Ib Christian Klausen

α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy

: We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between -2.5 and -6.0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC is the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.

Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication.

The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Are men carrying the apolipoprotein ε4- or ε2 allele less fertile than ε3ε3 genotypes?

The ɛ3 allele in the human gene coding for apolipoprotein E (apoE) is the most common worldwide, but ɛ4 is probably the ancestral allele. Since apoE is involved in many important biological processes, selection forces could have favoured ɛ3. We hypothesized that apoE genotypes may affect reproductive efficiency, and we therefore compared the distributions of 40-year-old married men with known genotypes by the numbers of their biological children. The distributions were statistically significantly different (P = 0.0026). On average, men with the ɛ3ɛ3 genotype (n = 212) had 1.93 children, men with the ɛ3ɛ4 or ɛ4ɛ4 genotype (n = 105) had 1.50, and men with the ɛ3ɛ2 or ɛ2ɛ2 genotypes (n = 53) had 1.66 children. Of the men in the three groups, 6%, 26% and 19%, respectively, reported being childless. These findings are unlikely to be due to gross error in the reported prevalence of childlessness, differences in socioeconomic status or other likely sources of bias. They are compatible with higher fertility in men with the ɛ3ɛ3 genotype than in those with the other common apoE genotypes.

Apo(a) Phenotypes and Lp(a) Concentrations in Offspring of Men With and Without Myocardial Infarction The EARS Study

In the European Atherosclerosis Research Study, genetic and environmental markers of risk of premature coronary heart disease were compared in offspring of men with and without myocardial infarction before the age of 55 years. Cases were 682 students with a paternal history of myocardial infarction, and control subjects were 1312 students without such a history. The students were enrolled in 14 universities in five European regions (Finland, Great Britain, and northern, middle, and southern Europe). Lipoprotein(a) [Lp(a)] concentrations were skewed towards lower concentrations in both cases (median, 7.3 mg/dL; 95% confidence interval, 6.3 to 8.1 mg/dL) and control subjects (median, 6.6 mg/dL; 95% confidence interval, 6.1 to 7.2 mg/dL) (P = .37). Significantly more northern European male cases than control subjects had Lp(a) levels exceeding 30 mg/dL (P = .040), but this did not pertain to females (P = .29), and overall, there was no difference between cases (16.5%) and control subjects (15.5%) in the frequency of Lp(a) concentrations above 30 mg/dL (P = .63). As expected, there was a significant (P < .01) inverse relationship between apo(a) molecular size and Lp(a) concentration. In Great Britain there was a significant difference in phenotype distribution between cases and control subjects (P = .035), due mainly to a high frequency of the apo(a) S2 isoform in cases. A similar but statistically insignificant tendency was seen in northern Europeans. In the three other regions, however, the distribution of apo(a) phenotypes among cases and controls was similar, and in the study population overall, the distribution of apo(a) phenotypes did not differ significantly (P = .74) between cases and control subjects.

Lp(a) and lipids in adult Turner’s syndrome: impact of treatment with 17β-estradiol and norethisterone

Turners syndrome is associated with a high incidence of cardiovascular disease and hypothyreosis; conditions which are associated with abnormal lipid metabolism. To test whether alterations of lipid metabolism is present in healthy Turners women, we compared lipids in a group of adult women with Turners syndrome with an age matched group of healthy women. In addition the impact of sex steroid replacement therapy was studied in the women with Turners syndrome. Patients were studied before and during treatment with hormonal replacement therapy, consisting of either oral 17beta-estradiol or transdermal 17beta-estradiol, and oral norethisterone. Control subjects were studied once in the early follicular stage of the menstrual cycle. The study group consisted of 26 (33.2+/-7.9 years) patients with Turners syndrome and an age matched control group of 24 (32.7+/-7.6 years) normal women. Body composition measures, apolipoprotein (apo) B and apo A-I, Lp(a), cholesterol, HDL, LDL, triglycerides, thyroxine (TT4), free thyroxine (FT4), triiodothyronine (TT3), free triiodothyronine (FT3), TSH, and leptin were determined. Apo A-I levels were higher in Turners patients (P45 g/l) Lp(a), more women with Turners syndrome had high levels of Lp(a) than controls (P=0.024), while all other measures of lipid metabolism were comparable to controls. The level of TSH, FT3, and FT4 were significantly higher in Turners patients, while TT4, TT3 and adjusted 24h energy expenditure were comparable to controls. Lp(a) (P=0.005), HDL (P=0.045) and apo A-I (P=0.039) decreased significantly, while there was a tendency towards a decrease in apo B (P=0.063) during treatment with sex hormones. In conclusion more women with Turners syndrome than controls have high levels of apolipoprotein A-I and Lp(a), but only after dichomitization, while other markers of lipid metabolism are normal. Replacement therapy with female sex hormones lowered Lp(a), HDL cholesterol and apolipoprotein A-I.

Growth hormone (GH) status is an independent determinant of serum levels of cholesterol and triglycerides in healthy adults.

Both severe growth hormone (GH) deficiency in hypopituitary adults and physiological ageing are associated with an increase in fat mass, dyslipidaemia, and an increased incidence of cardiovascular disease. Ageing is also associated with a physiological decrease in spontaneous as well as stimulated GH secretion. We wished to evaluate the effects of endogenous GH status on circulating lipoproteins.

Effect of Short-Term Treatment With Recombinant Human Growth Hormone on Lipids and Lipoproteins in Women and Men Without Growth Hormone Disturbances

The effect of recombinant human growth hormone (rHGH) on cholesterol, high- and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides (TG), apolipoprotein (apo) B, apo A-I, and lipoprotein(a) [Lp(a)] was studied in 40 postmenopausal women treated with 0.05, 0.1, or 0.2 IU/kg/d rHGH or placebo for 7 days. Cholesterol, LDL cholesterol, and HDL cholesterol decreased in a dose-dependent manner (P = .001, P = .001, and P = .003, respectively), whereas apo B decreased insignificantly (P = .15). Apo A-I decreased significantly only among women treated with rHGH at a dose of 0.1 IU/kg/d (P = .03). When all rHGH-treated women were grouped together, Lp(a) increased (P = .001). We also studied 20 young men treated with either 0.2 IU/kg/d rHGH or placebo. As in women, cholesterol and apo B decreased P = .005 and P = .02, respectively), whereas Lp(a) increased (P = .05). There was no detectable effect of rHGH on TG concentrations in men. As in women, there was no significant effect of 0.2 IU/kg/d rHGH on apo A-I concentrations. All lipid and lipoprotein measures reached pretreatment levels during the first week after treatment was stopped, except Lp(a), which remained elevated 2 weeks after rHGH cessation.

DIFFERENT EFFECTS OF CONTINUOUS AND INTERMITTENT PATTERNS OF GROWTH HORMONE ADMINISTRATION ON LIPOPROTEIN LEVELS IN GROWTH HORMONE-DEFICIENT PATIENTS

Background: Lipoprotein (a) (Lp(a)) is a risk marker for the development of atherosclerotic coronary heart disease. Growth hormone (GH) administration to GH-deficient (GHD) adults increases serum Lp(a) concentrations, and the levels of Lp(a) and GH are correlated in patients with acromegaly. Studies in rats have demonstrated differential effects of constant and intermittent GH patterns on levels of certain lipoproteins. The aim of the present studies was to describe the impact of intermittent and continuous patterns of GH delivery to GHD patients on serum levels of Lp(a) and other lipoproteins. Methods: In one study (A) 10 GHD patients received in random order a fixed GH dose intravenously as: (1) continuous infusion; (2) eight bolus injections, and (3) a combination of 1 and 2. Each study lasted 36 h and was preceded by at least 4 weeks without GH. In another study (B) 13 GHD patients received GH in random order as: (1) continuous subcutaneous (s.c.) infusion, and (2) daily s.c. injections in the evening for 1 month each. The patients were studied during steady-state conditions at the end of each treatment period. Results: In study A Lp(a) levels increased significantly following continuous (p < 0.05) and combined patterns (p < 0.02) of GH administration to GH-deprived GHD patients, whereas the increase after GH bolus injections alone was not significant (p = 0.14). In study B significantly higher (p < 0.05) serum levels of Lp(a) were obtained after continuous s.c. infusion as compared with daily s.c. injections of GH. Concentrations of the high-density lipoprotein (HDL) cholesterol were significantly lower (p < 0.02) after the continuous GH pattern. Similarly, the HDL fraction Apo A-1 tended to be lower with constant GH delivery (p = 0.052). Serum levels of total cholesterol, triglyceride and Apo B were similar on the two occasions. Conclusion: Short-term GH administration to GH-deprived GHD patients increased serum Lp(a), but only significantly with continuous delivery. During more prolonged GH exposure, constant s.c. infusion of GH resulted in slightly raised Lp(a) levels and reduced HDL and Apo A1 levels as compared with intermittently administered GH. The findings are consistent with the more effective induction of serum IGF-I levels after continuous patterns of GH delivery previously reported in GHD patients. Longer-term data are needed before conclusions with respect to the impact of the pattern of GH administration on, e.g., the risk of developing coronary heart disease can be drawn.

Effects of growth hormone on serum lipids and lipoproteins: Possible significance of increased peripheral conversion of thyroxine to triiodothyronine

The role of growth hormone (GH) and thyroid hormone in the regulation of lipid and lipoprotein metabolism is not fully established. Furthermore, the possible linkage between the well-known GH-induced increase in peripheral thyroxine (T4) to triiodothyronine (T3) generation and the effects of GH on lipid and lipoprotein metabolism has not been elucidated. In this double-blind placebo-controlled study, we compared the effects of GH and T3 administration alone and in combination on lipid and lipoprotein metabolism in a group of healthy young adults. The dose of T3 was selected to mimic the T2 increase seen during exogenous GH exposure. Eight normal male subjects (aged 21 to 27 years; body mass index, 21.11 to 27.17 kg/m2) were randomly studied during four 10-day treatment periods with (1) daily subcutaneous placebo injections and placebo injections and placebo tablets, (2) daily subcutaneous GH injections (0.1 IU/kg.d) and placebo tablets, (3) daily T3 administration (40 micrograms on even dates or 20 micrograms on uneven dates) plus placebo injections, and (4) daily GH injections plus T3 administration. GH administration increased free T3 (FT3) to the same level as during T3 administration. GH caused decreased levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides (TG) and lipoprotein(a) (Lp(a)), but no changes in high-density lipoprotein (HDL) cholesterol and apolipoprotein B (apo B). T3 administration caused no alteration in these parameters, except for decreased levels of TC comparable to those seen after GH administration. Combined GH and T3 administration caused changes identical to those seen after GH administration, in addition to decreased apo B levels and a further decrease of TC levels. We conclude that GH and iodothyronines in the physiologic range exert distinct but disparate effects on lipids and lipoproteins, and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels.

Lipoprotein(a) and oxygen free radicals in survivors of acute myocardial infarction: effects of captopril.

Long-term treatment of survivors of an acute myocardial infarction with angiotensin-converting enzyme inhibitors has a beneficial impact on their long-term outcome. We tested the hypothesis that captopril could reductively cleave the lipoprotein(a) molecule and in addition act as a scavenger of oxygen free radicals. In a double-blind trial, 20 patients were randomized to receive either captopril 50 mg daily or corresponding placebo. patients were followed for a period of 30 days. Blood samples were drawn prior to randomization and after 30 days of treatment. Plasma concentrations of lipoprotein(a) and malondialdehyde were evaluated. Captopril treatment produced a significant reduction in plasma content of lipoprotein(a) ( < 0.05) and at day 30 the plasma content of lipoprotein(a) was also significantly lower than that in the placebo group (p < 0.05). furthermore, on day 30 plasma concentrations of malondialdehyde, an indicator of oxidative damage, were significantly lower in the captopril group when compared to baseline values and corresponding placebo group values (p < 0.05). The observed effect of captopril treatment on lipoprotein(a) and malondialdehyde might be ascribed to the sulfhydryl group in the captopril molecule.