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Researchers using a novel imaging technique have provided the first systematic look at the prevalence of secondary right-to-left shunt (RLS) in patients undergoing percutaneous closure of patent foramen ovale (PFO). Such coexisting shunts may be a factor behind residual RLS seen at long-term follow-up and consequently could have important clinical implications, according to a paper published in the June 2009 issue of JACC: Cardiovascular Interventions.
Jill T. Jesurum, PhD, of the Swedish Heart and Vascular Institute (Seattle, WA), and colleagues assessed 84 patients who underwent transcatheter PFO closure to prevent recurrent paradoxical cerebral embolism from June 2005 to December 2006. Using a newly developed protocol involving balloon occlusion, intracardiac echocardiography, and power M-mode transcranial Doppler (TCD) they examined all patients for a secondary source of RLS during the percutaneous procedure. The group was 58% female, was 89% Caucasian, and had a mean age of 49 ± 14 years.
The researchers found evidence of secondary RLS in 17 patients (20%; 95% CI, 11.7-28.8%) at the time of PFO closure. Those with periprocedural secondary RLS had significantly larger PFO waist diameters than those without (14 ± 4 mm vs. 11 ± 3 mm, respectively; P = 0.013), although the prevalence of comorbidities and other septal characteristics were similar between the 2 groups. In addition, those with secondary RLS tended to have more embolic tracks and a higher prevalence of atrial septal aneurysm, but these differences were not significant.
Late residual RLS was evaluated at a mean of 192 days (95% CI, 161-223 days) in 66 patients using TCD and transthoracic echocardiography. There were no baseline differences between patients for whom follow-up data were available and those for whom it was not.
At late follow-up, a significantly higher proportion of patients with secondary RLS also showed evidence of residual RLS: 13 of 14 patients with secondary RLS (93%) had residual RLS vs. 23 of 52 patients without secondary RLS (44%; P = 0.002).
Twenty of the 66 patients (30%) assessed at late follow-up had large residual RLS (defined as 101-301 embolic tracks). A higher percentage of patients with secondary RLS at baseline had large residual shunting at follow-up compared with those who had no secondary RLS (71% vs. 19%; P < 0.0001).
Regression analysis showed that both PFO balloon waist diameter and the number of embolic tracks during balloon occlusion at baseline predicted residual RLS following PFO closure (balloon waist: beta = 0.34, P = 0.002; embolic tracks: beta = 0.43, P < 0.001).
Strikingly High Numbers for Secondary Shunt
“These numbers are frighteningly large,” Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview. “We’ve always known that there were residual leaks after PFO closure, but I don’t think we have had any way of knowing for sure if it was from the device or from another source.”
Over recent years, the issue of late residual shunting has “plagued a number of efforts to study PFO closure,” agreed Ted Feldman, MD, of Evanston Hospital (Evanston, IL). “In particular, in some of the early observations regarding migraine response to PFO, some of the patients who don’t get better apparently have persistent shunts.” Thus far, the proportion of these patients with shunts related to incomplete closure or to the device itself vs. those with another secondary source of shunting has not been very well defined, he said in a telephone interview with TCTMD.
Study coauthor Dr. Jesurum told TCTMD in a telephone interview that the researchers were very surprised to see the 20% prevalence of residual RLS, “but we were even more intrigued that 93% of those who had secondary source of shunt during the procedure also had a late residual shunt.” It is possible that there “may be an undescribed constellation of malformations that occurs at the time of embryogenesis,” she noted. “It perhaps describes a bigger problem than a single abnormality of the septum that hasn’t been understood or studied before.”
The inspiration behind the study, she said, was that “in our 7 years of experience in PFO closure, and having compiled a large patient database, we consistently noted and have reported a 30% to 40% rate of residual RLS on TCD at late follow-up.”
Caution Urged About Methodology
In an editorial accompanying the paper, Jason H. Rogers, MD, and Thomas W. Smith, MD, of the University of California Davis Medical Center (Sacramento, CA), congratulate the investigators for “attempting to broaden our understanding of RLS physiology in a PFO-closure population. However, as with all complex questions, the devil is ever present in the details.”
It is plausible, they say, that patients with observed secondary RLS actually were incorrectly diagnosed because of “incomplete occlusion of the PFO with the sizing balloon.”
“Even in the absence of color flow on [intracardiac echocardiography], it might be impossible to rule out small areas on the edge of the balloon (or associated microfenestrations) where bubbles could cross. Also, the balloon might appear occlusive at rest although not be occlusive with increased right-sided pressure during respiratory strain,” the editorialists explain. “The fact that the secondary RLS group had more atrial septal aneurysms and a larger balloon waist diameter would also suggest that incomplete balloon occlusion of large, floppy PFOs is a more likely source of RLS than intrapulmonary etiology.”
Dr. Jesurum agreed incomplete balloon occlusion is a possibility. “[However,] I think we took all the available and appropriate measures to decrease the possibility of having a nonocclusive balloon, including the use of color flow Doppler to confirm the tunnel was occluded,” she said. “Not only was that [test] negative, but following injection of agitated saline contrast, bubbles were not visualized in the left atrium on intracardiac echocardiography. This point really needs to be emphasized.”
To further confirm the presence of a pulmonary arteriovenous malformation, she added, a pulmonary angiogram could be performed at the time of PFO closure or a pulmonary CTA following the procedure.
Findings May Have Broad Applications
The ability to detect secondary RLS could be useful for both research and patient care, said Dr. Jesurum. “If you were conducting a clinical trial to evaluate the efficacy of PFO closure or [test] a new closure device, the possibility of secondary RLS is definitely something a manufacturer would want to consider in the trial design,” she said.
And in clinical practice, “patients expect that they will not have a shunt following PFO closure. They expect this type of result and associate the absence of residual shunt with closure success and having a reduced risk of recurrent stroke,” Dr. Jesurum continued. “It would be helpful to be able to tell patients if a secondary source of RLS was identified at the time of PFO closure and [inform them] that the likelihood of achieving complete resolution of shunt in follow-up is unlikely and does not imply a failed result. However, we do not know the clinical implications of secondary source of shunt. Further research is needed to confirm our results and to determine the clinical relevance in terms of outcomes.”
Dr. Feldman confirmed that the process of detecting secondary RLS is not difficult, “if you take the time and effort,” and said that there are techniques available other than the one presented in this study. “I think as the community is becoming more aware of the confounding coexistence of extracardiac shunts in some proportion of our PFO and ASD population, people are beginning to look,” he said, noting that he has begun doing this in his own practice. “There is greater awareness that this is an issue but there isn’t any standardized methodology to assess this.”
Dr. Sommer said that if this study prompts further research into alternative sources of RLS, “then it will be incredibly useful. If we can come up with strategies to detect and eliminate these sources, we may be able to eliminate the risk of additional strokes in this population.”
It just comes down to having the “wherewithal to define a method and do a trial,” said Dr. Feldman. “But we’re having enough of a challenge doing PFO closure trials for stroke, and certainly a huge challenge for migraine, that something like assessing the frequency of extracardiac shunts is all the more challenging.”
Dr. Jesurum reported that the next step for her research group will be to validate their method by testing it against pulmonary angiography.
Eligibility criteria for PFO closure were a presumed paradoxical embolic event, evidence that RLS could be provoked and its presence confirmed by TCD and transthoracic echocardiography or transesophageal echocardiography, and probe patency of the septal tunnel during catherization.
To document secondary source of RLS, a sizing balloon was inflated in the PFO tunnel before device deployment. Color-flow Doppler in conjunction with intracardiac echocardiography was used to confirm complete occlusion of the PFO tunnel at rest and during respiratory strain. If color-flow Doppler confirmed the absence of RLS during balloon inflation, agitated saline contrast was injected into the inferior vena cava during normal respiration and respiratory strain. Clinically significant secondary RLS was defined as > 10 embolic tracks observed on power M-mode TCD at rest or immediately after respiratory strain.
2. Rogers JH, Smith TW. Eliminating right-to-left shunt with patent foramen ovale closure: Not as simple as it seems. J Am Coll Cardiol Intv. 2009;568-569.