acknowledgment of neurological or cardiac symptoms during the annual standardized interview triggered an in-person assessment. All subjects who screened positive for possible stroke were assessed in person by a neurologist. In addition, active hospital surveillance of admission and discharge International Classification of Diseases-9th revision codes was performed. Stroke was defined by the first symptomatic occurrence of any type of stroke as defined by TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria (24). Diagnosis of ischemic stroke was determined by 2 neurologists independently, and the NOMAS principal investigator (R.L.S.) adjudicated any disagreements. Ischemic stroke, fatal and nonfatal, was used as the primary outcome of the present study. Stroke diagnostic subtypes (embolic vs. nonembolic) were defined by a neurologist unaware of subjects’ PFO status according to modified Stroke Data Bank criteria (25).

Statistical analysis.   Given the sample size of 1,100 and the observed PFO prevalence of 14.9%, the study had 80% power to detect a minimum relative risk of 2.08 at a 0.05 significance level. Data are presented as mean values ±1 standard deviation for continuous variables and as proportions for categorical variables. Kaplan-Meier event-free analysis was performed for ischemic stroke with and without PFO. The difference between groups was evaluated by means of the log-rank test. Cox proportional hazards survival models were used to assess the risk of stroke from PFO/ASA. Hazard ratios and 95% confidence intervals (CIs) for PFO/ASA and stroke were calculated after adjustment for other stroke risk factors (hypertension, diabetes, hypercholesterolemia, cigarette smoking, atrial fibrillation). To test the effect of age (≥ vs. <60 years), gender and race-ethnicity on the association between PFO and stroke, separate variables were fit in the model to quantify the effect of PFO independently for each subgroup. Differences between subgroups were tested using interaction terms. A p < 0.05 was considered significant for all analyses. Data were analyzed by 1 investigator (R.R.S.) using SAS software (version 9.0, SAS Institute, Cary, North Carolina).


   Results
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Discussion
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Characteristics of the study cohort.   The characteristics of subjects are shown in Table 1. Eleven hundred subjects (460 men, 640 women, mean age 68.7 ± 10.0 years) were enrolled. Twenty-six percent of the population was black, 49.3% was Hispanic, and 24.7% white. Women comprised more than 58% of the cohort.


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  		Table 1. Demographics, Risk Factors, and Atrial Septal Abnormalities
 
Prevalence of PFO and ASA.   A PFO was detected in 164 subjects (14.9%) (Table 1). An ASA was detected in 27 (2.5%), and both PFO and ASA were found in 19 (1.7%). Characteristics of subjects with and without a PFO are summarized in Table 2. The 2 groups were well balanced with respect to demographics and traditional stroke risk factors, with the only significant difference being a lower proportion of subjects with hypertension in the PFO group. Aspirin usage for non–PFO-related indications (recorded for its potential effect on stroke risk) was not significantly different between the 2 groups.


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  		Table 2. Demographics, Risk Factors, and Aspirin Usage by PFO Status
 
PFO, ASA, and the risk of ischemic stroke.   Subjects were followed for a mean duration of 79.7 ± 28.0 months (range 43 to 135 months). During the follow-up, an ischemic stroke occurred in 68 subjects (6.2%). Stroke incidence was 12.2 per 1,000 person-years in subjects with a PFO and 8.9 per 1,000 person-years in those without it (p = 0.5). Figure 1 shows the stroke-free survival in the 2 groups. The curves of subjects with and without PFO did not differ significantly (p = 0.28). After adjustments for other stroke risk factors, the hazard ratio of PFO for stroke was 1.64 (95% CI 0.87 to 3.09) (Table 3). The frequency of cryptogenic stroke was not significantly different between stroke patients with a PFO and those without it (18.2% vs. 21.2%; p = 0.6), and so was the frequency of embolic strokes (18.2% vs. 32.7%; p = 0.3).


Figure 1
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  		Figure 1 PFO and Risk of Ischemic Stroke

Kaplan-Meier estimate of stroke-free survival according to baseline patent foramen ovale (PFO) status.

 

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  		Table 3. Risk of Ischemic Stroke by PFO/ASA Status
 
The analysis of the stroke risk associated with an ASA, alone or in combination with a PFO, was hindered by the small number of subjects with this finding (n = 27). The coexistence of PFO and ASA was not found to increase the risk of stroke (Table 3). The few subjects with an isolated ASA showed an elevated risk of stroke (2 of 8, or 25%), but isolated ASA was not independently associated with stroke (adjusted hazard ratio 3.66, 95% CI 0.88 to 15.30) (Table 3).

Effect of age, gender, and race-ethnicity.   The lack of a significant association between PFO and stroke was observed in both men and women, and in patients younger or older than 60 years of age (Table 4), although with higher hazard ratios in men and in younger subjects. No significant association between PFO and stroke was observed in any race-ethnic subgroups. A similar analysis could not be performed for ASA because of the much smaller sample size.


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  		Table 4. Association Between PFO and Ischemic Stroke by Gender, Age, and Race-Ethnicity
 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Patent foramen ovale and ischemic stroke.   The present study shows no significant increase in the risk of ischemic stroke from a PFO in the general population during a mean follow-up of almost 7 years. This observation has great practical importance because a PFO is found in approximately one-quarter of the general population. The lack of an increase in risk was consistent across all age, gender, and race-ethnic subgroups analyzed. A PFO has been shown in the past by us and others to be associated with ischemic stroke, especially cryptogenic stroke (1–4). Those observations were made mostly in case-control studies, which paired subjects in whom a stroke had already occurred with stroke-free controls of same gender and similar age. Besides the possibility of selection and referral bias (26,27), those case-control studies only established an increased prevalence of PFO among stroke patients but were unable to evaluate the magnitude of the PFO-related stroke risk in the general population. Our study demonstrates that this absolute risk is low, at least over the period of observation considered. These 2 findings may not be as discordant as they appear. Although far from reaching statistical significance, the presence of a PFO in our study carried a not entirely negligible adjusted hazard ratio for stroke of 1.64. Moreover, the hazard ratios were slightly greater for men and for subjects younger than 60 years of age. It is possible that this slight increase in risk may stem from a minority of patients who are indeed at higher risk but whose influence on the overall trend would be diluted because of their relatively small number.

Although our data suggest that the absolute risk of stroke from a PFO in the general population is low, the search may still be on for individual subjects in whom PFO carries an increased risk, possibly because of associated cofactors that may turn a PFO from an innocent bystander into a causative mechanism for stroke. The studies that documented an increased risk of stroke from a PFO in the past may have included a much larger proportion of these subjects, because they were all conducted on stroke patients, either because of their case-control design (1–4) or because of their focus on stroke recurrence (28). The size of a PFO (29–31), presence of deep venous thrombosis (32,33), associated right atrial abnormalities (34), and hypercoagulability (35–38) have all been cited as possible cofactors in the risk of stroke associated with a PFO. Further research is needed to define their role, as well as to investigate the possibility that other potential cofactors may exist that are yet unknown.

The relationship of ASA and ischemic stroke.   Given the low prevalence of ASA in the population (1% to 4%) (18,26), our study was not powered to conclusively address the role of an ASA, alone or in combination with a PFO, on the stroke risk. However, the combination of PFO and ASA did not appear to increase the stroke risk, which is in agreement with what was recently reported by a similar study (27). Also in agreement with that study, an isolated ASA carried an unusually high incidence of stroke in the small number of subjects who had it (2 of 8, or 25%, in our study, and 2 of 5, or 40%, in the other). This finding seems to oppose the widely held opinion that an ASA is associated with stroke via the high frequency of associated PFO, but cannot be considered conclusive because of the small number of subjects analyzed. The possibility that an ASA may increase the risk of stroke through mechanisms other than PFO, such as atrial electrical instability (39) and consequent increased frequency of paroxysmal atrial fibrillation, requires assessment in appositely designed studies.

Comparison with previous studies.   Although a number of studies have evaluated the risk of recurrence in stroke patients with a PFO, only 1 recently published study has assessed the PFO-related stroke risk in the general population. In 577 subjects undergoing transesophageal echocardiography (TEE) as part of the SPARC (Stroke Prevention: Assessment of Risk in a Community) study, Meissner et al. (27) reported results similar to ours, with an adjusted hazard ratio of PFO and cerebrovascular events of 1.46 (95% CI 0.74 to 2.88). Similar conclusions on the PFO-related stroke risk were drawn by the same investigators using a case-control design (40). However, some important differences exist between SPARC and our study. Our sample size was almost double that of the SPARC study, and our follow-up duration was substantially longer. The larger sample size allowed the analysis of race-ethnic differences in the role of PFO on stroke risk, information largely missing in the literature. No patients with stroke/transient ischemic attack were present in our cohort at baseline versus 6.3% of subjects with a history of cerebrovascular disease or procedures in SPARC. Also, transient ischemic attacks were not included among our end points, which only included complete strokes with confirmation by computed tomography or magnetic resonance imaging. The presence of PFO/ASA was ascertained by TEE in SPARC and by transthoracic echocardiography in our study. Although TEE is more sensitive for PFO detection, most of its additional yield comes from very small PFO with minimal right to left shunts (41), whose role as a potential stroke risk factor is questionable.

Strengths and limitations.   This study is the largest to date that has prospectively assessed the role of PFO/ASA as a stroke risk factor in the general population. The results are important for a more comprehensive view of the relationship between PFO and stroke, as well as to provide context for the use of the different strategies currently suggested for stroke prevention in subjects with a PFO. The rather large sample size allowed us to obtain information in different race-ethnic groups, which is important in the light of previous suggestions of different PFO characteristics, and therefore different risk, among different races (42).

Transthoracic echocardiography was used for PFO detection instead of the more-sensitive TEE. However, TEE is a semi-invasive technique not suited for use in a low-risk population; therefore, our results may be more relevant to the reality of a PFO detected as an incidental finding in general practice. Because transthoracic echo does not visualize well the pulmonary veins, some shunts attributed to PFO may in fact have been secondary to intrapulmonary shunting, although this possibility was greatly reduced by the early timing of the shunt included in the diagnosis of PFO (within 3 cardiac cycles from right atrial opacification).

Conclusions.   Our study suggests that the medium-term risk of stroke associated with a PFO in the general population is low and that the relative risk of subjects with a PFO is not significantly increased in comparison with subjects without it. The possibility that the stroke risk may be increased in a subgroup of subjects, with yet-unidentified cofactors, cannot be excluded by this study. The stroke risk associated with an ASA requires further evaluation in appropriately designed and powered studies.


   Acknowledgments
 
The authors thank Rui Liu, MD, for her assistance in the interpretation of the echocardiographic studies.


   Footnotes
 
The study was supported in part by NINDS R01 NS29993 and NS33248.

1 Dr. Di Tullio is the recipient of a NINDS Mid-Career Award in Patient-Oriented Research (K24 NS02241). Back

2 Dr. Homma is a DSMB member for the RESPECT trial (AGA Medical). Back


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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