Severe Hypercholesterolemia Research Articles

Microvascular Function and Endothelial Progenitor Cells in Patients with Severe Hypercholesterolemia and the Familial Hypercholesterolemia Phenotype

Objective: To evaluate endothelial progenitor cells (EPCs) and systemic microvascular function in patients with severe hypercholesterolemia, comparing patients with the definite familial hypercholesterolemia (FH) phenotype (DFH) or probable/possible FH phenotype (PFH). There is a large spectrum of atherosclerotic disease between these two clinical phenotypes of FH, and to acquire further knowledge of the pathophysiology of vascular disease in both is desirable. Methods: Subjects with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol (LDL-C) >190 mg/dL, were classified as DFH or PFH and underwent measurement of the number of EPCs by flow cytometry and evaluation of cutaneous microvascular reactivity using a laser speckle contrast-imaging system with iontophoresis of acethylcholine (ACh) or sodium nitroprusside. EPCs were defined as CD45- or CD45^low, CD34+CD133+CD309+ cells. Categorical variables were compared using Fisher test and continuous variables with Student t test or Mann-Whitney test, and a value of p < 0.05 was considered statistically significant. Results: Patients with DFH had higher LDL-C than those with PFH. There was no difference in the median number of EPCs between patients with DFH or PFH, but there was a significant reduction of endothelial-dependent, ACh-induced vasodilatation in the former. Conclusion: Patients with DFH have impaired microvascular endothelial-dependent vasodilatation compared to those with PFH, indicating more severe vascular disease in the former.

Abstract 434: The Majority of Outpatients With Severe Hypercholesterolemia at an Academic Tertiary Centre Have Not Been Screened for FH

Background: National and International guidelines recommend, as a minimum, that individuals with LDL-C ≥190mg/dL are asked about a family history of ASCVD and hypercholesterolemia to screen for familial hypercholesterolemia (FH), a monogenic condition that carries considerable ASCVD risk. However, FH is grossly underdiagnosed and undertreated in the US. One reason for this may be failure to screen severely hypercholesterolemic individuals for FH. Hypothesis: We evaluated the hypothesis that poor identification of FH might be due to inadequate screening for FH among individuals with severe hypercholesterolemia. Methods: An EHR query was used to identify active adult patients in the University of Pennsylvania outpatient EHR database (N=310 802) with LDL-C≥220mg/dL, excluding secondary causes of hypercholesterolemia. The EHR was then systematically reviewed for structured notation of family history information. Result: The query identified 3,475 individuals with severely elevated LDL-C. Among them, only 47.9% (1666) had family history data relating to ASCVD (968), hypercholesterolemia (336) or both (362) in the EHR. The history was positive in 94.2% (1569) of these cases. Overall, patients with LDL-C ≥220mg/dL were more likely to be screened (OR 1.57; 95% CI 1.47-1.68) than those with LDL &lt;220mg/dL. Within the former group, the odds of being screened were higher in Caucasians (OR 1.52; 95% CI 1.33-1.75), with more severe LDL-C elevation or a history of ASCVD (OR 1.36; 95% CI 1.10 - 1.67). Conversely, the presence of diabetes (OR 0.73; 95% CI 0.61-0.86) or hypertension (OR 0.82; 95% CI 0.72-0.94), made screening less likely to occur. Interestingly, the setting of clinical care was also important; individuals seen in secondary care (OR 1.68; 95% CI 1.41-2.26), general (OR 1.69, 95% CI 1.47-1.95) or preventative cardiology (OR 1.82; 95% CI 1.47-2.25) were more likely to be screened. Finally, statin prescription was more common in those screened (OR 1.39; 95% CI 1.16-1.88), but this did not affect LDL-C goal achievement. Conclusion: At a large academic centre, the majority of outpatients with severe hypercholesterolemia had no record of being screened for FH. This report sheds light on factors that might be relevant to the underdiagnosis of FH in the US.

The Majority of Outpatients With Severe Hypercholesterolemia at an Academic Tertiary Centre Have Not Been Screened for FH

The Majority of Outpatients With Severe Hypercholesterolemia at an Academic Tertiary Centre Have Not Been Screened for FH

Abstract 435: An Electronic Health Records Query for Severe Hypercholesterolemia Identifies Individuals With Undiagnosed Clinical and Molecular FH at a Tertiary Academic Centre

Background: Familial hypercholesterolemia (FH) is a common heritable disorder of elevated low density lipoprotein cholesterol (LDL-C) with an estimated prevalence of 1/200-300 in the US; however, fewer than 10% of cases have been identified. We wanted to examine whether a simple EHR query for severe hypercholesterolemia could be used to identify clinically and genetically defined cases of FH. Objectives/Purpose: We tested the hypothesis that querying the EHR using an LDL-C criterion would be a novel way to screen for and ultimately identify undiagnosed cases of FH. Methods: An EHR screening query was used to identify active adult patients with LDL-C ≥ 220 mg/dL in the University of Pennsylvania outpatient EHR database. Patients with secondary causes of hypercholesterolemia and those who had previous genetic testing for FH were excluded. The query identified 3,475 individuals, 120 were subsequently consented and enrolled for molecular testing. This was performed with next-generation sequencing using Progenika’s SEQPRO LIPO IS platform, targeting LDLR, APOB, PCSK9 and LDLRAP1 . A literature search was performed to gather information on identified LDLR variants of unknown significance (VUS). In addition, in-silico analysis was employed to evaluate the pathogenicity of the LDLR and LDLRAP1 VUS. Results: Among the 120 subjects, 53 (44.2%) met the Dutch Lipid Clinic Network (DLCN) criteria for probable or definite clinical FH. Molecularly, 19 FH-related pathogenic mutations were found in 18 (15%) individuals. Four had a common APOB ( R3500Q) mutation, 14 had a LDLR mutation. One individual had a double heterozygous mutation in PCSK9 and LDLR. In addition, 17 LDLR VUS were identified in 16 (13.9%) individuals. A literature review and in-silico analysis predicted that 8 VUS found in 10 subjects were “disease causing”. Therefore, a total of 28 (24.3%) subjects from our cohort carried either a FH causal mutation or likely pathogenic variant. Overall, 59 subjects (49.2%) in our cohort were ascertained to have either a clinical or molecular diagnosis of FH. Conclusion: The use of an EHR screening query for severe hypercholesterolemia was a novel, low investment but relatively high yield approach for identifying undiagnosed cases of FH at a tertiary academic centre.

An Electronic Health Records Query for Severe Hypercholesterolemia Identifies Individuals With Undiagnosed Clinical and Molecular FH at a Tertiary Academic Centre

An Electronic Health Records Query for Severe Hypercholesterolemia Identifies Individuals With Undiagnosed Clinical and Molecular FH at a Tertiary Academic Centre

Lipoprotein apheresis in the treatment of dyslipidaemia - the Czech Republic experience.

In 1984, we started using therapeutic plasmapheresis (plasma exchange) as a method of extracorporeal lipoprotein elimination for the treatment of hypercholesterolemic patients. We evaluated the results of long-term therapy in 14 patients, 8 men and 6 women. The average age was 55.6+/-13.2 (range 28-70), median 59.5 years. 14 patients were diagnosed with familial hypercholesterolemia (FH): 5 homozygous, 9 heterozygous. Ten patients in the group were treated using immunoadsorption lipoprotein apheresis and 4 using hemorheopheresis. Immunoapheretic interventions decreased LDL-cholesterol (82+/-1 %), ApoB (73+/-13 %) and even Lp(a) by 82+/-19 %, respectively. Selected non-invasive methods are important for long-term and repeated follow-up. Carotid intima-media thickness showed improvement or stagnation in 75 % of the patients. Biomarkers of endothelial dysfunction such as endoglin (in the control group: 3.85+/-1.25 microg/l, in lipoprotein apheresis-treated hypercholesterolemic individuals 5.74+/-1.47 microg/l), CD40 ligand (before lipoprotein apheresis: 6498+/-2529 ng/l, after lipoprotein apheresis: 4057+/-2560 ng/l) and neopterin (before lipoprotein apheresis: 5.7+/-1.1 nmol/l, after lipoprotein apheresis: 5.5+/-1.3 nmol/l) related to the course of atherosclerosis, but did not reflect the actual activity of the disease nor facilitate the prediction or planning of therapy. Hemorheopheresis may improve blood flow in microcirculation in familial hypercholesterolemia and also in some other microcirculation disorders via significantly decreased activity of thrombomodulin (p<0.0001), tissue factor (p<0.0001), aggregation of thrombocytes (p<0.0001) and plasma and whole blood viscosity (p<0.0001). In conclusion, lipoprotein apheresis and hemorheopheresis substantially lowered LDL-cholesterol in severe hypercholesterolemia. Our experience with long-term therapy also shows good tolerance and a small number of complications (6.26 % non-serious clinical complications).

Phenotype vs. genotype in severe familial hypercholesterolemia: what matters most for the clinician?

Familial hypercholesterolemia is associated with a high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is variable. This review evaluates recent evidence related to ASCVD risk stratification in familial hypercholesterolemia considering aspects of phenotype and genotype. The heterogeneity in clinical, laboratory characteristics, and in ASCVD risk in both homozygous and heterozygous familial hypercholesterolemia individuals in part can be attributed to the type of molecular defect. In most individuals with LDL cholesterol more than 190 mg/dl, a familial hypercholesterolemia-causing variant is not encountered, however, when present, a variant implicates an even higher ASCVD risk for such individuals. Previous ASCVD events, elevated blood lipoprotein(a), cutaneous markers of cholesterol deposit are among other factors that indicate a higher ASCVD risk in familial hypercholesterolemia individuals underlying a more severe form of the phenotype. Both clinical and genetic parameters help identify higher ASCVD risk among severe familial hypercholesterolemia individuals.

SIRT3 Inactivation Impairs Endothelial Function and Promotes Vascular Calcification in Hypercholesterolemic Mice

Recent work by other investigators have shown that SIRT3 is an important regulator of endothelial function in obese patients or animals, as reductions in SIRT3 drive increased mitochondrial ROS (mtROS) production. The role of SIRT3 in atherosclerotic mice, however, remains unclear. Therefore, we hypothesized genetic inactivation of SIRT3 in hypercholesterolemic mice will impair vascular function, reduce antioxidant gene expression, and increase pro‐osteogenic signaling. We used Ldlr−⁄−/ApoB100/100 mice that were either wild‐type (LA‐SIRT3+/+) or null for SIRT3 (LA‐SIRT3−⁄−). After 12 weeks of western diet feeding, we assessed endothelial function of aorta using isolated organ bath chambers and measured changes in gene expression using qRT‐PCR. Consistent with our hypothesis, loss of SIRT3 significantly impaired relaxation to acetylcholine (Ach) (LA‐SIRT3−⁄−: 48.2%±3.0, LA‐SIRT3+/+: 57.6%±1.7). Incubation with Mito‐Tempol significantly improved endothelial‐dependent relaxation in LA‐SIRT3−⁄− mice (57.0%±2.9), but not in LA‐SIRT3+/+ mice. Interestingly, losses of SIRT3 did not alter expression of MnSOD, ecSOD, or CuZnSOD. Gene expression of the late‐stage osteoblast marker, osterix, tended to be increased in LA‐SIRT3−⁄− mice compared to wild‐type mice (p = 0.06). Collectively, losses of SIRT3 impair endothelial function and tend to increase osteogenic signaling in severe hypercholesterolemia. Importantly, these functional and molecular changes and may result from increased mtROS, which may serve as a viable therapeutic target to slow pathological processes during progression of atherosclerosis.Support or Funding InformationNHLBI R01‐HL111121

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation.

PREDICTORS OF STATIN USE FOR PATIENTS WITH LDL CHOLESTEROL ABOVE 190MG/DL: INSIGHTS FROM THE VETERANS AFFAIRS HEALTH CARE SYSTEM

Background: Individuals with LDL-C levels above 190 mg/dL are considered to have a severe hypercholesterolemia phenotype and are at markedly increased risk of adverse cardiovascular events. Therefore, the 2013 ACC/AHA cholesterol guidelines recommend high-intensity statins for this high-risk patient

Clinical determinants and treatment gaps in familial hypercholesterolemia: Data from a multi-ethnic regional health service.

Background Familial hypercholesterolemia is characterized by markedly increased low-density lipoprotein cholesterol and risk for premature atherosclerotic cardiovascular disease. Models of care vary and reflect differing health policies and resources. The availability of electronic databases may enable better identification and assessment of familial hypercholesterolemia in the community. Methods A regional healthcare database was utilized to identify patients with a high probability of familial hypercholesterolemia, clinically defined by age-dependent-peak low-density lipoprotein cholesterol cutoffs and exclusion of secondary causes of severe hypercholesterolemia. Clinical characteristics, low-density lipoprotein cholesterol goal attainment, and treatment gaps were investigated. Results Probable familial hypercholesterolemia was diagnosed in 1932 of 685,314 individuals (1:355; median age 47 years). Atherosclerotic cardiovascular disease was present in 16.3% of adults (38% in males aged 50-74 years). Median peak low-density lipoprotein cholesterol was 264 mg/dl (interquartile range 252-288). Statins and/or ezetimibe were prescribed to 83% of patients and high-intensity statins to 53%, whereas prescriptions were filled in 57% and 40% cases respectively over the last six months, p < 0.001. Treatment gaps were wider among ethnic minorities, younger individuals, and those without atherosclerotic cardiovascular disease. Low-density lipoprotein cholesterol < 100 mg/dl was attained in 10.1% overall and 28.7% of those with atherosclerotic cardiovascular disease. Predictors of low-density lipoprotein cholesterol goal attainment included recent issue of high-intensity statins, presence of atherosclerotic cardiovascular disease, diabetes, older age and lack of smoking. Conclusions The population with high probability for familial hypercholesterolemia was characterized by low attainment of low-density lipoprotein cholesterol treatment goals despite high prescription rates of lipid-lowering medications. Low utilization of intensified therapies, non-adherence, and ethnic disparities were contributing factors. These findings emphasize the need to improve awareness and quality of care of familial hypercholesterolemia in the community.

Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia.

The impact of positive clinical signs (xanthoma and/or family history) and positive familial hypercholesterolaemia (FH) mutation status on risk of coronary artery disease (CAD) over and above that predicted by low-density lipoprotein (LDL) cholesterol level alone has not been fully determined. We assessed whether positive clinical signs and genetic FH diagnosis affected CAD risk among subjects with significantly elevated LDL cholesterol levels (≥180 mg/dL, or ≥140 mg/dL in subjects <15 years of age). Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 636 patients with severe hypercholesterolaemia (mean age, 45 years; 300 males [47%], CAD diagnosis, 185 [29%]), and the presence of clinical FH signs (xanthoma and/or family history) were assessed. CAD prevalence was compared between four subject groups categorized based on these parameters. Compared with the reference group without FH mutations or clinical signs of FH, subjects with clinical signs of FH or FH mutations had three- to four-fold higher odds of developing CAD (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-14.5; P = 0.0011 and OR, 3.4; 95% CI, 1.0-10.9; P = 0.0047, respectively), whereas those with clinical signs of FH and FH mutation(s) had >11-fold higher odds of developing CAD (OR, 11.6; 95% CI, 4.4-30.2; P = 1.1 × 10-5) after adjusting for known risk factors including LDL cholesterol. Our findings revealed an additive effect of positive clinical signs of FH and positive FH mutation status to CAD risk among patients with significantly elevated LDL cholesterol.

Stent liberadores de medicamento en enfermedad coronaria prematura en jóvenes con hipercolesterolemia familiar homocigota y trasplante hepático previo

Familial hypercholesterolemia is a genetic disorder characterised by very high cholesterol and low-density lipoproteins serum levels, tendon xanthomas and premature atherosclerosis. Heterozygous form is the most common, with a prevalence of approximately 1 out of 300 to 500 people worldwide, whereas the homozygous, autosomal dominant, is the rarest form, with a prevalence of 1 out of 1 million people. It is characterised by severe hypercholesterolemia leading to premature cardiovascular disease, and it often does not respond to traditional therapy due to the lack of receptors for functional LDL-c. LDL-c levels can exceed between six and ten times the normal values, in which case liver transplantation has become the treatment of choice for patients who do not respond to routine pharmacological therapies. This study presents two cases of homozygous familial hypercholesterolemia in young patients aged 14 and 15, with prior liver transplantation and severe coronary disease in major vessels (anterior descending artery and right coronary artery) who underwent successful implant of a drug-eluting stent.

PCSK9 inhibitors: A new era of lipid lowering therapy.

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

Association and differences in genetic polymorphisms in PCSK9 gene in subjects with lacunar infarction in the Han and Uygur populations of Xinjiang Uygur Autonomous Region of China.

Polymorphisms in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are associated with severe hypercholesterolemia and stroke. Here, we investigated the relationship between single nucleotide polymorphisms in PCSK9 and stroke in 237 patients with lacunar infarction in the Uygur and Han populations in Xinjiang Uygur Autonomous Region of China. Using the SNaPshot single-base terminal extension method, four PCSK9 gene polymorphisms were analyzed. We found a significantly strong relationship between the PCSK9 rs17111503 (G > A) polymorphism and increased susceptibility to lacunar infarction by variant homozygote comparison, and using the dominant and recessive models in the Han population but not in the Uygur population. Low triglyceride levels were found in AA carriers (rs17111503, G > A) in the Han population but not in the Uygur population. Association analysis revealed that the rs17111503 (G > A) polymorphism was not significantly associated with smoking, alcohol drinking, history of hypertension or diabetes in the Han or Uygur lacunar infarction patients. rs11583680, rs483462 and rs505151 were not associated with risk of lacunar infarction in the Han or Uygur populations. Our findings suggest that the PCSK9 rs17111503 (G > A) polymorphism is associated with susceptibility to lacunar infarction in the Han population but not in the Uygur population.

SUBFRACTIONS OF ATHEROGENIC APOB-LIPOPROTEIDES IN PATIENTS WITH SEVERE HYPERCHOLESTEROLEMIA

Aim . To investigate on the relation of lipoproteide (a) (Lpa), subfractions of intermediate density lipoproteides (IDL) and low density lipoproteides (LDL) with the probability of familial hypercholestrolemia diagnosis (FHE). Material and methods . Totally, 114 patients included, with severe hypercholesterolemia (LDL-C &gt;4,9 mM/L), with no known coronary heart disease and not taking hypolipidemic therapy. For the probability assessment of FHE, Dutch Lipid Clinics Network criteria were applied. Lipid profile parameters were measured by enzymatic method; Lpa — by immune enzyme method; lipoproteides subfractions — with the Lipoprint® system (Quantimetrix, USA). Results . All patients were selected to subgroups in accordance with the Dutch criteria: I group — with low FHE probability (3-5 points, n=86) and II — with definite and porobable FHE (≥6 points, n=28). Patients from II group had higher atherogenic apoB100-containing lipoproteides (a) levels — 25,5±27,8 and 42,8±41,5 mg/dL (р=0,014), small dense subfractions of LDL — sdLDL: 2,3±3,7 and 7,1±10,1 mg/dL (р&lt;0,01) and IDL-C — 26,6±9,7 and 37,0±10,7 mg/dL (р&lt;0,0001). Monofactorial analysis revealed positive correlation of FHE presence with Lpa (r=0,261, p=0,005), IDL-A (r=0,212, p=0,024), IDL-В (r=0,256, p=0,006), IDL-С (r=0,324, p&lt;0,001), large subfractions of LDL-2 (r=0,218, p=0,020), sdLDL (r=0,362, p=0,0001) and negative correlation with the low density cholesterol (HDL-C) (r=-0,174, p=0,012); however, by the multifactorial analysis the negative correlation was noted only for Lpa (r=0,230, р=0,005) and IDL-С (r=0,411, p=0,009). Combination of the Lpa concentrations ≥30 mg/dL and sdLDL ≥2 mg/dL in relation to Lpa &lt;30 mg/dL and sdLDL &lt;2 mg/dL, as well as Lpa ≥30 mg/dL and IDL-С ≥30 mg/dL in relation with Lpa &lt;30 mg/dL and IDL-С &lt;30 mg/dL significantly increases the probability of FHE diagnostics (odds ratio =11,3 (95% confidence interval 2,9-43,7), р&lt;0,001, and odds ratio =9,0 (95% confidence ratio 2,3-34,9), р=0,002), respectively. Conclusion . In the patients with definite and probable FHE diagnosis, there is significantly increased concentration of the most atherogenic apoB100-containing lipoproteides: Lpa, IDL-C and sdLDL, and the levels of sdLDL ≥2 mg/dL or IDL-C ≥30 mg/dL together with hyperlipoproteidemia (a) increase the chance of FHE verification.

Causative mutations and premature cardiovascular disease in patients with severe hypercholesterolemia

Causative mutations and premature cardiovascular disease in patients with severe hypercholesterolemia

Juvenile goitre in a kid: Evaluation and treatment

Goitre, an iodine deficiency disorder is characterized by enlargement of the thyroid glands. Besides, low T4 and high T3 levels, there was a concomitant occurrence of severe hypoglycemia, hypercholesterolemia and heart rate. Goitre in kids can be treated by levothyroxine sodium therapy with iodine supplementation.

Pattern of Nephrotic syndrome among Libyan children in Benghazi for the year 2016

Introduction: Nephrotic syndrome (NS) is a clinical picture characterized by severe proteinuria, hypoalbuminemia, edema and hypercholesterolemia. Methods: A retrospective study was carried out to describe the disease pattern among Libyan children admitted to Benghazi children hospital during the year 2016. The medical data was analysed using SPSS software. Results: Out of 105 patients with NS aged between 6 days and 15 years, 69.5% were boys and 30.5% were girls, with a mean age 4.9±3.7 years. 89% of the nephrotic children had Idiopathic type. ,57% of the known cases who diagnosed before as nephrotic syndrome were steroid responsive and 21% of them had frequent relapses. Conclusion and Recommendations: Idiopathic NS was the most common type and males outnumber female patients Further studies of childhood NS in Libya are recommended to know the exact prevalence and incidence rate of the disease.

Estimation of Risk for Initial Atherosclerotic Cardiovascular Disease Events: Taking Stock and Moving Forward.

In 2013, the American College of Cardiology/American Heart Association published guidelines for atherosclerotic cardiovascular disease (ASCVD) risk assessment.1 They recommended that clinicians calculate ASCVD risk for adult patients and based cholesterol treatment recommendations on these estimates. Persons with severe hypercholesterolemia or those known to have ASCVD were considered to be at high risk for clinical ASCVD, and they fell outside the purview of risk assessment. The remainder, which included most middle-age and older Americans with and without diabetes mellitus, were candidates for ASCVD risk assessment. A reasonable interval has elapsed to evaluate the strategy put forward and to contemplate changes that might improve prevention. Critical issues include how well does the current ASCVD algorithm identify persons who subsequently develop ASCVD events, and can they be improved? Should segments of the US population receive more attention? How can the ASCVD risk estimates be augmented? The 2013 guidelines provided new functions to estimate ASCVD risk in a 10-year time frame, applicable to millions of American adults 40 to 79 years of age, and the committee also suggested considering 30-year and lifetime risk.1 Several American longitudinal population studies served as data sources …