Atherosclerotic Cardiovascular Disease Risk Research Articles

Symptoms and ASCVD score fail to identify majority of the patients at risk of first myocardial infarction

Abstract Background Cardiovascular disease screening has long relied on the presence of symptoms like chest pain or on the Atherosclerotic Cardiovascular Disease (ASCVD) risk score, which is typically initiated at age 40. However, current research suggests that the ASCVD risk score may not incorporate a comprehensive range of factors and should be started earlier. Furthermore, the absence of symptoms such as angina in some patients prior to acute coronary syndrome (ACS) casts doubt on the reliability of symptom-based screening methods. Purpose This study aimed to evaluate the effectiveness of the ASCVD risk score and chest pain as predictors for ACS. Methods We retrospectively analyzed the data of all patients of 65 or younger who presented with their first ACS event in a single US center from January 2020 to January 2024. We collected the demographic and clinical data, including age, sex, lipid panel, blood pressure, medical history, onset of symptoms, and calculated their individual ASCVD risk score. We explored whether these patients, if assessed one week before their ACS event, would have been identified as at risk and thus prescribed lipid lowering or recommended for further diagnostic tests. Results Among 166 patients presenting with ACS, 64 (39%) were considered low risk with an ASCVD risk score of <5 or too low to calculate. 20 (12%) patients were assessed as borderline risk with an estimated risk score of 5-7.5%. In the intermediate risk category, 20 patients (12%) had a score of 7.5% -10% and 42 patients (25%) were estimated to have a score of >10 to <20%. 14 patients (8%) fell in the high-risk category, and lastly 6 patients had an LDL that was above 190 mg/dl. Regarding symptoms of chest pain or shortness of breath, 14 patients (8%) did not experience any symptoms prior to their presentation, 98 (59%) patients experienced their first episode of symptoms within 48 hours, 19 patients (11%) within 2 days to a week, 10 patients (6%) had CP leading up to their event from a week to a month, 6 patients (4%) in the range of a month to 3 months and 19 patients (11%) had symptoms longer than 3 months prior to their presentation. To summarize if there were seen 1 week prior to their first ACS events, 51% of them were not recommended for statin therapy based on their ASCVD risk score and 67% of patients either had no chest pain until the event or chest pain within 48hrs of onset of their ACS and consequently would not have been routinely screened for coronary artery disease (CAD) by any anatomical or functional methods. Conclusion(s) ASCVD risk score and symptoms fail to identify majority of patient below 65 years of age with their first MI. Given high prevalence of CAD and associated mortality, improved screening tools, in addition to symptomatology or risk scores, would be more effective in identifying individuals at risk.

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) >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) > 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.

Peroxisome proliferator-activated receptor gamma regulates interleukin-6 induced lipoprotein(a) gene expression in human HepG2 cells

Abstract Background Lipoprotein(a)[Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and outcomes. The LPA gene promoter contains an interleukin 6 (IL-6) responsive binding site. IL-6 is a pro-inflammatory cytokine and data from patients with inflammatory diseases indicate an impact of the inflammatory milieu on LPA gene regulation and Lp(a) production. In a clinical study, the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone was associated with decreased Lp(a) levels. Publicly accessible ChIP-sequencing of human hepatocytes and measures of Lp(a) production by HepG2 cells provide an opportunity to explore PPARγ regulation of hepatic Lp(a) production. Purpose To investigate the role of PPARγ as a regulator of hepatic Lp(a) production. Methods Public ChIP-sequencing of human hepatocytes was analyzed. Commercially available HepG2 cells were incubated with one of the following: (1) scrambled small interfering RNA (siRNA) alone (control); (2) IL-6 (20ng/mL) and scrambled siRNA ; (3) IL-6 and PPARγ siRNA ; and (4) IL-6 and pioglitazone (25uM). LPA transcription was measured using the quantitative polymerase chain reaction. Results Analysis of the ChIP-sequencing data demonstrated that the LPA locus variant rs56393506, which is associated with increased Lp(a) levels and ASCVD risk in the general population, was within the location of the PPARγ binding site in the LPA promoter (Figure 1). IL-6 significantly increased LPA transcription in the HepG2 cells, compared to control (1.65±0.44 vs. 0.66±0.45, p=0.0027). In the presence of siRNA-mediated knock-down of PPARγ (58±17% PPARγ reduction, p<0.0001 vs. scrambled control), the effect of IL-6 on LPA transcription was significantly amplified (6.78±2.4 vs. 1.65±0.44, p=0.0009). IL-6 did not increase LPA transcription in the presence of the PPARγ agonist pioglitazone compared to control (0.16±0.03 vs. 0.66+0.45, p=0.11, Figure 2). Conclusion PPARγ is a negative regulator of IL-6 induced hepatic Lp(a) production and may represent a new therapeutic target in patients with inflammatory conditions.Figure 1Figure 2

Combination of moderate-intensity statins and ezetimibe versus high-intensity statins alone for primary prevention of cardiovascular events

Abstract Background Combination of a moderate-intensity statin with ezetimibe can lead to similar reductions in cardiovascular events as monotherapy with a high-intensity statin in patients with established atherosclerotic cardiovascular disease (ASCVD). The comparative effectiveness of these two cholesterol-lowering strategies in the primary prevention setting is unknown. Purpose To compare incident ASCVD events associated with a combination of moderate-intensity statin and ezetimibe versus monotherapy with a high-intensity statin in adults without prior history of cardiovascular disease. Methods We conducted a new-user active comparator retrospective population-based cohort study in Canada. We included all adults aged ≥ 67 years (eligible for drug coverage) with a first prescription of either a combination of moderate-intensity statin with ezetimibe ("combination therapy") or high-intensity statin alone between January 2010 and December 2022. Patients were excluded if they had not received any prior lipid lowering therapies or had a history of myocardial infarction (MI), stroke, heart failure, peripheral vascular disease or prior coronary revascularisation at any time before or within 3 months of treatment initiation. The primary outcome was a composite of all-cause death, hospitalization for MI or stroke, or coronary revascularization. An inverse probability of treatment weighting propensity score was used to account for confounding (demographics, comorbidities, laboratory tests, other medications). Results Among 67,884 patients (mean age: 74.0±5.5y; 53% females), 8,798 (13%) initiated combination therapy and 59,086 (87%) initiated a high-intensity statin. At 1 year, after weighting, the mean achieved LDL-C was ~1.9 mmol/L in both groups. The median follow-up was 6.5 years. The cumulative incidence of the primary outcome at 10 years in the weighted cohort was 32.7% in the combination therapy group and 36.1% in the high-intensity statin group (HR: 0.87; 95% CI: 0.82 to 0.92; p<0.001; absolute risk reduction: 3.5%; 95% CI: 0.8 to 6.1; Figure 1). This result was primarily driven by a lower risk of all-cause death (HR: 0.85; 95% CI: 0.80 to 0.91; p<0.001; Figure 2) and stroke (cause-specific [cs] HR: 0.86; 95% CI 0.74 to 0.99; p=0.04), whereas no differences were observed in the risk of MI (csHR: 0.97; 95% CI: 0.82 to 1.15) or coronary revascularization (csHR: 0.97; 95% CI 0.85 to 1.11). Conclusion The combination of moderate-intensity statins with ezetimibe was associated with a lower risk of incident ASCVD compared with high-intensity statins alone among primary prevention patients in a real-world setting. These results were driven by a lower risk of all-cause death and stroke, but not coronary events. The influence of statin intolerance on the allocated strategy and adherence to therapy cannot be addressed in this analysis, which, along with verifying these estimates, may be best determined in a prospective randomized trial.

Combination therapy with GalNAc-siRNA drugs targeting both PCSK9 and APOC3 resulted in enhanced lipid lowering in mice

Abstract Introduction Aggressive lowering of both atherogenic low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) could reduce residual atherosclerotic cardiovascular disease (ASCVD) risk. Drugs targeting PCSK9 or APOC3 have shown good lipid-lowering effects in clinic. Here, we have developed GalNAc-conjugated siRNAs, RBD7022 targeting PCSK9 and RBD5044 targeting APOC3, as novel therapeutic agents to lower LDL-C and triglyceride (TG) plasma levels respectively. Each drug shows potent and durable effect in silencing its own target. However, it is unknown whether the combined therapy with siRNA drugs targeting both PCSK9 and APOC3 will generate enhanced effects in lipid lowering. Purpose To investigate the effects of fixed-dose combination of RBD7022 and RBD5044 on LDL-C, TG and total cholesterol (TC). Methods RBD7022 and RBD5044 completely match the human PCSK9 and APOC3 transcripts respectively. RBD7022 has 2 nucleotide mismatches with mouse pcsk9, but still shows silencing activity in mice, while RBD5044 has no activity due to 5 mismatches with mouse apoc3. Therefore, humanized APOC3 transgenic mice were used in this study, which had serious hypertriglyceridemia with relatively high cholesterol and TG levels. They were randomized into 8 groups with treatment of RBD7022 (1 mg/kg or 3 mg/kg), RBD5044 (3 mg/kg or 6 mg/kg), or 3 different dose combinations of RBD7022 and RBD5044, as well as PBS control. All animals were administrated once on Day 1. Plasma was collected to quantify lipid biomarkers. Results RBD7022 showed a robust effect on LDL-C reduction, with inhibition rates of 45% in 3 mg/kg and 43% in 6 mg/kg, indicating 3 mg/kg was a saturated dose for RBD7022 in LDL-C lowering. RBD5044 showed a dose-dependent effect on LDL-C reduction, with inhibition rate of 52% at 1 mg/kg and 59% at 3 mg/kg. Interestingly, significantly enhanced LDL-C reduction was observed in the combination groups, with 67% reduction in LDL-C at RBD5044 1 mg/kg plus RBD7022 3 mg/kg, 73% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 3 mg/kg and 78% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 6 mg/kg, showing dose-dependent effects (Figure 1A). Enhanced TC reduction was also found in combination at RBD5044 3 mg/kg plus RBD7022 6 mg/kg compared with RBD5044 or RBD7022 alone. RBD5044 showed a dose dependent effect on TG reduction with inhibition rates of 56% at 1 mg/kg and 83% at 3 mg/kg. RBD7022 treatment alone did not show significant effect on TG reduction. No added effects of RBD7022 on TG levels was found in the combination with RBD5044, indicating the TG lowering was induced by RBD5044. Conclusions The combination of RBD7022 targeting PCSK9 and RBD5044 targeting APOC3 simultaneously reduce LDL-C and TC levels. The combination of RBD7022 and RBD5044 could be a better therapeutic option to further reduce LDL-C, particularly for mixed hyperlipidemia patients and other high-risk individuals with both high LDL-C and high TG levels.Figure 1

Systemic inflammation and risk of death in patients with atherosclerotic cardiovascular disease and chronic kidney disease

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease stage 3 - 4 (CKD) affects 7% and 10% of the Danish population, respectively. Systemic inflammation (SI) contributes to destabilisation of atherosclerotic plaques and is characterized by elevated levels of C-reactive protein (CRP) in the blood. CKD is associated with SI and is independently associated with an increased risk of ASCVD. CRP levels ≥2 mg/L have been identified as a risk factor for mortality and major adverse cardiovascular events (MACE). Purpose To provide real-world evidence on the clinical burden of SI in patients diagnosed with ASCVD and CKD, using national health registers. Method Data from the Danish National Patient Registry from 1994-2022 was used to identify ASCVD patients by ICD-10 codes. CKD was identified by eGFR test results in the range [15 -59mL/min/1.73m2], in the Register of Laboratory Results for Research (RLRR). The latter diagnosis of ASCVD and CKD was set as index date. CRP-test results were extracted from RLRR and only individuals with at least two CRP tests were included. If two CRP-test results ≥2mg/L to < 20mg/L were observed less than six month apart, and within two years of index date, the individual was classified to have SI. The eGFR data from RLRR was available from 2011 onwards, with some regional differences in reporting. Individuals observed with CKD or ASCVD in the first year of eGFR availability were excluded to ensure a study of incident individuals. Individuals using select medications or diagnosed with selected chronic conditions thought to influence CRP levels were excluded. Additional population characteristics were extracted from corresponding national health and administrative registers. Hazard of all-cause mortality and MACE was analysed in a Cox proportional risk regression. Results From 2012 to 2022, a total of 19,162 individuals were eligible for the study population (SI: 13,039, No SI: 6,123). Median follow-up time was 4.1 and 8.2 years for individuals with or without SI, respectively. Median CRP two years before and after index date in the two groups was 7mg/L and 1mg/L. No clinically significant differences were found for demographic or socioeconomic characteristics. Patients with SI had more frequent history of hypertension, atrial fibrillation, COPD, heart failure and Type 2 diabetes before index, and higher risk of hypertension, atrial fibrillation, stroke, heart failure and type 2 diabetes after index. SI population had significantly increased hazard of mortality in a crude model (HR: 2.35, 95% CI: [2.22 – 2.50]), and in adjusted analysis HR: 2.06 ([1.92 - 2.21]). The corresponding hazard ratios for MACE were 1.9 ([1.81 – 2.01]) and 1.66 ([1.57 – 1.77]). The results were consistent across different model specifications and subgroups. Conclusion SI is associated with a significantly higher clinical burden of disease and a higher risk of all-cause mortality.Flowchart of inclusion/exclusionHazard ratio, overall and by subgroup

Healthcare resource utilisation and cost of care of systemic inflammation in individuals with atherosclerotic cardiovascular disease and chronic kidney disease

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a chronic disease, progressed by localised or systemic inflammation (SI). Chronic kidney disease (CKD) facilitates the presence of SI and is associated with an increased risk of ASCVD. Previous studies have estimated that 1–2% of the population in Western countries suffer from both conditions. Purpose To investigates the healthcare costs and resource utilisation for individuals diagnosed with ASCVD and CKD, with or without SI. Method The study applied data from the Danish national health and administrative registries from 1994-2022. Patients with ASCVD were identified by ICD-10 codes. CKD was identified by eGFR [15-59mL/min/1.73m2], in the Register of Laboratory Results for Research (RLRR). The latter date of diagnosis of the two diseases were used as index date. CRP-test results were extracted from RLRR. Individuals with conditions associated with CRP-levels and tests observed in association with CVD events or antibiotic/antiviral drug use were excluded. Individuals with at least two valid CRP tests were included. If two CRP-test results ≥2mg/L to <20mg/L were observed less than six month apart, and within two years of index, the individuals were classified to have SI. Individuals diagnosed in the first year of available eGFR were excluded to ensure only incident individuals in the study. Outcomes included costs and use of inpatient (duration ≥12h) and outpatient (<12h) hospital care, cost of primary care and prescription drugs (adjusted to 2022 currency). Results were derived using linear regression models. Results A total of 19,162 individuals’ incident between 2012-2022 were identified – 68% had SI. SI individuals had higher healthcare costs from five years before to three years after index. Individuals generated a total healthcare cost of EUR 69,554 (SI) and EUR 39,540 (no SI) in the study period (difference EUR 30,014, p<0.001). In adjusted analysis, the attributable cost in the three years following index was 1.4 times higher for individuals with SI, compared to individuals with no SI (difference EUR 12,922, p<0.001). Inpatient care accounted for 85% of the cost. SI individuals had significantly more inpatient hospital contacts from four years before to five years after index (7 attributable contacts total, 4.7 attributable contacts after index, 1.2 times more, p<0.001), and more outpatient contacts from five years before to three years after index (6.2 attributable contacts total, 2.3 attributable contacts after index, 1.3 times more, p<0.001). The largest difference was found in the year following index, where the difference was EUR 7,666 (1.5 times higher, p<0.001) cost, 1.5 (1.3 times higher, p<0.001) inpatient hospital contacts, and 1.1 (1.3 times higher, p<0.001) outpatient hospital contacts (adjusted estimates). Conclusion Individuals with SI represent a significant burden to the healthcare system, both in terms of healthcare cost and healthcare resource utilisation.Total healthcare costsAttributable hospital contacts

Advanced biologic therapies are associated with fewer adverse cardiovascular events in patients with inflammatory bowel diseases

Abstract Background Chronic inflammation is an important contributor to the development of atherosclerotic cardiovascular disease (ASCVD) and associated events. Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions, and meta-analyses of cohort studies demonstrate an increased risk of ASCVD events in IBD patients. Advanced biologic therapies (ABT) targeting the immune system revolutionized treatment of IBD patients but the impact of these therapies on ASCVD events is not known. Purpose To investigate the impact of ABT on ASVCD events in IBD patients. Methods A retrospective cohort study was performed using the TriNetX Diamond Network, a multi-institutional database providing real-time access to de-identified electronic health records, with data updated on 02/14/2024. ABT were defined as one or more the following: infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, vedolizumab, or natalizumab. ASCVD events were based on ICD codes for ischemic heart, cerebrovascular, and peripheral vascular diseases. Individuals >40 years with IBD were included. ASCVD events in (1) patients on ABT and (2) patients not on ABT (NABT) were compared. Propensity score matching was performed on sex, aspirin use, and the following ASCVD risk factors: age, hypertension, hyperlipidemia, tobacco use, and type 2 diabetes mellitus. Results This study includes 72,650 individuals in each of the two matched cohorts. There were no differences in baseline characteristics between the two propensity-score matched cohorts (Table). The probabilities of experiencing any ASCVD event at one, three, and five years in the ABT group were all significantly lower than in the NABT group (8.3% vs. 12.4%, OR 0.64; 13% vs. 18.6%, OR 0.66; and 15% vs. 21.2%, OR 0.65; respectively, all p<0.01). Similarly, the probability of experiencing an ischemic heart disease event at one, three, and five years in the ABT group were all significantly lower than in the NABT group (5.2% vs. 7.9%, OR 0.64; 8% vs. 11.7%, OR 0.66; and 9.2% vs. 13.4% OR 0.66; respectively, all p<0.01). The probability of cerebrovascular disease events at one, three, and five years in the ABT group were all significantly lower than in the NABT group (2% vs. 3.3%, OR 0.59; 3.5% vs. 5.7%, OR 0.59; and 4.2% vs. 6.8% OR 0.60; respectively, all p<0.01) and the probability of a peripheral artery disease event at one, three, and five years in the ABT group were also all significantly lower than in the NABT group event (2.8% vs. 4.5%, OR 0.62; 5.1% vs. 7.6%, OR 0.65; and 6.2% vs. 9.3% OR 0.65; respectively, all p<0.01). Conclusions ABT are associated with significantly fewer ASCVD events in the IBD patient population. Future studies examining the differential benefit of drug subclasses on ASCVD outcomes and mechanisms responsible for the ABT benefit, as well as prospective study designs have the potential to identify new therapeutic targets in IBD patients and with applicability beyond IBD patients.Table

Circulating Amyloid beta 1-40 is independently associated with statin treatment and LDL cholesterol reduction: a prospective cohort study

Abstract Background Accumulating evidence suggests that circulating amyloid beta 1-40 (Aβ40), a pro-inflammatory and pro-atherogenic peptide, is associated with atherosclerotic cardiovascular disease (ASCVD), providing incremental prognostic value and risk stratification refinement in primary and secondary prevention settings. Existing evidence supports conflicting off-target effects of statins on plasma Aβ40. We aim to explore the impact of cardiovascular risk reduction through statin therapy on Aβ40 plasma levels in subjects with dyslipidemia and with/without ASCVD. Methods In this prospective study, patients with dyslipidemia who visited for the first time our lipid clinic for risk stratification and treatment plan assessment (n=146) were consecutively recruited. Αβ40 was measured in plasma samples by enzyme-linked immunosorbent assay at baseline and after a mean follow-up of 5.2 and 15 months. Patients in whom statin treatment was initiated or intensified in terms of dose or regimen (n= 68) were compared against patients not treated with statins or with unchanged statin intensity (n = 78). Statin intensity treatment was defined based on the European Society of Cardiology (ESC) guidelines. Results Increased Aβ40 plasma levels at baseline were associated with ASCVD presence, decreased glomerular filtration rate (GFR), and history of heart failure (p<0.05 for all). An increase in Aβ40 circulating levels between baseline and follow-up 1 was observed in patients in whom statin treatment was initiated or intensified (p=0.041). However, in patients not treated with statins or treated with unchanged statin intensity, an increase in Aβ40 circulating levels was observed between follow-up 1 and follow-up 2 (p=0.05, Figure 1A). These changes in Aβ40 were significantly different between the two groups during the short follow-up period (β=0.226, p for interaction =0.025) independently from age and changes in GFR, systolic blood pressure, and LDL-C. Additionally, patients who achieved a reduction in low-density lipoprotein cholesterol (LDL-C) ≥ 50% in follow-up 2 have unchanged Aβ40 levels during the long follow-up period, while an increase in Aβ40 was observed in the rest population (p=0.012, Figure 1B). These changes were significantly different between the two LDL-C groups independently of statin treatment and changes in high sensitive C-reactive protein (hs-CRP) (β= -0.231, p for interaction=0.035). Conclusion In a dyslipidemic population, statin initiation or intensification and LDL-C decrease showed a short-term increase and a long-term return to initial levels, respectively, in circulating Aβ40 levels. From a mechanistic point of view, our findings suggest that statins have an impact on Aβ40, possibly through an LDL-C-dependent and a non-LDL-C-dependent pathway. Further studies are needed to evaluate the utility of circulating Aβ40 as a novel biomarker in ASCVD risk reduction assessment.

Amyloid beta, a marker of vascular aging and cardiovascular disease, is associated with accelerated progression of renal dysfunction

Abstract Background Amyloid-beta (1-40) (Αb1-40), a proinflammatory and pro-atherosclerotic peptide, is involved in Alzheimmer’s disease and vascular aging and is considered an emerging prognostic marker of atherosclerotic cardiovascular disease (ASCVD) and heart failure. Because Ab1-40 clearance is largely dependent on renal function while clinical data consistently associate this peptide with renal function, we hypothesized that Ab1-40 circulating levels would serve as a predictor of progression of renal dysfunction. Purpose To examine the potential cross-sectional and prospective bidirectional association of Ab1-40 levels with renal function in a population with a wide range of ASCVD risk. Methods In the settings of the Athens Cardiometabolic registry, data from consecutively recruited subjects with (n=137) and without clinically overt ASCVD (n=674) with available both Ab1-40 plasma levels and GFR values (total n=811) were analyzed. Αb1-40 was measured by enzyme-linked immunosorbent assay and renal function was assessed by estimation of glomerular filtration rate (GFR). Of these subjects, 182 individuals consented to be followed up and re-assessed after a minimum period of 12 months in order to examine a potential bidirectional link between changes in Ab1-40 levels and GFR. Results Patients with increased Ab1-40 levels at baseline had significantly worse renal function, reflected as lower GFR values, compared with their counterparts with lower Ab1-40 levels (GFR= 74.8 vs 93.3 vs 100.2 ml/min/1.73m2 for high, middle and low tertile of Ab1-40 levels, p<0.001). Elevated Ab1-40 levels were associated with chronic kidney disease (CKD) stage 2 [odds ratio (OR)=2.29, 95% confidence intervals (CI)= 1.58-3.31, p<0.001] and CKD stage 3 (OR=3.67, 95% CI=2.37-5.70, p<0.001) at baseline. Furthermore, increased Ab1-40 at baseline was prospectively associated with accelerated progression of renal dysfunction as assessed by changes in GFR values between baseline and follow-up [mean adjusted rate of decrease=-7.20 (95% CI=-1.33, -13.07) for higher vs lowest tertiles of Ab1-40 levels across a follow-up period of 12 months, p=0.017 for interaction). On the contrary, baseline GFR values were not prospectively associated with Ab1-40 levels at follow-up visits (p>0.05). Conclusion In a population with a wide range of ASCVD risk, high Αb1-40 levels at baseline were associated both with renal function at baseline and with accelerated rate of progression of GFR deterioration at follow-up irrespective of its baseline levels. These findings suggest a mechanistic background for the established association of Ab1-40 with renal function and warrant further research to clarify the clinical value of monitoring its circulating levels as a novel biomarker which could reflect enhanced risk for renal dysfunction.

Are novel ASCVD risk factors more prevalent in young middle eastern women who have classical risk factors

Abstract Introduction Urbanization is an important contributor to atherosclerotic cardiovascular disease (ASCVD) in the Middle East, especially in the younger age groups. There is a scarcity of data on clinical profiles and cardiovascular risk factors (RFs) in urban young women compared with those who reside in rural areas in this region. Purpose To study the demographic and clinical profiles and prevalence of traditional and novel CV RFs in a cohort study of young urban Middle Eastern women compared with those in rural areas. Methods The prevalence of 19 traditional and novel cardiovascular RFs were compared in urban vs. rural young women residents (18-50 years of age), who were enrolled in 12 centers (August 2020 to October 2023). Results Of 627 young women enrolled (mean age 44.2 ± 5.1 years old), 463 (74%) were urban residents and 164 (26%) were rural residents. ASCVD was diagnosed in 32% of urban and 37.3% of rural young women. Table shows the prevalence of traditional and novel, sex-specific RFs with significant differences in the 2 groups. Other RFs with no significant differences included hypertension, diabetes and gestational diabetes, preterm delivery, persistent weight gain after delivery, radiation for breast cancer, and polycystic ovary syndrome. Conclusion In this cohort of Middle Eastern young women, despite heterogeneity, those who were urban residents had worse clinical profiles with higher prevalence of certain classical and sex-specific risk factors.

Comprehensive risk factor management through a dedicated secondary prevention clinic: experience from hamilton, Ontario

Abstract Introduction and Background Atherosclerotic cardiovascular diseases (ASCVD) remain a major source of morbidity and mortality. Modifiable ASCVD risk factors can be effectively treated, however, there is a lack of systematic implementation of secondary prevention therapies in ASCVD patients. We established a comprehensive secondary prevention program for patients with ASCVD to provide care for all modifiable risk factors in an integrated manner. Methods Patients with established coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral vascular disease (PVD) who had one or more uncontrolled risk factors, were referred to the center(s). Patients were assessed between November 2022 and October 2023. Uncontrolled risk factors were defined as dyslipidemia (LDL > 70 mg/dL [1.8 mmol/L]), hypertension (defined as BP >130/80 mmHg), diabetes (HbA1c >6.5%), chronic kidney disease (eGFR <60 ml/min/1.73m2) obesity (BMI >30 kg/m2) and current tobacco use. Data was collected at the initial visit and subsequent follow-up visits. Results A total of 274 patients were seen, with 85% were referred for CAD. Median age was 62 years,72% were men. The most common uncontrolled modifiable risk factor was hypertension (62% of patients), followed by dyslipidemia (60%) and obesity (50%). 39% of patients had diabetes, with 57% on a SGLT2i, 16% on a GLP-1 agonist and with 23% with HbA1c >8%. Blood pressure was above 140/90 mm Hg in 41% of patients, 20% were current smokers and 75% of patients had two or more uncontrolled risk factors. At the first visit, 56% of patients had a pharmacological intervention. The most common was for management of dyslipidemia, followed by diabetes and then hypertension. 17.8%(n=49) patients had a change in statin,13.8% (n= 38) patients were started on Ezetmibe, 9.1%(n=25) on Icosapent Ethyl, and 16.4% (n= 45) on a PCSK9i inhibitor (monoclonal antibody or Inclisiran). Among patients with diabetes, 5.1%(n=14) patients were started on a GLP-1 agonist and 2.5%(n=7) were started on a SGLT2i. 2.9%(n=8) patients were started on Varenicline and 2.9%(n=8) were started on NRT. Mean LDL (with LDL >1.8 at baseline) at visit 1 was at 3.03 ± 1.1 (n=157) mmol/dl, which reduced to 2.05 ± 0.9 (n=77) mmol/dl by 2nd visit and to 1.90 ± 1.3 (n=32) mmol/dl by visit 3. Average SBP (SBP >130 at baseline) at visit 1 was 143.3 ± 13.4 (n=114) mm Hg, this was subsequently reduced to 126.4 ± 14.0 (n=58) mm Hg at visit 2 and further reduced to 123.2 ± 14.7 (n=31) mm Hg by visit 3. Discussion and Impact: In our tertiary Cardiac Care center there are a significant number of patients with established ASCVD that remain on inadequate treatment for secondary prevention. Addressing these risk factors in a timely and integrated fashion in one clinic improves the implementation of guideline directed therapies for management of secondary risk factors in ASCVD and is expected to result in improved outcomes.

Exploring the association between hypertension and atherosclerotic cardiovascular disease in adults with familial hypercholesterolemia: insights from the HELLAS-FH registry

Abstract Aim While the link between hypertension and atherosclerotic cardiovascular disease (ASCVD) is well-established, its impact on patients with familial hypercholesterolemia (FH) remains less explored. This study aims to assess the association between hypertension and ASCVD in adult FH patients. Material-Methods: Participants from the HELLAS-FH registry were divided into two groups based on the presence or absence of hypertension. We compared demographic information, lipid profile and history of ASCVD between the two groups. Results The study included 2367 FH patients, of whom 602 (25.4%) had a diagnosis of hypertension. Hypertensive patients were generally older and exhibited higher rates of ASCVD risk factors such as increased body mass index (28.6 vs 26.3 kg/m2), waist circumference (98 cm in men and 97 cm in women compared with 95 cm and 88 cm in non-hypertensive counterparts), and more prevalent history of smoking (44.2% vs 35.8%) (p<0.01 for all comparisons). Patients with hypertension had higher triglyceride levels (148 vs 123 mg/dL; p<0.05), lower high-density lipoprotein cholesterol (HDL-C) levels (48 vs 53 mg/dL; p<0.05) while total cholesterol and non-HDL-C levels were not significantly different. When adjusted for age, sex, and major ASCVD risk factors, hypertension was significantly associated with prevalent coronary artery disease (CAD) (adjusted odds ratio [OR] 3.10; 95% CI 2.29-4.19; p<0.001), ischemic stroke (OR 1.89; 95% CI 1.02-3.49; p=0.04), and peripheral arterial disease (PAD) (OR 3.15; 95% CI 1.62-6.13; p<0.001). Conclusions Hypertension is frequent and is independently associated with an increased risk of CAD, stroke, and PAD in patients with FH.

Prediction of 10-year risk for recurrent atherosclerotic cardiovascular events in a secondary prevention population: Insights from CHART-2 and Suita studies in the Japanese population

Abstract Background Despite the European Society of Cardiology (ESC) guidelines advocating risk prediction models for secondary prevention in established atherosclerotic cardiovascular disease (ASCVD) patients, such models for Japanese individuals remain limited, owing to their comparatively lower ASCVD risk than Western populations. Given this gap, there is a need to develop tailored risk assessment tools for Japanese ASCVD patients to optimize secondary prevention strategies. Purpose Leveraging data from two large-scale, long-term cardiovascular cohorts in Japan, our aim was to develop and externally validate a 10-year risk model predicting recurrent cardiovascular events among patients with established ASCVD. Methods The CHART-2 and Suita studies, large-scale prospective observational multicenter cohort studies in Japan, served as the primary data sources for this investigation. From the CHART-2 study, which comprised 3,560 patients with a history of coronary artery disease or ischemic stroke, we derived our risk model. External validation was conducted using data from the Suita study, which included 445 patients with similar ASCVD backgrounds. The primary outcome of interest was a composite endpoint encompassing cardiovascular death, myocardial infarction, or stroke. Variable selection was performed based on clinically relevant factors previously employed in established risk scores (SMART, REACH, and TRS 2°P risk scores). Logistic regression was utilized for model development, and the predictive performance was assessed using the C-index. Results Over a median follow-up of 10.1 years, the derivation cohort experienced 756 cardiovascular events. Patients in the derivation cohort had an average age of 68.9 ± 10.6 years, with 91% and 24% having a history of coronary artery disease and ischemic stroke, respectively. Using logistic regression, the multivariate model revealed a higher recurrent risk associated with several factors including age, smoking status, systolic blood pressure, diabetes, renal function, number of ASCVD events, atrial fibrillation, lipid levels, left ventricular systolic dysfunction, and statin use. A simple risk score based on these predictors demonstrated a >5-fold gradient of 10-year recurrent risk with a C-index of 0.65 (95% CI 0.63-0.68, Figure). The prediction model was externally validated in the Suita study wit 245 cardiovascular events and a median follow-up of 10.4 years, showing good discriminative ability with a C-index of 0.64 (95% CI 0.60–0.68). Conclusion Our newly developed prediction model offers a valuable tool for identifying individuals at heightened risk of recurrent cardiovascular events over a 10-year period, thereby facilitating more targeted and effective secondary prevention strategies tailored to the unique characteristics of Japanese ASCVD patients.

The causal effects of placental weight on atherosclerotic cardiovascular disease: a Mendelian randomization and mediation analysis

IntroductionPrevious studies have linked placental weight (PW) to cardiovascular diseases, but the causality and potential mediators underlying this relationship are still unknown.Material and methodsWe conducted Mendelian randomization (MR) analysis via summary statistics from genome-wide association studies (GWAS), including PW adjusted for sex, 21 candidate mediators and atherosclerotic cardiovascular disease (ASCVD), which includes coronary heart disease (CHD) and ischemic stroke (IS).Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the association between PW and ASCVD. Additionally, we conducted a repeated analysis using PW adjusted for gestational age and sex.ResultsUnivariable MR (UVMR) analysis revealed that for each 1-SD decrease in fetal genotype-determined PW adjusted for sex only, the risk of CHD increased by 24% (95% CI: 1.05–1.46) and the risk of large artery stroke (LAS) increased by 46% (95% CI: 1.13–1.89). Similar results were obtained in repeated analyses. The mediation MR analysis revealed that the causal relationship between fetal genotype-determined PW and CHD risk was primarily mediated by birthweight, type 2 diabetes, and education, each mediating 3.66% to 40.80% of the total effect. The causal relationship between fetal genotype-determined PW and LAS risk was mediated mainly by type 2 diabetes, which accounted for 22.11% of the total effect.ConclusionsThis study elucidated a unidirectional causal relationship between lower PW and a greater ASCVD risk, with factors such as birthweight, type 2 diabetes, and education mediating the association between PW and ASCVD.

Risk-enhancing factors and social determinants of health in risk assessment for atherosclerotic cardiovascular disease.

The Pooled Cohort Equations (PCEs) do not accurately estimate atherosclerotic cardiovascular disease (ASCVD) risk in certain populations. The 2018 AHA/ACC cholesterol guideline identified risk-enhancing factors as a supplement to PCEs-based risk assessment. However, the role of each risk-enhancing factor in ASCVD risk assessment has not been well quantified. Further, social determinants of health (SDOH) are not included in the PCEs nor considered as risk-enhancing factors in the US cholesterol guideline. We sought to evaluate ASCVD risk associated with each risk-enhancing factor and commonly collected SDOH including education, income, and employment status, and to assess if adding risk-enhancing factors and SDOH to the PCEs improve ASCVD risk prediction. We included individuals aged 40 to 75 years, without ASCVD or diabetes at baseline, and with low-density lipoprotein cholesterol 70-189 mg/dL from two contemporary prospective cohort studies (MESA and REGARDS) and from Kaiser Permanente Southern California (KPSC). The primary endpoint was incident ASCVD defined as nonfatal myocardial infarction, fatal coronary heart disease, or fatal or nonfatal stroke over a 10-year period (median follow-up 10 years). We used Cox proportional hazards models to estimate associations between risk-enhancing factors and SDOH with ASCVD. We also assessed changes in model performance after adding risk-enhancing factors and SDOH to the PCEs. We included 13,863 adults (mean age 60.7 years) from the prospective cohorts and 307,931 adults (mean age 54.8 years) from KPSC. Risk-enhancing factors including hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and chronic kidney disease were associated with a higher ASCVD risk, independent of 10-year risk estimated by the PCEs. Low education, low income, and unemployment were also associated with higher ASCVD risk. While adding individual risk-enhancing factors or SDOH to the PCEs had limited impact on model performance, adding multiple risk-enhancing factors and SDOH simultaneously led to modest improvements in discrimination (C-index increased by up to 0.07), calibration (integrated Brier score reduced by up to 2.3%), and net reclassification improvement up to 41.4%. These findings suggest including SDOH and risk-enhancing factors may improve ASCVD risk assessment.

An equation for estimating low-density lipoprotein-triglyceride content and its use for cardiovascular disease risk stratification.

The triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG (eLDL-TG) based on the standard lipid panel and to compare it to estimated LDL-C as an ASCVD risk biomarker. Using least-square regression analysis, the following eLDL-TG equation was developed: . LDL-TG was measured by the β-quantification (BQ) reference method (N = 40,202). LDL-C was calculated by the Sampson-NIH equation. The association of LDL-C and eLDL-TG with ASCVD risk markers was performed in the National Heart and Nutrition Examination Survey (NHANES) (N = 37,053) and with ASCVD events in a primary prevention cohort from the UK Biobank (UKB) (N = 429,367) and the Atherosclerosis Risk in Communities (ARIC) study (N = 14,632). eLDL-TG showed better ASCVD risk stratification of UKB participants than LDL-C (Wilcoxon Chi-Square: 2,099.6 vs. 418.7, respectively). Receiving-operating characteristics analysis revealed that eLDL-TG had a stronger association with ASCVD events than LDL-C (AUC: 0.596 vs. 0.542, respectively) and other conventional lipid markers. Similar findings were found in ARIC. Discordance analysis in UKB showed that the group with low LDL-C/high eLDL-TG had a similar risk as the high LDL-C/high eLDL-TG group. Furthermore, these same two groups with the highest eLDL-TG levels and the highest ASCVD event rate also had higher mean levels of systolic blood pressure, Body Mass Index, hemoglobin A1C, and C-reactive protein than the two lower eLDL-TG groups. Using eLDL-TG > 44.6 mg/dl (80th percentile) as a cut-point leads to a hazard ratio of 1.32 (95% CI, 1.29-1.36) for ASCVD events, which remained significant after adjustment for LDL-C and apoB. Furthemore, using eLDL-TG as a risk-enhancer test leads to reclassification of 50% more high-risk individuals than current lipid-enhancer test rules. Like LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, eLDL-TG was a better risk marker for primary prevention and hence could improve initial ASCVD risk stratification.

Factors Associated with Lipoprotein(a) Testing Among Multiethnic Individuals.

Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and clinical guidelines recommend incorporating Lp(a) testing in routine care. Examine real-world, contemporary clinical testing patterns of Lp(a) among multiethnic populations. In this nested case-control study, we assessed the prevalence and factors associated with Lp(a) testing within a large Northern Californian health system between 2010 and 2021. Incident density matching was used to select controls matched with a case for a case:control ratio of up to 1:5. Conditional logistic regression was used to assess the relationship between Lp(a) testing, sociodemographic, and clinical characteristics. We included individuals aged 18years or older with ≥ 2 primary care visits during the study period. Lp(a) testing rates over time and factors associated with testing based on demographic, medical, and healthcare utilization variables. Of the 1,484,410 individuals in the cohort, 14,818 (1.0%) underwent Lp(a) testing. The median Lp(a) level was 35mg/dL and over a third of individuals had Lp(a) levels > 50mg/dL. After adjustment, South Asian individuals were three times more likely to have undergone Lp(a) testing, as compared to non-Hispanic White individuals [OR = 3.19, (95% CI = 2.98, 3.41)], while those identified as non-Hispanic Black and Hispanic were significantly less likely to have undergone Lp(a) testing [OR = 0.70, (95% CI = 0.62, 0.80) and 0.64 (95% CI = 0.59, 0.69), respectively]. Those with a history of ASCVD had over twice the odds of undergoing testing [OR = 2.14 (95% CI = 1.99, 2.29)], as did individuals with more frequent primary care visits [OR = 1.99 (95% CI = 1.84, 2.15)]. Lp(a) testing rates in real-world settings are low, with significant disparities by race, ethnicity, and healthcare utilization. Expanding access to Lp(a) testing may help reduce disparities within ASCVD risk assessment and treatment as new targeted therapeutic agents become available.

Impaired Renal Function With Higher Remnant Cholesterol Related to Risk of Atherosclerotic Cardiovascular Disease: CGPS.

Chronic kidney disease confers a high risk of atherosclerotic cardiovascular disease (ASCVD), partly due to hyperlipidemia. Although statins reduce the risk of ASCVD in chronic kidney disease, residual risk persists. We investigated whether higher remnant cholesterol is associated with an increased risk of ASCVD in statin users and nonusers with impaired renal function. We included 107 925 individuals from CGPS (Copenhagen General Population Study) initiated in 2003 to 2015, of whom 10 427 had impaired renal function (estimated glomerular filtration rate, <60 mL/min per 1.73 m2). Remnant cholesterol was calculated from a standard lipid profile. ASCVD was myocardial infarction, coronary heart disease death, ischemic stroke, coronary artery bypass graft, or percutaneous coronary intervention extracted from Danish nationwide health registries from baseline through 2018; individuals with events before the start of follow-up were excluded from relevant analysis. In individuals with impaired renal function during up to 15 years of follow-up, 597 were diagnosed with myocardial infarction, 618 with ischemic stroke, and 1182 with ASCVD. In these individuals, a 1-mmol/L (39 mg/dL) higher remnant cholesterol level was associated with multivariable-adjusted hazard ratios of 1.21 (95% CI, 1.03-1.43) for myocardial infarction, 1.12 (95% CI, 0.93-1.34) for ischemic stroke, and 1.19 (95% CI, 1.05-1.35) for ASCVD. Corresponding hazard ratios for ASCVD were 1.36 (95% CI, 1.01-1.81) in statin users and 1.16 (95% CI, 1.01-1.33) in nonusers. Of the 1.36-fold excess risk of ASCVD in impaired versus normal renal function, elevated remnant cholesterol and elevated LDL (low-density lipoprotein) cholesterol explained 25% (95% CI, 2.5%-47%) and 0% in statin users and 8.3% (95% CI, 2.4%-14%) and 14% (95% CI, 6.4%-22%) in nonusers, respectively. Our results suggest that higher remnant cholesterol is a good marker of increased risk of ASCVD in individuals with impaired renal function, while higher LDL cholesterol may not be. Patients with chronic kidney disease who have high levels of remnant cholesterol are identifiable through higher non-HDL (high-density lipoprotein) cholesterol or apoB levels.

Relationship between the risk of atherosclerotic cardiovascular disease and decreased functional bladder capacity.

Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Recently, non-classical risk factors for cardiovascular disease, such as lower urinary tract symptoms (LUTS), have gained attention. Both CVD and LUTS are prevalent among aging populations and share common vascular risk factors. The purpose of this study was to investigate the potential relationship between Atherosclerotic Cardiovascular Disease risk and functional bladder capacity among men with LUTS. This study was conducted on 86 men aged 40-79 with complaints of LUTS who were asked for digital rectal examinations, blood tests on serum total cholesterol and high-density lipoprotein (HDL), and mid-stream urine tests for microscopy and culture. For evaluating patients' LUTS, a 24-h voiding diary was asked. The atherosclerotic cardiovascular diseases (ASCVD) score comprises the patient's current age, sex, race, diabetes mellitus status, smoking status, hypertension status, systolic and diastolic blood pressure, total cholesterol, and HDL levels. According to the ASCVD score, 46 and 40 patients were categorized as low and high risks for cardiovascular diseases, respectively. Based on the FBC, 47 patients had decreased FBC and the rest were normal. According to logistic regression, it was determined that age can be considered a predictive variable for decreased FBC and the lower FBC can be considered as a predictive factor in the high-risk group for cardiovascular diseases (p = 0.002). It seems that decreased FBC is related to a higher predicted cardiovascular event rate in men with LUTS and could be considered a predictor of ASCVD risk.