Apolipoproteins B, (a), and E Accumulate in the Morphologically Early Lesion of ‘Degenerative’ Valvular Aortic Stenosis

O’Brien, Kevin D.; Reichenbach, Dennis D.; Marcovina, Santica M.; Kuusisto, Johanna; Alpers, Charles E.; Otto, Catherine M.

doi:10.1161/01.atv.16.4.523

Cited by 476 publications

(341 citation statements)

References 50 publications

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“…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%

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%

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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“…Hence, an increased ratio of apoB/apoA‐I might reflect a predominance of pro‐atherogenic effects over anti‐atherogenic effects of lipoprotein lipids, thus contributing to lipid‐mediated inflammation in the arteries and the valves. Experimental studies have reported an accumulation of apoB and several other apolipoproteins within surgically explanted stenotic aortic valves, suggesting an infiltration of atherogenic apoB‐containing lipoproteins into the valve leaflets 32. Interestingly, apoA‐I was also found in explanted stenotic aortic valves 33.…”

Section: Discussionmentioning

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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“…Lipoproteins and inflammatory cells, such as macrophages and T cells,42 have been identified in early AV lesions,43 and inflammatory activity, visualized by positron emission tomography imaging, has been documented in patients with even mild stenosis 44. This lipid deposition has also been associated with increased angiotensin‐converting enzyme activity in the valve, with profibrotic effects 45.…”

Section: Discussionmentioning

confidence: 99%

Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients

Sengeløv

Cheng

Biering‐Sørensen

et al. 2018

JAHA

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BackgroundThe relationship between ideal cardiovascular health reflected in the cardiovascular health score (CVHS) and valvular heart disease is not known. The purpose of this study was to determine the association of CVHS attainment through midlife to late life with aortic stenosis prevalence and severity in late life.Methods and ResultsThe following 6 ideal cardiovascular health metrics were assessed in ARIC (Atherosclerosis Risk in Communities) Study participants at 5 examination visits between 1987 and 2013 (visits 1–4 in 1987–1998 and visit 5 in 2011–2013): smoking, body mass index, total cholesterol, blood pressure, physical activity, and blood glucose. Percentage attained CVHS was calculated in 6034 participants as the sum of CVHS at each visit/the maximum possible score. Aortic stenosis was assessed by echocardiography at visit 5 on the basis of the peak aortic valve velocity. Aortic stenosis was categorized sclerosis, mild stenosis, and moderate‐to‐severe stenosis. Mean age was 76±5 years, 42% were men, and 22% were black. Mean percentage attained CVHS was 63±14%, and the prevalence of aortic stenosis stages were 15.9% for sclerosis, 4.3% for mild stenosis, and 0.7% for moderate‐to‐severe stenosis. Worse percentage attained CVHS was associated with higher prevalence of aortic sclerosis (P<0.001 for trend), mild stenosis (P<0.001), and moderate‐to‐severe stenosis (P=0.002), adjusting for age, sex, and race.ConclusionsGreater attainment of ideal cardiovascular health in midlife to late life is associated with a lower prevalence of aortic sclerosis and stenosis in late life in a large cohort of older adults.

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Apolipoproteins B, (a), and E Accumulate in the Morphologically Early Lesion of ‘Degenerative’ Valvular Aortic Stenosis

Cited by 476 publications

References 50 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

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

Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients

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