Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS(-/-) mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by N(G)-nitro-l-arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS(-/-) mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS(-/-) aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS(-/-) and wild-type mice, but collagen-3 was preferentially increased in eNOS(-/-) mice. Calcification and apoptosis were significantly increased in BAV of eNOS(-/-) mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs.
Objective Development of calcific aortic valve stenosis (CAVS) involves multiple signaling pathways, which may be modulated by peroxisome proliferator-activated receptor-gamma (PPARγ). This study tested the hypothesis that pioglitazone, a ligand for PPARγ, inhibits calcification of the aortic valve in hypercholesteremic mice. Methods and Results LDLr-/-/ApoB100/100 mice were fed a Western-type diet with or without pioglitazone (20 mg/kg/day) for 6 months. Pioglitazone attenuated lipid deposition and calcification in the aortic valve, but not aorta. In the aortic valve, pioglitazone reduced levels of active caspase-3 and TUNEL staining. Valve function (echocardiography) was significantly improved by pioglitazone. To determine whether changes in gene expression are associated with differential effects of pioglitazone on aortic valves vs. aorta, Reversa mice were fed Western diet with or without pioglitazone for 2 months. Several pro-calcific genes were increased by Western diet, and the increase was attenuated by pioglitazone, in aortic valve, but not aorta. Conclusions Pioglitazone attenuates lipid deposition, calcification, and apoptosis in aortic valves of hypercholesterolemic mice, improves aortic valve function, and exhibits preferential effects on aortic valves vs. aorta. We suggest that pioglitazone protects against CAVS, and pioglitazone or other PPARγ ligands may be useful for early intervention to prevent or slow stenosis of aortic valves.
Background-The aim of this study was to evaluate the influence of statins on the growth of small abdominal aortic aneurysms (AAA).
BackgroundThere are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr −/− Apob 100/100 mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.ObjectivesTo determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr −/− Apob 100/100 mice.MethodsYoung Ldlr −/− Apob 100/100 mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr −/− Apob 100/100 mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.ResultsIn Young Ldlr −/− Apob 100/100 mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr −/− Apob 100/100 mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.ConclusionsOPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr −/− Apob 100/100 mice.
Objective Hypercholesterolemia (HC) and hypertension (HT) are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in HC/HT mice. Approach and Results Control, hypertensive (HT), hypercholesterolemic (Apoe−/−) (HC), and HC/HT mice were studied. Severe aortic stenosis (echocardiography) occurred only in HC/HT mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or “seam” between leaflets) was longer in HC/HT mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In HC/HT mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA-Sequencing (RNA-Seq) was used to identify molecular targets during the developmental phase of stenosis. Genes related to structure of the valve were identified that differentially expressed before FAVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1 (PAI-1), were increased greatly in HC/HT mice. Conclusions HC/HT mice are the first model of fibrotic AVS. HC/HT mice develop severe AVS in the absence of significant calcification, a feature which resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to development of FAVS.
Objective We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice. Approach and Results At 1.5 months of age, prior to development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, pro-fibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age. Conclusions We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction, and are epiphenomena arising from structurally incompetent “myxomatous” valves.
Background Acute coronary syndrome (ACS) is a rare, but serious complication of infective endocarditis, and diagnosis can be challenging given clinical overlap with other syndromes. A rare cause of ACS in infective endocarditis is mechanical obstruction of the coronary artery. We present the case of a patient with infective endocarditis who developed ST segment myocardial infarction due to occlusion of the right coronary artery ostium by a vegetation. Case presentation A 53-year-old female with no prior history of coronary artery disease was transferred to our tertiary care facility for evaluation and treatment of suspected myopericarditis. After transfer she developed inferior ST segment elevations on ECG along with fever and positive blood cultures for methicillin susceptible Staphylococcus aureus (MSSA). A transesophageal echocardiogram revealed a vegetation on the aortic valve that intermittently prolapsed into the right coronary ostium. She decompensated from a hemorrhagic brain infarct and subsequently transferred to the intensive care unit. She underwent surgical aortic valve debridement without prior cardiac catheterization given the danger of septic coronary embolization. After a prolonged hospital course with multiple complications, she was able to discharge home, with no neurologic deficits on follow-up. Conclusions ACS presents a diagnostic and therapeutic challenge in the setting of infective endocarditis. Careful attention to the history, physical exam and testing can help differentiate infective endocarditis from other conditions sharing similar symptoms. Traditional atherosclerotic ACS management may cause great harm when treating patients with infective endocarditis. The presence of a multidisciplinary endocarditis team is ideal to provide the best clinical outcomes for this population.
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