Platypnea-Orthodeoxia Syndrome Caused by Patent Foramen Ovale with Right-To-Left Shunt

Background

Patent foramen ovale (PFO) is a vital part of fetal circulation that allows the oxygenated blood to bypass the nonfunctioning fetal lungs by passing through the inferior caval vein to the left side of fetal systemic arterial systems. Following birth, the expansion of the lungs leads to a sudden decrease in the pulmonary vascular pressure and right-sided heart pressure, which overturns the shunt through the PFO or atrial septal defect (ASD) from right to left to left to right, as the left-side of the heart has higher pressures. This effect presses the septum primum and septum secundum against each other, and complete fusion occurs in the next 2 years after birth in about 70% to 80% of the general population. PFO can be associated with other anatomical defects, including ASD, atrial septal aneurysm, and Chiari network with a lace-like structure, a remnant of the right valve of the sinus venosus and the septum spurium [1]. Here, we report an interesting case of a middle-aged man who presented with POS caused by a right-to-left shunt due to PFO, with review of the definition, pathogenesis, and management of PFO in the setting of POS.

Case Report

A 63-year-old man had underlying systemic lupus erythematosus and immune thrombocytopenia, for which he was on 6 monthly doses of intravenous rituximab. He also had positive IgG antiphospholipid antibodies. He was an amateur scuba diver with a previous history of loss of consciousness after a deep-sea dive, which was concerning for a transient ischemic attack (TIA). His other comorbidities included diabetes mellitus, dyslipidemia, well-controlled asthma, a non-functioning pituitary macroadenoma, and bilateral sensorineural deafness, for which he had cochlear implants.

The patient presented with documented fever, night sweats, and sore throat lasting for 10 days. Two months before, he had tested positive for SARS-CoV-2 after experiencing fever and cough, which had resolved. On admission, he was maintaining normal oxygen saturation on room air and was hemo-dynamically stable. The chest examination revealed bilateral fine crepitations at the bases. His cardiovascular examination revealed a normal regular pulse and normal heart sounds, with no additional sounds or audible murmurs.

Initial laboratory test results showed a white blood count of 2.8×109/L, absolute neutrophil count of 1.5×109/L, and lymphopenia. The C-reactive protein level was 31 mg/L, and there were mildly raised liver enzymes; however, the coagulation profile, albumin levels, and bilirubin levels were within the reference range. His kidney function tests were within the reference range. Electrocardiography showed normal sinus rhythm. His initial chest X-ray showed no abnormality; however, high-resolution computerized tomography showed bilateral ground-glass opacities, suggestive of post-COVID-19 sequelae and possible organizing pneumonia.

Of note, a PCR test for SARS-COV2 came back as still positive, with a significant cycle threshold value, suggesting the possibility of an active infection or re-infection in an immunocom-promised patient. Thus, the patient was treated with paxlovid and dexamethasone. Despite that, his oxygen requirements continued to worsen, and therefore a CT scan was repeated, showing improving bilateral infiltrates. However, there were ribbon-like filling defects in the pulmonary arteries, suggestive of a chronic thromboembolic process; therefore, he was started on low-molecular-weight heparin.

Despite that, the patient’s oxygen requirements were increasing. In addition, he was noted to have postural hypotension (setting 110/74 mmHg, standing 81/53 mmHg) and postural drop of oxygen saturations (recombinant SpO2 90%, standing 80%). He also had worsening dyspnea when sitting or standing up. Given the clinical picture that was suggestive of platypnea, a transthoracic echocardiography (TTE) with 8 mL of intravenous agitated saline at rest and with the Valsalva maneuver was performed, which showed evidence of an intracardiac shunt. Transesophageal echo-cardiography (TEE) showed PFO with a significant right-to-left shunt increase with the Valsalva maneuver (Figure 1).

The right heart study showed no evidence of pulmonary hypertension (mPA=12 mmHg). The right atrium pressure was 4 mmHg, and left atrium, 5 mmHg. Owing to the background of systemic lupus erythematosus and high risk of thrombosis, along with a previous history suggestive of TIA, he underwent successful closure of the PFO using a single Amplatzer 25-mm PFO device, with the device location assessed by TEE (Figure 2). After the procedure, the patient remained hemo-dynamically stable, and repeated electrocardiogram and TTE showed satisfactory results with no complications.

The patient’s oxygen requirements improved, and he was weaned off high-flow oxygen 7 days after the procedure. His platypnea resolved, and he was discharged home on a home oxygen concentrator.

Discussion

POS is defined as dyspnea on assuming an upright position that is improved by recumbency and is associated with hypoxemia when the position changes from supine to upright [2]. POS was first described in 1949 by Bruchell and Wood [3]. One of the most common associations over the years with POS has been the presence of PFO. In a study that analyzed the identification of PFO, 25% of autopsies of the general population showed an incidental PFO [4].

One of the most recognized complications of PFO is cryptogenic stroke. PFOs are associated with a 3.4% recurrence rate of stroke and TIA, and if combined with atrial septal aneurysms, the rate increases to 4.4%, according to a study done by the French Study Group on PFO and atrial septal aneurysms [5]. PFOs can be related to other conditions, including a weak association with migraine, type II decompression sickness, and to a lesser extent, postsurgical venous air embolisms [6].

Although the physiological mechanism of right-to-left shunting through the PFO and ASD is not fully understood, there have been some hypotheses. In the normal physiological state, the left ventricle has higher pressure than the right ventricle, thus left-to-right shunting is usually observed if there are any structural defects in the septum. Interestingly, in POS, the right-to-left shunting happens with no underlying raised right-sided pressures, which suggests other combined factors causing the blood to follow to the left side [7]. Several theories have been postulated regarding the possible mechanism, including the blood flow theory, which suggests an alteration of the blood flow from the superior and inferior cava in a way that becomes pointed toward the defects (PFO or ASD), so it causes right-to-left shunting due to the stream effect. This alteration happens either due to abnormalities with the stream from the vena cava, for example, prominent Eustachian valve, or repositioning of the PFO or ASD due to atrial septal aneurysm, intracardiac lipomas, cardiac surgeries, and occasionally aortic root dilatation or elongation and aneurysms [8]. Hsu et al suggested another rare possibility of tricuspid regurgitation that also causes blood flow toward the ASD or PFO, causing right-to-left shunting [9]. In our case, we found a prominent Eustachian valve evident on the TEE, which could have increased our patient’s risk of POS. The other hypothesis for the cardiac causes of POS is the hemodynamic hypothesis. Due to the greater left heart pressure in normal physiological states, asymptomatic PFOs can go unnoticed, as mostly left-to-right-sided shunts produce no symptoms. Symptoms often result from a reversal of the shunts in states in which there is an increase in the right-sided pressure. Hence, any change in the hemodynamics, such as an acute rise in the pulmonary vascular pressures due to pulmonary embolism or an ischemia-induced rise in the right-sided ventricle due to reduced compliance, can be associated with POS [10,11].

POS also has been linked to other non-cardiac causes, including pulmonary shunts and ventilation-perfusion mismatch disorders. One of the most common causes of intrapulmonary shunts is arteriovenous malformation [12]. Lung parenchymal diseases that result in dead space formation and physiological shunts were reported as a cause of POS [13], which in fact could have played an additional role in the pathogenesis of our patient’s POS. POS occurs in lung diseases predominantly affecting the bases of the lungs, with preservation of the apical parts by a process described as diffuse zone I phenomena. In a normal population, the apical part assumes zone I ventilation-perfusion. This means that due to the gravitational effect, this area is less perfused compared with the ventilation it receives, while the basal parts of the lungs assume the zone III ventilation-perfusion type, as it has better perfusion than zone I. Recumbency relatively eliminates the zone I pattern, converting the lungs zones to type III; thus, in diseased lung bases, standing leads to the conversion of the apical parts to zone I, while the bases are relatively nonfunctioning with a physiological shunt, leading to hypoxia, which is improved after laying down again, as the perfusion to the apical parts of the lungs improves [14]. Thamer and James reported a similar case of POS caused by PFO with a right-to-left shunt, aggravated by orthostatic alterations. They suggested an underlying aggravator factor such as lung disease that can provoke the right-to-left shunt, as their case reported reduced diffusion capacity in spirometry and lung interstitial fibrosis in lung biopsy, and no other coincidental structural abnormalities were detected [15]. Finally, a reduction in the pulmonary vascular resistance caused by liver diseases (hepatopulmonary syndrome) or autonomic neuropathy was also associated with POS in some previous reports [16,17].

PFOs with shunts can be evaluated, if suspected, to aid proper planning for the closure with TTE, TEE, and to a lesser extent transcranial Doppler [18]. The first investigation of choice is the contrast-enhanced TTE, given the limited diagnostic ability of Doppler in detecting intracardiac shunts (5%–10%). Detection of the microbubbles after injecting the agitated saline is the key to the diagnosis; however, distinguishing the intracardiac from intrapulmonary shunts is sometimes challenging. The presence of bubbles in the left atrium within the first 3 beats after the opacification of the right atrium is considered highly suggestive of an intracardiac shunt. The presence of the microbubbles after the third beat suggests an intrapulmonary shunt. The Valsalva maneuver can increase the intracardiac shunts, thus increasing the sensitivity of the detection of defects [19,20]. On the other hand, TEE is more sensitive and provides a better morphological description of the defects, which helps better plan the transcatheter closure. TEE can be also considered if there was a high index of suspicion despite negative TTE [21]. Recent reports have suggested the use of transcranial Doppler in the detection of PFOs. A Doppler detection of microbubbles in the middle cerebral artery 40 s after injecting agitated saline has been found sensitive in the detection of the shunts. The greatest drawback is the lack of a technique for differentiating between intracardiac and intrapulmonary shunts [22]. Another less-described, yet important method includes intra-cardiac echocardiography, which can provide excellent delineation of the defect during the closure process [23].

In a review regarding the management of PFOs, Cruz-González et al reported a 100% success rate of percutaneous closure and a low incidence rate of complications, with statistically significant improvement in the SpO2 percentages (82.6% vs 96.1%, P<0.001) [18]. The complications of the transcatheter device closure have 2 major classifications, one related to the technique and the other related to the device. Despite the rarity of the complications, it is crucial to be recognized. Technique-related complications preclude arrhythmia resulting from local manipulations, mostly supraventricular tachyarrhythmia, perforation, rapture, and venous puncture-related local complications. Device complications include device embolization and thrombosis [24]. A previous study found that the device thrombosis rate was 2.5% in the 4 weeks after closure, whereby atrial fibrillation and atrial septal aneurysms were the most common risk factors. Almost all cases of device thrombosis were successfully treated medically, with no complications of the thrombosis [25]. Given the excellent comparable results and lower frequency of complications, surgical closure of PFOs is rarely performed today [26].

Conclusions

PFO is a common heart defect. One of the rare, yet important complications of PFOs is POS. Contrast-enhanced TTE can effectively diagnose PFO as a cause of POS, and percutaneous closure has been shown to be an efficacious treatment option in alleviating symptoms. This case report highlights the necessity of actively exploring the possibility of PFOs with right-to-left shunts in patients exhibiting POS symptoms, while considering other potential etiologies.