Atherosclerotic Cardiovascular Disease Risk Research Articles

Enhancing Air Quality Index Activity Guidelines for Preventing Cardiovascular Events in the General Adult Population

BackgroundThe public health relevance of daily Air Quality Index (AQI) activity guidelines for the general adult public in the United States to prevent atherosclerotic cardiovascular disease (ASCVD) events is questionable. ObjectivesThe purpose of the study was to explore the utility of a policy tailoring activity guidance to calculated ASCVD risk rather than uniform recommendations to the general adult public as currently provided. MethodsWe calculated the number needed to treat (NNT) to prevent one ASCVD event per day by following activity recommendations across 10-year ASCVD risk scores (1% to 20%). Second, we modeled the benefits of tailoring recommendations to ASCVD risk. ResultsThe NNT decreased as ASCVD risk and/or AQI levels increased. At AQIs up to 151 (68% of days with AQIs above moderate in the United States), the NNTs remained untenably high (>2.7-55.3 million) across ASCVD risk. Under unhealthy conditions (AQIs 151-200), 28% of elevated AQIs, NNTs <1 million could be achieved by current guidance (15% exposure reduction), but only among the highest-risk individuals (ASCVD 18% to 20%) on the most polluted days (AQIs 192-200). Tailoring guidance to ASCVD risk could yield NNTs <1 million at risk thresholds of 7.5% and 10% if activity restrictions were more stringent (35% to 50% exposure reductions) during unhealthy conditions. ConclusionsASCVD risk has a major influence on the NNT to prevent cardiovascular events by following AQI guidance. It may be possible for a future policy to improve the utility of AQI activity guidance for the general adult public by tailoring activity recommendations to ASCVD risk.

Assessment of lipid profile and its correlation with ASCVD risk in the general population

Background: Atherosclerotic cardiovascular disease (ASCVD) is a major global health issue with high morbidity, mortality, and healthcare costs, emphasizing the need for effective risk assessment for prevention and management. This study aimed to assess the lipid profile of the general population and establish correlations with their ASCVD risk. Methods: This cross-sectional study was conducted among the general population in India. Participants were invited through advertisements to attend the ASCVD camp for a lipid profile check-up. Results: A total of 1068 participants were included, with a mean age of 52.7 years. The majority of participants were male (69.8%). Approximately 33% of participants had low ASCVD risk, followed by 31.6% with high risk, and 26.7% with intermediate risk. In the high ASCVD risk group, participants aged ≥60 years were significantly higher compared to those in the low risk, borderline risk and intermediate risk groups (P&lt;0.001). The mean total cholesterol and low-density lipoprotein (LDL) were significantly increased in participants with high ASCVD risk compared to intermediate, borderline and low risk (P&lt;0.001 and P=0.001). The mean HDL cholesterol level was significantly lower in male participants compared to female participants (P&lt;0.001). There was a positive correlation between age (r=0.783), total cholesterol (r=0.372) and the ASCVD risk score (P&lt;0.001 for both). There was negative correlation between HDL and ASCVD risk score (r=-124; P&lt;0.001). Conclusion: This study demonstrates a significant association between lipid profiles and ASCVD risk. Age, total cholesterol, and LDL levels are positively correlated with ASCVD risk, while HDL levels show a negative correlation.

Lipoprotein(a) cardiovascular disease risk not captured by low density lipoprotein cholesterol and apolipoprotein B

Abstract Background Elevated lipoprotein(a) affects 1 in 5 individuals and is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis (AVS). However, lipoprotein(a) measurements are not widely implemented in clinical practice. Low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) measurements include contributions from lipoprotein(a), yet whether these measurements can replace measurements of lipoprotein(a) in assessing cardiovascular disease risk from this causal risk factor is unknown. Purpose We tested the hypotheses that lipoprotein(a) risk of ASCVD and AVS is captured by LDL cholesterol or ApoB. Methods We included 70,189 individuals from a prospective contemporary cohort study of the general population. Mediated risk by LDL cholesterol and ApoB in the association between lipoprotein(a) and risk of ASCVD and AVS was examined using four-way decomposition analyses stratified by statin treatment at baseline. Results During a median follow-up of 10.8 years, 7,127 developed ASCVD and 1,516 AVS. Per 50 mg/dL higher lipoprotein(a), multivariable adjusted hazard ratios were 1.22 (95% CI: 1.18-1.26) for ASCVD and 1.36 (1.28-1.46) for AVS. In individuals without statin use, LDL cholesterol mediated 19% (15%-24%) of the risk of ASCVD from lipoprotein(a) and 7.7% (1.5%-14%) of the risk of AVS from lipoprotein(a) (Figure 1). Corresponding values for ApoB were 14.0% (11%-18%) and 6.6% (2.8%-10%). In statin users (n=9,570), LDL cholesterol did not mediate risk of ASCVD from lipoprotein(a) but mediated 8.0% (0.8%-15%) of the risk of AVS from lipoprotein(a). Correspondingly, ApoB mediated 9.8% (2.2%-17%) of the risk of ASCVD and 4.2% (0.4%-8.0%) of the risk of AVS from lipoprotein(a). Conclusion Lipoprotein(a) risk of ASCVD and AVS is not adequately captured by LDL cholesterol and ApoB. Therefore, lipoprotein(a) measurement is needed in all individuals to capture the cardiovascular disease risk from this causal risk factor.

Differences in cardiovascular risk in the general population of low and high altitude residents in Peru. HIGH Altitude CArdiovascular REsearch Latin America Population Study (HIGHCARE-LAPS)

Abstract Introduction Living at high altitude (HA) is associated with profound changes in cardiovascular physiology, mostly caused by chronic hypoxia. Available data from high income countries (Switzerland, Austria) suggest beneficial effects of moderate altitude residence in terms of cardiovascular risk. Little is known, however, about cardiovascular risk profile in long-term residents of higher altitudes from low-income countries. Aim To compare cardiovascular risk estimated with validated score in population-based samples of permanent residents of low and high-altitude communities in Peru. Methods Study participants (adults permanently residing at either low or high altitude) were recruited by sex- and age-stratified random multistage cluster sampling from the general population of urban areas at different altitudes in Peru (lowlanders: &amp;lt;500 m above sea level, highlanders: cities at 3287 m, 3824 m and 4330 m). For all participants questionnaire-based information, conventional blood pressure (BP; 3 seated measurements with a validated oscillometric device) and laboratory variables were obtained. Based on the collected data atherosclerotic cardiovascular disease (ASCVD) risk was estimated according to Pooled Cohort Equations (PCE, previously calibrated in South American population). Participants below 40 years of age, with ASVCD history, with LDL-C≥190 mg/dL or on LDL-C lowering therapy were excluded from this analysis. Results The analysis included 146 lowlanders and 373 highlanders, most of whom had low 10-year ASVCD risk, with the median estimated risk being significantly higher among lowlanders. Comparisons between the groups in terms of principal variables of interest are reported in the Table. The highlanders were slightly younger, had lower BMI, conventional BP, HDL cholesterol, lower prevalence of antihypertensive medication and of diabetes, and higher heart rate. In a multivariable model the difference in ASCVD risk between lowlanders and highlanders was significant (p=0.0009) after adjusting for BMI and socio-economic variables but not after systolic BP was included in the model (p=0.800). Conclusions Residence at HA is associated with a lower estimated ASCVD risk in the general population of Peru, mainly because of lower BP levels. Considering that the prognostic value of cardiovascular risk estimates in highland populations is unknown, longitudinal cohort studies would be required to assess whether this finding is associated with a lower rate of cardiovascular events.

Enhancing primary prevention: the incremental predictive value of NTproBNP beyond ASCVD risk assessment

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a global health challenge, prompting widespread use of conventional risk assessment tools (SCORE2 in Europe and the ASCVD Risk calculator in the United States) to guide preventive strategies. Emerging evidence indicates that NTproBNP may help refine risk stratification. We investigate whether measuring NTproBNP in primary prevention correlates with mortality and enhances prediction compared to conventional risk score stratification. Methods Utilizing National Health and Nutrition Examination Survey (NHANES) data (1999 to 2004) linked to the National Death Index, our cohort included individuals without a history of CVD at baseline and suitable for assessment of the ASCVD ACC/AHA risk score. Individuals were grouped based on computed 10-year risk (low: &amp;lt;5%; borderline: 5-7.5%; intermediate: 7.5-20%; high: ≥ 20%). NTproBNP levels were measured (Roche assay, cut-off &amp;gt; 125pg/mL considered as positive). Cox regression estimated the association between ASCVD risk categories, with or without NTproBNP, and all-cause and cardiovascular mortality. Results Among 5257 adults, 47% male, mean age 54 ± 9.1 years, the mean 10-year ASCVD risk was 8.17 ± 8.2%, grouped as: low: 53.3%; borderline: 11.5%; intermediate: 23.9%; and high: 11.3%. NTproBNP &amp;gt; 125pg/mL was measured in 12.2%, 16%, 23.2% and 48.6% individuals, respectively (p &amp;lt; 0.001). Over 16.2 ± 3.4 years, all-cause and cardiovascular death was 22.3% and 5.6%, respectively. Compared to low-risk, the hazard ratio (HR) for all-cause death increased to 2.85 (2.2-3.7), 5.6 (4.2-7.5), and 15.3 (11.7-19.9) for borderline, intermediate, and high-risk, respectively. A significant interaction with NTproBNP was observed (low: HR 1.96 (1.33-2.9); borderline: HR 2.5 (1.6-3.9); intermediate: HR 2 (1.6-2.6), high: HR 1.7 (1.4-2.2), p&amp;lt;0.01 for all interactions, see Fig. 1). For cardiovascular death, a significant interaction also occurred across the groups, but of higher magnitude in low and borderline groups (low: HR 3.2 (1.4-7.3); borderline: HR 5.5 (2.5-12.4), p &amp;lt; 0.001 for both). Conclusion Our findings suggest that NTproBNP provides incremental predictive value, approximately doubling the hazard of all-cause death across all risk categories, and more than tripling the hazard of CV death in low/borderline risk groups, compared to ASCVD risk alone. The integration of NTproBNP measurements into risk assessment strategies could refine primary prevention approaches.

Enhancing primary prevention: the incremental predictive value of high-sensitivity cardiac troponin T beyond ASCVD risk assessment

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a global health challenge, prompting widespread use of conventional risk assessment tools (SCORE2 in Europe and the ASCVD Risk calculator in the United States) to guide preventive strategies. Emerging evidence indicates that high-sensitivity cardiac troponin (hsTn) may refine risk stratification. Objective We investigate whether measuring hsTnT in primary prevention correlates with mortality and enhances prediction compared to conventional risk score stratification. Methods Utilizing National Health and Nutrition Examination Survey (NHANES) data (1999 to 2004) linked to the National Death Index, our cohort included individuals without a history of CVD at baseline and suitable for assessment of the ASCVD ACC/AHA risk score. Individuals were grouped based on computed 10-year risk (low: &amp;lt;5%; borderline: 5-7.5%; intermediate: 7.5-20%; high: ≥ 20%). hsTroponin T levels were measured (Roche assay, 99 th percentile 22ng/L for men and 17ng/L for women). Cox regression estimated association between ASCVD risk categories, with or without hsTnT, and all-cause and cardiovascular mortality. Results Among 5257 adults, 47% male, mean age 54 ± 9.1 years, the mean 10-year ASCVD risk was 8.17 ± 8.2%, grouped as: low: 53.3%; borderline: 11.5%; intermediate: 23.9%; and high: 11.3%. hsTnT above the 99 th percentile was measured in 1.1%, 2.7%, 4.9% and 13.4%, respectively (p &amp;lt; 0.001). Over 16.2 ± 3.4 years, all-cause and cardiovascular death was 22.3% and 5.6%, respectively. Compared to low-risk, the hazard ratio (HR) for all-cause death increased to 2.85 (2.2-3.7), 5.6 (4.2-7.5), and 15.3 (11.7-19.9) for borderline, intermediate, and high-risk, respectively. A significant interaction with hsTnT above 99 th percentile was observed (low: HR 3.5 (1.3-9.2); borderline: HR 4.75 (2.1-10.8); intermediate: HR 2.6 (1.8-3.7), high: HR 2.2 (1.7-2.9), p&amp;lt;0.01 for all interactions, see Fig. 1). For cardiovascular death, a significant interaction occurred in intermediate (HR 3.3 (2-5.4), p&amp;lt;0.001) and high-risk (HR 3.6 (2.2-6), p&amp;lt;0.001) groups. Conclusion Our findings suggest that hsTnT provides incremental predictive value, at least doubling the hazard of all-cause death across all risk categories, and tripling the hazard of CV death in intermediate and high-risk groups, compared to ASCVD risk stratification alone. The integration of troponin measurements into risk assessment strategies could refine primary prevention approaches.

Artificial intelligence-enhanced electrocardiography predicts 10-year risk of atherosclerotic cardiovascular disease

Abstract Background The ACC/AHA pooled cohort equations (PCE) calculates the 10-year primary risk of atherosclerotic cardiovascular disease (ASCVD), an indication to initiate primary prevention statin therapy in international guidelines. The validity of PCE is limited by its overestimation of risk in high-risk cohorts and an ethnic heterogeneity. Electrocardiography (ECG) has not been incorporated in current ASCVD risk estimation tools. Artificial Intelligence (AI)-based models are capable to capture patterns that are informative for cardiovascular prognosis. Purpose We explored the predictive value of a discrete-time survival model in 10-year ASCVD risk in comparison to PCE. Methods We developed an AI-ECG model to predict the 10-year ASCVD risk in an unselected secondary care population from the USA comprised of 1,163,401 ECGs from 189,539 patients. Data was split into training/validation and hold-out test sets by patient ID. Our AI-ECG model uses deep learning with a residual convolutional neural network with a discrete-time survival loss function to output subject-specific survival curves, accounting for both time to event and censorship (i.e., loss to follow up). We compared the performance of out AI-ECG model using a subset of outpatient data (n=4590) of the BIDMC dataset to PCE and ASCVD risk factors including systolic blood pressure, total cholesterol, HDL cholesterol, hypertension, smoking history, diabetes mellitus, and ethnicity. Performances were evaluated using cox survival analysis. Our AI-ECG model was externally validated in the UKB Biobank (UKB), where we compared the performance of our AI-ECG model to predictions of existing AI-ECG models such as the Stanford Estimator of Electrocardiogram Risk (SEER) model. Results Our AI-ECG successfully predicted future ASCVD events in individuals (C-index 0.721 (0.719-0.723), 5-year AUC 0.761 (0.758-0.763), and differentiated between high and low risk group with an adjusted HR of 2.33 (2.26-2.41). Upon internal validation our AI-ECG model showed a superior performance (C-index 0.679 (0.651-0.708)) than PCE (0.605 (0.577-0.634)) and all risk factors combined (C index 0.642 (0.613-0.672)). When combining AI-ECG predictions with all risk factors, the model showed additional predictive value (0.686 (0.657-0.715)) (Figure 1). Our AI-ECG model showed modest predictive value within the UKB dataset (C-index 0.655 (0.637-0.673)), but significantly outperformed the SEER model (C-index 0.547 (0.527-0.567), p &amp;lt;0.0001 for comparison with AIRE). Conclusion We have shown the potential of AI-ECG models in predicting future ASCVD risks. AI-ECG models demonstrated accurate discrete time survival prediction and good classification performance superior to that of the SEER model, as well as PCE and ASCVD risk factors. . Accurate risk assessment of ASCVD may help prevent adverse events in high risk subjects and save unnecessary pharmacological interventios in low risk subjects.Figure 1

Red cell distribution width as a predictor of cardiovascular events in high-risk patients with statin intolerance: post-hoc analysis of the CLEAR Outcomes trial

Abstract Background Despite optimal lipid-lowering therapy there is up to 70% residual risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, motivating further testing of alternative risk factors and disease pathways. Red cell distribution width (RDW) is a simple and reproducible marker of heterogeneity of cell size in the peripheral blood. High RDW is associated with an increased risk of ASCVD and death, independent of established risk factors. Recent data suggest no significant impact of PCSK9 inhibitors on hsCRP or RDW. In CLEAR Outcomes, baseline hsCRP predicted risk for future cardiovascular (CV) events and death more strongly than elevated LDL-C. It has been shown that bempedoic acid (BA) reduces hsCRP, but its effects on RDW are unknown. Purpose To analyze the effect of BA on a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death (MACE-4) and for CV death by baseline RDW, and to confirm the association of increased RDW with elevated risk of MACE. Methods A total of 13,970 individuals with statin intolerance, with or at high risk for ASCVD, were randomized in the multinational CLEAR Outcomes trial with a median follow up of 3.4 years. Compared to placebo, BA reduced mean LDL-C by 21% and median hsCRP by 22% at 6 months. Quartiles of increasing baseline RDW were assessed as predictors of future adverse events after adjustment for traditional risk factors, hsCRP, and randomized treatment assignment. Results Compared to placebo, BA reduced mean RDW by 0.28% at 6 months and 0.13% at 36 months (p&amp;lt;0.0001). There was a weak positive correlation between hsCRP and RDW at baseline (Figure 1). In the placebo group, higher baseline RDW was associated with an increase in the likelihood of MACE-4 and CV death, and the hazard ratios (HR) associated with a 1% increase in RDW after adjusting for covariates and hsCRP were 1.06 (95% CI 1.02-1.11) and 1.22 (1.15-1.29), respectively. When grouped by quartiles of baseline RDW, compared with a reference group with lowest RDW (&amp;lt;13.7%), there was a notable increase in the risk of MACE-4 and CV death among the higher quartiles in the placebo group (Table 1). Those in the 4th quartile demonstrated a 3-fold increase in the risk of CV death (HR, 3.03, 2.00-4.60). The adjusted HRs (95% CI) for BA vs placebo for MACE-4 were generally lower in individuals with elevated baseline RDW than in those in the first quartile [Q1: RDW≤13.7%; 0.96 (0.79-1.17), Q2: RDW 13.7%-14.4%; 0.81 (0.67-0.97), Q3: RDW 14.4%-15.2%; 0.90 (0.75-1.09), and Q4: RDW&amp;gt;15.2%; 0.84 (0.7-1.01)]. Conclusions In a large randomized controlled clinical trial setting, we confirmed an association between elevated RDW and MACE-4. Compared with placebo, BA demonstrated efficacy in reducing CV risk in patients with moderately increased RDW.Figure 1.Correlation of hsCRP and RDWTable 1.Risk of Outcome by RDW Quartile

Dapagliflozin versus empagliflozin and major adverse cardiovascular events in type 2 diabetes: a nationwide cohort study

Abstract Background Large randomized clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus (T2DM) at high risk of atherosclerotic cardiovascular disease. Whether these effects might differ between individual SGLT2-inhbitors remain unclear given the lack of head-to-head comparisons. Purpose To examine the association between treatment with dapagliflozin versus empagliflozin and the long-term rate of major adverse cardiovascular events (MACE) in patients with T2DM. Methods Using nationwide registries, all Danish residents with T2DM, who initiated treatment with dapagliflozin or empagliflozin from 2015 to 2020, were identified. Only treatment with dapagliflozin or empagliflozin was considered in the present analysis, since approximately 3% initiated treatment with other SGLT2-inhibitors (i.e., canagliflozin and ertugliflozin). Patients were followed from date of the first claimed prescription of dapagliflozin or empagliflozin until the outcome of interest, emigration, death, or end of study (December 31, 2021). The primary outcome was a composite endpoint of major adverse cardiovascular events (i.e., time to first heart failure hospitalisation, acute myocardial infarction (AMI), stroke, or all-cause mortality). The primary outcome was compared between the dapagliflozin and empagliflozin group, overall and in prespecified subgroups of interest, with multivariable Cox proportional hazards regression models. Results In total, 61,031 patients with T2DM initiated treatment with dapagliflozin (N=21,028; 34.5%) or empagliflozin (N=40,003; 65.5%). The median age of study population was 62.6 years (25th-75th percentile, 54.2-70.8 years), and 62.6% were men. There were no clinically significant differences between the dapagliflozin and empagliflozin group with respect to age, sex, and clinical characteristics. The median follow-up was 3.1 years (25th-75th percentile, 1.9-4.5 years). The adjusted long-term hazard ratios of the primary outcome, overall and in prespecified subgroups of interest, are displayed in the Figure. Compared with empagliflozin, treatment with dapagliflozin was not associated with a significantly different rate of the primary outcome (HR 1.02 [95% CI, 0.97-1.07]). The observed association was consistent across clinically relevant subgroups, including in patients with and without heart failure, chronic kidney disease, and atherosclerotic cardiovascular disease. Conclusion In a large, nationwide cohort of patients with T2DM, treatment with dapagliflozin was associated with a similar rate of major adverse cardiovascular outcomes compared with empagliflozin, and this association was consistent across clinically relevant subgroups. These findings suggest that the benefits of SGLT2-inhibitors can be characterized as a class-effect.

Effect of green coffee on miR-133a, miR-155 and inflammatory biomarkers in obese individuals

ObjectivesMetabolic syndrome is a cluster of conditions that increases the risk of atherosclerotic cardiovascular diseases. The current study was a randomized, double blind, placebo-controlled study that aimed to determine the impact of green coffee (GC) in obese patients with metabolic syndrome through analysis of miRNA-155, miRNA-133a and the inflammatory biomarkers such as resistin, TNF-α, total sialic acid, homocysteine, high sensitivity C-reactive protein (hs-CRP), and the anti-inflammatory cytokine, adiponectin.MethodsOne hundred-sixty obese patients were randomly supplemented either with GC capsules (800 mg) or placebo daily for six months. Both groups were advised to take a balanced diet. Blood samples were collected at baseline and after six months of supplementation.ResultsGC supplementation for 6 months reduced BMI (p = 0.002), waist circumference (p = 0.038), blood glucose (p = 0.002), HbA1c% (p = 0.000), Insulin (p = 0.000), systolic blood pressure (p = 0.005), diastolic BP (p = 0.001) compared with placebo. GC significantly decreased total cholesterol (TC, p = 0.000), LDL-C (p = 0.001), triglycerides (TG, p = 0.002) and increased HDL-C (p = 0.008) compared with placebo group. In addition, GC significantly (p ≤ 0.005) reduced total sialic acid, homocysteine, resistin, TNF-α, hs-CRP and the oxidative stress marker malondialdehyde (MDA), but increased serum adiponectin (p = 0.000) compared to placebo group. There was a significant reduction in the gene expression of miR-133a (p = 0.000) in GC group as compared with baseline levels and with the control placebo group (p = 0.001) after 6 months.ConclusionGC administration modulated metabolic syndrome by decreasing BMI, high BP, blood glucose, dyslipidemia, miRNA-133a and inflammatory biomarkers that constitute risk factors for cardiovascular diseases.ClinicalTrials.gov registration No. is NCT05688917.Graphical

Utility of the triglycerides/HDL cholesterol ratio in older adult patients in Colombia

Abstract Introduction Alterations in lipid metabolism are responsible for atherogenesis and an increased risk of atherosclerotic cardiovascular disease. The triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) is used to assess the risk of cardiovascular diseases; however, it has not been evaluated in older adults. The aim of the present study is to evaluate the TG/HDL-C ratio in elderly patients and analyze its correlation and discriminatory capacity with cardiovascular risk factors according to data from the SABE Colombia survey. Purpose Describe the sociodemographic characteristics, cardiovascular history, lifestyle, and cardiovascular risk score in the older adult population included in the SABE Colombia Study.Describes the distribution of triglyceride levels, cholesterol, and the TAG-HDL ratio in the older adult population included in the SABE Colombia Study. Evaluate the relationship between the TAG/HDL Cholesterol Index and cardiovascular risk factors such as hypertension, prediabetes, type 2 diabetes mellitus, cardiovascular disease, cerebrovascular disease Determine if there is a correlation and the degree of correlation between the TAG/HDL Cholesterol ratio and variables related to higher cardiovascular risk and stablish cutoff points of the triglyceride to HDL cholesterol ratio as indicators of the onset of risk factors Materials and Methods Cross-sectional study in adults aged 60 years and older included in the national SABE Colombia survey (National Survey of Health, Well-being, and Ageing conducted in Colombia in 2015), which included 244 municipalities from all departments of the country. A correlation test was performed to assess the presence and degree of correlation between the TAG/HDL index and cardiovascular risk factors, and ROC curve analysis was conducted to evaluate the performance of the TAG/HDL index in identifying risk factors. Results A total of 23,694 patients with the necessary information for the study were included. The median age was 69 years, 57.3% were women, and 34.3% were of white race. 23.5% had hypertension, and 16.4% had diabetes mellitus. 13.4% had a history of cardiovascular disease, and 2.5% had cerebrovascular disease. While the specific correlation between the index and different cardiovascular risk factors is generally low to moderate, good discriminatory capacity was found for diabetes and metabolic syndrome with the following values: diabetes, with an area under the curve (AUC) of 0.871 and a cut-off point of 9.17; and for metabolic syndrome, the AUC was 0.840, with a cut-off point of 8.81. Conclusions Our findings show that the TG/HDL ratio has intermediate correlation for different cardiovascular risk factors; however, it has excellent predictive ability for the presence of diabetes and metabolic syndrome. These findings are very useful in the clinical evaluation, screening, and detection of cardiovascular risk factors in the population aged 60 years and older in Colombia.Scatter plots of TAG/HDL ratio comparedROC curves for diabetes and metabolic s

High prevalence of coronary artery calcium and aortic calcification in adults with repaired coarctation of the aorta and interrupted aortic arch

Abstract Background There is a high rate of late cardiovascular mortality in patients with repaired coarctation of the aorta (CoA) and interrupted aortic arch (IAA). Coronary artery calcium (CAC) is a marker of cardiovascular disease and there is growing evidence for aortic calcification as a predictor. Recent research in the general population suggests any CAC in males &amp;lt;35 years old and females ≤45 years places them at ≥90th percentile. Aims We aimed (1) to determine the prevalence of CAC, thoracic aorta calcification (TAC), and abdominal aorta calcification (AAC) in patients with CoA or IAA repair, and (2) to compare patients to a control group of Tetralogy of Fallot (TOF) patients, a condition with no known increased risk of atherosclerotic cardiovascular disease. Methods Retrospective cohort study of adult survivors of CoA/IAA repair followed up at an adult congenital heart disease (ACHD) clinic. Patients with at least 1 chest, abdomen, or pelvis computerised tomography (CT) scan for any indication were included. The presence/absence of calcification in the coronary arteries or aorta was assessed qualitatively. Patients on antihypertensive and statin therapy were considered hypertensive and hypercholesterolaemic, respectively. Patients were compared to adult survivors of TOF repair with CT scans for any indication (controls). Results Ninety-three CoA/IAA patients (87% CoA/13% IAA, median age at latest follow-up 34 years) had a total of 169 chest and 37 abdomen/pelvis CTs; 82, 93, and 37 patients had at least 1 CT suitable for CAC, TAC, and AAC review, respectively. CAC was present in 22% (18/82), TAC in 33% (31/93), and AAC in 23% (5/22) of CoA/IAA patients. CAC was present in 12% (18/153) and TAC in 11% (18/158) of TOF patients. CoA/IAA patients were more likely to have CAC and TAC than TOF patients (p=0.04 and p&amp;lt;0.0001; respectively) and be younger at the time of diagnosis (CAC p=0.03, TAC p=0.0001) despite TOF patients being older at time of latest CT scan (p=0.0003) (Table 1). Males aged &amp;lt;35 years and females ≤45 years represented 44% (8/18) of CoA/IAA patients with CAC. CoA/IAA patients with CAC were more likely to be hypertensive and hypercholesterolaemic than those without (78% [14/18] vs 48% [31/64], p=0.03; and 28% [5/18] vs 0% [0/64], p&amp;lt;0.0001; respectively) and was similar for TAC (hypertension p=0.005, hypercholesterolaemia p=0.04) but not AAC. After a mean follow-up of 11±7 years from first ACHD clinic, of the 93 patients, 2 patients died, 5 had coronary artery disease (at least mild stenosis on invasive angiography), 3 had a stroke, and 70% (65/93) were considered hypertensive at latest follow-up. Conclusions There is a high prevalence of CAC, aortic calcification, and hypertension in young adults with repaired CoA/IAA. Coronary and thoracic aortic calcification occurs at a younger age compared to controls. Further studies are warranted to assess the impact of aggressive cardiovascular risk reduction in this high-risk group.

An epigenetic editor targeting human PCSK9 efficiently and durably lowers Low Density Lipoprotein Cholesterol (LDL-C) in non-human primates

Abstract Background Reducing the risk of atherosclerotic cardiovascular disease is dependent on both the magnitude and cumulative duration of LDL-C lowering. However, in clinical practice achieving treatment goals is often hampered by low adherence to standard of care. Although PCSK9 inhibitors represent an effective option for LDL-C lowering, they require chronic life-long treatment. Epigenetic editing is a new therapeutic approach designed to durably silence genes by leveraging nature’s endogenous cellular mechanism for gene regulation via CpG methylation without the inherent genotoxic risks of genome editing approaches that nick or cut the DNA. We are developing a PCSK9 epigenetic editor (PCSK9-EE) to durably silence PCSK9, with the promise of lifelong reduction in LDL-C. Methods Here, we describe the development of an epigenetic editor targeting human PCSK9. This epigenetic editor consists of a DNA targeting component fused to a transcriptional repressor domain and a DNA methyltransferase domain. PCSK9-EE was first screened and evaluated for specificity and efficacy in primary human hepatocytes (PHH). In vivo efficacy and durability were then evaluated in a transgenic mouse carrying the human PCSK9 genomic locus (hPCSK9-Tg mouse) and non-human primates (NHP). Results Our initial screen of PCSK9-EEs identified several hits that efficiently suppressed secreted PCSK9 levels in immortalized liver cells. We confirmed that our top PCSK9-EE candidates robustly decreased PCSK9 secretion in PHH and were found to be highly specific at targeting PCSK9 as assessed by RNA-seq, methylation array, and whole-genome methylation sequencing. To examine in vivo activity, we treated hPCSK9-Tg mice with a single administration of a lipid nanoparticle delivering mRNA encoding our PCSK9-EE and observed &amp;gt;97% reduction in liver PCSK9 mRNA, and &amp;gt;98% reduction in plasma PCSK9 for the duration of the study (one year). We then delivered PCSK9-EE in NHP and observed a robust reduction in plasma PCSK9 with a concomitant reduction in LDL-C. These effects were found to be durable for at least 6 months following a single administration of PCSK9-EE in NHP. To establish a mechanistic relationship between PCSK9-EE’s molecular action and durable PCSK9 silencing, we performed serial liver biopsies in each NHP approximately 2 months apart. Robust CpG methylation at the PCSK9 genomic locus was observed in the first liver biopsy and was comparable to that observed in the second liver biopsy suggesting that PCSK9-EE induced stable CpG methylation in NHP livers. Conclusions We believe PCSK9-EE may offer an effective, safe, and durable approach to suppress hepatic PCSK9 expression and achieve long-lasting reduction in LDL-C. Furthermore, epigenetic editing may hold promise for one-and-done approaches for the treatment of atherosclerotic cardiovascular disease without cutting, nicking, or altering the DNA sequence.

Pregnancy complications and long-term risk of cardiovascular events in women with heart disease

Abstract Background/Introduction Women with congenital heart or acquired heart disease are at increased risk of atherosclerotic cardiovascular disease. Pregnancy complications are established risk factors for cardiovascular disease in the general population, but their prognostic value for cardiovascular outcomes in the population with congenital or acquired heart disease is unknown. Purpose To determine the frequency and prognostic value of pregnancy complications for the risk of cardiovascular outcomes in women with congenital or acquired heart disease. Methods This nationwide registry-based cohort study included women in Sweden with heart disease (pulmonary arterial hypertension, congenital heart disease or acquired valvular heart disease) with singleton births registered in the national Medical Birth Register between 1973 and 2014. Exposures of pregnancy complications (preeclampsia/gestational hypertension, preterm birth or birth of an infant small for gestational age) were collected from the Medical Birth Register, and cardiovascular outcomes (mortality and hospitalizations) from the Cause of Death Register and the National Inpatient Register. Cox regression models were performed with time-dependent covariates, to determine the possible prognostic value of the studied pregnancy complications for cardiovascular outcomes including atherosclerotic cardiovascular disease, heart failure and arrythmias after adjustment for major confounding including smoking and body mass index. Results Among the total of 2,134,239 women included from the Medical Birth Register, 2,554 women with 5,568 singleton births were affected by heart disease. Preeclampsia/gestational hypertension affected 5.8% of pregnancies, preterm birth 9.7%, and birth of an infant small for gestational age 2.8%. Preterm birth (adjusted HR 1.91 (95% CI 1.38-2.64)) was associated with an increased risk of maternal all-cause mortality. Preeclampsia/gestational hypertension (adjusted HR 1.64 (95% CI 1.18-2.29)) and preterm birth (adjusted HR 1.56 (95% CI 1.19-2.04)) were associated with an increased risk of hospitalizations for atherosclerotic cardiovascular disease. Conclusions Pregnancy complications were frequent in women with congenital or acquired heart disease. With a median follow-up time of 22 years, preterm birth was associated with a higher risk of cardiovascular mortality, and preeclampsia/gestational hypertension and preterm birth were associated with cardiovascular morbidity. In women with heart disease, pregnancy complications may provide additional information for the risk assessment of future cardiovascular outcomes.Overview of study designPrevalence and risk estimation

Lipoprotein(a) metabolomic and proteomic features and atherosclerotic cardiovascular disease in young, asymptomatic adults

Abstract Background Lipoprotein (a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. Although Lp(a) is a powerful genetic risk factor for ASCVD, the pathways that mediate this risk and the associated metabolomic and proteomic features that capture this risk are unknown. Methods In young, asymptomatic Coronary Artery Risk Development in Young Adults (CARDIA) participants, we defined the relationships between Lp(a) and metabolomic (n=563)/proteomic (n=184) features, derived quantitative Lp(a)-omic scores from these features, and related these quantitative scores to ASCVD phenotypes. Results CARDIA subjects had a mean age of 32 years and a median follow-up of 27 years. In the overall cohort (n=3920), Lp(a) levels at year 7 (Y7) were significantly associated with ASCVD endpoints, including hs-CRP, coronary artery calcification (CAC), death, and incident CHD (Figure 1A). In the subcohort (n=2290) that had measurements of Lp(a), proteomics, and metabolomics, Y7 Lp(a) levels were associated with distinct proteomic and metabolomic features indicative of immune responses, lipoprotein metabolism, atherogenesis, and arginine/steroid biosynthesis. Using machine learning approaches, Lp(a) metabolomic, proteomic, and transomic quantitative scores were derived. After adjustment, the Lp(a) transomic score was more strongly related to incident CAC, degree of CAC, CRP, and incident CHD than Lp(a) itself (Figure 1B). Conclusions To our knowledge, this is the first study to examine the relationship between Lp(a), metabolomic/proteomic features, and ASCVD phenotypes in young, asymptomatic adults. The multi-omics approaches employed here provide insight into the pathobiology of Lp(a)-driven ASCVD and enable more nuanced mechanistic risk assessment compared with Lp(a) alone.

Physician disagreement with treatment guidelines as a critical barrier to achieving low-density lipoprotein cholesterol targets in very high-risk patients: an implementation science study

Abstract Background/Introduction The challenges that physicians face in implementing evidence-based lipid-lowering therapy in patients at high risk of atherosclerotic cardiovascular disease (ASCVD) are relatively undocumented. Purpose This study aimed to provide insights into the challenges that Korean physicians face in assisting their high-risk ASCVD patients in achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels. Methods We enrolled 704 patients from 10 tertiary hospitals in South Korea, between November 2020 and November 2022. These patients were at very high risk of ASCVD, with baseline LDL-C levels ≥70mg/dL (1.8 mmol/L) while receiving maximally tolerated statins and/or ezetimibe. We measured the proportion of participants achieving LDL-C levels &amp;lt;70mg/dL at visit 1(0)/ visit 2(6-16)/ visit 3 (18-30 weeks), and recorded physician feedback on lipid-lowering treatment strategies. Results Out of the 704 enrolled patients (mean [IQR] age, 66.0 [59–72] years; 580 men [82.4%]), the median (IQR) baseline LDL-C level was 82.0 (74.0–94.5) mg/dL. Lipid-lowering therapy at baseline included statins in 99.0% (with 1.0% statin intolerant) or statins and ezetimibe in 56.4%. The proportion of participants achieving LDL-C levels &amp;lt;70mg/dL at each visit were 0%, 56.3%, and 58.7%, respectively. Among 307 patients on maximally tolerated statins at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 171 (55.7%) of those patients. (Figure 1) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (70.8%), followed by the patient’s refusal for reasons other than the cost (8.2%), medical limitations such as comorbidities (7.0%), and drug costs (6.4%). Among 397 patients on maximally tolerated statins and ezetimibe at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 299 (75.3%) of those patients. (Figure 2) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (46.2%), followed by the patient’s refusal for reasons other than the cost (15.7%), medical limitations such as comorbidities (14.4%), and drug costs (12.7%). Conclusion In this implementation science study, the proportion of patients at very high risk of ASCVD who achieved LDL-C levels &amp;lt;70mg/dL via lipid-lowering therapy was less than 60%. Physician disagreement with the guidelines was the main reason for not adopting the recommended intensified LDL-C lowering therapy.Figure 1Figure 2

Rationale and design of the SHASTA-3 and SHASTA-4 studies: randomized, double-blind, placebo-controlled, phase 3 studies of plozasiran in patients with severe hypertriglyceridemia

Abstract Severe hypertriglyceridemia (sHTG) confers an increased risk of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP). sHTG-associated AP is a substantial source of morbidity, mortality, reduced quality of life and financial burden to health care systems. Currently available therapeutic approaches for sHTG are often insufficient to reduce triglyceride (TG) levels and prevent AP. Plozasiran, an investigational siRNA therapeutic, inhibits hepatic production of apolipoprotein C3 (APOC3), a key regulator of lipoprotein lipase-mediated TG metabolism and clearance. In a phase 2 study of sHTG patients [TG ≥500 mg/dL (≥5.65 mmol/L)], plozasiran demonstrated durable reductions in TG levels of up to -80%, 12 weeks after the last dose, and decreased TG below 500 mg/dL (5.65 mmol/L), a threshold of increased risk for AP in most participants. The SHASTA-3 and SHASTA-4 trials will evaluate safety and efficacy of plozasiran, including AP rates, in patients with sHTG. SHASTA-3 and SHASTA-4 are phase 3, randomized, double-blind, placebo-controlled, multi-center trials. Key inclusion criteria are prior sHTG and fasting TG ≥500 mg/dL (≥5.65 mmol/L), at screening. Key exclusion criteria include use of any hepatocyte targeted siRNA treatments that target lipids and/or TGs within 1 year (except inclisiran at least 4 weeks prior to enrollment), siRNA or ASO within 60 days, known FCS diagnosis, and AP within 4 weeks of screening. 700 adults with sHTG will be enrolled in these two trials in several sites across multiple countries. Patients will be randomized 2:1 to receive 4 quarterly subcutaneous injections of plozasiran 25 mg or matching placebo over a 1-year double-blinded period, followed by post-treatment evaluation or entry into the open-label extension study. The randomization will be stratified based on TG levels (≥880 mg/dL vs &amp;lt;880 mg/dL [≥ vs &amp;lt;10 mmol/L]) and prior history of AP, within 5 years of screening. The primary efficacy endpoint of the studies is placebo-adjusted percent change in fasting TG from baseline to month 12 with plozasiran. Secondary endpoints include percent change in fasting TG from baseline to month 10 compared to placebo, percent of patients achieving fasting TGs of &amp;lt;500 mg/dL (&amp;lt;5.65 mmol/L) and TGs of &amp;lt;150 mg/dL (&amp;lt;1.69 mmol/L) at month 10 and 12 compared to placebo, and event rate of adjudicated abdominal clinical events including ER visits and hospitalization for abdominal pain attributed to HTG and events of documented pancreatitis. The effect of plozasiran on other lipids and lipoproteins, inflammatory biomarkers, and liver fat content using magnetic resonance imaging-proton density fat fraction will be assessed. Adjudicated major adverse cardiovascular event rates, safety and tolerability will be assessed. SHASTA-3 and SHASTA-4 are designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran, added to standard of care, safely reduces TG levels and the rate of AP in patients with sHTG.

Body mass index as a contributor to the accumulation of lipidic plaque materials in statin-treated type 2 diabetic patients with coronary artery disease: sub-analysis from the OPTIMAL randomized study

Abstract Background Patients with type 2 diabetes mellitus more likely exhibit obesity. Pathophysiologically, obesity promotes a range of metabolic disturbances including insulin resistance, dyslipidemia and hypertension, in addition to the secretion of adipokines and pro-inflammatory cytokines from excessive fat accumulation. These atherogenic features may promote instability of atherosclerotic plaques, which ultimately result in elevating a risk of atherosclerotic cardiovascular disease. However, it remains to be fully elucidated how obesity affects atherosclerotic plaque features in type 2 diabetic patients with coronary artery disease (CAD). Near-infrared spectroscopy (NIRS) imaging enables to quantitatively visualize lipidic plaque materials in vivo. This imaging modality provides insights into lipidic plaque features in obese patients with type 2 diabetes mellitus. Purpose To elucidate the association of body mass index (BMI, kg/m2) with lipidic plaque materials in type 2 diabetic patients. Methods The OPTIMAL study was a prospective randomized controlled trial to evaluate the efficacy of continuous glucose monitoring (CGM) guided glycemic control on coronary atherosclerosis in statin-treated type 2 diabetic participants with CAD requiring PCI. 94 patients were randomized into CGM-guided or HbA1c-guided glycemic control. Serial NIRS imaging was conducted to monitor non-culprit lesions at baseline and week 48. The current sub-analysis included 78 patients with both baseline BMI data and evaluable baseline NIRS/IVUS images. Results All of study subjects received a statin (high-intensity statin use=36%), and the averaged LDL-C level was 86.7±26.3 mg/dL. The average BMI and HbA1c level were 24.7±3.1 kg/m2 and 7.5±0.9%, respectively (Table 1). On NIRS imaging analysis, maxLCBI4mm at non-culprit lesions was 286.2±167.0, and 21.8% of study subjects exhibited maxLCBI4mm &amp;gt;400 (Table 2). BMI was associated with maxLCBI4mm (p&amp;lt;0.001). Multivariate analysis adjusting clinical characteristics and LDL-C demonstrated that BMI was an independent contributor to maxLCBI4mm [estimate=17.15 (12.88-21.42), p&amp;lt;0.001] (Table 2). Even in patients receiving high-intensity statin, BMI was still associated with maxLCBI4mm (p&amp;lt;0.001). Conclusions A greater accumulation of lipidic plaque materials was observed in association with BMI in statin-treated type 2 diabetic patients with CAD. This presence of enhanced plaque vulnerability at non-culprit lesions, in the setting of obesity, may contribute to an increased risk of cardiovascular events in type 2 diabetic patients with CAD. The current finding suggests the need to adopt further therapeutic approaches to favourably modify plaque vulnerability in type 2 diabetic patients exhibiting obesity.Table 1:Clinical DemographicsTable 2:Factors Associated with maxLCBI

Composition of non-HDL cholesterol and residual cardiovascular risk in secondary prevention

Abstract Background Non-high-density lipoprotein cholesterol (non-HDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD) and is a recommended secondary prevention treatment target. However, the composition of non-HDL-C, that is, the relative contribution of remnant cholesterol (remnant-C) and low-density-lipoprotein cholesterol (LDL-C), is not considered for cardiovascular risk prediction. Purpose To examine ASCVD risk by composition of non-HDL-C. Methods Based on the Western Denmark Heart Registry, we established a cohort of patients with ischemic heart disease, including patients with acute coronary syndrome or stable angina pectoris, undergoing coronary angiography for evaluation of coronary artery disease between 2011 and 2020. A complete lipid panel within 1 year after coronary angiography on statin treatment was required. Patients with triglycerides &amp;gt;4.5 mmol/L were excluded. Exposures were remnant-C, LDL-C, non-HDL-C, and composition of non-HDL-C. The latter was defined as remnant-C of non-HDL-C, and LDL-C of non-HDL-C, in percentages. Cox regression analyses obtained adjusted hazard ratios (aHR) for myocardial infarction, ASCVD (myocardial infarction, ischemic stroke, and cardiovascular death), and all-cause death occurring from 1 year after coronary angiography to end of follow-up November 1, 2022. Results The secondary prevention cohort included 42,341 statin-treated patients (67.7% were men; median [IQR] age 66 [58-73] years). During median 4.1 years of follow-up, 3,846 patients developed ASCVD. Per 1 mmol/L increase in remnant-C, LDL-C, and non-HDL-C, the aHR for ASCVD was 1.41 (95% CI 1.28-1.55), 1.12 (95% CI 1.08-1.17), and 1.17 (95% CI 1.13-1.21), respectively (Figure 1). The relative contribution of remnant-C and LDL-C was median (IQR) 24.6% (18.5-33.1) and 75.4% (66.9-81.5) of non-HDL-C, respectively. When remnant-C constituted a larger percentage of non-HDL-C (and LDL-C a lower percentage), the aHR for ASCVD showed a linear increase in risk whereas the opposite trend was observed for LDL-C (Figure 2). Thus, per 10% increase in remnant-C of non-HDL-C, the aHR of ASCVD was 1.06 (95% CI 1.03-1.09) compared to 0.94 (95% CI 0.91-0.97) per 10% increase in LDL-C of non-HDL-C. Results were comparable for myocardial infarction and all-cause death, and by age, sex, and other clinically relevant subgroups. Conclusions The composition of non-HDL-C is strongly associated with ASCVD risk, with the risk escalating as remnant-C constitutes a larger percentage, and LDL-C a smaller percentage, of non-HDL-C. These findings challenge current guidelines and demonstrate the value of considering composition of non-HDL-C in clinical practice for more accurate risk assessment.Figure 1Figure 2

Lipoprotein(a) levels and cholesterol efflux capacity: inverse association and impact on atherosclerosis in familial hypercholesterolemia patients on lipid-lowering therapy

Abstract Backgrounds Familial hypercholesterolemia (FH) patients have higher serum lipoprotein(a) (Lp(a)) levels than non-FH patients, and high Lp(a) levels raise atherosclerotic cardiovascular disease (ASCVD) risk 1). We previously reported that decreased cholesterol efflux capacity (CEC) is a risk marker for ASCVD in patients with statin-treated FH 2). Others have reported that Lp(a) interferes with the enhancement of ABCA1-mediated cholesterol efflux by plasminogen and that ABCA1-mediated CEC is lower in patients with Lp(a) &amp;gt;50 mg/dL. However, the association of CEC, not necessarily ABCA1-mediated, with Lp(a) is not clear and has not been studied in patients with FH. It is also unclear whether high Lp(a) and low CEC in patients with FH are associated with the severity of atherosclerosis. Purpose We examined whether Lp(a) levels are negatively associated with ABCA1-independent CEC in patients with FH receiving lipid-lowering therapy. We also examined the impact of the combination of high Lp(a) and low CEC on the presence of corneal arcus, Achilles tendon thickness, carotid intima-media thickness (IMT), and pre-existing ASCVD. Methods This cross-sectional study included 371 patients clinically diagnosed with FH receiving lipid-lowering therapy. CEC was measured in apolipoprotein B-depleted plasma and 3H-cholesterol-labeled J774.1 cells without cAMP-stimulated ABCA1 overexpression. Lp(a) was measured by enzymatic methods (Sekisui Medical, Tokyo, Japan) using an automated analyser. Achilles tendon thickness was measured by X-ray and carotid IMT by ultrasound. Results Mean age was 55±16 years, and 191 (51%) were women. The median serum Lp(a) level was 18.7 mg/dL, higher than the previously reported median level (13 mg/dL) in a Japanese population. One hundred nineteen patients (32%) had serum Lp(a) levels of 30 mg/dL or higher, and they had significantly lower CEC (P=0.0015). This negative association persisted after adjusting for age, sex, BMI, smoking status, serum LDL-cholesterol, serum triglycerides, and eGFR in a multiple linear regression model (beta-coefficient: -0.047, 95% CI: -0.075 - -0.019, P=0.0011). In addition, patients with both Lp(a) &amp;gt; 30 mg/dL and CEC lower than the median had a higher percentage of corneal arcus, thicker Achilles tendons, greater carotid IMT, and a higher prevalence of pre-existing ASCVD compared to patients with either or neither. Conclusions We found an inverse relationship between Lp(a) levels and CEC in FH patients receiving lipid-lowering therapy. Our results suggest that Lp(a) may also inhibit ABCA1-independent CEC, including passive cholesterol diffusion from peripheral cells. Furthermore, the combination of high Lp(a) and low CEC may be a residual risk for patients with FH receiving lipid-lowering therapy. Future studies are needed to determine whether agents that decrease Lp(a) levels will increase CEC and thereby resolve part of the residual ASCVD risk in FH.