Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome.

OBJECTIVES: This study used monophasic action potentials to investigate the effects of verapamil and propranolol on epinephrine-induced repolarization abnormalities in congenital long QT syndrome. BACKGROUND: Early afterdepolarizations have been suggested to play a significant role in QT prolongation and ventricular arrhythmias in congenital long QT syndrome. Calcium channel blocking as well as beta-adrenergic blocking agents are reported to be effective in the management of this syndrome. METHODS: Monophasic action potentials from 2 to 4 sites were recorded simultaneously in eight patients with the long QT syndrome (22 sites) and in eight control patients (23 sites) and were obtained during constant atrial pacing 1) before epinephrine infusion; 2) during epinephrine infusion (0.1 microgram/kg body weight min); 3) after verapamil injection (0.1 mg/kg) during epinephrine infusion; and 4) after both propranolol (0.1 mg/kg) and verapamil injections. RESULTS: Early afterdepolarizations were recorded in two of the eight patients (2 of 22 sites) during the control state. During epinephrine infusion, early afterdepolarizations were recorded in six patients (six sites), and ventricular premature complexes were induced in three and torsade de pointes in one. Epinephrine prolonged 90% monophasic action potential duration from 348 +/- 48 (mean +/- SD) to 381 +/- 49 ms (22 sites, p < 0.0005) and increased the dispersion of action potential duration (difference between the longest and shortest action potential duration) from 36 +/- 20 to 64 +/- 34 ms (p < 0.005). Verapamil eliminated (two sites) or reduced (four sites) early afterdepolarizations and abolished ventricular premature complexes in two of the three patients as well as suppressing torsade de pointes. Verapamil shortened the action potential duration to 355 +/- 28 ms (p < 0.01 vs. epinephrine) and decreased the dispersion to 44 +/- 19 ms (p < 0.05 vs. epinephrine). Propranolol further eliminated (two sites) or reduced (two sites) early after depolarizations, abolished ventricular premature complexes in the remaining one patient and further shortened the action potential duration to 337 +/- 32 ms (p = 0.09 vs. verapamil). In the control patients, none of the early afterdepolarizations, ventricular arrhythmias or marked prolongations of action potential duration were induced by epinephrine, and neither verapamil nor propranolol changed repolarization variables. CONCLUSIONS: These results indicate that both verapamil and propranolol can improve repolarization abnormalities induced by epinephrine in congenital long QT syndrome.

Lipoprotein(a) in nonhuman primates. Presence and characteristics of Lp(a) immunoreactive materials using anti-human Lp(a) serum.

Lipoprotein(a) (Lp(a] immunoreactive materials were examined in serum samples from 77 nonhuman primates of 24 species by Ouchterlony's double diffusion procedure and an enzyme-linked immunosorbent assay (ELISA) using rabbit antisera to human Lp(a). The precipitates obtained with sera from orang-utan and chimpanzee formed reactions of complete identity with the Lp(a) precipitate with human serum. When sera from Old World monkeys and human subjects were tested in wells next to each other, spurs developed between the 2 precipitates, indicating that Lp(a)-like lipoproteins in Old World monkeys have partial identity with human Lp(a). Lp(a) immunoreactive materials were identified in association with lipids by means of fat staining of the precipitates. On the other hand, reactants which could be precipitated with anti-human Lp(a) sera were not detectable in prosimians and New World monkeys. These results suggest that serum Lp(a)-like lipoprotein is phylogenetically acquired in Old World monkeys. However, the possibility that the structures of serum Lp(a)-like lipoproteins in prosimians and New World monkeys are too different to react with anti-human Lp(a) sera cannot be ruled out.

Transient changes of serum lipoprotein(a) as an acute phase protein.

Serum lipoprotein(a) (Lp(a)) was serially determined after acute attacks of myocardial infarction and after surgical operations. Acute phase proteins, such as C-reactive protein, alpha 1-acid glycoprotein, alpha 1-antitrypsin and haptoglobin, increased rapidly and markedly after the episodes. Initial values of serum Lp(a) concentrations were almost the same in both groups. Increases in serum Lp(a) levels were also observed during the first few days, with a return to the initial levels after more than 1 month. The periods for reaching maximal levels of acute phase proteins were similar in both groups of patients. On the contrary, the period required for Lp(a) to reach the maximal level in the myocardial infarction group was significantly longer than in the post-operative group. The present study suggests that Lp(a) has the characteristics of an acute phase reactant and may play an important role in recovery from tissue damage.

Normotriglyceridemic abetalipoproteinemia in infancy: an isolated apolipoprotein B-100 deficiency.

The plasma lipoproteins of a 1-year-old Japanese infant were studied because of malnutrition, severe decrease in plasma lipid level, and acanthocytosis. Plasma lipoprotein analysis revealed that low-density lipoproteins were deficient; however, low levels of triglyceride-rich lipoproteins were found in the plasma. On sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis, apoprotein B-48 and a faint band corresponding to apoprotein B-100 were detected in the lipoprotein fraction of density less than 1.006 g/mL when the infant was 6 months old. Apoprotein B-48 was more clearly detected after 1 year, but the band corresponding to apoprotein B-100 on the sodium dodecylsulfate gel electrophoresis had disappeared. The apoprotein B-48 content of the fraction with density less than 1.006 g/mL was about 0.05 to 0.3 mg/dL. The patient's lipoproteins consisted mainly of high-density lipoproteins. These results suggest that the disorder in this patient is caused by apoprotein B-100 deficiency.

Enzyme-linked immunosorbent assay of lipoprotein(a) in serum and cord blood.

We have developed a new sensitive method for quantifying lipoprotein(a) (Lp(a] in human serum, using a 'sandwich' type noncompetitive enzyme-linked immunosorbent assay (ELISA). The solid-phase used was a polystyrene plate. The anti-Lp(a) antibody-enzyme conjugate was labelled by linking Fab' fragments to peroxidase (EC 1.11.1.7) by the maleimide method. The minimum detectable concentration was 0.5 ng/well. Routinely, the assay was carried out with 1,000-fold diluted serum, and Lp(a) was quantified between 4.0 and 500 mg/l. Within-run coefficients of variation (CVs) ranged from 3.5% to 10.4% and between-run CVs from 5.0% to 11.1%. Results by the ELISA were in good agreement with those by radial immunodiffusion (r = 0.955). The distribution of Lp(a) in serum from 820 healthy donors was highly skewed: mean 141.1 mg/l, medium 97.9 mg/l. In cord blood, the mean and median were 15.6 and 9.8 mg/l, respectively. This ELISA for Lp(a) has the advantages of being highly sensitive and specific, simple to perform, and does not use radioisotopes.

Antitumor effects of a new polysaccharide-protein complex (ATOM) prepared from Agaricus blazei (Iwade strain 101) "Himematsutake" and its mechanisms in tumor-bearing mice.

The antitumor activity of the i.p. or p.o. administration of polysaccharide-protein complex, ATOM (antitumor organic substance Mie) prepared from cultured mycelia of Agaricus blazei (Iwade strain 101) "Himematsutake" examined against four kinds of established mouse tumors. ATOM was highly effective at the doses of 10 and 20 mg/kg/day x 10 on subcutaneously implanted Sarcoma 180 in mice, and was also active against Ehrlich ascites carcinoma, Shionogi carcinoma 42 and Meth A fibrosarcoma at doses of 50 and 100 mg/kg/day x 10. ATOM has no direct cytotoxic action on tumor cells in vitro. Thus the tumor growth-inhibitory effect of ATOM is apparently due to immunological host-mediated mechanisms. The number of peritoneal macrophages, the phagocytosis of polystyrene latex beads and the proportion of the third component of complement (C3)-positive fluorescent cells were increased in the mice treated with ATOM. These results suggest that the macrophage activa-tion and alterations of the C3 are necessary for the induction of an antitumor effect of ATOM.

[Sequential changes in plasma lipoprotein(a) as acute phase protein after myocardial infarction and surgery group].

The plasma lipoprotein(a), apo AI, apo B, and acute phase proteins, were studied in 21 patients with myocardial infarction and in 11 patients after surgery. In the both groups, C-reactive protein showed a rapid increase, and alpha 1 acid glycoprotein, alpha 1 antitrypsin and lipoprotein(a) followed by a moderate increase and restored to normal values after one month. Lipoprotein(a) increased to a maximum on day 11 in the myocardial infarction group, and on day 8 in the surgery group. Only slight changes in apolipoprotein AI and B were noted. We speculate that lipoprotein(a) is an acute phase protein that plays an important roles in recovery from trauma. Recently it was reported that the amino acid sequence of apolipoprotein(a) is partly identical to that of plasminogen. This sequence suggests that lipoprotein(a) and plasminogen are related immunochemically. We examined by immunoblotting technique whether our antibody for lipoprotein(a) is influenced by a plasminogen in plasma. By enzyme-linked immunosorbent assay, it was found that the purity of plasminogen does not influence determination of lipoprotein(a).