Original Research Pulmonary Vascular Disease
Patent Foramen Ovale and Stroke in Intermediate-Risk Pulmonary Embolism Denis Doyen, MD; Mathieu Castellani, MD; Pamela Moceri, MD; Olivier Chiche, MD; Rémi Lazdunski, MD; David Bertora, MD; Pierre Cerboni, MD; Claire Chaussade, PhD; and Emile Ferrari, MD
Patent foramen ovale (PFO) in pulmonary embolism (PE) is associated with an increased risk of complications. However, little is known about PFO and ischemic stroke prevalence, particularly in acute intermediate-risk PE. In addition, in this context, the so-called “gold standard” method of PFO diagnosis remains unknown. We aimed to evaluate PFO and ischemic stroke prevalence and determine which of transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) is the best PFO diagnostic method in this context. BACKGROUND:
We conducted a prospective monocentric study of consecutive patients with intermediate-risk PE in whom a TEE and TTE with contrast were performed. Brain MRI was used to confirm clinically obvious strokes or to diagnose subclinical ones.
Forty-one patients with intermediate-risk PE were identified over a 9-month period. Contrast TEE revealed PFO in 56.1%, whereas contrast TTE showed PFO in only 19.5% (P , .001). Of note, all PFOs observed with TTE were also diagnosed by TEE. Ischemic stroke occurred in 17.1% and was always associated with PFO and large shunt.
PFO and related ischemic strokes are frequent in intermediate-risk PE. TEE is much more efficient than TTE for PFO diagnosis. Considering the high risk of intracranial bleeding with thrombolysis in PE, which may be partly due to hemorrhagic transformation of subclinical strokes, screening PFO with TEE should be considered in intermediate-risk PE when thrombolytic treatment is discussed. CHEST 2014; 146(4):967-973
Manuscript received January 12, 2014; revision accepted May 2, 2014; originally published Online First May 29, 2014. ABBREVIATIONS: ASA 5 atrial septal aneurysm; ICH 5 intracerebral hemorrhage; PE 5 pulmonary embolism; PFO 5 patent foramen ovale; TCD 5 transcranial Doppler; TEE 5 transesophageal echocardiography; TTE 5 transthoracic echocardiography AFFILIATIONS: From the Department of Cardiology (Drs Doyen, Castellani, Moceri, Chiche, Bertora, Cerboni, Chaussade, and Ferrari) and Department of Neurology (Dr Lazdunski), Pasteur University Hospital, Nice, France. Part of this article has been presented in abstract form at the European Society of Cardiology Congress, August 31-September 4, 2013, Amsterdam, The Netherlands.
FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Denis Doyen, MD, Department of Cardiology, Pasteur University Hospital, 30 Av de la Voie Romaine, 06002 Nice, France; e-mail: [email protected]
© 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0100
Pulmonary embolism (PE) is a frequent and serious condition associated with high mortality.1 The presence of patent foramen ovale (PFO) in PE correlates with a high incidence of paradoxical embolism, especially brain embolism. PE-related mortality increases in the presence of PFO.2 With transthoracic echocardiography (TTE), PFO has been found in up to 25% of PE and identified as an independent predictor of
silent brain infarcts.3 However, this prevalence has mainly been found in patients with low-risk PE without transesophageal echocardiography (TEE).3 The best method to identify PFO is still being discussed. We sought to evaluate PFO and ischemic stroke prevalence in intermediate-risk PE and to determine the best PFO diagnostic method between TEE and TTE.
Materials and Methods
Atrial septal aneurysm (ASA) was defined by a 10-mm excursion of the atrial septum into the left or right atrium or both.6
Study End Points We aimed to evaluate PFO and ischemic stroke prevalence. We sought also to determine whether TEE or TTE is the best PFO diagnostic method in this context. Patients We performed a prospective monocentric observational study between October 2011 and June 2012 at the cardiac ICU of Pasteur University Hospital (Nice, France). Consecutive patients hospitalized for acute intermediate-risk PE were included. All PEs were confirmed with multidetector CT angiography. Intermediate risk was defined according to European Society of Cardiology guidelines1 and based on at least one of the following criteria: systolic pulmonary arterial pressure . 40 mm Hg, right ventricular dilation (defined on the apical four-chamber view as a right-to-left ventricular telediastolic diameter ratio . 0.6), right ventricular systolic dysfunction (defined on the apical four-chamber view as a tricuspid annular plane systolic excursion , 16 mm or a systolic tricuspid annular velocity , 11 cm/s), or elevated cardiac biomarkers (B-type natriuretic peptide level . 100 pg/mL [Beckman Triage method] or troponin I level . 0.06 ng/mL [Beckman Access method]). Patients aged , 18 years, pregnant or breastfeeding, contraindicated for MRI, or not consenting to the study were excluded from this protocol. Approval by ethics committee (Agence Nationale de Sécurité du Médicament et des Produits de Santé; project approval number: 2014-A00253-44) was obtained. Each patient gave written informed consent. Contrast Echocardiography Technique Within 3 days of patient admission, contrast TTE and TEE were performed consecutively within the same hour by a single experienced echocardiologist. Two different echocardiologists participated in the study. TEE was performed systematically after TTE using a matrix array transducer (X7-2t, Philips iE33 ultrasound system; Philips Healthcare Nederland). Local anesthesia for the orolarynx was delivered by 5% lidocaine pump spray without sedation. TTE was performed using a variable frequency harmonic phased-array transducer (S5-1) and a Philips iE33 ultrasound system. Harmonic imaging modality was used to improve imaging quality. Acoustic windows used for contrast TTE were of both the four-chamber and the subcostal views. Agitated saline contrast was injected into a peripheral vein during the strain phase of the Valsalva maneuver. The atrial septum was imaged during the release phase of the maneuver. All patients were submitted to a carefully standardized Valsalva maneuver. First, they were asked to contract abdominal muscles, and the echocardiologist checked for effective contraction with his hand. Second, Valsalva efficiency was defined by a 20 cm/s decrease in transmitral E-wave velocity and atrial septal bulging visualization.4 The presence of PFO was defined by the visualization of contrast (at least three bubbles) in the left-side cavities within the first three cardiac cycles after opacification of the right atrium during the maneuver. Two injections were performed for each acoustic window (TEE, TTE four-chamber and subcostal transthoracic views). A large shunt was considered when . 20 bubbles appeared in the left atrium.5
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Contrast Echocardiography Analysis Two trained observers blinded to each other and to the patients’ clinical status evaluated the images off-line. In case of discrepancy, a third interpretation was required, and consensus was obtained. General TTE Analysis Right ventricular dysfunction was assessed according to American Society of Echocardiography guidelines.7 The mitral Doppler inflow E velocity/annular tissue Doppler e9-wave velocity ratio was obtained with the average of early diastolic lateral and medial velocities according to American Society of Echocardiography guidelines.8 Brain MRI To diagnose ischemic stroke, a diffusion-perfusion MRI was performed during the hospitalization using echoplanar imaging on a 1.5-T magnet (OPTIMA MR450w 1.5T with GEM Suite; GE Healthcare). The number of cerebral lesions and their topographies were reported. Images were analyzed by a single experienced neuroradiologist blinded from any other clinical or paraclinical data. An ischemic lesion was considered to be recent if hyperintense on diffusion-weighted images and associated with a decrease of the apparent diffusion coefficient.9 To confirm clinical suspicion of stroke, a neurologist blinded to the MRI results examined every patient the very same day the brain MRI was performed. Carotid Duplex Ultrasound To rule out carotid stenosis, which could possibly be the cause of stroke, duplex ultrasound of the supraaortic trunks was performed during the hospitalization with a 9.0-MHz transducer on a Philips iE33 ultrasound system. According to North American Symptomatic Carotid Endarterectomy Trial criteria, a significant carotid stenosis was defined by a reduction of the lumen of ⱖ 60% without neurologic symptoms and ⱖ 50% in the presence of neurologic symptoms.10 Cardiovascular Monitoring and ECG Analysis Every patient was monitored with continuous ECG throughout the ICU stay to determine the potential for cardioembolic arrhythmias. ECG signs of right ventricular strain were defined with the presence of at least one of the following according to European Society of Cardiology guidelines1: inversion of T waves in leads V1 to V4, a QR pattern in lead V1, the classic S1Q3T3 type, new incomplete or complete right bundle branch block, and tachycardia (sinus tachycardia or atrial arrhythmias). Statistical Analysis Statistical analysis was performed with SPSS version 19 (IBM) software. Data are presented as mean ⫾ SD for normally distributed data or median and 25th-75th percentile for skewed data. Fisher exact test was used for comparison of percentages. Mann-Whitney U and Student t tests were used for other comparisons. Differences between parameters diagnosed with TTE and those diagnosed with TEE (prevalence of PFO, ASA, and large shunt) were compared using the Wilcoxon paired test. Differences were considered statistically significant at P , .05.
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Results Over a 9-month period, 49 consecutive patients presenting with intermediate-risk PE were assessed. Six patients refused to participate in the study, one presented a contraindication to TEE (bleeding esophageal varices), and one presented a contraindication to MRI (pacemaker). Forty-one patients were finally included in the study. Characteristics of the Population
Mean age was 73 ⫾ 13 years. Female sex was predominant (62.5%). Mean BMI was 28.4 ⫾ 6.2 kg/m2, with 78.0% of the patients having a BMI ⱖ 25 kg/m2. No patient presented with a history of heart failure. Four patients had known previous coronary heart disease without left ventricular systolic dysfunction or intracardiac thrombus. One patient had a history of atrial fibrillation; this patient did not have PFO or stroke in further examinations. Apart from this patient, no others had a history of atrial fibrillation, atrial flutter, or atrial tachycardia. Median troponin I and B-type natriuretic peptide levels were 0.18 (25th-75th percentile, 0.06-0.57) ng/mL and 436.0 (25th-75th percentile, 250.0-683.5) pg/mL, respectively. Two patients (4.9%) had obvious clinical signs of stroke on admission. One patient (2.4%) died during hospitalization because of massive intracerebral hemorrhage (ICH). General characteristics of the population are shown in Table 1. One patient had new-onset atrial fibrillation during hospitalization but without any clinical or MRI evidence of stroke. Right Ventricular Function
Mean systolic pulmonary arterial pressure was elevated, and right ventricular dysfunction markers were impaired overall (elevated right-to-left ventricular telediastolic diameter ratio, low tricuspid annular plane systolic excursion, and systolic tricuspid annular velocity). Right ventricular parameters found on TTE at admission and on contrast echocardiography day are shown in Table 2. PFO, ASA, and Large Shunt Prevalence
TEE was successfully performed in all patients without any complications. Contrast echocardiography was performed with a median delay of 2 days (range, 1-3 days). TEE revealed a PFO in 23 patients (56.1%), whereas TTE revealed a PFO in only eight (19.5%, P , .001) (Table 3). ASA was found in 22 patients (53.7%) with TEE and 14 (34.1%) with TTE (P 5 .005). All PFO and
ASA found with TTE were also found with TEE. A large shunt was observed in 39.0% of patients by TEE (ie, 69.6% of patients with PFO) but in only 12.2% by TTE (P 5 .001). Regarding PFO screening, of the 82 examinations (41 TTE and 41 TEE), the two initial observers had three (3.7%) opposite conclusions. MRI Features
The mean delay between admission and MRI was 5 ⫾ 4 days. MRI showed a recent ischemic lesion in seven patients (17.1%). The mean number of recent ischemic lesions was 2.4 ⫾ 1.5. For three patients, ischemic lesions were bilateral. Characteristics of Patients Presenting With Stroke and Noncerebral Systemic Embolism
Overall, seven patients showed a recent stroke on MRI. Two of them complained of abdominal pain, so we performed an abdominal CT scan examination and found one splenic and one hepatic embolism. On TTE, PFO was diagnosed in only three of these seven patients (42.9%), but TEE revealed PFO in all seven (100%; P 5 .046). In other words, TTE failed to identify PFO in four of seven patients presenting with stroke. In all, 30.4% of all patients with PFO diagnosed using TEE had a stroke. Of note, shunts observed with TEE and TTE in patients with stroke were always large, as defined previously. None of these patients exhibited significant carotid stenosis on carotid duplex ultrasound, aortic stenosis on TEE, or cardioembolic arrhythmia. They did not have more cardiovascular risk factors than other patients (Table 4).
Discussion Patients with intermediate-risk PE present a high incidence of paradoxical embolism. Excluding other stroke causes, brain embolism in the context of PE cannot happen in the absence of a shunt, essentially a PFO. As such, looking for PFO is important in this context. To our knowledge, this study is the first to show such a high incidence (17.7%) of paradoxical embolism in submassive PE. Clergeau et al3 demonstrated a lower PFO prevalence in mainly low-risk PE, with a paradoxical embolism incidence of 10%. However, the diagnostic tool was TTE with bubble study, which failed to show PFO in 65.2% of patients in the current series. In diagnosing submassive PE with TEE, previous work found a PFO prevalence of 34.1%,11 whereas the current study
] Characteristics of the Population
Patients With PFO (n 5 23)
Patients Without PFO (n 5 18)
71.0 ⫾ 13.7
77.6 ⫾ 10.9
Female (male) sex
History of VTE
Chronic thromboembolic pulmonary hypertension
History of stroke
History of migraine History of cardiomyopathy History of arrhythmias
BMI, kg/m2 Concomitant DVT New neurologic sign on admission Heart rate on admission, beats/min Systolic BP on admission, mm Hg Diastolic BP on admission, mm Hg ECG signs of right ventricular strain Troponin I, ng/mL B-type natriuretic peptide, pg/mL Creatinine, mmol/L Platelet count, /mm3
28.4 ⫾ 6.6
28.5 ⫾ 5.9
93.5 ⫾ 13.7
89.6 ⫾ 16.2
134.6 ⫾ 22.3
126.5 ⫾ 15.1
75.3 ⫾ 12.9
70.8 ⫾ 10.0
96.8 ⫾ 35.2
96.8 ⫾ 31.1
218,391 ⫾ 75,037
201,722 ⫾ 51,206
Initial treatment Low-molecular-weight heparin Unfractionated heparin
Data are presented as mean ⫾ SD, %, and median (25th-75th percentile). PFO 5 patent foramen ovale.
showed a higher prevalence of 56.1% while using systematic TEE screening for PFO in the diagnosis of consecutive submassive PE. These data are of particular interest, given that in this series, about one in three patients with a PFO presented with a stroke. Furthermore, up to one in two patients with a large shunt (ie, 69.6% of patients with PFO) presented with a stroke. PFO prevalence in this series is much higher than usually described in the general population. Hagen et al12 showed a prevalence of 25.4% during the fourth through eighth decades of life in patients with normal hearts. In the current study population, we hypothesized that overall elevated right-sided heart pressures lead to a reopening of PFO, thus, explaining such differences. 970 Original Research
After the Management Strategies and Prognosis of Pulmonary Embolism-3 Trial (MAPPET), Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET), and Pulmonary Embolism Thrombolysis (PEITHO) trials, a thrombolytic treatment strategy in acute intermediate-risk PE has been promoted.13-15 However, in all these studies, mortality was not improved, and ICH incidence was about ninefold higher in the PEITHO thrombolytic group.15 This ICH risk could be attributed to the hemorrhagic transformation of a brain paradoxical embolism, which is asymptomatic most of the time.16 A diagnosis of not only stroke but also PFO, which in the current series was associated with stroke in 30% of patients, should be taken into account when a thrombolytic treatment must be considered.1
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] Transthoracic Echocardiographic Characteristics Patients With PFO (n 5 23)
Patients Without PFO (n 5 18)
On admission Left ventricular ejection fraction, %
0.8 ⫾ 0.2
65 (55-65) 0.8 ⫾ 0.2
1.0 ⫾ 0.2
1.1 ⫾ 0.3
Systolic pulmonary arterial pressure, mm Hg
56.2 ⫾ 17.0
57.2 ⫾ 11.1
15.4 ⫾ 5.3
13.9 ⫾ 3.7
Systolic tricuspid annular velocity, cm/s
Contrast study day Left ventricular ejection fraction, %
0.8 ⫾ 0.2
65 (60-65) 0.8 ⫾ 0.2
0.9 ⫾ 0.2
1.0 ⫾ 0.3
Systolic pulmonary arterial pressure, mm Hg
53.8 ⫾ 14.5
53.4 ⫾ 14.4
19.4 ⫾ 6.9
17.1 ⫾ 3.9
Systolic tricuspid annular velocity, cm/s
Data are presented as median (25th-75th percentile) or mean ⫾ SD. E/A 5 mitral Doppler inﬂow E velocity/mitral Doppler inﬂow A velocity; E/e9 5 mitral Doppler inﬂow E velocity/annular tissue Doppler e9-wave velocity; RVTD/LVTD 5 right ventricular telediastolic diameter/left ventricular telediastolic diameter; TAPSE 5 tricuspid annular plane systolic excursion. See Table 1 legend for expansion of other abbreviation.
A limit of this work may be the delay in performing the TEE contrast study (mean, 2 days), with a possible closure of PFO following a drop in pulmonary pressure. In contrast, despite being relatively long, a brain MRI mean delay of 5 days allowed us to detect very recent stroke given that diffusion MRI normalized approximately 7 days after stroke.17
ones.5 Other studies found no relationship between shunt size and cryptogenic stroke.20,21 Classification of stroke associated with PE remains unclear in the literature.22,23 However, we believe that this condition should not be classified as cryptogenic given the existence of thrombus and a relevant paradoxical embolism mechanism.
The PFO definition is still debated. In this study, PFO was assessed by at least three bubbles in the left side of the heart within three beats of right-sided heart opacification. Some have defined PFO when any microbubble appears18,19; therefore, we might have underestimated PFO incidence with both TTE and TEE. The potential missed PFO would only be the small ones not correlated with stroke according to this study as well as previous
Transcranial Doppler (TCD) was not used in this study as a tool for PFO screening. Mojadidi et al24 showed in a recent meta-analysis a high sensitivity and specificity for TCD in PFO diagnosis. Moreover, TCD is noninvasive compared with TEE, which is particularly attractive in diagnosing potentially unstable submassive PE. However, specificity of TCD is lower than TEE, with a greater propensity for detecting arteriovenous pulmonary shunts than
] Prevalence of PFO, Large PFO, and ASA TEE (n 5 41)
TTE (n 5 41)
P Value , .001
PFO associated with ASA
PFO associated with ASA and large shunt
Data are presented as %. ASA 5 atrial septal aneurysm; TEE 5 transesophageal echocardiography; TTE 5 transthoracic echocardiography. See Table 1 legend for expansion of other abbreviation.
] Characteristics of Patients Presenting With Recent Stroke
Variable PFO (using TEE) ASA (using TEE) Major shunt (using TEE) PFO associated with ASA (using TEE)
Recent Ischemic Stroke (n 5 7)
No Recent Ischemic Stroke (n 5 34)
100 71.4 100 71.4
65.6 ⫾ 8.6
75.6 ⫾ 12.9
Female (male) sex
Hypertension BMI, kg/m2 History of VTE
25.6 ⫾ 5.1
29.0 ⫾ 6.4
New neurologic sign on admission
Noncerebral systemic embolism
History of stroke History of cardiomyopathy History of arrhythmias
ECG signs of right ventricular strain New onset of arrhythmias Concomitant DVT
B-type natriuretic peptide, pg/mL In-hospital mortality
Aortic atherosclerosis plaque
Carotid atherosclerosis plaque
Signi¿cant carotid atherosclerosis plaque
Data are presented as mean ⫾ SD, %, or median (25th-75th percentile). See Table 1 and 3 legends for expansion of abbreviations.
PFO. More studies are needed to evaluate this technique in this setting. Although we studied a relatively limited number of patients in a single center, to our knowledge, this work is the first to use TEE for systematic PFO screening in patients with intermediate-risk PE. Taken together, the results (1) highlight the high prevalence of PFO; (2) confirm the association with paradoxical embolism, particularly brain embolism; and (3) demonstrate clearly the diagnostic superiority of TEE in this setting. The 2011 American Heart Association guidelines consider screening for PFO by echocardiogram together with agitated saline bubble study for risk stratification in massive and submassive PE, without favoring one method over the other.25 This recommendation appears with a 972 Original Research
low level of evidence (grade IIb, level of evidence C). The current results confirm the usefulness of PFO screening in this setting and demonstrate that in submassive PE, TEE represents the diagnostic method of choice for PFO diagnosis.
Conclusions Intermediate-risk PE is associated with high PFO and related stroke prevalence. Diagnosis of PFO with TEE is clearly more efficient than with TTE. Approximately two-thirds of PFOs diagnosed with TEE are not detected with TTE. On TEE, one in three patients presenting with a PFO and up to one in two with a large shunt had a stroke. If these results are confirmed in larger cohorts and given the high ICH risk of thrombolysis in intermediate-risk PE, screening for PFO should be integrated into the overall decision algorithm for thrombolysis.
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Acknowledgments Author contributions: D. D., M. C., and E. F. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D. D., M. C., D. B., and E. F. contributed to the study conception; D. D., M. C., O. C., R. L., P. C., and E. F. contributed to the data acquisition, analysis, and interpretation; D. D., M. C., P. M., C. C., and E. F. contributed to drafting the manuscript; and D. D., M. C., P. M., O. C., R. L., D. B., P. C., C. C., and E. F. contributed to revising the manuscript for important intellectual content and approving the final copy. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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