Risk Of Aortic Valve Stenosis Research Articles

Genetic proxy of lipid-lowering drugs and calcific aortic valve stenosis: A Mendelian randomization study

BackgroundLipid metabolism plays an important role in the pathogenesis and development of calcific aortic valve stenosis. Our aim was to evaluate the causal effect of lipid-lowering drugs, such as low-density lipoprotein cholesterol (LDL-C) lowering and triglyceride lowering drugs, on the outcome of aortic valve stenosis using a two-sample Mendelian randomization (MR) study. MethodsWe used two genetic tools to represent the exposure of lipid-lowering drugs, including expression quantitative trait loci for the expression of drug target genes, and genetic variants within or near drug target genes that are associated with LDL-C and triglyceride concentrations from Genome-Wide Association Studies (GWAS). Effect estimates were calculated using summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis. ResultsBased on the results of SMR and IVW-MR analysis, LDL-C-lowering PCSK9 inhibitors have potential in reducing the risk of aortic valve stenosis (for SMR, OR: 1.044; 95%CI: 1.002–1.404; P = 0.047; for IVW-MR, OR: 1.647, 95%CI: 1.316–2.062, P < 0.001). However, no significant association was observed between triglyceride target gene expression, as well as triglyceride-lowering drugs, and aortic valve stenosis. ConclusionThis two-sample drug-targeted MR study suggests a potential causal relationship between PCSK9 inhibitors and the reduction of calcific aortic valve stenosis risk.

Epigenetic age acceleration and risk of aortic valve stenosis: a bidirectional Mendelian randomization study

BackgroundAortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly accurate predictor of the aging process and associated health outcomes. This study aimed to explore the causal relationship between epigenetic clock and AVS by conducting a bidirectional Mendelian randomization (MR) analysis.MethodsSummary genome-wide association study statistics of epigenetic clocks (HannumAge, HorvathAge, PhenoAge, and GrimAge) and AVS were obtained and assessed for significant instrumental variables from Edinburgh DataShare (n = 34,710) and FinnGen biobank (cases = 9870 and controls = 402,311). The causal association between epigenetic clock and AVS was evaluated using inverse variance weighted (IVW), weighted median (WM), and MR-Egger methods. Multiple analyses (heterogeneity analysis, pleiotropy analysis, and sensitivity analysis) were performed for quality control assessment.ResultsThe MR analysis showed that the epigenetic age acceleration of HorvathAge and PhenoAge was associated with an increased risk of AVS (HorvathAge: OR = 1.043, P = 0.016 by IVW, OR = 1.058, P = 0.018 by WM; PhenoAge: OR = 1.058, P = 0.005 by IVW, OR = 1.053, P = 0.039 by WM). Quality control assessment proved our findings were reliable and robust. However, there was a lack of evidence supporting a causal link from AVS to epigenetic aging.ConclusionThe present MR analysis unveiled a causal association between epigenetic clocks, especially HorvathAge and PhenoAge, with AVS. Further research is required to elucidate the underlying mechanisms and develop strategies for potential interventions.Graphical abstract

Lipoprotein(a): Role in atherosclerosis and new treatment options.

Atherosclerosis is a chronic process characterized by inflammation and the progressive accumulation of inflammatory cells and lipids in the blood vessel wall, resulting in narrowing of the blood vessel's circumference. Treatment of people with dyslipidemia aims to reduce the risk of developing atherosclerotic disease and prevent major adverse cardiovascular events (MACE). The results of previous studies indicated that lipoprotein(a) (Lp(a)) is a critical causal factor in the estimated risk of developing a cardiovascular (CV) incident even after achieving desirable low-density lipoprotein (LDL) cholesterol levels. Lp(a) is a low-density lipoprotein particle, like LDL cholesterol. The levels of Lp(a) in plasma are genetically determined. Lp(a) catabolism is still controversial. The pathogenic potential of Lp(a) can be divided into three categories: promotion of plaque formation, thrombogenicity, and proinflammatory effects. Lp(a) levels above the 75th percentile reduced the risk of aortic valve stenosis and myocardial infarction, whereas higher levels (above 90th percentile) were associated with an increased risk of heart failure. However, no hypolipidemic agents have been approved for targeted use in patients with high Lp(a) levels. There are insufficient randomized controlled trials assessing CV outcomes that would support the evidence that current treatment options, which effectively lower Lp(a) levels, also effectively prevent CV event. However, according to some studies, there is strong evidence that better CV outcome is one of the benefits of such therapy. The results of ongoing clinical trials are eagerly awaited.

High Lipoprotein(a) Levels and Risk of Aortic Valve Stenosis Related Clinical Events: A Systematic Review

Background: Several studies have evaluated the association between lipoprotein(a) plasma levels [Lp(a)] and the occurrence of aortic valve stenosis related events, with contradictory results. Objective: The main objective of this systematic review was to analyze the predictive capacity of elevated Lp(a) levels on major clinical events associated with aortic valve stenosis. Methods: This systematic review was conducted in accordance with PRISMA and STROBE recommendations. A search was carried out in order to identify studies with a cohort design evaluating the association between Lp(a) levels and the events of interest. The primary endpoint was the incidence of clinical events related with aortic valve stenosis (aortic valve replacement, death or hospitalization). This review was registered in PROSPERO. Results: Seven observational studies with a total of 58 783 patients were eligible for analysis. Our findings showed that the presence of elevated Lp(a) levels was associated with an increased risk of events related with aortic valve stenosis in most of the studies evaluated (between 70% and approximately 3-fold higher risk), despite adjusting for other risk factors. Conclusion: This review suggests that elevated Lp(a) levels are associated with a higher incidence of aortic valve stenosis related clinical events. However, considering the limitations of this study, the clinical usefulness of Lp(a) as a prognostic marker in aortic valve disease should be confirmed in future investigations.

Familial Hypercholesterolemia and Lipoprotein(a): Two Partners in Crime?

Familial hypercholesterolemia is a high cardiovascular risk disorder. We will review the role of lipoprotein(a) in cardiovascular risk and in aortic valve stenosis in familial hypercholesterolemia, as well as its association with their phenotype, and strategies to identify this high-risk population. Patients with familial hypercholesterolemia have higher lipoprotein(a) levels mainly due to an increased frequency of LPA variants, and the cardiovascular risk is increased twofolds when both conditions coexist. Also, an increased risk for aortic valve stenosis and valve replacement has been observed with high lipoprotein(a) levels. Assessment of lipoprotein(a) during the cascade screening for familial hypercholesterolemia is a good opportunity to identify this high-risk population. High cardiovascular risk in familial hypercholesterolemia is increased even more when lipoprotein(a) is also elevated. Measurement of lipoprotein(a) in these patients is crucial to identify those subjects who need to intensify LDL-cholesterol reduction pending availability of lipoprotein(a)-specific treatments.

Incidence of elevated lipoprotein (a) levels in Pakistani population

Background and Aims: Lipoprotein (a) [LP(a)] is a risk marker for Cardiovascular diseases. Elevated levels of LP(a) are pro-atherogenic and correspond to an increased risk of aortic valve stenosis. Twenty six percent of European population has LP(a) levels of more than 30 mg/dl and have a 3 fold higher risk of developing severe cardiovascular events among patients within 15 years of CABG. Incidence of elevated LP(a) in Pakistan population has not been analyzed.

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

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

Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study.

We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis. We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87-1.19] for individuals with triglycerides of 1.0-1.9 mmol/L (89-176 mg/dL), 1.22 (1.02-1.46) for 2.0-2.9 mmol/L (177-265 mg/dL), 1.40 (1.11-1.77) for 3.0-3.9 mmol/L (266-353 mg/dL), 1.29 (0.88-1.90) for 4.0-4.9 mmol/L (354-442 mg/dL), and 1.52 (1.02-2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0-4.9 mmol/L (177-442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5-1.4 mmol/L (19-57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13-16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20-1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17-18, 1.41 (1.31-1.52; +25%; +22%) for allele score 19-20, and 1.51 (1.22-1.86; +51%; +44%) for individuals with allele score 21-23. Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

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

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.

Obesity as a Causal Risk Factor for Aortic Valve Stenosis

BackgroundCausal risk factors for aortic valve stenosis are poorly understood, limiting the possibility of preventing the most common heart valve disease. ObjectivesThe hypothesis was tested that genetically based obesity measured by body mass index is causally associated with risk of aortic valve stenosis and replacement. MethodsThe authors included 108,211 individuals from the Copenhagen General Population Study. Participants had measurements of body mass index, waist-hip ratio, and waist circumference, and information on 5 genetic variants associated with obesity. A Mendelian randomization design was used to investigate genetic and observational associations of obesity with incident aortic valve stenosis (n = 1,215) and replacement (n = 467) for a median follow-up time of 8.7 years. ResultsGenetically increased body mass index was causally associated with increased risk of aortic valve stenosis. Compared with an unweighted allele score of 0 to 3, individuals with an allele score 7 to 10 had a mean increase in body mass index of 0.87 kg/m2, and the age and sex–adjusted hazard ratio for aortic valve stenosis was 1.3 (95% confidence interval [CI]: 1.0 to 1.7) for allele score 4, 1.4 (95% CI: 1.1 to 1.8) for allele score 5 to 6, and 1.6 (95% CI: 1.3 to 2.1) for allele score 7 to 10 (p for trend: 9 × 10−5). A 1-kg/m2 increase in body mass index was associated with causal risk ratios for aortic valve stenosis and replacement, respectively, of 1.52 (95% CI: 1.23 to 1.87) and 1.49 (95% CI: 1.07 to 2.08) genetically, and with corresponding hazard ratios of 1.06 (95% CI: 1.05 to 1.08) and 1.06 (95% CI: 1.03 to 1.08) observationally. ConclusionsObesity from human genetics was causally associated with higher risk of aortic valve stenosis and replacement.

Obesity As A Causal Risk Factor For Aortic Valve Stenosis

Abstract Background Causal risk factors for aortic valve stenosis are poorly understood, limiting the possibility of preventing the most common heart valve disease. Objectives The hypothesis was tested that genetically based obesity measured by body mass index is causally associated with risk of aortic valve stenosis and replacement. Methods The authors included 108,211 individuals from the Copenhagen General Population Study. Participants had measurements of body mass index, waist-hip ratio, and waist circumference, and information on 5 genetic variants associated with obesity. A Mendelian randomization design was used to investigate genetic and observational associations of obesity with incident aortic valve stenosis (n = 1,215) and replacement (n = 467) for a median follow-up time of 8.7 years. Results Genetically increased body mass index was causally associated with increased risk of aortic valve stenosis. Compared with an unweighted allele score of 0 to 3, individuals with an allele score 7 to 10 had a mean increase in body mass index of 0.87 kg/m2, and the age and sex–adjusted hazard ratio for aortic valve stenosis was 1.3 (95% confidence interval [CI]: 1.0 to 1.7) for allele score 4, 1.4 (95% CI: 1.1 to 1.8) for allele score 5 to 6, and 1.6 (95% CI: 1.3 to 2.1) for allele score 7 to 10 (p for trend: 9 × 10−5). A 1-kg/m2 increase in body mass index was associated with causal risk ratios for aortic valve stenosis and replacement, respectively, of 1.52 (95% CI: 1.23 to 1.87) and 1.49 (95% CI: 1.07 to 2.08) genetically, and with corresponding hazard ratios of 1.06 (95% CI: 1.05 to 1.08) and 1.06 (95% CI: 1.03 to 1.08) observationally. Conclusions Obesity from human genetics was causally associated with higher risk of aortic valve stenosis and replacement.

Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study.

AimsThe causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes.Methods and resultsSingle-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m2 increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02–1.11; P = 2.6 × 10−3] for pulmonary embolism to 1.13 (95% CI 1.05–1.21; P = 1.2 × 10−3) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P < 0.05). The strongest magnitude of association was with aortic valve stenosis (OR per 1 kg/m2 increase in fat mass index 1.46, 95% CI 1.13–1.88; P = 3.9 × 10−3). There was suggestive evidence of inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm.ConclusionThis study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions.

Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis

BackgroundAortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. MethodsWe genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. ResultsIn the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). ConclusionsOur study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.

Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases

BackgroundThe association between type 1 diabetes mellitus (T1DM) and specific cardiovascular diseases (CVD) is uncertain. Furthermore, data on type 2 diabetes mellitus (T2DM) in relation to risk of aortic valve stenosis, atrial fibrillation, abdominal aortic aneurysm, and intracerebral hemorrhage are scarce and inconclusive. We examined the associations of T1DM and T2DM with incidence of seven CVD outcomes. MethodsThis study comprised 71,483 Swedish adults from two population-based prospective cohorts. T1DM and T2DM diagnosis and incident CVD cases were ascertained through linkage with the population-based registers. ResultsT1DM was associated with myocardial infarction (hazard ratio [HR] 3.26; 95% confidence interval [CI] 2.47–4.30), heart failure (HR 2.68; 95% CI 1.76–4.09), and ischemic stroke (HR 2.61; 95% CI 1.80–3.79). Increased risk of myocardial infarction, ischemic stroke, and heart failure was also observed in T2DM patients and the magnitude of the associations increased with longer T2DM duration. T2DM was also associated with an increased risk of aortic valve stenosis (HR 1.34; 95% CI 1.05–1.71) and with lower risk of abdominal aortic aneurysm (HR 0.57; 95% CI 0.40–0.82) and intracerebral hemorrhage (HR 0.51; 95% CI 0.30–0.88). Only long-term T2DM (≥20 years) was associated with an increased risk of atrial fibrillation (HR 1.44; 95% CI 1.02–2.04). ConclusionT1DM and T2DM are associated with increased risk of major CVD outcomes. Trial registrationThe Cohort of Swedish Men and the Swedish Mammography Cohort are registered at clinicaltrials.gov as NCT01127711 and NCT01127698, respectively.

AORTIC VALVE STENOSIS IN PATIENTS WITH EXTREMELY ELEVATED LIPOPROTEIN(A) LEVELS

Degenerative aortic valve stenosis (AVS) is a common valvular heart disease in patient older than 65 years with a prevalence of 2-7% in the European and North American population. It has been shown that elevated LP (a) levels are associated with an increased risk for AVS across various ethnic groups

Coffee consumption and risk of aortic valve stenosis: A prospective study

Background and aimsCoffee contains many biologically active compounds with potential adverse or beneficial effects on the cardiovascular system. Whether coffee consumption is associated with the risk of aortic valve stenosis (AVS) is unknown. The purpose of this study was therefore to examine the association between coffee consumption and AVS incidence. Methods and resultsThis prospective study included 71 178 men and women who provided information on their coffee consumption through a questionnaire at baseline. Incident cases of AVS were identified through linkage with the Swedish National Patient and Cause of Death Registers. During a mean follow-up of 15.2 years, 1295 participants (777 men and 518 women) were diagnosed with AVS. Coffee consumption was positively associated with risk of AVS in a dose–response manner after adjustment for age, sex, smoking, and other risk factors (P-trend = 0.005). The multivariable hazard ratios were was 1.11 (95% confidence interval 1.04–1.19) per 2 cups/day increase of coffee consumption and 1.65 (95% confidence interval 1.10–2.48) when comparing the highest (≥6 cups/day) with the lowest (<0.5 cup/day) category of coffee consumption. The association was not modified by other risk factors. ConclusionsThis study provides novel evidence that high coffee consumption is associated with an increased risk of AVS.

Alcohol consumption, cigarette smoking and incidence of aortic valve stenosis.

Alcohol consumption and cigarette smoking are modifiable lifestyle factors with important impact on public health. It is unclear whether these factors influence the risk of aortic valve stenosis (AVS). To investigate the associations of alcohol consumption and smoking, including smoking intensity and time since cessation, with AVS incidence in two prospective cohorts. This analysis was based on data from the Swedish Mammography Cohort and the Cohort of Swedish Men, comprising 69 365 adults without cardiovascular disease at baseline. Participants were followed for AVS incidence and death by linkage to the Swedish National Patient and Causes of Death Registers. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards regression. Over a mean follow-up of 15.3 years, 1249 cases of AVS (494 in women and 755 in men) were recorded. Compared with never drinkers of alcohol (lifelong abstainers), the risk of AVS was significantly lower in current light drinkers (1-6 drinks per week [1 drink = 12 g alcohol]; multivariable HR 0.82; 95% CI: 0.68-0.99). The risk of AVS increased with increasing smoking intensity. Compared with never smokers, the HR was 1.46 (95% CI: 1.16-1.85) in current smokers of ≥30 pack-years. Former smokers who had quit smoking 10 or more years previously had similar risk for AVS as never smokers. This study suggests that current light alcohol consumption is associated with a lower risk of AVS, and indicates that the association between smoking and AVS risk is reversible.

PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis.

Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. We used two prospective cohort studies of the general population and one patient-based cohort. Cohort studies selected at random individuals of Danish descent. We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10(-52)). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction. PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.

Abstract 390: Human Aortic Valve Interstitial Cells Exhibit Decreased Cholesterol Efflux Associated with Hypo- α1-nascent HDL Particles

Objectives: High plasma levels of lipoprotein (a) (Lp(a)) are associated with increased risk of aortic valve stenosis. The purpose of this study was to determine ability of human aortic valve interstitial cells (HAVICs) to generate HDL particles from plasma of patients with high Lp(a), and understand the mechanism involved. Methods: HAVICs were isolated from consented participants and cultured in DMEM, 10% FBS, 5% glucose. ABCA1 proteins expression was tested in HAVICs lyses after detection by polyclonal anti-ABCA1 antibody. Cholesterol efflux was determined in HAVICs against HDL isolated by PEG from patients with aortic valve stenosis exhibiting mild or severe plasma Lp(a), compared to normolipidemic controls. FPLC and 2D-PAGGE were used to illustrate HDL profiles from these patients after incubation with HAVICs. Results: Our data showed abundant expression of ABCA1, and a significant decrease in HAVICs cholesterol efflux (5%, for 8h) in response to HDL from plasma of patients with high Lp(a) and aortic valve stenosis (mild 16±0.01%cpm, severe 23.4±0.21%cpm) compared to normolipidemic HDL (29.57cpm; P&lt;0.01). This was consistent with FPLC profiles indicating a similar reduction in in cholesterol within nascent HDL (nHDL) when compared to nHDL generated from HDL isolated from plasma of normal controls. Importantly, we noticed a generation of smaller population of HDL particles formed following cholesterol efflux. Plasma from patient with aortic valve stenosis showed a distinct decrease in preβ- and α1-migrating HDL, but no in other α-migrating HDL particles, when compared to plasma from normolipidemic controls. We also observed a defect in α1-HDL in the nHDL generated from patient with high Lp(a) and aortic valve stenosis compared to nHDL from plasma of normal controls. Conclusion: These findings demonstrate a defect in HAVICs ABCA1 cholesterol removal associated a loss of α1 species of nHDL in patient with high Lp(a) and aortic valve stenosis. Therefore, the HAVICs cholesterol efflux defect associated with the elevated plasma Lp(a) may explain the pathological changes associated aortic valve calcification.

Increased risk of aortic valve stenosis in patients with psoriasis: a nationwide cohort study.

Psoriasis is a chronic inflammatory disease associated with increased risk of cardiovascular disease including atherosclerosis. The pathogenesis of aortic valve stenosis (AS) also includes an inflammatory component. We therefore investigated the risk of AS in patients with psoriasis compared with the general population in a nationwide cohort. The study comprised the entire Danish population aged ≥18 years followed from 1 January 1997 until diagnosis of AS, 31 December 2011, or death. Information on comorbidity, concomitant medication, and socioeconomic status was identified by individual-level linkage of administrative registers. Incidence rates for AS were calculated and incidence rate ratios (IRRs) adjusted for age, gender, calendar year, comorbidity, medications, and socioeconomic status, were estimated in Poisson regression models. A total of 5 107 624 subjects were eligible for analysis. During the study period, we identified 58 747 patients with mild psoriasis and 11 918 patients with severe psoriasis. The overall incidence rates for AS were 8.09, 16.07, and 20.08 per 10 000 person-years for the reference population (48 539 cases [mean follow-up 12.3 years]), mild psoriasis (509 cases [mean follow-up 6.2 years]), and severe psoriasis (99 cases [mean follow-up 5.4 years]), respectively. Correspondingly, the fully adjusted IRRs for AS were markedly increased in patients with psoriasis with IRR 1.22 (95% confidence interval [CI] 1.12-1.33) and IRR 1.61 (CI 1.32-1.96) for subjects with mild and severe disease, respectively. In a nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of AS. The mechanisms underlying this novel finding require further study.