scholarly journals Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Nazarzadeh ◽  
A.-C Pinho-Gomes ◽  
Z Bidel ◽  
A Dehghan ◽  
D Canoy ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Mitral Regurgitation ◽  
Aortic Stenosis ◽  
Aortic Valve Stenosis ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Funding Source ◽  
Causal Association ◽  
Lipid Levels

Abstract Background Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. Purpose We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. Methods Causality of association was assessed using two-sample Mendelian Randomization (MR) framework through different statistical methods. MR approach uses instrumental variable analysis to mimic the randomization process that underpins causal inference in clinical trials. It takes advantage of the naturally-occurring random allocation of alleles inherited by offspring from their parents during the formation of the zygote. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188,577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432,173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. Results The odds ratio (OR) for developing aortic stenosis per unit increase in lipid parameter was 1.52 (95% confidence interval [CI], 1.22 to 1.90; per 0.98 mmol/L) for low-density lipoprotein (LDL) cholesterol, 1.03 (95% CI, 0.80 to 1.31; per 0.41 mmol/L) for high-density lipoprotein (HDL) cholesterol, and 1.38 (95% CI 0.92 to 2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. Conclusion Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

scholarly journals Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study

2020 ◽  
Vol 41 (40) ◽  
pp. 3913-3920 ◽  
Author(s):  
Milad Nazarzadeh ◽  
Ana-Catarina Pinho-Gomes ◽  
Zeinab Bidel ◽  
Abbas Dehghan ◽  
Dexter Canoy ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Mitral Regurgitation ◽  
Aortic Stenosis ◽  
Aortic Valve Stenosis ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
European Ancestry ◽  
Causal Association ◽  
Lipid Levels

Abstract Aims  Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. Methods and results  Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22–1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80–1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92–2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. Conclusion  Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.

scholarly journals Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation

2019 ◽  
Author(s):  
Elias Allara ◽  
Gabriele Morani ◽  
Paul Carter ◽  
Apostolos Gkatzionis ◽  
Verena Zuber ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Aortic Stenosis ◽  
Aortic Valve Stenosis ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Cardiovascular Outcomes ◽  
Lipid Lowering ◽  
Abdominal Aortic

ABSTRACTAimsTo systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.Methods and ResultsIn the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.ConclusionLowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism.

Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.K Ghadge ◽  
M Messner ◽  
H Seiringer ◽  
T Zeller ◽  
D Boernigen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Smooth Muscle Cells ◽  
Aortic Valve Stenosis ◽  
Cardiac Fibrosis ◽  
Muscle Cells ◽  
Funding Source ◽  
Lineage Tracking

Abstract Background Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model. Methods SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P). Results SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway. Conclusion Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis. Ghadge_SM-SDF-1−/− Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency

scholarly journals Genetic Determinants of Lipids and Cardiovascular Disease Outcomes

2019 ◽  
Vol 12 (12) ◽  
Author(s):  
Elias Allara ◽  
Gabriele Morani ◽  
Paul Carter ◽  
Apostolos Gkatzionis ◽  
Verena Zuber ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Aortic Valve Stenosis ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Cardiovascular Outcomes ◽  
Lipid Lowering ◽  
Abdominal Aortic ◽  
Cad Risk

Background: Evidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. Methods: In the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188 577 participants, and genetic associations with cardiovascular outcomes from 367 703 participants in UK Biobank. Results: For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35–1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40–2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25–1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12–1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04–1.61]), and hypertension (OR, 1.17 [95% CI, 1.07–1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67–0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62–0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. Conclusions: Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.

Use and outcomes of emergency treatment strategies in patients with aortic valve stenosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.M Piepenburg ◽  
K Kaier ◽  
C Olivier ◽  
M Zehender ◽  
C Bode ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Aortic Valve ◽  
Aortic Valve Replacement ◽  
Hospital Mortality ◽  
Valve Replacement ◽  
Aortic Valve Stenosis ◽  
Emergency Treatment ◽  
Funding Source ◽  
Artery Disease

Abstract Introduction and aim Current emergency treatment options for severe aortic valve stenosis include surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR) and balloon valvuloplasty (BV). So far no larger patient population has been evaluated regarding clinical characteristics and outcomes. Therefore we aimed to describe the use and outcome of the three therapy options in a broad registry study. Method and results Using German nationwide electronic health records, we evaluated emergency admissions of symptomatic patients with severe aortic valve stenosis between 2014 and 2017. Patients were grouped according to SAVR, TAVR or BV only treatments. Primary outcome was in-hospital mortality. Secondary outcomes were stroke, acute kidney injury, periprocedural pacemaker implantation, delirium and prolonged mechanical ventilation >48 hours. Stepwise multivariable logistic regression analyses including baseline characteristics were performed to assess outcome risks. 8,651 patients with emergency admission for severe aortic valve stenosis were identified. The median age was 79 years and comorbidities included NYHA classes III-IV (52%), coronary artery disease (50%), atrial fibrillation (41%) and diabetes mellitus (33%). Overall in-hospital mortality was 6.2% during a mean length of stay of 22±15 days. TAVR was the most common treatment (6,357 [73.5%]), followed by SAVR (1,557 [18%]) and BV (737 8.5%]). Patients who were treated with TAVR or BV were significantly older than patients with SAVR (mean age 81.3±6.5 and 81.2±6.9 versus 67.2±11.0 years, p<0.001), had more relevant comorbidities (coronary artery disease 52–91% vs. 21.8%; p<0.001), worse NYHA classes III-IV (55–65% vs. 34.5%; p<0.001) and higher EuroSCORES (24.6±14.3 and 23.4±13.9 vs. 9.5±7.6; p<0.001) than SAVR patients. Patients treated with BV only had the highest in-hospital mortality compared with TAVR or SAVR (20.9% vs. 5.1 and 3.5%; p<0.001). Compared with BV only, SAVR patients (adjusted odds ratio [aOR] 0.25; 95% confidence interval [CI] 0.14–0.46; p<0.001) and TAVR patients (aOR 0.37; 95% CI 0.28–0.50; p<0.001) had a lower risk for in-hospital mortality. Conclusion In-hospital mortality for emergency patients with symptomatic severe aortic valve stenosis is high. Our results showed that BV only therapy was associated with highest mortality, which is in line with current research. Yet, there is a trend towards more TAVR interventions and this study might imply that balloon valvuloplasty alone is insufficient. The role of BV as a bridging strategy to TAVR or SAVR needs to be further investigated. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Heart Center Freiburg University, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany

scholarly journals Pressure constrained mitral annular dysfunction determines severity of regurgitation in Barlow's disease – a 3D echocardiographic study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.A Dumont ◽  
R Persson ◽  
J.P Kvitting ◽  
R Lundblad ◽  
R Haaverstad ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Aortic Valve ◽  
Mitral Regurgitation ◽  
Surface Area ◽  
Systemic Blood Pressure ◽  
Funding Source ◽  
Healthy Controls ◽  
Systemic Blood ◽  
Barlow’S Disease ◽  
3D Echo

Abstract Background Barlow's disease provides both diagnostic and therapeutic challenges. The impact of systemic blood-pressure on severity of regurgitation is still unclear. Purpose We hypothesized that mitral annulus behaves passively with enlargement during ventricular systole, and secondly, we tested the hypothesis that severity of regurgitation correlates to systemic blood-pressure (BP) of the patient. Methods Ten patients with Barlow's disease were compared with 10 healthy controls. Brachial blood-pressure was measured according to guidelines. Transthoracic 3D echo was obtained from an apical view (38.6±8.2 frames per second). Data was analyzed using a holographic display. We measured commissure width (CW), septallateral length (SL) and mitral annular surface area throughout the cardiac cycle. Aortic flow ejection time was derived from continuous Doppler across the aortic valve. Timing of aortic valve closure was visually assessed by 3D echo. Onset and end of mitral regurgitation was derived from continuous wave Doppler of transmitral flow. Results Systolic BP in controls and patients were 122±5 and 133±12 mmHg, respectively (p<0.05). Enddiastolic volume was 87±7 ml/m2 (controls) and 100±14 ml/m2 (Barlow), p<0.02. Left ventricular EF in controls and patients were 59±5 and 62±5%, respectively, p=NS. Barlow patients had moderate or severe late systolic regurgitation with mean regurgitation volume of 51±18 ml. Annular surface area, CW and SL behaved passively with enlargement during ventricular systole (Figure 1). Peak systolic surface area, CW and SL in healthy controls and Barlow patients were 8.7±0.5 vs 20.7±3.2 cm2 (p<0.001), 30.1±1.5 vs 49.5±4.9 mm (p<0.001) and 30.9±1.5 vs 44.9±3.3 mm (p<0.001). Peak annular surface area and regurgitation volume in patients showed a positive correlation with systolic BP (y = 0.156x − 0.077, r=0.60 and y = 1.136x − 99.7, r=0.80, respectively). Conclusions We have demonstrated pressure constrained mitral annular dysfunction in Barlow's disease, indicating that systemic blood pressure may modify the severity of regurgitation. The study provides novel insights into mechanisms of mitral regurgitation and potential therapeutic actions in the future. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Grieg Foundation

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