Histopathologic Validation of the Intravascular Ultrasound Diagnosis of Calcified Coronary Artery Nodules Jin-Bae Lee, MD a , Gary S. Mintz, MD a , Jennifer B. Lisauskas, MS b , Sinan G. Biro, MSc a , Jun Pu, MD a , Stephen T. Sum, PhD b , Sean P. Madden, PhD b , Allen P. Burke, MD c , James Goldstein, MD d , Gregg W. Stone, MD a , Renu Virmani, MD e , James E. Muller, MD b , and Akiko Maehara, MD a, * A calcified nodule is a type of potentially vulnerable plaque accounting for approximately 2% to 7% of coronary events. Because its intravascular ultrasound (IVUS) features have never been validated, the aim of this study was to assess the IVUS characteristics of calcified nodules in comparison to histopathology. IVUS was performed in 856 pathologic slices in 29 coronary arteries (11 left anterior descending, 5 left circumflex, and 13 right coronary arteries) in 18 autopsy hearts. Pathologic sections were analyzed every 2 mm; qualitative and quantitative findings of matched IVUS were analyzed. IVUS detected calcification in 285 frames; 17 (6.0%) were calcified nodules, and 268 (94.0%) were non- nodular calcium by histopathology. Two calcified nodules (11.8%) were solitary, and 15 (88.2%) were adjacent to non-nodular calcium. IVUS characteristics of calcified nodules were (1) a convex shape of the luminal surface (94.1% in calcified nodules vs 9.7% in non-nodular calcium, p <0.001), (2) a convex shape of the luminal side of calcium (100% vs 16.0%, p <0.001), (3) an irregular luminal surface (64.7% vs 11.6%, p <0.001), and (4) an irregular leading edge of calcium (88.2% vs 19.0%, p <0.001). Luminal area at the calcified nodule site was larger (6.2  2.4 vs 4.3  1.6 mm 2 ,p <0.001) and plaque burden less (57  6% vs 68  5%, p <0.001) than at the minimum luminal area site. In conclusion, calcified nodules have distinct IVUS features (irregular and convex luminal surface) permitting their prospective identification in vivo. © 2011 Elsevier Inc. All rights re- served. (Am J Cardiol 2011;108:1547–1551) Intravascular ultrasound (IVUS) has high sensitivity and specificity for the detection of intracoronary calcium, 1–5 but the differentiation between calcified nodules and non-nod- ular calcium has never been validated. To assess the fre- quency and distribution of calcified nodules in vivo, it is first necessary to validate their detection using intravascular imaging techniques. Therefore, we used coronary arteries from human autopsied hearts to validate the IVUS charac- teristics of calcified nodules in comparison to histopathol- ogy. Methods The arteries used in the present analysis have been re- ported previously. 6 Vessels were obtained over a 2-year period from 84 autopsied human hearts. Among them, there were 7 arteries in 5 patients with 1 calcified nodule and a randomly chosen group of 22 arteries in 13 patients without calcified nodules (control group). IVUS was compared to the histopathologic standard. Hearts were acquired from the National Disease Research Interchange or the International Institute for the Advancement of Medicine as per a protocol approved by the institutional review board. Hearts were received 48 hours after death, maintained on ice at 4°C, and imaged 96 hours after death. Each arterial segment was then mounted in a custom fixture, and the 2 ends of the segment were attached to lure connectors that allowed fluid flow and catheter entry. 6 The segment was perfused with pulsatile human blood using a varistaltic pump (Manostat; Barnant Corporation, Barrington, Illinois) at body temper- ature. IVUS imaging was performed with an Atlantis SR Pro 40-MHz catheter (Boston Scientific Corporation, Fremont, a Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York; b InfraReDx, Inc., Burlington, Massa- chusetts; c University of Maryland Medical Center, Baltimore, Maryland; d William Beaumont Hospital, Royal Oak, Michigan; and the e CVPath Institute, Gaithersburg, Maryland. Manuscript received May 6, 2011; re- vised manuscript received and accepted July 7, 2011. Dr. Mintz has received consulting fees from Boston Scientific (Natick, Massachusetts), Volcano (Rancho Cordova, California), and Abbott Vas- cular (Abbott Park, Illinois). Ms. Lisauskas and Drs. Sum, Madden, and Muller are current employees of InfraReDx. Dr. Pu has received research grant from Boston Scientific China (Beijing, China). Drs. Burke and Virmani were consultants to InfraReDx for histologic studies. Dr. Gold- stein is a consultant for and equity owner of InfraReDx. Dr. Stone has served on the advisory boards for and received honoraria from Boston Scientific and Abbott Vascular and has received research grants from InfraReDx and Volcano. Dr. Virmani is an advisory board member for Abbott Vascular, Arsenal Medical (Watertown, Massachusetts), Atrium (Hudson, New Hampshire), Lutonix (Maple Grove, Minnesota), Medtronic (Minneapolis, Minnesota), and W. L. Gore & Associates (Newark, Dela- ware). Dr. Maehara has received research grants from Boston Scientific and Volcano. *Corresponding author: Tel: 646-434-4569; fax: 646-434-4464. E-mail address: amaehara@crf.org (A. Maehara). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. www.ajconline.org doi:10.1016/j.amjcard.2011.07.014