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[18e35]. The presence of a PFO increases the risk of DC I by 2.5- to e5-fold, due to increased ability of venous gas
emboli to gain access to the arterial circulation [22,35]. Furthermore, PFO is associated with more severe phenotypes
of DCI that may require longer-duration hyperbaric treatment [19]. PFO-mediated DCI occurs commonly in less pro-
vocative dives and is associated with more neurological manifestations of DCI. When associated with a PFO, the
onset of the neurologic symptoms occurs within 30 min of resurfacing and may present with cutaneous DCI or car-
diovascular symptomatology, but less likely with late neurological DCI (onset of symptoms more than 30 min after
resurfacing) and musculoskeletal DCI [18,24,26,28,33,34].
Factors Associated with Increased Risk of Decompression Illness in the Presence of PFO
Not all divers with PFO develop DCI. In recreational diving, DCI occurs in only 0.005%e 0.08% of dives [36].Inan
observational study, Torti et al. demonstrated that the incidence of DCI in divers without PFO was 0.015% of all
dives. This number ranged from 0.01% to 0.09% in the PFO population [22].
Several factors related to diving per se may increase the risk of DCI in the presence of a PFO. Immersion in cold
water during diving increases venous return as a result of peripheral vasoconstriction, and subsequently raises right
atrial pressure and right-to-left shunting [37,38]. Passage of increased volume of gaseous bubbles in the pulmonary
circulation after a deep dive or after a rapid ascent, lifting heavy diving equipment at the end of a dive, or perform-
ing Valsalva maneuver to equalize middle ear pressure can all raise right heart pressure, increasing the chances of
entrance of bubbles to the systemic circulation [6]. Failure to make changes in the time and depth of diving after prior
DCI is also an independent risk factor for a recurrent episode [30].
Regarding PFO-related factors, PFO size is probably the most important. It has been shown that PFOs with a
wider diameter, larger shunt flow, and higher membrane mobility, especially those with evidence of spontaneous
shunting, are associated with increased risk of DCI as compared with smaller-sized PFOs [22,26,27,30,32]. Wilm-
shurst et al. evaluated the relation of PFO size and shunt-related DC I and reported that while in the general popu-
lation the median size of PFO is 5 mm and only 1.3% have a PFO size of 10 mm or higher, in divers with a history of
DCI the median diameter of PFO was 10 mm [31]. A meta-analysis of 5 case-control studies compared the prevalence
of right-to-left shunt (RLS) in a group of 654 divers with neurologic DCI and without DCI; they reported a combined
odds ratio for neurological DCI of 4.23 in divers with RLS, with the odds ratio increasing to 6.49 when limited to
high-grade RLS [39]. One study claimed that divers can have an increase in PFO size over time, making them
more susceptible to developing type II DCI [40]. We suspect that this observation is dependent on the method of
measurement of a PFO such as by echocardiography. There are no data that show that the stretched balloon size
of a PFO changes over time.
PFO and White Matter Lesions in Divers without Decompression Illness
There has been interest in investigating the occurrence of white matter lesions in the brain of divers who have not
suffered any prior DCI, as it is believed that these wh ite-matter magnetic resonance imaging (MRI) intensities may
represent silent ischemic damage to the brain. There is conflicting evidence on this matter. Gempp et al. performed a
study on 32 asymptomatic military divers and 32 nondiving healthy subjects; they found that divers had a signifi-
cantly higher rate of hyperintense spots on MRI as compared to nondivers. Divers were further analyzed and it was
concluded that those with a high-grade right-to-left shunt had increased prevalence of brain MRI hyperintense sig-
nals as compared to those with slight or no right-to-left shunt (75% vs. 25% respectively) [41]. Similarly, Schwerz-
mann et al. in a retrospective cohort study of 52 sports divers and 52 nondiving controls concluded that while
diving itself, regardless of the presence of a PFO, is associated with ischemic brain lesions, almost twice as many
ischemic brain lesions were seen in divers with PFO than without PFO [42]. In a prospective study of 87 sport divers,
Knauth et al. reported that the prevalence of multiple brain lesions was significantly higher in divers with a large
PFO as compared to all other divers (23% vs. 0%) [39]. Fig. 13.2 depicts the brain magnetic resonance images and
the transcranial Doppler ultrasonography of a diver with PFO [43].
Other studies did not show an association between brain lesions and presence of PFO in asymptomatic divers
[44e46]. Balestra et al. described a significant decrease in neuropsychometric performance in terms of working
memory and visual-spatial skills in a population of divers [46]. This was true irrespective of the presence of PFO
in this group. The proposed mechanism of this observation was nitrogen narcosis. Based on this evidence, it can
be concluded that diving appears to be associated with an increased number of ischemic brain lesions in asymptom-
atic individuals, and the presence of PFO may exacerbate this tendency. However, the clinical significance and
causality of these MRI white matter lesions have not been well established.
VI. OTHER CONDITIONS AND PFO
DECOMPRESSION ILLNESS AND PFO 157
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Imaging Tests for Detection of PFO
A PFO or RLS can be detected by transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE),
and transcranial Doppler (TCD) sonography of the middle cerebral artery [47]. Most clinicians regard TEE as the
reference standard for PFO assessment [48]; TEE has the disadvantage of rendering the performance of provocative
maneuvers like Valsalva more difficult, without which false-negative results can occur [49,50]. TTE was found to
have a similar diagnostic accuracy as TEE in diagnosing PFO if combined with Valsalva maneuver [49]. TTE can
also be used to detect venous bubbles after a dive. Identification of agitated saline bubbles by TCD of the middle
cerebral artery is diagnostic of an RLS, although it cannot reliably locate the level of shunting (i.e., PFO vs. atrial
septal defect vs. pulmonary arteriovenous shunt) [51]. A study comparing standardized TCD and TEE in young
adults following ischemic stroke or myocardial infarction showed that TCD is sensitive in the diagnosis of PFO
and can assess the functional importance of an RLS more accurately than TEE if used co ncomitantly with contrast
agents and provocative maneuvers maki ng it a valuable screening tool [52]. PFO imaging for diagnostic and inter-
ventional purposes are discussed in Chapters 2 and 3, respectively.
Candidates for Investigation
Although there is an association between PFO and DCI, the absolute incidence of DCI in divers is too low to justify
routine PFO screening for recreational divers [22,36]. In 2015, a joint statement issued by the South Pacific Under-
water Medicine Society and the United Kingdom Sports Diving Medical Committee recommended that investiga-
tions to detect PFO can be considered for people who have a history of neurological or cutaneous DCI, a current
or past history of migraine with aura, personal history of cryptogenic stroke, or a first-degree relative with a PFO
[53]. Additionally, divers with recurrent or unprovoked DCI may benefit from PFO workup if they wish to continue
diving for either recreational or occupational purposes [19,26]. Regardless of what test is used for screening, it
should be carried out with some form of bubble contrast and in conjunction with provocative maneuvers like Val-
salva release or sniffing to induce a right-to-left shunt [53].
FIGURE 13.2 Results for 46-year-old male diver (856 dives) without symptoms, no history of decompression incidents, and no history of
cerebrovascular disease or known vascular risk factors. Top: magnetic resonance images show multiple lesions in the central white matter of the
brain (hyperintense spots visible on all 3 images). Bottom: transcranial Doppler ultrasonography after injection of contrast medium shows
multiple air microbubbles in left middle cerebral artery after Valsalva maneuver (arrow). Reproduced from Ref. [43].
VI. OTHER CONDITIONS AND PFO
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Interventions for PFO-Mediated Decompression Illness
Once a PFO is detected in a diver and is thought to be the most likely mechanism contributing to the DCI, there are
3 potential interventions that can mitigate further episodes.
a) Cessation of diving [53].
b) Adopting a conservative dive profile reduces the total nitrogen load during diving. A conservative dive profile
involves the use of nitrox, decompression times calculated on air tables, avoiding repetitive and deep dives more
than 25 m, and minimizing the Valsalva maneuver. This was shown to have a significant reduction in DCI risk in
those both with and without a PFO [54]. Decreasing the nitrogen load by using a special mixture with a higher
percentage of oxygen (such as nitrox) may increase the diver ’s risk for oxygen toxicity [55].
c) PFO closure: Percutaneous PFO closure is an option for divers with PFO-mediated DCI, such as professional
divers who wish to continue diving and are not able to comply with conservative diving profiles. Device closure
is effective in elimi nation of arterial bubbles after a simulated dive, as demonstrated by Honek et al. in their case-
controlled observational study of 47 divers [56]. There was no difference in occurrence of venous bubbles in the
PFO closure and nonclosure group after either an 18-meter dive or a deeper 50-meter simulated dive, but
transcatheter PFO closure led to complete elimination of bubbles in the arterial circulation. Pearman et al.
performed an audit of PFO closure in 105 divers and concluded that transcatheter PFO closure is associated with
low complication rates and a high rate of return to unrestricted diving [57]. Collateral benefits, such as
improvement of migraine (if present) and lifelong protection against stroke and myocardial infarction by
paradoxical embolism, further support PFO closure.
Henzel et al. conducted a prospective follow-up of 11 divers who underwent PFO closure after suffering at least 1
episode of DCI. After a median follow-up time of 91 months during which all divers returned to deep and unre-
stricted diving, no further episodes of DCI or complications related to the procedure were reported [55]. Although
this was not a randomized trial, it suggests that PFO closure may be effective in secondary prevention of symptom-
atic DCI.
In another prospective study, 29 divers without PFO, 30 divers with PFO but without closure, and 25 divers with
PFO who underwent closure were followed for a median period of 5.3 years for the occurrence of any neurological
DCI or ischemic brain lesions on cerebral MRI [58]. The number of major neurological DCI events per 10,000 dives
was 0 in the no-PFO group, 0.5 in the PFO-closure group, and 35.8 in the PFO nonclosure group (P ¼ .045). The num-
ber of ischemic brain lesions on MRI per 10,000 dives was 16 in the no-PFO group, 6 in the PFO-closure group, and
104 in the PFO nonclosure group (P ¼ .039). This study also concluded that in a person who continues diving, PFO
closure helps prevent symptomatic and asymptomatic neurological events. Table 13.1 provides a synopsis of studies
regarding PFO closure in patients with DCI.
It should be noted that despite PFO closure, arterial gas embolism is theoretically still possible from mechanisms
such as barotrauma and intrapulmonary arteriovenous shunts. A repeat bubble contrast echocardiogram to demon-
strate that the shunt has been eliminated should be performed after the PFO closure procedure, befo re unrestricted
diving is resumed [53].
Summary
It has been well established that having a PFO, particularly a high-grade shunt PFO, increases the risk of devel-
oping serious phenotypes of DCI in divers. Since the absolute incidence of DCI is very low, routine PFO screening for
all divers is not recommended. However, screening for PFO should be considered in divers on a case-by-case basis
and if present, consideration should be given to PFO closure if cessation of diving or conservative diving cannot be
achieved.
CARCINOID HEART DISEASE AND PFO
Carcinoid Tumors
Carcinoid tumors are rare malignancies that arise from extrapancreatic neuroendocrine cells. These cells contain
neurosecretory granules composed of a variety of hormones and biogenic amines. Serotonin, the best characterized
of those substances, is derived from the amino acid tryptophan and its precursor is 5-hydroxytryptophan. In
VI. OTHER CONDITIONS AND PFO
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TABLE 13.1 Characteristics of Studies Regarding PFO Closure in Patients With Decompression Illness.
Study Objective Sample Size (N) Description and Results Complications
Henzel et al., 2018 [55] Long-term follow-up after PFO
closure for secondary prevention
of DCI in a single center
N ¼ 11 Median follow-up: 91 months No major
complications
All divers returned to unrestricted, deep
diving with no recurrent episodes of DCI
Pearman et al., 2015 [57] Retrospective audit of safety and
efficacy of transcatheter PFO closure
for prevention of DCI
N ¼ 104 Mean shunt diameter: 6.95 mm Major complications
(atrial fibrillation/
flutter and stroke) in
3/104 divers
2 divers required second procedure because
of residual shunt; 81/95 divers in whom
follow-up bubble contrast echocardiogram
was available returned to unrestricted diving
Honek et al., 2014 [56] Case-control study evaluating the effect of
transcatheter PFO closure on occurrence of
arterial bubbles after simulated dives
N ¼ 47 18-m dive
Arterial bubbles in 32%
in nonclosure group
versus 0% in closure
group (P ¼ .02)
50-m dive
Arterial bubbles in
88% in nonclosure group
versus 0% in closure
group (P < .01)
No major
complications
Billinger et al., 2011 [58] Prospective nonrandomized trial testing
the effect of PFO closure on neurological
events in divers
N ¼ 83
Divers with a history
of major DCI
- 28 no PFO
- 30 PFO without closure
- 25 PFO with closure
Median follow-up: 5.3 years
Major DCI events per 10,000 dives: 0 in the
no-PFO arm, 0.5 in closure arm, and 35.8 in the
nonclosure arm (P ¼ .045). Ischemic brain lesions per
10,000 dives: 16 in the no-PFO arm, 6 in the closure
arm, and 104 in the nonclosure arm (P ¼ .039)
No major
complications
DCI, decompression illness; PFO, patent foramen ovale.
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addition, other substances may be contained in the granules, such as prostaglandins, dopamine, histamine, and
kallikrein [59]. About 60% of carcinoid tumors develop in the gastrointestinal tract, particularly in the small intes-
tine, rectum, stomach, colon, and liver; 25% develop in the lungs, and the remaining 15% in other organs or are of
unknown origin [60].
Carcinoid Syndrome and Carcinoid Heart Disease
The serotonin released by gastrointestinal tumors is primarily inactivated by the hepatic enzyme monoamine ox-
idase and subsequently metabolized to 5-hydroxyindolacetic acid that is secreted in urine. However, in the presence
of hormonally active hepatic metastases, serotonin and other vasoactive molecules bypass the degradation capacity
of the liver and reach the systemic circulation, leading to the carcinoid syndrome and its manifestations: broncho-
spasm, tachycardia, hypotension, secretory diarrhea, ileus, skin flushing, and valvular heart disease, which is known
as carcinoid heart disease [61e63]. Fig. 13.3 illustrates the pathophysiology of carcinoid syndrome and carcinoid
heart disease [62].
5-HIAA
5-HIAA
5-HT
5-HT
5-HT
Bronchopulmonary
carcinoid
tumor
Hepatic metastasis
Aldehyde/
dehydrogenase
Aldehyde/
dehydrogenase
MAO
MAO
Right-sided Carcinoid Heart Disease
Left-sided Carcinoid Heart Disease
•More common as vasoactive
substances are inactivated by the lung
•Involves myofibroblast infiltration
and activation of valvular interstitial
cells leading to fibrosis
caused by
•Bronchopulmonary Carcinoid
•Right-to-left intracardiac shunt
Biochemical Pathway for the synthesis and
Degradation of Serotonin (5-Hydroxytryptamine)
Tryptophan
5-Hydroxytryptophan
5-Hydroxytryptamine
5-Hydroxyindole Acetaldehyde
5-Hydroxyindole Acetic Acid
5-Hydroxylase
Decarboxylase
Monoamine oxidase
Aldehyde dehydrogenase
Visual Art © 2017
The University of Texas
MD Anderson Cancer Center
•High burden of disease
FIGURE 13.3 Systemic circulation of 5-hydroxytryptamine (5-HT) leading to carcinoid heart disease and biochemical pathway for the syn-
thesis and degradation of serotonin. 5-HIAA, 5-hydroxyindole acetic acid, MAO, monoamine oxidase. Reproduced from Ref. [62].
VI. OTHER CONDITIONS AND PFO
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Carcinoid heart disease affects 20%e50% of patients with carcinoid syndrome and is characterized by plaquelike
fibrous deposits and carcinoid plaques that involve the tricuspid valve, pulmonary valve, right-sided cardiac cham-
bers, pulmonary artery, vena cava, and coronary sinus. Right-sided carcinoid heart disease is more common than
left-sided carcinoid heart disease. The prevailing theory is that the left side is protected by the inactivation of humor-
al substances as the venous blood passes through the lung vasculature. Left-sided carcinoid heart disease is seen in
only 4%e10% of cases and has been associated with intracardiac shunting, such as a PFO, which allows venou s
blood to bypass the lungs. It has also been associated with bronchial carcinoid tumors and extensive liver metastasis
that produce a large amount of vasoactive substances [62,64,65].
PFO in Carcinoid Syndrome and Carcinoid Heart Disease
It is well known that a PFO is prevalent in about 25% of adults [66]. However, the prevalence of PFO appears to be
higher in patients with carcinoid syndrome compared to the general population. A case-control study of 54 patients
with carcinoid syndrome and an equal number of healthy controls showed that 41% of patients with the carcinoid
syndrome had a PFO, while only 22% of the control group was found to have a PFO. The prevalence of PFO was even
higher (59%) in patients who had already developed carcinoid heart disease [67]. These findings are consistent with
a prospective study from the United Kingdom, which demonstrated that 47% (14/30) of patients with carcinoid
heart disease had a PFO [68]. A possible explanation of the observed increased prevalence is that tricuspid or pul-
monary valve involvement in right-sided carcinoid heart disease leads to progressive dilatation of right-sided cham-
bers, which increases right ventricular pressure and exacerbation of PFO-mediated RLS. Therefore, the presence of a
PFO has been proposed as an indicator that carcinoid heart disease could progress [69].
Bhattacharyya et al. investigated the imaging features of carcinoid heart disease in 252 patients with carcinoid
syndrome. Of 52 patients who had evidence of carcinoid heart disease, only 15 had left-sided valvular disease,
but 13 of these 15 had a PFO, while the 2 remaining patients had multiple bronchial carcinoid metastases [64].
Another study of 132 carcinoid syndrome patients reported that 74 had carcinoid heart disease and only 5 had
left-sided involvement. Three out of the five had a PFO-mediated right-to-left shunt, 1 had bronchial metastasis,
and 1 was found to have markedly increased urinary 5-hydroxyindolacetic acid [65]. Although the above-
mentioned observational studies demonstrate an ostensible relation between PFO and left-sided cardiac disease
in carcinoid syndrome patients, there are a few case reports of patients with left-sided involvement without PFO
[70e73], 2 of which provide no alternative explanation, such as bronchial tumor or extremely elevated serotonin
levels [72,73]. On the other hand, there are cases where a PFO is present without aortic or mitral disease [74e82].
A plausible explanation is that either left-sided disease needs more time to develop or that some structures are
more susceptible than others. Other possible reasons could be that the development of left-sided carcinoid heart dis-
ease depends on PFO features, such as the shunt size or that PFO is not causally associated with left-sided carcinoid
heart disease, but rather an innocent bystander. The latter theory has been supported by Bhattacharyya et al., who
conducted a case-control study to evaluate the association between platelet 5-hydroxytryptophan and plasma 5-
hydroxytryptophan and valvular dysfunction, showing that there was no difference in their levels between the right
and left side of the heart irrespective of the presence of PFO [83].
PFO and Cyanosis in Patients with Carcinoid Syndrome
Several case reports describe cyanosis in patients with carcinoid syndrome and PFO. All patients were found to
have severe hypoxemia [80e82,84]. The cyanosis was believed to be due to the hypoxemia itself (partial pressure of
oxygen 43e45 mm Hg) predominantly from the right-to-left shunt, and not a manifestation of acral cyanosis from
arteriolar vasoactive substances.
PFO Closure in Patients with Carcinoid Heart Disease
Mansencal et al. performed transcatheter PFO closure in 3 patients with New York Heart Association (NYHA)
heart failure class III or IV symptoms and a large right-to-left shunt. An Amplatzer Septal Occluder was used. At
postoperative day 1, all 3 patients had minimal right-to-left shunt, while at the 6-month follow-up, 2 patients
continued to have minimal shunts and the third one developed a significant shunt associated with severe tricuspid
regurgitation. Progression of right-sided carcinoid heart disease was observed in 1 patient (33%), while no progres-
sion of left-sided carcinoid heart disease was observed. All 3 patients had clinical improvement of 1 NYHA class
VI. OTHER CONDITIONS AND PFO
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and improved mean oxygen saturation (85%e92%, P ¼ .04) [67]. Transcatheter PFO closure with an Amplatzer
Septal Occluder has been used also in several patients with carcinoid heart disease who had hypoxemia secondary
to the right-to-left shunt through the PFO, with subsequent resolution of hypoxemia [79,85e87].
Summary
The prevalence of PFO appears to be higher in patients with carcinoid syndrome and carcinoid heart disease as
compared to the general population. Most patients with left-sided carcinoid heart disease have a PFO, which may
indicate a causal relationship. The re is limited evidence showing that transcatheter PFO closure may improve symp-
toms in patients with carcinoid heart disease and advanced New York Heart Association class and it may decrease
the risk of developing left-sided cardiac lesions.
CORONARY SPASM AND PFO
Coronary Vasospasm
Coronary vasospasm was first described by Dr. Myron Prinzmetal in 1959 as a variant of classic angina pectoris
not brought on by increased myocardial demand [88]. Although the syndrome of myocardial ischemia resulting
from coronary vasospasm is well established, the mechanism behind vasospastic angina remains poorly understood.
The pathogenesis is multifactorial and ultimately determined by characteristics of the vessel and its physiological
milieu [89]. One proposed factor is the presence of a PFO which may expose the arterial circulation to vasoactive
substances to which it otherwise would not be subjected.
PFO and Vasoactive Substances
The role of the lungs goes beyond mere gas exchange. The pulmonary vascular bed is lined with metabolically
active endothelium responsible for the inactivation of vasoactive amines, such as serotonin, norepinephrine, and
phenylethylamine [90]. The presence of a PFO may permit the passage of these substances from the right side of
the circulation to the left, protecting them from degradation by pulmonary monoamin e oxidases. This phenomenon
can become clinically significant in the presence of a carcinoid tumor secreting vasoactive substances like serotonin,
histamine, bradykinin, and others. Serotonin in its active form can cause vasospasm by binding to
5-hydroxytryptamine-1 and 5-hydroxytryptamine-2 receptors [91] . The net effect of serotonin on coronary vessels
may depend on the state of the endothelium and the degree of atherosclerosis [91].
PFO and Coronary Vasospasm in Carcinoid Syndrome
In a case report by Bourgault et al., a 60-year-old male patient with stable coronary artery dise ase and a PFO
developed vasospastic angina attributed to serotonin secreted by a carcinoid tumor. The patient presented with chest
pain at rest and was admitted out of concern for unstable angina. Electrocardiograms (ECGs) during the episodes
showed ST-segment elevations in the inferior leads and a junctional rhythm. Coronary angiography was performed,
revealing stenosis in the left anterior descending artery and a diagonal branch. The right coronary artery was free of
obstructive lesions. The lesions in the left anterior descending artery were stented, but despite intervention, the pa-
tient continued to have chest pain and corresponding ST-segment elevations in the inferior leads. The angiogram
was again reviewed and was suspicious for vasospasm of the right coronary artery. When the initial echocardiogram
was performed, the sonographer noted suspicious hepatic lesions and blood-work revealed an elevated
5-hydroxyindoleacetic acid level, a urinary metabolite of serotonin. Liver biopsy confirmed the diagnosis of carci-
noid tumor and the patient was started on octreotide therapy and high-dose calcium channel blockers with complete
resolution of anginal symptoms. Weeks after discharge, an echocardiogram was repeated for complaints of progres-
sive dyspnea, showing severe tricuspid and pulmonic valve fibrosis and regurgitation that was consistent with a
diagnosis of carcinoid heart disease, with a significant right-to-left shu nt across a PFO. The authors hypothesized
that high serotonin levels secreted by hepati c metastasis of a carcinoid tumor combined with a significant right-
to-left shunt through a PFO, in a patient with atherosclerotic vessels, was the cause of this patient’s coronary vaso-
spasm [92].
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Several other cases of carcinoid disease and coronary vasospasm have been described in the literature. In a case
published by Topol et al. a patient with primarily right-sided carcinoid heart disease developed ST-segment eleva-
tions, arrhythmias, and cardiac arrest due to coronary vasospasm [93]. In other cases, patients developed chest pain
and ST-segment elevations during flushing episodes with evidence of vasospasm on coronary angiography [94e97].
It is not wel l understood how vasoactive substances reached the coronary circulation unmetabolized. Occult PFOs
are very common in the general population and they may be especially common in patients with carcinoid syn-
drome and carcinoid heart disease. One study found that the prevalence of PFO in patients with carcinoid syndrome
was 41%, and 59% in patients with carcinoid heart disease, a significant difference compared to 21% in controls
(P ¼ .03 and P ¼ .009, respectively) [67].
PFO and Coronary Vasospasm Status Post Sclerotherapy
Other associations between PFO and coronary vasospasm have been implicated in cases of foam sclerotherapy, a
procedure to treat venous incompetence, where a sclerosing agent is injected to occlude the lumen. The procedure
has been associated with neurological complications (stroke, transient ischemic attacks, amaurosis fugax, migraines)
that are thought to be from paradoxical emboli of the sclerosing agent. Another pathogenic hypothesis for intrapro-
cedural complications is high production of endothelin-1, a potent vasoconstrictor, following injection of the scle-
rosing agent, causing retinal and cerebral vasospasm [95]. A case of coronary vasospasm following foam
sclerotherapy has been published which described a 61-year-old female who unde rwent the treatment and devel-
oped chest discomfort, ECG changes, and elevated serum troponin levels. Her coronary angiogram was normal
and her bubble study was positive for a PFO, later confirmed on transesophageal echocardiogram [96]. An alterna-
tive hypothesis is that the sclerosing agent crosses the PFO and embolizes directly to the coronary or cerebral arteries
to cause myocardial or cerebral infarction.
PFO and Coronary Vasospasm without History of Carcinoid or Sclerotherapy
Dao and Tobis described the case of a 49-year-old female with a long history of migraines whose initial presen-
tation included intermittent chest pain over several years. One episode occurred in an emergency room, and ven-
tricular tachycardia was documented with subsequent cardiac arrest requiring defibrillation. Coronary
catheterization showed diffuse narrowing in a diagonal branch and in the distal left anterior descending artery
without evidence of an obstructing thrombus. Coronary artery spasm was suspected since initially there was signif-
icant narrowing of the vessel without atherosclerosis on intravascular ultrasound (IVUS) imaging, and the stenoses
were no longer present on the second heart catheterization. Her history of migraine with aura led the clinicians to
pursue a TEE with bubble study, which revealed a PFO. She was treated with percutaneous PFO closure. Her chest
pain resolved and the migraines disappeared. Although coronary vasospasm cannot be proven in this case, the
angiogram performed during PFO closure, which utilized IVUS showed no angiographic stenosis and no luminal
dissection or plaque, which makes the diagnosis of coronary vasospasm more likely. Similar to Bourgault, the au-
thors hypothesized that right-to-left shunting of vasoactive substances triggered multiple episodes of coronary vaso-
spasm and migraine with aura in this patient [98].
Summary
In summary, the data on PFO and coronary vasospasm are limited. However, the theory whereby a PFO acts as a
pathway for substrates causing coronary vasospasm, for which carcinoid syn drome and foam sclerotherapy act as a
model, is pathophysiologically plausible. Additional studies are needed to investigate whether a PFO plays a role in
otherwise unexplained vasospastic angina, and to assess the efficacy of device intervention as a treatment option. In
the context of carcinoid syndrome and foam sclerotherapy, it may be reasonable to screen for a PFO to prevent car-
diac morbidity and mortality.
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VI. OTHER CONDITIONS AND PFO
13. LESS RECOGNIZED CONDITIONS ASSOCIATED WITH PFO166
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