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A Mystery Featuring Right-to-Left Shunting Despite Normal Intracardiac Pressure* FREE TO VIEW

Mario Zanchetta, MD; Gianluca Rigatelli, MD; Siew Yen Ho, MD
Author and Funding Information

*From the Department of Cardiovascular Disease (Drs. Zanchetta and Rigatelli), Cittadella General Hospital, Padua, Italy; and the Department of Paediatrics (Dr. Ho), Imperial College School of Medicine, London, UK.

Correspondence to: Mario Zanchetta, MD, Dipartimento di Malattie Cardiovascolari, Ospedale Civile, Via Riva Ospedale, 35013, Cittadella, Padova, Italy; e-mail: emodinacit@ulss15.pd.it



Chest. 2005;128(2):998-1002. doi:10.1378/chest.128.2.998
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Published online

The cause of right-to-left atrial shunting despite normal intracardiac pressures and normal or near-normal pulmonary function through a patent foramen ovale has still not been completely clarified. It is probably responsible for several linked diseases, such as paradoxical embolism, platypnea-orthodeoxia syndrome, migraine with aura, transient global amnesia, and decompression sickness in sport divers. Despite modern diagnostic methods, the underlying anatomophysiologic and pathogenic mechanisms of right-to-left atrial shunting without abnormal intracardiac pressures remain a matter of debate and controversy. Holistically speaking, a return to a direct study of embryology, gross anatomy, and physiology may help us elucidate the real mechanism of this paradoxical shunting.

Figures in this Article

When you have eliminated the impossible, whatever remains, however improbable, must be the truth.

“Sherlock Holmes: The Sign of the Four,” Arthur Conan Doyle (1859–1930) in Lippincott’s Magazine, February 1890

The mechanism of right-to-left atrial shunting despite normal intracardiac pressures and normal or near-normal pulmonary function through a patent foramen ovale (PFO) has not still been completely clarified. In 1987, this puzzle was described as “water flowing up a hill,” and several possible hypotheses have been postulated to explain the mechanism of what causes water to flow uphill.1

First, despite the fact that the mean right atrial pressure is normally lower than the mean left atrial pressure, a physiologically transient spontaneous reversal of the left-to-right atrial pressure differential is present during early diastole and during isovolumetric contraction of the right ventricle of each cardiac cycle.2This reversal gradient may drastically increase under the substantial hemodynamic changes caused by physiologic maneuvers that increase the right atrial pressure, such as posture, inspiration, cough, or Valsalva maneuver, or under some pathologic conditions resulting in high pulmonary vascular resistances,3such as acute pulmonary embolism,4hypoxemia due to obstructive sleep apnea,5severe COPD,6right ventricular infarction,7and positive end-expiratory pressure during neurosurgical procedures performed in the sitting position,8 causing right-to-left shunting when they are coupled with a secondary PFO.

Second, another anatomophysiologic theory to explain the right-to-left shunting with both normal atrial and pulmonary vascular pressures involves the flow phenomenon (ie, a preferential blood flow streaming from the inferior vena cava toward the atrial septum as a part of the remnant prenatal circulatory pattern),9but there is still only a limited understanding of its potential significance in relation to right atrial anatomy and physiology. Third, in the same way, a physiologic change in the relationship of the compliance of right-sided and left-sided chambers,10which is probably exacerbated with age, with the right-sided chambers becoming stiffer than the left-sided chambers, has been advocated. Finally, an anatomic disarray of the inferior vena cava relative to the atrial septum due to mediastinal shift or counterclockwise heart rotation and/or distortion following an ascending aorta enlargement,11right pneumonectomy,12or pericardial effusion13 may result in a atypically horizontal reorientation of the plane of the atrial septum, which overlies the inlet of the inferior vena cava into the right atrium, facilitating part of the flow to stream directly into the left atrium via a PFO.

Despite modern diagnostic methods, the underlying anatomophysiologic and pathogenic mechanisms of right-to-left atrial shunting without abnormal intracardiac pressures remain a matter of debate and controversy. Holistically speaking, a return to a direct study of embryology, gross anatomy, and physiology may help us to elucidate the real mechanism of this paradoxical shunting.

Anatomically, the right atrium can be divided into the following two areas with different embryologic origins: the anterior area and the posterior area. The anterior area of the right atrium is constituted by the true primary atrium, and it has a rough wall (the so-called muscular component). Its three key features are the auricle, the pectinate muscles, and the crista terminalis. The posterior area is composed of the right horn of the sinus venosus, which is absorbed to form the smooth-walled sinus venarum (the so-called venous component, merging with the definitive right atrium), the atrial septum, and the cavotricuspid isthmus. Its reliable diagnostic markers are the superior and inferior vena cava inlets, the coronary sinus, and the sinus venosus-related structures such as the eustachian and thebesian valves (even though, occasionally the superior vena cava may return to the left atrium).

Muscular Component

The right atrial auricle, when viewed exteriorly, is quite a broad structure, triangular in shape, resembling a thumb or Snoopy’s nose, and in continuity with the anterior wall of the right chamber. From the endocardial aspect, the dominant feature is the tenia sagittalis, which corresponds to the exterior bridge of Snoopy’s nose; it is the remnant of the septum spurium, and it is the most prominent pectinate muscle arising from the crista terminalis directed forward and toward the left side, overlapping the root of the ascending aorta up to the left margin of the root of the pulmonary trunk.

Unlike the left atrium, the pectinate muscles extend not only into the right atrial auricle, but also on the anterolateral surface of the anterior wall, meaning that they are present in the whole area derived from the embryologic true atrium. They arise from the lateral part of the crista terminalis, extending in almost parallel fashion throughout the auricle (where they are particularly numerous within its tip) and spreading roughly perpendicular and forward to the superior ring of the right atrioventricular orifice.

On the endocardial surface, the crista terminalis marks the dividing zone between the posterior smooth venous and the anterior rough muscular walled components, and it is represented as the sulcus terminalis on the epicardial aspect of the heart. The crista terminalis is a horseshoe-shaped ridge of smooth myocardium, which extends laterally and inferiorly from the right side of the superior vena cava, arching anterior to its orifice, up to the inferior vena cava, turning beneath its orifice, and finally it branches into the cavotricuspid isthmus in continuity with the eustachian and thebesian valves.14

Venous Component

The major part of the right atrium is the venous component. This is an obliquely formed quadrangular area of smooth venous tissue connecting the great veins (ie, the superior and inferior caval veins) and the coronary sinus, bounded by the atrial septum and the crista terminalis.

The superior vena cava develops from two embryologic sources, the right anterior and the common cardinal veins, and opens into the upper part of the atrium with its orifice angled downward and forward. The inferior vena cava represents the development of the right vitelline vein and posterior cardinal veins, and opens into the lower and back part of the right atrium, with the direction of its orifices oriented upward and backward. The coronary sinus lies between the inferior vena cava and the atrioventricular orifice, and it is the remnant of the left sinus horn of the posterior cardinal vein incorporated into the left atrioventricular junction.

The eustachian and thebesian valves are derivatives of the right sinus venosus valve. They are semicircular in shape and guard the anterior-inferior aspect of the inferior vena cava and the inferior margin of the coronary sinus orifices, respectively. The fibrous or fibromuscular tissue inserted between the fossa ovalis and these two valves is the remnant of the junction of the left and right sinus horns with the developing right atrium, which persists as the so-called sinus septum.

The Atrial Septum

The true septal structure is only a small part of the right atrium, when the septum is defined as “that part which can be removed without exiting from the cavities of the heart.”15 It is constituted by the flap valve of the fossa ovalis, which represents the embryonic primary atrial septum and the anterior-inferior rim of the fossa ovalis. This ridge is additionally complicated because it has a core originating from the muscularization of the vestibular spine (ie, a mass of extracardiac mesenchymal tissue, the so-called dorsal mesocardium, penetrating the heart via the caudal hiatus in the myocardial wall of the right atrium in order to close the primary atrial foramen).

Consequently, it is a fundamental inaccuracy concerning the embryology and the anatomy of the heart to consider the three remaining rims as parts of the septal structure. First, the posterior-superior and the posterior-inferior rims, extending between the fossa ovalis and the inlet of the superior or inferior vena cava, are a deep infolding of the atrial wall filled with extracardiac adipose tissue, although it is traditionally described as the septum secundum. Second, the anterior-superior is nothing but the “cul-de-sac” of the transverse pericardial sinus separating the atrial wall from the root of the aorta.

Cavotricuspid Isthmus

The cavotricuspid isthmus is the area immediately anterior to the inferior vena cava and inferior both to the coronary sinus and the hinge of the tricuspid valve, derived from the expansion of the right atrioventricular junction subsequent to the definitive embryonic septation. It comprises the pouch-like recess and the tricuspid vestibule. In contrast to the shorter cavotricuspid isthmus formed by the only smooth vestibule, three morphologic zones are usually distinguishable in the longest cavotricuspid isthmus, as follows: the posterior fibrous zone; the middle trabeculated zone, which is made up of the extensions of the pectinate muscles; and the anterior smooth vestibular zone.1617 When the posterior and middle sectors are taken together, they form the pouch-like inferior recess.

After the aforementioned embryologic and anatomic issues, the definitive right atrium may be divided into the following two chambers: the anterior chamber and the posterior chamber. The anterior half of the right atrial chamber is composed of the venous component of the mouth of the superior vena cava orifice into the right atrium, the fibrous supraregion of sinus septum, the shorter smooth cavotricuspid isthmus zone, and the hinge of the tricuspid valve. The posterior half of the right atrial chamber is constituted by the venous component of the mouth of the inferior vena cava orifice, the atrial septum, and the longest cavotricuspid isthmus zone. In the anterior half of the right atrial chamber, the blood enters from the superior vena cava, flowing downward and forward through the tricuspid valve orifice, and the crista terminalis (arching anterior to the superior vena cava orifice) plays a fundamental role in deflecting the blood flow through the tricuspid valve. In the posterior half of the right atrial chamber, the blood enters from the inferior vena cava, flowing upward and backward through the flap valve of the fossa ovalis, and the eustachian valve (guarding the anterior-inferior aspect of the inferior vena cava) has a crucial role in deflecting the blood flow through the foramen ovale. In such a way, the blood flow enters into the right atrium during the ventricular systole downward in the anterior half and upward in the posterior half of the cavity from the superior and inferior caval veins, respectively. These blood flows course through each half of the chambers, and they do not collide with each other head on, turning forward in a clockwise concentric loop and contributing to the expanding right atrial chamber (Fig 1 ). The resulting dominant flow feature is a spiral rotation of the blood, with the stream from the inferior vena cava arching up, anteriorly and down toward the inlet of the tricuspid valve, in order to minimize the dissipative interactions among the entering, recirculating, and outflowing streams. In early ventricular diastole, further inflow of blood is again redirected forward and down the front of the right atrium and through the open tricuspid valve.18

As long as the flap valve is of a greater dimension than the floor of the fossa ovalis, there will be potential for right-to-left shunting if the two structures are not anatomically fused (ie, in the presence of PFO). The aforementioned hypothesis (including a physiologic, transient, spontaneous reversal left-to-right atrial pressure gradient, a preferential blood flow streaming from the inferior vena cava toward the atrial septum, a physiologic change in the relationship of the compliance of the right-sided and left-sided chambers, and an anatomic disarray of the inferior vena cava relative to the atrial septum) inspires a strong opinion that each of these hypotheses might be itself responsible for right-to-left shunting and linked diseases such as paradoxical embolism, platypnea-orthodeoxia syndrome,19migraine with aura,2022 transient global amnesia,23and decompression sickness in sport divers.24

However, the major issue regarding the right-to-left shunting despite normal intracardiac pressures is how the definitive right atrium repositions and remodels itself, after the right horn of the sinus venosus is incorporated into the right posterior wall of the developing atrium, giving rise to the sinus venarum. This extensive remodeling of the right atrium allows blood to stream from the superior and inferior caval veins through the respective anterior and posterior chambers without colliding with each other, thus redirecting the momentum toward the atrioventricular valve. This unique right atrial flow pattern may explain the right-to-left shunting through the PFO despite normal intracardiac pressures (“The Sign of the Four”) as the result of the separate stream from the inferior vena cava toward the fossa ovalis, forcing the formation of a non-anatomically fused flap valve. The other physiologic and anatomic causes (ie, physiologic transient spontaneous reversal gradient, changes of right chambers compliance, and anatomic disarray) may also interfere with the venous inflow in the adult human heart, but they only play a concomitant role. This basic but fundamental knowledge of embryology, anatomy, and physiology is capable of leading us to the unanswered question of “what causes water to flow uphill?” and to understanding the mystery of right-to-left atrial shunting despite normal intracardiac pressures.

Abbreviations: PFO = patent foramen ovale

Figure Jump LinkFigure 1. Anatomic and diagrammatic representation of the right atrium viewed on a frontal or coronal plane, showing the preferential streamline maps of the flow paths from the superior and inferior caval veins. CS = coronary sinus; CT = crista terminalis; FO = fossa ovalis; IVC = inferior vena cava; SVC = superior vena cava.Grahic Jump Location
Strunk, BL, Cheitlin, MD, Stulbarg, MS, et al (1987) Right-to-left shunting through a patent foramen ovale despite normal intracardiac pressures.Am J Cardiol60,413-415. [CrossRef] [PubMed]
 
Langholz, D, Louie, EK, Konstadt, SN, et al Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension.J Am Coll Cardiol1991;18,1112-1117. [CrossRef] [PubMed]
 
Nootens, MT, Berarducci, LA, Kaufmann, E, et al The prevalence and significance of a patent foramen ovale in pulmonary hypertension.Chest1993;104,1673-1675. [CrossRef] [PubMed]
 
Konstantinides, S, Geibel, A, Kasper, W, et al Patent foramen ovale is an important predictor of adverse outcome in patients with mayor pulmonary embolism.Circulation1998;97,1946-1951. [CrossRef] [PubMed]
 
Shanoudy, H, Soliman, A, Raggi, P, et al Prevalence of patent foramen ovale and its contribution to hypoxemia in patients with obstructive sleep apnea.Chest1998;113,91-96. [CrossRef] [PubMed]
 
Soliman, A, Shanoudy, H, Liu, J, et al Increased prevalence of patent foramen ovale in patient with severe chronic obstructive pulmonary disease.J Am Soc Echocardiogr1999;12,99-105. [CrossRef] [PubMed]
 
Rietveld, AP, Merrman, L, Essed, CE, et al Right-to-left shunt, with severe hypoxemia, at the atrial level in a patient with hemodynamically important right ventricular infarction.J Am Coll Cardiol1983;2,776-779. [CrossRef] [PubMed]
 
Giebler, R, Kollenberg, B, Pohlen, G, et al Effect of positive end-expiratory pressure on the incidence of venous air embolism and on the cardiovascular response to the sitting position during neurosurgery.Br J Anaesth1998;80,30-35. [CrossRef] [PubMed]
 
Gallaher, ME, Sperling, DR, Gwinn, JL, et al Functional drainage of the inferior vena cava into the left atrium-three cases.Am J Cardiol1963;12,561-566. [CrossRef] [PubMed]
 
Schoevaerdts, D, Gonzalez, M, Evrard, P, et al Patent foramen ovale: a cause of significant post-coronary and bypass grafting morbidity.Cardiovasc Surg2002;10,615-617. [CrossRef] [PubMed]
 
Laybourn, KA, Martin, ET, Cooper, RA, et al Platypnea and orthodeoxia: shunting associated with an aortic aneurysm.J Thorac Cardiovasc Surg1997;113,955-956. [CrossRef] [PubMed]
 
Smeenk, FW, Postmus, PE Interatrial right-to-left shunting developing after pulmonary resection in the absence of elevated right-sided pressure.Chest1993;103,528-531. [CrossRef] [PubMed]
 
Klepper, JI, Seifert, F, Lawson, WF, et al Intracardiac right-to-left shunting following cardiac surgery.Am Heart J1988;116,189-192. [CrossRef] [PubMed]
 
Sanchez-Quintana, D, Anderson, RH, Cabrera, JA, et al The terminal crest: morphological features relevant to electrophysiology.Heart2002;88,406-411. [CrossRef] [PubMed]
 
Anderson, RH, Brown, NA The anatomy of the heart revisited.Anat Rec1996;246,1-7. [CrossRef] [PubMed]
 
Cabrera, JA, Sanchez-Quintana, D, Ho, SY, et al Angiographic anatomy of the inferior right atrial isthmus in patients with and without history of common atrial flutter.Circulation1999;99,3017-3023. [CrossRef] [PubMed]
 
Ho, SY, Anderson, RH, Sanchez-Quintana, D Atrial structure and fibres: morphologic bases of atrial conduction.Cardiovasc Res2002;54,325-336. [CrossRef] [PubMed]
 
Kilner, PJ, Yang, GZ, Wilkes, AJ, et al Asymmetric redirection of flow through the heart.Nature2000;404,759-761. [CrossRef] [PubMed]
 
Robin, ED, McCauley, RF An analysis of platypnea-orthodeoxia syndrome including a “new” therapeutic approach.Chest1997;112,1449-1451. [CrossRef] [PubMed]
 
Del Sette, M, Angeli, S, Leandri, M, et al Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study.Cerebrovasc Dis1998;8,327-330. [CrossRef] [PubMed]
 
Anzola, GP, Magoni, M, Guindani, M, et al Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study.Neurology1999;52,1622-1625. [CrossRef] [PubMed]
 
Wilmshurst, P, Nightingale, S Relationship between migraine and cardiac and pulmonary right-to-left shunts.Clin Sci (Lond)2001;100,215-220. [CrossRef] [PubMed]
 
Klotzsch, C, Sliwka, U, Berlit, P, et al An increased frequency of patent foramen ovale in patients with transient global amnesia: analysis of 53 consecutive patients.Arch Neurol1996;53,504-508. [CrossRef] [PubMed]
 
Knauth, M, Ries, S, Pohimann, S, et al Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale.BMJ1997;314,701-705. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Anatomic and diagrammatic representation of the right atrium viewed on a frontal or coronal plane, showing the preferential streamline maps of the flow paths from the superior and inferior caval veins. CS = coronary sinus; CT = crista terminalis; FO = fossa ovalis; IVC = inferior vena cava; SVC = superior vena cava.Grahic Jump Location

Tables

References

Strunk, BL, Cheitlin, MD, Stulbarg, MS, et al (1987) Right-to-left shunting through a patent foramen ovale despite normal intracardiac pressures.Am J Cardiol60,413-415. [CrossRef] [PubMed]
 
Langholz, D, Louie, EK, Konstadt, SN, et al Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension.J Am Coll Cardiol1991;18,1112-1117. [CrossRef] [PubMed]
 
Nootens, MT, Berarducci, LA, Kaufmann, E, et al The prevalence and significance of a patent foramen ovale in pulmonary hypertension.Chest1993;104,1673-1675. [CrossRef] [PubMed]
 
Konstantinides, S, Geibel, A, Kasper, W, et al Patent foramen ovale is an important predictor of adverse outcome in patients with mayor pulmonary embolism.Circulation1998;97,1946-1951. [CrossRef] [PubMed]
 
Shanoudy, H, Soliman, A, Raggi, P, et al Prevalence of patent foramen ovale and its contribution to hypoxemia in patients with obstructive sleep apnea.Chest1998;113,91-96. [CrossRef] [PubMed]
 
Soliman, A, Shanoudy, H, Liu, J, et al Increased prevalence of patent foramen ovale in patient with severe chronic obstructive pulmonary disease.J Am Soc Echocardiogr1999;12,99-105. [CrossRef] [PubMed]
 
Rietveld, AP, Merrman, L, Essed, CE, et al Right-to-left shunt, with severe hypoxemia, at the atrial level in a patient with hemodynamically important right ventricular infarction.J Am Coll Cardiol1983;2,776-779. [CrossRef] [PubMed]
 
Giebler, R, Kollenberg, B, Pohlen, G, et al Effect of positive end-expiratory pressure on the incidence of venous air embolism and on the cardiovascular response to the sitting position during neurosurgery.Br J Anaesth1998;80,30-35. [CrossRef] [PubMed]
 
Gallaher, ME, Sperling, DR, Gwinn, JL, et al Functional drainage of the inferior vena cava into the left atrium-three cases.Am J Cardiol1963;12,561-566. [CrossRef] [PubMed]
 
Schoevaerdts, D, Gonzalez, M, Evrard, P, et al Patent foramen ovale: a cause of significant post-coronary and bypass grafting morbidity.Cardiovasc Surg2002;10,615-617. [CrossRef] [PubMed]
 
Laybourn, KA, Martin, ET, Cooper, RA, et al Platypnea and orthodeoxia: shunting associated with an aortic aneurysm.J Thorac Cardiovasc Surg1997;113,955-956. [CrossRef] [PubMed]
 
Smeenk, FW, Postmus, PE Interatrial right-to-left shunting developing after pulmonary resection in the absence of elevated right-sided pressure.Chest1993;103,528-531. [CrossRef] [PubMed]
 
Klepper, JI, Seifert, F, Lawson, WF, et al Intracardiac right-to-left shunting following cardiac surgery.Am Heart J1988;116,189-192. [CrossRef] [PubMed]
 
Sanchez-Quintana, D, Anderson, RH, Cabrera, JA, et al The terminal crest: morphological features relevant to electrophysiology.Heart2002;88,406-411. [CrossRef] [PubMed]
 
Anderson, RH, Brown, NA The anatomy of the heart revisited.Anat Rec1996;246,1-7. [CrossRef] [PubMed]
 
Cabrera, JA, Sanchez-Quintana, D, Ho, SY, et al Angiographic anatomy of the inferior right atrial isthmus in patients with and without history of common atrial flutter.Circulation1999;99,3017-3023. [CrossRef] [PubMed]
 
Ho, SY, Anderson, RH, Sanchez-Quintana, D Atrial structure and fibres: morphologic bases of atrial conduction.Cardiovasc Res2002;54,325-336. [CrossRef] [PubMed]
 
Kilner, PJ, Yang, GZ, Wilkes, AJ, et al Asymmetric redirection of flow through the heart.Nature2000;404,759-761. [CrossRef] [PubMed]
 
Robin, ED, McCauley, RF An analysis of platypnea-orthodeoxia syndrome including a “new” therapeutic approach.Chest1997;112,1449-1451. [CrossRef] [PubMed]
 
Del Sette, M, Angeli, S, Leandri, M, et al Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study.Cerebrovasc Dis1998;8,327-330. [CrossRef] [PubMed]
 
Anzola, GP, Magoni, M, Guindani, M, et al Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study.Neurology1999;52,1622-1625. [CrossRef] [PubMed]
 
Wilmshurst, P, Nightingale, S Relationship between migraine and cardiac and pulmonary right-to-left shunts.Clin Sci (Lond)2001;100,215-220. [CrossRef] [PubMed]
 
Klotzsch, C, Sliwka, U, Berlit, P, et al An increased frequency of patent foramen ovale in patients with transient global amnesia: analysis of 53 consecutive patients.Arch Neurol1996;53,504-508. [CrossRef] [PubMed]
 
Knauth, M, Ries, S, Pohimann, S, et al Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale.BMJ1997;314,701-705. [CrossRef] [PubMed]
 
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