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ContextDifferentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management.ObjectiveTo assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions.MethodsThe analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity.ResultsThe primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%).ConclusionsIn the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.

Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

Elevated levels of lipoprotein(a) in the plasma are a risk factor for cardiovascular disease, and lowering levels can be achieved with antisense oligonucleotide targeting LPA messenger RNA, which encodes lipoprotein(a). This trial tested whether the same effect can be achieved in persons with established cardiovascular disease.

Purpose of Review Familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) are relatively common disorders, posing a significant health burden due to increased risk of atherosclerotic cardiovascular disease (ASCVD). Development of electronic health record–based strategies with a linkage to the genetic test results has increased awareness, detection, and control of heritable lipid disorders. This review attempts to critically examine available data to provide a summary of the current evidence for lipoprotein apheresis in FH and elevated lipoprotein(a) (Lp(a)). Review Findings Availability and indications for lipoprotein apheresis vary across the globe. On average, greater than 60% of atherogenic apoB-containing lipoproteins are immediately reduced following a single procedure, translating in substantial reduction of incident ASCVD events, and preventing accelerated vascular aging. Simultaneous lipid-lowering therapy targeting low-density lipoprotein (LDL) and Lp(a) enhances the efficacy of lipoprotein apheresis. Lipoprotein apheresis alters the proteomics of the lipoprotein particles, including reduction in the concentration of the oxidized-LDL and Lp(a) particles, and proinflammatory apoE bound to HDL particles and remnant lipoproteins. Other effects attributed to lipoprotein apheresis include improvement in blood rheology, endothelial function, microvascular flow, myocardial perfusion, reduction in circulating inflammatory markers. Development of lipoprotein apheresis registries provides data on benefits, challenges, and barriers to inform pertinent healthcare policies. Summary Lipoprotein apheresis is a safe and effective procedure for lowering cholesterol in patients with combined and isolated FH and elevated Lp(a). It reduces the burden of ASCVD and improves long-term prognosis. A team approach is required by the patient, medical staff, and healthcare provider to initiate and maintain a lipoprotein apheresis program.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n  = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n  = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n  = 19). Fifty-one patients (males, n  = 27; females, n  = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 . The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.

Purpose of ReviewThe COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications.Recent FindingsThe Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase–type increase in Lp(a) levels following a cytokine storm from COVID-19.SummaryThus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.

The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular risk-reduction. We hypothesized that regular lipoprotein apheresis over the course of 10 years might slow down progression of CIMT in patients with severe hypercholesterolemia. This case series describes 10 Caucasian patients (mean age 60 ± 9 years, 70% female, 80% statin intolerant) with a severe hypercholesterolemia phenotype treated with lipoprotein apheresis between 2005 and 2020 (mean duration, 10 ± 4 years). The median pretreatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/100 ml (95% confidence interval, 145 to 248), lipoprotein(a) (Lp[a]), 26 mg/100 ml (15 to 109; 40% with Lp(a)>60 mg/100 ml). Three patients were diagnosed with a monogenic cause. The baseline mean CIMT was 850 ± 170 µm, and maximum CIMT was 1,040 ± 220 µm across the age range of 46 to 70 years. Acute effects of lipoprotein apheresis determined as a difference before and immediately after the procedure were estimated as a median of 72 ± 8% and 75 ± 7% reduction in the LDL-C and Lp(a) levels, respectively. Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and Lp(a) were 141 mg/100 ml (interquartile range, 89 to 152; 38% reduction from the baseline) and 24 mg/100 ml (interquartile range, 12 to 119; 19% reduction from baseline), respectively. The number of patients with CIMT above their “vascular age” decreased from 80% to 30% over the treatment course. In conclusion, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with lipoprotein apheresis with an estimated annual rate of change in mean common CIMT of −4 µm/y and maximum CIMT of −3 µm/y. [Display omitted]

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.