Introduction to Aortic Stenosis

Carabello, Blasé A.

doi:10.1161/circresaha.113.300156

Cited by 119 publications

(74 citation statements)

References 75 publications

(51 reference statements)

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“…Because of comparable risk factors and functional processes of aortic valve sclerosis and atherosclerosis, a related pathogenesis of both entities is very likely. Certainly, modified lipoproteins are intimately involved 3. eLDL is thought to be one of the initiators of atherosclerosis 7, 8, 10, 11.…”

Section: Discussionmentioning

confidence: 99%

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Twardowski

Cheng

Michaelsen

et al. 2015

JAHA

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BackgroundWe have demonstrated previously that enzymatically degraded low‐density lipoprotein (eLDL) is an essential causative component for the initiation of atherosclerosis. Here, we investigated the different stages of human aortic valve sclerosis for the presence of eLDL and effectors of the innate immune system, as well as the interaction of eLDL with isolated valvular interstitial cells/myofibroblasts to discover possible pathways leading to aortic valve sclerosis.Methods and ResultsHuman aortic valvular tissue was obtained from 68 patients undergoing valve replacement surgery. Patients were classified into 3 groups (mild, moderate, or severe aortic valve sclerosis), and clinical data for statistical analysis were gathered from all patients. Immunohistochemical staining demonstrated extensive extracellular deposits of eLDL throughout all grades of aortic valve sclerosis. Complementary analysis of lipid composition revealed higher concentrations of the decisive components of eLDL (ie, unesterified cholesterol and linoleic acid) compared with internal control tissues. Further, the complement component C3d and terminal complement complexes colocalized with eLDL compatible with the proposal that subendothelially deposited eLDL is enzymatically transformed into a complement activator at early stages of valvular cusp lesion development. Gene expression profiles of proteases and complement components corroborated by immunohistochemistry demonstrated an upregulation of the protease cathepsin D (a possible candidate for LDL degradation to eLDL) and the complement inhibitor CD55. Surprisingly, substantial C‐reactive protein expression was not observed before grade 2 aortic valve sclerosis as investigated with microarray analysis, reverse transcription–polymerase chain reaction analysis, and immunohistochemistry. Finally, we demonstrated cellular uptake of eLDL by valvular interstitial cells/myofibroblasts.ConclusionsThe present study is a startup of a hypothesis on the pathogenesis of aortic valve sclerosis declaring extracellular lipoprotein modification, subsequent complement activation, and cellular uptake by valvular interstitial cells/myofibroblasts as integral players.

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Section: Discussionmentioning

confidence: 99%

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Twardowski

Cheng

Michaelsen

et al. 2015

JAHA

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“…Several atherosclerotic risk factors associate with risk of AS in epidemiological studies 15 and genetic predisposition to both elevated lipoprotein (a) (Lp(a)) and LDL-cholesterol, established risk factors of CAD, have been associated with risk of AS 4,16 . We thus tested the novel AS variants for association with traditional cardiovascular risk factors and found nominally significant association between rs1830321 and systolic and diastolic blood pressure in Iceland (Supplementary Table 3) and in data from the UK-Biobank (https://biobankengine.stanford.edu/search#).…”

mentioning

confidence: 99%

Genome-wide analysis yields new loci associating with aortic valve stenosis

Helgadóttir

Þorleifsson

Grétarsdóttir

et al. 2017

Preprint

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Aortic valve stenosis (AS) is the most common valvular heart disease, characterized by a thickened and calcified valve causing left ventricular outflow obstruction. Severe AS is a significant cause of morbidity and mortality, affecting approximately 5% of those over 70 years of age1,2,3. Little is known about the genetics of AS, although recently a variant at the LPA locus4 and a rare MYH6 missense variant were found to associate with AS5. We report a large genome-wide association study (GWAS) with a follow-up in up to 7,307 AS cases and 801,073 controls. We identified two new AS loci, on chromosome 1p21 near PALMD (rs7543130; OR=1.20, P=1.2×10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR=1.15, P=1.8×10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR=1.28, P=6.6×10−10) and aortic root diameter (P=1.30×10−8) and rs1830321 associates with BAV (OR=1.12, P=5.3×10−3 and coronary artery disease (CAD) (OR=1.05, P=9.3×10−5). These results indicate that AS is partly rooted in the same processes as cardiac development and atherosclerosis.

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“…1,2 Several mouse models of AS have been reported, 3 and myocardial reponses to pressure-overload have been extensively investigated. Mechanisms of volume-overload heart failure are less completely understood.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Hajj

Chu

Lund

et al. 2015

ATVB

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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.

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Introduction to Aortic Stenosis

Cited by 119 publications

References 75 publications

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Genome-wide analysis yields new loci associating with aortic valve stenosis

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

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