| 1. |
- Perrot, Nicolas, et al.
(author)
-
Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis
- 2020
-
In: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 5:7, s. 649-661
-
Journal article (peer-reviewed)abstract
- The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.
|
|
| 2. |
- Perrot, Nicolas, et al.
(author)
-
Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans
- 2020
-
In: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 106:18, s. 1407-1412
-
Journal article (peer-reviewed)abstract
- Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans. Methods and results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351). Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
|
|
| 3. |
- Vamvakidou, Anastasia, et al.
(author)
-
Clinical Value of Stress Transaortic Flow Rate During Dobutamine Echocardiography in Reduced Left Ventricular Ejection Fraction, Low-Gradient Aortic Stenosis : A Multicenter Study
- 2021
-
In: Circulation Cardiovascular Imaging. - 1941-9651 .- 1942-0080. ; 14:11
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Low rest transaortic flow rate (FR) has been shown previously to predict mortality in low-gradient aortic stenosis. However limited prognostic data exists on stress FR during low-dose dobutamine stress echocardiography. We aimed to assess the value of stress FR for the detection of aortic valve stenosis (AS) severity and the prediction of mortality.METHODS: This is a multicenter cohort study of patients with reduced left ventricular ejection fraction and low-gradient aortic stenosis (aortic valve area <1 cm2 and mean gradient <40 mm Hg) who underwent low-dose dobutamine stress echocardiography to identify the AS severity and presence of flow reserve. The outcome assessed was all-cause mortality.RESULTS: Of the 287 patients (mean age, 75±10 years; males, 71%; left ventricular ejection fraction, 31±10%) over a mean follow-up of 24±30 months there were 127 (44.3%) deaths and 147 (51.2%) patients underwent aortic valve intervention. Higher stress FR was independently associated with reduced risk of mortality (hazard ratio, 0.97 [95% CI, 0.94-0.99]; P=0.01) after adjusting for age, chronic kidney disease, heart failure symptoms, aortic valve intervention, and rest left ventricular ejection fraction. The minimum cutoff for prediction of mortality was stress FR 210 mL/s. Following adjustment to the same important clinical and echocardiographic parameters, among the three criteria of AS severity during stress, ie, the guideline definition of aortic valve area <1cm2 and aortic valve mean gradient ≥40 mm Hg, or aortic valve mean gradient ≥40 mm Hg, or the novel definition of aortic valve area <1 cm2 at stress FR ≥210 mL/s, only the latter was independently associated with mortality (hazard ratio, 1.72 [95% CI, 1.05-2.82]; P=0.03). Furthermore aortic valve area <1cm2 at stress FR ≥210 mL/s was the only severe aortic stenosis criterion that was associated with improved outcome following aortic valve intervention (P<0.001). Guideline-defined stroke volume flow reserve did not predict mortality.CONCLUSIONS: Stress FR during low-dose dobutamine stress echocardiography was useful for the detection of both AS severity and flow reserve and was associated with improved prediction of outcome following aortic valve intervention.
|
|
