Cerebrovascular atherosclerosis in type III hyperlipidemia is modulated by variation in the apolipoprotein A5 gene.

OBJECTIVE: Type III Hyperlipoproteinemia is a rare lipid disorder with a frequency of 1-5 in 5000. It is characterized by the accumulation of triglyceride rich lipoproteins and patients are at increased risk of developping atherosclerosis. Type III HLP is strongly associated with the homozygous presence of the ε2 allele of the APOE gene. However only about 10% of subjects with APOE2/2 genotype develop hyperlipidemia and it is therefore assumed that further genetic and environmental factors are necessary for the expression of disease. It has recently been shown that variation in the APOA5 gene is one of these co-factors. The aim of this study is to investigate the development of cerebrovascular athero?sclerosis in patients with Type III hyperlipopro?teinemia (Type III HLP) and the role of variation in the APOA5 gene as a risk factor. METHODS: 60 patients with type III hyperlipidemia and ApoE2/2 genotype were included in the study after informed consent. The presence of cerebrovascular atherosclerosis was investigated using B-mode ultrasonography of the carotid artery. Serum lipid levels were measured by standard procedures.The APOE genotype and the 1131T>C and S19W SNPs in the APOA5 gene and the APOC3 sstI SNP were determined by restriction isotyping. Allele frequencies were determined by gene counting and compared using Fisher's exact test. Continuous variables were compared using the Mann Whitney test. A p value of 0.05 or below was considered statistically significant. Analysis was performed using Statistica 7 software. RESULTS: The incidence of the APOA5 SNPs, -1131T>C and S19W and the APOC3 sstI SNP were determined as a potential risk modifier. After correction for conventional risk factors, the C allele of the -1131T>C SNP in the APOA5 gene was associated with an increased risk for the development of carotid plaque in patients with Type III HLP with an odds ratio of 3.69. Evaluation of the genotype distribution was compatible with an independent effect of APOA5. CONCLUSIONS: The development of atherosclerosis in patients with Type III HLP is modulated by variation in the APOA5 gene.

Usefulness of high-dose anticoagulants in preventing left ventricular thrombus in acute myocardial infarction.

Fifty-three patients with a suspected first anterior wall acute myocardial infarction (AMI) were randomized to intervention with intravenous heparin followed by oral warfarin (26 patients) or matching placebo (27 patients). The regimen was started within 12 hours after the onset of AMI. Anticoagulation was maintained at a therapeutic level (for heparin, activated partial thromboplastin time 70 to 140 seconds; for warfarin, thrombotest 5 to 10%) for 10 days, and no bleeding episodes occurred. The baseline characteristics of the 2 study groups were well matched. In 7 patients in the placebo group and in none in the anticoagulant group, left ventricular thrombus developed during the study, as detected by serial 2-dimensional echocardiography. Early intervention with high-dose anticoagulant drugs may prevent the development of left ventricular thrombus in anterior wall AMI.

Clinical applicability of creatine kinase MB mass and the electrocardiogram versus conventional cardiac enzymes in the diagnosis of acute myocardial infarction.

We compared creatine kinase MB (CK-MB) mass and total creatine kinase (CK) sampled three times daily with conventional cardiac enzymes. The influence of the electrocardiogram (ECG) on admission, frequency of blood sampling, thrombolytic therapy, different upper reference limits of the biochemical markers and duration of symptoms were assessed in 100 consecutive patients with suspected AMI of whom 63 were confirmed according to WHO criteria. Early sensitivity but not specificity of CK-MB mass, with and without ECG, for cut points <8 microg/l was significantly better than total CK sampled frequently. The sensitivity of ECG on admission (52%) was significantly improved by CK-MB analysis (79%) but not by total CK. Duration of symptoms (range of means 3.5-9 h) or thrombolytic treatment had no influence on the sensitivity and specificity of CK-MB mass. In AMI with inconclusive ECG, CK-MB mass performed best of the markers with a sensitivity of 70% versus 17% of total CK (P<0.001) on admission. CK-MB mass was also elevated in 8 patients classified conventionally as unstable angina. We conclude that CK-MB mass is a more useful marker of AMI during the first 16 h of chest pain than frequently sampled total CK, ECG and conventional cardiac enzymes.

Increased occurrence of exercise-induced silent ischemia after treatment with aspirin in patients admitted for suspected acute myocardial infarction.

Patients admitted for suspected acute myocardial infarction within 6 hours (mean 3 hours 42 minutes) after onset of symptoms were randomised to double-blind treatment with low-dose oral aspirin or placebo. Early exercise ischemic responses, exercise capacity and resting left ventricular ejection fraction (radionuclide ventriculography) were estimated in 77 survivors 2-4 weeks later. Exercise performance and ejection fraction in patients with confirmed acute myocardial infarction were equal in the two groups. During exercise, patients treated with aspirin had significantly more silent ischemia (ST depression without chest pain) compared to placebo (28% versus 6%; P = 0.015). The occurrence of positive exercise tests (chest pain or ST-segment depression), however, was similar in the two groups. The results indicate that the administration of aspirin early after acute myocardial infarction increases the occurrence of silent ischemia but has no effect on left ventricular function.

The absorption of vitamin B12 after subtotal pancreatectomy in the rat.

Subtotal pancreatectomy in the rat was performed by a new method. Except for a small remnant along the splenal hilus, the gland was completely removed. Exocrine pancreatic insufficiency was confirmed by fat and nitrogen malabsorption. A moderate diabetes mellitus was seen. Insulin substitution or diet restriction was unnecessary. The absorption of vitamin B12 after oral administration of 10 ng 57CoB12 was 5.0 +/- 0.2 (ng 57CoB12 +/- S.E.M.) in unoperated rats and 5.1 +/- 0.1 in pancreatectomized rats (p greater than 0.5). Pancreatic extract (PE) (100 mg) increased the absorption of 57CoB12 in unoperated rats (p less than 0.01), but not in pancreatectomized rats (p greater than 0.2). PE (300 mg) reduced the absorption in unoperated rats (p less than 0.01). The results indicate that an optimal amount of pancreatic secretion may stimulate the absorption of vitamin B12.

Inhibitory effect of pancreatic juice on the intestinal uptake of vitamin B12.

Rat pancreatic juice (RPJ) reduced the mean uptake of 57CoB12 bound to rat intrinsic factor (IF) by perfused rat intestinal segments from 30.1 +/- 2.4 (pg 57CoB12 per cm intestine +/- S.E.M.) to 26.7 +/- 2.4 (p less than 0.05). RPJ activated with enterokinase reduced the uptake from 22.8 +/- 2.8 to 16.1 +/- 1.9 (p less than 0.05). RPJ also reduced the uptake from 15.8 +/- 2.3 to 8.3 +/- 2.0 (p less than 0.01) in segments from partially pancreatectomized rats. Rat bile abolished the inhibitory effect of RPJ. The results indicate that in the absence of bile the exocrine pancreatic secretion is capable of inhibiting the intestinal uptake of vitamin B12.

[Infarction in the inferior myocardium with and without damage to the right ventricle. Treatment and prognosis]. / Nedreveggsinfarkt med samtidig høyre ventrikkel-skade. Behandling og prognose.

Acute inferior infarction often involves the right ventricle as well. For these patients, the prognosis is not as good as for patients with inferior infarction alone. Right ventricular infarction can be diagnosed with a high level of sensitivity and specificity by recording right precordial leads. We used V4R. 100 patients admitted to the Coronary Care Unit with an electrocardiographic diagnosis of inferior infarction were registrated consecutively. V4R was recorded in 95 patients; the right ventricle was affected in 35 of them. The mortality during the stay in hospital was 3% in the group with inferior infarction and 11% when the right ventricle was involved (p > 0.05). An unusually large proportion of the patients in both groups received thrombolytic therapy (more than 70%). The result may indicate that thrombolytic therapy is of particular benefit to patients with inferior infarction and involvement of the right ventricle.

Serum potassium concentrations are inversely related to ventricular, but not to atrial, arrhythmias in acute myocardial infarction.

In a study of 1033 consecutive patients with acute myocardial infarction, serum potassium concentrations were determined on admission to hospital and studied with respect to the subsequent occurrence of atrial fibrillation and flutter and of ventricular tachycardia and fibrillation. The study cohort fulfilled the inclusion criteria for the Norwegian timolol trial in which they later took part. In multivariate analysis, with serum potassium concentrations as a continuous variable, age, the presence of ventricular tachycardia and fibrillation, and maximum level of aspartate aminotransferase greater than four times the upper limit of normal were significantly associated with the occurrence of atrial fibrillation and flutter, while serum potassium concentration was not. Serum potassium concentrations and time from onset of the infarction to hospital admission were significantly negatively associated with the occurrence of ventricular tachycardia and fibrillation; while age, cardiomegaly, transient hypotension, pathological Q-waves in the electrocardiogram, atrial fibrillation and flutter, and ventricular premature beats were positively related to these arrhythmias. Thus, there is an independent inverse relationship between serum potassium concentrations and ventricular arrhythmias in acute myocardial infarction.

Prognostic importance of predischarge exercise capacity for long-term mortality and non-fatal myocardial infarction in patients admitted for suspected acute myocardial infarction and treated with metoprolol.

To evaluate the influence of acute beta-blockade on the ability of predischarge exercise test data to predict long-term prognosis in patients admitted for suspected acute myocardial infarction, patients randomized at hospital admission to intravenous metoprolol or placebo were studied. Among 190 patients discharged alive, total 4-year mortality was 20.5% (n = 39); (33 cardiac deaths, 6 non-cardiac deaths). Non-fatal infarction rate was 6.8% (n = 13). Multiple logistic regression analysis revealed that total mortality and non-fatal infarctions were independently predicted by (a) inability to perform predischarge stress testing (event-free survival for patients exercise tested 79.5% vs 56.9% for patients not eligible for testing; relative risk (RR) 1.40, 95% confidence interval (CI) 1.10-1.78; P = 0.01), and (b) low predischarge exercise capacity (RR 1.44, CI 1.08-1.93; P = 0.034). ST segment shift > or = 1 mm did not predict mortality or reinfarction. Administration of metoprolol in the acute phase did not influence the predictive value of these parametres. It is concluded that assessment of exercise capacity at early exercise testing yields independent information for later death and myocardial infarctions, and that beta-blockade with metoprolol does not influence the predictive value of early exercise testing.

Hypokalaemia and ventricular fibrillation in acute myocardial infarction.

Serum potassium concentrations obtained on admission to hospital were inversely related to the incidence of ventricular fibrillation in 289 women and 785 men with acute myocardial infarction, 92 of whom developed ventricular fibrillation. Hypokalaemia (serum potassium concentration less than or equal to 3.5 mmol/l) was found in 122 patients (11.4%). The incidence of ventricular fibrillation was significantly greater in patients with hypokalaemia compared with those classified as normokalaemic (serum potassium concentration greater than or equal to 3.6 mmol/l) (17.2% v 7.4%). The increased risk of ventricular fibrillation in the hypokalaemic group was about the same for women and men. While they were in hospital patients with hypokalaemia developed ventricular fibrillation significantly earlier than did normokalaemic patients (median 0.3 hours v 7 hours). Hypokalaemia was more common in women (17.3%) than in men (9.2%), and 55% of the hypokalaemic patients had been treated with diuretics before admission compared with 22% of the normokalaemic group. Hypokalaemia on admission to hospital predicts an increased likelihood and early occurrence of ventricular fibrillation in patients with acute myocardial infarction.

The effect of proteolytic enzymes on the vitamin B12-binding proteins of human gastric juice and saliva.

Pepsin had no effect on the vitamin B12 binder in human saliva (R-binder), while trypsin was found to reduce the apparent molecular weight of the R-binder and to release vitamin B12 from the R-B12complex of human saliva and human gastric juice (HGJ). Trypsin had no effect on the molecular weight and biological activity of intrinsic factor (IF) in HGJ, as demonstrated by gel filtration on Sephadex G-150 and the uptake of IF-B12 by guinea pig intestinal brush borders. An extract of purified guinea pig intestinal lysosomes was also without effect on the molecular weight and the biological activity of IF but was found to release vitamin B12 from the R-B12 complex. The results support the observation that the external pancreatic secretion corrects malabsorption of vitamin B12 by an effect on the non-IF protein in the intestinal juice. Moreover, the results indicate that lysosomal enzymes are not involved in the intestinal absorption of vitamin B12.

Demonstration of a vitamin B12 binder in pancreatic juice. Effect on the intestinal uptake of vitamin B12.

Determination of vitamin-B12-binding capacity and gel filtration of human pancreatic juice (HPJ) and rat pancreatic juice (RPJ) demonstrated a vitamin B12 binder different from gastric intrinsic factor (IF). The results also indicated the presence of the pancreatic B12 binding in human duodenal juice. The binder in RPJ had no significant effect on the uptake of 57CoB12 and 57CoB12 bound to rat IF by perfused rat intestinal segments (p greater than 0.5; p greater than 0.1). The binder in HPJ had no effect on the uptake of unbound 57CoB12 or 57CoB12 bound to human IF by guinea pig intestinal brush borders (p greater than 0.05; p greater than 0.1). The results indicate that the pancreatic vitamin B12 binder does not influence the intestinal uptake of vitamin B12.

Effect of timolol on late ventricular arrhythmias after acute myocardial infarction.

This is a subproject of the Norwegian timolol myocardial infarction study carried out at one of the clinical centers. High risk patients surviving either a reinfarction or large initial infarction were randomized to placebo (44 pts) or timolol (37 pts). A 24 hour ECG was obtained the day before randomization (at baseline, 7-28 days after the acute attack) then 3 days, 1 month and 6 months after start of therapy. During this period the number of patients with one or more of ventricular couplets, bigemini, ventricular tachycardia or early cycle premature ventricular contractions (PVC) (i.e. complex ventricular arrhythmias) and the average number of PVC per hour increased significantly in the placebo group but not in the timolol group. The results indicate that there is an increased severity and incidence of ventricular arrhythmias in the first 6 months after myocardial infarction. Timolol effectively inhibited this trend. The importance of timolol as an antiarrhythmic agent may therefore be to prevent subclinical infarction extension and secondary ventricular arrhythmias related to the size of the myocardial damage.

Intestinal absorption of vitamin B12 in patients with chronic pancreatic insufficiency and the effect of human duodenal juice on the intestinal uptake of vitamin B12.

The mean absorption of vitamin B12 (Schilling test) was 13.1 +/- 1.0 (% +/- S.E.M.) in 21 patients with chronic pancreatic insufficiency and 17.6 +/- 1.4 in 13 control patients (p less than 0.01). There was no correlation between pancreatic bicarbonate production after secretion stimulation and vitamin B12 absorption in the patient group (r = 0.117). Human duodenal juice reduced the uptake of 57CoB12-rat intrinsic factor (IF) by perfused rat small intestinal segments in vivo (p less than 0.01) as well as the uptake of 57CoB12-human IF by purified guinea-pig intestinal brush borders in vitro (p less than 0.01). The results confirm reduced absorption of vitamin B12 in chronic pancreatic insufficiency, but the mechanism remains uncertain.

Pancreatic extract and the intestinal uptake of vitamin B12. III. Stimulatory effect in the presence of a non-intrinsic factor vitamin B12 binder.

To determine the mechanism by which pancreatic extract (PE) corrects the malabsorption of vitamin B12 in chronic pancreatic insufficiency (CPI), the following hypotheses were investigated: Firstly, PE might stimulate the absorption of vitamin B12 by changing the intestinal pH, secondly PE might stimulate the intestinal uptake of unbound vitamin B12, thirdly PE might abolish the inhibitory effect of vitamin B12 binders on the intestinal uptake of vitamin B12 bound to intrinsic factor (IF). PE had no effect on the pH in the small intestine and did not stimulate the uptake of unbound 57CoB12 by perfused rat intestinal segments. Preincubation of 57CoB12-IF with a non-IF B12-binder from human saliva (R-binder) reduced the uptake of 57CoB12 from 18.5 pg per cm intestine +/- 3.4 S.E.M. to 7.8 +/- 1.6 (p less than 0.02). PE abolished this inhibitory effect (p less than 0.05). The results indicate that PE corrects the malabsorption of vitamin B12 in CPI by an effect on non-IF B12- binders.

[Cholesterol determination at conscription. A method to identify persons with high risk of developing cardiovascular disease]. / Kolesterolbestemmelse ved sesjon. En måte å identifisere personer med høy risiko for å utvikle hjerte- og karsykdom.

In the adult population, serum cholesterol level and risk of cardiovascular disease are related to some extent to habits and lifestyle established at an early age. We have estimated serum total cholesterol levels by means of a dry chemical method and have collected information on established cardiovascular risk factors among 1,203 young Norwegian men at conscription. 30 of the recruits with the highest serum cholesterol levels were later examined in the hospital's out-patient clinic. A total of 30.8% of the recruits were daily smokers. Mean serum total cholesterol was 4.05 mmol/l with a 97.5 percentile value of 6.31 mmol/l. The prevalence of coronary heart disease among parents was significantly higher among recruits from the upper cholesterol quintile (4.2%) compared with those in the lowest quintile (0.8%) (p = 0.02). These findings show that cholesterol screening at conscription is feasible and can be used to identify a group of men at high risk of subsequently developing cardiovascular disease.

Increased occurrence of left ventricular thrombi during early treatment with timolol in patients with acute myocardial infarction.

To examine whether early intervention with timolol influences the occurrence of left ventricular thrombi in acute anterior myocardial infarction, 40 patients with acute anterior myocardial infarction admitted to hospital within 6 hr of onset of symptoms were randomly assigned to receive intravenous followed by oral timolol maleate or placebo. Five (25%) of 20 patients in the placebo group and 14 (73.7%) of 19 patients with confirmed infarction in the timolol group developed a left ventricular apical thrombus as detected by two-dimensional echocardiography from 2 to 10 days after inclusion (p less than .005). Patients received anticoagulants only after a left ventricular thrombus had been diagnosed. Only one patient with thrombus suffered peripheral embolization (timolol group). The treatment groups were comparable with respect to location of regional left ventricular dysfunction, electrocardiographic changes, and infarct size estimated by creatine kinase release. However, computer-assisted regional wall motion analysis demonstrated significantly reduced apical wall motion in the timolol group compared with the placebo group (p less than .01). Also, the mean heart rate during the first 10 days after the acute infarction was reduced by 13% in the timolol group (p less than .001). The reduction in heart rate and left ventricular apical wall motion caused by timolol in patients with acute anterior myocardial infarction may increase the occurrence of left ventricular thrombi.

Left ventricular thrombi after short-term high-dose anticoagulants in acute myocardial infarction.

To examine the effect of short-term, high-dose anticoagulation on the subsequent occurrence of left ventricular (LV) thrombi after a first anterior wall acute myocardial infarction (AMI), 21 patients received placebo and 21 high-dose anticoagulants during the first 10 days of the acute infarction. They were studied with cross-sectional echocardiography 10 days and 1.3 and 6 months post infarction. At 1 month, 6 of 7 thrombi present in the placebo group at 10 days were still visible. No thrombi were detected at 10 days in the anticoagulation group, but 6 patients had developed a LV thrombus at 1 month. These 12 patients with LV thrombi were subsequently treated with oral warfarin for 2 months, after which all thrombi had disappeared. Warfarin was then discontinued, and a thrombus had recurred in 5 patients after 6 months. Apical akinesis at 10 days was a predictor for thrombus with a sensitivity and specificity of 100% and 72.2%, respectively. Three of the 13 patients with LV thrombi suffered stroke in contrast to none without thrombi (P = 0.025). We conclude that after discontinuation of short-term high-dose anticoagulation therapy in anterior AMI, LV thrombi may develop rapidly and lead to embolic complications, particularly in patients with persisting apical akinesis.