Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil.

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia.

OBJECTIVE: Patients with familial hypercholesterolemia (FH) are at high risk for premature atherosclerotic cardiovascular disease (ASCVD), especially because of long-term exposure to high low-density lipoprotein cholesterol levels. It has been reported that low-density lipoprotein-lowering therapy delays the onset of ASCVD. However, it still remains difficult to prevent it. Therefore, novel biomarkers and therapeutic targets are necessary to evaluate and prevent atherosclerosis in FH. The aim of this study was to investigate associations of cholesterol efflux capacity with the presence of ASCVD and clinical features in patients with heterozygous FH. APPROACH AND RESULTS: We measured cholesterol efflux capacity in 227 patients with heterozygous FH under pharmaceutical treatment. Seventy-six (33.5%) of them were known to have ASCVD. In a logistic-regression analysis adjusted for risk factors, increased efflux capacity was associated with decreased risk of ASCVD even after the addition of high-density lipoprotein cholesterol level as a covariate (odds ratio per 1-SD increase, 0.95; 95% confidence interval, 0.90-0.99; P<0.05). Decreased cholesterol efflux capacity was associated with the presence of corneal arcus after adjusting for age and sex. In addition, inverse relationships between cholesterol efflux capacity and Achilles tendon thickness, as well as carotid intima-media thickness, were observed after adjustment for age, sex, and traditional cardiovascular risk factors. CONCLUSIONS: Cholesterol efflux capacity was independently and inversely associated with the presence of ASCVD in heterozygous FH. In view of residual risks after treatment with statins, cholesterol efflux capacity might be a novel biomarker and a therapeutic target for preventing atherosclerosis in patients with FH.

Corneal arcus is a sign of cardiovascular disease, even in low-risk persons.

PURPOSE: To examine the association of corneal arcus to cardiovascular disease (CVD) in an adult, ethnic Indian population. DESIGN: Population-based cross-sectional study. METHODS: Population-based study of ethnic South Asian Indians 40 to 80 years of age in Singapore from June 2007 through March 2009. We obtained a 75.5% response rate (3397/4497). All participants underwent standardized interview and systemic and ocular examinations, followed by nonfasting blood sampling. Corneal arcus was detected using a standardized slit-lamp examination. The main outcome measure was CVD, defined from a self-reported history of previous myocardial infarction, angina, or stroke. RESULTS: Corneal arcus, found in 1701 (50.1%) of 3397 participants, was associated with older age (odds ratio [OR], 3.07; 95% CI, 2.78 to 3.40; P < .001), male gender (OR, 2.17; 95% CI, 1.81 to 2.62; P < .001), higher levels of total cholesterol (OR, 1.14; 95% CI, 1.05 to 1.24; P = .002), hypertension (OR, 1.14; 95% CI, 1.05 to 1.24; P = .013), and cigarette smoking (OR, 1.59; 95% CI, 1.25 to 2.03; P < .001). Corneal arcus was associated with CVD (OR, 1.31; 95% CI, 1.02 to 1.7; P = .0038) independent of the above-named cardiovascular risk factors. Participants with low-risk Framingham scores were more likely to be associated with CVD if they had corneal arcus (men: OR, 2.02; 95% CI, 1.20 to 3.40; P = .008; women: OR, 2.78; 95% CI, 1.36 to 3.01; P < .001). Corneal arcus was associated with CVD independent of the Framingham score (men: Akaike information criterion, 1524.39 for Framingham Score and corneal arcus vs 1527.38 for Framingham Score alone; women: 1000.14 vs 1003.54, respectively). CONCLUSIONS: Corneal arcus is associated with CVD, independent of risk factors in ethnic Indian adults, even in those at low risk for vascular disease.

Corneal arcus as coronary artery disease risk factor.

Corneal arcus is a lipid-rich and predominantly extracellular deposit that forms at the corneoscleral limbus. It represents the most common peripheral corneal opacity and is not associated with tissue breakdown but rather with the deposition of lipids. The deposition of cholesterol in the peripheral cornea and arterial wall are similar in that both are accelerated by elevated serum levels of atherogenic lipoproteins, such as low-density lipoproteins (LDL). Corneal arcus is more prevalent in men than in women and in Blacks than in Whites. Its prevalence increases with advancing age. It has been associated with hypercholesterolemia, xanthelasmas, alcohol, blood pressure, cigarette smoking, diabetes, age, and coronary heart disease. Nevertheless, it is not clear whether or not corneal arcus is an independent risk factor for coronary heart disease (CHD). The present systematic review examines the relationship of corneal arcus and CHD to determine if corneal arcus is an independent CHD risk factor. We conclude that there is no consensus that corneal arcus is an independent risk factor. The presence of corneal arcus in a young person should prompt a search for lipid abnormalities. Also, because corneal arcus represents physical evidence of early lipid deposition, its presence suggests the need for aggressive lipid therapy.

Serum lipid parameters and the prevalence of corneal arcus in a dyslipidaemic patient population.

AIM: To determine whether an association exists between plasma lipoprotein constituents and the prevalence of corneal arcus in dyslipidaemic patients. METHODS: Adult patients (n = 115) were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile or their serum low-density lipoprotein (LDL) : high density lipoprotein (HDL) ratios exceeded 5. Slit-lamp assessment of the corneas was performed. RESULTS: The study group divided into a subgroup with arcus 37% (43) and a subgroup without arcus 63% (72). Total serum cholesterol and triglyceride levels were not associated with corneal arcus. A significant difference was found (p < 0.05) between the mean levels of LDL cholesterol (LDL-C) in the group without arcus (5.61 +/- 1.74 mmol/l) and the group with arcus (5.96 +/- 1.71 mmol/l). The mean serum HDL-cholesterol (HDL-C) in the group with corneal arcus was 1.04 +/- 0.30 mmol/l as opposed to 1.31 +/- 0.38 mmol/l in the group without arcus (p < 0.005 for difference). The mean LDL-C : HDL-C ratio in the group without arcus was 4.28 (SD: 1.99), and 5.73 (SD: 2.09) in the group with a corneal arcus (p < 0.05). CONCLUSIONS: Low HDL-C levels, high LDL-C levels and LDL-C : HDL-C ratios > 5 have been implicated as risk factors of numerous circulatory diseases. The observations in this study suggest that the presence of corneal arcus in the dyslipidaemic patient correlates strongly with these same risk indicators.

Corneal arcus and hyperlipidemia: findings from an older population.

PURPOSE: To quantify the association between arcus and hyperlipidemia in an older population. DESIGN: Cross-sectional population-based study. METHODS: Arcus and serum lipids were measured in the Blue Mountains Eye Study (n = 3,654, aged >49 years). Arcus was graded as absent, partial (<180 degrees) or circumferential (> or =180 degrees). Associations between arcus and hyperlipidemia were assessed using logistic regression, adjusting for age and vascular risk factors. RESULTS: Arcus was strongly associated with age (P <.0001). After age adjustment, arcus was associated with male sex (P <.01) and diabetes (P <.02) but not with hypertension or smoking. Corneal arcus was significantly associated with progressively higher levels of total cholesterol over 5 mmol/l. Adjusted odds increased from 1.6 for cholesterol 6.0 to 6.9 mmol/l to 4.6 for cholesterol >8.0 mmol/l, and was 1.9 for high triglyceride >3.0 mmol/l. CONCLUSION: This population-based finding confirms that corneal arcus was associated with hypercholesterolemia and hypertriglyceridemia in older persons.

Association between corneal arcus and some of the risk factors for coronary artery disease.

The relationships between coronary artery disease risk factors and corneal arcus were examined in 150 adults aged 55 years and above of both sexes and from different ethnic origins. The width of the corneal arcus was measured accurately by a digitiser, and the risk factors for coronary artery disease were examined according to the standard procedure used by the Lipid Research Clinics. The results show that the corneal arcus is more frequent in males; the frequency and size of corneal arcus are positively associated with age; there is a positive correlation between the size of corneal arcus and the levels of cholesterol and low-density lipoprotein in males; and that there is negative correlation between corneal arcus and diastolic blood pressure in both sexes. No associations were found between corneal arcus and other coronary artery disease risk factors such as triglyceride, high-density lipoprotein, very low-density lipoprotein, weight, Quetelet's ratio, glucose, and smoking.

Presenile corneal arcus in healthy persons. A possible cardiovascular risk indicator in younger adults.

The results of blood-lipid screening of 200 39--49-year-old participants with incidentally diagnosed corneal arcus from the Copenhagen City Heart Study are reported. A large sample of study-participants of the same age-group without arcus served as controls. In general, the arcus-group had higher se.-cholesterol than the control-group (P less than 0.01 in males and less than 0.02 in females). The se.-triglycerides in the two groups did not differ. A trend towards positive correlation between arcus-intensity and cholesterol-level was demonstrated by non-parametrical statistics. By use of the same statistics, an association between lipids and arcus-localisation was searched out. Dense arcus in the nasal/lower limbal regions occurred together with hypercholesterolemia more often than did a marked upper/outer arcus. Consequently, based on the present investigation, se.-cholesterol-screening of middle-aged persons with marked lower/nasal arcus seems justified, since hypercholesterolemia might will be an underlying cause. Finally, the importance of diagnosing and treating hypercholesterolemia is briefly discussed.