Author + information
- Received April 5, 2011
- Revision received May 24, 2011
- Accepted June 16, 2011
- Published online November 15, 2011.
- Gianluca Rigatelli, MD, PhD⁎,⁎ (, )
- Fabio Dell'Avvocata, MD⁎,
- Paolo Cardaioli, MD⁎,
- Massimo Giordan, MD⁎,
- Gabriele Braggion, MD⁎,
- Silvio Aggio, MD⁎,
- Mauro Chinaglia, MD†,
- Sangeeta Mandapaka, MD‡,
- John Kuruvilla, MD‡,
- Jack P. Chen, MD⁎,§ and
- Aravinda Nanjundappa, MD‡
- ↵⁎Reprint requests and correspondence:
Dr. Gianluca Rigatelli, Section of Adult Congenital Heart Disease, Cardiovascular Diagnosis and Endoluminal Interventions, Rovigo General Hospital, Viale Tre Martiri, 45100 Rovigo, Italy
Objectives We sought to prospectively evaluate risk of stroke and impact of transcatheter patent foramen ovale (PFO) closure in patients with permanent right-to left shunt compared with those with Valsalva maneuver-induced right-to-left shunt.
Background Pathophysiology and properly management of PFO still remain far from being fully clarified: in particular, the contribution of permanent right-to-left shunt remains unknown.
Methods Between March 2006 and October 2010, we enrolled 180 (mean age 44 ± 10.9 years, 98 women) of 320 consecutive patients referred to our center for transcatheter PFO closure, who had spontaneous permanent right-to-left shunt on transcranial Doppler and transthoracic/transesophageal echocardiography. All patients fulfilled the standard current indications for transcatheter closure and underwent preoperative transesophageal echocardiography and brain magnetic resonance imaging, with subsequent intracardiac echocardiographic-guided transcatheter PFO closure. We compared the clinical echocardiographic characteristics of these patients (Permanent Group) with the rest of 140 patients with right-to-left shunt only during Valsalva maneuver (Valsalva Group).
Results Compared with the Valsalva Group patients, patients of the Permanent Group had increased frequency of multiple ischemic brain lesions on magnetic resonance imaging, previous recurrent stroke, previous peripheral arteries embolism, migraine with aura, and—more frequently—atrial septal aneurysm and prominent Eustachian valve. The presence of permanent shunt confers the highest risk of recurrent stroke (odds ratio: 5.9, 95% confidence interval: 2.0 to 12, p < 0.001). No differences were recorded between the 2 groups with regard to recurrence of ischemic events after the closure procedure.
Conclusions Despite its small-sample nature, our study suggests that patients with permanent right-to-left shunt have potentially a higher risk of paradoxical embolism compared with those without.
Pathophysiology and proper management of patent foramen ovale (PFO) still remain far from being fully clarified: in particular, the anatomical and functional characteristics of PFO conferring an actual risk of recurrent stroke are still poorly understood. Our group (1,2) and other authors recently suggested large PFO, atrial septal aneurysm (ASA), long tunnelized PFO, and prominent Eustachian valve (EV) as concurrent risk factors for recurrent stroke. The contribution of spontaneous right-to-left shunt still remains debated. Recently, different studies (3,4) about shunt grade resulted in contrasting data in favor of or against an increasing risk conferred by a large or permanent shunt. We sought to prospectively evaluate risk of stroke and impact of transcatheter PFO closure in patients with permanent right-to left shunt, compared with those with Valsalva maneuver-induced right-to-left shunt.
Between March 2006 and October 2010, we prospectively enrolled 320 consecutive patients referred to our center for transcatheter PFO closure. All patients fulfilled the standard current indications for transcatheter closure (5) and underwent pre-operative transcranial Doppler (TCD), TEE, and brain magnetic resonance imaging (MRI), with subsequent intracardiac echocardiographic-guided transcatheter PFO closure. We compared the clinical and echocardiographic characteristics of patients with permanent (Permanent group) versus Valsalva only-induced right-to-left shunt (Valsalva group) and the potential impact of transcatheter closure. In particular, the 2 groups were matched by combined cardiological and neurological team members for previous medical history, brain MRI, number of clinically confirmed stroke episodes, and migraine presence and severity. Written informed consent was obtained from all patients enrolled in the study.
Echographic protocols and definitions
The TEE was conducted with a GE Vivid 7 (General Electric Corporation, Norfolk, Virginia) with contrast injection and Valsalva maneuver under local anesthesia: right-to-left shunts were defined as permanent, small, medium, and large following Homma et al. (6), whereas ASA and prominent EV were defined following standard nomenclature (7). The PFO diameter was calculated with electronic caliper, measuring the maximum opening of the PFO in the end-diastolic frames.
The TCD was performed with intravenous bubble study by a seasoned neurologist experienced in this examination, according to current standard (8) with a TCD monitoring device (DWL MultidopX, ScanMed Medical, Gloucestershire, United Kingdom). Both middle cerebral arteries were simultaneously monitored through the temporal window by the use of 2-MHz probes. The contrast was obtained by mixing 100 ml of saline solution with 2 to 3 ml of Emagel and loading a 10 cc syringe with this mixture. The solution, agitated between 2 10-ml syringes and connected by a 3-way stopcock, was immediately injected with a 20-gauge/32-mm catheter placed in the antecubital vein to obtain a bolus of air microbubbles. This procedure was performed 3 times during normal breathing and the same number of times during a Valsalva maneuver. The bolus of microbubbles was injected in 1 to 2 s when this 7-s period ended. We quantified the importance of right-to-left shunt by counting the number of signals in 1 middle cerebral artery within 7 s of the injection, as previously reported (8).
For intracardiac echocardiography (ICE), all the right atrial and interatrial septal characteristics other than PFO and mild ASA (1 right or 2 left by Olivares classification) (9) were recorded, including: prominent EV (defined as valve thickness ≥1 mm with at least 10-mm protrusion within the right atrium, as measured from the border of the inferior vena cava) (7), moderate-to-severe ASA (3 right-to-left, 3 left-to-right up to 5 right-to-left by Olivares classification) (9), and PFO diameter (as a mean of 2 measurements, obtained by measuring with the electronic caliper the maximum opening of the PFO in the end-diastolic frames in both the aortic valve and 4-chamber view planes). Patients who fulfilled the criteria for PFO closure underwent ICE evaluation with the mechanical 9-F, 9-MHz UltraICE catheter (EP Technologies, Boston Scientific Corporation, San Jose, California). The ICE study was conducted as previously described (10), by performing a manual pull-back from the superior vena cava to the inferior vena cava through 5 sectional planes; ICE monitoring of the implantation procedure was conducted in the 4-chamber plane (11).
Migraine with and without aura were diagnosed according to the International Headache Society criteria and Migraine Disability Assessment Score (12) as a part of clinical assessment of PFO.
Combined antibiotic therapy (gentamicin 80 mg + ampicillin 1 g or vancomycin 1 g if allergy has been recorded on anamnesis) was administered intravenously 1 h before the procedure. The operators selected the Amplatzer Occluder family (PFO Occluder, Cribriform Occluder, AGA Medical Corporation, Golden Valley, Minnesota) or the Premiere Closure System (St. Jude Medical, Inc., St. Paul, Minnesota), on the basis of ICE study and the presence/absence of moderate-to-large ASA and long tunnel-like PFO (tunnel length >12 mm).
Follow-up was conducted with TEE at 1 month (with repeat study at 6 months if at least a small shunt was detected); transthoracic echocardiography at 1, 6, and 12 months; TCD at 1 month; electrocardiographic Holter monitoring at 1 month; and combined cardiological and neurological visit at 1, 6, and 12 months. Residual shunt was assessed by contrast TEE and TCD (13). Brain MRI was repeated at 12-month follow-up.
Chi-square, analysis of variance, and Student t tests were used to compare frequencies and continuous variables between the groups. Stepwise logistic regression analysis was used to determine independent determinants of preoperative recurrent strokes. The analyzed variables were age >45 years, sex, moderate-to-severe ASA, shower pattern on TCD, curtain pattern on TCD, permanent shunt on TEE or TCD, medium-to-large shunt on TEE, and prominent EV. Statistical analysis was performed with a statistical software package (SAS for Windows, version 8.2, SAS Institute, Cary, North Carolina). A probability value of <0.05 was considered to be statistically significant.
On both TCD and TEE, 180 patients (mean age 44 ± 10.9 years, 128 women) had permanent shunt (Permanent Shunt group) (Table 1), whereas 140 patients had only Valsalva-induced shunt (Valsalva Shunt group) (Table 1). Compared with the Valsalva Group, patients of Permanent Group more frequently had ASA and prominent EV (Table 2) and increased frequency of multiple ischemic brain lesions on MRI, previous recurrent stroke, previous peripheral arteries embolism, and migraine with aura (Fig. 1).
No differences were recorded between the 2 groups with regard to procedure success, ischemic events recurrence, or new ischemic lesions appearance on brain MRI after the closure procedure; moreover, in the Permanent group residual shunts were more frequent at follow-up (Table 3).
Multiple stepwise logistic regression analysis of enrolled baseline and clinical variables demonstrated that permanent shunt confers the highest risk of recurrent stroke (odds ratio: 5.9, 95% confidence interval: 2.0 to 12.0, p < 0.001), whereas ASA (odds ratio: 3.9, 95% confidence interval: 0.5 to 7.0, p < 0.001) was the only other strong independent predictor.
Our study suggests that patients with permanent right-to-left shunt represent a subgroup at potentially higher risk of paradoxical embolism and that permanent right-to-left shunt can be considered an independent risk factor for recurrent paradoxical embolism. In addition, our data demonstrate that permanent right-to-left shunt—being linked with ASA, in particular moderate or large—might be related also with a higher proportion of residual shunts after closure, compared with patients with Valsalva-induced right-to-left shunt.
Past and recent published reports have shown the contribution of shunt degree to be both enhanced and limited. A higher embolic risk has been reported with medium-to-large shunts, particularly in association with migraine or coagulation abnormalities (14). Furthermore, TCD studies have correlated the shower or curtain shunt pattern with significant PFO on TEE (15) as well as history of paradoxical embolism. In further concordance with published reports, the higher frequency of large ASA and prominent EV in our study is closely linked to the presence and severity of spontaneous right-to-left shunt (16). More recently, the CODICIA (Right-to-Left Shunt in Cryptogenic Stroke) study (17) concluded that neither massive nor massive shunt associated with ASA was an independent risk factor for recurrent stroke. Unfortunately no mention was made about faith of patients with presence of permanent shunt in this study or in the study by Goel et al. (18), which clearly demonstrated that in symptomatic patients the PFO is associated with larger shunt and longer tunnel and more frequently with ASA.
Permanent shunt usually corresponds to large shunt induced by Valsalva maneuver, but the correlation is not always linear in clinical practice: sometimes permanent shunt might correspond only to moderate (shower pattern) shunt after Valsalva: this might explain the mixed results observed in the aforementioned studies.
We believe, by contrast, that permanent shunt is the most nonphysiological condition among the different flow pattern of right-to-left shunt: this hypothesis seems to be supported also by our previous studies, in which both ASA and permanent right-to-left shunt seemed correlated with a certain degree of left atrial dysfunction (19). The improvement of left atrial dysfunction when the permanent shunt was abolished after device closure in patients with a permanent shunt and ASA supports the role of permanent shunt in the pathophysiology of paradoxical embolism, even if a portion of ASA remains uncovered. The current study further confirmed this hypothesis and also the link between prominent EV and permanent shunt, a correlation already suggested by Schuchlens et al. (20).
To our knowledge, our study is the first systematic analysis evaluating the clinical and procedural implications of permanent right-to-left shunt. Further larger prospective studies probably should take into account that the presence and severity of spontaneous right-to-left shunt might be closely related to ASA and that prominent EV and large ASA might be potential markers of a high-risk profile for paradoxical embolism.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial septal aneurysm
- Eustachian valve
- intracardiac echocardiography
- magnetic resonance imaging
- patent foramen ovale
- transcranial Doppler
- transesophageal echocardiography
- Received April 5, 2011.
- Revision received May 24, 2011.
- Accepted June 16, 2011.
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