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{{Patent foramen ovale}}
{{Patent foramen ovale}}


{{CMG}}; '''Associate Editors-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; '''Assistant Editor-In-Chief:''' [[Kristin Feeney|Kristin Feeney, B.S.]] [mailto:kfeeney@elon.edu]
{{CMG}}; '''Associate Editors-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com], {{IO}}, [[Kristin Feeney|Kristin Feeney, B.S.]] [mailto:kfeeney@elon.edu]


==Overview==
==Overview==


There is a lack of consensus about the association of patent foramen ovale and [[Paradoxical embolism|cryptogenic stroke]]. While some studies have demonstrated an increased incidence of patent foramen ovale (PFO) in younger patients with [[Paradoxical embolism|cryptogenic stroke]]. Factors that might increase the occurrence of recurrent stroke in patients with patent foramen ovale are atrial septal aneurysm, bigger shunts and longer tunnels. Some systematic reviews done to compare medical versus percutaneous closure, found the rate of recurrent [[strokes]] with medical treatment to be greater than that with percutaneous closure. However, the results of these systematic reviews should be carefully interpreted , as the individual studies included in the review were very heterogeneous.
There is a lack of consensus on the association of patent foramen ovale and [[Paradoxical embolism|cryptogenic stroke]]. While some studies have demonstrated an increased incidence of patent foramen ovale in younger patients with [[Paradoxical embolism|cryptogenic stroke]]. Factors that might increase the occurrence of recurrent [[stroke]] in patients with patent foramen ovale are atrial septal aneurysm, bigger [[Shunt (medical)|shunts]] and longer tunnels. Some systematic reviews done to compare medical versus [[percutaneous]] closure, found the rate of recurrent [[strokes]] with medical treatment to be greater than that with [[percutaneous]] closure. However, the results of these systematic reviews should be carefully interpreted, as the individual studies included in the review were very heterogeneous.


==Patent Foramen Ovale and Stroke==
==Patent Foramen Ovale and Stroke==
===Association of Cryptogenic Stroke/Transient Ischemic Attacks with Patent Foramen Ovale===
===Association of Cryptogenic Stroke/Transient Ischemic Attacks with Patent Foramen Ovale===
*A cryptogenic stroke is one with undetermined pathogenesis.<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
*A cryptogenic [[stroke]] is one with undetermined pathogenesis.<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
*Patent foramen ovale can serve as a route for platelet aggregates, gas bubbles, thrombi, and other particulate matter to travel through from the systemic venous circulation to the brain.<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
*Patent foramen ovale can serve as a route for [[platelet]] aggregates, gas bubbles, [[Thrombus|thrombi]], and other particulate matter to travel through from the systemic [[venous]] circulation to the [[brain]].<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
*One in every four cases of [[ischemic stroke]] does not have an identifiable cause other than [[Paradoxical embolism|cryptogenic stroke]] which is a diagnosis of exclusion<ref name="pmid2712533">{{cite journal| author=Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR et al.| title=Infarcts of undetermined cause: the NINCDS Stroke Data Bank. | journal=Ann Neurol | year= 1989 | volume= 25 | issue= 4 | pages= 382-90 | pmid=2712533 | doi=10.1002/ana.410250410 | pmc= | url= }} </ref>
*One in every four cases of [[ischemic stroke]] does not have an identifiable cause other than [[Paradoxical embolism|cryptogenic stroke]] which is a diagnosis of exclusion<ref name="pmid2712533">{{cite journal| author=Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR et al.| title=Infarcts of undetermined cause: the NINCDS Stroke Data Bank. | journal=Ann Neurol | year= 1989 | volume= 25 | issue= 4 | pages= 382-90 | pmid=2712533 | doi=10.1002/ana.410250410 | pmc= | url= }} </ref>
*The association between the presence of a patent foramen ovale and [[Paradoxical embolism|cryptogenic stroke]] is controversial and inconsistent. While some studies have demonstrated an increased incidence of patent foramen ovale (PFO) in younger patients with [[Paradoxical embolism|cryptogenic stroke]], others failed to show an association <ref name="pmid18851751">{{cite journal| author=Poppert H, Morschhaeuser M, Feurer R, Bockelbrink A, Schwarze J, Esposito L et al.| title=Lack of association between right-to-left shunt and cerebral ischemia after adjustment for gender and age. | journal=J Negat Results Biomed | year= 2008 | volume= 7 | issue=  | pages= 7 | pmid=18851751 | doi=10.1186/1477-5751-7-7 | pmc=PMC2577085 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18851751  }} </ref><ref name="pmid11071496">{{cite journal| author=Overell JR, Bone I, Lees KR| title=Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. | journal=Neurology | year= 2000 | volume= 55 | issue= 8 | pages= 1172-9 | pmid=11071496 | doi= | pmc= | url= }} </ref><ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
*The association between the presence of a patent foramen ovale and [[Paradoxical embolism|cryptogenic stroke]] is controversial and inconsistent. While some studies have demonstrated an increased incidence of patent foramen ovale in younger patients with [[Paradoxical embolism|cryptogenic stroke]], others failed to show an association <ref name="pmid18851751">{{cite journal| author=Poppert H, Morschhaeuser M, Feurer R, Bockelbrink A, Schwarze J, Esposito L et al.| title=Lack of association between right-to-left shunt and cerebral ischemia after adjustment for gender and age. | journal=J Negat Results Biomed | year= 2008 | volume= 7 | issue=  | pages= 7 | pmid=18851751 | doi=10.1186/1477-5751-7-7 | pmc=PMC2577085 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18851751  }} </ref><ref name="pmid11071496">{{cite journal| author=Overell JR, Bone I, Lees KR| title=Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. | journal=Neurology | year= 2000 | volume= 55 | issue= 8 | pages= 1172-9 | pmid=11071496 | doi= | pmc= | url= }} </ref><ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>


===Patent Foramen Ovale and First Stroke===
===Patent Foramen Ovale and First Stroke===
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===Patent Foramen Ovale and Recurrent Stroke===
===Patent Foramen Ovale and Recurrent Stroke===


* There exists a discrepancy between influence of patent foramen ovale (PFO) on recurrent [[stroke]] (after first episode of [[Paradoxical embolism|cryptogenic stroke]]).
* There exists a discrepancy on the influence of patent foramen ovale (PFO) on recurrent [[stroke]] (after first episode of [[Paradoxical embolism|cryptogenic stroke]]).


* Several factors have been found associated with a patent foramen ovale (PFO) that might increase the incidence of recurrent [[strokes]] namely, atrial [[septal aneurysm]] <ref name="pmid11742048">{{cite journal| author=Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G et al.| title=Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 24 | pages= 1740-6 | pmid=11742048 | doi=10.1056/NEJMoa011503 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11742048 }} </ref>, (ASA) in association with [[PFO]], bigger shunts and longer tunnels <ref name="pmid19101242">{{cite journal| author=Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP, Krasuski RA et al.| title=Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients. | journal=Am J Cardiol | year= 2009 | volume= 103 | issue= 1 | pages= 124-9 | pmid=19101242 | doi=10.1016/j.amjcard.2008.08.036 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19101242 }} </ref>.
* Several factors have been found to be associated with a patent foramen ovale (PFO) that may increase the incidence of recurrent [[strokes]] namely, atrial [[septal aneurysm]], (ASA) in association with [[PFO]], bigger shunts and longer tunnels <ref name="pmid19101242">{{cite journal| author=Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP, Krasuski RA et al.| title=Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients. | journal=Am J Cardiol | year= 2009 | volume= 103 | issue= 1 | pages= 124-9 | pmid=19101242 | doi=10.1016/j.amjcard.2008.08.036 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19101242 }} </ref><ref name="pmid11742048">{{cite journal| author=Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G et al.| title=Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 24 | pages= 1740-6 | pmid=11742048 | doi=10.1056/NEJMoa011503 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11742048 }} </ref>


* Nevertheless, some studies have found no association between PFO or abnormal septal morphology with recurrent [[strokes]] <ref name="pmid18818401">{{cite journal| author=Serena J, Marti-Fàbregas J, Santamarina E, Rodríguez JJ, Perez-Ayuso MJ, Masjuan J et al.| title=Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. | journal=Stroke | year= 2008 | volume= 39 | issue= 12 | pages= 3131-6 | pmid=18818401 | doi=10.1161/STROKEAHA.108.521427 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18818401  }} </ref>.
* Nevertheless, some studies have found no association between patent foramen ovale or abnormal septal morphology with recurrent [[strokes]] <ref name="pmid18818401">{{cite journal| author=Serena J, Marti-Fàbregas J, Santamarina E, Rodríguez JJ, Perez-Ayuso MJ, Masjuan J et al.| title=Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. | journal=Stroke | year= 2008 | volume= 39 | issue= 12 | pages= 3131-6 | pmid=18818401 | doi=10.1161/STROKEAHA.108.521427 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18818401  }} </ref>.


* Studies have failed to show that patent foramen ovale increases the risk of recurrent stroke in cryptogenic stroke patients with a patent foramen ovale when compared with those without a patent foramen ovale.<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
* Studies have failed to show that patent foramen ovale increases the risk of recurrent stroke in cryptogenic [[stroke]] patients with a patent foramen ovale when compared with those without a patent foramen ovale.<ref name="KuttySengupta2012">{{cite journal|last1=Kutty|first1=Shelby|last2=Sengupta|first2=Partho P.|last3=Khandheria|first3=Bijoy K.|title=Patent Foramen Ovale|journal=Journal of the American College of Cardiology|volume=59|issue=19|year=2012|pages=1665–1671|issn=07351097|doi=10.1016/j.jacc.2011.09.085}}</ref>
 
* Studies are not able to establish a clear association of patent foramen ovale with recurrent [[strokes]]. A possible explanatation for these findings could be-
** The studies didn’t control the nature of treatment after the index episode of [[stroke]] i.e. patients with one episode of [[Paradoxical embolism|cryptogenic stroke]] were given either medical ([[antiplatelet]]), percutaneous closure or no treatment depending on physician’s decision. Thus, a possibility could be that medical treatment might be highly effective and obscures the risk of patent foramen ovale<ref name="pmid19439720">{{cite journal| author=Almekhlafi MA, Wilton SB, Rabi DM, Ghali WA, Lorenzetti DL, Hill MD| title=Recurrent cerebral ischemia in medically treated patent foramen ovale: a meta-analysis. | journal=Neurology | year= 2009 | volume= 73 | issue= 2 | pages= 89-97 | pmid=19439720 | doi=10.1212/WNL.0b013e3181aa2a19 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19439720  }} </ref>.
 
===Treatment Options in Patent Foramen Ovale with Recurrent Strokes===
 
====Medical Therapy====
A metanalysis done by Almekhlafi et al. found that recurrent [[stroke]]s were about half as likely on [[warfarin]] as compared with [[antiplatelet]] treatment <ref name="pmid19439720">{{cite journal| author=Almekhlafi MA, Wilton SB, Rabi DM, Ghali WA, Lorenzetti DL, Hill MD| title=Recurrent cerebral ischemia in medically treated patent foramen ovale: a meta-analysis. | journal=Neurology | year= 2009 | volume= 73 | issue= 2 | pages= 89-97 | pmid=19439720 | doi=10.1212/WNL.0b013e3181aa2a19 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19439720  }} </ref>.
====Surgery====
Interventional or surgical therapy includes:
* Percutaneous device closure (commonest)
* Suture closure
* Radioablative therapy (under-development)
* Open heart surgery (uncommon)
 
Surgical closure of patent foramen ovale is uncommon these days especially after development of percutaneous device closure. Some systematic reviews done to compare medical versus percutaneous closure, found that the rate of recurrent [[strokes]] with medical treatment (5.2%) is greater than that with percutaneous closure (1.3%) <ref name="pmid14597460">{{cite journal| author=Khairy P, O'Donnell CP, Landzberg MJ| title=Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. | journal=Ann Intern Med | year= 2003 | volume= 139 | issue= 9 | pages= 753-60 | pmid=14597460 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14597460  }} </ref><ref name="pmid16103257">{{cite journal| author=Homma S, Sacco RL| title=Patent foramen ovale and stroke. | journal=Circulation | year= 2005 | volume= 112 | issue= 7 | pages= 1063-72 | pmid=16103257 | doi=10.1161/CIRCULATIONAHA.104.524371 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16103257  }} </ref><ref name="pmid16876648">{{cite journal| author=Wöhrle J| title=Closure of patent foramen ovale after cryptogenic stroke. | journal=Lancet | year= 2006 | volume= 368 | issue= 9533 | pages= 350-2 | pmid=16876648 | doi=10.1016/S0140-6736(06)69087-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16876648  }} </ref> . However, the results of these systematic reviews should be interpreted carefully, because there was lack of uniformity in the selection criteria, duration of follow up and end points in the individual studies that were used for the systematic review.


==References==
==References==

Latest revision as of 18:09, 27 February 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, M.B.B.S. [2], Ifeoma Odukwe, M.D. [3], Kristin Feeney, B.S. [4]

Overview

There is a lack of consensus on the association of patent foramen ovale and cryptogenic stroke. While some studies have demonstrated an increased incidence of patent foramen ovale in younger patients with cryptogenic stroke. Factors that might increase the occurrence of recurrent stroke in patients with patent foramen ovale are atrial septal aneurysm, bigger shunts and longer tunnels. Some systematic reviews done to compare medical versus percutaneous closure, found the rate of recurrent strokes with medical treatment to be greater than that with percutaneous closure. However, the results of these systematic reviews should be carefully interpreted, as the individual studies included in the review were very heterogeneous.

Patent Foramen Ovale and Stroke

Association of Cryptogenic Stroke/Transient Ischemic Attacks with Patent Foramen Ovale

  • A cryptogenic stroke is one with undetermined pathogenesis.[1]
  • Patent foramen ovale can serve as a route for platelet aggregates, gas bubbles, thrombi, and other particulate matter to travel through from the systemic venous circulation to the brain.[1]
  • One in every four cases of ischemic stroke does not have an identifiable cause other than cryptogenic stroke which is a diagnosis of exclusion[2]
  • The association between the presence of a patent foramen ovale and cryptogenic stroke is controversial and inconsistent. While some studies have demonstrated an increased incidence of patent foramen ovale in younger patients with cryptogenic stroke, others failed to show an association [3][4][1]

Patent Foramen Ovale and First Stroke

  • Although, two prospective cohort studies namely, ‘ The Northern Manhattan Study’ (NOMAS) and 'Stroke Prevention: Assessment of Risk in a Community' (SPARC), found an increased incidence of first stroke in patients with patent foramen ovale, both these studies did not reach a statistical significance.[5][6]

Patent Foramen Ovale and Recurrent Stroke

  • There exists a discrepancy on the influence of patent foramen ovale (PFO) on recurrent stroke (after first episode of cryptogenic stroke).
  • Several factors have been found to be associated with a patent foramen ovale (PFO) that may increase the incidence of recurrent strokes namely, atrial septal aneurysm, (ASA) in association with PFO, bigger shunts and longer tunnels [7][8]
  • Nevertheless, some studies have found no association between patent foramen ovale or abnormal septal morphology with recurrent strokes [9].
  • Studies have failed to show that patent foramen ovale increases the risk of recurrent stroke in cryptogenic stroke patients with a patent foramen ovale when compared with those without a patent foramen ovale.[1]

References

  1. 1.0 1.1 1.2 1.3 Kutty, Shelby; Sengupta, Partho P.; Khandheria, Bijoy K. (2012). "Patent Foramen Ovale". Journal of the American College of Cardiology. 59 (19): 1665–1671. doi:10.1016/j.jacc.2011.09.085. ISSN 0735-1097.
  2. Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR; et al. (1989). "Infarcts of undetermined cause: the NINCDS Stroke Data Bank". Ann Neurol. 25 (4): 382–90. doi:10.1002/ana.410250410. PMID 2712533.
  3. Poppert H, Morschhaeuser M, Feurer R, Bockelbrink A, Schwarze J, Esposito L; et al. (2008). "Lack of association between right-to-left shunt and cerebral ischemia after adjustment for gender and age". J Negat Results Biomed. 7: 7. doi:10.1186/1477-5751-7-7. PMC 2577085. PMID 18851751.
  4. Overell JR, Bone I, Lees KR (2000). "Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies". Neurology. 55 (8): 1172–9. PMID 11071496.
  5. Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S (2007). "Patent foramen ovale and the risk of ischemic stroke in a multiethnic population". J Am Coll Cardiol. 49 (7): 797–802. doi:10.1016/j.jacc.2006.08.063. PMID 17306710.
  6. Meissner I, Khandheria BK, Heit JA, Petty GW, Sheps SG, Schwartz GL; et al. (2006). "Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study". J Am Coll Cardiol. 47 (2): 440–5. doi:10.1016/j.jacc.2005.10.044. PMID 16412874.
  7. Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP, Krasuski RA; et al. (2009). "Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients". Am J Cardiol. 103 (1): 124–9. doi:10.1016/j.amjcard.2008.08.036. PMID 19101242.
  8. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G; et al. (2001). "Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both". N Engl J Med. 345 (24): 1740–6. doi:10.1056/NEJMoa011503. PMID 11742048.
  9. Serena J, Marti-Fàbregas J, Santamarina E, Rodríguez JJ, Perez-Ayuso MJ, Masjuan J; et al. (2008). "Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study". Stroke. 39 (12): 3131–6. doi:10.1161/STROKEAHA.108.521427. PMID 18818401.

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