Journal of clinical lipidology最新文献

Background: Non-insulin-based insulin resistance (IR) indices, simple and reliable surrogates for IR calculated without insulin level, have been reported to be associated with cardiovascular and cerebrovascular diseases.

Methods: Participants without diabetes from the cross-sectional baseline survey of the PRECISE (Poly-Vascular Evaluation for Cognitive Impairment and Vascular Events) cohort study were included in present study. Non-insulin-based IR indices, including triglyceride and glucose (TyG) index, triglyceride glucose-body mass (TyG-BMI) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, and metabolic score for insulin resistance (METS-IR) index, were calculated and stratified into quartiles. Intracranial, extracranial, coronary, subclavian, aorta, renal, ilio-femoral, and peripheral arteries were also assessed at baseline.

Results: Of 2759 included participants, the average age was 60.9 ( ± 6.6) years, and 1460 (52.9 %) were female. Compared with the first quartile of TyG index, the fourth quartile of TyG index was associated with an increased presence and extent of atherosclerotic plaques (OR, 3.51; 95 %CI,1.30-1.87; cOR, 2.22; 95 %CI,1.76-2.79) and presence and extent of atherosclerotic stenosis (OR, 1.60; 95 %CI,1.24-2.06; cOR, 1.66; 95 %CI,1.30-2.12). Such associations were also observed for the relationship of TyG-BMI index, TG/HDL-C ratio, and METS-IR index with the presence and extent of atherosclerotic plaques and stenosis. Addition of 4 non-insulin-based IR indices to the basic model with traditional risk factors improved the predictive performance of the presence of atherosclerotic plaque and stenosis.

Conclusions: Elevated non-insulin-based IR indices levels were associated with an increased risk of presence and extent of atherosclerotic plaques and stenosis in non-diabetic, older individuals in the PRECISE study. Further, these IR surrogate markers have certain predictive performance to assess the risk of multi-territorial atherosclerosis.

Sitosterolemia is a rare autosomal recessive disorder characterized by impaired excretion of plant sterols, leading to their accumulation in tissues and organs. We identified a hitherto unreported homozygous variant, in ATP-binding cassette sub-family G member 5 (ABCG5) (NM_022436.3) c.274A>G p.(Lys92Glu), segregating in two affected sibs (Sit1C and Sit1F) of a consanguineous Pakistani family, during genetic workup for hereditary hemolytic anemia. Both patients had anemia, history of gum bleed and easy bruising. Peripheral film revealed stomatocytes and macrothrombocytopenia. Plasma sitosterol level was found to be significantly high (27.7 mg/dL and 25.1 mg/dL for Sit1C and F respectively), confirming diagnosis of sitosterolemia in both patients. Treatment with Ezetimibe, a sterol absorption inhibitor, resulted in significant decrease in sitosterol as well as LDL-cholesterol, in these patients. This study confirms the potential of panel sequencing as a diagnostic tool for sitosterolemia. Definitive diagnosis has significant clinical implications for genetic counseling and management strategies, such as dietary modifications and successful management with Ezetimibe.

A 40-year-old woman at 35 weeks of gestation presented with abdominal pain and hypertriglyceridemia of above 5000 mg/dL. Following lab tests and imaging studies, she was diagnosed with hypertriglyceridemia-related acute pancreatitis in pregnancy. She was managed with NPO, IV insulin, and peripheral parenteral nutrition, but her condition further complicated with preeclampsia, and she was induced and delivered at 36 weeks of gestation. Genetic testing revealed a heterozygous variant in the CREB3L3 gene predisposing to severe hypertriglyceridemia. Postpartum lifestyle modifications, including a low-fat diet and routine exercise, significantly improved her lipid profile.

Background and objective: Low HDL-cholesterol and corneal opacity are associated with fish-eye disease (FED), familial LCAT deficiency (FLD), ApoAI deficiency, and Tangier disease. The differential diagnosis is made by clinical and biochemical tests. Measuring the LCAT activity is the ideal way to distinguish conditions caused by LCAT gene variants (FED and FLD) from the other two diseases. However, this is not accessible from all clinics. The CE/TC ratio, which is below the reference range in most cases with LCAT gene variants, has been proposed as an alternative. We report a case of compound heterozygous FED with a CE/TC ratio within the reference range.

Methods: LCAT activity assays and genetic analyses were performed using patients' blood samples. Identified LCAT gene variants were examined by an in vitro expression assay.

Results: The proband showed approximately 20 % LCAT α-activity relative to the normolipidemic controls, whereas a patient with a typical FED-causing variant (p.Thr147Ile) showed only 3 % activity. We identified compound heterozygous variants (c.101C>T/c.460A>G) resulting in a p.Pro34Leu/p.Asn154Asp amino acid residue substitution in the LCAT gene of the proband. The former variant has been reported previously, but the latter was newly identified. An in vitro expression assay demonstrated that the LCAT α-activity of the p.Asn154Asp variant significantly decreased regarding the wild type, but it was relatively well preserved compared to the typical FED-causing variants (p.Pro34Leu and p.Thr147Ile).

Conclusion: These results suggest that the residual 20 % LCAT α-activity is sufficient to normalize CE/TC, but not sufficient to prevent the development of corneal opacity in FED.

Objective: The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with LDL or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increase to assess whether VLDL-C is a valid proxy for VLDL-apoB.

Methods: We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed this data in quartiles of TG or apoB.

Results: There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80 % of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90 % of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high.

Conclusions: In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB.

Background: Autosomal recessive hypercholesterolemia (ARH) is an ultrarare dyslipidemia caused by variants in the LDLRAP1 gene. Clinically, this condition is indistinguishable from other homozygous familial hypercholesterolemia (HoFH).

Case: We present the cases of two siblings diagnosed with ARH caused by LDLRAP1 gene c.617-14C>A splicing homozygous variant. Over a five-year treatment period, the older sibling experienced an 81 % reduction in low-density lipoprotein cholesterol (LDL-C) levels with the maximal dose of pitavastatin plus ezetimibe, while the younger sibling achieved a 75 % reduction. After three sessions, the older brother no longer required LDL apheresis, and the sibling never had LDL apheresis.

Conclusion: Our findings demonstrate a rapid and significant response to lipid-lowering therapy (LLT) in patients with ARH caused by c.617-14C>A splicing VUS variant, a condition that mimics HoFH at diagnosis. Long-term follow-up studies in large pediatric cohorts of ARH patients treated with pitavastatin plus ezetimibe from childhood are necessary to better define the risk of cardiovascular disease (CVD) development.

Background: The present study was performed to determine the association between changes in the HDL-C concentration and incident CVD.

Methods: Time-dependent Cox regression models were used to evaluate the association between changes in the HDL-C concentration and the risk of incident CVD. Participants were followed up from 2015 to 2021.

Results: In total, 24,123 participants with a median follow-up of 4.26 years were analyzed, and the mean age of the cohort was 56.24 years, 57.8 % were female, 24.3 % were current smokers, and 12.8 % had a history of alcohol use. Low, normal, and high HDL-C was defined as <40, 40-80, and >80 mg/dL, respectively. The average time for the two HDL-C measurements was 2.8 years,compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was higher in those whose HDL-C changed to a low level, remained unchanged at a low level(HR, 1.24; 95 % CI, 1.01-1.40,P < 0.001), similarly, the risk of CVD was higher in those whose HDL-C changed from very high level to normal level(HR, 0.81; 95 % CI, 0.67-0.99,P = 0.039). Also compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was lower in those whose HDL-C increased from low to normal and high(HR, 0.80; 95 % CI, 0.66-0.98,P = 0.029).

Conclusions: Participants whose HDL-C changed to a low level and whose low HDL-C level was maintained had a higher risk of CVD, whereas participants whose HDL-C changed from low to high had a lower risk of CVD.

Background: Patients suffering from sitosterolemia with ABCG5/8 mutation typically present with early-onset or rapidly progressive atherosclerosis. Their kindreds with partial genetic deficiencies of ABCG5/8 are often considered healthy. However, discerning sitosterolemia from its familial kindreds and hyperlipidemia subjects has remained challenging.

Methods: Here we retrospectively recruited seven families including 8 individuals diagnosed with sitosterolemia subjects, and 14 kindreds carrying single gene mutations. Additionally, 17 individuals with hyperlipidemia and 130 healthy controls served as positive and negative controls, respectively. A total of 6 phytosterols combined with cholesterol absorption indices (including sitosterol, campesterol, stigmasterol, and cholestanol) and cholesterol synthesis markers (desmosterol and 7-dehydrocholesterol), was compared across the aforementioned four groups.

Results: As expected, the sitosterolemia subjects with double mutations demonstrated significantly elevated levels of sitosterol and other cholesterol absorption indices. Meanwhile, sitosterolemia kindreds with single gene mutation showed a similar pattern of activated cholesterol-absorption ability to the hyperlipidemia group, but not as high as the double mutation group. Notably, the cholesterol-synthesis enzyme 7-dehydrocholesterol reductase displayed an increase in the hyperlipidemia group but a decrease in the sitosterolemia kindred group, suggesting a potential discriminative role of 7-dehydrocholesterol in distinguishing between these two groups. The combination of phytosterols was more valuable than clinical lipid index for sitosterolemia diagnosis.

Conclusion: Our study revealed mild disruptions of cholesterol absorption capacities in sitosterolemia kindreds with single mutations. Furthermore, the combination of 6 phytosterols proved effective in distinguishing between sitosterolemia, its single mutation carriers, and hyperlipidemia patients.