Familial hypercholesterolemia and triglyceride metabolism.

Familial hypercholesterolemia (FH) is a common autosomal disorder associated with hypercholesterolemia which usually results from a mutation in the coding region of the low density lipoprotein (LDL) receptor (R) activity. Only 20% of untreated heterozygote (h) FH men reach 70 years of age. Therefore, the diagnosis of hFH is a better predictor of coronary heart disease than risk-based algorithms. Fasting and postprandial hypertriglyceridemia are also considered as risk factors for atherosclerosis. The plasma triglycerides (TG)s are formed from two major sources; intestinally-derived chylomicrons and hepatically-derived very low density lipoproteins (VLDL). Potentially, atherogenic remnants of TG-rich lipoproteins accumulate in the postprandial state. In addition, TG-rich lipoproteins may promote the formation of atherogenic small dense LDL. In FH subjects, lipoprotein metabolism seems to be impaired and may contribute to premature atherosclerosis. This was documented in many studies in which mice lacking LDLR present hypercholesterolemia, increased plasma TG-rich lipoprotein remnants and develop premature spontaneous atherosclerosis. In this review, we focus on the current knowledge regarding TG metabolism on a selected clinically condition such as FH. Variation in clinical characteristics has been described between studies which may occur due to dissimilarity in the molecular defect of FH. Additionally, the relationship between TG levels in FH subjects and the development of atherosclerosis, as well as the appropriate treatment for these patients is analysed.

Postprandial metabolic heterogeneity in men with primary dyslipidaemia.

INTRODUCTION: Familial combined hyperlipidaemia (FCH) and familial hypercholesterolaemia (FH) have been strongly linked to premature coronary artery disease. Postprandial hypertriglyceridaemia is also associated with atherosclerotic disease. We evaluated the postprandial lipaemia in men with FCH and FH and compared them to a group of healthy men. MATERIAL AND METHODS: The study population consisted of 83 men: 34 FCH, 29 FH and 20 healthy. The FCH and FH groups were further divided into five subgroups, according to their lipid phenotype: FCH-IIA (n = 13), FCH-IIB (n = 10), FCH-IV (n = 11), FH-IIA (n = 21) and FH-IIB (n = 8). Postprandial lipaemia was evaluated by the areas under the curve for triglyceride (TG) concentrations (TG-AUC). RESULTS: The TG levels after oral fat tolerance test were significantly higher in FCH, compared to FH and healthy groups (TG-AUC in mg/dl/h; 2678 ±1415 vs. 1503 ±1147 and 1011 ±652 respectively, p < 0.001). The postprandial response was higher in FCH-IV and FCH-IIB, compared to FCH-IIA (TG-AUC in mg/dl/h; 3220 ±824 or 3409 ±770 vs. 1863 ±577 respectively, p < 0.001, for both comparisons). The FCH-IIA group showed higher postprandial TG levels when compared to FH-IIA (TG-AUC in mg/dl/h; 1863 ±577 vs. 1374 ±428 respectively, p = 0.008). There were no significant differences between FH-IIB and FCH-IIB subgroups. There was a significant correlation (r = 0.907, p < 0.001) between the postprandial TG-AUC and fasting TG levels in all FCH subjects. CONCLUSIONS: All phenotypes of FCH and the FH IIB phenotype demonstrate an exaggerated postprandial response that could partially contribute to the high cardiovascular risk. These patients should be identified and treated early with the appropriate hypolipidaemic agents.

Sex-associated effect of CETP and LPL polymorphisms on postprandial lipids in familial hypercholesterolaemia.

BACKGROUND: This study assessed the gender-specific influence of the cholesteryl ester transfer protein (TaqIB, I405V) and lipoprotein lipase (S447X) polymorphisms on the response to an oral fat tolerance test in heterozygotes for familial hypercholesterolaemia. METHODS: We selected and genotyped 80 men and postmenopausal women heterozygous for familial hypercholesterolaemia (main group) as well as 11 healthy control subjects. Patients were subgrouped based on their response to oral fat tolerance test. The oral fat tolerance test was defined as pathological when postprandial triglyceride concentration was higher than the highest triglyceride concentration observed in healthy subjects (220 mg/dl) at any time (2, 4, 6 or 8 h). RESULTS: In the pathological subgroup, men had significantly higher incremental area under the curve after oral fat tolerance test than postmenopausal women. Furthermore, multivariate analysis revealed a gender association of TaqIB and I405V influence on postprandial lipaemia in this subgroup. CONCLUSION: In conclusion, it seems that gender and TaqIB polymorphism of the cholesteryl ester transfer protein gene were both associated with the distribution of triglyceride values after oral fat tolerance test, only in subjects with a pathological response to oral fat tolerance test. Specifically, men carrying the B2 allele of the TaqIB polymorphism showed a higher postprandial triglyceride peak and a delayed return to basal values compared with women carrying B2. However, further investigations in larger populations are required to replicate and confirm these findings.

Apolipoprotein E gene polymorphism and obesity status in middle-aged men with coronary heart disease.

BACKGROUND: Apolipoprotein (apo) E polymorphism has been associated with coronary heart disease (CHD) and obesity. We aimed to determine whether apoE polymorphism is related to CHD in patients with different body mass index (BMI). PATIENTS AND METHODS: A total of 359 CHD men and 248 healthy controls with BMI <27 kg/m2 were genotyped for the apoE polymorphism. The CHD patients were divided into: normoweight (BMI: 24 +/- 1 kg/m2, n=98), overweight (BMI: 27 +/- 1 kg/m2, n=189) and obese (BMI: 32 +/- 2 kg/m2, n=72) groups. RESULTS: There was a significant difference in apoE genotype frequency between normoweight CHD patients and healthy controls (epsilon2epsilon2 + epsilon2epsilon3: 6% vs. 15%, p=0.029; epsilon3epsilon3: 83% vs. 70%, p=0.045, respectively). The apo epsilon3epsilon4 + epsilon4epsilon4 frequency was higher in obese compared with normoweight CHD patients (p=0.043). The severity of CHD was similar in all patients with CHD. CONCLUSION: Normoweight CHD patients, despite having a lower BMI and more favorable lipid profile, did not display any significant difference in CHD severity. This could be partially attributed to the lower frequency of the epsilon2 cardio-protective allele in normoweight CHD patients compared with normoweight healthy individuals.

Primary and secondary hypertriglyceridaemia.

Familial hypertriglyceridaemia is inherited in an autosomal dominant manner. The responsible genetic abnormality is unknown but recently, a novel gene encoding apolipoprotein AV has been linked to familial hypertriglyceridaemia. All patients develop the same phenotype with elevated levels of very low density lipoproteins (VLDL) in plasma. The main disorder of this dyslipidaemia is decreased intestinal absorption of biliary acids, leading to a compensatory increase of VLDL production. In familial hypertriglyceridaemia, a marked increase in plasma triglyceride (TG) levels can cause acute pancreatitis. Moreover, patients with other genetic factors, like familial chylomicronaemia, familial combined hyperlipidaemia, familial dysbetalipoproteinaemia and other rare disorders (e.g. Tangier disease and fish eye disease) may present increase of TG levels or cholesterol levels or both. Secondary hypertriglyceridaemias include hypothyroidism, kidney abnormalities (e.g. nephrotic syndrome or chronic kidney failure), diabetes mellitus, heavy alcohol consumption and obesity. In men and postmenopausal women, it seems that estrogen deficiency is responsible for higher TG levels compared with premenopausal women postprandially. In every state -fasting or postprandial-, women demonstrate lower plasma TG levels compared with men. This fact is due not only to increased muscular TG uptake and storage but also to higher TG clearance. Many studies demonstrated an age impact on plasma TG increase and larger variation of fasting TG levels caused by age. Also, hypertriglyceridaemia (TG >150 mg/dl; 1.7 mmol/l) is one of the diagnostic criteria of metabolic syndrome. Finally, several drugs may increase TG levels (e.g. chlorthalidone or beta-blockers).

Gender differences in the lipid profile of dyslipidemic subjects.

OBJECTIVE: We evaluated the gender-associated differences in lipid profile of subjects intended to receive lipid-lowering therapy with emphasis on the associations between triglycerides (TG) and other plasma lipid variables. DESIGN: Lipid profiles of 1385 patients [aged 55+/-11 years, 549 women (40%)] were evaluated. Eligible subjects fulfilled one or more of the following criteria: total cholesterol (TC)>or=6.2 mmol/l, TG>or=1.7 mmol/l, and high-density lipoprotein cholesterol (HDL-C)<1.0 mmol/l. Patients were divided into subgroups according to TG and HDL-C levels. RESULTS: Women aged on average 3.5 years older, had higher TC and HDL-C, lower TG and a correspondingly lower TC/HDL-C ratio than men. High TG and low HDL-C in tandem appeared twice more frequently in men. Inverse correlations between HDL-C and TG levels were found to exist in the entire cohort (r=-0.354, p<0.001) and in all various subgroups. In the subgroup with TG<1.7 mmol/l, women had higher TC and HDL-C, lower TG levels and lower TC/HDL-C ratio compared with men. In the subgroup with TG>or=1.7 mmol/l, women had higher TC and HDL-C levels and lower TC/HDL ratio compared with men. In the subgroup with HDL-C>or=1.0 mmol/l women had higher HDL-C, lower TG levels and lower TC/HDL-C ratio compared with men. CONCLUSIONS: Elevated TG levels and low HDL-C in tandem are common lipid abnormalities in the clinical setting of primary and secondary preventions. Gender-associated differences in the lipid profile are evident in subjects presenting with dyslipidemia and might be of potential relevance for diagnostics and therapy for the prevention of atherosclerosis.

Apolipoprotein E gene polymorphism and myocardial infarction.

Apolipoprotein (apo) E polymorphism has been widely studied and associated with coronary heart disease (CHD). Apo E is polymorphic, with three common alleles: epsilon 2, epsilon 3, and epsilon 4. Several studies have shown that epsilon 2 carriers have lower low-density lipoprotein and apo B levels and higher high-density lipoprotein cholesterol and apo A-I levels than epsilon 3 carriers. The opposite being found for epsilon 4 carriers compared with epsilon 3 carriers. Allele as well as genotype frequencies may vary in different populations. In Northern European populations, the epsilon 4 allele is more prevalent which may account for the higher CHD mortality rates. However, its positive association with the risk of CHD may be extended to all epsilon 4 allele carriers worldwide.

Therapeutic effects of fibrates in postprandial lipemia.

Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.

Gender influence on postprandial lipemia in heterozygotes for familial hypercholesterolemia.

The aim of this study was to evaluate the influence of gender differences on triglyceride (TG) response after a fatty meal in clinically defined heterozygous (h) patients with familial hypercholesterolemia (FH). Nineteen hFH men were age-matched with an equal number of premenopausal women. Plasma TG was measured before and 2, 4, 6, and 8 hr after a standardized fat load. The men with hFH had a greater body mass index (BMI) than hFH women. An abnormal postprandial response was observed in 63% and 16% of hFH men and women, respectively. The mean TG-area under the curve value was higher in hFH men compared to hFH women. Both gender (p = 0.032) and BMI (p = 0.006) equally affected postprandial TG response, but fasting TG levels (p <0.001) were the main determinant. In summary, hFH men have higher BMI, fasting TG level, and postprandial TG level, compared to age-matched premenopausal hFH women, which may partially explain the earlier onset of coronary heart disease in hFH men.

The prevalence of metabolic syndrome in various populations.

The insulin resistance/metabolic syndrome is characterized by the variable co-existence of hyperinsulinemia, obesity, dyslipidemia (small dense low-density lipoprotein, hypertriglyceridemia, and decreased high-density lipoprotein cholesterol), and hypertension. The pathogenesis of the syndrome has multiple origins. However, obesity and sedentary lifestyle coupled with diet and still largely unknown genetic factors clearly interact to produce the syndrome. This multifactorial and complex trait of metabolic syndrome leads to increased risk of cardiovascular disease. The scope of this review is to examine the differences in prevalence of the metabolic syndrome in various groups (eg, according to age, sex, ethnicity, social status, or presence of obesity) that could help with the better understanding of the pathogenesis of this syndrome. This review also considers the impact of metabolic syndrome on cardiovascular disease.

The effect of statins on postprandial lipemia.

Several studies showed that postprandial plasma triglyceride (TG) concentrations are higher in patients with coronary heart disease. TG-rich lipoprotein remnants accumulated in the postprandial state are involved in atherogenesis and in events leading to thrombosis. Lipid lowering drugs, such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) are of significant benefit in the primary and secondary prevention of atherosclerosis. Statins can decrease total cholesterol and low density lipoprotein cholesterol as well as TG concentrations and improve postprandial lipoprotein metabolism. Since abnormal postprandial lipemia is associated with pathological conditions, its treatment is relevant. This review considers the effect of statins on postprandial lipemia.

Stress testing response in women heterozygous for familial hypercholesterolemia.

We evaluated 62 exercise treadmill tests (ETTs) in equal numbers of heterozygous for familial hypercholesterolemia (hFH) and healthy (HLY) women, matched for age, baseline systolic and diastolic blood pressure (BP) and baseline heart rate (HR), using the Bruce protocol. Both groups had similar rate pressure product (RPP) and workload in metabolic equivalents (METs) (27,563+/-3124 vs. 29,090+/-4077, p=0.103 and 11.2+/-1.7 vs. 11.5+/-1.8, p=0.473, respectively). Women with hFH had lower delta (difference of peak to baseline) and peak exercise systolic and diastolic BP (systolic: 48+/-12 vs. 58+/-17 mmHg, p=0.010 and 167+/-19 vs. 177+/-17 mmHg, p=0.042, respectively; diastolic: 11+/-7 vs. 15+/-7 mmHg, p=0.028 and 85+/-7 vs. 91+/-7 mmHg, p<0.001, respectively). Furthermore, women with hFH had higher delta percentage (%) of HR, compared to HLY; (106+/-25 vs. 95+/-20, p=0.047). In conclusion, hFH women possibly have an inadequate rise in systolic BP during ETT. Diastolic BP increased more in the HLY than in the hFH group, but still remained within normal limits. These findings may reflect preclinical changes of atherosclerosis in hFH women, however further research should be undertaken.

Apolipoprotein E polymorphism, age and coronary heart disease.

Plasma concentrations of lipids, lipoproteins, and apolipoproteins (apo) are established risk factors for coronary heart disease (CHD). The knowledge of lipid profile may predict the potential victims of cardiovascular disease before its initiation and progression and offer the opportunity for primary prevention. The most common apo E polymorphism has been found to influence blood lipid concentrations and its correlation with CHD has been extensively investigated in the last decade. At younger ages, death from CHD is influenced by genetic factors, while the genetic effect decreases at older ages where environmental factors may play a more prominent role. If apo E polymorphism is an important genetic factor in the pathogenesis of atherosclerosis, it could affect the age of CHD onset. This review analyses the influence of apo E polymorphism on blood lipids and CHD in respect to age.

Lipid profile of women qualifying for hypolipidaemic treatment.

OBJECTIVE: Death rates from coronary heart disease continue to rise in women despite a marked decrease in men for the past two decades. Our study aimed to evaluate essential risk factors in high-risk adult women. METHODS: Lipid profiles of 547 dyslipidaemic adult women aged 57.5 +/- 10.6 years (mean +/- standard deviation) were evaluated and stratified according to fasting plasma lipid levels. Classification of the cohort was performed based on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) levels and correlations between TG and HDL-C were estimated. RESULTS: Patients with TG > or =150 mg/dl had lower HDL-C levels compared to those with TG <150 mg/dl (p < 0.001). Patients with HDL-C <40 mg/dl had lower TC levels and higher TG levels compared to those with HDL-C > or =40 mg/dl (p = 0.012 and p < 0.001, respectively). In the cohort and the subgroups an inverse correlation between TG and HDL-C was observed (r = -0.428, slope = -0.048, p < 0.001). CONCLUSIONS: The expected inverse correlation between fasting high TG and low HDL levels was confirmed. The novelty of the study is that this correlation persists even in the case of low fasting TG levels.

Metabolic syndrome and gender differences in postprandial lipaemia.

BACKGROUND: Postprandial hyperlipidaemia may be a predictor of vascular risk. DESIGN: We evaluated postprandial lipaemia after an oral fat tolerance test (OFTT) in men (n=41) and women (n=21) with metabolic syndrome (MetS). METHODS: Triglyceride (TG) levels were measured before and 2, 4, 6 and 8 h after the fat load. RESULTS: Men showed a greater plasma TG response 8 h after the fat load (284+/-117 versus 224+/-126 mg/dl, P=0.029). Only fasting TG levels significantly predicted the TG area under the curve (AUC) and incremental AUC. CONCLUSIONS: Men had a more pronounced postprandial hypertriglyceridaemia and seem to have delayed TG clearance.

Definitions of metabolic syndrome: Where are we now?

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including abdominal obesity, glucose intolerance, hypertension and dyslipidaemia and is associated with an increased risk of vascular events. Since the initial description of the MetS, several expert groups produced different definitions. This variability led to confusion and absence of comparability between studies. Although there is agreement that the MetS is a major public health challenge worldwide and consistent evidence stresses the need for intervention, the definition of the syndrome remains a matter of debate. This review considers the different definitions of the MetS. These include those proposed by the World Health Organisation, the European Group for the Study of Insulin Resistance, the National Cholesterol Education Program Adult Treatment Panel III, the American College of Endocrinology and American Association of Clinical Endocrinologists and the latest International Diabetes Federation definition which includes ethnic-specific waist circumference cut-off points. These definitions share several features but also include important differences; all have limitations. Selected (after a Medline search) studies comparing the different definitions are also considered. There is a need for a standardised definition of the MetS. Furthermore, a definition tailored for children and adolescents is essential. Prospective long-term studies are needed to validate the prognostic power of these definitions. As new information becomes available the definition of the MetS might be further modified.

Influence of triglycerides on other plasma lipids in middle-aged men intended for hypolipidaemic treatment.

INTRODUCTION: The present investigation aimed to evaluate the influence of serum triglycerides (TG) on other plasma lipids in male patients less than 65 years of age intended for hypolipidaemic treatment. METHODS: Lipid profiles of a cohort of 412 dyslipidaemic male patients aged 53.4 +/- 7.7 years (mean +/- standard deviation) were evaluated. Patients were stratified in accordance with their fasting plasma lipid levels. They were divided into multiple groups on the basis of serum TG (> or = 150 or < 150 mg/dl) and high-density lipoprotein cholesterol (HDL-C > or = 40 or < 40 mg/dl). RESULTS: Patients with TG > or = 150 mg/dl had higher total cholesterol and lower HDL-C levels compared with those with TG < 150 mg/dl (p = 0.005 and p < 0.001, respectively). Patients with HDL-C < 40 mg/dl had similar total cholesterol levels and higher TG levels compared to those with HDL-C > or = 40 mg/dl (p < 0.001). In all patients, an inverse correlation between TG and HDL-C was found (r = -0.286, p < 0.001). Additionally, HDL-C levels were inversely correlated with the TG concentration in patients with TG < 150 mg/dl (r = -0.135, p = 0.042) and TG > or = 150 mg/dl (r = -0.188, p = 0.002). CONCLUSIONS: An inverse correlation between TG and HDL-C levels seems to exist in the sampled population, revealing a close link between the metabolic pathways for TG and HDL-C. This inverse correlation appears to persist even in patients with low fasting TG levels.

Alcohol use, vascular disease, and lipid-lowering drugs.

Many epidemiological and clinical studies have shown that light-to-moderate alcohol (Alc) consumption is associated with reduced risk of coronary heart disease (CHD) and total mortality in middle-aged and elderly men and women. The plausible mechanisms for the putative cardioprotective effects include increased levels of high-density lipoprotein cholesterol, prevention of clot formation, reduced platelet aggregation, promotion of blood clot dissolution, and lowering of plasma lipoprotein (a) concentration. Individuals who need to be treated with lipid-lowering drugs, such as dyslipidemic or CHD patients, may benefit from these effects of Alc. Because hypolipidemic treatment is usually continued for life, an important issue is the suitability of Alc consumption in these patients. In the present review, the beneficial effects of Alc consumption on CHD risk, its side effects, and its safety and suitability when coadministered with hypolipidemic drugs are discussed.

Cholesteryl ester transfer protein gene polymorphisms and severity of coronary stenosis.

PURPOSE: Cholesteryl ester transfer protein (CETP) gene is involved in the reverse cholesterol transport in humans. Thus, it is a candidate for studying the susceptibility to coronary heart disease (CHD). The goal of the current investigation was to determine any association between CETP polymorphisms (I405V and TaqIB), and severity of coronary stenosis, since the extent of coronary artery narrowing has been considered as a primary determinant of survival in CHD patients. METHODS: The severity of coronary stenosis was estimated by Gensini (GS) and Duke Jeopardy (JS) scores in 130 men with documented CHD (mean age 61 +/- 10 yr). Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The allele frequencies for both TaqIB and I405V were found in Hardy-Weinberg equilibrium. Homozygotes for I had lower GS compared with heterozygotes (IV) and homozygotes for V [72(95% CI 51-92) vs. 122(95% CI 88-157) and 136 (95% CI 74-198), P = 0.009, P = 0.010, respectively]. In addition, GS differed between carriers of I and carriers of V allele [86(95% CI 72-101) vs. 128(95% CI 102-154), P = 0.003]. A correlation was found between the GS and I405V polymorphism (r = 0.250, P = 0.005), but not with JS. CONCLUSION: Homozygosity for I405 favours less severe coronary stenosis. Our findings indicate that the I405V polymorphism may have potential importance in screening individuals at high risk for developing CHD, establishing efficient prevention measures, and searching for other risk factors for CHD. However, further prospective investigations in larger populations are required to confirm these findings.