Coronary and Extra-coronary Subclinical Atherosclerosis to Guide Lipid-Lowering Therapy.

PURPOSE OF REVIEW: To discuss and review the technical considerations, fundamentals, and guideline-based indications for coronary artery calcium scoring, and the use of other non-invasive imaging modalities, such as extra-coronary calcification in cardiovascular risk prediction. RECENT FINDINGS: The most robust evidence for the use of CAC scoring is in select individuals, 40-75 years of age, at borderline to intermediate 10-year ASCVD risk. Recent US recommendations support the use of CAC scoring in varying clinical scenarios. First, in adults with very high CAC scores (CAC ≥ 1000), the use of high-intensity statin therapy and, if necessary, guideline-based add-on LDL-C lowering therapies (ezetimibe, PCSK9-inhibitors) to achieve a ≥ 50% reduction in LDL-C and optimally an LDL-C < 70 mg/dL is recommended. In patients with a CAC score ≥ 100 at low risk of bleeding, the benefits of aspirin use may outweigh the risk of bleeding. Other applications of CAC scoring include risk estimation on non-contrast CT scans of the chest, risk prediction in younger patients (< 40 years of age), its value as a gatekeeper for the decision to perform nuclear stress testing, and to aid in risk stratification in patients presenting with low-risk chest pain. There is a correlation between extra-coronary calcification (e.g., breast arterial calcification, aortic calcification, and aortic valve calcification) and incident ASCVD events. However, its role in informing lipid management remains unclear. Identification of coronary calcium in selected patients is the single best non-invasive imaging modality to identify future ASCVD risk and inform lipid-lowering therapy decision-making.

The year in cardiovascular medicine 2021: dyslipidaemia.

The past year was an exciting time for clinical lipidology when we learnt more about existing therapies as well as therapies targeting novel pathways discovered through genetic studies. LDL cholesterol remained the main target and a variety of drugs to lower LDL cholesterol through different mechanisms were explored. Emerging evidence on the atherogenity of triglyceride-rich lipoproteins led to renewed interest in lowering them with new treatments. Lp(a) was back in focus with evidence on causality and new targeted therapeutics which dramatically lower Lp(a) levels. We will be able to personalise lipid lowering therapy further with this enriched armamentarium once we have the results of the cardiovascular outcome studies with some of these new agents.

A Review of Statin Intolerance: a Focus on Statin-Attributed Muscle Symptoms.

PURPOSE OF REVIEW: To provide a systematic approach to management of the patient with statin-attributed muscle symptoms. RECENT FINDINGS: We examined the prevalence of statin intolerance, the role of the nocebo effect, key findings in the patient's history and laboratory studies, the potential value of coronary calcium scoring, and the importance of shared decision-making in considering statin re-initiation. Most patients with statin-attributed muscle symptoms can be successfully treated with statins or a combination of statins and non-statins to achieve successful ASCVD risk reduction.

How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol.

Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.

Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes.

OBJECTIVE: Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns and potential immunologic correlates of ACS. APPROACH AND RESULTS: We used polychromatic flow cytometry to analyze the cytokine production profiles of naïve, effector, and memory CD8 T cells in patients with ACS compared with control subjects with stable coronary artery disease. ACS was associated with an altered distribution of circulating CD8(+) T-cell maturation subsets with reduced proportions of naïve cells and expansion of effector memory cells. ACS was also accompanied by impaired interleukin-2 production by phenotypically naïve CD8 T cells. These results were validated in a second replication cohort. Naïve CD8 cells from patients with ACS also had increased expression of programmed cell death-1, which correlated with interleukin-2 hypoproduction. In vitro, stimulation of CD8 T cells with oxidized low-density lipoprotein was sufficient to cause programmed cell death-1 upregulation and diminished interleukin-2 production by naïve CD8 T cells. CONCLUSIONS: In this exploratory analysis, naïve CD8(+) T cells from patients with ACS show phenotypic and functional characteristics of immune exhaustion: impaired interleukin-2 production and programmed cell death-1 upregulation. Exposure to oxidized low-density lipoprotein recapitulates these features in vitro. These data provide evidence that oxidized low-density lipoprotein could play a role in immune exhaustion, and this immunophenotype may be a biomarker for ACS.

Overcoming barriers to implementation: Improving incidental coronary calcium reporting on non-EKG gated chest CT scans.

BACKGROUND: Current guidelines recommend the reporting of incidental CAC on non-EKG-gated CT scans of the chest. The finding of incidental moderate or severe CAC on non-cardiac non-contrast chest CT correlates with a CAC score ≥ 100 Agatston units, a guideline-based indication for a clinician-patient discussion regarding the initiation of statin therapy. In contemporary practice, whether the presence and severity of incidental CAC are routinely reported on such CT scans of the chest is unknown. METHODS: At a major university hospital, we collected a one-month convenience sample of 297 patients who had chest CT imaging for indications other than lung cancer screening (OICT) and 42 patients who underwent lung cancer chest CT screening (LSCT). We evaluated reporting patterns of incidental CAC in the body and impression of the reports as compared to the overreading of such studies by a board-certified CT chest radiologist. We hypothesized and demonstrated that there was underreporting of incidental CAC on these scans. We then undertook an initiative to educate reporting radiologists on the importance of reporting CAC and implemented a reporting template change to encourage routine reporting. Then we repeated another one-month sample (n= 363 for the OICT and n= 63 for the LSCT groups) to evaluate reporting patterns following our intervention. RESULTS: The presence of incidental moderate and severe CAC was systematically underreported in the OICT group (0 and 4.8 %) and the severity was never mentioned in the impression of reports. In the LSCT group, the presence of incidental moderate and severe CAC was also underreported (66.7 % and 75 %) and the severity of CAC was mentioned 50 % of the time in the impression of the reports. Following the initiation of an educational program and radiology reporting template change, there was a significant increase in reporting of moderate or severe CAC in the OICT group (0 vs. 80.0 %, p < 0.001) and (4.8 vs. 93.5 %, p < 0.001) respectively and a significant increase in the reporting of the severity of incidental CAC for those with severe CAC in the LSCT group (50 vs. 94.1 %, p=0.006). CONCLUSION: Despite guideline recommendations, Incidental CAC was underreported at a large academic center. We implemented a system that significantly improved reporting patterns of incidental CAC. Failure to report incidental CAC represents a missed opportunity to initiate preventive therapies. Hospital systems interested in improving the quality of their radiology reporting procedures should examine their practices to assure that CAC quantification is routinely performed.

Assessment of coronary artery calcium using dual-energy subtraction digital radiography.

Cardiovascular disease is the leading cause of global mortality, yet its early detection remains a vexing problem of modern medicine. Although the computed tomography (CT) calcium score predicts cardiovascular risk, relatively high cost ($250-400) and radiation dose (1-3 mSv) limit its universal utility as a screening tool. Dual-energy digital subtraction radiography (DE; <$60, 0.07 mSv) enables detection of calcified structures with high sensitivity. In this pilot study, we examined DE radiography's ability to quantify coronary artery calcification (CAC). We identified 25 patients who underwent non-contrast CT and DE chest imaging performed within 12 months using documented CAC as the major inclusion criteria. A DE calcium score was developed based on pixel intensity multiplied by the area of the calcified plaque. DE scores were plotted against CT scores. Subsequently, a validation cohort of 14 additional patients was independently evaluated to confirm the accuracy and precision of CAC quantification, yielding a total of 39 subjects. Among all subjects (n = 39), the DE score demonstrated a correlation coefficient of 0.87 (p < 0.0001) when compared with the CT score. For the 13 patients with CT scores of <400, the correlation coefficient was -0.26. For the 26 patients with CT scores of ≥400, the correlation coefficient yielded 0.86. This pilot study demonstrates the feasibility of DE radiography to identify patients at the highest cardiovascular risk. DE radiography's accuracy at lower scores remains unclear. Further evaluation of DE radiography as an inexpensive and low-radiation imaging tool to diagnose cardiovascular disease appears warranted.

Under-reporting and under-representation of non-Hispanic Black subjects in lipid-lowering atherosclerotic cardiovascular disease outcomes trials: A systematic review.

BACKGROUND: Non-Hispanic (NH) Black participants have been under-represented in studies of cardiovascular disease. OBJECTIVE: We sought to determine the trends of reporting and representation of NH Black subjects in randomized controlled trials (RCTs) of lipid-lowering therapies demonstrating atherosclerotic cardiovascular disease (ASCVD) risk reduction benefit. METHODS: The electronic databases of MEDLINE, EMBASE and ClinicalTrials.gov were searched from 1990-2020. Studies of lipid-lowering therapies (i.e., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9], and icosapent ethyl) with proven ASCVD benefit, sample sizes of at least 1000 subjects and follow-up of at least 1 year were included (40 RCTs, N=306 747 total participants). We examined articles and supplementary material for participant-level race data. Using United States disease prevalence data, the participation-to-prevalence ratio (PPR) metric was used to estimate the representation of NH Black subjects compared with their reported disease burden (i.e., < 0.8 indicated under-representation; > 1.2, over-representation; and 0.8 to <1.2, adequate representation). RESULTS: The median (interquartile range) number of participants per trial was 4871 (2434-10077). NH Black enrollees comprised 7.3% (95% CI, 0.9%-15.4%) of the total number of subjects reported. During the time intervals 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015 and 2016-2020, NH Black participation was 0%, 1.1%, 4.4%, 4.8%, 0.2% and 0.7% respectively (P for trend <0.001). For statin trials, the participation of NH Black subjects was reported in 0 studies between 1990-1995 and in 9 of 28 trials from 1996-2020. For ezetimibe and icosapent ethyl, NH Black participants were reported in 0 of 3 and 0 of 1 studies, respectively. For trials of PCSK9 inhibitors, NH Black subjects were reported in 2 of 5 (40%). NH Black participants were under-represented compared with their disease burden in studies evaluating subjects with diabetes, hypercholesterolemia, stable coronary artery disease, and acute coronary syndrome (PPR < 0.8 for all). CONCLUSION: NH Black participants are markedly under-represented, and results are under-reported. The inclusion of population and disease specific representation of NH Black persons and their related social determinants of health will help to address the disparity in preventive care for this historically undertreated population.

Global think tank on the clinical considerations and management of lipoprotein(a): The top questions and answers regarding what clinicians need to know.

Evidence from Mendelian randomization studies suggest that lipoprotein(a) (Lp(a)) has a causal role in the development of atherosclerotic cardiovascular disease risk. However, guidelines and consensus statement recommendations vary regarding how clinicians should incorporate Lp(a) into patient care. To provide practical answers to key questions pertaining to Lp(a) that clinicians will find useful when assessing and treating patients, a global think tank was convened. Representatives from seven national and international stakeholder organizations answered questions that were focused on: Lp(a) measurement; ethnic, gender, and age considerations; factoring Lp(a) into risk assessment; and current and emerging treatment options for elevated Lp(a). This manuscript summarizes the finding from this global think tank. Areas requiring further investigation were identified, and the need to standardize reporting of Lp(a) levels to ensure harmonization and comparability across laboratories and research studies is emphasized.

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

Managing Atherosclerotic Cardiovascular Risk in Young Adults: JACC State-of-the-Art Review.

There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood.

Coronary artery calcium scoring in patients with statin associated muscle symptoms: Prescribing statins for those most likely to benefit.

For primary prevention, statin therapy reduces the incidence of atherosclerotic cardiovascular disease (ASCVD) events in adults with intermediate or high estimated 10-year risk using traditional population-based risk calculators. While a variety of reported symptoms may limit statin adherence, muscle complaints, whether typical or atypical of that associated with statin therapy, are the most common reported by patients. Because additional testing, alteration in the patient's medical regimen and subsequent medical visits are often required, an informed clinician-patient discussion and shared decision making are necessary to achieve the best outcomes. The authors provide support for the perspective that coronary calcium scoring, by individualizing estimated risk and helping to identify those most likely to benefit, plays a vital role in preventive therapy decision-making for the primary prevention patient with troublesome muscle complaints attributed to statin therapy.

High-Intensity Statins Benefit High-Risk Patients: Why and How to Do Better.

Review of the US and European literature indicates that most patients at high risk for atherosclerotic cardiovascular disease (ASCVD are not treated with high-intensity statins, despite strong clinical-trial evidence of maximal statin benefit. High-intensity statins are recommended for 2 categories of patients: those with ASCVD (secondary prevention) and high-risk patients without clinical ASCVD. Most patients with ASCVD are candidates for high-intensity statins, with a goal for low-density lipoprotein cholesterol reduction of 50% or greater. A subgroup of patients with ASCVD are at very high risk and can benefit by the addition of nonstatin drugs (ezetimibe with or without bile acid sequestrant or bempedoic acid and/or a proprotein convertase subtilisin/kexin type 9 inhibitor). High-risk primary prevention patients are those with severe hypercholesterolemia, diabetes with associated risk factors, and patients aged 40 to 75 years with a 10-year risk for ASCVD of 20% or greater. In patients with a 10-year risk of 7.5% to less than 20%, coronary artery calcium scoring is an option; if the coronary artery calcium score is 300 or more Agatston units, the patient can be up-classified to high risk. If high-intensity statin treatment is not tolerated in high-risk patients, a reasonable approach is to combine a moderate-intensity statin with ezetimibe. In very high-risk patients, proprotein convertase subtilisin/kexin type 9 inhibitors lower low-density lipoprotein cholesterol levels substantially and hence reduce risk as well.

The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduction.

An Expert Panel of the National Lipid Association reviewed the evidence related to the use of coronary artery calcium (CAC) scoring in clinical practice for adults seen for primary prevention of atherosclerotic cardiovascular disease. Recommendations for optimal use of this test in adults of various races/ethnicities, ages and multiple domains of primary prevention, including those with a 10-year ASCVD risk <20%, those with diabetes or the metabolic syndrome, and those with severe hypercholesterolemia were provided. Recommendations were also made on optimal timing for repeat calcium scoring after an initial test, use of CAC scoring in those taking statins, and its role in informing the clinician patient discussion on the benefit of aspirin and anti-hypertensive drug therapy. Finally, a vision is provided for the future of coronary calcium scoring.