1.Unclosed oval hole and paradoxical embolism
1.1 Paradoxical embolism
It is a thrombus in the venous system and right atrium that enters the left cardiac system from the right cardiac system through intracardiac traffic, causing ischemic stroke and embolism of the heart, kidney and peripheral system.In 1972, Meister et al. proposed that the diagnosis of paradoxical embolism should meet the following 4 points.
(1) Systemic or cerebral arterial embolism without a left-sided cardiac embolic source;
(2) The patient has venous thrombosis and/or pulmonary artery embolism;
(3) There is a right-to-left cardiac shunt;
(4) there is persistent right intracardiac pressure elevation (e.g., pulmonary hypertension) or transient right intracardiac pressure elevation Since the phenomenon that emboli originating from the venous system can enter the circulation via a right-to-left shunt from the atria to form a paradoxical embolism was first described, cerebral thrombosis, gas embolism or fat embolism and neurological decompression sickness occurring during diving have been clinically found to be associated with paradoxical embolism.
1.2 PFO and paradoxical embolism
Although PFOs were described centuries ago, no one thought that PFOs caused clinical consequences because the fractional flow of PFOs was thought to be too small to cause hemodynamic changes. With the advent of echocardiography, large clots can be seen in some cases attached to the foramen ovale and riding across the interatrial septum. These large clots usually enter the pulmonary circulation and produce emboli in the pulmonary circulation. It can be speculated that some small venous emboli may pass through the PFO from the right atrium to the left atrium and then enter the body circulation. If a small embolus enters the brain, it may cause some adverse consequences such as stroke. If the foramen ovale has been closed, small emboli of 1 to 3 mm in diameter will usually flow into the pulmonary circulation. Because the pulmonary vessels are relatively thick, small emboli usually do not have any clinical symptoms.
1.3 Influencing factors of paradoxical embolism
(1) Size of PFO.
The size of the PFO and the amount of right-to-left shunt in the atria are related to the occurrence of paradoxical embolism, and the larger the PFO and the more shunts, the higher the incidence of paradoxical embolism. A retrospective study found that a wide PFO (fissure >5 mm) complicated by severe shunts (left atrial contrast concentration >50%) was an ultrasound predictor of increased risk of paradoxical embolism.Serena et al. applied contrast transcranial Doppler ultrasound (TCD) to study 208 patients with transient ischemic attack (TIA) or acute stroke versus 100 healthy controls, after adjusting for concomitant vascular After adjusting for concomitant risk factors, a large right-to-left shunt (>25 microbubble signals in contrast TCD) was found to be a high risk factor for the development of stroke (especially unexplained stroke) (ORs 3.5 and 12.4, respectively).
Schuchlenz et al. reported that PFO aperture size was an independent risk factor for local ischemic events (especially recurrent stroke). a PFO diameter greater than 4 mm was associated with an increased risk of TIA and ischemic stroke. PFO with an orifice diameter greater than 4 mm was also found to be strongly associated with 2 or more strokes. This suggests that large notches may make it easy for thrombus to enter the body and cerebral circulatory systems.
(2) PFO complicated by atrial septal distension tumor.
PFO is a primary or secondary cardiac abnormality that occurs in the atrial septal fossa, which is a developmental defect of the fossa ovalis during embryonic life, and is a risk factor for cerebral infarction. According to echocardiographic findings, the incidence of atrial septal expansion tumors ranges from 2% to 4% in the normal population, and more than 70% of patients with atrial septal expansion tumors have a combined PFO. The incidence of atrial septal expansion tumors is much higher in stroke patients than in controls; the coexistence of PFO and atrial septal expansion tumors is more likely to result in paradoxical embolism and stroke or stroke recurrence, and more likely to result in embolism of the body circulation. deCastro et al. applied comparative TEE studied 187 patients with TIA or acute stroke and found that patients with PFO with right-to-left shunts at rest and highly mobile atrial septum were at high risk for the occurrence and recurrence of stroke.
2. Paradoxical embolism and unexplained stroke
The cause of ischemic stroke is unknown in 35% to 40% of cases. Some form of embolic mechanism is present in these cases despite the lack of an obvious source of emboli. Although direct detection of thrombus in patients with PFO is rare and there is no evidence of a causal relationship between PFO and paradoxical embolism, it is still hypothesized that unexplained strokes, especially in younger patients (<60 years), may be caused by paradoxical embolization of small venous emboli through the foramen ovale, except that this hypothesis cannot be directly confirmed with any medical imaging test.
2.1 Clinical evidence of PFO and unexplained stroke
Numerous observational clinical studies have found a higher incidence of PFO in patients with unexplained stroke. Some studies have shown a significant positive correlation between PFO and the risk of paradoxical embolism or stroke. The relative risk of thromboembolic events was four times higher in PFO compared with normal controls, and the risk of thromboembolic events was 33 times higher in PFO complicated by atrial septal tumors. Moreover, there is ample evidence that patients with PFO complicated by paradoxical embolism have an increased risk of cerebrovascular events.
These observations also suggest that the presence of a PFO is more important than parallel atheromatous plaques in elderly patients with embolic stroke. In other words, the presence of mild atheromatous plaque in the carotid and aortic arches in a 70-year-old stroke patient does not mean that the cause of stroke is atherosclerosis; stroke is more likely to be due to paradoxical embolism through the foramen ovale. It is hypothesized that the risk of venous thrombosis increases with age and that decreased right ventricular compliance causes an increase in right atrial pressure, thus increasing the risk of paradoxical embolism. Although this hypothesis needs to be further confirmed in randomized prospective pilot studies in elderly stroke as well as PFO patients, we can assume that elderly stroke patients need both atherosclerotic treatment and closure of abnormal channels for intracardiac paradoxical embolism.
3. Paradoxical embolism and neurological decompression sickness
Neurological decompression sickness is a sudden and rapid upward movement of a person under deep water, decompression is too fast, the gas dissolved in the body can not be expelled by the lungs and stored in the blood and tissues, causing vascular embolism, making the body multiple systems morbidity. Symptoms may be mild and include fatigue, weakness, presenile, arthralgia, lymphadenopathy and pruritus (type I decompression sickness). Patients with more severe decompression sickness (type II) may develop neurological and pulmonary symptoms. Neurological damage includes damage to the spinal cord (especially in the lower thoracic spinal cord) or the brain. Neurological symptoms may include sensory abnormalities, paraplegia, urinary and fecal incontinence, ataxia, memory deficits, speech and visual impairment, and personality changes. Pulmonary manifestations include dyspnea, wheezing, chest pain, and irritation of the pharynx. Death may occur in untreated patients.
There is an increased incidence of PFO in patients with neurological decompression sickness. Patients with PFO have a significantly increased risk of developing neurological decompression sickness compared to controls. One study showed that divers with PFO had a 4.5-fold increased risk of developing neurodecompressional disease compared to divers without PFO. The incidence of ischemic brain injury was twice as high in divers with PFOs as in divers without PFOs. Another study of sport diving showed that the presence of large-aperture PFOs even in asymptomatic patients was associated with multiple brain injuries. Transcatheter occlusion of PFOs may successfully prevent recurrent neurodecompression sickness in divers.
4. Recumbent breathing-erect hypoxemia
Reclined breathing-erect hypoxemia is a rare and little recognized disorder in which patients present with dyspnea and arterial hypoxemia in the upright position. This disorder is due to the right-to-left shunt through the interatrial traffic (usually the PFO) exacerbated by the upright position. This syndrome is most common in patients with a history of major lung disease, such as pneumonectomy, recurrent pulmonary embolism, or chronic lung disease. Pulmonary artery pressure is mostly normal. The pathogenesis is unclear. Transcatheter closure of interatrial traffic may improve the patient’s symptoms and increase oxygen saturation.
Patients with arterial hypoxemia associated with PFO may present with hypoxemia in the upright position only, while others may present with hypoxemia in both the supine and upright positions. Hypoxemia may be exacerbated when there is concomitant pulmonary hypertension and hypoxemia. Although some patients have improved arterial oxygenation and relief of symptoms after PFO occlusion, others remain symptomatic after the procedure, suggesting that the etiology of arterial hypoxemia may be primary to the lungs. In patients with pulmonary hypertension, PFO acts as a pop-up switching valve intermittently releasing pressure in the right atrium and preventing the onset of right heart failure. In these patients, it has been suggested that a blocking balloon be placed in the PFO first, and if the right atrial pressure is more than 5 mmHg higher than before, blocking is not appropriate.
5. Migraine
The specific mechanism of migraine caused by PFO is still unclear, but the possible pathogenesis is that the unclosed foramen ovale opens during deep breathing and coughing, and the tiny thrombus of the venous system enters the body circulation through the foramen ovale and causes cerebral embolism, or some neurohumoral substances metabolized and degraded by the pulmonary circulation enter the body circulation directly without degradation and cause migraine symptoms. The symptoms of migraine are caused by the direct entry of certain neurohumoral substances degraded by the pulmonary circulation without degradation.
Other clinical problems associated with PFO are fat embolism from orthopedic surgery and gas embolism from neurosurgery. Due to surgical injuries, fat and gas can enter the venous system and if the volume of fat and gas is not too large, they will be hidden in the lungs without causing any clinical consequences. However, if a PFO is present, the fat or gas emboli will embolize the brain, producing associated neurological sequelae.
6. Outlook
However, we must see that the causal relationship between PFO and paradoxical embolism has not been fully established because the diagnosis of paradoxical embolism is often speculative; there is a risk of recurrent stroke; preventive measures are difficult to determine; and there are no prospective, randomized experimental studies comparing the efficacy of various therapeutic measures for PFO complicated by paradoxical embolism. Further studies and validation are needed for the treatment of PFO-control of paradoxical embolism-stroke of unknown origin.