A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

Cowell, S. Joanna; Newby, David E.; Prescott, R. J.; Bloomfield, Peter; Reid, John H.; Northridge, David B.; Boon, Nicholas A.

doi:10.1056/nejmoa043876

Cited by 957 publications

(520 citation statements)

References 37 publications

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“…In the SALTIER trial, 155 patients with asymptomatic aortic valve calcium deposits were followed for 25 months 40. LDL levels were lowered by 53% in the treatment arm, but no differences in aortic‐jet velocity were identified.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Ljungberg

Holmgren

Bergdahl

et al. 2017

JAHA

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BackgroundAortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.Methods and ResultsWe identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni‐ and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07‐1.55]), but not in 132 patients without CAD (1.04 [0.83‐1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16‐1.76]) but not in those without CAD (0.87 [0.69‐1.10]).ConclusionsHigh levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

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Section: Discussionmentioning

confidence: 99%

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Ljungberg

Holmgren

Bergdahl

et al. 2017

JAHA

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“…A recent Mendelian randomization study also suggests a causal association between elevated LDL‐C and incidence of AS 15. However, three randomized clinical trials failed to demonstrate any significant effect of statins to reduce the progression rate of AS or the occurrence of valve‐related events, despite important reduction in LDL‐C level 16, 17, 18. Hence, it has been hypothesized that LDL‐C could be involved mainly in the initiation and early stages of the disease but has less influence in the more advanced stages.…”

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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“…This finding is also significant because it provides a new and important therapeutic strategy for AVF. Recent clinical trials showed that statin failed to attenuate the progression of aortic stenosis (Cowell et al ., 2005; Houslay et al ., 2006; Rossebo et al ., 2008; Chan et al ., 2010), suggesting that antihyperlipidemia therapy alone is insufficient for treatment of the disease. The findings from the current study suggest that pharmacological activation of AMPKα should be tested for treating FAVD.…”

Section: Discussionmentioning

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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A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

Cited by 957 publications

References 37 publications

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery 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

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

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