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• W2923583270 abstract "Alkaptonuria is rare genetic disorder of tyrosine metabolism manifesting with signs of tissue pigmentation, dark urine, and ochronotic arthropathies. Commonly undiscovered by late adulthood, alkaptonuria can manifest as cardiac ochronosis with cardiovascular disorders such as valvulopathies, but rarely coronary artery disease. This case report describes 2 patients with aortic stenosis and coronary artery disease in whom alkaptonuria was diagnosed during open heart surgery. Alkaptonuria is rare genetic disorder of tyrosine metabolism manifesting with signs of tissue pigmentation, dark urine, and ochronotic arthropathies. Commonly undiscovered by late adulthood, alkaptonuria can manifest as cardiac ochronosis with cardiovascular disorders such as valvulopathies, but rarely coronary artery disease. This case report describes 2 patients with aortic stenosis and coronary artery disease in whom alkaptonuria was diagnosed during open heart surgery. Alkaptonuria is a rare autosomal recessive disorder caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA) [1Aquaron R. Alkaptonuria: a very rare metabolic disorder.Indian J Biochem Biophys. 2013; 50: 339-344PubMed Google Scholar]. HGA is oxidized, irreversibly bound to collagen, and deposited in various tissues, where is causes black and blue discoloration. Unnoticed until adulthood, alkaptonuria usually manifests as joint disorders with gray-brown scleral pigment, ear pigmentation, and urine discoloration [2Mistry J.B. Bukhari M. Taylor A.M. Alkaptonuria. Rare Dis. 2013; 1e27475Crossref PubMed Google Scholar]. Rare manifestations include renal, urethral, and prostate calculi and cardiovascular abnormalities, usually valve disease, but rarely coronary artery involvement [3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. We present 2 patients with severe aortic stenosis who had concomitant coronary artery disease (CAD) and in whom alkaptonuria was discovered intraoperatively. A 70-year-old woman with bilateral gonarthrosis and prior right total knee replacement surgery had a newly discovered systolic murmur over the aortic valve. A transthoracic echocardiogram (TTE) revealed severe aortic stenosis with a mean pressure gradient of 46 mm Hg, an aortic valve area of 0.6 cm2 with preserved left ventricle ejection fraction (LVEF) of 70%, and a moderately hypertrophied left ventricle. Coronary angiography showed significant stenosis of the proximal left anterior descending (LAD) and proximal right coronary artery (RCA). Her phenotype was typical for alkaptonuria, with blue dots in the sclerae (Fig 1A), discolored nails (Fig 1B), and a history of urine turning dark on exposure to air (Fig 1C). Bioprosthetic aortic valve replacement (AVR) surgery (21-mm C-E Magna Perimount, Edwards Lifesciences Corp, Irvine, CA) and double coronary artery bypass grafting with the left internal thoracic artery to the LAD and the saphenous vein to the RCA was performed. Endothelial discoloration of the LAD and RCA manifesting as tiny blue dots was observed. The postoperative course was uneventful, and TTE showed good LV function and normal functioning of the aortic bioprosthesis. A second case was a 63-year-old women with a history of arterial hypertension and vitiligo who presented with shortness of breath on exertion. Of note was her observation that her urine turned dark on air exposure. Clinical examination revealed blue-blackish discoloration of the sclera, ear cartilage, and nails, along with a systolic, crescendo-decrescendo murmur that was loudest at the upper right sternal border. TTE confirmed severe aortic stenosis with a mean pressure gradient of 65 mm Hg, an aortic valve area of 0.5 cm2, and a moderately hypertrophied left ventricle. LVEF was 55%. Coronary angiography revealed significant proximal stenosis of the LAD coronary artery. Given this workup, the decision was made to proceed with AVR and LAD artery bypass grafting. After sternotomy, black discoloration of sternal cartilage was observed (Fig 2A). After initiating cardiopulmonary bypass and aortotomy, similar blackish discoloration of the inner aortic wall was noticed (Fig 2B), as well as discoloration of the aortic valve leaflets, which were thickened and blue-black (Fig 2C). The endothelial surface of the LAD artery was also discolored. On uneventful AVR with bioprosthesis (19-mm St. Jude Trifecta, St. Paul, MN) and left internal thoracic artery–-to-LAD bypass, the patient was admitted to the intensive care unit in stable condition. Postoperative TTE showed good function of the aortic bioprosthesis with an LVEF of 60%. Alkaptonuria is a rare autosomal recessive metabolic disease, with incidence of one in 200,000 to one in 1,000,000 births. Up until now, it has been reported in more than 40 countries, with the highest prevalence in Slovakia [1Aquaron R. Alkaptonuria: a very rare metabolic disorder.Indian J Biochem Biophys. 2013; 50: 339-344PubMed Google Scholar, 2Mistry J.B. Bukhari M. Taylor A.M. Alkaptonuria. Rare Dis. 2013; 1e27475Crossref PubMed Google Scholar]. Over years, HGA is been accumulated with high levels in the blood and urine, thus causing the triad of homogentisic aciduria, arthropathies, and tissue pigmentation. This HGA accumulation induces oxidative stress at the cellular level that results in inflammation and calcium deposition in different tissues and possibly leads to cardiovascular ochronosis manifesting as valvular dysfunction and vascular calcification [4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. Cardiovascular ochronosis is usually discovered in the sixth or seventh decade of life, as was the case in our patients. With previous reports, the association has been made between alkaptonuria and aortic valve stenosis, but more rarely have pulmonary, mitral, or tricuspid valves been involved in the disease process [3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. Even though both of our patients had classical histories and clinical appearances of alkaptonuria, they were not previously given a diagnosis of this entity. Finally, cardiovascular problems also developed in both patients. Although degenerative aortic stenosis was previously described in multiple reports about alkaptonuria [1Aquaron R. Alkaptonuria: a very rare metabolic disorder.Indian J Biochem Biophys. 2013; 50: 339-344PubMed Google Scholar, 2Mistry J.B. Bukhari M. Taylor A.M. Alkaptonuria. Rare Dis. 2013; 1e27475Crossref PubMed Google Scholar, 3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar, 5Vavuranakis M. Triantafillidi H. Stefanadis C. Toutouzas P. Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome.Cardiology. 1998; 90: 302-304Crossref PubMed Scopus (20) Google Scholar], concomitant CAD is rare [3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. CAD is commonly present in patients with aortic stenosis because the process of proliferative and inflammatory changes with lipid accumulation and infiltration of macrophages into aortic valve leaflets is similar to that of atherosclerosis [6Rajamannan N.M. Gersh B. Bonow R.O. Calcific aortic stenosis: from bench to the bedside—emerging clinical and cellular concepts.Heart. 2003; 89: 801-805Crossref PubMed Scopus (121) Google Scholar]. Conversely, it has also been concluded that HGA-oxidized depositions have effects on the endothelial surface that cause dysfunction and possible development of CAD. Such vascular abnormalities have been previously described in several cases of cardiovascular ochronosis [3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar, 5Vavuranakis M. Triantafillidi H. Stefanadis C. Toutouzas P. Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome.Cardiology. 1998; 90: 302-304Crossref PubMed Scopus (20) Google Scholar]. We believe that alkaptonuria had caused aortic stenosis and CAD in both our patients. Both patients had definitive diagnoses made intraoperatively during cardiac surgery, a situation that is surprisingly common [3Rios J.C. Reyes A. Esquivel H. Lescano M. Aortic stenosis and coronary artery disease in alkaptonuria. Case report.Rev Esp Cardiol. 2010; 63: 1100-1109Google Scholar, 4Gottschalk B.H. Blankenstein J. Guo L. Ochronosis of mitral valve and coronary arteries.Ann Thorac Surg. 2018; 106: e19-e20Abstract Full Text Full Text PDF Scopus (6) Google Scholar, 5Vavuranakis M. Triantafillidi H. Stefanadis C. Toutouzas P. Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome.Cardiology. 1998; 90: 302-304Crossref PubMed Scopus (20) Google Scholar], probably resulting from the rarity of this genetic disorder with uncommon cardiovascular manifestations and its striking black appearance inside the human heart." @default.
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• W2923583270 title "The Dark Side of the Heart: Cardiovascular Manifestation of Ochronosis" @default.
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