Interactive CardioVascular and Thoracic Surgery Advance Access published May 13, 2014

Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy Tomohiro Tsunekawa*, Kent W. Jones and John R. Doty Division of Cardiovascular and Thoracic Surgery, Intermountain Medical Center, Murray, UT, USA * Corresponding author. Division of Cardiovascular and Thoracic Surgery, Intermountain Medical Center, 5169 Cottonwood St Bldg 2 Ste 600, Murray, UT 84107, USA. Tel: +1-801-5073600; fax: +1-801-5073625; e-mail: [email protected] (T. Tsunekawa). Received 23 December 2013; received in revised form 24 February 2014; accepted 25 February 2014

Abstract Minocycline, a derivative of tetracycline, is a broad-spectrum antibiotic used in the treatment of various infections. Black discolouration of the skin, teeth, bones and the thyroid gland are sequelae of long-term minocycline therapy. We report an unusual case of minocyclineinduced pigmentation of the aortic valve and sinuses of Valsalva. Keywords: Heart valve disease • Aortic valve • Surgery

INTRODUCTION Minocycline, a derivative of tetracycline, is a broad-spectrum antibiotic used in the treatment of various infections. Black discolouration of the skin, thyroid gland, teeth and bones are sequelae of long-term minocycline therapy [1]. Pigmentation on the heart valves is rarely reported. We report a case of minocycline-induced blue-black pigmentation of the aortic valve and the sinuses of Valsalva.

superficial medial layers of the sinuses of Valsalva and in the aortic wall (Fig. 2B; H&E ×100). Fontana staining of the aortic valve leaflet demonstrated relative accentuation of pigment staining in the valve tissue, suggesting a positive reaction (Fig. 2C; FontanaMasson ×100). The patient’s postoperative recovery was uneventful and she remained well when last seen for her 1-year postoperative evaluation.

DISCUSSION CASE REPORT A 65-year-old woman was referred for surgical treatment of aortic valve stenosis. She had been taking minocycline hydrochloride for >30 years for treatment of hidradenitis. Her medical history included iron-deficiency anaemia, for which she was on a longterm oral iron replacement therapy. She had noticed persistent blue-black pigmentation of both of her lower extremities. She was otherwise well and denied having discoloured urine. At operation, the ascending aorta was faintly stained with a blue-black pigment. Viewing from inside the aorta, blue-black discolouration was found on the aortic valve leaflets, the sinuses of Valsalva and in the left ventricular outflow tract (Fig. 1A). The aortic valve was found to be tricuspid, sclerotic, severely calcified and had dense discolouration near the commissural attachment to the aortic root (Fig. 1B). The aortic valve was excised and was replaced with a 23-mm Trifecta™ bovine pericardial prosthesis (St Jude Medical, Inc., St Paul, MN, USA). Microscopic examination of the excised valve revealed finely granular dark pigment deposited diffusely in the fibrous layer of the aortic valve cusp near the commissural attachment to the aortic root, the coapting surface of the valve leaflet and in the mid-portion of the leaflet (Fig. 2A; H&E, ×100). Similar granular dark pigment was deposited diffusely in the intimal and most

Minocycline is a semi-synthetic tetracycline used for the treatment of a wide range of various infections. Although minocycline has proved to be a very safe drug, various drug-specific, treatmentrelated side effects were reported (i.e. tissue pigmentation, systemic lupus erythematosus-like syndrome, autoimmune hepatitis and polyarteritis nodosa). Minocycline side effects most commonly involved the skin (54%); the other most common adverse minocycline effects were dizziness (9.5%) and nausea (5.1%) [2]. Pigment deposition in human tissue can occur in association with long-term minocycline therapy. Most reports of minocyclineinduced pigmentation involve the skin, thyroid gland, sclera, nails and bones [1]. Pigmentation is rarely reported in heart valves. We reviewed the literature regarding minocycline-induced pigmentation in the ascending aorta or heart valves, using MEDLINE, and found only two clinical reports and one cadaveric report describing minocycline-induced heart valve pigmentation, each accidentally found during cardiac surgery or at autopsy [3–5]. Belcher et al. reported impressive pictures of minocycline-induced pigmentation of the aortic valve and the sinuses of Valsalva in their case report [3]. The characteristic histopathological findings of minocyclineinduced pigmentation are deposition of blue-black, Fontana-Masson and Perl’s positive granules deposited both within macrophages and free in the valvular connective tissue [4, 5].

© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

CASE REPORT

CASE REPORT – ADULT CARDIAC

Interactive CardioVascular and Thoracic Surgery (2014) 1–2 doi:10.1093/icvts/ivu142

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T. Tsunekawa et al. / Interactive CardioVascular and Thoracic Surgery

Figure 1: (A) Aortotomy revealed the dark blue-black discolouration of the sinuses of Valsalva and left ventricular outflow tract. (B) Histological macroscopic examination of the valve leaflets demonstrated black discolouration.

The differential diagnosis of blue-black pigmentation of the aortic valve includes minocycline therapy and ochronosis. Ochronosis is a manifestation of chronic alkaptonuria, confirmed by histopathological analysis and the presence of homogentistic acid in the urine. It has been postulated that the presence of the ochronotic pigment predisposes to increased calcification and results in valvular malfunction. However, in terms of minocycline-induced aortic valve pigmentation, the functional impairment of the aortic valve can be explained entirely by the degree of fibrosis and calcification and is unlikely to be related to the deposition of pigment. Conflict of interest: none declared.

Figure 2: (A) Photomicrograph of the aortic valve. Finely granular dark pigment deposited diffusely in the fibrous layer of the aortic valve cusp near the commissural attachment to the aortic root, the coapting surface of the leaflet and the mid-portion of the leaflet (arrow) (H&E ×100). (B) Photomicrograph of the aortic wall. Finely granular dark pigment (arrow) is deposited diffusely in the intimal and most superficial medial layers (H&E ×100). (C) Fontana staining of aortic valve. Photomicrograph demonstrating relative accentuation of pigment staining in the valve tissue, suggesting a positive reaction (Fontana, ×100). A control tissue (normal skin) is shown at the lower left corner with appropriate black staining of epidermal melanocytes (Fontana, ×200).

REFERENCES [1] Attwood H, Dennett X. A black thyroid and minocycline treatment. Br Med J 1976;2:1109–10. [2] Smith CJ, Sayles H, Mikuls TR, Michaud K. Minocycline and doxycycline therapy in community patients with rheumatoid arthritis: prescribing patterns, patient-level determinants of use, and patient-reported side effects. Arthritis Res Ther 2011;13:R168.

[3] Belcher E, Soni M, Azeem F, Sheppard MN, Petrou M. Minocyclineinduced pigmentation of the aortic valve and sinuses of Valsalva. Ann Thorac Surg 2009;88:1704. [4] Sant’Ambrogio S, Connelly J, DiMaio D. Minocycline pigmentation of heart valves. Cardiovasc Pathol 1999;8:329–32. [5] Butler JM, Marks R, Sutherland R. Cutaneous and cardiac valvular pigmentation with minocycline. Clin Exp Dermatol 1985;10:432–7.

Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy.

Minocycline, a derivative of tetracycline, is a broad-spectrum antibiotic used in the treatment of various infections. Black discolouration of the ski...
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