The Relationship of Ultrasonic Characteristics of the Patent Foramen Ovale and Interventional Closure

doi:10.21203/rs.3.rs-3600526/v1

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The Relationship of Ultrasonic Characteristics of the Patent Foramen Ovale and Interventional Closure

https://doi.org/10.21203/rs.3.rs-3600526/v1

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Objective

Percutaneous interventional closure of patent foramen ovale (PFO) is the main method for the treatment of PFO. However, closure failed in some patients. This study aimed to investigate the relationship between ultrasonic characteristics of PFO and the results of PFO closure.

Method

Contrast transthoracic echocardiography (c-TTE) of right heart and transesophageal echocardiography (TEE) were performed to obtain data regarding the degree of the right-to-left shunt (RLS), the width and length of the PFO, the color shunt, the granular echo in the PFO gap, and atrial septal aneurysm (ASA). The effect of each factor on closure was analyzed by logistic regression.

Results

A total of 222 cases were included in the analysis. PFO with granular echo in the PFO gap, with ASA, grade I RLS, and without TEE color shunt had higher probabilities of failed PFO closure. Long PFO also had higher probability of failed PFO closure.

Conclusions

C-TTE and TEE ultrasonic characteristics of PFO may be indicative of PFO closure results. For patients about to undergo PFO closure, it is beneficial to observe the ultrasonic characteristics of PFO to provide patients with more ideal treatment.

Health sciences/Cardiology

Health sciences/Medical research

Health sciences/Risk factors

ultrasound

the Patent Foramen Ovale

interventional closure

PFO is a normal channel for oxygenated blood circulation in the placenta during fetal life. By age 2, the primary and secondary septum naturally coalesces and closes in 75% of patients; the rest develop PFO. However, most patients have no clinical symptoms and their quality of life and life span are not affected. When the pressure of the right atrium is greater than that of the left atrium in patients with PFO, RLS at the atrial level may lead to crypto-apoplexy, dizziness, migraine, syncope and other symptoms; therefore, PFO should be effectively diagnosed and treated[1, 2]. The treatment of PFO is mainly medical treatment and percutaneous closure. For migraine individuals, PFO closure was safe and significantly reduced the average number of monthly migraine days and monthly migraine attacks, and resulted in more subjects experiencing complete migraine cessation[3]. For cryptogenic stroke individuals, the reduction in risk of recurrent stroke after PFO closure depended on the probability that stroke was causally related to PFO[4]. Although the superiority of PFO closure over medical treatment in unselected populations has not been demonstrated, large randomized clinical trials have found transcatheter PFO closure to be superior to medical treatment for the prevention of recurrent stroke in young patients with stroke[5]. Large PFO, long gap PFO, ASA, and overactive atrial septa usually need to be treated[6, 7]. At present, closure of PFO with occluder can be achieved by percutaneous interventional therapy and chest small incision ways. The former method is inserting an occluder through a catheter in femoral vein to occlude the PFO. This method is simple, safe, less traumatic and widely used in clinical practice. The most critical step is to get the wire through the foramen ovale, which can be affected by the morphological and structural characteristics of PFO. Guide wires could not pass through the PFO gap in very few cases, resulting in failed closure, hence, a more complete evaluation of the PFO is required before intervention. Transcranial Doppler has been used as a screening method, but it cannot distinguish whether the shunt is of extracardiac origin[8, 9]. C-TTE and TEE are common clinical ultrasonographic methods for PFO diagnosis. TEE can visually display the flow shunts in the heart and the anatomical structure of the atrial septum to guide doctors to classify PFO and, thus, guide treatment[10]. Different morphologies of the PFO may have an impact on the manner in which PFO closure is implemented, however, there are few relevant studies. This study is designed to analyze the c-TTE and TEE ultrasonic characteristics of PFO and determine their relationship to PFO interventional closure, thereby enabling better clinical decision-making for PFO patients.

2.1 Research object

The study included 354 patients with suspected PFO who were admitted to the hospital between March 1, 2020, and March 1, 2022. The exclusion criteria were as follows: ① Presence of merger cardiomyopathy, severe valvular heart disease, arrhythmia or cardiopulmonary insufficiency; ② Presence of moderate or severe pulmonary hypertension; ③ Presence of other types of congenital cardiovascular malformations; ④Inability to complete the Valsalva maneuver for c-TTE due to various reasons. This study was approved by the Ethics Committee, and the patients signed informed consent forms.

2.2 Instruments and methods

2.2.1 Right heart contrast echocardiography procedure

TTE was performed with a GE Vivid E9 ultrasonic instrument (M5S probe, frequency 2.5). The patient was positioned to lie on the left side, the infusion channel was established, and 10 ml normal saline was injected periodically at rest and during the Valsalva maneuver. The probe was placed in the fifth intercostal space at the left midclavicular line, and the apical four-cavity view was scanned to observe the timing and number of microbubbles in the left atrium within 3 cardiac cycles after release in the Valsalva maneuver.

2.2.2 TEE procedure

TEE was performed with a GE Vivid E9 ultrasonic instrument (6TC probe, frequency 6 MHz). The patient was positioned to lie on the left side, the infusion channel was established, and vital signs and ECG changes were monitored. After administration of local mucosal anesthesia with oral lidocaine gum, a probe was placed in the esophagus to scan the atrial septum and its blood flow. Adjusting the angle of the TEE probe at 20°-120° in the middle of the esophagus to show the overlap between the primary and secondary septum, the length and width of the PFO gap were measured (figure 1A,1B). Whether there is granular echo in the PFO gap (figure 2), color shunt (figure 3), and ASA (figure 4) were recorded. ASA was diagnosed when the atrial septum appeared abnormally redundant and mobile and exhibited a > 10 mm excursion beyond the septal plane into either the left or the right atrium [11]. If there was no left-to-right color shunt in the PFO gap, contrast transesophageal ultrasonography (c-TEE) was performed, and the number of microbubbles in the left atrium within 3 cardiac cycles after the Valsalva maneuver release was observed during c-TEE.

2.3 Closure of PFO

Amplazer PFO occluders were used in all the PFO patients. The size of the occlude was determined by the PFO length measured by TEE. Endotracheal intubation was performed under general anesthesia, heparin was injected intravenously at 80~100 U/kg, and a 6F lower limb vascular sheath was inserted after puncture of the right femoral vein. The distance from the right third of the parasternal intercostal space to the puncture site was estimated and marked. A guide wire and 6F multifunctional catheter were inserted, and an appropriate TEE section was selected to guide the wire and the catheter to the left atrium through the PFO gap. It is often necessary to adjust the position of the guide wire several times during this process to allow it to pass through the PFO gap. Then the catheter entered the left atrium, the catheter and the vascular sheath of the lower limb were removed, and the depth of catheter insertion was marked. The guide wire was retained and inserted into the left atrium to transport the sheath tube. The length of delivery should be 2~3 cm longer than the depth of catheter insertion. The guide wire and inner sheath-core of the conveying tube were withdrawn. Under the guidance of TEE, the occluder was sent into the left atrium along the conveying sheath tube, and the left umbrella surface of the occluder was released. After the location of the occluder was monitored, release the right umbrella surface, and the push and pull test was used to determine whether the position of the occluder was stable. A suitable TEE view was used to assess the placement of the occluder and its possible effects on the surrounding structure. The delivery sheath was removed without abnormalities, and the puncture site was compressed or sutured.

2.4 Image analysis

Two senior physicians retrospectively analyzed the imaging data obtained by c-TTE and TEE, confirmed the presence of color shunts and granular echoes in the PFO gap and ASA, and measured the size of the PFO. Diagnosis of PFO involved the following considerations: The gap between the primary and secondary septum accompanied by the left to right color shunt in the gap was found by TEE, and then PFO could be directly diagnosed. If only a gap was observed between the primary and secondary septum but no color shunt was observed, c-TEE was performed at the same time to observe whether there were microbubbles in the left atrium within three cardiac cycles after the release in the Valsalva maneuver. RLS semiquantitative grading criteria were as follows: 1) undetected microbubbles in the left heart—negative; 2) a small number of microbubbles ≤10 in each frame—Grade I; 3) 11~30 microbubbles—Grade II; 4) a large number of microbubbles (>30) were observed—Grade III[12].

2.5 Statistical analysis

Statistical analysis was performed using SPSS 22.0 statistical analysis software. X±S was used to represent the measured materials conforming to a normal distribution. An independent sample T test was used to evaluate the difference in continuous variables between the two groups. The chi-square test or Fisher's exact probability method was used to compare the difference in the composition ratio of each parameter between the two groups. The effect of each parameter on the closure result was analyzed by logistic regression. P < 0.05 was considered statistically significant.

3.1 General information

Of the 354 patients, 17 were excluded for unable to cooperate with the Valsalva maneuver, 5 were excluded for unable to cooperate with TEE, 48 were excluded due to absence of RLS, 24 were found to have atrial septal defects (ASDs) by TEE, and 38 did not have complete surgical records. A total of 222 cases were included in the analysis. There were 19 cases of failed PFO closure and 203 cases of successful PFO closure (Fig. 5). There was significant difference in the sex composition ratio between the two groups. There was no significant difference in symptom composition between the two groups (Table 1).

Table 1

General information of patients with PFO closure
	Successful closure N = 203	Failed closure N = 19	χ²/t	P value
Male, n (%)	83(41)	7(37)	0.118	0.731
Age, year	42 ± 13	49 ± 13	2.151	0.033
Symptom, n (%)
Stroke	32(15.8)	6(31.6)	2.05	0.152
Migraine	124(61.1)	8(42.1)	2.596	0.107
Syncope	28(13.8)	3(15.8)	0	1.000
Other	19(9.4)	2(10.5)	0	1.000
Hypertension, n (%)	27(13.3)	5(26.3)	1.447	0.229

3.2 Parameters of c-TTE and TEE

There were differences in the proportion of grade I and grade III RLS as determined by c-TTE. There were differences in the width of PFO, the proportion of color shunt, and granular echo in the PFO gap detected by TEE. There were no significant differences in the proportion of ASA, grade II, and the length of PFO (Table 2).

Table 2

Ultrasonic characteristics of patients with PFO closure in c-TTE and TEE
	Successful closure N = 203	Failed closure N = 19	χ²/t	P value
RLS Grade, n (%)
Grade I	32(16)	14(74)	32.043	<0.001
Grade II	24(12)	2(10)	0	1.000
Grade III	147(72)	3(16)	25.421	<0.001
ASA, n (%)	8(4)	3(16)	2.969	0.085
PFO width (mm)	1.512 ± 0.865	0.874 ± 0.437	-4.511	<0.001
PFO length (mm)	11.226 ± 3.684	11.737 ± 3.034	0.675	0.501
No TEE color shunt, n (%)	23(11)	15(79)	51.326	<0.001
Granular echo, n (%)	4(2)	8 (42)	47.165	<0.001
PFO patent foramen ovale; ASA atrial septal aneurysm; TEE transesophageal echocardiography; RLS right-to-left shunt; c-TEE contrast transthoracic echocardiography

3. 3 Effect on PFO closure

The effect of the above variables on PFO closure was analyzed by logistic regression. It was found that the length of PFO, the presence of color shunt by TEE, the degree of RLS, the presence of ASA, and the granular echo in the PFO gap were independent predictors of failed closure. PFO with granular echo in the PFO gap, with ASA, grade I RLS, and without TEE color shunt had higher probabilities of failed PFO closure (OR = 14.143,6.533,9.434,7.59, respectively). Long PFO also had higher probability of failed PFO closure(OR = 1.312). The width of the PFO and medium and severe RLS were not sensitive to the prediction of closure (Fig. 6).

This study found that parameters related to failed PFO closure were the absence of TEE color shunt, grade I RLS in c-TTE, ASA, granular echo at the PFO gap, and long PFO. The probability of failed closure increased when PFO showed these ultrasonic characteristics.

A total of 222 patients were treated with TEE-guided percutaneous interventional therapy, and in all cases (19 cases) with failed PFO closure, the guide wire could not be inserted into the left atrium through the PFO gap.

4.1 TEE color shunt, granular echo, and PFO

TEE color shunt was specific for PFO diagnosis but less sensitive. Protrusions of adipose tissue seen in small gaps during TEE indicate local adhesion between the primary and secondary septa. The gap is segmentally shaped, with an internal diameter generally less than 2.0 mm. The left-to-right color shunt is not obvious due to discontinuous or short rod-shaped blood flow signals inside [13], but microbubbles can pass through during c-TEE. Therefore, c-TEE is more sensitive than TEE color shunt and is usually used as the gold standard [14]. In this study, 23 of 203 patients with successful PFO closure were color shunt-free during TEE. However, some patients cannot perform the Valsalva maneuver successfully during TEE, so c-TEE is not feasible for all patients with PFO. c-TEE can be performed only when patients do not have a left-to-right color shunt during TEE so that part of the PFO can be detected. However, in these patients, the absence of color shunt may be due to partial adhesion rather than complete fit in the open channel; in this case, the small microbubbles during c-TTE or c-TEE can pass through while catheter may not. In this study, there were 19 cases with failed closure, among which the proportion without color shunt was 79 percent, indicating that the absence of color shunt was related to failed PFO closure. Similar to TEE color shunt, granular echo in the PFO gap can also be related to closure. Forty-two percent of the failed closure patients showed granular echo in the PFO gap, which means these patients have higher probabilities of partial adhesion of the PFO gap and can affect the passage of the hard wire.

4.2 c-TTE and PFO

c-TTE can be used to assess the degree of RLS shunt of PFO, which can affect treatment decisions in PFO. Although its sensitivity is lower than that of c-TCD, its specificity is higher [8]. It has been suggested that the number of microbubbles in the left atrium during the three cardiac cycles after the release of the Valsalva maneuver represents the size of the RLS shunt. Medium or large numbers of microbubbles usually indicate large gaps and are defined as high-risk PFO. Some factors can affect the results of c-TTE and cause inaccurate results, including the normalization of the Valsalva maneuver, the degree of patient cooperation, and the resolution of the instrument [15]. These factors may cause negative results by c-TTE, so c-TTE must be combined with TEE to diagnose PFO. Excluding imaging errors, a small number of microbubbles suggest small gaps in the foramen ovale or partial adhesions, which make it difficult for the catheter to pass through during closure. In this study, 13 of the 19 patients with failed closure had grade I RLS. The proportion of failed closure in grade I RLS patients was significantly higher than that in grade II and grade III RLS patients.

4.3 Length and width of the PFO

The size of the PFO refers to the maximum distance between the primary and secondary septa during the rest state or Valsalva maneuver, and a PFO larger than 2 mm is considered large [16]. In a cardiac cycle, the size of the PFO is usually variable, with the maximum at the entrance and the minimum at the exit [17]. A wide PFO is usually more likely to allow the embolus to pass through, and the catheter is also more likely to pass through during closure, with a lower probability of failure. This study found that the width of the PFO had no significant effect on closure, which may be due to the small number of cases. Of course, some narrow PFO gaps may have partial adhesion. After catheter compression against the atrial septum, the originally narrow PFO became wide and easy to pass through. Previous studies have suggested that long and hard gaps may affect the fixation of the occluder [18]. In this study, it was found that a long PFO gap was not easy to pass through, and it was speculated that the longer PFO was, the more likely there was adhesion in the middle, thus affecting the entry of the catheters.

4.4 ASA and PFO

ASA means that the atrial septum shifts too much from the midline to the left or right sides, and the definition values of amplitude in different studies are different. In our study, ASA was diagnosed when the value > 10 mm[11]. ASA is considered to indicate a high-risk PFO and requires surgical intervention [19]. Nevertheless, the presence of ASA will reduce the atrial septal tension and increase the difficulty of catheter passage through the gap during closure. In this study, it was found that the probability of failed PFO closure with ASA was higher than that of PFO without ASA, which was speculated to be due to the decreased atrial septal tension. After the catheter reaches the atrial septum, due to low tension, it cannot separate the misaligned primary septum from the secondary septum; thus, the catheter cannot pass through.

4.5 Limitation: There were still only a small number of failed closure cases among the included cases in this study, and the sample size was small, which may have affected the results. In future studies, the sample size will need to be increased to provide a more accurate result on the relationship of c-TTE and TEE ultrasonic characteristics of patent foramen ovale to PFO closure.

C-TTE and TEE ultrasonic characteristics of patent foramen ovale can be related to interventional PFO closure results. For patients about to undergo interventional PFO closure, it is helpful to observe the ultrasonic characteristics of PFO so that more ideal treatment can be provided.

Acknowledgments

Not applicable.

Ethics Statement

This study was approved by the Ethics Committee of Tongji Medical College of Huazhong University of Science and Technology. The ethical approval number is S205. Written informed consent to participate in this study was provided by the participants. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author Contributions

Yu-bo Wang and Shan Lin contributed to the conception of the study and manuscript writing. Hui Huang contributed to the clinical data collection. Kun Liu and Jie Sun proposed critical revision to the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest Statement

The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability Statements

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Funding

The study was supported by the National Natural Science Foundation of China (81601507), the Health and Family Planning Commission foundation of Hubei Province (WJ2017M080), the Science and Technology Department of Hubei Province Foundation (Grant No.2019CFC895), the Wuhan Young and Middle-Aged Talent Plan Foundation (2016), and the Foundation of Key Laboratory of Hubei Province on the Occurrence and Intervention of Rheumatic Diseases (2015).

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No competing interests reported.

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The Relationship of Ultrasonic Characteristics of the Patent Foramen Ovale and Interventional Closure

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Abstract

Figures

1 Introduction

2 Materials and Methods

3 Results

3.1 General information

3.2 Parameters of c-TTE and TEE

3. 3 Effect on PFO closure

4 Discussion

4.1 TEE color shunt, granular echo, and PFO

4.2 c-TTE and PFO

4.3 Length and width of the PFO

4.4 ASA and PFO

5 Conclusion

Declarations

References

Additional Declarations

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