ARTICLE IN PRESS Journal of the American College of Cardiology Vol. 46, No. 9, 2005 © 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2005.08.038 EXPEDITED REVIEW State-of-the-Art Paper Patent Foramen Ovale: Current Pathology, Pathophysiology, and Clinical Status Hidehiko Hara, MD,* Renu Virmani, MD,† Elena Ladich, MD,† Shannon Mackey-Bojack, MD,‡ Jack Titus, MD,‡ Mark Reisman, MD,§ William Gray, MD,§ Masato Nakamura, MDʈ Michael Mooney, MD* Anil Poulose, MD* Robert S. Schwartz, MD* Minneapolis and St. Paul, Minnesota; Gaithersburg, Maryland; Seattle, Washington; and Tokyo, Japan Patent foramen ovale (PFO) is experiencing increased clinical interest as a congenital cardiac lesion persisting into adulthood. It is implicated in several serious clinical syndromes, including stroke, myocardial infarction, and systemic embolism. The PFO is now amenable to percutaneous interventional therapies, and multiple novel technologies are either available or under development for lesion closure. The PFO should be better understood to take advantage of emerging percutaneous treatment options. This paper reviews PFO anatomy, pathology, pathophysiology, and clinical impact and discusses current therapeutic options. (J Am Coll Cardiol 2005;46:1768–76) © 2005 by the American College of Cardiology Foundation Patent foramen ovale (PFO) is experiencing much clinical cushions are formed on the dorsal and ventral walls of the interest as a congenital cardiac lesion that persists into atrioventricular canal, approach each other, and fuse, divid- adulthood (1,2). It is a risk factor for several serious clinical ing the atrioventricular canal into right and left sides. The syndromes, including paradoxic systemic embolism, such as foramen primum results, allowing oxygenated blood flow ischemic stroke (3), myocardial infarction (4), decompres- from the right to the left atrium. As the septum primum sion sickness (DCS) in divers (5–7), and complications of grows toward the endocardial cushions, perforations de- pulmonary embolism (8). Recent evidence further impli- velop. These perforations form a large central window, cates PFO as a possible cause of migraine headache through through programmed cell death, before the septum primum mechanisms not yet understood. The PFO is now amenable and endocardial cushions fuse. to interventional percutaneous therapy (9), and multiple The window made as these perforations fuse is the novel technologies are either available or under development foramen secundum, which also supplies shunt blood flow for lesion closure. The PFO pathology, pathophysiology, from the right to the left atrium. On the right side of the and clinical impact should be better understood as multiple septum primum, another crescent-shaped membrane grows approaches to percutaneous closure become available for from the ventrocranial atrial wall: the septum secundum. It clinical application. This paper reviews current knowledge gradually grows and overlaps part of the foramen secundum, of this interesting lesion and summarizes future therapeutic forming an incomplete septal partition as an oval-shaped directions. window. It is this window that becomes the foramen ovale. The remaining septum primum forms a flap-like valve over PFO EMBRYOLOGY the foramen ovale, which typically closes by fusing with the growing septum secundum after birth. The foramen ovale is necessary for blood flow across the As oxygenated blood flow in utero from the inferior vena fetal atrial septum. Beginning at four weeks of pregnancy cava enters the right atrium, it crosses the patent foramen the primordial single atrium divides into right and left sides ovale and becomes the systemic circulation. Most blood by formation and fusion of two septa: the septum primum flow from the superior vena cava is routed through the and septum secundum (Fig. 1)(10). The septum primum is tricuspid valve and enters the right ventricle. At birth, right at first crescent-shaped, creating a large window connecting heart pressure and pulmonary vascular resistance drop as the left and right atrium. It grows from the primordial atrial pulmonary arterioles open in reaction to oxygen filling the roof toward the endocardial cushions, partially dividing the alveolus. Left atrial pressure may also rise as the amount of common atrium into right and left halves. The endocardial blood returning from the lungs increases. Either or both of these mechanisms may cause flap closure against the septum From the *Minneapolis Heart Institute and Foundation, Minneapolis, Minnesota; †CV Path, International Registry of Pathology, Gaithersburg, Maryland; ‡Jesse E. secundum. This fusion is complete by age two in about 75% Edwards Registry of Cardiovascular Disease, St. Paul, Minnesota; §Swedish Medical of individuals, but patency occurs in the other 25%. It is a Center, Seattle, Washington; and the ʈDivision of Cardiovascular Medicine, Toho residual, oblique, slit-shaped defect resembling a tunnel. University Ohashi Hospital, Tokyo, Japan. Manuscript received May 15, 2005; revised manuscript received June 16, 2005, The reasons PFOs fail to close are unknown, but they likely accepted August 1, 2005. relate to multifactorial inheritance (11). ARTICLE IN PRESS JACC Vol. 46, No. 9, 2005 Hara et al. 1769 November 1, 2005:1768–76 Patent Foramen Ovale Review Table 1. Patent Foramen Ovale Incidence Versus Age (12) Abbreviations and Acronyms 1–29 yrs 30% ASA ϭ atrial septal aneurysm 30–79 yrs 25% ASD ϭ atrial septal defect Ն80 yrs 20% DCS ϭ decompression sickness INR ϭ international normalized ratio MRI ϭ magnetic resonance imaging remain patent and smaller defects close. Greater PFO size PFO ϭ patent foramen ovale increases the risk of paradoxic embolism (13,14). Hetero- TCD ϭ transcranial Doppler geneity of size and morphology are pertinent to interven- ϭ TEE transesophageal echocardiography tional device closure selection (15). TIA ϭ transient ischemic attack TTE ϭ transthoracic echocardiography PFO ASSOCIATIONS: ATRIAL SEPTAL ANEURYSM AND CHIARI NETWORKS PFO ANATOMY Atrial septal aneurysm. The PFO is associated with sev- The autopsy-derived prevalence of probe-patent PFO is eral anatomic anomalies. A common association is atrial about 27%, with decreasing prevalence at each decade of life septal aneurysm (ASA), where part or all of the atrial (Table 1)(12). Patent foramen ovale slit width in the adult septum shows aneurysmal dilatation (16), protruding into ranges from 1 to 19 mm (mean 4.9 mm), derived from either atria (17). The ASA is defined as phasic septal postmortem formalin-fixed specimens. Figure 2 shows the excursion of at least 15 mm during the cardiorespiratory gross anatomy of the PFO. The PFO size increases with cycle (18). The prevalence of ASA is 1% in autopsy-based each decade of life. The mean diameter in the first decade is studies (19), a number differing from echocardiographic 3.4 mm and in the tenth decade is 5.8 mm, perhaps studies. One transthoracic echo study found an ASA in reflecting size-based selection over time where larger PFOs 0.22% of patients (18), and another reported a 1.9% Figure 1. Diagrammatic representation of patent foramen ovale development from embryology. Right sagittal and coronal views. Adapted from Konstantinides et al. (8). LA ϭ left atrium; RA ϭ right atrium. ARTICLE IN PRESS 1770 Hara et al. JACC Vol. 46, No. 9, 2005 Patent Foramen Ovale Review November 1, 2005:1768–76 Figure 2. Gross anatomy of the patent foramen ovale. (a) View from the right atrium showing a patent foramen ovale. Patency is determined by probing. The limbus (arrow) is seen forming a rounded cuff around the valve of the foramen ovale. The anatomic locations relative to the coronary sinus (CS) and tricuspid valve (S ϭ septal leaflet; A ϭ anterior leaflet) can be appreciated. (b) Same case viewed from the left atrium with probe demonstrating patency. The anterior leaflet of the mitral valve is seen below the probe. prevalence using a definition of more than 10 mm excursion valve is common but should be distinguished from Chiari (16). M-mode transesophageal echocardiography (TEE) or networks because it does not attach to the upper wall of the intracardiac echocardiography is essential for precisely mea- right atrium or atrial septum, although it may be mobile and suring septal excursion in ASA. fenestrated. The prevalence of the Chiari network is 2% to The prevalence of ASA is higher when examined by 3% in one autopsy study (25). A recent study using TEE TEE. One biplane TEE study reported ASA prevalence as with contrast suggested the clinical importance of Chiari 2.2% and another reported 4% (20,21). In echocardio- networks (26). In 1,436 consecutive adult patients, 29 had graphic studies of stroke patients, the prevalence is substan- confirmed Chiari networks (prevalence, 2%). This study tially increased. Atrial septal aneurysm was found in 7.9% of found a frequent association between Chiari networks and stroke patients by biplane TEE (20) and 15% by single- PFO, with 83% of patients affected by both. Large right- plane TEE (21). to-left shunting was found significantly more often in Patent foramen ovale was detected by TEE using contrast patients with Chiari networks than in controls (55% vs. or Doppler color in 70% of ASA patients (17), suggesting 12%, p Ͻ 0.001). This study also found Chiari networks that PFO detection is possible by intracardiac echocardiog- associated with ASA in 24% of patients. The Chiari raphy. Intracardiac echocardiography may be more comfort- network is more common in cryptogenic stroke patients able for the patient, and the Valsalva maneuver easier during than in patients evaluated for other indications (4.6% vs. this procedure. However, it is more invasive (with potential 0.5%), and it may facilitate paradoxic embolism. complications) and more costly, and systematic evidence- based recommendations have not yet been established (22). Moreover, TEE may have better resolution. PFO MICROANATOMY A study in adults showed that 33% of patients with ASA also had PFO, although 32% had isolated ASA Little has been published about PFO histopathology, a (23).