Impaired spatial navigation and age-dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice.

Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD), which has been proposed to be driven by an abnormal neuroinflammatory response affecting cognitive function. However, the impact of T2DM on hippocampal function and synaptic integrity during aging has not been investigated. Here, we investigated the effects of aging in T2DM on AD-like pathology using the leptin receptor-deficient db/db mouse model of T2DM. Our results indicate that adult T2DM mice exhibited impaired spatial acquisition in the Morris water maze (MWM). Morphological analysis showed an age-dependent neuronal loss in the dentate gyrus. We found that astrocyte density was significantly decreased in all regions of the hippocampus in T2DM mice. Our analysis showed that microglial activation was increased in the CA3 and the dentate gyrus of the hippocampus in an age-dependent manner in T2DM mice. However, the expression of presynaptic marker protein (synaptophysin) and the postsynaptic marker protein [postsynaptic density protein 95 (PSD95)] was unchanged in the hippocampus of adult T2DM mice. Interestingly, synaptophysin and PSD95 expression significantly decreased in the hippocampus of aged T2DM mice, suggesting an impaired hippocampal synaptic integrity. Cytokine profiling analysis displayed a robust pro-inflammatory cytokine profile in the hippocampus of aged T2DM mice compared with the younger cohort, outlining the role of aging in exacerbating the neuroinflammatory profile in the diabetic state. Our results suggest that T2DM impairs cognitive function by promoting neuronal loss in the dentate gyrus and triggering an age-dependent deterioration in hippocampal synaptic integrity, associated with an aberrant neuroinflammatory response.

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

BACKGROUND AND AIMS: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. METHODS: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. RESULTS: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. CONCLUSIONS: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.

Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry.

BACKGROUND: Familial hypercholesterolemia (FH) is a well-understood Mendelian disorder that increases the risk of cardiovascular disease (CVD), a leading cause of mortality in Middle Eastern and North African (MENA) countries. OBJECTIVE: Review the reporting status of FH mutations across MENA and propose a systemic and strategic method for building a MENA FH registry. METHODS: Systematic literature search for statistics pertaining to CVD and comparison of number of FH mutations reported in MENA countries and countries with established FH registries. RESULTS: Only 57 mutations were reported in 17 MENA countries, whereas more than 500 mutations reported in 3 Western countries. Mortality rates due to CVD were significantly higher in MENA countries compared with Western countries. CONCLUSIONS: The relatively low reporting of FH mutations in the consanguineous MENA communities with higher prevalence of CVD indicates poor awareness of CVD genetic risk and warrants a registry to prevent premature CVD due to FH. This registry will help in identifying novel and reported FH mutations, all of which will have clinical and research benefits in MENA countries.

Low prevalence of type 2 diabetes mellitus among patients with high levels of high-density lipoprotein cholesterol.

BACKGROUND: Diabetes mellitus and low levels of high-density lipoprotein cholesterol (HDL-C) are among several known risk factors for coronary artery disease. Recent research has shown potential mechanistic links between these two diseases. OBJECTIVES: The aim of our study was to characterize, by examining particular coronary artery disease risk factors, patients with extremely high and low levels of HDL-C who were referred to a prevention clinic. METHODS: We compared the phenotypes of 113 patients with HDL-C levels greater than the 90th percentile with 212 patients with levels less than the 10th percentile by using a retrospective chart review. RESULTS: The cohort with high HDL-C had a remarkable difference in the incidence of type 2 diabetes (1.8% vs 21.7%). The high HDL-C cohort also had a greater age (52.1 years vs 46.7 years), more light or moderate alcohol consumption (70.8% vs 49.4%), more healthy diet (30.1% vs 22.4%), more light or moderate exercise (90.8% vs 52.2%), and a lower body mass index (25.2 kg/m² vs 28.1 kg/m²). CONCLUSIONS: Compared with the low HDL-C group--and also the general population--the high HDL-C cohort had a remarkably low prevalence of diabetes mellitus.

Cardiovascular risk and atherosclerosis prevention.

Until recently, coronary artery disease (CAD) was the leading cause of death in the developed countries. Its remarkable decline can be attributed to our knowledge of the major risk factors identified by several studies resulting in better prevention and treatment. Of the major risk factors, the ratio of apolipoprotein (apo) B/apo A1 followed by smoking, diabetes, and hypertension are the most important. A number of risk scores for men and women are now available to estimate the likelihood of development of CAD. However, because of the risk of CAD differs in various populations, some of the algorithms are more appropriate for some countries but not suitable for others. These risk assessment algorithms differ in the parameters they use. All the risk scores have some limitations such as different study populations; the age of the study is also different, and number of points awarded for age categories also differs among the various algorithms. In an effort to further improve the risk prediction, a number of biomarkers have been studied. In addition to plasma lipids, a lot of interest has focused on apo measurements; particularly of apo B. Another valuable biomarker is lipoprotein (a) [Lp(a)]. Lp(a) is not only atherogenic as low-density lipoprotein (LDL) but also prothrombotic, and several studies indicate that Lp(a) is an independent risk factor for CAD. The lipid profile provides a framework for appropriate management. This includes therapeutic lifestyle changes and medications. Lifestyle interventions are the cornerstone of CAD prevention strategies and are the first step in risk factor management. Of particular importance are smoking cessation, achievement and maintenance of ideal body weight, regular exercise, reduction in the intake of saturated fat and sugars, and decreasing level of stress. Of medications, lipid-lowering, anti-hypertensive, and anti-coagulant can be effectively used. The current strategies for risk assessment and prevention have been very successful contributing to the more than 50% decrease in CAD mortality over the last 20 years. Thus, in Canada, cardiovascular disease is no longer the leading cause of death.

Paediatric type III dyslipidaemia: a case of vanishing hyperlipidaemia.

An 11-year-old girl presented with palmar and tuberoeruptive xanthomas, and elevated triglycerides and total cholesterol levels. She had an apolipoprotein E2/E2 genotype. A diagnosis of type III dyslipidaemia was made and the patient started on niacin, fenofibrate and salmon oil. At age 18, her lipid levels were well controlled with fenofibrate once weekly. At age 21, the fenofibrate was discontinued and her lipid profile has been normal for the last 4 years. This case history may be consistent with a transient dyslipidaemia.

Use of once-weekly statin in combination with ezetimibe in a patient with mitochondrial disease.

The authors describe a patient with personal and family history of muscle pains highly suggestive of mitochondrial disease. She presented with familial combined hyperlipidaemia with family history of premature coronary artery disease. After 4-week therapy of 5 mg of rosuvastatin once a week combined with 10 mg of ezetimibe daily, the low-density lipoprotein cholesterol level was markedly decreased from 3.88 to 2.82 mmol/l (27.3% reduction). She has experienced no adverse effects after 6 month treatment. The results suggest that the combination therapy of low-dose once-weekly rosuvastatin and daily ezetimibe could be used as an effective regimen for patients with mitochondrial disease.

Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study.

BACKGROUND: Severe hypertriglyceridemia (HTG) is one cause of acute pancreatitis, yet the level of plasma triglycerides likely to be responsible for inducing pancreatitis has not been clearly defined. METHODS AND RESULTS: A retrospective cohort study was conducted on patients presenting non-acutely to the Healthy Heart Program Lipid Clinic at St. Paul's Hospital with a TG level > 20 mM (1772 mg/dl) between 1986 and 2007. Ninety-five patients with TG > 20 mM at the time of referral were identified, in who follow up data was available for 84. Fifteen patients (15.8%), with a mean outpatient TG level of 38.1 mM, had a history of acute pancreatitis. Among 91 additional patients with less severe HTG, none had a history of pancreatitis when TG were between 10 and 20 mM. Among patients with TG > 20 mM on presentation, 8 (8.5%), with a mean TG level of 67.8 mM, exhibited eruptive xanthomata. A diet high in carbohydrates and fats (79%) and obesity (47.6%) were the two most frequent secondary causes of HTG at initial visit. By 2009, among patients with follow up data 53% exhibited either pre-diabetes or overt Type 2 diabetes mellitus. Upon referral only 23 patients (24%) were receiving a fibrate as either monotherapy or part of combination lipid-lowering therapy. Following initial assessment by a lipid specialist this rose to 84%, and remained at 67% at the last follow up visit. CONCLUSIONS: These results suggest hypertriglyceridemia is unlikely to be the primary cause of acute pancreatitis unless TG levels are > 20 mM, that dysglycemia, a diet high in carbohydrates and fats, and obesity are the main secondary causes of HTG, and that fibrates are frequently overlooked as the drug of first choice for severe HTG.

Statin resistant dyslipidemia in a patient treated with amiodarone.

The authors describe a patient treated with amiodarone presented with high low-density lipoprotein cholesterol (LDL-C) levels who did not respond to treatment with a statin. Both amiodarone and amiodarone induced hypothyroidism influence the synthesis of LDL-receptor which may explain the lack of effect of statin. This was confirmed by normalisation of LDL-C upon discontinuation of amiodarone and treatment with thyroxine.

Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature.

Complete apo A1 deficiency is a rare genetic disorder that has been associated with premature atherosclerosis. We describe a family of Iraqi Mandaean background with complete apo A1 deficiency caused by a new nonsense mutation in the APOA1 gene. Interestingly, there were marked differences in the clinical presentation of the two homozygotes in this family. A 35-year-old woman presented with xanthelasmas and xanthomas but showed only minimal changes on cardiovascular examinations and no clinical symptoms. However, her 37-year-old brother was diagnosed with myocardial infarction at age 35. In addition, both the homozygotes had elevated C-reactive protein levels. The C-reactive protein levels increased three-fold during pregnancy, then decreased postpartum and further decreased with statin treatment. Cholesterol ester transfer protein mass was close to the upper reference range, whereas the activity was low, likely because of the lack of the substrate. Here, we characterize the phenotype and genotype of the first Middle Eastern family with apo A1 deficiency and compare and contrast the findings in the two homozygous siblings and review the previously reported cases of apo A1 deficiency.

Central pontine myelinolysis after orthotopic liver transplant-a rare complication.

Central pontine myelinolysis is a rare but devastating cause of morbidity and mortality after orthotopic liver transplant. The exact cause of central pontine myelinolysis is uncertain. However, rapid correction of hyponatremia has been described as a major factor. We describe a patient with central pontine myelinolysis after orthotopic liver transplant in the absence of significant hyponatremia. Although rapid correction of hypernatremia has been reported in association with central pontine myelinolysis, to our knowledge, in this case, where the serum sodium went from normal to hypernatremic, later diagnosis of central pontine myelinolysis in a postliver transplant setting is unique. We also discuss factors that may contribute to the development of central pontine myelinolysis after orthotopic liver transplant and its pathophysiology.

Hepatic lipase deficiency in a Middle-Eastern-Arabic male.

Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles.