Fritz Hoppichler

Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia

Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.

Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.

Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.

Apolipoprotein(a) Kringle IV Repeat Number Predicts Risk for Coronary Heart Disease

A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n = 69) and control subjects matched for age, sex, and ethnicity (n = 69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number ( < 22) and high Lp(a) concentration were significantly more frequent in the CHD group (P < .001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.

Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.

Liver transplantation provides a unique opportunity to investigate the contribution in vivo of the liver to the synthesis and degradation of genetically polymorphic plasma proteins. We have determined the genetic polymorphisms plasma proteins. We have determined the genetic polymorphisms of apo A-IV, apo E, and of the Lp(a) glycoprotein (apo (a] in the plasma of subjects undergoing liver transplantation and in respective organ donors. The results show that in humans, greater than 90% of the plasma apo E and virtually all apo (a) are liver derived, whereas this organ does not significantly contribute to plasma apo A-IV levels.

Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).

Patients with terminal renal insufficiency suffer from an increased incidence of atherosclerotic diseases. Elevated plasma concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases. Variable alleles at the apo(a) gene locus determine to a large extent the Lp(a) concentration in the general population. In addition, other genetic and nongenetic factors also contribute to the plasma concentrations of Lp(a). We therefore investigated Apo(a) phenotypes and Lp(a) plasma concentrations in a large group of patients with end-stage renal disease (ESRD) and in a control group. Lp(a) concentrations were significantly elevated in ESRD patients (20.1 +/- 20.3 mg/dl) as compared with the controls (12.1 +/- 15.5 mg/dl, P < 0.001). However, no difference was found in apo(a) isoform frequency between the ESRD group and the controls. Interestingly, only patients with large size apo(a) isoforms exhibited two- to fourfold elevated levels of Lp(a), whereas the small-size isoforms had similar concentrations in ESRD patients and controls. Beside elevated Lp(a) concentrations, ESRD patients had lower levels of plasma cholesterol and apolipoprotein B. These results show that elevated Lp(a) plasma levels might significantly contribute to the risk for atherosclerotic diseases in ESRD. They further indicate that nongenetic factors related to renal insufficiency or other genes beside the apo(a) structural gene locus must be responsible for the high Lp(a) levels.

Changes of serum antibodies to heat-shock protein 65 in coronary heart disease and acute myocardial infarction

Accumulating evidence indicates the involvement of heat shock proteins (hsp), a family of stress-inducible proteins, in atherosclerosis. For carotid atherosclerosis an association with an increase in hsp65 antibodies has been demonstrated. To investigate whether such antibodies are also associated with coronary heart disease (CHD) and acute myocardial infarction (MI), an age- and sex-matched study with patients suffering from CHD (n = 114) and MI (n = 89) and healthy controls (n = 76) was performed. All study participants (n = 279) were consecutively recruited according to typical diagnostic criteria. Determination of antibody titres to hsp65 was performed by an enzyme-linked immunosorbent assay (ELISA). Hsp65 antibody titres in CHD showed a significant increase compared to the healthy control group (P = 0.029), however, hsp65 antibody titres were found to be significantly lower in acute MI, compared to CHD (P = 0.005). Alteration in hsp65 antibody titres showed no correlation to established cardiovascular risk factors, e.g. serum total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood pressure, smoking, alcohol intake and body weight. In conclusion, serum concentrations of hsp65 antibodies were elevated independently in coronary heart diseases and declined in patients with acute myocardial infarction, indicating a possible involvement of the antibodies in the pathogenesis of this disease.

Low-density lipoproteins of the postprandial state induce cellular cholesteryl ester accumulation in macrophages.

Chemically or biologically modified low-density lipoproteins (LDL) but not native unmodified LDL lead to foam cell formation in monocyte-derived macrophages. Since the magnitude of postprandial lipemia after a challenge test seems to be associated with coronary artery disease, we tested the hypothesis that in the course of postprandial lipemia, LDL appear in plasma that are capable of leading to foam cell formation even without prior modification. We incubated the macrophage-like cell line P388 with unmodified postabsorptive and postprandial LDL from 17 healthy donors and measured the cellular cholesterol and triglyceride contents and amounts of exogenous [14C]oleic acid incorporated into the cholesteryl ester fraction. Postprandial LDL induced a significantly more pronounced cholesteryl ester accumulation than did postabsorptive LDL (477 +/- 286% versus 212 +/- 173%, respectively; P < .003). The increase in cellular total cholesterol was significantly higher as a result of cell incubation with postprandial LDL (107 +/- 61%) than with postabsorptive LDL (54 +/- 40%, P < .003), whereas no increase in triglyceride content was observed (P < .589) in either case. After CuSO4 incubation and incubation with P388 cells, postprandial LDL revealed more thiobarbituric acid-reacting substances than did postabsorptive LDL (55 +/- 10 versus 28 +/- 9 nmol/mg protein, P < .018; 28 +/- 4 versus 20 +/- 3 nmol/mg protein). The increase in cellular cholesteryl ester synthesis caused by postprandial LDL was reduced by more than 50% when lipoproteins and cells were incubated in the presence of ascorbic acid (P < .007).(ABSTRACT TRUNCATED AT 250 WORDS)

Valproate, weight gain and carbohydrate craving: A gender study

PURPOSE To compare the incidence and magnitude of weight gain associated with valproic acid (VPA) monotherapy in male and female epilepsy patients and to determine possible gender-specific differences in frequency of carbohydrate craving, body-composition, glucose homeostasis and lipid metabolism. METHODS Epilepsy patients on VPA monotherapy were consecutively recruited at the outpatient clinic of the Department of Neurology, Innsbruck Medical University. Weight gain during VPA-therapy, frequency of carbohydrate craving and physical exercise, sociopsychological problems and family history for diabetes were obtained from all patients. Clinical data also comprised body-impedance analysis, body mass index and waist-to-hip ratio. Morning fasting blood samples were drawn to determine serum leptin, glucose and lipid concentrations, as well as insulin, C-reactive protein and TNF-alpha. RESULTS One hundred and six patients (55 women) were enrolled in the study. Significant weight gain was seen during VPA-therapy in both genders (each p<0.001) with women experiencing increment of weight more frequently and more pronounced than did men. Analyses of patients who gained weight during VPA-therapy revealed significantly higher serum leptin concentrations in women than in men (p<0.001). Women also revealed significantly higher high-density lipoprotein-cholesterol and lower triglyceride concentrations than men (p=0.004 and 0.014, respectively). Frequency of carbohydrate craving was 25.8% in women and 14.3% in men. More women tried to lose or control weight through diet than did men (22.6% versus 7.1%). Moreover, weight gain as a sociopsychological problem was more numorous in women than in men. CONCLUSION Women are more prone to gain weight during VPA therapy though higher frequency of diet and sociopsychological burden than men, which might possibly be related to leptin-resitance and a higher frequency of carbohydrate craving.

Adiponectin and visfatin concentrations in children treated with valproic acid

Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA‐associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin‐mimetic hormone in VPA‐associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA‐therapy.

Lipoprotein(a) is increased in triglyceride-rich lipoproteins in men with coronary heart disease, but does not change acutely following oral fat ingestion

Association of apo(a)/Lp(a) with triglyceride-rich lipoproteins (TGR-Lps) is determined by different factors that are poorly understood. Some previous studies suggested that apo(a) in TGR-Lps may affect the atherogenicity of the TGR particles. To study whether there are any peculiarities in postprandial (pp) Lp(a) metabolism, we have determined apo(a) phenotypes and Lp(a) concentrations in 46 subjects with coronary heart disease (CHD) and in six normolipidemic individuals at different time points (4, 6 and 8 h) following an oral fat tolerance test. While mean triglyceride concentration reached its maximum 6 h after a standardized fat meal, no change in total cholesterol and in mean Lp(a) plasma concentration was detected at any time point after the fat load. In 6 normolipidemic probands and in 8 patients with CHD, who were matched for apo(a) phenotype, lipoprotein levels, age and body weight, we followed the distribution of apo(a) in plasma density gradient fractions in the fasting and pp state. In the CHD patients a significant larger percentage of apo(a) reactivity was detected in TGR-Lps in the pre- as well as in the postprandial state, compared to control subjects. The fat intake did not induce a significant change of apo(a) reactivity in the TGR-Lp fractions in both groups. The apo(a) isoform-size and the Lp(a) plasma concentration in the fasting state had no influence on the individual variation of the Lp(a) concentration in pp TGR-Lp fractions. Our results provide evidence that TGR-Lp fractions of CHD patients are enriched in apo(a) reactivity compared to healthy controls, but do not support the hypothesis that Lp(a) acts atherogenically through a pp increase of its plasma concentration.