Supplemental Material
Web Appendix
PARADOXICAL EMBOLISM
Stephan Windecker, MD, Stefan Stortecky, MD and Bernhard Meier, MD
Swiss Cardiovascular Center Bern,
Department of Cardiology, Bern University Hospital, Bern, Switzerland
Address for correspondence:
Stephan Windecker, MD
Professor and Chief of Cardiology
Department of Cardiology
Swiss Cardiovascular Center Bern
Bern University Hospital
3010 Bern
Switzerland
e-mail: stephan.windecker@insel.ch
TABLE OF CONTENTS
GENETICS OF INTRA-ATRIAL DEFECTS ............................................................................................................... 3
TYPE AND SOURCE OF EMBOLIC PARTICLES ........................................................................................................ 3
CLINICAL MANIFESTATIONS OF RIGHT TO LEFT SHUNT ........................................................................................ 4
PLATYPNEA ORTHODEOXIA ........................................................................................................................ 4
DECOMPRESSION ILLNESS .......................................................................................................................... 5
HIGH ALTITUDE PULMONARY EDEMA ........................................................................................................... 5
OBSTRUCTIVE SLEEP APNEA SYNDROME ...................................................................................................... 6
ARTERIAL DESATURATION.......................................................................................................................... 6
GUIDELINES OF PROFESSIONAL SOCIETIES......................................................................................................... 7
ADDITIONAL REFERENCES .............................................................................................................................. 9
GENETICS OF INTRA-ATRIAL DEFECTS
While ASDs are associated with several mutations in human genes causing dominant forms
(encoding factors responsible for the development including homeodomain factor NKX2-5,
T-box factor TBX5, zinc finger factor GATA4; and myofilament gene targets ACTC, and MYH6)
(1), the genetic susceptibility to PFO is largely unknown. However, familial predisposition for
PFO with a higher prevalence of PFO in siblings suggests a genetic link (2). Furthermore,
experimental studies suggest, that ASD, ASA, and PFO share the same anatomical and
pathological continuum and may have a common genetic basis (3).
TYPE AND SOURCE OF EMBOLIC PARTICLES
Embolic particles can be of diverse origin:

Thromboembolism: Inappropriate activation of the coagulation cascade by vascular
injury, abnormal blood flow, and hypercoagulability predispose to thrombus formation
(4). The majority of thrombotic emboli originate from deep leg and pelvic veins (5).

Gas or air bubbles: Traumatic (neck wound) or iatrogenic causes (large central vein
catheters, hemodialysis, surgical interventions, Cesarean section, or instrument-assisted
delivery) may facilitate the inadvertent entrance of air into the circulation (6). Air
bubbles usually coalesce and physically obstruct the blood flow in the lungs or the brain.
Gas bubbles may emerge during deep sea diving and can cause decompression sickness
(7).

Fat or Bone marrow particles: Fat or bone marrow particle embolization usually occurs
after traumatic fracture of bones or during hip and knee surgery. The principal reason for
fat release is explained by intramedullary pressure hypertension after bone fracture or
surgical manipulation, leading to bone marrow release through small distal metaphysis
veins into the circulation (8).

Tumor: Malignant tumors may invade the local vasculature, hematogenously spread
metastases and in case of paradoxical embolism may lead to MI, cerebrovascular
accident or peripheral ischemia.

Infective or Septic particles: Emboli may originate from septic thrombophlebitis, central
venous catheter infections or pacemaker leads or endocarditis and can spread infections
leading to brain abscesses or infectious aneurysms (9).

Amniotic fluid: Amniotic fluid embolism is a rare obstetric emergency in which amniotic
fluid, fetal cells, hair, placenta or other particles enter the mother’s circulation.
Abdominal trauma, amniocentesis, Cesarean or instrumental vaginal delivery are
associated with an increased risk (10).
CLINICAL MANIFESTATIONS OF RIGHT TO LEFT SHUNT
PLATYPNEA ORTHODEOXIA
Platypnea-orthodeoxia is a rare clinical entity and describes the unusual complaint of
dyspnea related to arterial oxygen desaturation in the upright position with significant
improvement in supine position (11,12). Functional cardiac causes coexist and have been
associated with the platypnea-orthodeoxia syndrome including pericardial effusion (13),
constrictive pericarditis, and ascending aortic aneurysm (14,15). As contributing
pathophysiological mechanism compression of the right atrium by the aorta when upright
has been documented (16). While usually a transient or permanent pressure gradient is
required for right-to-left shunt via PFO, the hemodynamic characteristics of platypneaorthodeoxia include normal right-sided pressures (17) without changes during upright
posture (18), which is explained due to redistribution of blood flow with a persistent
Eustachian valve (19), or unequal compliance between right and left heart chambers (20).
DECOMPRESSION ILLNESS
Decompression illness in divers occurs as a result of gas-bubbles forming within the tissue
and the vessels, when the dissolved gas tensions and water vapor exceeds the local absolute
pressure which is low in the venous circulation. The formation of gas bubbles begins during
the ascent of divers, and can cause significant arterial embolic complications in the presence
of a PFO (7). Symptoms usually occur at the peak-time of bubble liberation from the tissue,
approximately 30 minutes after surfacing (21), and may comprise neurological cerebral, or
spinal symptoms (22), or arterial desaturation suggesting gas embolism as principle
mechanism. As decompression illness is rare and with an estimated risk between 0.002 –
0.03% of dives, routine screening for the presence of right-to-left shunt is currently not
generally recommended.
HIGH ALTITUDE PULMONARY EDEMA
Pulmonary hypertension plays a significant role in the development of high altitude
pulmonary edema (HAPE) and is preceded by altitude-induced arterial desaturation and
hypoxemia (23). HAPE is characterized by increased pulmonary capillary transmural
pressure, resulting in permeability edema and subsequent alveolar flooding and progressive
hypoxemia. Hypoxia induced pulmonary hypertension is caused by augmented sympathetic
activation, increased levels of endothelin-1 and decreased availability of nitric oxide and may
be accompanied by additional hypoxic pulmonary vasoconstriction, thereby worsening
hypoxemia (24). The incidence of HAPE is reported between 0.57% at an altitude of 3,500m
to 3,750m (25,26), and has a considerably higher incidence (up to 10%) among people who
ascend to 4,500m (27). While the development of this complication is mainly related to rates
of ascend, the absolute altitude obtained, male gender, cold ambient temperatures,
preexisting respiratory infection as well as intense exercise (24), there are some individuals
that appear predisposed to develop HAPE (28). Interestingly, among individuals susceptible
to HAPE, the prevalence of PFO is 4 to 5 times more frequent compared to individuals
resistant to HAPE, suggesting a significant effect on the underlying mechanism (29).
Moreover, the anatomical and functional size of PFO with spontaneous right-to-left shunt is
associated with more pronounced arterial hypoxemia compared to patients with small or no
PFO, suggesting that the size, rather than its mere presence, has an influence on clinical
presentation.
OBSTRUCTIVE SLEEP APNEA SYNDROME
Obstructive sleep apnea syndrome (OSAS) is the most common form of disordered breathing
and characterized by repetitive closure of the upper respiratory tract leading to arterial
oxygen desaturation. OSAS is frequent in the general patient population and associated with
a higher risk of cerebrovascular disease (30), stroke, or death (31). A link between OSAS and
stroke may be the presence of a right-to-left shunt most commonly a PFO, which is observed
in more than 40% of patients with severe OSAS (32,33). Intermittent and repetitive arterial
hypoxemia during sleep leads to reactive polycythemia and an increase in blood viscosity
(34). The combination of these hematological disorders with obstructive sleep apnea, which
has similar hemodynamic consequences as a Valsalva maneuver, may lead to intermittent
right-to-left shunt, which opens the passage for venous microemboli to the cerebral
circulation.
ARTERIAL DESATURATION
Increased right-sided diastolic cardiac pressure promotes interatrial right-to-left shunt,
permitting paradoxical embolism and resistant hypoxemia in case of a permanent and
significant shunt. This phenomenon has been described among patients with right
ventricular infarction (35,36) and patients with severe primary or secondary pulmonary
hypertension (37,38). In these patients, hemodynamically significant shunts may be
observed during inspiration with a decrease in left-atrial pressure leading to hypoxemia. A
substantially increased risk of stroke and death presumably related to paradoxical
thromboembolism has been observed among patients with pulmonary embolism and rightsided pressure increase.
GUIDELINES OF PROFESSIONAL SOCIETIES
To date percutaneous PFO closure has not been approved by the United States Food and
Drug Administration (FDA) for secondary prevention of cryptogenic stroke or embolism.
Available guideline recommendations were written in the absence of evidence from the
above mentioned randomized controlled trials and are largely based on observational data.
(39). The AHA/ASA document states, that patients with ischemic stroke or TIA in the
presence of PFO, antiplatelet therapy is reasonable (class IIa; Level of Evidence B).
Insufficient evidence is available to establish whether anticoagulation is superior to
acetylsalicylic acid for secondary stroke prevention in patients with PFO (class IIb; Level of
Evidence B). Furthermore, there are insufficient data to make a recommendation regarding
PFO closure in patients with stroke and PFO (class IIb; level of evidence C).
The American College of Chest Physicians Evidence Based Clinical Practice Guidelines (9th
edition, 2012) provides the following recommendations (40): asymptomatic PFO or ASA does
not require any antithrombotic therapy (grade 2C). Among patients with clinical history of
cryptogenic stroke and diagnosis of PFO or ASA, acetylsalicylic acid (50-100 mg/d) is
recommended over no acetylsalicylic acid (grade 1A). In patients with recurrent ischemic
events and PFO or ASA, despite acetylsalicylic acid therapy, treatment with vitamin-Kantagonist (VKA) therapy (target INR, 2.5; range, 2.0-3.0) is recommended over
acetylsalicylic acid therapy (grade 2C) and device closure should be considered. And finally in
the presence of deep vein thrombosis, VKA therapy for 3 months (target INR, 2.5; range, 2.03.0) (grade 1B) and consideration of device closure over no VKA therapy or acetylsalicylic
acid therapy (grade 2C) is recommended.
In 2008 the European Stroke Organization (ESO) provided an update on guidelines for the
management of ischemic stroke and TIA, which present the current clinical recommendation
until today (41). In this paper the ESO differentiates between patients with PFO and
substantial risk for recurrent event (combination of PFO with ASA, Eustachian valve, or Chiari
network) and patients with low risk of stroke recurrence. Among high-risk patients,
endovascular closure of the PFO may be considered (class IV). The guideline taskforce
further points out that endovascular closure of PFOs with or without ASA is feasible in
patients with cryptogenic stroke and may lower the risk of recurrent stroke compared to
medical treatment. In view of novel evidence from randomized clinical trials and metaanalyses suggesting a potentially large treatment effect in favor of percutaneous PFO
closure, it appears timely to revise guideline recommendations to assist clinical decision
making.
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