Hyperlipidemias: Ricart W

Esteve E, Ricart W, Fernández-Real JM. · Sección de Diabetes, Endocrinología y Nutrición, Hospital Universitario de Girona "Dr Josep Trueta", Avenida de Francia s/n, 17007 Girona, Spain. · Clin Nutr. · Pubmed #15681098 No free full text.

Abstract: Inflammation leads to changes in lipid metabolism aimed at decreasing the toxicity of a variety of harmful agents and tissue repair by redistributing nutrients to cells involved in host defence. Acute phase response, mediated by cytokines, preserves the host from acute injury. When this inflammation becomes chronic, it might lead to chronic disorders as atherosclerosis and the metabolic syndrome. The activation of the inflammatory cascade will induce a decrease in HDL-cholesterol (HDL-C), with impairment in reverse cholesterol transport, and parallel changes in apolipoproteins, enzymes, anti-oxidant capacity and ATP binding cassette A1-dependent efflux. This decrease in HDL-C and phospholipids could stimulate compensatory changes, as synthesis and accumulation of phospholipid-rich VLDL which binds bacterial products and other toxic substances, resulting in hypertriglyceridemia. The final consequence is an increased accumulation of cholesterol in cells. When the compensatory response (inflammation) is not able to repair injury, it turns into a harmful reaction, and the lipid changes will become chronic, either by repeated or overwhelming stimulus, enhancing the formation of atherosclerotic lesions. Thus, the classical lipid changes associated with the metabolic syndrome (increased triglycerides and decreased HDL-C) may be envisioned as a highly conserved evolutionary response aimed at tissue repair. Under this assumption, the problem is not the response but the persistence of the stimulus.

Fernández-Real JM, Ricart W. · Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr. Josep Trueta, 17007 Girona, Spain. · Endocr Rev. · Pubmed #12788800 links to  free full text

Abstract: Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Hyperinsulinemia and insulin action were initially proposed as the common preceding factors of hypertension, low high-density lipoprotein cholesterol, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary heart disease. The similarities of insulin resistance with another inflammatory state, atherosclerosis, have been described only in the last few decades. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, mainly due to the actions of the two major proinflammatory cytokines, TNF-alpha and IL-6. Genetic predisposition to increased transcription rates of these cytokines is associated with metabolic derangement and simultaneously with coronary heart disease. Dysregulation of the inflammatory axis predicts the development of insulin resistance and type 2 diabetes mellitus. The knowledge of how interactions between metabolic and inflammatory pathways occur will be useful in future therapeutic strategies. The effective administration of antiinflammatory agents in the treatment of insulin resistance and atherosclerosis is only the beginning of a promising approach in the management of these syndromes.

Pintó X, Corbella E, Figueras R, Biarnés J, Ricart W, Morales C, Falkon L, Masana L, Anonymous00306. · Unidad de Lípidos, Servicio de Medicina Interna, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain. · Rev Esp Cardiol. · Pubmed #17394870 links to  free full text

Abstract: INTRODUCTION AND OBJECTIVES: We investigated the pattern of cardiovascular disease and the factors that predict such disease in outpatients with type-2 diabetes and hypercholesterolemia. METHODS: This prospective open observational study included outpatients of both sexes (mean age 62 [8] years) with type-2 diabetes and hypercholesterolemia. Clinical manifestations of cardiovascular disease (e.g., angina, myocardial infarction, stroke and peripheral arterial disease), glucose and HbA1c levels, and cardiovascular risk factors were recorded every 4 months throughout the 2-year follow-up period. Overall, 838 patients completed follow-up. RESULTS: During follow-up, 81 patients (9.6%) presented with a cardiovascular event, nine of which were fatal. Cardiovascular events were more frequent in patients with a history of an ischemic condition than in those without: 58 of 258 (22.5%) and 23 of 579 (4%), respectively (P<.01). Previous angina or myocardial infarction was the strongest predictor of cardiovascular risk (relative risk [RR]=4.08, 95% confidence interval [CI] 2.39-6.95), followed by previous stroke (RR=2.96, 95% CI 1.26-6.93), high low-density lipoprotein (LDL)-cholesterol level > or =135 mg/dL (RR=2.79, 95% CI 1.56-5.01), peripheral arterial disease (RR=2.44, 95% CI 1.27-4.68), a high HbA1c level (RR=2.08, 95% CI 1.22-3.57), and obesity (RR=1.69, 95% CI 1.0-2.86). CONCLUSIONS: The incidence of cardiovascular disease in this southern European population of patients with type-2 diabetes and hypercholesterolemia was high. A history of an ischemic condition and a high LDL-cholesterol level during follow-up were the strongest predictors of cardiovascular disease.

López-Bermejo A, Chico-Julià B, Castro A, Recasens M, Esteve E, Biarnés J, Casamitjana R, Ricart W, Fernández-Real JM. · Unit of Diabetes, Endocrinology, and Nutrition, Dr Josep Trueta Hospital, Av. Francia s/n, 17007 Girona, Spain. · Arterioscler Thromb Vasc Biol. · Pubmed #17303777 links to  free full text

Abstract: OBJECTIVES: Alpha-defensins are natural antibiotics made by neutrophils that have been reported to modulate cholesterol metabolism and vascular function; however, their role in vivo remains largely unknown. We hypothesized that alpha-defensins 1 to 3 (DEFA1-3) are associated with serum lipids and vascular reactivity in humans. METHODS AND RESULTS: One hundred thirteen apparently-healthy White men, participants in a prospective study of cardiovascular risk factors, were assessed for a lipid profile, insulin sensitivity (S(I), frequently-sampled intravenous glucose tolerance test), and non-stressed circulating DEFA1-3 (ELISA). In a subset of 52 subjects, vascular reactivity (high-resolution ultrasound of the brachial artery) was also assessed. Subjects in the highest quartile for plasma DEFA1-3 were found to be leaner and more insulin sensitive, and to have significantly reduced total and LDL-cholesterol, compared with subjects in the lowest quartile for circulating DEFA1-3 (P<0.0001 to P=0.002 for linear trend ANOVA). The associations with serum lipids persisted after adjustment for age, body mass index, insulin sensitivity, and smoking (which was associated with reduced plasma DEFA1-3 concentrations). Finally, endothelium-independent vasodilation increased with increasing circulating DEFA1-3 (P=0.003) and this association was not explained by age, body mass index, serum cholesterol, insulin sensitivity, or smoking. CONCLUSIONS: Circulating DEFA1-3 are associated with serum cholesterol and vascular reactivity in humans. Alpha-defensins may have clinical implications in patients with either hypercholesterolemia or vascular dysfunction.

Biarnés J, Masana L, Morales C, Pintó X, Ricart W, Anonymous00471. · Unidad de Diabetes, Endocrinología y Nutrición, Hospital Universitari Dr. Josep Trueta, Girona, Spain. · Med Clin (Barc). · Pubmed #16216183 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: High cholesterol levels might contribute to the presence of albuminuria. The objective of our study was to evaluate the influence of lipid levels on the development of incipient diabetic nephropathy. Secondary objectives were to evaluate the effects of diabetes control, high blood pressure, age, sex, years of diabetes evolution, body mass index and smoking. PATIENTS AND METHOD: 930 subjects were enrolled in an open observational prospective cohort study of subjects with type 2 diabetes mellitus and high cholesterol levels (ESODIAH study) for 2 years. In our nephropathy study we selected 590 patients who had albuminuria measurements done. In every 4-month interval visit we made a clinical evaluation and blood analysis including HbA1c, lipid profile and microalbuminuria. Statistical analysis included t-Student, chi2 test, and binary logistic regressions. RESULTS: 51.7% men, aged 62.08 years of age and with an evolution of their diabetes of 8.49 years were studied. 40.6% had microalbuminuria and 59.4% had normoalbuminuria. High HbA1c correlated with the presence of albuminuria (odds ratio [OR] = 1.3; 95% confidence interval [CI], 1.12-1.55; p = 0.001). The development of microalbuminuria was more frequent in younger (OR = 0.93; 95% CI, 0.89-0.98), smoker (OR = 3.19; 95% CI, 1.02-9.96), subjects with high systolic blood pressure (OR = 1.02; 95% CI, 1-1.05). Total cholesterol levels at the end of the study were higher in new microalbuminuric (group I) than normoalbuminuric patients (group II) (group I: 211.08 [34.75] mg/dl vs group II: 200.67 [30.50]; p = 0.042). CONCLUSIONS: Tobacco, blood pressure and diabetes control influences the presence and development of microalbuminuria. More studies are required to study the influence of hypercholesterolemia.

Fernández-Real JM, Molina A, Broch M, Ricart W, Gutiérrez C, Casamitjana R, Vendrell J, Soler J, Gómez-Sáez JM. · Unitat de Diabetes, Endocrinologia, i Nutrició, University Hospital of Girona Dr. Josep Trueta, Spain. · Diabetes. · Pubmed #10331417 links to  free full text

Abstract: Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated with progressive muscle wasting and weakness. The striking metabolic abnormality in MyD is insulin resistance. The mechanism by which target tissues are insensitive to insulin action remains uncertain. In a recent study, plasma soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be associated with muscle tissue mass and insulin resistance. Given these associations, we speculated that disorders of the muscle cell membrane could lead simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat mass-matched control subjects. Both MyD men and women showed higher plasma insulin levels in the presence of comparable glucose concentrations than did control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold higher in MyD patients. In parallel with these findings, the fasting insulin resistance index (FIRI) was also higher in MyD patients. In fact, in the whole population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64, P = 0.001, respectively). sTNFR2 levels were also associated with the insulin sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT) according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014) and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT, both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to 48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2 levels were found to be strongly associated with plasma cholesterol, LDL cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75, P<0.0001, respectively). In conclusion, here we describe, for the first time to our knowledge, a relationship between insulin action and plasma sTNFR2 concentration in MyD patients. We have also found increased concentrations of plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2 concentrations in MyD patients. We speculate that the latter associations are dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha action. Whether TNF action is implicated in the pathogenesis of MyD or is a simple marker of disease activity awaits further studies.