Persistent foramen ovaleQ21.1

The Italian surgeon Leonardo Botallo first described the Foramen ovale in 1564. Julius Cohnheim, a German pathologist, in 1877 considered a persistent foramen ovale to be the cause of a fatal brain embolism (Mass 2008).

A persistent foramen ovale (PFO) is a connection between the two atria that is not yet closed or opens when there is increased right-atrial pressure (Michels 2010). It is not a septal defect in the narrower sense, as the PFO is merely a functionally open connection (Dießel 2017). It is rather called a norm variant (Herold 2019).

In adults, a persistent Foramen ovale is found in up to 30 % (Bauriedel 2003). The prevalence depends on age and decreases with increasing age: 34 % are found in the first 3 decades of life and 20 % in the 9th and 10th decade (Hermann 2010). The slit width is between 1 - 19 mm (Pinger 2019).

The foramen ovale is a physiological short-circuit connection between the right and left atrium with a right-left shunt that exists during intrauterine development. As soon as respiration starts postnatally, the pulmonary resistance decreases and - with increasing perfusion of the lungs - an increased inflow into the left ventricle occurs (Dießel 2017).

The resulting increase in pressure in the left ventricle reverses the previously existing right-left shunt and causes an apposition of the septum primum to the septum secundum. Apposition results in functional closure of the foramen ovale, which also closes morphologically over the next few months (Hermann 2010).

In PVO, closure of the foramen ovale has not occurred. As a result, a transient intracardiac right-to-left shunt is found during short periods of time ( e.g., during coughing, sneezing, pressing, defecation, or spontaneously within the cardiac cycle). In diseases associated with increased resistance in the pulmonary circulation, a permanent shunt may also develop (Hermann 2010). Due to this shunt, paradoxical emboli can occur in venous thrombi (Pinger 2019).

PVO occurs equally frequently in both sexes. Only in the case of an increased incidence of PFO within a family is there a gender preference, which points to a possible genetic basis of the open foramen ovale (Hermann 2010).

In fact, studies of 62 patients under 60 years of age with apoplexy have shown that their female siblings have a significantly higher prevalence (78.5% compared to 25% in the normal population) of a PVO; there is no significant difference between male siblings (Arquizan 2001).

For a persistent Foramen ovale typical symptoms are:

• young patients - without risk constellation for an apoplexy, without manifest peripheral sclerosis - in whom a peripheral or central embolism occurs (such as PRINT, TIA, apoplexy). Occasionally, a typical pathophysiology is found with an occurrence of symptoms following right-atrial pressure increase (such as coughing, sneezing, pressing, etc.) (Michels 2010).
• Migraine with aura: Several studies have shown an association between PFO and migraine with aura (Majunke 2015). Patients with PFO have a 2.5 times higher prevalence of migraine [Bauriedel 2003]).
• In most cases the shunt is not haemodynamically effective. However, if it does, the following symptoms may occur:
• Dyspnea
• Sign of right heart strain (Michels 2010)

Echocardiography

Transthoracic echocardiography has a sensitivity with respect to PFO diagnosis of 50% to 60%, while transesophageal (TEE) has a sensitivity and also specificity of 100% when performed correctly. The latter is therefore the gold standard in the diagnosis of PFO.

PFO is detected when 1-3 bubbles of contrast medium appear in the left atrium or left ventricle (after application of an echo contrast medium [Nabavi 2007] or 9 ml NaCl solution shaken with 0.5-1 ml air) with adequate Valsalva maneuver to increase the pressure in the right ventricle (Pinger 2019).

However, the right-left shunt is not limited to the Valsalva shunt because in early ventricular systole the right atrial pressure is temporarily higher than the pressure in the left atrium (Schön 2018). 5 attempts are recommended (Pinger 2019)

If blisters appear in the left atrium only after 3 heart actions, they are more likely to be caused by a pulmonary arteriovenous shunt than by a PFO (Schön 2018).

Intracardiac Echocardiography

With the help of intracardiac echocardiography, a direct visualization of the atrial septum is possible. However, this examination technique is rarely used in practice (Schön 2018).

Transcranial Doppler or Transcranial Doppler

A right-left shunt can also be detected with high sensitivity and specificity in contrast medium enhanced transcranial Doppler examination (TCD) of the middle cerebral artery (Arquizan 2001). However, localization (intracardial or intrapulmonary) is not possible, nor is morphological characterization. However, due to the time delay of the contrast agent during transthoracic, transesophageal or intracardial to left atrium localization, there are indications to differentiate between intracardial and intrapulmonary shunt:

• if the bubbles appear in the left atrium within 3 cardiac cycles after contrasting the right atrium, an intracardiac shunt is more likely
• if the bubbles only appear after 3 cardiac cycles in the left atrium, a pulmonary arteriovenous shunt is more likely

Since this examination is less stressful for the patient, it can be used as a screening procedure (Ghanem 2018).

• Thromboembolism from the ascending aorta
• intrapulmonary shunts (so-called arteriovenous malformation) (Pinger 2019)

Auscultation

In the majority of cases, auscultation findings are unremarkable. However, during screening examinations, for example, the following may be noticed:

• a fixed split 2nd heart sound (due to late pulmonary valve closure)
• a systolic (pointum maximum is the 2nd ICR left parasternal) (Dießel 2017).

As long as patients with PFO are asymptomatic, no therapy is necessary.

However, if symptoms develop (primarily cerebral embolism), there are several treatment options:

• 1. antiplatelet therapy
• 2. anticoagulation
• 3. surgical closure of the oval foramen (either open heart surgery or percutaneous catheter-assisted closure)

There is no significant difference in the recurrence rate between antiplatelet therapy and anticoagulation, according to a 2015 study.

This study included a total of 2385 patients. The RoPE score (Risk of Paradoxical Embolism) was 6.3 in patients treated with oral anticoagulation (n = 803) and 6.4 in patients treated with antiplatelet therapy (n = 1582) (Kent 2015).

The value of surgical closure of a PFO is discussed very controversially.

The AHA / ASA 2014 guidelines contain a cautious, EBM-oriented assessment:

• It is unclear whether oral anticoagulation is superior to antiplatelet therapy after aoplex or TIA in persistent foramen ovale.
• If a venous source of embolism is present in a PFO, anticoagulation is recommended (class IIa).
• There is a IIa recommendation for PFO closure when a PFO is combined with deep vein thrombosis (DVT of DVT).
• There is a class III- recommendation for the combination of a PFO with Z. n. a cryptogenic apoplexy or TIA (Pinger 2019).

Several studies (e.g., the CLOSURE I, PC study, and RESPECT published between 2012 and 2013) have shown that the benefit of PFO closure is not superior to medical therapy. 3 Studies (REDUCE, CLOSE, and RESPECT extended follow-up) presented in 2017 show clear evidence in favor of interventional PFO closure. However, it should be noted that the trials presented in 2017 included only patients between 18 and 60 years of age who had an at least moderately severe PFO or a concomitant atrial septal aneurysm. They were also found to have a longer follow-up period (Schön 2018).

Additionally, as other cardiovascular risks increase, the possibility of preventing re- apoplexy decreases. However, it remains unclear whether closure of the persistent foramen ovale is indicated in elderly patients after an ischemic insult (cut-off value of studies was < 60 years) (Schön 2018). Yuan (2018) recommends that the decision of PFO closure be made in consultation with the patient, neurologist, and cardiologist.

Regarding drug treatment, no significant differences in the efficacy of antiplatelet agents (e.g., aspirin, clopidogrel, or aspirin dipyridamole) versus vit K antagonists (warfarin) or direct oral anticoagulants (DOAKs; e.g., rivaroxaban, apixaban, edoxaban) have been demonstrated. Therefore, unless there is another indication for anticoagulation, the patient should start long-term therapy with AP- regardless of whether the PFO has been closed or not (Yuan 2018).

In conclusion, the interdisciplinary S2e recommendations of 2018 are:

• Recommendation grade A, evidence level I:

Exists in patients between 16 and 60 years of age with cryptogenic ischemic apoplexy and patent foramen ovale with at least moderate right-to-left shunt after neurological and cardiological exclusion of other causes of apoplexy.

• Recommendation grade B, evidence level II:

Includes patients with cryptogenic ischemic apoplexy or TIA and patent foramen ovale who refuse closure of the PFO. Here, secondary prevention should be with acetylsalicylic acid or clopidogrel

• Recommendation grade B, evidence level IIb:

Following interconventional PFO closure, dual antiplatelet therapy should be given for 1 - 3 months with:

• 100 mg acetylsalicylic acid/day +
• 75 mg clopidogrel/day

Followed by monotherapy for 12 - 24 months:

• 100 mg acetylsalicylic acid/day or
• 75 mg clopidogrel/day

If the patient also has manifest atherosclerosis, continuous therapy with antiplatelet agents is recommended.

• Recommendation grade A, evidence level Ia:

Complications of occluder implantation such as atrial fibrillation, pulmonary embolism, and pericardial tamponade are very rare events and should not influence the grade of recommendation for implantation.

• Recommendation grade A, evidence level Ia:

In terms of safety and effectiveness, disc occluders have been shown to be more beneficial than non-circular disc occluders (Ghanem 2018).

In terms of surgical options, cardiac surgery and catheter interventional PFO closure are available (Bauriedel 2003). Thanks to the development of the Double- Disc- System by King and Mills, interventional closure of the PFO can be performed since 1976. Previously, closure was only possible surgically by open-heart surgery using a heart-lung machine (Dießel 2017). Nowadays, occluder systems such as Amplatzer ASD-Septal Occluder, Cribriform Occluder, Solysafe Septal Occluder , BioSTAR Septal Occluder or GORE Helex Septal etc. are used.

Closure by catheter intervention is now a standard therapy performed internationally, as both the complication rate and the length of hospital stay are lower than for cardiac surgery closure.

However, a residual shunt is less likely to occur after surgical closure.

A 2017 study showed:

• in surgically operated patients, closure without residual shunt was possible in 95 of a total of 99 patients
• in interventional patients, closure without no residual shunt was possible in 159 of a total of 210 patients (p- value < 0.001) (Dießel 2017).

Contraindications to interventional therapy are:

• the diameter of the ASD is greater than 30 mm
• there is pulmonary vein malperfusion
• the location of the ASD is not central (Dießel 2017)

Migraine with aura: In the randomized MIST study, no decrease in migraine attacks after closure of the foramen ovale could be demonstrated, so that the surgical measure cannot currently be recommended for migraine patients (Majunke 2015). This recommendation is also in line with the guidelines for migraine therapy of 2018 (Diener 2018). The exclusion or detection of a persistent foramen ovale may be important for professional divers (Michels 2010).

Clarification of the cause of cardiac embolism. Causes of cardiac embolism other than PFO should be clarified as the cause of an apoplexy. These can be:

• Atrial fibrillation
• papillary fibroelastoma (heart tumour; also known as Giant Lambl's excrescence)
• Lambl's excrescence (also called Lambl's excrescence; these are filiform structures of the valve edges with a length of < 11 mm and a width of < 1.1 mm resulting from endothelialized traumatic abrasion of the valve surface)
• Myxoma
• Mitral valve prolapse

1. Arquizan C et al (2001) Is pataent foramen ovale a family trait? A transcranial Doppler sonographic study. Stroke (32) 1563 - 1566
2. Bauriedel G et al. (2003) Therapeutic options for symptomatic open foramen ovale: A current inventory of catheter-interventional procedures. Dtsch Arztebl (34 - 35) A- 2230 / B: 1857 / C: 1760
3. Dießel J D (2017) Comparison between interventional and surgical closure of an atrial septal defect / Persistent Foramen ovale: a retrospective, monocentric, non-randomized study at the Children's Heart Center Giessen. Inaugural dissertation of the Justus Liebig University Giessen.
4. Diener H C et al (2018) Therapy of migraine attacks and prophylaxis of migraine. Guidelines for diagnosis and therapy in neurology. DGN and DMKG, AWMF-Registry number: 030/057
5. Dießel J D (2017) Comparison between interventional and surgical closure of an atrial septal defect / Persistent Foramen ovale: a retrospective, monocentered, non-randomized study at the Children's Heart Center Giessen, Germany Inaugural dissertation of the Justus Liebig University Giessen, Faculty of Medicine
6. Ghanem A et al (2018) Interventional PFO- Closure: Consensus Paper of the Working Group Interventional Cardiology (AGIK) of the German Society of Cardiology - Cardiovascular Research (DGK) together with the German Society of Neurology (DGN) and the German Stroke Society (DSG). Cardiology (12) 415 - 423
7. Hermann D et al (2010) Vascular Neurology: Cerebral ischemia, hemorrhages, vascular malformations, vasculitis and vascular dementia. Georg Thieme Publisher 68 - 71
8. Herold G et al (2019) Internal Medicine. Herold Publisher 186
9. Kent D M et al (2015) Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. Eropean Heart Journal (36) 2381 - 2389
10. Majunke N et al (2015) Persistent foramen ovale and atrial septal defect. Aktuel Cardiol (4) Georg Thieme Publisher 37 - 41
11. Messe S R et al (2008) Patent foramen ovale in cryptogenic stroke: Not to close. Circulation (118) 1999 - 2004
12. Michels G et al (2010) Clinical Manual Internal Medicine. Springer Publishing House 18 - 19
13. Nabavi D G et al (2007) Special cerebrovascular diseases: Intracranial hemorrhage, thrombosis and ischemia. W. Kohlhammer Publisher
14. Pinger S (2019) Repetitorium Kardiologie: For clinic, practice, specialist examination. German medical publisher. 393 – 393
15. Schön S P et al (2018) Persistent Foramen ovale - current procedure.cardio up (02) 143 - 154
16. Yuan K et al (2018) Patent foramen ovale and cryptogenic stroke: diagnosis and updates in secondary stroke prevention. Stroke Vasc Neurol. (3) 84 - 91