Clinical Factors Associated With Calcific Aortic Valve Disease

Stewart, B. Fendley; Siscovick, David S.; Lind, Bonnie K.; Gardin, Julius M.; Gottdiener, John S.; Smith, Vivienne E.; Kitzman, Dalane W.; Otto, Catherine M

doi:10.1016/s0735-1097(96)00563-3

Cited by 1,698 publications

(437 citation statements)

References 27 publications

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“…Previous studies have also reported an association of elevated serum LDL‐C with development and faster progression of AS 6, 46, 47, 48. In the present study, higher apoB/apoA‐I ratio was associated with faster AS progression independently of the level of LDL‐C, which did not reach significance level.…”

Section: Discussioncontrasting

confidence: 92%

“…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. A recent Mendelian randomization study also suggests a causal association between elevated LDL‐C and incidence of AS 15.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 92%

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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“…In humans, male sex is associated with a 2‐fold increase in the risk of aortic valve disease 13. Moreover, recent work has shown sex‐related differences at the cellular level between male and female VICs isolated from fresh porcine leaflets,64 wherein male VICs appeared to be predisposed to assuming a diseased phenotype when compared to female VICs.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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“…On the other hand, fibrotic collagen accumulation, which leads to thickened and stiffened aortic valve leaflets and subsequent degeneration of valve function, could cause aortic stenosis (Miller et al ., 2011). The epidemiological risk factors of AVD resemble those of atherosclerosis, including elevated serum cholesterol, hypertension, smoking, diabetes, and male gender (Lindroos et al ., 1994; Stewart et al ., 1997). Low‐density lipoprotein accumulation was found in stenotic aortic valves in humans, and dietary hypercholesterolemia induced aortic valve stenosis in small animal models (Weiss et al .…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

2016

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SummaryFibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti‐aging Klotho gene (KL) promotes high‐fat‐diet‐induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho‐deficient (KL +/−) mice and WT littermates were fed with a high‐fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL +/− mice than of WT mice, indicating that Klotho deficiency promotes HFD‐induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL +/− mice fed with a HFD. Treatment with AICAR markedly attenuated HFD‐induced AVF in KL +/− mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL +/− mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho‐deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol‐induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD‐induced fibrosis in aortic valves, likely through the AMPKα–RUNX2 pathway.

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Clinical Factors Associated With Calcific Aortic Valve Disease

Abstract: Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.

Cited by 1,698 publications

References 27 publications

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

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

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

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

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