A 36-year-old female non-smoker applied for $250,000 of life insurance two years after an isolated, 18-hour episode of dysarthria (slurred speech). She had been admitted to the hospital at that time for investigation. There was no previous medical history and, by the time she was seen in the emergency department, there were no abnormal physical signs. Cardiac rhythm was normal and blood pressure registered 126/84 mmHg. Her resting ECG was within normal limits.
She had a normal Computed Tomography (CT) brain scan, normal hematology and blood biochemistry. She was seen by a cardiologist who ordered a 24-hour Holter ECG, which showed normal sinus rhythm with rare, isolated supraventricular extrasystoles. She also underwent transesophageal echocardiography with intravenous contrast injection which demonstrated a patent foramen ovale (PFO).
Since her discharge from the hospital on anticoagulant treatment with apixaban, there has been no recurrence and she has a normal clinical examination.
What is PFO, and what are the mortality implications of transient ischemic attack (TIA) and PFO?
PFO is an atrial malformation that traces its beginnings to embryonic gestation. At around four weeks of pregnancy, the embryonic single atrium divides into right and left sides by the formation and fusion of two septa: the septum primum and septum secundum.
The septum primum grows from the top of the atrium down towards the endocardial cushion. The area between the leading edge of the septum primum and the endocardial cushion is known as the ostium primum, which closes when the septum primum fuses with the endocardial cushion.
A second orifice, the ostium secundum, develops at the top of the septum primum following the coalescence of multiple small perforations. The septum secundum then develops on the right atrial side of the septum primum. The septum secundum covers the ostium secundum but does not completely divide the atria. This persisting orifice within the septum secundum is the foramen ovale.
Fetal circulation of blood through the foramen ovale allows oxygenated blood from the umbilical cord to pass from the right atrium into the left atrium and, thereafter, into systemic circulation. Following birth, the changes in pressure within the atria lead to closure of the foramen ovale in most individuals. A PFO results from a failure to close, allowing a right atrial-to-left-atrial shunt because of the flap covering the foramen from the left side. There are no risk factors for the development of PFO, but familial cases have shown an autosomal dominant mode of transmission.
A functional opening of the foramen ovale is likely only in a situation in which resistance to flow in the right side of the heart is higher than in the systemic circuit, causing right atrial pressure to be higher than on the left.
Clinically, this pressure could occur in the cases of obstruction at the right ventricular level, pulmonary valvular or vascular level, which are usually associated with right ventricular and right atrial hypertension. A PFO with a large right-to-left shunt could cause cyanosis on crying, breath-holding or any activity which raises right atrial pressure. PFO can worsen hypoxemia in conditions such as valvular pulmonary stenosis, Ebstein’s anomaly, right ventricular myocardial infarction, chronic obstructive pulmonary diseases or pulmonary hypertension (primary or secondary). Severity depends on the size of the PFO, the pressure gradient between the right and left atria and the direction of inferior vena caval blood flow.
A potential hazard is an increased risk of nitrogen gas embolism across PFO in deep-sea divers. As only a small percentage of divers with PFO develop decompression sickness (“the bends”), the feasibility of screening them all is a controversial issue. However, PFO can worsen hypoxemia at great depths and may even lead to death in untrained divers.
Some causes of increased left atrial pressure (for example, mitral stenosis) can dilate the foramen ovale causing it to become patent and result in a left-to-right inter-atrial shunt, which is generally silent clinically.
The main clinical concerns of PFO are its association with neurological conditions. PFO is thought to predispose to hemostasis and clot formation, with reports of increased incidences of PFO in patients with thrombophilia.
Patients with headache (migraine with aura) were also found to have a high incidence of PFO, and migraine symptoms improved on medical treatment in the form of antiplatelet and anticoagulant drugs or disappeared on the closure of PFO.
More importantly, PFO is associated with neurological signs and symptoms such as hemiplegia, visual disturbances and slurred speech due to paradoxical embolism causing cryptogenic (i.e., in absence of any obvious cause) brain infarction. These emboli may originate from any thrombosis of systemic veins or from a clot within the right atrium.
High-risk PFOs are those associated with atrial septal aneurysm and spontaneous right-atrial-to-left-atrial passage of bubble on contrast echocardiogram in the absence of any provocative measures.
Echocardiography is the diagnostic investigation of choice, while Transesophageal Echo (TEE) is more sensitive than transthoracic echo in diagnosing PFO. Sometimes it is possible to visualize the gap in the atrial septum or demonstrate a septal aneurysm with septal perforation on the echocardiogram.
Intravenous injection of contrast/micro bubbles (agitated saline) is extremely helpful in the diagnosis, which manifests via the appearance of the contrast medium in the left atrium within three cardiac cycles of its appearance in the right atrium (Figure 2). The sensitivity of the TEE can be improved further by asking the patient to perform a Valsalva manoeuver during the injection, thereby increasing the right atrial pressure and exposing the right–to-left shunt.
Discovering an asymptomatic PFO during echocardiography performed for another indication is relatively common as studies show it to be present in approximately 25% of adults. In these cases, no treatment is usually prescribed. However, there is a case for treating patients with “high risk” PFO with antiplatelet drugs, but there are no formal recommendations.
The risk of neurologic insult is different after a stroke or transient ischemic attack with no other obvious cause. In this situation the prescription of antiplatelet drugs, traditional oral Vitamin K antagonists or one of the novel oral anticoagulants (anti-thrombin or anti-Xa) is justified. Recurrent cerebrovascular attacks despite optimal anticoagulation may require closure of the PFO which is usually performed by an endovascular approach with a Cardioseal umbrella or Amplatser device (Figure 3). Surgical direct suture or patch closure is rarely performed.
Returning to the Case
When there are no heart defects resulting in abnormal pressures, the PFO is usually asymptomatic and is associated with normal health and life expectancy. The chance finding of an asymptomatic PFO would therefore qualify as a standard risk.
When found in association with other congenital heart malformations, the rating of the latter would cover the risk associated with the PFO. Even when detected “incidentally” during echocardiography to investigate a cryptogenic ischemic cerebrovascular accident, there is no additional risk beyond that for the TIA or CVA.
This applicant would be insurable with a moderate substandard loading to cover the possible risk of recurrent cerebral ischemia and of bleeding due to the oral anticoagulant drug. A major medical issue here would be the duration of her anticoagulant therapy, which normally would be life-long.
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