Atherosclerotic Cardiovascular Disease Events Research Articles

Omega-3 fatty acids for cardiovascular event lowering.

Low-density lipoprotein cholesterol (LDL-C) is the main target for therapeutics aimed at reducing the risk of atherosclerotic cardiovascular disease (ASCVD) and downstream cardiovascular (CV) events. However, multiple studies have demonstrated that high-risk patient populations harbour residual risk despite effective LDL-C lowering. While data support the causal relationship between triglycerides and ASCVD risk, triglyceride-lowering therapies such as omega-3 fatty acids have shown mixed results in CV outcomes trials. Notably, icosapent ethyl, a purified formulation of eicosapentaenoic acid (EPA), has garnered compelling evidence in lowering residual CV risk in patients with hypertriglyceridaemia and treated with statins. In this review, we summarize studies that have investigated omega-3-fatty acids for CV event lowering and discuss the clinical implementation of these agents based on trial data and guidelines.

Impact of genetic background as a risk factor for atherosclerotic cardiovascular disease: A protocol for a nationwide genetic case-control (CV-GENES) study in Brazil.

Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).

Controlling Risk Factors Reduces Cancer Risk in Patients with Atherosclerotic Cardiovascular Disease: A Cohort Study

BackgroundThe association of atherosclerotic cardiovascular disease (ASCVD) with cancer occurrence is not well examined, and the impact of common risk factors on the risk of cancer in ASCVD patients is not known. This study aimed to explore the effect and possible causes of ASCVD on cancer risk through a cohort study. MethodsA total of 14,665 age- and sex-matched pairs of participants were recruited from the Kailuan cohort (ASCVD vs non-ASCVD). A competing risk model was used to calculate the risk of cancer after ASCVD. ResultsA total of 1124 cancers occurred after 5.80 (3.05-9.44) years of follow-up. The ASCVD group had a reduced risk of cancer (hazard ratio 0.74; 95% confidence interval, 0.65-0.85). Also, the risk of cancer in the digestive system, respiratory system, urinary system, and reproductive system was reduced by 17%, 16%, 14%, and 52%, respectively. According to the status of systolic and diastolic blood pressure, fasting blood glucose, high-sensitivity C-reactive protein and body mass index after ASCVD, the risk of overall cancer and digestive system cancer decreased with the increase in the number of ideal indicators (P for trend < .01). With the increase of follow-up time, the risk of cancer and the 5 site-specific cancers gradually decreased. ConclusionsCancer risk can be reduced by controlling for common risk factors after ASCVD event. This risk reduction is site-specific-, time-, and the number of ideal indicator-dependent.

Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear. The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials. Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I2 statistic. In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12-52), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p<0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p<0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6-15), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01). PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by >40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.

Atherosclerotic Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Retrospective Cohort Study

Immune checkpoint inhibitors (ICIs) are effective therapies for numerous cancers, but have been associated with atherosclerotic cardiovascular disease (ASCVD). This study aimed to identify predictors for ASCVD events among cancer patients treated with ICIs and the cardiovascular risk factor (CVRF) control of those who developed ASCVD. A single-centre retrospective study of 366 cancer patients who received ICIs from 2018 to 2020 was performed. Demographic, baseline CVRF, cancer history, and ICI regimen data were obtained from medical records. The primary end point of ASCVD events was defined as myocardial infarction, coronary revascularisation, ischaemic stroke, or acute limb ischaemia. Cox proportional multivariable modelling and competing risks analysis were performed to assess ASCVD predictors. Descriptive analysis was performed to describe CVRF management among those who developed ASCVD events. Over a median follow-up of 3.4 years (2.8-4.3), 26 patients (7.1%) experienced 27 ASCVD events (seven myocardial infarction, one coronary revascularisation, 13 ischaemic stroke, and six acute limb ischaemia events). There were 226 (61.8%) cancer-related deaths and no cardiac deaths. History of ASCVD before ICI initiation was independently associated with ASCVD events on traditional Cox modelling (hazard ratio [HR] 4.00; 95% confidence interval [CI] 1.79-8.91; p<0.01) and competing risks analysis (HR 4.23; 95% CI 1.87-9.60; p<0.01). A total of 17 patients developed ASCVD events after ICI cessation (median 1.4 years). Among those with ASCVD events, 12 had prior ASCVD, 16 had hypertension, nine had hypercholesterolaemia, and four had diabetes, and nine were actively smoking. Variable prescription of cardiovascular preventative therapies was noted. History of ASCVD was associated with subsequent ASCVD events among patients treated with ICIs, which could occur even after active treatment was stopped. Identification and aggressive management of modifiable CVRFs should be considered throughout cancer survivorship in patients who received ICI treatment.

Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events.

Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non-high-density lipoprotein cholesterol (non-HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non-HDL-C and LDL-C levels with adult ASCVD events and determined whether non-HDL-C has better utility than LDL-C in predicting adult ASCVD events. This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non-HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non-HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14-1.41] to 1.35 [95% CI, 1.13-1.60] per unit increase in the risk factor z score). Non-HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006-0.0102] and 0.0038 [95% CI, 0.0008-0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non-HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non-HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98-3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23-3.06]). Childhood non-HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non-HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non-HDL-C. These findings suggest that both non-HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non-HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.

Atherosclerotic cardiovascular disease events among adults with high predicted risk without established risk factors

ObjectiveAge is the strongest contributor to 10-year predicted atherosclerotic cardiovascular disease (ASCVD) risk. Some older adults have a predicted ASCVD risk ≥7.5 %, without established risk factors. We sought to compare ASCVD incidence among adults with predicted ASCVD risk ≥7.5 %, with and without established ASCVD risk factors, to adults with predicted risk <7.5 %. MethodsWe analyzed data from REasons for Geographic and Racial Differences in Stroke study participants, 45–79 years old, without ASCVD or diabetes, not taking statins and with low-density lipoprotein cholesterol 70–189 mg/dL. Participants were categorized into 3 groups based on their 10-year predicted ASCVD risk and presence of established risk factors: <7.5 %, ≥7.5 % with established risk factors and ≥7.5 % without established risk factors. Established risk factors included smoking, systolic blood pressure ≥130 mmHg or antihypertensive medication use, total cholesterol ≥200 mg/dL, or high-density lipoprotein cholesterol <50 mg/dL for women (<40 mg/dL for men). Participants were followed for ASCVD events. ResultsAmong 11,115 participants, 911 incident ASCVD events occurred over a median of 11.1 years. ASCVD incidence rates were 3.6, 12.8, and 9.8 per 1,000 person-years for participants with predicted risk <7.5 %, predicted risk ≥7.5 % with established risk factors and predicted risk ≥7.5 % without established risk factors, respectively. Compared to adults with predicted risk <7.5 %, hazard ratios for incident ASCVD in participants with risk ≥7.5 % with and without established risk factors were 3.58 (95 %CI 3.03 – 4.21) and 2.72 (95 %CI 1.91–3.88), respectively. ConclusionsAdults with a 10-year predicted ASCVD risk ≥7.5 % but without established risk factors had a high ASCVD incidence.

Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late.

Recent decades have seen spectacular advances in understanding and managing atherosclerotic cardiovascular disease, but paradoxically, clinical progress has stalled. Residual risk of atherosclerotic cardiovascular disease events is particularly vexing, given recognized lifestyle interventions and powerful modern medications. Why? Atherosclerosis begins early in life, yet clinical trials and mechanistic studies often emphasize terminal, end-stage plaques, meaning on the verge of causing heart attacks and strokes. Thus, current clinical evidence drives us to emphasize aggressive treatments that are delayed until patients already have advanced arterial disease. I call this paradigm "too much, too late." This brief review covers exciting efforts that focus on preventing, or finding and treating, arterial disease before its end-stage. Also included are specific proposals to establish a new evidence base that could justify intensive short-term interventions (induction-phase therapy) to treat subclinical plaques that are early enough perhaps to heal. If we can establish that such plaques are actionable, then broad screening to find them in early midlife individuals would become imperative-and achievable. You have a lump in your coronaries! can motivate patients and clinicians. We must stop thinking of a heart attack as a disease. The real disease is atherosclerosis. In my opinion, an atherosclerotic heart attack is a medical failure. It is a manifestation of longstanding arterial disease that we had allowed to progress to its end-stage, despite knowing that atherosclerosis begins early in life and despite the availability of remarkably safe and highly effective therapies. The field needs a transformational advance to shift the paradigm out of end-stage management and into early interventions that hold the possibility of eradicating the clinical burden of atherosclerotic cardiovascular disease, currently the biggest killer in the world. We urgently need a new evidence base to redirect our main focus from terminal, end-stage atherosclerosis to earlier, and likely reversible, human arterial disease.

Complete blood count, lipid profiles, and inflammatory markers associated with atherosclerotic cardiovascular disease in patients with diabetes

Background: Complete blood count (CBC) and inflammatory markers derived from hematology parameters, as well as lipid profiles, have emerged as novel biomarkers that aid in predicting the progression of atherosclerotic cardiovascular disease (ASCVD) in people with diabetes. This study aimed to evaluate the alterations in CBC, lipid profiles, and inflammatory markers derived from CBC in Type 2 diabetes mellitus (T2DM)-associated ASCVD and the associations between glycated hemoglobin and hematology, lipid profiles, and inflammatory markers. Methods: Overall, 75 patients with T2DM ASCVD from the National Cardiovascular Center Harapan Kita were investigated. Patients with diabetes were classified into high-risk (HR), very high-risk (VHR), and acute coronary syndrome (ACS) groups. VHR-ASCVD was defined as having ≥2 major ASCVD events, or one major ASCVD event and ≥2 high-risk conditions. HR-ASCVD were patients with &gt;3 major risk factors, diabetes, chronic kidney disease stage 3B or 4, and a very high LDL-C level. ECG and cardiac biomarker tests ensured an ACS diagnosis. CBC, lipid profiles, and IL-6 were estimated in all groups. Results: Patients with T2DM ACS demonstrated significantly different levels of red blood cell distribution width (RDW), leucocytes, basophils, eosinophils, lymphocytes, monocytes, segmented neutrophils, absolute lymphocytes, absolute monocytes, neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), total cholesterol, LDL, HDL/total cholesterol ratio, hemoglobin A1c (HbA1c), and IL-6. HbA1c was significantly correlated with leucocytes (p&lt;0.05), segmented neutrophils (p&lt;0.001), NLR (p&lt;0.05), PLR (p&lt;0,05), total cholesterol (p&lt;0.05), LDL (p&lt;0.05), total cholesterol/ HDL ratio (p&lt;0.05), and IL-6 (p&lt;0.001), eosinophils (p&lt;0.05), lymphocytes (p&lt;0.05), monocytes (p&lt;0.05), and absolute lymphocytes (p&lt;0.05). Logistic regression analysis showed that monocytes, MLR, leucocytes, eosinophils, and absolute monocytes were found to be valuable predictors for T2DM ACS (p&lt;0.05). Conclusions: CBC, inflammatory biomarkers derived from CBC, and lipid ratios were inexpensive parameters that could serve as inflammatory biomarkers of increased risks and complications in T2DM ASCVD.

Impact of cardiorenal syndrome on clinical outcomes of atrial fibrillation patients undergoing catheter ablation

Abstract Background Heart failure (HF) coexists with both atrial fibrillation (AF) and chronic kidney disease (CKD) and exacerbate each other. All of them are increasing in the aging society all over the world. Little is known regarding the impact of cardiorenal syndrome (CRS) on clinical outcomes of patients with AF undergoing catheter ablation (AFCA) in the real-world setting. Purpose In the present study, we investigated clinical outcomes of CRS patients with de novo AFCA. Method: Consecutive 494 patients (68.1±11.1 yrs, male 68.0%) undergoing de novo AF catheter ablation in our hospital from April 2019 to March 2021 were enrolled. CRS was defined as having both HF and CKD. HF was defined as having a history of HF admission and/or BNP≥100 pg/mL. CKD was defined as eGFR&amp;lt; 60 ml/min/1.73m2. The primary outcome was composite outcomes of; all-cause death, redo ablation, thromboembolisms, atherosclerotic cardiovascular disease (ASCVD) events, major bleeding, HF admission, and dialysis initiation. Result The incidence of primary outcome in CRS patients during median follow-up periods of 739.5 days was significantly higher than the non-CRS patients (54.9% in CRS vs. 30.3% in non-CRS; P&amp;lt;0.01, Figure 1). In CRS patients, all-cause death, ASCVD events, and HF admission were significantly worse (7.7% in CRS vs. 0.3% in non-CRS; P&amp;lt;0.01, 10.3% in CRS vs. 1.8% in non-CRS; P&amp;lt;0.01, 11.5% in CRS vs. 0.9% in non-CRS; P&amp;lt;0.01, respectively, Table), however redo ablation, thromboembolism, major bleeding and dialysis initiation were similar compared with non-CRS patients (10.3% in CRS vs. 14.5% in non-CRS; P=0.25, 1.3% in CRS vs. 0.6% in non-CRS; P=0.59, 5.1% in CRS vs. 2.1% in non-CRS; P=0.09, 1.3% in CRS vs. 0.3% in non-CRS; P=0.24, respectively, Table). The incidence of primary outcome in CRS patients was similar in those with ejection fraction (EF)≤40% and in those with EF&amp;gt;40% (47.6% in EF≤40% vs. 54.7% in EF&amp;gt;40%; P=0.48, Figure 2), however it was significantly higher in those with eGFR&amp;lt;45 compared with those with eGFR≥45 (74.8% in eGFR&amp;lt;45 vs. 26.2% in eGFR≥45+ P&amp;lt;0.01, Figure 3). Conclusion CRS patients with AFCA had significantly worse outcomes with more all-cause death, ASCVD events and HF admission compared with non-CRS patients. In the CRS patients undergoing AFCA, worse kidney function, rather than the cardiac systolic function, had a significant prognostic impact on the over-all clinical outcomes.

Surviving critical COVID-19 requiring mechanical ventilation is associated with a high risk of cardiovascular events post discharge

Abstract Background The long-term risk for cardiovascular adverse events after severe COVID-19 requiring intensive care are largely unknown. Purpose The primary aim of this study was to investigate the composite risk of incident atherosclerotic cardiovascular disease (ASCVD) during six months after discharge from an intensive care unit (ICU) for severe COVID-19 requiring mechanical ventilation. Secondary aims were to assess the risk for individual cardiovascular and thrombotic events. Methods We performed a nationwide case-control study on all patients with severe COVID-19 treated with mechanical ventilation and discharged alive from an intensive care unit in Sweden between March 2020 and June 2021. Each case was matched (age, sex, district of residence) with up to 10 population-based controls. The study database was merged with multiple national registries. Patients with pre-existing diagnosis for MI longer than one month ago, CVL or Heart failure were excluded. Also COVID-19 patients receiving the same diagnosis during their ICU-stay as in the follow up period were excluded, making sure all post-covid events were new. The primary outcome was a composite of ASCVD defined as a fatal or non-fatal myocardial infarction, unstable angina pectoris requiring urgent revascularization, fatal and non-fatal ischemic stroke and cardiovascular death. Secondary outcomes were pre-specified as, fatal or nonfatal MI, fatal or nonfatal stroke, myocarditis, pericarditis, PE and DVT. To compare groups, Hazard ratios (HR) with (95% CI) were calculated with adjustments for age, sex, comorbidities (hypertension, hyperlipedemia, diabetes 1&amp;2, obesity, chronic kidney failure, atrial fibrillation, COPD, asthma, malignancy), level of education, marital status, and income quintile. Results In total, included 3 023 patients with severe Covid-19 that were treated with mechanical ventilation at a Swedish ICU and were subsequently discharged alive and compared with 28,463 control subjects. All results in Table 1. The incidence rate for ASCVD was 22.2 (14.9-33.2) per 1,000 person years in patients discharged after severe COVID-19 compared to 2.9 (2.3-3.8) in control subjects. When adjusted for confounders, the risk for ASCVD during the follow-up period was increased compared to control subjects (HR 4.0, 95% CI 2.4-6.7). The incidence rate for pulmonary embolism was 97.4 (80.6-120.0) per 1,000 person years after severe COVID-19 compared to 1.0 (0.6-1.7) in control subjects with a markedly increased risk HR 89.8 (95% CI 48.6-166.1) in patients discharged after severe Covid-19 compared to controls. Conclusions Among patients treated at the intensive care due to severe Covid-19, we found a significant and substantial increased risks for ASCVD and thrombotic events within 6 months from discharge. This finding implies that these patients should be closely monitored after discharge with a low threshold to initiate preventive treatment for ASCVD and thrombotic events during this period.

Early initiation of PCSK9 inhibitor therapy versus placebo in patients with acute coronary syndrome: a systematic review and meta-analysis

Abstract Background In patients with stable atherosclerotic cardiovascular disease (ASCVD) and prior atherosclerotic events, PCSK9 inhibitors (PCSK9i) have shown a 50-60% reduction in LDL-C from baseline, on a background of high-intensity or maximally tolerated statin therapy, leading to a 15% relative reduction in the incidence of major adverse cardiovascular events. However, less is known about the impact of PCSK9i initiation acutely in the setting of an acute coronary syndrome (ACS). Purpose To assess the efficacy of early initiation of PCSK9i therapy in lipid parameters among patients presenting with ACS. Methods We performed a systematic review and meta-analysis comparing PCSK9i with placebo in the setting of ACS, added to guideline directed high-intensity or maximally tolerated statin therapy. Inclusion was restricted to randomized controlled trials (RCTs) with initiation of PCSK9i or placebo within 1 week of presentation or percutaneous coronary intervention for ACS. PubMed, EMBASE, and Cochrane Central were searched. The systematic review and meta-analysis followed Cochrane and PRISMA recommendations. Results Six RCTs with a total of 996 patients were included, of whom 503 (50.5%) received PCSK9i. Mean follow-up ranged from 4 to 52 weeks. Mean time from presentation to administration of first dose ranged from 3.6 hours to 6.5 days. LDL-C levels were significantly lower at follow-up in the PCSK9i group (mean difference [MD] -44 mg/dL; 95% CI -54.3 to -33.8 mg/dL; p&amp;lt;0.001; Figure 1A). Lp(a) was also significantly decreased with PCSK9i therapy (MD -24.0 nmol/L; 95% CI -43.0 to -4.9 nmol/L; p=0.01; Figure 1B). Similarly, total cholesterol (MD -49.2 mg/dL; 95% CI -59 to -39.3 mg/dL; p&amp;lt;0.001) and triglycerides (MD -19 mg/dL; 95% CI -29.9 to -8.2 mg/dL; p&amp;lt;0.001) were significantly reduced with PCSK9i therapy, respectively. HDL-C was marginally increased in this same group (MD 2.5 mg/dL; 95% CI 0.9 to 4.2 mg/dL; p=0.003). Conclusions In patients with ACS, early initiation of PCSK9i, in addition to statin therapy, leads to a significant reduction in LDL-C and Lp(a) as compared with placebo. Whether the differences in these lipoproteins translate into a reduction in clinical endpoints is yet to be determined.

European and US guideline-based statin eligibility, genetically predicted coronary artery disease, and the risk of major coronary events

Abstract Objectives To investigate whether polygenic risk score for coronary artery disease (CAD-PRS) can guide the initiation of lipid-lowering treatment as well as deferral beyond the statin eligibility criteria. Methods 311,799 individuals aged 40 to 73 years and free of atherosclerotic cardiovascular disease (ASCVD), diabetes, chronic kidney disease, and lipid-lowering treatment at baseline were included from the UK Biobank. Participants were categorized by statin eligibility using the European and US guidelines on statin use. Results For a median (IQR) follow-up of 11.9 (11.2-12.6) years, 8,196 individuals experienced major coronary events. CAD-PRS added to European-SCORE2 and US-PCE models identified 18% and 12% of individuals with class II indication for statin use whose risk of major coronary events were same or higher than the average risk of those with class I indication and 16% and 12% of individuals with class I indication whose major coronary event risks were same or lower than the average risk of those with class II indication. For ASCVD events, CAD-PRS added to European-SCORE2 and US-PCE models resulted in a net reclassification improvement of 13.6% (95% CI 11.8 to 15.5) and 14.7% (95% CI 13.1 to 16.3) among class I indicated, 10.8% (95% CI 9.6 to 12.0) and 15.3% (95% CI 13.2 to 17.5) among class II indicated, and 0.9% (95% CI 0.6 to 1.3) and 3.6% (95% CI 3.0 to 4.2) among class III indicated individuals. Conclusions CAD-PRS may guide statin initiation as well as deferral among individuals with class I and class II indication for statin use as defined by the European and US guidelines. However, the CAD-PRS had little clinical utility among individuals who were not eligible for statins.

Kidney function and future risk of atherosclerotic cardiovascular disease: a study from, approximately half million adults

Abstract Background Data are lacking regarding contribution of kidney function towards atherosclerotic cardiovascular diseases (ASCVD) in young to middle aged adults. Purpose To evaluate the impact of kidney function on future risk of ASCVD in a large, young contemporary population without prior ASCVD. Methods This observational cohort study included young to middle aged adults (ages 30-55 years) without established ASCVD (as of January 1, 2006) who were members of an integrated healthcare delivery system in Northern California. Adjusted multivariate models (age, sex, race, diabetes, hypertension, HDL-C, LDL-C, total cholesterol, smoking, albuminuria) were specified to estimate risk ratios (RRs) for incident ASCVD events by kidney function (eGFR mL/min/1.732). Incident ASCVD events were defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through December 31, 2020. Results A total of 426,735 individuals met the selection criteria. Mean age was 45.4 (±7.0) years. Fifty-five percent were women, and the median follow-up was 12.7 (IQR=11) years. In fully adjusted models, risk of future ASCVD, compared to patients with eGFR ≥ 60 was 1.7 (95% CI 1.5-1.9) for eGFR 30-59 RR and RR of 2.2 (95% CI 1.8- 2.7) for eGFR &amp;lt; 30. The kidney function-ASCVD associations were similar by sex for eGFR 30-59, but risks were accentuated among women with eGFR&amp;lt;30 (figure). Conclusions There was increased risk of future ASCVD with worsening kidney function. This risk was more pronounced among women. Using eGFR as part of risk assessment can inform targeting early interventions to prevent both kidney disease and subsequent ASCVD, especially in the era where effective pharmacotherapy such as SGLT2-Inhibitors have demonstrated renal and cardioprotective effects in high-risk populations.

Colchicine prevents accelerated atherosclerosis development in TET2-mutant clonal hematopoiesis

Abstract Background Somatic mutations in the TET2 gene that lead to clonal hematopoiesis are associated with accelerated atherosclerosis development in mice and a higher risk of atherosclerotic cardiovascular disease events in humans. Mechanistically, these observations have been linked to exacerbated vascular inflammation. Purpose Here, we sought to evaluate whether colchicine, a widely available and inexpensive anti-inflammatory drug, prevents the accelerated atherosclerosis associated with TET2-mutant clonal hematopoiesis. Methods In mice, we mimicked TET2-mutant clonal hematopoiesis using a competitive bone marrow transplantation approach in atherosclerosis prone Ldlr/- mice. We generated hematopoietic chimeras carrying initially 10% Tet2-/- hematopoietic cells, which were fed a high-cholesterol diet and treated with colchicine or placebo. Atherosclerosis development was evaluated histologically. In humans, we analyzed whole exome sequencing data and electronic medical records from 50,291 participants in a hospital-based cohort to examine the potential modifying effect of colchicine prescription on the association between clonal hematopoiesis and myocardial infarction. Results Colchicine prevented the development of accelerated atherosclerosis in the mouse model of TET2-mutant clonal hematopoiesis, without affecting serum cholesterol levels or the expansion of TET2-deficient hematopoietic cells. In humans, consistent with experimental findings, patients who were prescribed colchicine had attenuated associations between TET2-mutant clonal hematopoiesis and myocardial infarction (ORno colchicine [95% CI]: 1.18 [0.93-1.48]; ORcolchicine [95% CI]: 0.78 [0.45-1.35]; Pinteraction=0.03). This interaction was not observed for carriers of other clonal hematopoiesis-related mutations, such as those affecting DNMT3A or ASXL1. Conclusions Our results highlight the potential value of colchicine as a targeted preventive care strategy to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific somatic mutations linked to clonal hematopoiesis.

Abstract 14460: Impact of Carotid Artery Plaque Detection on Cardiovascular Disease Risk and the Importance of Age in the Multi-Ethnic Study of Atherosclerosis

Background Carotid artery plaque (CAP) predicts future atherosclerotic cardiovascular disease (ASCVD) events; however, its prevalence increases with age and differs by sex and race/ethnicity, so how its presence influences ASCVD risk in clinical settings is uncertain. Hypothesis: We hypothesized that the impact of CAP detection on relative ASCVD risk declines with age. Methods: CAP was detected and quantified by ultrasound in adults free of clinical ASCVD at Exam 1 of the Multi-Ethnic Study of Atherosclerosis who were followed longitudinally for coronary death, myocardial infarction, angina, stroke, and ASCVD death. Cox proportional hazards models investigated associations of CAP and incident ASCVD events in subsets defined by age categories. These models were adjusted for confounders and an age*CAP interaction. Results: The 5198 participants were a mean (standard deviation) 61.8 (10.1) years old (53% female, 27% Black, 22% Hispanic, 12% Chinese) and experienced 880 ASCVD events over 14.3 (5.7) years. Prevalence of CAP and the age at which 50% of participants had detectable CAP differed by age, sex, and race/ethnicity, ranging from 13% in Chinese women &lt;50 years old to 97% in Non-Hispanic White men 80-84 years old (Figure). CAP presence independently predicted ASCVD events (hazard ratio, 1.35, [95% confidence interval 1.17-1.57], p&lt;0.001), however the strength of this association declined with increasing age (p interaction =0.029, Figure). CAP detection in younger individuals conferred higher relative ASCVD risk than in older participants who had higher absolute risk, regardless of CAP. Conclusions: Prevalence of CAP varies by sex and race/ethnicity. CAP becomes very common with increasing age and its relative association with future ASCVD events declines. These data can assist in guiding ASCVD risk assessment in younger adults and provide perspective for incidentally detected CAP on clinical imaging studies in older adults who have higher absolute ASCVD risk.

Abstract 12444: Pulse Pressure and Cardiovascular and Renal Outcomes by Age in the Chronic Renal Insufficiency Cohort

Pulse pressure (PP) is associated with cardiovascular events and the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). While PP is known to widen with age, it is less clear what other clinical factors affect PP and whether the risks associated with wide PP are the same across all ages. We used Cox proportional hazards models to investigate the association of PP with development of 1) atherosclerotic cardiovascular disease (ASCVD) events (congestive heart failure hospitalization, myocardial infarction, stroke and peripheral artery disease) or death and 2) 50% reduction in estimated glomerular filtration rate (eGFR) or ESKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. In sensitivity analyses, we evaluated the association of time-updated PP with these outcomes, accounting for potential time-updated confounders using inverse probability of treatment weighting. We evaluated for effect modification by age (divided into tertiles), apparent treatment-resistant hypertension (HTN), baseline diabetes mellitus (DM) status, baseline CKD stage and baseline cardiovascular disease (CVD). Among 5,621 participants with CKD followed for ~5.4 years, mean PP was 57±19 mmHg, 1,396 (25%) had an ASCVD event, 1,186 (21%) died and 1,783 (32%) participants experienced the composite renal outcome. Every 10 mm Hg wider PP was associated with 6% higher risk of an ASCVD event or death (time-updated adjusted hazard ratio [HR]=1.06, 95% CI 1.04, 1.08) and 17% higher risk of the composite renal outcome (time-updated adjusted HR=1.17, 95% CI 1.16, 1.18). Wider PP was associated with a higher risk of ASCVD events or death among participants in the lowest age tertile (21-61 years; Figure 1A ), but a higher risk of the composite renal outcome in the oldest age tertile (71-79 years; Figure 1B ), suggesting PP may be associated with different pathophysiology across ages.

Abstract 14359: Life’s Essential 8 and Cardiovascular Health of Veterans: The Million Veteran Program

Background and Hypothesis: The American Heart Association (AHA) recently proposed the Life’s Essential 8 (LE8) score as an enhanced measurement tool for cardiovascular health. No studies to date have estimated its association with the risk for atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis. Methods: A prospective cohort study of 384,518 Veterans enrolled in the VA Million Veteran Program (MVP) (2011-2021). LE8 score was developed using AHA guidelines. Primary outcome was total ASCVD. Secondary outcome was hard ASCVD which included non-fatal myocardial infarction, non-fatal stroke, and fatal CVD. Results: Based on 1.16 million person-years of follow-up among Veterans with no ASCVD at baseline, 46,295 Veterans had ASCVD events during follow-up. LE8 score was associated with ASCVD and its subtypes in a linear dose-response manner (Figure 1A). The overall population-attributable fractions for all non-ideal LE8 scores was 59% (95%CI: 51%-66%) for ASCVD, where non-ideal blood pressure was most influential (Figure 1B). Based on 0.6 million person-years of follow-up among patients with ASCVD at baseline, the hazard ratio for incident or recurrent hard ASCVD was 0.52 (95%CI: 0.48-0.56) comparing veterans with ≥650 to those with LE8 score &lt;350, with a dose-response linear association pattern. Conclusions: Based on 1.76 million person years of follow-up among Veterans, a high LE8 score was associated with a significantly lower ASCVD risk and a lower likelihood of developing adverse cardiovascular events regardless of ASCVD status at baseline. Theoretically, an ideal LE8 could potentially prevent almost 59% of ASCVD in this study. Our results support the importance of AHA’s promotion of LE8.

Abstract 15416: High Neighbourhood-Level Material Deprivation is Associated With Increased Rates of Cardiovascular Outcomes in Patients With ASCVD: A Population-Based Cohort Study

Background: Disparities in atherosclerotic cardiovascular disease (ASCVD) may persist even in jurisdictions with universal health care. The aim of this study was to examine the relationship between material deprivation and cardiovascular (CV) events in a population with established ASCVD. Methods: This population-based cohort study identified individuals in Ontario, Canada ≥66 years old as of January 1, 2019, with an ASCVD event in the prior 10 years. The primary exposure was neighbourhood-level material deprivation, denoting the inability to attain basic material needs, categorized into quintiles, from Q1 (least deprived) to Q5 (most deprived). Cause-specific hazard models estimated the association between material deprivation and CV outcomes over 3 years, adjusted for baseline characteristics. Trend tests across deprivation quintiles were performed. Results: Among 195,742 individuals with established ASCVD (median age 76 years, 37.3% female), individuals in the most deprived neighbourhoods (Q5) had higher rates of co-morbid conditions and CV disease, including myocardial infarction (MI), angina, peripheral artery disease, and coronary artery bypass grafts, compared to those in the least deprived neighbourhoods (Q1). Q5 residents had higher hazards of the composite outcome of all-cause death, MI, or stroke (hazard ratio [HR], 1.20 [95% CI, 1.16-1.24]), and component outcomes: all-cause death (HR, 1.23 [95% CI, 1.19-1.28]), MI (HR, 1.20 [95% CI, 1.11-1.31]), stroke (HR, 1.13 [95% CI, 1.03-1.23]), and heart failure (HR, 1.22 [95% CI, 1.16-1.28]), compared to Q1 residents. There were no significant differences for Q5 versus Q1 for coronary revascularization (HR, 0.97 [95% CI, 0.90-1.04]). We observed a progressive increase in risk across each quintile of deprivation (P-trend &lt;0.05 for all outcomes). Conclusion: Despite universal health care, increasing deprivation was independently associated with higher rates of CV outcomes.

Abstract 16212: Sex-Based Statin Utilization and Cardiovascular Disease Outcomes: A Real World Secondary Prevention Cohort

Introduction: Current guidelines recommend using high-intensity statins in patients with clinical ASCVD.However, real world adherence to GDSI use and recurrent events remains less known. Sex difference in statin use have been previously reported. We evaluated sex-based disparities in GDSI use and recurrent ASCVD outcomes in a large healthcare network. Methods: Using EMR, we assessed statin use and intensity amongst patients with established prior ASCVD events (MI, ischemic stroke/TIA) and PAD from 2010-2022. Statins were categorized into GDSI (high intensity), &lt;gdsi (moderate="" or="" low="" intensity)="" or no statin use. Outcomes of interest included repeat MI, stroke/TIA and all-cause mortality. Incident rates (IR) and Cox regression hazard ratios (HR) of ASCVD outcomes were calculated across statin categories stratified by sex. Results: Amongst 45,949 patients,31% were women. Women had more diabetes (29% vs 24%) and higher LDL-C (94.9 ± 40.8 vs 87.6 ± 37.1 mg/dL) than men. During a follow-up period of 5 years, women were less likely to be started on GDSI (61.6% vs 65.8%, p&lt;0.01) and achieve LDL-C&lt;70mg/dL (41% vs and 49%, p&lt;0.01) as compared to men. GDSI use lowered IRs for all outcomes in both sexes (Table 1). Women on GDSI had higher risk of MI (HR 1.21 [1.12-1.31)],stroke (1.21 [1.08-1.34] and mortality (1.12 [1.05-1.20]), all p&lt;0.01) than men. Conclusions: In a contemporary cohort of secondary prevention patients, women were less likely to be prescribed GDSI than men and less likely to achieve guideline concordant LDL-C&lt;70mg/dL. This was associated with a higher risk of recurrent ASCVD events in women as compared to men. More sex specific interventions are needed to ensure adequate preventive treatment for both sexes. Abbreviations: Atherosclerotic cardiovascular disease (ASCVD), guideline directed statin intensity (GDSI), Electronic medical records (EMR),Myocardial Infarction (MI), Peripheral arterial disease (PAD), Transient Ischemic attack (TIA)