Patent Foramen Ovale or Pulmonary Arteriovenous Malformation

University of Alberta Hospitals, Edmonton, AB, T6G2B7 Canada; e-mail: [email protected] DOI: 10.1378/chest.07-0563

References 1 Michelakis ED. Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications. Circ Res 2006; 98:172–175 2 Zhao YD, Courtman DW, Deng Y, et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005; 96:442– 450 3 Cowan KN, Heilbut A, Humpl T, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000; 6:698 –702 4 McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005; 115:1479 –1491 5 McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004; 95:830 – 840 6 Voelkel NF, Quaife RA, Leinwand LA, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006; 114:1883–1891 7 Zaffran S, Kelly RG, Meilhac SM, et al. Right ventricular myocardium derives from the anterior heart field. Circ Res 2004; 95:261–268 8 Tandri H, Daya SK, Nasir K, et al. Normal reference values for the adult right ventricle by magnetic resonance imaging. Am J Cardiol 2006; 98:1660 –1664 9 Dambrauskaite V, Delcroix M, Claus P, et al. The evaluation of pulmonary hypertension using right ventricular myocardial isovolumic relaxation time. J Am Soc Echocardiogr 2005; 18:1113–1120 10 Gan C, Holverda S, Marcus T, et al. Right ventricular diastolic dysfunction and acute effects of sildenafil in pulmonary hypertension patients. Chest 2007; 132:11–17 11 McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:78S–92S 12 Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105:2398 –2403 13 Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med 2005; 171: 1292–1297 14 Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 2006; 114:1482–1489 15 Nagendran J, Archer S, Gurtu V, et al. Phosphodiesterase Type 5 is highly expressed in the hypertrophied human right ventricle: direct implications for patients with pulmonary hypertension. Circulation 2006; 114s:ii-667 16 Hill JM, Dick AJ, Raman VK, et al. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 2003; 108:1009 –1014 17 Sosnovik DE, Schellenberger EA, Nahrendorf M, et al. Magnetic resonance imaging of cardiomyocyte apoptosis with www.chestjournal.org

a novel magneto-optical nanoparticle. Magn Reson Med 2005; 54:718 –724 18 Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353:1412–1413 19 Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908 –916

Patent Foramen Ovale or Pulmonary Arteriovenous Malformation An Appeal for Diagnostic Accuracy are life-threatening complications caused T here by abnormal venous-to-arterial communications. These may be intracardiac, such as seen in a ventricular septal defect, atrial septal defect, or patent foramen ovale (PFO). Pulmonary arteriovenous malformation (PAVM) is an extracardiac cause of an abnormal communication. Complications resulting from such abnormalities include cerebrovascular accidents, transient cerebral ischemic events, and cerebral abscesses. PAVM complications include the above complications plus hemoptysis and hemothorax. The article by Zukotynski et al1 in this issue of CHEST (see page 18) shows that there is a positive predictive value when saline solution contrast transthoracic echocardiography is used to determine the degree of severity of right-to-left shunting caused by PAVMs. Their results utilized CT as the standard. Positive results were scored for delay (number of cardiac cycles) before appearance of bubbles in the left atrium, and were graded for opacification of the left ventricular chamber according to a grading system of 1 thru 4 as proposed by Barzilai et al.2 Grade 1 was minimal left ventricular opacification, and grade 4 was extensive left ventricular opacification with endocardial definition. Conclusions showed that the degree of shunt grade was statistically related to the probability of PAVM. From a cardiology perspective, there is interest in this study because it may be difficult to differentiate an intracardiac right-to-left shunt as caused by a PFO from a PAVM. There is ample evidence in the literature that transthoracic echocardiography with saline solution contrast is as accurate as transesophageal echocardiography (TEE) with saline solution contrast to determine the presence of a right-to-left shunt.3 However, there is little evidence in the CHEST / 132 / 1 / JULY, 2007

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literature that transthoracic echocardiography is equivalent to TEE in determining the source of the right-to-left shunt. The accepted echocardiographic standard for differentiating a PFO from PAVM relies on a delay of three to eight cardiac cycles or 2 to 5 s of agitated saline bubbles to arrive in the left atrium after right atrial opacification. Earlier opacification would indicate an intracardiac shunt.4 In their study, the authors1 state that bubbles could have appearance in the left atrium as early as three cardiac cycles after right atrial opacification, especially in patients with grade 3 or 4 PAVM. They also noted bubbles appearing in the left atrium in less than three cardiac cycles in patients with a PFO, PAVMs, and false-positive findings. Although three cardiac cycles is the accepted cutoff point, this is where the situation becomes tenuous, and the authors correctly believe that the time of appearance of bubbles is often not a reliable indicator of shunt location. What is thought to be a PFO may be a PAVM; the reverse may be true; and both abnormalities may coexist. Indeed, it only requires one case report5 to illustrate the diagnostic value of TEE when transthoracic echocardiography with saline solution contrast falsely indicates the source of a shunt. Zukotynski et al1 relied on only one echocardiographer to evaluate contrast echoes. This is a weakness in the study and may be somewhat responsible for inaccuracy of timing and appearance of bubbles. However, it is not infrequent in practice to rely on the opinion of one echocardiographer, and from a practical point of view it indicates the need for TEE: a definitive procedure for determining whether an intracardiac shunt exists. TEE is a definitive procedure because its nearfield advantage provides significantly improved resolution imagery of the right atrium, left atrium, interatrial septum, and adjacent structures compared to current harmonic-based transthoracic echocardiography. TEE allows a determination of whether contrast crosses the interatrial septum and can definitively determine whether an intracardiac shunt exists. TEE allows improved timing when contrast arrives in the right atrium, and improved timing when contrast crosses the interatrial septum and where bubbles cross the interatrial septum. All maneuvers to enhance right-to-left bubble crossing such as inferior vena cava compression (abdominal), cough, and Valsalva have improved accuracy compared to transthoracic echocardiography. Additionally, information is supplied regarding septal mobility when evaluation of interatrial septal aneurysm is necessary, and color 6

Doppler TEE provides shunt evaluation in the absence of a saline contrast injection. The Eustachian valve is also visualized by TEE. This structure appears to direct blood flow to the interatrial septum and may prevent PFO closure after birth.6 In addition, TEE allows visualization of the right and left pulmonary veins, which are the exit for bubbles entering the left atrium from a pulmonary arteriovenous malformation. Zukotynski at al1 used transthoracic contrast echocardiography as an initial screening test to detect PAVMs. They do not mention TEE as a solution to the difficulty of timing contrast appearance and its origin, which they state is problematic in their study. There are life-threatening complications resulting from intracardiac or pulmonary right-to-left shunts. TEE should be relied on to provide an accurate echocardiographic diagnosis of shunt location when transthoracic saline solution contrast study findings are positive. Leon J. Frazin, MD Chicago, IL Dr. Frazin is Director of Echocardiography Laboratories at Sts. Mary and Elizabeth Hospitals and Jesse Brown VA Hospital; and Associate Professor of Clinical Medicine, University of Illinois, Chicago, IL. The author has no conflict of interest to disclose. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Leon J. Frazin, MD, Jesse Brown VA Hospital, 820 S Damen, Chicago, IL 60612; e-mail: [email protected] DOI: 10.1378/chest.07-0577

References 1 Zukotynski K, Chan R, Chow C, et al. Contrast echocardiography grading predicts pulmonary arteriovenous malformations on CT. Chest 2007; 132:18 –23 2 Barzilai B, Waggoner AD, Spessert C, et al. Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol 1991; 68:1507–1510 3 Daniels C, Weytjens C, Cosyns B, et al. Second harmonic transthoracic echocardiography: the new reference screening method for the detection of patent foramen ovale. Eur J Echocardiogr 2004; 5:449 – 452 4 Gossage J, Kanj G. Pulmonary arteriovenous malformations-a state of the art review. Am J Respir Crit Care Med 1998; 158:643– 661 5 Yeung M, Khan K, Antecol D, et al. Transcranial Doppler ultrasonography and transesophageal echocardiography in the investigation of pulmonary arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia presenting with stroke. Stroke 1995; 26:1941–1944 6 Schuchlenz H, Saurer G, Weihs W, et al. Persisting Eustachian valve in adults: relation to patent foramen ovale and cerebrovascular events. J Am Soc Echocardiogr 2004; 17:231– 233 Editorials