Patent Foramen Ovale, Atrial Septal Defect, Left Atrial Appendage, and Ventricular Septal Defect Closure

Introduction

A potential causal relationship between patent foramen ovale (PFO) and stroke was first described by Cohnheim in 1877. In the last two decades several studies have investigated the role of PFO in cryptogenic ischemic stroke, migraine headaches, platypnea-orthodeoxia, and decompression sickness. Percutaneous PFO closure has emerged as a treatment option in the last decade, with significant controversy around its indications. Results of randomized trials of transcatheter PFO closure have only been recently reported.

Developmental Anatomy of the Atrial Septum ( Figure 32-1 )

During fetal life, there is a single atrial cavity. A septum primum (SP) develops from the cranial wall of the single atrium and grows toward the endocardial cushions, thereby dividing the single atrium into left- and right-sided chambers. The area between the SP and the endocardial cushions is known as ostium primum (OP). Fenestrations then develop in the middle of the septum primum and coalesce to form ostium secundum (OS). The OS allows right-to-left shunting of oxygenated blood. To the right of septum primum, another septum known as septum secundum (SS) then develops, and covers the OS and in most instances covers the OP as well. A flaplike valve known as PFO is formed between the two septae, which now allows oxygenated placental blood to cross over from right-to-left atrium during the remainder of intrauterine life. Spontaneous fusion of SP with SS occurs in about 75% of the individuals by 2 years of age, leading to closure of PFO. In the remaining individuals there is an oblique crescent-shaped defect resembling a tunnel, which is called PFO. The prevalence of probe-patent PFO is about 27% in necropsy studies with decreasing prevalence for each decade of life.

Clinical Presentation

Paradoxical embolism of a thrombus originating in pelvic or lower extremity veins has been implicated as a mechanism to explain association between PFO and ischemic stroke. The incidence of pelvic deep vein thrombosis (DVT) has been found to be significantly higher in patients with cryptogenic stroke and PFO compared with patients with stroke of determined origin. Some PFOs have a long overlap between the SP and SS referred to as the tunnel. There are several reports of thrombus visualized “in transit” through PFO on transthoracic (TTE) as well as transesophageal echocardiography (TEE). This has also led to speculation that stagnated blood in the tunnel may lead to thrombus formation, which may subsequently embolize in the systemic circulation—an explanation often referred to as the “lurking clot theory.” Studies have shown an association between the presence of atrial septal aneurysm (ASA) and risk of stroke.

Platypnea-orthodeoxia is a rare clinical syndrome characterized by dyspnea and oxygen desaturation in the upright position that is relieved by lying down or recumbence. In the absence of elevated right-sided pressures, or lung disease, this can occur due to an anatomical abnormality that predisposes to right-to-left shunt from a PFO, such as a prominent eustachian valve that directs blood from the inferior vena cava (IVC) toward the interatrial septum, an aortic aneurysm, or an enlarged or elongated and horizontal aortic root that distorts the interatrial septum thereby predisposing to right-to-left shunting during upright position. TTE or TEE in the sitting position may be required to demonstrate flow across the septum by color or contrast if negative in supine position. Cardiac magnetic resonance imaging (MRI) or computed tomography (CT) may help demonstrate aortic abnormalities. Transcatheter PFO closure has been shown to be associated with marked improvement in symptoms.

Decompression sickness occurs when a diver ascends from a dive and nitrogen bubbles entering venous circulation, which usually get diffused in the lungs, enter the systemic circulation via a right-to-left shunting source such as PFO, and embolize to the brain leading to ischemic lesions. A recent prospective study of 104 scuba divers with history of major decompression sickness showed that transcatheter PFO closure appears to prevent symptomatic and asymptomatic (ischemic brain lesions on MRI) decompression sickness.

Migraine is a common disorder affecting about 10% of the adult population and is more common in women. In the last two decades, studies have shown an association between PFO and migraine, especially migraine with aura. Several retrospective observational studies have reported an improve­ment in migraine after PFO closure. In contrast, the only completed prospective randomized double blind trial (Migraine Intervention with STARFLEX Technology—MIST trial) in patients undergoing PFO closure primarily for migraine control failed to show any significant difference of PFO closure on the primary endpoint of migraine cessation, or secondary endpoints of improvement in migraine compared with a sham procedure. However, the MIST trial was found to have several limitations including unrealistic endpoint of migraine cessation, inadequacy of TTE in screening for PFO as indicated by absence of PFO during closure, and shorter duration of follow-up. This implies that there may be some patients who benefit from device closure who remain to be identified. Recently, a significant reduction in frequency and severity of migraine was demonstrated with PFO closure in patients with large PFO (based on TCD) and subclinical brain MRI lesions. These brain lesions may indicate silent thromboembolism and these patients may be high risk for future embolic events. Similarly, Rigatelli and colleagues recently showed that PFO closure resulted in significant reduction in migraine in patients with high-risk PFO characteristics such as curtain shunt pattern on TCD and TEE (implying larger degrees of shunting), right-to-left shunting during normal respiration, ASA, and presence of eustachian valve. Not all patients with migraine have a PFO and not all patients with PFO suffer from migraine. The onus is on future trials to identify patients who would benefit most from PFO closure based on high-risk PFO morphology, which is best assessed with TEE, and possibly also those with subclinical lesions on brain imaging.

Diagnosis

PFO can be detected using various echocardiographic techniques, including TTE, TEE, and transcranial Doppler (TCD). More recently, three-dimensional echocardiography (3DE), CT, and MRI have been used, although none as the primary diagnostic tool in routine practice. Agitated saline is commonly used for diagnosing right-to-left shunts. Although the definition of positive contrast study on TTE or TEE remains controversial, it is generally accepted that a right-to-left shunt is diagnosed if at least 3 micro-bubbles appear in the left atrium, either spontaneously or after provocative maneuvers such as cough or Valsalva, within 3 cycles of complete opacification of the right atrium ( Figure 32-2 ). A provocative maneuver increases right atrial filling, thus increasing the RA pressure and opening the foramen ovale. Valsalva maneuver can be calibrated (40 mm Hg strain measured by spirometry and sustained for 10 seconds). A good Valsalva maneuver is sometimes more difficult to obtain during TEE, especially if the patient is heavily sedated, as compared with TTE or TCD. Some studies have shown that sensitivity of detection of PFO was increased when a femoral vein was used for contrast injection instead of the antecubital vein. This is likely due to different inflow pattern into the RA after injection through the femoral vein. Contrast through the inferior vena cava is directed toward the interatrial septum, often potentiated by a eustachian valve ( Figure 32-2 ), whereas contrast through the superior vena cava is directed toward the tricuspid valve. Different morphological characteristics of PFO such as size, degree of shunting, and tunnel length should be taken into account when evaluating a patient with PFO and cryptogenic stroke ( Figure 32-2 ). TCD of the middle cerebral artery after injection of contrast can similarly be used to diagnose right-to-left shunting.

TEE has been shown to correlate very well with autopsy findings, with a sensitivity and specificity approaching 100% in the diagnosis of PFO. Due to its high sensitivity and greater image resolution of the interatrial septal area allowing detailed characterization of PFO morphology, TEE is the current gold standard to diagnose and characterize PFO ( Figure 32-2 ). The drawbacks of TEE are its semi-invasiveness and occasional inability to obtain a good Valsalva maneuver in sedated patients.

The 3DE using reconstruction techniques as well as real-time analysis have been used to evaluate a wide range of pathologies including patent foramen ovale. In a recent comparison, diagnostic accuracy of real-time 3D TTE was significantly higher than that of contrast TTE: sensitivity 83% versus 44% (p <0.001) and close to that of contrast TEE.

Small studies using contrast-enhanced MRI and cardiac CT ( Figure 32-2 ) showed good concordance with TEE in the diagnosis of PFO. However, larger studies have shown both modalities to be inferior compared with TEE in detecting PFO.

Management

Currently the best therapeutic modality for primary or secondary prevention of stroke in patients with PFO is debatable. There are data to suggest that PFO is more common in patients with cryptogenic stroke compared with those with a known cause of ischemic stroke. However, a PFO is fairly common in the “control” population without stroke (prevalence of about 25%), and there are many unknown causes of “cryptogenic stroke.” The available options include antiplatelet therapy, anticoagulant therapy with warfarin, transcatheter closure, and surgical closure. It is very likely that not all PFOs are “culprits” responsible for PTE, especially due to the high prevalence of PFO in the general population. Supporting this, a recent meta-analysis showed that one third of detected PFOs in patients with cryptogenic stroke are likely to be incidental and not benefit from closure, suggesting the importance of patient selection in therapeutic decision making.

Medical Therapy

At present, there is no consensus regarding antiplatelet versus anticoagulant therapy in patients with cryptogenic stroke and PFO, as reflected by the heterogeneity in the medical arms of the published randomized PFO closure trials. Data from the Warfarin-Aspirin Recurrent Stroke Study (WARSS) show that there was no difference between treatment with warfarin or aspirin in the prevention of recurrent ischemic stroke or death in a large cohort of patients with cryptogenic stroke. The Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), which is a substudy of WARSS with patients undergoing TEE examination, showed that there was a nonsignificant trend toward lower 2-year risk of stroke or death among warfarin-treated cryptogenic stroke patients with PFO compared with those receiving antiplatelet treatment (9.5% vs. 17.9%; hazard ratio [HR] 0.52; confidence interval [CI], 0.16-1.67). In the PFO-ASA study, consisting of over 580 patients with ischemic stroke of unknown origin, recurrent stroke occurred more commonly despite aspirin therapy in patients with PFO and ASA compared with those with PFO, or ASA alone (HR for combination of PFO and ASA, 4.17; 95% CI, 1.47-11.84), suggesting that preventive strategies in addition to aspirin may be needed for such patients with high-risk PFO anatomy. A recent meta-analysis of retrospective studies also suggests benefit of anticoagulation over antiplatelet therapy for prevention of recurrent neurologic events in patients with PFO and cryptogenic stroke.

Transcatheter Patent Foramen Ovale Closure

Retrospective studies and meta-analyses have shown potential benefit of PFO closure in patients with cryptogenic stroke. However, the completed prospective randomized trials failed to show such benefit as detailed below. This suggests that the real-world selection of high-risk patients where PFO-related PTE is the cause of stroke may potentially be a beneficial approach. Of course, results from retro­spective studies, meta-analyses and randomized trials, and their limitations must be discussed with patients. Pending further studies, informed individualized therapeutic decisions should be made depending on patient preferences and perceived risk of PFO and recurrent stroke.

Randomized Trials of Patent Foramen Ovale Closure for Cryptogenic Stroke

In the first randomized report of transcatheter PFO closure, the CLOSURE 1 (Evaluation of the STARFlex septal closure system in patients with stroke and/or transient ischemic attack due to presumed paradoxical embolism through a PFO) trial, 909 patients with cryptogenic stroke or TIA were randomized to medical therapy or transcatheter PFO closure using the STARFlex device. With a success rate of 89% for closure, there was no difference in the outcomes of recurrent stroke (2.9% vs. 3.1%; p = 0.79) or TIA (3.1% vs. 4.1%; p = 0.44) with closure compared with medical therapy. There were many limitations of the CLOSURE 1 trial. The majority of recurrent events in this study (20 of 23 patients in closure group and 22 of 29 patients in medical therapy group) were not related to PTE, and alternative explanations for recurrent neurologic events were observed, including atrial fibrillation, subcortical lacunar infarcts, aortic arch atheroma, complex migraine, vasculitis, etc. This increases the likelihood that the initial neurologic event may not have been related to PFO and PTE. Thus, patients in the CLOSURE 1 trial may not have been the ideal population to study PFO closure. Only a third of patients in this trial had high-risk features such as ASA, and only about a half had significant shunting. Closure of insignificant or incidental PFOs may have diluted the beneficial effects of PFO closure. Patients with hypercoagulable testing or DVT were excluded from this study, thus excluding patients in whom the mechanism of stroke was perhaps most likely to be related to PTE. Moreover, even though the CLOSURE trial is being viewed as a “negative” trial, it shows that PFO closure is an effective alternative to medical therapy in reducing stroke.

In RESPECT (Randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment) trial, 980 patients with cryptogenic stroke were randomized to medical therapy or transcatheter PFO closure. In the intention-to-treat cohort, recurrent stroke occurred in 9 patients in the closure group and 16 in the medical therapy group (HR with closure 0.49; 95% CI, 0.22-1.11; p = 0.08). In contrast, there was statistically significant reduction in the risk of recurrent stroke with PFO closure when analyses were performed in prespecified per-protocol cohort (HR 0.37; 95% CI, 0.14-0.96, p = 0.03), and as-treated cohort (HR 0.27; 95% CI, 0.10-0.75, p = 0.007). In addition, closure was found to provide greater benefit in patients with severe right-to-left shunt and in those with an atrial septal aneurysm. Strengths of the RESPECT trial over CLOSURE 1 trial include longer follow-up, more stringent inclusion criteria with exclusion of patients with TIA and lacunar infarcts, and use of Amplatzer PFO occlude device, which provides more effective closure rates with much less device-related complications such as thrombosis and atrial fibrillation. Limitations of the RESPECT trial include high drop-out rate (17% in medical therapy group and 9% in closure group) and nonadherence to protocol in some patients with important implications on outcomes (3 out of 9 patients with recurrent ischemic stroke in the closure group of the intention-to-treat population did not have a device at the time of recurrent stroke).

In the PC (Comparing Percutaneous closure of PFO using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism) trial, 414 patients were randomized to transcatheter PFO closure or medical therapy. Recurrent stroke occurred less frequently in the closure group compared with the medical therapy group; however, this was not statistically significant (0.5% vs. 2.4%; HR, 0.20; 95% CI, 0.02-1.72; p = 0.14). Closure also did not reduce recurrent TIAs compared with medical therapy alone (2.5% vs. 3.3%; HR, 0.71; 95% CI, 0.23-2.24; p = 0.56). Limitations of the PC trial include inclusion of TIA in the primary endpoint and difficulty recruiting patients with a long recruitment period.

Despite lack of benefit in reduction of recurrent neurologic events with PFO closure compared with medical therapy in randomized trials, there are signals pointing toward benefit with closure, particularly in a select group of patients at high risk, such as those with ASA and large shunting. Whenever possible, patients with cryptogenic neurologic events and PFO must be enrolled in ongoing randomized trials such as Patent Foramen Ovale Closure or Anticoagulation versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE, ClinicalTrials.gov number, NCT00562289), Device Closure versus Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale (DEFENSE-PFO, NCT01550588), and Gore Helex Septal Occluder/Gore Septal Occluder for Patent Foramen Ovale (PFO) Closure in Stroke Patients (REDUCE, NCT00738894).

Indications for Transcatheter Patent Foramen Ovale Closure

In the United States, transcatheter PFO closure is not Food and Drug Administration (FDA) approved. As discussed, this procedure is still controversial, given discordance in retrospective and randomized trial data. Off-label PFO closure has been performed in patients with cryptogenic stroke, other paradoxical embolic events presumed to be related to PFO, platypnea-orthodeoxia syndrome, decompression sickness, and migraine headaches. The author found no difference in the risk of stroke in patients with PFO and an implantable intracardiac device such as pacemaker or defibrillator compared with those without an intracardiac device. Another study found an increased risk of stroke/TIA in patients with implantable devices with PFO compared with those without PFO. The authors study was different from this study in that the patient population consisted of PFO patients only with the goal of studying whether device implantation had any impact on the outcome of stroke in patients with PFO. Additionally, the latter study included patients with prior stroke/TIA while the authors did not, as prior stroke itself is an important predictor of future stroke. The authors have also found no difference in stroke risk between patients with atrial fibrillation with and without PFO. As such, PFO closure cannot be recommended in patients with pacemakers, implantable defibrillators, or atrial fibrillation.

Devices

Transcatheter PFO closure has been performed off-label with devices that are used for transcatheter atrial septal defect (ASD) closure ( Figure 32-3 ). These include the Helex septal occlude (WL Gore, Flagstaff, Arizona), Amplatzer atrial septal occluder (ASO) (St. Jude Medical), Amplatzer multifenestrated, or cribriform ASO. In addition, Amplatzer PFO occluder, CardioSEAL, STARFlex, and Premere PFO closure system have also been used. Currently only the Amplatzer and Helex systems are used in the United States.

Procedural Details

Transcatheter PFO closure is performed in the cardiac catheterization laboratory under conscious sedation (we use midazolam and fentanyl) with fluoroscopic and ultrasound guidance (TEE, or now usually intracardiac echocardiography [ICE]) ( Figures 32-4 and 32-5 ) ( Videos 32-1 and 32-2 ). Aspirin 325 mg is usually administered before the procedure and Clopidogrel 600 mg loading dose at the end of the procedure. Femoral venous access is obtained in bilateral groins with an 8 Fr or 9 Fr sheath each (or both sheaths in the same vein), one of which is for ICE. We prefer a long 30-cm sheath for the ICE catheter to easily traverse the iliac vein into the inferior vena cava, particularly if inserted into the left vein. The ICE catheter is advanced into the right atrium and the interatrial septum adequately interrogated, and bubble study is performed through the contralateral femoral venous sheath. A Goodale-Lubin (GL) catheter is advanced with a 0.035-inch J-tipped guidewire into the SVC. The guidewire is removed and the GL catheter connected to the manifold. Right atrial angiography can then be performed if needed. The GL catheter is then directed toward the interatrial septum and the PFO crossed with or without the 0.035-inch J-tipped guidewire using ICE and fluoroscopic guidance. Once across the PFO, intravenous heparin is administered in order to achieve ACT >250 seconds. The catheter and guidewire are placed in the left superior pulmonary vein, taking care to ensure that the wire tip is not in the left atrial appendage to avoid perforation. The 0.035-inch J-tipped guidewire is exchanged for a 0.035-inch J-tipped Amplatz extra-stiff wire, again taking care to ensure that the tip is not in the appendage. PFO diameter is then measured with a sizing balloon, taking care to inflate the balloon gently to avoid tearing the interatrial septum ( Figures 32-4 and 32-5 ). The next steps depend on the device used.

For Helex device, the system is prepped and flushed as recommended by the manufacturer. A device to balloon-stretched diameter of at least 2 : 1 is recommended. A 9 Fr sheath is used without guidewire, or an 11 Fr sheath with guidewire. After initial prepping, the green delivery catheter is placed in the left atrium over the 0.035-inch extra-stiff guidewire. The guidewire is removed and the left atrial disk is deployed using the “push-pinch-pull” technique under fluoroscopic and ICE guidance to ensure positioning in the left atrium away from the roof and appendage. The entire system is then pulled against the left side of the interatrial septum. The right atrial disk is then deployed. Placement and positioning is confirmed with ICE, and left anterior oblique (LAO) projection on fluoroscopy, with the right and left atrial disks straddling the septum ( Figures 32-4 and 32-5 ). Once acceptable placement is confirmed, the mandrel is pulled, which moves the locking loop off the left atrial eyelet to around the right atrial eyelet. The device can be retrieved and redeployed at any point prior to lock release. It can also be retrieved from the body after lock release if the position is not favorable. Once correct positioning is confirmed, the device is released.

For Amplatzer devices, the initial steps are similar to the Helex device. The device is loaded on the delivery cable and prepped as per the manufacturer's instructions to ensure no air in the system. The device is then introduced from the loader into the delivery sheath, which is placed in the mid-left atrium, and carefully pushed under fluoroscopy to ensure absence of air bubbles. Once the device reaches the tip of the delivery sheath, the sheath is withdrawn gently, exposing the left atrial disk, under fluoroscopic and ICE guidance. After making sure there is adequate opening of the left atrial disk in the left atrium, the system is pulled against the left atrial side of the interatrial septum such that the left atrial disk abuts the septum. The sheath is then withdrawn, exposing the right atrial disk on the right atrial side under fluoroscopic and ICE guidance. Once the device position is confirmed with fluoroscopy and ICE, and felt to be stable and fully expanded without obstruction or impingement of nearby structures, the device is released. Bubble study or right atrial angiogram may be performed at the end of the procedure. Femoral venous sheaths are removed and hemostasis achieved by manual compression.

Postprocedure Care

It is our practice to administer two doses of antibiotics 12 hours apart. Patients are monitored with telemetry overnight, and chest x-ray and TTE with bubble study are performed the following morning to confirm accurate positioning. Aspirin 81 mg daily and Clopidogrel 75 mg daily for 6 months are prescribed. TTE with bubble study is repeated at 6 months. Endocarditis prophylaxis is advised for 6 months.

Complications

Transcatheter PFO closure is a safe procedure; however, complications can occur in 1% to 4% of patients with most complications being mild. The most frequent reported complication after PFO closure is the occurrence of atrial arrhythmias including atrial fibrillation and atrial flutter. In retrospective studies, new atrial fibrillation (AF) was observed in 3.9% of patients, while the rate of AF was very low in the RESPECT trial (0.2%). Device thrombosis occurs in 0.6% patients and device embolization can occur in 0.07% of patients. Device fracture was observed in older generation devices, but extremely rare in the current devices. Serious bleeding from vascular complications occurred in ≤0.5% in the RESPECT and PC trials. Pericardial effusion or tamponade has been reported in 0.3% of patients. Air embolism is a potentially disastrous complication that can occur due to inadequate flushing of the device systems or while introducing the device systems into the delivery sheath. This complication can be easily avoided by careful flushing and paying meticulous attention to fluoroscopy while advancing the device through the delivery sheath.

Introduction

ASD is the most common congenital heart defect presenting in adults after bicuspid aortic valve and accounts for 6% to 10% of all defects at birth. It affects twice as many females as males. Left-to-right shunting at the atrial level with right-sided volume overload and eventually pulmonary vascular disease and pulmonary hypertension are responsible for the clinical presentation. Since FDA approval of a device for transcatheter ASD closure in December 2001, there has been a shift from surgical closure to transcatheter closure with excellent results and good prognosis in treated patients.

Anatomy

The development of the interatrial septum has been discussed in the section on PFO ( Figure 32-1 ). There are 4 types of ASDs depending on location. The most common is secundum ASD (75% of all ASDs), which is a defect in the region of the fossa ovalis. The primum ASD (15% to 20%) is located in the inferior portion of the atrial septum near the crux of the heart and occurs due to deficiency of endocardial cushion tissue. It is often associated with a cleft in the anterior mitral valve leaflet or ventricular septal defect (common atrioventricular canal defects). The sinus venosus type of ASD (5% to 10%) is located in the superior or inferior part of the septum, near the entrance of the superior or inferior vena cava into the right atrium or SVC. The superior sinus venosus ASD is often associated with anomalous pulmonary venous drainage into the right atrium. Coronary sinus septal defect (<1%) is located in the wall separating the ostium of the coronary sinus from the left atrium. Only the secundum ASDs can be repaired by transcatheter closure; the other types require surgical closure. ASDs are associated with Down syndrome (particularly ostium primum ASD), Holt-Oram syndrome, and DiGeorge syndrome. In addition to the above, other associated lesions with ASD can include mitral valve prolapse and valvular pulmonic stenosis.

Pathophysiology

ASD leads to shunting at the atrial level. The magnitude and direction of shunting depends on defect size and the relative compliance of the ventricles. Usually the shunt is from left-to-right atrium due to higher compliance of the right ventricle. With increasing age, the left ventricular compliance decreases and left atrial pressure rises, and the magnitude of left-to-right shunt increases. This leads to volume overload and enlargement of the right atrium, right ventricle, and pulmonary artery. Over time, high pulmonary blood flow occurring for several years leads to pulmonary vascular bed remodeling, increase in pulmonary vascular resistance, and pulmonary hypertension. Left untreated, pulmonary vascular changes become irreversible, leading to severe pulmonary hypertension, right-sided pressure overload, and reversal of shunting leading to right-to-left shunting.

Clinical Presentation

During childhood, patients with ASD are usually asymptomatic and may have a pulmonary outflow murmur or fixed splitting of the second heart sound detected incidentally during routine examination. Some children may present with recurrent respiratory infections or even heart failure. Typically, most young adults have a prolonged asymptomatic course. With increasing age, symptoms of reduced exercise tolerance, progressive exertional dyspnea, and heart failure occur with progressive left-to-right shunting as a result of decreased left ventricular compliance and increased left atrial pressure. Arrhythmias including supraventricular arrhythmias, atrial fibrillation, or atrial flutter may be the presenting sign. Paradoxical embolism resulting in stroke or ischemia of other organ systems may also occur. Untreated ASDs can lead to pulmonary vascular disease and pulmonary hypertension in the absence of other causes, but typically not until adulthood.