Massive Diffuse Calcification of the Ascending Aorta and Minimal Focal Calcification of the Abdominal Aorta in Heterozygous Familial Hypercholesterolemia

Massive Diffuse Calcification of the Ascending Aorta and Minimal Focal Calcification of the Abdominal Aorta in Heterozygous Familial Hypercholesterolemia

Massive Diffuse Calcification of the Ascending Aorta and Minimal Focal Calcification of the Abdominal Aorta in Heterozygous Familial Hypercholesterolemi...

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Massive Diffuse Calcification of the Ascending Aorta and Minimal Focal Calcification of the Abdominal Aorta in Heterozygous Familial Hypercholesterolemia William C. Roberts, MDa,b,*, Vera S. Won, BSa, Matthew R. Weissenborn, MDc, Adnan Khalid, MDd, and Brian Lima, MDe A 41-year-old woman, the mother of 3 offspring, with likely heterozygous familial hypercholesterolemia, had been asymptomatic until age 38 when angina pectoris and exertional dyspnea appeared leading to the discovery of severe multivessel coronary artery disease and a massively calcified ascending aorta. Coronary bypass grafting using the right and left internal mammary arteries did not alleviate the symptoms. Evidence of overt heart failure subsequently appeared and that led to heart transplantation at age 41. She died 22 days later. The occurrence of massive diffuse calcification of the ascending aorta and minimal focal calcification of the abdominal aorta is rare and in the patient described it appears to be the consequence of heterozygous familial hypercholesterolemia. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:1381e1385)

Heavy calcific deposits in the ascending aorta are infrequent. Patients with huge abdominal aortic aneurysms or huge calcific deposits in the wall of the abdominal aorta infrequently, for example, have significant calcific deposits in the ascending aorta. Patients with familial hypercholesterolemia, particularly the homozygous variety, typically have heavy calcific deposits in ascending aorta and few if any calcific deposits in abdominal aorta,1 the reverse of the usual situation. Patients with non-familial hypercholesterolemia typically have heavy calcific deposits in their abdominal aorta and few, if any, in the ascending aorta. We recently studied a 41-year-old woman who had huge diffuse calcific deposits in the ascending aorta and minimal focal deposits in the abdominal aorta, and evidence of familial hypercholesterolemia of the heterozygous variety. Patients with a “porcelain” aorta are infrequently considered to have familial hypercholesterolemia.2 A description of this occurrence in this setting is the purpose of this report. Description of Patient This 41-year-old white woman was born in January 1973 and died in December 2014. Her family tree is shown in Figure 1. She underwent heart transplantation 22 days before death. (An autopsy was not performed.) A coronary a Department of Baylor Heart and Vascular Institute, bDepartment of Pathology, cDepartment of Radiology, dDivision of Cardiology, Department of Internal Medicine, and eDepartment of Cardiothoracic Surgery, Baylor University Medical Center, Dallas, Texas. Manuscript received December 18, 2015; revised manuscript received and accepted January 22, 2016. This study was funded by the Baylor Health Care System Foundation through the Cardiovascular Research Review Committee and in cooperation with the Baylor Heart and Vascular Institute. See page 1385 for disclosure information. *Corresponding author: Tel: þ(214) 820-7911; fax: þ(214) 820-7533. E-mail address: [email protected] (W.C. Roberts).

0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.01.034

Table 1 Finding in our 41-year-old woman Angina pectoris Dyspnea on exertion Precordial murmur Diabetes mellitus (type II) Systemic hypertension (by history) Body mass index (Kg/m2) Mitral regurgitation Aortic valve stenosis Hematocrit (%) Total cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Blood urea nitrogen (mg/dl) Creatinine (mg/dl) B-type natriuretic peptide (pg/ml) Magnesium (mg/dl) Thyroid stimulating hormone (uIU/ml) Creatinine clearance (ml/min) Coronary artery narrowing (% diameter reduction): Right Left main Left anterior decending Left circumflex Coronary bypass Intracardiac defibrillator Ejection fraction (%) Pulmonary artery (mmHg) (s/d) Pulmonary arterial wedge (mmHg) Left ventricle (mmHg) (s/d) Left ventricular angiogram

þ þ þ (grade3/6) þ þ 26 2þ/4þ 0 29 135 87 40 88 25 1.2 1970 1.9 0.95 48

90%(ostial) 10% 99% 10% þ þ 25 35/26 a17 b17 m16 113/10 Global hypokinesis (severe)

s/d ¼ peak systole; end diastole.

artery bypass grafting procedure had been done in April 2012 because of angina pectoris and exertional dyspnea. Before that operation, coronary angiography had shown www.ajconline.org

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Figure 1. Diagram of patient’s genetic pedigree. The large circle represents the patient described in this report. CAD ¼ coronary artery disease.

Figure 2. Noncontrast computed tomographic images from the patient before surgical intervention. (A) Coronal reformatted image of the left ventricular outflow tract, and (B) axial image through the level of the pulmonary trunk showing calcific deposits in the aortic sinuses (black arrow), heavy diffuse deposits in the ascending thoracic aorta (white arrow), and smaller focal deposits in the descending thoracic aorta (white arrowhead). Each is of normal caliber. (C) Axial image through the abdomen showing focal calcific deposits in the abdominal aorta (black arrowhead), which is also normal in caliber. LV ¼ left ventricle; PA ¼ main pulmonary artery.

severe multivessel coronary disease (Table 1). A stent had been inserted in the proximal right coronary artery. Heavy calcific deposits had been noted in the left main, left anterior descending, and left circumflex coronary arteries and in the ascending aorta. In November 2014, the patient was referred to Baylor University Medical Center. Computed tomography confirmed the massive calcific deposits in the ascending aorta and only a few focal deposits in the abdominal aorta (Figure 2). Serum cholesterol and other values are shown in the table. She was on simvastatin 40 mg daily before these

cholesterol values were evaluated. She had evidence of severe heart failure, a very low ejection fraction, and, global left ventricular hypokinesis. The radiograph of the excised native heart (weight 495 g) is shown in Figure 3. All major epicardial coronary arteries were severely narrowed by atherosclerotic plaque. Scars were present in the left ventricular wall anteriorly, laterally, and posteriorly, and also in the ventricular septum (Figure 4). The left ventricular cavity was dilated (up to 4.5 cm). Heavy calcific deposits were present on the

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Figure 3. Radiograph of the patient’s explanted heart showing massive diffuse calcific deposits in the ascending aorta, proximal epicardial coronary arteries, aortic valve cusps, and anterior mitral leaflet.

Figure 4. Photograph of the basal aspect of the heart showing both ventricular cavities to be dilated and the left ventricular free wall and ventricular septum to be focally scarred.

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Figure 5. Photomicrographs of left ventricular subendocardial region, mainly papillary muscle, showing focal but extensive scarring and extensive vacuolization of myofibers. Trichrome stains: 100 (A); 40 (B); 40 (C), and 400 (D).

ventricular aspect of anterior mitral leaflet and on the aortic aspect of each of the 3 aortic valve cusps (Figure 3). Photomicrographs of sections of the left ventricular wall are shown in Figure 5. The entire ascending aorta was diffusely and heavily calcified, and the abdominal aorta was focally and minimally calcified (Figure 6). Discussion

Figure 6. Drawing illustrating the heavy diffuse calcific deposits in the tubular portion of ascending aorta and arch and minimal focal calcific deposits in the abdominal aorta. Focal calcific deposits are present on the aortic aspects of each of the 3 cusps and on the ventricular aspect of anterior mitral leaflet. LA ¼ left atrium; LV ¼ left ventricle.

The causes of “porcelain” aorta (diffuse calcific deposits in the tubular portion of ascending aorta) have recently been listed in a published review by Abramowitz and colleagues.2 The list included diabetes mellitus, chronic kidney diseases, and mediastinal irradiation, but not hyperlipidemia, whether familial or nonfamilial. Diabetes mellitus and chronic kidney disease of course affect millions of people, but diffuse calcification of the ascending aorta is extremely rare (depending on how “porcelain” is defined), and we were not able to find any reports demonstrating a diffusely calcified ascending aorta in either of these conditions. In contrast, most patients with homozygous familial hypercholesterolemia have diffuse calcification of the ascending aorta.1,3 This condition, however, is rare (1/1,000,000). The heterozygous variety of familial hypercholesterolemia (occurrence 1/500) also is associated with calcific deposits in the ascending aorta but usually they are not as heavy as in the homozygous variety. Our patient appears to be the exception. Although we were unable to obtain serum lipid values in our patient before statin therapy (40 mg simvastatin) was began, the lipid values obtained were not those

Case Report/Porcelain Aorta and Hypolipidemia

seen after statin therapy in patients with the homozygous variety of hyperlipidemia. The latter group of patients before lipid-lowering therapy generally have total cholesterol values >800 mg/dl and low-density lipoprotein (LDL) cholesterol levels >500 mg/dl. It would be impossible to reach the total and LDL-cholesterol levels that our patient had with simvastatin 40 mg dose if she had had the homozygous variety of familial hypercholesterolemia. The patients with the heterozygous variety of familial hypercholesterolemia generally have total cholesterol levels about 300 mg/dl and LDL-cholesterol levels about 200 mg/dl. Also, our patient’s age (namely 38 years) when she was first discovered to have heart disease is obviously characteristic of the heterozygous variety and not of the homozygous variety. The latter group without lipid-lowering therapy usually dies in the teens, not in the fourth or fifth decade, as did our patient. Thus, although our patient did have diabetes mellitus (discovered at age 38 years), we believe the evidence is strongeincluding the strong family historyethat our patient had heterozygous familial hypercholesterolemia and that the latter is the cause of the diffuse calcification of the ascending aorta, and the minimal focal

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calcification of the abdominal aorta, a finding characteristic of the homozygous variety but possibly a more common finding they previously recognized in the heterozygous variety. Although patients with diabetes mellitus or chronic renal disease for long periods of time may have calcific deposits in the ascending aorta, they are focal and smaller and not diffuse and large as in the patients with familial hypercholesterolemia.

Disclosures The authors have no conflicts of interest to disclose. 1. Sprecher DL, Schaefer EJ, Kent KM, Gregg RE, Zech LA, Hoeg JM, Mcmanus B, Roberts WC, Brewer HB. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol 1984;54:20e30. 2. Abramowitz Y, Jilaihawi H, Chakravarty T, Mack MJ, Makkar RR. Porcelain aorta. A comprehensive review. Circulation 2015;131:827e836. 3. Grenon SM, Lachapelle K, Marcil M, Omerogulu A, Genest J, Varennes BD. Surgical strategies for severe calcifications of the aorta (porcelain aorta) in two patients with homozygous familial hypercholesterolemia. Am J Cardiol 2007;23:1159e1161.