Postprandial Hyperchylomicronemia and Thin-Cap Fibroatheroma in Nonculprit Lesions.

Objective- Although postprandial hypertriglyceridemia can be a risk factor for coronary artery disease, the extent of its significance remains unknown. This study aimed to investigate the correlation between the postprandial lipid profiles rigorously estimated with the meal tolerance test and the presence of lipid-rich plaque, such as thin-cap fibroatheroma (TCFA), in the nonculprit lesion. Approach and Results- A total of 30 patients with stable coronary artery disease who underwent a multivessel examination using optical coherence tomography during catheter intervention for the culprit lesion were enrolled. Patients were divided into 2 groups: patients with TCFA (fibrous cap thickness ≤65 µm) in the nonculprit lesion and those without TCFA. Serum remnant-like particle-cholesterol and ApoB-48 (apolipoprotein B-48) levels were measured during the meal tolerance test. The value of remnant-like particle-cholesterol was significantly greater in the TCFA group than in the non-TCFA group ( P=0.045). Although the baseline ApoB-48 level was similar, the increase in the ApoB-48 level was significantly higher in the TCFA group than in the non-TCFA group ( P=0.028). In addition, the baseline apolipoprotein C-III levels was significantly greater in the TCFA group ( P=0.003). These indexes were independent predictors of the presence of TCFA (ΔApoB-48: odds ratio, 1.608; 95% confidence interval, 1.040-2.486; P=0.032; apolipoprotein C-III: odds ratio, 2.581; 95% confidence interval, 1.177-5.661; P=0.018). Conclusions- Postprandial hyperchylomicronemia correlates with the presence of TCFA in the nonculprit lesion and may be a residual risk factor for coronary artery disease.

Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator. METHODS: DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient's current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis. RESULTS: Recruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017. CONCLUSIONS: ODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint. Trial registration NCT02642159 (registered December 24, 2015).

[The fixed combination of pravastatin and fenofibrate: what can it provide?]. / Combinación fija pravastatina/fenofibrato: ¿qué puede aportar?

The treatment of patients with high cardiovascular risk and mixed hyperlipidemia is difficult due to multiple quantitative and qualitative lipid abnormalities. The priority is to reduce LDL-c levels, for which statins are the drug of choice. Despite the benefits of statins, the residual cardiovascular risk is very high in patients with atherogenic dyslipidemia. To reduce this risk, we also need to control non-HDL cholesterol levels, decreasing triglyceride levels and increasing HDL-c levels. To achieve these objectives and lifestyle changes, the use of combined therapy is often required. Fibrates are drugs that can be used in combination with statins to reduce this residual risk. Fenofibrate is well tolerated in combination with statins. The fixed combination of pravastatin/ fenofibrate has been shown to have complementary benefits in the atherogenic lipid profile in general. The combination is well tolerated and is indicated in patients with high risk and mixed hyperlipidemia who have controlled or are close to their objectives for LDL-c levels, using 40-mg pravastatin in monotherapy. The beneficial eff ect of the combination on LDL-c levels is minimal and is primarily observed in non-HDL cholesterol, triglycerides and HDL-c. The combination of pravastatin 40 and fenofibrate 160 can provide a considerable clinical benefit to patients with high risk and mixed atherogenic dyslipidemia, to patients with LDL-c levels that are controlled or near the objectives for decreasing their residual risk of lipid origin and is especially useful for patients with type 2 diabetes, obesity and combined metabolic syndrome and familial hyperlipidemia.

Medical resource use and costs associated with chylomicronemia.

BACKGROUND: The prevalence of severe hypertriglyceridemia (TG > 1000 mg/dl) is estimated at 150-400 per 100,000 individuals in North America. Severe hypertriglyceridemia in the fasting state is associated with increased acute pancreatitis risk and is a sign of chylomicronemia which reflects the accumulation in the bloodstream of chylomicrons, the large lipoprotein particles produced in the gut after a meal. OBJECTIVE: To assess medical resource use and costs associated with chylomicronemia. METHODS: Patients with chylomicronemia of different causes (≥2 diagnoses with ICD-9 code 272.3) were identified from a large US claims database (years 2000 to 2009) and matched 1:1 to controls free of chylomicronemia based on age, gender, demographics, comorbidities, and use of lipid lowering drugs. During a 1-year study period, medical resource use and costs associated with chylomicronemia or acute pancreatitis were compared between matched cases and controls. RESULTS: Among 6472 matched pairs, annual per-patient medical costs, calculated independently of the occurrence of acute pancreatitis, were significantly greater by $808 for chylomicronemia cases vs controls ($8029 vs $7220, p < 0.01), half of which was attributable to chylomicronemia-related services (p < 0.01). Chylomicronemia cases with a history of acute pancreatitis (n = 46) had greater rates of inpatient visits (p < 0.05) and greater average costs for subsequent acute pancreatitis or abdominal pain (p < 0.01) as well as greater total medical costs ($33,587 vs $4402, p < 0.01) vs matched controls. The average episode of acute pancreatitis (n = 104 episodes) generated medical costs of $31,820, almost entirely due to inpatient stays. LIMITATIONS: Triglyceride levels were not available to characterize disease severity. CONCLUSIONS: Patients with chylomicronemia, and especially those with a history of acute pancreatitis, incurred significantly greater total medical costs compared with individuals without chylomicronemia but with an otherwise comparable health profile.

The work-up for mixed hyperlipidemia: a case study.

This case demonstrates that a history, physical exam, and laboratory studies are all needed to determine if the disorder is primary, secondary, or both.

Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia.

OBJECTIVES: The aim of this study was to assess retrospectively the prevalence and the predictive factors of acute pancreatitis (AP) in a population of patients referred in our endocrinology department for evaluation of very high triglyceride (TG) levels. METHODS: One hundred twenty-nine patients (119 with type IV phenotypes and 10 with type V phenotypes according to Fredrickson's classification) were referred to our hospital between 2000 and 2005. RESULTS: Twenty-six subjects (20.2% of the population) presented with AP. This population was significantly younger at diagnosis of hyperlipidemia (32 vs 40 years, P < 0.001) and at age of investigation (43 vs 48 years, P = 0.05) and had maximum TG levels greater than the population without AP (44.7 vs 24.5, P < 0.001). Subjects of the third tertile of TG levels had a 4.0-fold increased risk (95% confidence interval, 1.3-12.3) of AP compared with the first tertile. Severe pancreatitis (need for intensive care, C-reactive protein >150 mg/L, or Balthazar score >C) was observed in 71.5% of the patients. CONCLUSIONS: Twenty percent of patients with severe hypertriglyceridemia experience at least 1 attack of AP. Pancreatitis seems to occur in young patients at higher levels of TG than previously thought (85% of patients >30 g/L) and is associated with a severe clinical course.

Acute hyperlipidemic pancreatitis in pregnancy.

BACKGROUND: Pancreatitis in pregnancy remains a rare event and is most often associated with gallstone disease. Hyperlipidemic gestational pancreatitis usually occurs in women with a preexisting abnormality of the lipid metabolism and poses particular problems in diagnosis and clinical management. CASES: We describe 5 patients with acute episodes of pancreatitis during pregnancy caused by hyperlipidemia. CONCLUSION: Acute pancreatitis in pregnancy causes significant morbidity. Even though it is often associated with gallstones, we describe 5 cases in which the etiology of the pancreatitis was maternal hyperlipidemia. Etiology, diagnosis, and management will be discussed.

Progression of severe atherosclerosis and increased arterial pulse pressure in the newly developed heritable mixed hyperlipidaemic rabbits.

We have recently segregated a new line of rabbit, named TGH, with severely high levels of plasma triglyceride and cholesterol. The aim of the present study was to investigate the progression of atherosclerosis and haemodynamic parameters in TGH rabbits. 2. Japanese white (JW) and TGH rabbits (24-27 months old) were anaesthetized with ketamine and xylazine. Plasma concentrations of triglyceride were 63.1 8.0 and 446.0 35.2 mg/dL in JW and TGH rabbits, respectively. Blood pressure was measured by a catheter implanted in the femoral artery. Histological examinations were performed using haematoxylin-eosin and elastica-Masson trichrome staining to detect atherosclerotic lesions. 3. The JW rabbits had no atherosclerotic lesions. In TGH rabbits, severe atherosclerotic lesions were observed throughout the aorta, especially in the aortic arch. Basal femoral arterial pressure was not significantly different between JW and TGH rabbits. However, the basal pulse pressure in TGH rabbits (48.3 4.5 mmHg) was significantly greater than that of JW rabbits (28.0 5.6 mmHg). Intravenous infusion of N(G)-nitro-L-arginine methyl ester (L-NAME; 26.9 mg/kg) increased the blood pressure of TGH and JW rabbits. There was no significant difference in the response to L-NAME between the two rabbit strains. 4. The present study shows that severe atherosclerotic changes develop in TGH rabbits and suggests that the hyperlipidaemia combined with hypercholesterolaemia and hypertriglyceridaemia is an important factor for promoting atherosclerosis in TGH rabbits. The greater pulse pressure in TGH rabbits may be due to the increased vascular stiffness with atherosclerosis. 5. This newly developed TGH rabbit line of heritable hypertriglyceridaemia with hypercholesterolaemia will become a useful animal model for studies on the role of hyperlipidaemia in the progression of atherosclerosis and in many atherosclerosis-related diseases.

High frequency of Fredrickson's phenotypes IV and IIb in Brazilians infected by human immunodeficiency virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles. METHODS: In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy (224 treated with protease inhibitors plus nucleoside reverse transcriptase inhibitors, 14 treated only with the latter, 12 naive and 7 had no records of treatment). The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry. RESULTS: The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels >or= 200 mg/dL, 61% LDL-cholesterol >or= 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides >or= 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio >or= 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09). CONCLUSION: The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment.

A case of hypothyroidism and type 2 diabetes associated with type V hyperlipoproteinemia and eruptive xanthomas.

Primary hypothyroidism and type 2 diabetes are both typically associated with the increased level of triglycerides. To date, there have been only a few case reports of type 2 diabetes patients with both type V hyperlipoproteinemia and eruptive xanthomas, but there have been no reports of hypothyroidism patients associated with eruptive xanthomas. We report here on a case of a 48-yr old female patient who was diagnosed with type 2 diabetes and primary hypothyroidism associated with both type V hyperlipoproteinemia and eruptive xanthomas. We found rouleaux formation of RBCs in peripheral blood smear, elevated TSH, and low free T4 level, and dyslipidemia (total cholesterol 18.1 mM/L, triglyceride 61.64 mM/L, HDL 3.0 mM/L, and LDL 2.54 mM/L). She has taken fenofibrate, levothyroxine, and oral hypoglycemic agent for 4 months. After treatment, both TSH level and lipid concentration returned to normal range, and her yellowish skin nodules have also disappeared.

Lipemia retinalis associated with branch retinal vein occlusion.

PURPOSE: To report a patient with a branch retinal vein occlusion associated with lipemia retinalis. DESIGN: Observational case report. METHODS: A 58-year-old woman presented with decreased vision and was found to have a branch retinal vein occlusion with massive lipid exudation in the setting of lipemia retinalis. Laboratory testing demonstrated an abnormal lipid profile with a markedly elevated triglyceride level. The setting was a retina service in a major referral center. RESULTS: Management of the hypertriglyceridemia with medication, exercise, and dietary modification resolved the lipemia retinalis and was associated with improvement in visual function. CONCLUSIONS: Although usually not visually significant, lipemia retinalis may be associated with vascular pathology, such as a branch retinal vein occlusion with marked exudative response and decreased visual acuity. Because of potential systemic and ocular complications of lipemia retinalis, these patients should be referred for management of their lipid disorder.

Scalp pain and hyperlipidaemia.

Acute pancreatitis and eruptive xanthomata are the only recognised direct complications of severe hypertriglyceridaemia, although peripheral neuropathy has been described in patients with hyperlipidaemia. We describe a patient with mixed hyperlipidaemia presenting with severe scalp pain and eruptive xanthomata. Both resolved with treatment. We suspect that high triglyceride concentration can affect the function of sensory nerve fibres.

Dyslipidaemia in a boy with recurrent abdominal pain, hypersalivation and decreased lipoprotein lipase activity.

UNLABELLED: An 8-year-old boy with frequently recurring pancreatitis-like abdominal pain, Fredrickson type V dyslipidaemia, and significantly decreased post-heparin plasma lipoprotein lipase (LPL) activity is described. In order to exclude familial LPL deficiency, the complete LPL coding gene sequence was analysed revealing compound heterozygosity for two mutations (Asp9Asn, Ser447Ter) which are not supposed to considerably impair lipolytic enzyme activity. However, until now the combination of both these mutations in one patient has not been observed. In addition to the common symptoms of LPL deficiency, a striking feature of unknown origin was hypersalivation. Treatment including a fat-restricted diet, omega-3 fatty acids, and nicotinic acid led to long symptoms-free intervals. Symptoms recurred however when the diet was not strictly adhered to. CONCLUSION: LPL deficiency is a rare cause of abdominal pain in childhood and deserves careful treatment in order to avoid pancreatitis. The presented patients is a unique compound heterozygote for two mutations which do not abolish lipolytic activity in the homozygote state. Identification of other individuals with this genotype is necessary to understand the phenotype in our patient.