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Objective: Statins lower cardiovascular event risk, yet, they paradoxically increase coronary artery calcification, a marker consistently associated with increased cardiovascular risks. As calcium deposits influence rupture risk due to stress from compliance mismatch at their surfaces, we hypothesized that statins may lower cardiovascular risk by altering the microarchitecture of calcium deposits. Thus, using mice with preexisting vascular calcification, we tested whether pravastatin reduces the mineral surface area of calcium deposits. Approach and Results: Aged Apoe − /− mice were treated with pravastatin or vehicle for 20 weeks. Aortic calcification was assessed by in vivo sodium fluoride labeled with fluoride 18 isotope-micro-positron emission tomography/micro-computed tomography imaging at weeks 0, 10, and 20 and by histomorphometry at euthanasia. Micro-computed tomography analysis showed that, in both groups, the amount of vascular calcification increased significantly over the 20-week period, but pravastatin treatment did not augment over the controls. In contrast, the micro-positron emission tomography analysis showed that, at week 10, the pravastatin group had less 18 F uptake, suggesting reduced surface area of actively mineralizing deposits, but this decrease was not sustained at week 20. However, a significant difference in the mineral deposit size was found by histomorphometry. The pravastatin group had significantly more aortic microcalcium deposits (<50 µm in diameter) than the controls. The pravastatin group also had more vascular cells positive for alkaline phosphatase activity than the controls. The amount of collagen and osteopontin, additional osteoblastic markers, were not significantly different between the 2 groups. Conclusions: These results suggest that pravastatin treatment alters the microarchitecture of aortic calcium deposits with potential effects on plaque stability.

Calcification, fibrosis, and chronic inflammation are the predominant features of calcific aortic valve disease, a life-threatening condition. Drugs that induce serotonin (5-hydroxytryptamine [5-HT]) are known to damage valves, and activated platelets, which carry peripheral serotonin, are known to promote calcific aortic valve stenosis. However, the role of 5-HT in valve leaflet pathology is not known. We tested whether serotonin mediates inflammationinduced matrix mineralization in valve cells. Real-time reverse transcriptionpolymerase chain reaction analysis showed that murine aortic valve interstitial cells (VICs) expressed both serotonin receptor types 2A and 2B (Htr2a and Htr2b). Although Htr2a expression was greater at baseline, Htr2b expression was induced several-fold more than Htr2a in response to the pro-calcific tumor necrosis factor-α (TNF-α) treatment. 5-HT also augmented TNF-α-induced osteoblastic differentiation and matrix mineralization of VIC, but 5-HT alone had no effects. Inhibition of serotonin receptor type 2B, using specific inhibitors or lentiviral knockdown in VIC, attenuated 5-HT effects on TNF-αinduced osteoblastic differentiation and mineralization. 5-HT treatment also augmented TNF-α-induced matrix metalloproteinase-3 expression, which was also attenuated by Htr2b knockdown. Htr2b expression in aortic roots and serum levels of peripheral 5-HT were also greater in the hyperlipidemic Apoe −/− mice than in control normolipemic mice. These findings suggest a new role for serotonin signaling in inflammation-induced calcific valvulopathy.

Summary:A double aortic arch is usually an isolated abnormality. We describe a case with a previously undescribed combination of tetralogy of Fallot with pulnion a y atresia, complete atrioventricular septal defect, and left patent arterial duct in association with a double aortic arch. A complete diagnosis was made by echocardiography . Meticulous suprasternal echocardiography must be employed to avoid overlooking an unsuspected aortic arch abnomiality .Key words: double aortic arch, tetralogy of Fallot, atrioventricular septal defect Case ReportA male infant weighing 3.29 kg was bom at term after an uncomplicated delivery to a 21-year-old mother. The infant had clinical features of Down syndrome, which was later confirmed by chromosomal analysis. He was noted to be cyanosed shortly after birth. Cardiac examination confinned central cyanosis and moderate tachypnea, with no signs of upper airway obstruction. The second heart sound was single and there was a short, grade I W I e,:jection systolic mumiur localized to the upper left stcmal edge.Chest x-ray demonstrated cardiomegaly (cardiothoracic ratio 0.58) and normal pulmonary vascular markings. The tracheal air shadow appeared normal. Electrocardiogram revealed a superior axis of -100" with no atrial enlargement and nonnal precordial voltages for age.Echocardiography showed a large ostium primum atrial septal defect, a large ventricular septal defect, and connion atrioventricular valve. The ventricular septal defect extended from the inlet to outlet muscular septum with deviation of the outlet septum and override of a dilated aortic root (Fig. IA). The pulmonary valve was atretic with hypoplastic but confluent pulmonary arteries (Fig. 1 B). There was severe infundibular hypertrophy. Suprastemal views outlined a double aortic arch with ii larger dominant right arch and smaller left arch. The right arch had four branches and the left arch had two ( Fig. 2A, B). A patent arterial duct passed from the underside of the left aortic arch to the left pulmonary artery but n o right patent duct was demonstrated. These echocardiographic findings were consistent with tetralogy of Fallot with pulmonary atresia, complete atrioventricular septal defect, and double aortic arch with left patent arterial duct.The parents declined surgical intervention. The infant has survived and is now 12 months of age. He has not developed stridor, respiratory or swallowing difficulties, but remains severely cyanosed with poor physical growth and markedly delayed developmental milestones. DiscussionA double aortic arch is a rare congenital cardiac abnormality. In 20% of cases, it has been described with other cardiac abnormalities' including ventricular septal defect, aortic coarctation, left patent arterial duct, tetralogy of Fallot,2 complete transposition, and common arterial trunk. l We describe a combination of tetralogy of Fallot with pul-