Calcific Aortic Valve Disease: Not Simply a Degenerative Process

Rajamannan, Nalini M.; Evans, F.J.; Aikawa, Elena; Grande-Allen, K. Jane; Demer, Linda L.; Heistad, Donald D.; Simmons, Craig A.; Masters, Kristyn S.; Mathieu, Patrick; O’Brien, Kevin D.; Schoen, Frederick J.; Towler, Dwight A.; Yoganathan, Ajit P.; Otto, Catherine M

doi:10.1161/circulationaha.110.006767

Cited by 689 publications

(415 citation statements)

References 96 publications

(95 reference statements)

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“…This correlation is not entirely unexpected, given that CAVD has been associated with hyperlipidemia,10 and stenotic valves are rich in oxidized lipids and apolipoproteins B and E 11, 12. However, in contrast to coronary artery disease (CAD), elevated LDL is considered a relatively weak risk factor for CAVD 10, 13…”

Section: Introductionmentioning

confidence: 99%

“…Although less studied than atherosclerosis in FH, the increased incidence of CAVD in FH patients is significant, with over half of homozygous FH (HoFH) males and 21% to 41% of HoFH females exhibiting aortic regurgitation or more‐advanced valvular dysfunction 8, 9. This correlation is not entirely unexpected, given that CAVD has been associated with hyperlipidemia,10 and stenotic valves are rich in oxidized lipids and apolipoproteins B and E 11, 12. However, in contrast to coronary artery disease (CAD), elevated LDL is considered a relatively weak risk factor for CAVD 10, 13…”

Section: Introductionmentioning

confidence: 99%

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Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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“…Risk factors for the development of aortic valve sclerosis include older age, male sex, hypertension, smoking, diabetes mellitus, and hypercholesterolemia 1. This listing already suggests a comparable pathogenesis of atherosclerosis and aortic valve sclerosis 2.…”

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confidence: 92%

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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“…Until recently, AS was considered as a purely passive degenerative process because of time‐dependent wear and tear of the valve leaflets leading to passive calcium deposition. However, there is now compelling evidence suggesting that AS is an active and multifactorial disease involving numerous pathophysiological processes, such as atherosclerotic‐like processes 1, 2, 3, 4, 5. In this regard, well‐known atherosclerotic risk factors, including age, male sex, smoking, hypertension, hypercholesterolemia, obesity, metabolic syndrome, diabetes mellitus, as well as elevated plasma level of lipoprotein(a) (Lp[a]) have been associated with the development and/or progression of AS 6, 7, 8, 9, 10, 11, 12, 13, 14.…”

Section: Introductionmentioning

confidence: 99%

ApoB/ApoA‐I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study

Tastet

Capoulade

Shen

et al. 2018

JAHA

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BackgroundPrevious studies reported that middle‐aged patients with atherogenic lipoprotein‐lipid profile exhibit faster progression of aortic valve stenosis (AS). The ratio of apolipoprotein B/apolipoprotein A‐I (apoB/apoA‐I) reflects the balance between atherogenic and anti‐atherogenic lipoproteins. The aim of this study was to examine the association between apoB/apoA‐I ratio and AS hemodynamic progression and to determine whether this association varies according to age.Methods and ResultsA total of 159 patients (66±13 years, 73% men) with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. Hemodynamic progression of AS was determined by the change in peak aortic jet velocity (Vpeak) measured by Doppler‐echocardiography between baseline and 2‐year follow‐up. Patients in the top tertile of apoB/apoA‐I ratio (≥0.62) had a faster progression rate of AS compared with those in the bottom/mid tertiles (Vpeak progression: 0.30 [0.09˗0.49] versus 0.16 [0.01˗0.36] m/s, P=0.02). There was a significant interaction (P=0.007) between apoB/apoA‐I ratio and age. Among younger patients (ie, aged <70 years; median value of the cohort), those in the top tertile of apoB/apoA‐I ratio had a 3.4‐fold faster AS progression compared with those in the bottom/mid tertiles (Vpeak progression: 0.34 [0.13˗0.69] versus 0.10 [−0.03˗0.31] m/s, P=0.002), whereas there was no significant difference between tertiles in the subgroup of older patients (P=0.83). After comprehensive adjustment, higher apoB/apoA‐I ratio was significantly associated with faster AS progression in the subset of younger patients (all, standardized β≥0.36; P≤0.01).ConclusionsHigher apoB/apoA‐I ratio is significantly associated with faster hemodynamic progression of AS in the younger patients. These findings suggest that atherogenic lipid factors may play a crucial role in the pathogenesis of AS in younger patients, but may be are less important in older patients.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01679431.

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Calcific Aortic Valve Disease: Not Simply a Degenerative Process

Cited by 689 publications

References 96 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

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

ApoB/ApoA‐I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study

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