platypnoea - orthodeoxia syndrome ( pos ) is an uncommon clinical condition , characterised by position - dependent dyspnoea and oxygen desaturation in an upright position which resolves by lying supine .
in addition to cardiac defects , pulmonary and abdominal defects have also been reported in association with pos ( tables  1 and 2 ) .
pos was first described in a patient with an atrial septal defect ( asd ) ; however , cardiac pos has subsequently been more often observed in patients with a patent foramen ovale ( pfo ) .
what seems essential for cardiac pos to exist are both an anatomical communication between the right and left atrium as well as a structural component that redirects shunt flow causing right - to - left shunting in the upright position .
usually this structural component is a deformation of the right atrium or of the inter - atrial septum .
pos is primarily characterised by normal right atrial and pulmonary artery pressures contrary to eisenmenger s syndrome .
the exact mechanism of position - dependent change in shunting , including the gravitational forces on the cardiac structures involved , remains elusive .
the final common pathway appears to be a position - dependent opening of the pfo with right - to - left shunting .
we present four cases of pos treated at the centre for congenital heart disease amsterdam leiden ( cahal ) , and discuss the pathophysiological mechanism of pos and its diagnostic and therapeutic pitfalls.table 1conditions associated with cardiac posgroup a : anatomic preferential blood flow across the inter - atrial communicationgroup b : transient reversal of left - to right pressure gradientcongenital abnormalitypulmonary  absent superior vena cava  chronic obstructive pulmonary disease  ascending aortic aneurysm  pneumonectomy  atrial septal aneurysm  pulmonary embolism  ebstein s anomaly  pulmonary hypertension  partial anomalous venous returncardiac  persistent left superior vena cava  constrictive pericarditis  prominent eustachian valve  pericardial adipose deposition  transposition of the great vessels  pericardial effusion  unroofed coronary sinuspost - surgical repair  aortic valve replacement  ascending aorta repair  atrial switch procedure  fontan proceduretumours  cardiac cyst / mass  lipomatous hypertrophy of the inter - atrial septumother  eosinophilic endomyocardial disease  hepatic cyst  tortuous ascending aorta  tricuspid regurgitation or stenosisdiseases associated with pos in case of inter - atrial communication .
conditions in group a cause pos through anatomical distortion of the right atrium ( e.g. congenital abnormality , post - surgical repair , cardiac or hepatic cyst ) or the atrial septum ( e.g. a thin , floppy septum primum in lipomatous hypertrophy of the inter - atrial septum ) , or by disposition of the right ventricle ( e.g. an inflamed , thick - walled ventricle due to eosinophilic endomyocardial disease ) leading to preferential flow through the inter - atrial septum . in group b the pulmonary and cardiac conditions cause pos in the presence of a right - to - left pressure gradient due to pulmonary vascular resistance and compression of the right ventricular inflow tract respectively . adapted from knapper et al .
2non - cardiac conditions associated with platypnoea - orthodeoxia syndromepulmonaryabdominalotheracute respiratory distress syndromeparalytic ileuschest wall traumachronic obstructive pulmonary diseasehepatopulmonary syndromediabetic autonomic neuropathycryptogenic fibrosing alveolitisalcoholic liver cirrhosisorganophosphate poisoningfat embolismautoimmune hepatititsparaoesophageal hernia repairhemidiaphragmatic dysfunctionhepatitis aparkinson s diseasepleural effusionnoncirrhotic portal hypertensionvertebral fracturespneumocystis and cmv pneumoniaschistosomiasiskyphoscoliosispneumonectomypulmonary arteriovenous malformationspulmonary embolismradiation - induced bronchial stenosistraumatic bronchial rupturenon - cardiac associations with pos include pulmonary conditions which cause pulmonary vascular shunting ( e.g. arteriovenous malformation ) , ventilation - perfusion mismatching ( e.g. pleural effusion , pneumonia , bronchial stenosis ) or an anatomic distortion of the right atrium or ventricle ( e.g. hemidiaphragmatic dysfunction ) .
hepatopulmonary syndrome causes pos through a high alveolar - arterial gradient ( e.g. in portal hypertension , hepatitis ) .
orthostatic hypotension as a symptom of autonomic dysfunction ( e.g. parkinson , diabetic autonomic neuropathy , organophosphate poisoning ) causes pos through an increase in orthostatic alveolar dead space and subsequent ventilation - perfusion mismatching .
conditions associated with cardiac pos diseases associated with pos in case of inter - atrial communication . conditions in group a cause pos through anatomical distortion of the right atrium ( e.g. congenital abnormality , post - surgical repair , cardiac or hepatic cyst ) or the atrial septum ( e.g. a thin , floppy septum primum in lipomatous hypertrophy of the inter - atrial septum ) , or by disposition of the right ventricle ( e.g. an inflamed , thick - walled ventricle due to eosinophilic endomyocardial disease ) leading to preferential flow through the inter - atrial septum . in group
b the pulmonary and cardiac conditions cause pos in the presence of a right - to - left pressure gradient due to pulmonary vascular resistance and compression of the right ventricular inflow tract respectively . adapted from knapper et al . .
non - cardiac conditions associated with platypnoea - orthodeoxia syndrome non - cardiac associations with pos include pulmonary conditions which cause pulmonary vascular shunting ( e.g. arteriovenous malformation ) , ventilation - perfusion mismatching ( e.g. pleural effusion , pneumonia , bronchial stenosis ) or an anatomic distortion of the right atrium or ventricle ( e.g. hemidiaphragmatic dysfunction ) .
hepatopulmonary syndrome causes pos through a high alveolar - arterial gradient ( e.g. in portal hypertension , hepatitis ) .
orthostatic hypotension as a symptom of autonomic dysfunction ( e.g. parkinson , diabetic autonomic neuropathy , organophosphate poisoning ) causes pos through an increase in orthostatic alveolar dead space and subsequent ventilation - perfusion mismatching .
a 46-year - old woman was referred to our hospital for percutaneous pfo closure , after having experienced symptoms of dyspnoea in the upright and left supine position for several months .
she had a history of chronic obstructive pulmonary disease gold ii and had undergone left pneumonectomy 6 months earlier , to remove an adenocystic carcinoma . in the weeks , thereafter , she developed progressive and position - dependent shortness of breath .
physical examination revealed a blood pressure of 100/65  mmhg with a resting heart rate of 122 beats / min .
she had central cyanosis , with a transcutaneous oxygen saturation of 91  % , while breathing 1.5  l oxygen as measured by pulse oximetry .
1a1 ) and computed tomography ( ct ) scan of the thorax showed a midline shift of the right lung with a consequent position of the heart to the left thoracic wall .
no evidence was found of cancer recurrence or other pulmonary causes such as pleural effusion or atelectasis .
1a2 ) and a right - to - left shunt fraction measured 20  % when breathing 100  % oxygen in an upright position .
at this point the patient was severely incapacitated ; she could only lie on her right side , which had resulted in severe muscular atrophy .
cardiac catheterisation was performed , which showed a normal right atrial and pulmonary artery pressure , and pulse oximetric saturations of 90  % and 83  % in right and left supine positions , respectively .
the pfo was successfully closed with a 25  mm amplatzer pfo occluder ( st .
jude , minneapolis , usa ) after which the arterial saturation improved immediately to 97  % in the upright position .
she was able to gradually resume her daily routine and her exercise capacity improved significantly .
no complications have been reported in 3 years of clinical follow - up . on her last transthoracic echocardiogram ( tte ) ,
the estimated systolic pulmonary artery pressure was 28  mmhg and no residual shunt was seen over the closed pfo.fig .
1different imaging modalities of case 1(a ) , 2 ( b ) , 3(c ) and 4 ( d ) , respectively , for the purpose of diagnosing pos by pfo .
a2 four chamber view of a doppler tee with a right - to - left shunt by pfo .
b1 cmr showing malposition of the right thoracic wall resulting in a heart shift to the right and presence of pfo ( arrow ) .
b2 short axis basal view of a bubble contrast tee showing no resting right - to - left shunting over the pfo .
c1 ct angiography showing the dilated ascending aorta ( a ) and aorta root ( b ) .
d2 cmr shows a right hemithorax filled with pleural effusion and a compressed right atrium ( arrow ) .
ra right atrium , la left atrium , rv right ventricle , lv left ventricle , r right , ao aorta , pa pulmonary artery , svc superior vena cava different imaging modalities of case 1(a ) , 2 ( b ) , 3(c ) and 4 ( d ) , respectively , for the purpose of diagnosing pos by pfo . a1 chest x - ray showing the heart position against the left thoracic wall .
a2 four chamber view of a doppler tee with a right - to - left shunt by pfo .
b1 cmr showing malposition of the right thoracic wall resulting in a heart shift to the right and presence of pfo ( arrow ) .
b2 short axis basal view of a bubble contrast tee showing no resting right - to - left shunting over the pfo .
c1 ct angiography showing the dilated ascending aorta ( a ) and aorta root ( b ) .
d2 cmr shows a right hemithorax filled with pleural effusion and a compressed right atrium ( arrow ) .
ra right atrium , la left atrium , rv right ventricle , lv left ventricle , r right , ao aorta , pa pulmonary artery , svc superior vena cava
a 36-year - old woman with a history of right mid and lower lobe resection due to a carcinoid in the right main bronchus 3 years earlier was referred to our hospital .
she complained of progressive pain and dyspnoea since her operation , which was most prominent during exercise and when lying in the right supine position . before the bilobectomy she had participated in competitive long distance running , but now the referring pulmonologist noted that she desaturated from 96 to 87  % with severe dyspnoea after performing only10 squats .
previously , a bronchoscopy revealed an open but narrow bronchus to the right upper lobe .
this narrowing worsened in the right supine position and was therefore thought to be the cause of her dyspnoea in the right supine position .
one year later , cardiac magnetic resonance ( cmr ) imaging and resting transoesophageal echocardiography ( tee ) showed a pfo without a right - to - left shunt as measured in normal supine position so no pos was suspected ( fig . 
none of the previous diagnostic tests could explain the coexistent position - dependent and exercise - induced dyspnoea .
a cardiopulmonary exercise test showed an early arterial partial co2 pressure ( paco2 ) increase during exercise .
also , an increase of end - tidal o2 pressure and decreased end - tidal co2 pressure were seen at an acute load of 150  w , with a desaturation from 96 to 93  % seen on pulse oximetry .
both her pulmonologist and cardiologist agreed that her symptoms had to be attributed to a mechanism involving her pfo .
firstly , the exercise - induced right - to - left shunt itself , and secondly , the consequently triggered ventilatory impairment related to the loss of alveolar tissue after pulmonary resection preventing adequate compensatory hyperventilation to normalise the paco2 .
subsequently , the pfo was closed successfully with a premere 25  mm device ( st . jude , minneapolis , usa ) .
she underwent extensive cardiac rehabilitation and on her latest outpatient visit , after 4 years of follow - up , no complications were found .
a 73-year - old woman presented to our emergency department with acute dyspnoea and a severe hypoxaemia with a saturation of 63  % measured by pulse oximetry in the upright position .
she had a history of frequent recurrent pulmonary embolism due to essential thrombocytosis ; however , a ct scan of the thorax excluded recurrent pulmonary embolism as a cause of dyspnoea this time . a tte was performed to exclude pulmonary hypertension .
surprisingly , the echocardiogram in the left supine position revealed a pfo and a mildly elevated systolic pulmonary artery pressure of 36  mmhg .
a subsequent tee confirmed the existence of pos ; pulse oximetric saturations dropped from 100  % and 82  % within 60  s when the patient changed from supine to upright position .
coincidentally , she was known with a stable aortic root and ascending aorta dilatation ( diameters of 42  mm and 49  mm respectively , fig . 
the pfo was successfully closed with an amplatzer 18  mm pfo occluder . due to a residual shunt on the procedural tee , an additional 6  mm asd septal occluder device
she had no residual shunt and she had physically recovered from her former incapacitated condition .
a 61-year - old male patient was referred to our hospital s congenital team for pfo closure due to pos .
he had a history of pulmonary adenocarcinoma and had undergone a right pneumonectomy 6 months earlier .
after the subsequent chemotherapy , he complained of progressive general deterioration and dyspnoea in the upright position . on presentation
physical examination showed saturations of 97  % versus 90  % in the supine and upright position , respectively , measured by pulse oximetry with 3  l oxygen .
analysis by contrast echocardiography revealed a right - to - left shunt due to a pfo with a measured shunt fraction of 26  % .
the chest x - ray showed a complete shift of the heart to the right ( fig . 
1d2 ) and no evidence was found for shunting in the supine position . during diagnostic heart catheterisation , systolic and diastolic pulmonary artery pressures were 33  mmhg and 16  mmhg , respectively , when lying supine , and 48  mmhg and 28  mmhg , respectively , in the upright position .
arterial blood gas during catheterisation provided oxygen saturations of 96  % and 85  % in supine and upright position . due to the patient s debilitated condition and severe hypoxaemia with 5  l oxygen ,
an urgent percutaneous pfo closure was performed with an 8  mm amplatzer septal occluder .
he recovered rapidly and was able to walk around the ward within 2 days with saturations of 97  % in both supine and upright positions , after having only been able to lie in a supine position for the previous 3 weeks of his hospital stay .
his follow - up after 4 months was uneventful with a near - normal exercise capacity .
we describe four cases with platypnoea - orthodeoxia syndrome caused by the combination of patent foramen ovale and a pulmonary condition with loss of pulmonary volume .
the mechanism by which pos develops in the absence of pulmonary hypertension is often unclear .
two explanations have been postulated to explain pos in the presence of an inter - atrial communication : ( 1 ) a position - dependent transient pressure gradient across the inter - atrial septum and ( 2 ) an anatomical preferential blood flow through the inter - atrial communication [ 46 ] .
case 1 , 2 and 4 had undergone pulmonary resection , in one patient this was left - sided and in two patients right - sided , after which they started developing dyspnoea . according to the first explanation , after pneumonectomy the right ventricular afterload increases and compliance decreases due to the reduced pulmonary vascular bed ( fig .  1a1 , b1 , d1 ) and the subsequent increase in pulmonary vascular resistance .
right ventricular afterload is also increased by post - pneumonectomy fluid overload in the operated hemithorax [ 7 , 8 ] .
these haemodynamic changes cause a right - to - left shunt due to a transient pressure gradient since right atrial pressure increases .
orthodeoxia might consequently develop due to an increase in the alveolar dead space known as  pulmonary zone i ( fig . 
2 ) , in which the pressure in alveoli exceeds the orthostatic decrease in pulmonary arteriolar pressures , causing an additional ventilation - perfusion mismatch . though not reported in our cases , a different cause of dyspnoea after lung surgery can be phrenic nerve injury , particularly after right - sided pneumonectomy [ 9 , 10 ] .
the elevated right hemidiaphragm causes right ventricular compression and subsequent outflow impairment , which in turn causes a transient pressure gradient resulting in the right - to - left shunt . in these particular cases , plication of the diaphragm is preferred over pfo closure to remove the underlying cause .
2a physiological model of the pulmonary vasculature in the upright position in a normal lung ( a ) versus a lung post - pneumonectomy ( b ) . due to gravitation , in the upright position blood flow in the apex of the lung
is physiologically prevented since alveolar pressure exceeds the pulmonary arteriolar pressure ( pulmonary zone i phenomenon ) .
a high pulmonary vascular resistance in the post - pneumonectomy situation causes an increase in right ventricular afterload .
when right ventricular output reduces in the upright position , this afterload can not be compensated .
consequently , pulmonary arteriolar pressure drops even more , causing a larger pulmonary zone i. i pulmonary zone i with restricted blood flow , ii zone ii with normal blood flow , iii zone iii with maximum blood flow ; palv alveolar pressure , part arteriolar pressure , pven venous pressurefig .
3schematic view of the haemodynamic mechanism explaining the position - dependent dyspnoea after pneumonectomy in case of an inter - atrial communication . through several pathways pneumonectomy
can result in dyspnoea by a position - dependent transient pressure gradient or an anatomical preferential flow across the inter - atrial septum . in
rv right ventricle , r right , l left a physiological model of the pulmonary vasculature in the upright position in a normal lung ( a ) versus a lung post - pneumonectomy ( b ) . due to gravitation , in the upright position blood flow in the apex of the lung
is physiologically prevented since alveolar pressure exceeds the pulmonary arteriolar pressure ( pulmonary zone i phenomenon ) .
a high pulmonary vascular resistance in the post - pneumonectomy situation causes an increase in right ventricular afterload .
when right ventricular output reduces in the upright position , this afterload can not be compensated . consequently , pulmonary arteriolar pressure drops even more , causing a larger pulmonary zone i. i pulmonary zone i with restricted blood flow , ii zone ii with normal blood flow , iii zone iii with maximum blood flow ; palv alveolar pressure , part arteriolar pressure , pven venous pressure schematic view of the haemodynamic mechanism explaining the position - dependent dyspnoea after pneumonectomy in case of an inter - atrial communication . through several pathways pneumonectomy
can result in dyspnoea by a position - dependent transient pressure gradient or an anatomical preferential flow across the inter - atrial septum . in
rv right ventricle , r right , l left the second explanation is the relocation of the atrial septum which facilitates preferential flow of caval venous blood into the opening of the atrial defect .
intrathoracic post - pneumonectomy changes also account for this positional change of the inter - atrial communication , along with the haemodynamic shift as described above .
a spontaneous mediastinal relocation to the opposite side , which occurs approximately 3 weeks to 7 months after pneumonectomy , predisposes to stretching and distortion of the atrial septum as the inferior caval vein remains in place . in the upright position additional
stretching occurs due to gravity , which enlarges the inter - atrial communication and causes right - to - left shunting despite normal right atrial pressures [ 3 , 4 ] . in a review of reported pos cases , marini et al
.   noted a significantly higher prevalence of pos in post - pneumonectomy patients who developed respiratory symptoms within 6    7 months compared with those with a symptomless interval of <  1 month .
case 1 , 2 and 4 indeed developed progressive dyspnoea within weeks to months after lung resection .
the gradual synergic effect of atrial septal stretching along with a possible transient pressure gradient could explain the late onset of pos as seen in most reported cases [ 1 , 6 , 12 ] .
case 3 demonstrates pos caused by a pfo in a patient with elevated pulmonary artery pressure secondary to chronic pulmonary embolism .
the haemodynamic mechanism involves elevated right atrial pressures due to relatively decreased right ventricular compliance , comparable with the post - pneumonectomy situation . furthermore , in accordance with the preferential transseptal flow mechanism , she had a dilated aortic root and ascending aorta which in the upright position can horizontalise the atrial septum increasing caval venous flow through the defect , as well as compressing the right atrium to make the pfo more mobile and permeable for shunting [ 1315 ] .
firstly , in all presented cases pos was diagnosed several months after the onset of symptoms and clinical presentation . beside the fact that clinicians are relatively unfamiliar with pos as compared with other causes of dyspnoea , its complicated underlying mechanism often requires different diagnostic imaging modalities which add to the delay in establishing a plausible diagnosis .
therefore clinicians must consider diagnosing pos when patients present with position - dependent dyspnoea , even before the common causes of dyspnoea have been excluded .
secondly , an immediate symptom relief is present as soon as the pfo is successfully closed , as confirmed in this case series .
clinical verification of the efficacy of pfo closure is indicated when symptom continuation implies a residual shunt . in conclusion ,
diagnosing pos remains a challenge since clinicians must recognise the heterogeneous presentation in severely dyspnoeic patients .
initial assessment of pos can be made by observing the platypnoea , pulse oximetry and positional echocardiography . in some cases ,
physicians should be reminded that a pfo , in combination with a pulmonary condition , can become symptomatic at older age as shown in this case series . in such cases
, the debilitating dyspnoea can be successfully relieved by closure of the inter - atrial communication .
 cardiac platypnoea - orthodeoxia syndrome ( pos ) is a position - dependent condition of dyspnoea and hypoxaemia due to right - to - left shunting . 
 it often remains unrecognised in clinical practice , possibly because of its complex underlying pathophysiology . 
 we present four consecutive patients with pos and patent foramen ovale ( pfo ) who underwent a successful percutaneous pfo closure , describe the mechanism of their pos and provide a review of the literature . 
Introduction
Case 1
Case 2
Case 3
Case 4
Discussion