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Importance of Abdominal Compression Valsalva Maneuver and Microbubble Grading in Contrast Transthoracic Echocardiography for Detecting Patent Foramen Ovale
Importance of Abdominal Compression Valsalva Maneuver and Microbubble Grading in Contrast Transthoracic Echocardiography for Detecting Patent Foramen Ovale Yoichi Takaya, MD, Nobuhisa Watanabe, RDCS, Madoka Ikeda, RDCS, Teiji Akagi, MD, Rie Nakayama, MD, Koji Nakagawa, MD, Norihisa Toh, MD, and Hiroshi Ito, MD, Okayama, Japan
Background: Although transthoracic echocardiography (TTE) may be useful for patent foramen ovale (PFO) screening, the optimal methodologies remain unclear. The aims of this study were to evaluate the efficacy of the abdominal compression Valsalva maneuver and identify the optimal cutoff value of microbubbles in contrast TTE for detecting PFO, compared with transesophageal echocardiography and catheterization as the reference. Methods: One hundred thirty-four patients with cryptogenic stroke or migraine who had suspected PFO and underwent TTE and transesophageal echocardiography plus catheterization were enrolled. The sensitivity, specificity, and accuracy of TTE for PFO detection were analyzed according to different provocations (spontaneous Valsalva maneuver, abdominal compression Valsalva maneuver) and different cutoff values of microbubbles for a positive result (at least one microbubble, at least five microbubbles). Results: Eighty patients had PFO confirmed by transesophageal echocardiography and catheterization. When the cutoff was at least one microbubble, the sensitivity of TTE in detecting PFO was 93% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. When the cutoff was at least five microbubbles, sensitivity was 85% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. With the abdominal compression Valsalva maneuver, specificity was increased using the cutoff of at least five microbubbles compared with at least one microbubble (89% vs 57%). The abdominal compression Valsalva maneuver with the cutoff of at least 5 microbubbles provided the greatest accuracy of 95%. Conclusions: TTE with the abdominal compression Valsalva maneuver had excellent sensitivity. The cutoff of at least five microbubbles increased specificity. Our findings suggest that TTE with these criteria is valuable for PFO diagnosis. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Patent foramen ovale, Transthoracic echocardiography, Valsalva maneuver
Patent foramen ovale (PFO) is linked to various diseases, including cryptogenic stroke and migraine.1-6 Recent studies have demonstrated that transcatheter closure of PFO reduces the recurrence of stroke at higher rates compared with medical From the Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science (Y.T., T.A., R.N., K.N., N.T., H.I.) and the Division of Medical Support, Okayama University Hospital (N.W., M.I.), Okayama, Japan. Conflicts of Interest: None. Reprint requests: Yoichi Takaya, MD, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.09.018
therapy.7-9 These data make it essential to accurately diagnose PFO in patients being considered for transcatheter closure. Contrast transesophageal echocardiography (TEE) remains the standard reference for PFO diagnosis,10,11 but TEE is semi-invasive and is not ideal for screening. Contrast transthoracic echocardiography (TTE) is noninvasive and may be used for PFO detection. However, the optimal methodologies of TTE have not been established. Several provocation techniques are used. There is variation in the numbers of microbubbles appearing in the left chambers used as the cutoff value for a positive result.12-15 The detection of PFO requires an adequate Valsalva maneuver.16,17 Compared with a spontaneous Valsalva maneuver performed by the patient, the abdominal compression Valsalva maneuver, which forcibly depresses the patient’s abdominal wall during a spontaneous Valsalva maneuver, can augment the effects of the Valsalva maneuver on venous return to the right heart, leading to an increase in the rate of PFO detection. Furthermore, the determination 1
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of the optimal microbubble cutoff value could improve the acPFO = Patent foramen ovale curacy of PFO diagnosis.18 The aims of this study were to evalTEE = Transesophageal uate the efficacy of the abdomechocardiography inal compression Valsalva TTE = Transthoracic maneuver and identify the echocardiography optimal cutoff value of microbubbles in contrast TTE for detecting PFO, compared with TEE and cardiac catheterization as the reference. Abbreviations
METHODS Study Population A total of 134 consecutive patients with cryptogenic stroke or migraine who had suspected PFO and underwent TTE and TEE plus cardiac catheterization at our institution from May 2015 to September 2018 were enrolled. These patients were being considered for transcatheter closure. All patients gave written informed consent. The study was approved by the ethics committee of our institution. Contrast TTE TTE (iE33 [Philips Medical Systems, Andover, MA] and Atrida [Canon Medical Systems, Tokyo, Japan]) was performed before TEE and cardiac catheterization. Transthoracic echocardiographic images were obtained in an apical four-chamber view or a subcostal four-chamber view, which best visualized the interatrial septum. Gain settings were individually adjusted to optimize the visualization of the interatrial septum and the agitated saline contrast. The saline contrast was produced by 1 mL air, 1 mL blood, and 8 mL saline. Blood was used with 20-gauge cannulas in an antecubital vein because of its enhanced contrast appearance.19 The content was agitated between two 10-mL syringes connected with a three-way stopcock and was injected rapidly from an antecubital vein. Contrast TTE was performed in three conditions: rest (without Valsalva maneuver), spontaneous Valsalva maneuver, and abdominal compression Valsalva maneuver. First, contrast TTE was performed at rest to assess the potential of pulmonary arteriovenous malformations. Second, contrast TTE with a spontaneous Valsalva maneuver was performed. The agitated saline contrast was injected during the strain phase of the Valsalva maneuver, and the Valsalva maneuver was released immediately after opacification of the right atrium. Finally, contrast TTE with the abdominal compression Valsalva maneuver was performed. The examiner placed a hand on the right side of the epigastrium of the patient and depressed the abdominal wall simultaneously with spontaneous Valsalva maneuver (Figure 1). Abdominal muscular contraction and adequacy of the Valsalva maneuver were checked. Next, the agitated saline contrast was injected during the strain phase of the abdominal compression Valsalva maneuver, and then both abdominal compression and the Valsalva maneuver were released immediately after opacification of the right atrium. All transthoracic echocardiographic images were digitally stored. The maximum number of microbubbles appearing in the left chambers was counted. The result of TTE was defined as positive if at least one microbubble or at least five microbubbles were seen in the left
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chambers within three cardiac cycles during the strain phase or the release phase of Valsalva maneuver. PFO Confirmation The presence or absence of PFO was confirmed by TEE and cardiac catheterization. TEE (iE33 with an X7-2t probe; Philips Medical Systems) was performed under local anesthesia. If needed, an intravenous bolus of 1% propofol (20-30 mg) was administered at the time of probe insertion. PFO was evaluated at the end of the routine examinations when the patient was less sedated to enable the performance of a spontaneous Valsalva maneuver. Images of the interatrial septum were obtained from the best imaging plane for septal membrane visualization, typically 60 to 90 . The agitated saline contrast was injected during the strain phase of the Valsalva maneuver, and the Valsalva maneuver was released immediately after opacification of the right atrium. The Valsalva maneuver was considered effective if leftward bulging of the interatrial septum was observed. The presence of PFO was confirmed by actual visualization of microbubbles crossing the interatrial septum through the separation between the septum primum and septum secundum. The contrast injections were repeated at least five times if microbubble crossing was not obtained.20 Cardiac catheterization was then performed in patients in whom the presence or absence of PFO could not be determined by TEE and in those who were scheduled for transcatheter closure of PFO confirmed by TEE. The femoral vein was accessed with sheaths. Under the guidance of fluoroscopy and TEE or intracardiac echocardiography, a multipurpose catheter and a J-tipped guidewire were used to attempt to cross the interatrial septum. The presence of PFO was confirmed by the guidewire crossing the interatrial septum into the left atrium. Interobserver Variability A second observer independently evaluated the accuracy of the decision of at least one microbubble or at least five microbubbles, which was the cutoff value for a positive result of TTE. Percentage agreement was used to assess interobserver variability, which was analyzed in 20 randomly selected studies. Statistical Analysis Data are presented as mean 6 SD for continuous variables and as number and percentage for categorical variables. We analyzed the sensitivity, specificity, and accuracy of TTE for PFO detection according to the different provocations (spontaneous Valsalva maneuver and abdominal compression Valsalva maneuver) and the different cutoff values of microbubbles for a positive result (at least one microbubble and at least five microbubbles) compared with TEE and cardiac catheterization as the reference. Accuracy was defined as (true positive) + (true negative)/total in sample. Comparisons for variables were analyzed using the Cochran Q test and the McNemar test. Statistical analysis was performed using SPSS version 24.0 (IBM, Armonk, NY), and significance was defined as P < .05.
RESULTS Patient Characteristics Patient characteristics are shown in Table 1. The mean age was 42 6 15 years, and 71 patients were men. Sixty-two patients had
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HIGHLIGHTS The optimal methodologies of TTE for PFO detection have not been established. TTE with abdominal compression Valsalva maneuver demonstrated excellent sensitivity. A cutoff of at least five microbubbles increased specificity. TTE with these criteria is valuable for PFO diagnosis.
cryptogenic stroke, and 72 patients had migraine. All patients underwent TEE. Cardiac catheterization was also performed in 77 of the 134 patients, including 14 patients in whom the presence or absence of PFO could not be determined by TEE and 63 patients who were scheduled for transcatheter closure. Of the 134 patients, 80 had PFO confirmed by TEE and cardiac catheterization. Contrast TTE for PFO Detection With the spontaneous Valsalva maneuver, at least one microbubble appeared in the left chambers in 87 patients, and at least five microbubbles appeared in 74 patients. With the abdominal compression Valsalva maneuver, at least one microbubble appeared in the left chambers in 102 patients, and at least five microbubbles appeared in 85 patients. The sensitivity, specificity, and accuracy of TTE for PFO detection are shown in Table 2. When at least one microbubble was used as the cutoff value for a positive result, sensitivity for detecting PFO was 93% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. When at least five microbubbles were used as the cutoff value, sensitivity was 85% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. With the spontaneous Valsalva maneuver, specificity in detecting PFO was 76% using the cutoff of at least one microbubble and 89% using the cutoff of at least five microbubbles. With the abdominal compression Valsalva maneuver, specificity was significantly increased using the cutoff of at least five microbubbles compared with the cutoff of at least one microbubble (89% vs 57%, P < .001). The accuracy in diagnosing PFO with the abdominal compression Valsalva maneuver and the cutoff of at least five microbubbles was greater than that with the abdominal compression Valsalva maneuver and the cutoff of at least one microbubble (95% vs 82%, P = .001), that with the spontaneous Valsalva maneuver and the cutoff of at least five microbubbles (95% vs 87%, P = .001), and that with the spontaneous Valsalva maneuver and the cutoff of at least one microbubble (95% vs 86%, P = .001). Figure 2 shows a representative case. No microbubbles appeared with the spontaneous Valsalva maneuver, but at least five microbubbles were seen with the abdominal compression Valsalva maneuver. The patient had PFO confirmed by TEE and cardiac catheterization. Similar findings were observed in some patients. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles resulted in six false-positive results and one false-negative result. In two of the six patients with false-positive results, TEE showed no microbubbles in the left atrium, and the guidewire could not cross the interatrial septum at cardiac catheterization. In the remaining four patients, a few microbubbles were seen in the
Figure 1 The technique of the abdominal compression Valsalva maneuver. left atrium on TEE, but microbubbles crossing the separation between the septum primum and septum secundum were not observed, and the guidewire could not cross the interatrial septum. When the contrast was injected from the pulmonary artery using a catheter in two of the four patients, microbubbles appeared in the left atrium on intracardiac echocardiography with the abdominal compression Valsalva maneuver, but not at rest. Pulmonary angiography and computed tomography did not detect pulmonary arteriovenous malformations in these patients. Interobserver Variability There was 100% agreement between the two observers for the decision of at least one microbubble or at least five microbubbles as a positive result of TTE. DISCUSSION The major findings of the present study were as follows: (1) the abdominal compression Valsalva maneuver had excellent sensitivity for PFO detection, (2) the cutoff of at least five microbubbles increased the specificity for PFO detection with the abdominal compression Valsalva maneuver without compromising sensitivity, and (3) the abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy for PFO diagnosis. PFO Diagnosis Recent studies have demonstrated that transcatheter closure of PFO is superior to medical therapy in reducing the recurrence of stroke.7-9 The issue of PFO detection has become the focus of increasing interest. Although TEE plays an important role in the evaluation of PFO,16,21 TEE has the disadvantages of being uncomfortable and time consuming. In contrast, TTE may be preferable for PFO screening because it is noninvasive, easily available, and lower cost.22-24 However, the methodologies for performing TTE vary, including the technique of provocation and the cutoff number of microbubbles appearing in the left chambers for a positive result.12-15 There is no consensus on which methodology is more suitable. In the present study we evaluated the effects of TTE with different techniques of provocation and different cutoff values of microbubbles on PFO detection using TEE and cardiac catheterization as the
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Table 1 Patient characteristics (N = 134) Variables
Value
42 6 15
Age, y Sex, male
71 (53)
Cryptogenic stroke
62 (46)
Migraine
72 (54)
PFO diagnosis confirmed by TEE and/or cardiac catheterization Presence of PFO
80 (60)
Absence of PFO
54 (40)
Data are expressed as mean 6 SD or as number (percentage) of patients.
Table 2 Contrast TTE for PFO detection Sensitivity, %
Specificity, %
Accuracy, %
Spontaneous Valsalva maneuver, at least one microbubble
93
76
86
Spontaneous Valsalva maneuver, at least five microbubbles
85
89
87
Abdominal compression Valsalva maneuver, at least one microbubble
99
57
82
Abdominal compression Valsalva maneuver, at least five microbubbles
99
89
95
reference. The abdominal compression Valsalva maneuver had sensitivity of 99% using both cutoff values of at least one microbubble and at least five microbubbles. With the abdominal compression Valsalva maneuver, the elevation in the microbubble threshold for a positive result from at least one microbubble to at least five microbubbles significantly increased the specificity from 57% to 89%. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy of 95%. This study is unique in comparison with previous studies. TEE sometimes fails to diagnose PFO,25 but this study certainly confirmed the presence of PFO by actual visualization of microbubbles crossing the separation between the septum primum and septum secundum. The contrast injections were repeated at least five times until we could judge whether the microbubbles crossed the separation.20 Furthermore, we performed cardiac catheterization to confirm the presence or absence of PFO when it could not be determined by TEE, while previous studies compared TTE with TEE but not with cardiac catheterization.15,22-24,26-28 Abdominal Compression Valsalva Maneuver The goal of provocation is to increase right atrial pressure above left atrial pressure, opening the flaplike foramen ovale and facilitating
the right-to-left shunt. The Valsalva maneuver increases intrathoracic pressure and decreases venous return and left atrial pressure during the strain phase. Rebound venous return after release increases right atrial pressure and the right-to-left atrial pressure gradient, leading to the right-to-left shunt. Therefore, an adequate Valsalva maneuver is essential to detect PFO. However, a spontaneous Valsalva maneuver performed by the patient may be insufficient.16,17 The present study showed that forced abdominal compression during a spontaneous Valsalva maneuver provided excellent sensitivity for PFO detection. The abdominal compression Valsalva maneuver has several benefits. Abdominal compression increases abdominal pressure, with a consequent increase in intrathoracic pressure. The further increased intrathoracic pressure decreases venous return and left atrial pressure and subsequently enhances the right-to-left atrial pressure gradient by rebound venous return after release. Furthermore, compression of the right side of the epigastrium can cause interruption of inferior vena cava flow.29 This compression results in decreased venous return and left atrial pressure. After the release of abdominal compression, the sudden influx of augmented inferior vena cava flow into the right atrium elevates right atrial pressure and the right-to-left atrial pressure gradient. In addition, the leftward shift of the interatrial septum on TTE is useful to assess the Valsalva maneuver, but it is often hampered because the Valsalva maneuver causes lung inflation and diaphragm shift, which result in a transient loss of image. If the examiners do not observe the leftward shift of the interatrial septum, they can check for abdominal muscular contraction and confirm the adequacy of the Valsalva maneuver. Also, because abdominal compression is a patient-independent procedure, it may be useful for patients, particularly children, who cannot effectively perform the Valsalva maneuver. Microbubble Cutoff Value There is variation regarding how many microbubbles must appear for PFO diagnosis. In several studies, the result of TTE was considered positive if at least one microbubble was seen in the left chambers.22,27,28 However, there are several factors by which TTE produces the spontaneous contrast in the left chambers following Valsalva maneuver, such as the stagnation of pulmonary venous blood with rouleaux formation,12,30 and the cavitation resulting from a sudden increase in venous return.31 Therefore, the cutoff of at least one microbubble can produce some false-positive cases. The present study showed that a cutoff of at least five microbubbles improved specificity for PFO detection without compromising sensitivity, suggesting that this cutoff value is effective for diagnosing PFO on TTE with the abdominal compression Valsalva maneuver. False-Positive Results on TTE A previous study reported that PFO could not be detected at cardiac catheterization in five of 74 patients who were proved to have PFO by TTE.32 Similarly, this study had false-positive results of TTE. Among 85 patients with at least five microbubbles with the abdominal compression Valsalva maneuver in this study, the presence of PFO was not confirmed in six by TEE and cardiac catheterization. In some patients, when the contrast was injected from the pulmonary artery, microbubbles appeared in the left chambers with the abdominal compression Valsalva maneuver, but not at rest. As a reason for the false-positive results, this finding suggests that the appearance of microbubbles in the left chambers on TTE occurs because of the physiologic passing through the lungs during the strong provocation.22
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Figure 2 Contrast transthoracic echocardiographic images. Contrast TTE with spontaneous Valsalva maneuver shows no microbubbles in the left chambers (left). With the abdominal compression Valsalva maneuver, at least five microbubbles are seen in the left chambers (right).
In the present study, the increase in specificity induced by elevating the threshold from at least one microbubble to at least five microbubbles might also be related to the physiologic transpulmonary transit caused by the provocation. Clinical Implications With the advent of transcatheter closure of PFO, there is an increasing demand for PFO detection in clinical practice. Screening with TEE is not appropriate because of the cost and the impracticality of performing it in all patients with stroke. Alternatively, TTE is low cost and feasible. If patients have a clinical indication for PFO closure and a positive result of TTE, TEE can be performed to identify the precise anatomy before transcatheter closure. Study Limitations First, the number of patients was small. However, the assessments of TTE and TEE plus cardiac catheterization were uniform because they were performed at our single institution. Second, there was selection bias because this study included patients who had suspected PFO and underwent TTE and TEE plus cardiac catheterization. In our experience, patients with no microbubbles appearing in the left chambers on TTE did not have PFO. Therefore, many of these patients did not undergo TEE and cardiac catheterization and were not included in this study. Third, the contrast on TTE was not injected from the femoral vein. Fourth, this study defined the appearance of microbubbles within three cardiac cycles as positive result on TTE, but it is possible that microbubbles appearing in four or five cardiac cycles could be due to PFO. Finally, the presence of PFO might have been missed on TEE, although we performed TEE with repeated contrast injections.
CONCLUSION TTE with the abdominal compression Valsalva maneuver had excellent sensitivity for PFO detection. The cutoff of at least five
microbubbles increased specificity with the abdominal compression Valsalva maneuver without compromising sensitivity. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy. Our findings suggest that TTE with these criteria is valuable for PFO diagnosis.
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11. de Belder MA, Tourikis L, Griffith M, Leech G. Camm AJ Transesophageal contrast echocardiography and color flow mapping: methods of choice for the detection of shunts at the atrial level? Am Heart J 1992;124:1545-50. 12. Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006;19:215-22. 13. Attaran RR, Ata I, Kudithipudi V, Foster L, Sorrell VL. Protocol for optimal detection and exclusion of a patent foramen ovale using transthoracic echocardiography with agitated saline microbubbles. Echocardiography 2006;23:616-22. 14. Lam YY, Yu CM, Zhang Q, Yan BP, Yip GW. Enhanced detection of patent foramen ovale by systematic transthoracic saline contrast echocardiography. Int J Cardiol 2011;152:24-7. 15. Mojadidi MK, Winoker JS, Roberts SC, Msaouel P, Gevorgyan R, Zolty R. Two-dimensional echocardiography using second harmonic imaging for the diagnosis of intracardiac right-to-left shunt: a meta-analysis of prospective studies. Int J Cardiovasc Imaging 2014;30:911-23. 16. Silvestry FE, Cohen MS, Armsby LB, Burkule NJ, Fleishman CE, Hijazi ZM, et al. Guidelines for the echocardiographic assessment of atrial septal defect and patent foramen ovale: from the American Society of Echocardiography and Society for Cardiac Angiography and Interventions. J Am Soc Echocardiogr 2015;28:910-58. 17. Johansson MC, Eriksson P, Guron CW, Dellborg M. Pitfalls in diagnosing PFO: characteristics of false-negative contrast injections during transesophageal echocardiography in patients with patent foramen ovales. J Am Soc Echocadiogr 2010;23:1136-42. 18. Mojadidi MK, Roberts SC, Winoker JS, Romero J, Goodman-Meza D, Gevorgyan R, et al. Accuracy of transcranial Doppler for the diagnosis of intracardiac right-to-left shunt: a bivariate meta-analysis of prospective studies. JACC Cardiovasc Imaging 2014;7:236-50. 19. Fan S, Nagai T, Luo H, Atar S, Naqvi T, Bimbaum Y, et al. Superiority of the combination of blood and agitated saline for routine contrast enhancement. J Am Soc Echocardiogr 1999;12:94-8. 20. Johansson MC, Helgason H, Dellborg M, Eriksson P. Sensitivity for detection of patent foramen ovale increased with increasing number of contrast injections: a descriptive study with contrast transoesophageal echocardiography. J Am Soc Echocardiogr 2008;21:419-24. 21. Mojadidi MK, Mahmoud AN, Elgendy IY, Agarwal N, Tobis JM. Transesophageal echocardiography for the detection of patent foramen ovale. J Am Soc Echocardiogr 2017;30:933-4. 22. Madala D, Zaroff JG, Hourigan L, Foster E. Harmonic imaging improves sensitivity at the expense of specificity in the detection of patent foramen ovale. Echocardiography 2004;21:33-6.
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23. Kuhl HP, Hoffmann R, Merx MW, Franke A, Klotzsch C, Lepper W, et al. Transthoracic echocardiography using second harmonic imaging: diagnostic alternative to transesophageal echocardiography for the detection of atrial right to left shunt in patients with cerebral embolic events. J Am Coll Cardiol 1999;34:1823-30. 24. Clarke NR, Timperley J, Kelion AD, Banning AP. Transthoracic echocardiography using second harmonic imaging with Valsalva manoeuvre for the detection of right to left shunts. Eur J Echocardiogr 2004;5:176-81. 25. Schneider B, Zienkiewicz T, Jansen V, Hotmann T, Noltenius H, Meinertz T. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202-9. 26. Rodrigues AC, Picard MH, Carbone A, Arruda AL, Flores T, Klohn J, et al. Importance of adequately performed Valsalva maneuver to detect patent foramen ovale during transesophageal echocardiography. J Am Soc Echocardiogr 2013;26:1337-43. 27. Daniels C, Weytjens C, Cosyns B, Schoors D, De Sutter J, Paelinck B, et al. Second harmonic transthoracic echocardiography: the new reference screening method for the detection of patent foramen ovale. Eur J Echocardiogr 2004;5:449-52. 28. Van Gamp G, Franken P, Melis P, Cosyns B, Schoors D, Vanoverschelde JL. Comparison of transthoracic echocardiography with second harmonic imaging with transesophageal echocardiography in the detection of right to left shunts. Am J Cardiol 2000;86:1284-7. 29. Yamashita E, Murata T, Goto E, Fujiwara T, Sasaki T, Minami K, et al. Inferior vena cava compression as a novel maneuver to detect patent foramen ovale: a transesophageal echocardiographic study. J Am Soc Echocardiogr 2017;30:292-9. 30. Van Camp G, Cosyns B, Vandenbossche JL. Non-smoke spontaneous contrast in left atrium intensified by respiratory manoeuvres: a new transoesophageal echocardiographic observation. Br Heart J 1994;72: 446-51. 31. Kim HH, Tam JW, Chan KL. A prospective transesophageal echocardiographic study to assess a new type of left atrial spontaneous contrast at rest and during respiratory manoeuvres. Can J Cardiol 1999;15: 1217-22. 32. Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, et al. Migraine intervention with STARFlex technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117: 1397-404.
Background: Although transthoracic echocardiography (TTE) may be useful for patent foramen ovale (PFO) screening, the optimal methodologies remain unclear. The aims of this study were to evaluate the efficacy of the abdominal compression Valsalva maneuver and identify the optimal cutoff value of microbubbles in contrast TTE for detecting PFO, compared with transesophageal echocardiography and catheterization as the reference. Methods: One hundred thirty-four patients with cryptogenic stroke or migraine who had suspected PFO and underwent TTE and transesophageal echocardiography plus catheterization were enrolled. The sensitivity, specificity, and accuracy of TTE for PFO detection were analyzed according to different provocations (spontaneous Valsalva maneuver, abdominal compression Valsalva maneuver) and different cutoff values of microbubbles for a positive result (at least one microbubble, at least five microbubbles). Results: Eighty patients had PFO confirmed by transesophageal echocardiography and catheterization. When the cutoff was at least one microbubble, the sensitivity of TTE in detecting PFO was 93% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. When the cutoff was at least five microbubbles, sensitivity was 85% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. With the abdominal compression Valsalva maneuver, specificity was increased using the cutoff of at least five microbubbles compared with at least one microbubble (89% vs 57%). The abdominal compression Valsalva maneuver with the cutoff of at least 5 microbubbles provided the greatest accuracy of 95%. Conclusions: TTE with the abdominal compression Valsalva maneuver had excellent sensitivity. The cutoff of at least five microbubbles increased specificity. Our findings suggest that TTE with these criteria is valuable for PFO diagnosis. (J Am Soc Echocardiogr 2019;-:---.) Keywords: Patent foramen ovale, Transthoracic echocardiography, Valsalva maneuver
Patent foramen ovale (PFO) is linked to various diseases, including cryptogenic stroke and migraine.1-6 Recent studies have demonstrated that transcatheter closure of PFO reduces the recurrence of stroke at higher rates compared with medical From the Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science (Y.T., T.A., R.N., K.N., N.T., H.I.) and the Division of Medical Support, Okayama University Hospital (N.W., M.I.), Okayama, Japan. Conflicts of Interest: None. Reprint requests: Yoichi Takaya, MD, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2019 by the American Society of Echocardiography. https://doi.org/10.1016/j.echo.2019.09.018
therapy.7-9 These data make it essential to accurately diagnose PFO in patients being considered for transcatheter closure. Contrast transesophageal echocardiography (TEE) remains the standard reference for PFO diagnosis,10,11 but TEE is semi-invasive and is not ideal for screening. Contrast transthoracic echocardiography (TTE) is noninvasive and may be used for PFO detection. However, the optimal methodologies of TTE have not been established. Several provocation techniques are used. There is variation in the numbers of microbubbles appearing in the left chambers used as the cutoff value for a positive result.12-15 The detection of PFO requires an adequate Valsalva maneuver.16,17 Compared with a spontaneous Valsalva maneuver performed by the patient, the abdominal compression Valsalva maneuver, which forcibly depresses the patient’s abdominal wall during a spontaneous Valsalva maneuver, can augment the effects of the Valsalva maneuver on venous return to the right heart, leading to an increase in the rate of PFO detection. Furthermore, the determination 1
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of the optimal microbubble cutoff value could improve the acPFO = Patent foramen ovale curacy of PFO diagnosis.18 The aims of this study were to evalTEE = Transesophageal uate the efficacy of the abdomechocardiography inal compression Valsalva TTE = Transthoracic maneuver and identify the echocardiography optimal cutoff value of microbubbles in contrast TTE for detecting PFO, compared with TEE and cardiac catheterization as the reference. Abbreviations
METHODS Study Population A total of 134 consecutive patients with cryptogenic stroke or migraine who had suspected PFO and underwent TTE and TEE plus cardiac catheterization at our institution from May 2015 to September 2018 were enrolled. These patients were being considered for transcatheter closure. All patients gave written informed consent. The study was approved by the ethics committee of our institution. Contrast TTE TTE (iE33 [Philips Medical Systems, Andover, MA] and Atrida [Canon Medical Systems, Tokyo, Japan]) was performed before TEE and cardiac catheterization. Transthoracic echocardiographic images were obtained in an apical four-chamber view or a subcostal four-chamber view, which best visualized the interatrial septum. Gain settings were individually adjusted to optimize the visualization of the interatrial septum and the agitated saline contrast. The saline contrast was produced by 1 mL air, 1 mL blood, and 8 mL saline. Blood was used with 20-gauge cannulas in an antecubital vein because of its enhanced contrast appearance.19 The content was agitated between two 10-mL syringes connected with a three-way stopcock and was injected rapidly from an antecubital vein. Contrast TTE was performed in three conditions: rest (without Valsalva maneuver), spontaneous Valsalva maneuver, and abdominal compression Valsalva maneuver. First, contrast TTE was performed at rest to assess the potential of pulmonary arteriovenous malformations. Second, contrast TTE with a spontaneous Valsalva maneuver was performed. The agitated saline contrast was injected during the strain phase of the Valsalva maneuver, and the Valsalva maneuver was released immediately after opacification of the right atrium. Finally, contrast TTE with the abdominal compression Valsalva maneuver was performed. The examiner placed a hand on the right side of the epigastrium of the patient and depressed the abdominal wall simultaneously with spontaneous Valsalva maneuver (Figure 1). Abdominal muscular contraction and adequacy of the Valsalva maneuver were checked. Next, the agitated saline contrast was injected during the strain phase of the abdominal compression Valsalva maneuver, and then both abdominal compression and the Valsalva maneuver were released immediately after opacification of the right atrium. All transthoracic echocardiographic images were digitally stored. The maximum number of microbubbles appearing in the left chambers was counted. The result of TTE was defined as positive if at least one microbubble or at least five microbubbles were seen in the left
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chambers within three cardiac cycles during the strain phase or the release phase of Valsalva maneuver. PFO Confirmation The presence or absence of PFO was confirmed by TEE and cardiac catheterization. TEE (iE33 with an X7-2t probe; Philips Medical Systems) was performed under local anesthesia. If needed, an intravenous bolus of 1% propofol (20-30 mg) was administered at the time of probe insertion. PFO was evaluated at the end of the routine examinations when the patient was less sedated to enable the performance of a spontaneous Valsalva maneuver. Images of the interatrial septum were obtained from the best imaging plane for septal membrane visualization, typically 60 to 90 . The agitated saline contrast was injected during the strain phase of the Valsalva maneuver, and the Valsalva maneuver was released immediately after opacification of the right atrium. The Valsalva maneuver was considered effective if leftward bulging of the interatrial septum was observed. The presence of PFO was confirmed by actual visualization of microbubbles crossing the interatrial septum through the separation between the septum primum and septum secundum. The contrast injections were repeated at least five times if microbubble crossing was not obtained.20 Cardiac catheterization was then performed in patients in whom the presence or absence of PFO could not be determined by TEE and in those who were scheduled for transcatheter closure of PFO confirmed by TEE. The femoral vein was accessed with sheaths. Under the guidance of fluoroscopy and TEE or intracardiac echocardiography, a multipurpose catheter and a J-tipped guidewire were used to attempt to cross the interatrial septum. The presence of PFO was confirmed by the guidewire crossing the interatrial septum into the left atrium. Interobserver Variability A second observer independently evaluated the accuracy of the decision of at least one microbubble or at least five microbubbles, which was the cutoff value for a positive result of TTE. Percentage agreement was used to assess interobserver variability, which was analyzed in 20 randomly selected studies. Statistical Analysis Data are presented as mean 6 SD for continuous variables and as number and percentage for categorical variables. We analyzed the sensitivity, specificity, and accuracy of TTE for PFO detection according to the different provocations (spontaneous Valsalva maneuver and abdominal compression Valsalva maneuver) and the different cutoff values of microbubbles for a positive result (at least one microbubble and at least five microbubbles) compared with TEE and cardiac catheterization as the reference. Accuracy was defined as (true positive) + (true negative)/total in sample. Comparisons for variables were analyzed using the Cochran Q test and the McNemar test. Statistical analysis was performed using SPSS version 24.0 (IBM, Armonk, NY), and significance was defined as P < .05.
RESULTS Patient Characteristics Patient characteristics are shown in Table 1. The mean age was 42 6 15 years, and 71 patients were men. Sixty-two patients had
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HIGHLIGHTS The optimal methodologies of TTE for PFO detection have not been established. TTE with abdominal compression Valsalva maneuver demonstrated excellent sensitivity. A cutoff of at least five microbubbles increased specificity. TTE with these criteria is valuable for PFO diagnosis.
cryptogenic stroke, and 72 patients had migraine. All patients underwent TEE. Cardiac catheterization was also performed in 77 of the 134 patients, including 14 patients in whom the presence or absence of PFO could not be determined by TEE and 63 patients who were scheduled for transcatheter closure. Of the 134 patients, 80 had PFO confirmed by TEE and cardiac catheterization. Contrast TTE for PFO Detection With the spontaneous Valsalva maneuver, at least one microbubble appeared in the left chambers in 87 patients, and at least five microbubbles appeared in 74 patients. With the abdominal compression Valsalva maneuver, at least one microbubble appeared in the left chambers in 102 patients, and at least five microbubbles appeared in 85 patients. The sensitivity, specificity, and accuracy of TTE for PFO detection are shown in Table 2. When at least one microbubble was used as the cutoff value for a positive result, sensitivity for detecting PFO was 93% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. When at least five microbubbles were used as the cutoff value, sensitivity was 85% with the spontaneous Valsalva maneuver and 99% with the abdominal compression Valsalva maneuver. With the spontaneous Valsalva maneuver, specificity in detecting PFO was 76% using the cutoff of at least one microbubble and 89% using the cutoff of at least five microbubbles. With the abdominal compression Valsalva maneuver, specificity was significantly increased using the cutoff of at least five microbubbles compared with the cutoff of at least one microbubble (89% vs 57%, P < .001). The accuracy in diagnosing PFO with the abdominal compression Valsalva maneuver and the cutoff of at least five microbubbles was greater than that with the abdominal compression Valsalva maneuver and the cutoff of at least one microbubble (95% vs 82%, P = .001), that with the spontaneous Valsalva maneuver and the cutoff of at least five microbubbles (95% vs 87%, P = .001), and that with the spontaneous Valsalva maneuver and the cutoff of at least one microbubble (95% vs 86%, P = .001). Figure 2 shows a representative case. No microbubbles appeared with the spontaneous Valsalva maneuver, but at least five microbubbles were seen with the abdominal compression Valsalva maneuver. The patient had PFO confirmed by TEE and cardiac catheterization. Similar findings were observed in some patients. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles resulted in six false-positive results and one false-negative result. In two of the six patients with false-positive results, TEE showed no microbubbles in the left atrium, and the guidewire could not cross the interatrial septum at cardiac catheterization. In the remaining four patients, a few microbubbles were seen in the
Figure 1 The technique of the abdominal compression Valsalva maneuver. left atrium on TEE, but microbubbles crossing the separation between the septum primum and septum secundum were not observed, and the guidewire could not cross the interatrial septum. When the contrast was injected from the pulmonary artery using a catheter in two of the four patients, microbubbles appeared in the left atrium on intracardiac echocardiography with the abdominal compression Valsalva maneuver, but not at rest. Pulmonary angiography and computed tomography did not detect pulmonary arteriovenous malformations in these patients. Interobserver Variability There was 100% agreement between the two observers for the decision of at least one microbubble or at least five microbubbles as a positive result of TTE. DISCUSSION The major findings of the present study were as follows: (1) the abdominal compression Valsalva maneuver had excellent sensitivity for PFO detection, (2) the cutoff of at least five microbubbles increased the specificity for PFO detection with the abdominal compression Valsalva maneuver without compromising sensitivity, and (3) the abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy for PFO diagnosis. PFO Diagnosis Recent studies have demonstrated that transcatheter closure of PFO is superior to medical therapy in reducing the recurrence of stroke.7-9 The issue of PFO detection has become the focus of increasing interest. Although TEE plays an important role in the evaluation of PFO,16,21 TEE has the disadvantages of being uncomfortable and time consuming. In contrast, TTE may be preferable for PFO screening because it is noninvasive, easily available, and lower cost.22-24 However, the methodologies for performing TTE vary, including the technique of provocation and the cutoff number of microbubbles appearing in the left chambers for a positive result.12-15 There is no consensus on which methodology is more suitable. In the present study we evaluated the effects of TTE with different techniques of provocation and different cutoff values of microbubbles on PFO detection using TEE and cardiac catheterization as the
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Table 1 Patient characteristics (N = 134) Variables
Value
42 6 15
Age, y Sex, male
71 (53)
Cryptogenic stroke
62 (46)
Migraine
72 (54)
PFO diagnosis confirmed by TEE and/or cardiac catheterization Presence of PFO
80 (60)
Absence of PFO
54 (40)
Data are expressed as mean 6 SD or as number (percentage) of patients.
Table 2 Contrast TTE for PFO detection Sensitivity, %
Specificity, %
Accuracy, %
Spontaneous Valsalva maneuver, at least one microbubble
93
76
86
Spontaneous Valsalva maneuver, at least five microbubbles
85
89
87
Abdominal compression Valsalva maneuver, at least one microbubble
99
57
82
Abdominal compression Valsalva maneuver, at least five microbubbles
99
89
95
reference. The abdominal compression Valsalva maneuver had sensitivity of 99% using both cutoff values of at least one microbubble and at least five microbubbles. With the abdominal compression Valsalva maneuver, the elevation in the microbubble threshold for a positive result from at least one microbubble to at least five microbubbles significantly increased the specificity from 57% to 89%. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy of 95%. This study is unique in comparison with previous studies. TEE sometimes fails to diagnose PFO,25 but this study certainly confirmed the presence of PFO by actual visualization of microbubbles crossing the separation between the septum primum and septum secundum. The contrast injections were repeated at least five times until we could judge whether the microbubbles crossed the separation.20 Furthermore, we performed cardiac catheterization to confirm the presence or absence of PFO when it could not be determined by TEE, while previous studies compared TTE with TEE but not with cardiac catheterization.15,22-24,26-28 Abdominal Compression Valsalva Maneuver The goal of provocation is to increase right atrial pressure above left atrial pressure, opening the flaplike foramen ovale and facilitating
the right-to-left shunt. The Valsalva maneuver increases intrathoracic pressure and decreases venous return and left atrial pressure during the strain phase. Rebound venous return after release increases right atrial pressure and the right-to-left atrial pressure gradient, leading to the right-to-left shunt. Therefore, an adequate Valsalva maneuver is essential to detect PFO. However, a spontaneous Valsalva maneuver performed by the patient may be insufficient.16,17 The present study showed that forced abdominal compression during a spontaneous Valsalva maneuver provided excellent sensitivity for PFO detection. The abdominal compression Valsalva maneuver has several benefits. Abdominal compression increases abdominal pressure, with a consequent increase in intrathoracic pressure. The further increased intrathoracic pressure decreases venous return and left atrial pressure and subsequently enhances the right-to-left atrial pressure gradient by rebound venous return after release. Furthermore, compression of the right side of the epigastrium can cause interruption of inferior vena cava flow.29 This compression results in decreased venous return and left atrial pressure. After the release of abdominal compression, the sudden influx of augmented inferior vena cava flow into the right atrium elevates right atrial pressure and the right-to-left atrial pressure gradient. In addition, the leftward shift of the interatrial septum on TTE is useful to assess the Valsalva maneuver, but it is often hampered because the Valsalva maneuver causes lung inflation and diaphragm shift, which result in a transient loss of image. If the examiners do not observe the leftward shift of the interatrial septum, they can check for abdominal muscular contraction and confirm the adequacy of the Valsalva maneuver. Also, because abdominal compression is a patient-independent procedure, it may be useful for patients, particularly children, who cannot effectively perform the Valsalva maneuver. Microbubble Cutoff Value There is variation regarding how many microbubbles must appear for PFO diagnosis. In several studies, the result of TTE was considered positive if at least one microbubble was seen in the left chambers.22,27,28 However, there are several factors by which TTE produces the spontaneous contrast in the left chambers following Valsalva maneuver, such as the stagnation of pulmonary venous blood with rouleaux formation,12,30 and the cavitation resulting from a sudden increase in venous return.31 Therefore, the cutoff of at least one microbubble can produce some false-positive cases. The present study showed that a cutoff of at least five microbubbles improved specificity for PFO detection without compromising sensitivity, suggesting that this cutoff value is effective for diagnosing PFO on TTE with the abdominal compression Valsalva maneuver. False-Positive Results on TTE A previous study reported that PFO could not be detected at cardiac catheterization in five of 74 patients who were proved to have PFO by TTE.32 Similarly, this study had false-positive results of TTE. Among 85 patients with at least five microbubbles with the abdominal compression Valsalva maneuver in this study, the presence of PFO was not confirmed in six by TEE and cardiac catheterization. In some patients, when the contrast was injected from the pulmonary artery, microbubbles appeared in the left chambers with the abdominal compression Valsalva maneuver, but not at rest. As a reason for the false-positive results, this finding suggests that the appearance of microbubbles in the left chambers on TTE occurs because of the physiologic passing through the lungs during the strong provocation.22
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Figure 2 Contrast transthoracic echocardiographic images. Contrast TTE with spontaneous Valsalva maneuver shows no microbubbles in the left chambers (left). With the abdominal compression Valsalva maneuver, at least five microbubbles are seen in the left chambers (right).
In the present study, the increase in specificity induced by elevating the threshold from at least one microbubble to at least five microbubbles might also be related to the physiologic transpulmonary transit caused by the provocation. Clinical Implications With the advent of transcatheter closure of PFO, there is an increasing demand for PFO detection in clinical practice. Screening with TEE is not appropriate because of the cost and the impracticality of performing it in all patients with stroke. Alternatively, TTE is low cost and feasible. If patients have a clinical indication for PFO closure and a positive result of TTE, TEE can be performed to identify the precise anatomy before transcatheter closure. Study Limitations First, the number of patients was small. However, the assessments of TTE and TEE plus cardiac catheterization were uniform because they were performed at our single institution. Second, there was selection bias because this study included patients who had suspected PFO and underwent TTE and TEE plus cardiac catheterization. In our experience, patients with no microbubbles appearing in the left chambers on TTE did not have PFO. Therefore, many of these patients did not undergo TEE and cardiac catheterization and were not included in this study. Third, the contrast on TTE was not injected from the femoral vein. Fourth, this study defined the appearance of microbubbles within three cardiac cycles as positive result on TTE, but it is possible that microbubbles appearing in four or five cardiac cycles could be due to PFO. Finally, the presence of PFO might have been missed on TEE, although we performed TEE with repeated contrast injections.
CONCLUSION TTE with the abdominal compression Valsalva maneuver had excellent sensitivity for PFO detection. The cutoff of at least five
microbubbles increased specificity with the abdominal compression Valsalva maneuver without compromising sensitivity. The abdominal compression Valsalva maneuver with the cutoff of at least five microbubbles provided the greatest accuracy. Our findings suggest that TTE with these criteria is valuable for PFO diagnosis.
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