Journal of Cardiovascular Development and Disease Review Patent Foramen Ovale—A Not So Innocuous Septal Atrial Defect in Adults Veronica Romano 1, Carlo Maria Gallinoro 1, Rosita Mottola 1, Alessandro Serio 1, Franca Di Meglio 1, Clotilde Castaldo 1, Felice Sirico 1,* and Daria Nurzynska 2,* 1 Department of Public Health, University of Naples “Federico II”, 80131 Naples, Italy; [email protected] (V.R.); [email protected] (C.M.G.); [email protected] (R.M.); [email protected] (A.S.); [email protected] (F.D.M.); [email protected] (C.C.) 2 Department of Medicine, Surgery and Dentistry “ScuolaMedicaSalernitana”, University of Salerno, 84081 Baronissi, Italy * Correspondence: [email protected] (F.S.); [email protected] (D.N.) Abstract: Patent foramen ovale (PFO) is a common congenital atrial septal defect with an incidence of 15–35% in the adult population. The development of the interatrial septum is a process that begins in the fourth gestational week and is completed only after birth. During intrauterine life, the foramen ovale allows the passage of highly oxygenated blood from the right to the left atrium and into the systemic arteries, thus bypassing the pulmonary circulation. In 75% of the general population, the foramen ovale closes after birth, and only an oval depression, called fossa ovalis, remains on the right side of the interatrial septum. Patent foramen ovale can be associated with various clinically important conditions, including migraine and stroke, or decompression illness in divers. The aim Citation: Romano, V.; Gallinoro, of this review is to summarize the PFO developmental and anatomical features and to discuss the C.M.; Mottola, R.; Serio, A.; Di clinical risks associated with this atrial septal defect in adults. Meglio, F.; Castaldo, C.; Sirico, F.; Nurzynska, D. Patent Foramen Keywords: foramen ovale; patent foramen ovale; atrial septal defect; diving; decompression illness Ovale—A Not So Innocuous Septal Atrial Defect in Adults. J. Cardiovasc. Dev. Dis. 2021, 8, 60. https://doi.org/ 10.3390/jcdd8060060 1. Introduction Academic Editor: Maurice Van den Patent foramen ovale (PFO) is a common defect of the interatrial septum, with an Hoff incidence of 15–35% in the adult population [1]. During intrauterine life, the existence of the foramen ovale allows the placental oxygen-rich blood entering the right atrium Received: 16 April 2021 to be shunted into the fetal arterial systemic circulation. During fetal life, the lungs are Accepted: 22 May 2021 collapsed and filled with amniotic fluid, the pressure in the pulmonary circulation is low, Published: 25 May 2021 and the amount of blood required is low [2]. The placental oxygenated blood reaches the right atrium through the inferior vena cava, where it mixes with a small amount of poorly Publisher’s Note: MDPI stays neutral oxygenated blood coming from the venae cavae, and is introduced through the foramen with regard to jurisdictional claims in ovale into the left atrium and then ventricle, thus bypassing the pulmonary circulation [3]. published maps and institutional affil- Once the oxygenated blood has reached the left ventricle, it will preferentially be directed iations. into the coronary arteries and the carotids, while only a small amount will be directed into the descending aorta, thus favoring a greater development of the heart, brain, and head than the rest of the body. When pressures in the systemic and pulmonary circulation increase after birth, the Copyright: © 2021 by the authors. greater pressure in the left atrium allows the closure of the foramen ovale by coalescence of Licensee MDPI, Basel, Switzerland. the septum primum and septum secundum, producing a depression called fossa ovalis on This article is an open access article the right atrial surface [1,3]. In 15–35% of the population, it does not occur and the foramen distributed under the terms and ovale persists. In most cases, the PFO is completely asymptomatic. In some subjects, conditions of the Creative Commons however, it can be associated with stroke due to paradoxical embolization [1,4–9], migraine Attribution (CC BY) license (https:// with aura [10], decompression sickness [11,12], or hypoxemic medical conditions, such as, creativecommons.org/licenses/by/ sleep apnea, chronic obstructive pulmonary disease, and pulmonary hypertension [13,14]. 4.0/). J. Cardiovasc. Dev. Dis. 2021, 8, 60. https://doi.org/10.3390/jcdd8060060 https://www.mdpi.com/journal/jcdd J. Cardiovasc. Dev. Dis. 2021, 8, 60 2 of 10 2. Development of Interatrial Septum and Foramen Ovale The heart begins to develop from the splanchnic mesoderm of the first heart field, which gives origin to two heart tubes that merge to form a single primitive heart tube. It is composed of a layer of myocardium and a layer of acellular matrix, called cardiac jelly, lined by endocardium. In the early stages of development, the primitive heart tube is attached to the pharyngeal mesoderm by a dorsal mesocardium. The pharyngeal mesoderm, indeed, will give origin to the second wave of cardiac progenitor cells (second heart field), which contribute to the elongation of the heart tube at its poles and the formation of the right ventricle wall [15]. During the fourth gestational week, as the heart tube begins to loop, most of the dorsal mesocardium will disappear, leaving a dorsal mesenchymal protrusion at the cardiac venous pole [16]. With the onset of ballooning, leading to the partitioning of the atrioventricular canal, the cardiac jelly protrudes at the ventricular outflow tract and at the atrioventricular junction. The atrioventricularendocardial cushions, formed at the latter location as a result of epithelial–mesenchymal transition, contribute to the formation of the valves and membranous parts of the cardiac septa [17]. Directly prior to the partitioning of the primordial atrium, the heart detaches from the dorsal mesocardium, and the cardiac jelly of the atria begins to retract so that the endocardium adheres to the myocardium, except at a small ridge of mesenchyme that crosses the atrial roof from the ventral part of the atrioventricular cushions to the dor- sal mesenchymal protrusion [18]. This mesenchymal bridge, with a cap expressing the transcription factor Tbx3 at the leading edge, grows caudally towards the atrioventricular cushions to form the primary septum [19]. The gap between the atrioventricular cushions and the leading edge of the septum primum is the primary foramen (or foramen primum), which shrinks as the septum grows (Figure1A). Around the fifth gestational week, the mesenchymal cap arrives in contact with the atrioventricular cushions, and the growth of the septum primum terminates. At the same time, however, the cranial part of the septum primum develops one or several fenestrations, which coalesce to form the secondary foramen (or foramen secundum, Figure1B). This ensures right-to-left shunting of oxygenated blood that would have been otherwise impossible with the closure of the septum primum. During fetal life, this shunt to the left atrium is responsible for about 20–30% of the total cardiac output. During the sixth week, a folding of the right atrial roof begins between the primary septum and the ostium of the superior vena cava, which represents the first step of the development of the dorsocranial margin of the septum secundum, gradually overlapping the foramen secundum in the septum primum (Figure1B). During the last 20 weeks of gestation, fetal growth occurs very quickly; nonetheless, the foramen ovale, which now includes a gap between the primary septum and the secondary septum, remains proportional to the size of the right atrium (Figure1C) [ 20]. The upper part of the septum primum degenerates, while its lower part acts as a one-way flap, called valve of the foramen ovale (Figure1D). In fact, as can be seen by echocardiography, this flap closes the foramen ovale for about 20% of the cardiac cycle duration [21]. Occasionally, the foramen ovale closes during intrauterine life; this results in sig- nificant hypertrophy of the right atrium and ventricle, which can lead to arrhythmias, pleural effusion, right heart failure, ascites, and hydrops. Death usually occurs shortly after birth [20]. J. Cardiovasc. Dev. Dis. 2021, 8, 60 3 of 10 J. Cardiovasc. Dev. Dis. 2021, 8, x 3 of 10 FigureFigure 1. 1.Development Development ofof thethe interatrialinteratrial septumseptum and foramenforamen ovale at at the the end end of of the the fourth fourth week week (A(A),), during during the the sixth sixth week week (B (),B), and and at at the the beginning beginning of of the th seventhe seventh gestational gestational week week (C,D (C,D). Modified). Modified with permission [22]. with permission [22]. 3.3. 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Dis.2021 2021, ,8 8,, 60 x 4 ofof 1010 orificethe orifice of the of inferior the inferior vena cavavena [1cava]. It is[1]. surrounded It is surrounded by a raised by a muscularraised muscular rim, called rim, limbus called fossaelimbus ovalis, fossae and ovalis, its floor and isits formed floor is by formed the septum by the primum.septum primum.