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.

[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.

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.

[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.

Functional capacity in healthy volunteers before and following beta-blockade with controlled-release metoprolol.

The effects of the beta 1-selective beta-adrenergic blocker metoprolol on physiological responses, exercise capacity and gas exchange parameters were measured in healthy men using different graded bicycle exercise protocols on separate days before and following administration of 200 mg controlled-release metoprolol. Eleven men performed in randomised order maximal cardiopulmonary exercise testing on 50-W/6-min stage, 50-W/3-min stage and ramp (15-W/min-1) protocols. Peak heart rate and peak heart rate-blood pressure products were similar on all exercise protocols, and were significantly reduced by metoprolol. Submaximal and peak oxygen consumption were similar before and following beta-adrenoceptor blockade. Depending on the exercise protocol applied, an insignificant decrease of 4-10% in maximal cumulated exercise capacity (work-rate x time integral) was observed following administration of metoprolol. It is concluded that in healthy men evaluated with different exercise protocols the beta 1-selective controlled-release beta-adrenoceptor blocker metoprolol does not influence exercise capacity despite a marked reduction of heart rate and rate-pressure product.

Importance of the exercise programme for the assessment of functional capacity after myocardial infarction.

To evaluate the effect of different bicycle exercise programmes on estimates of functional capacity in cardiac patients, the cumulated exercise capacity, physiologic and gas exchange responses were measured in eleven men 5-10 weeks after an acute myocardial infarction. The patients were not limited by angina and all were treated with a beta-blocker. On separate days and in randomized order the patients performed symptom-limited cardiopulmonary exercise testing on 50 W/3 min stage, 50 W/6 min stage and continuous 'ramp' (15 W per min) programmes. Submaximal and peak oxygen consumption, peak heart rate, rate pressure product, workload and minute ventilation were independent of the various exercise programmes, but exercise time and maximal cumulated exercise capacity (workload x time integral) were significantly higher on the 50 W/6 min stage (50.3 +/- 20.0 kJ) and ramp (41.1 +/- 16.4 kJ) programmes compared to the 50 W/3 min stage programme (32.8 +/- 11.9 kJ). The variation of exercise time and cumulated work capacity, but not oxygen consumption between different exercise programmes has to be considered when estimating functional capacity early after 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.

[Perimyocarditis caused by Yersinia enterocolitica serotype 0:3]. / Perimyokarditis durch Yersinia enterocolitica Serotyp 0:3.

Three days after the end of a bout of diarrhoea of 3 days' duration, a 19-year-old patient developed severe nocturnal thoracic pain unresponsive to isosorbitol dinitrate. There were no abnormal findings on physical examination, except a sweaty skin. SGOT (38 U/l), creatinine kinase (291 U/l, CK-MB 29 U/l) and lactate dehydrogenase (246 U/l) were all elevated. The ECG showed ST segment elevations in leads I, II, III, aVF and V1-V6 as well as negative terminal T waves in I, II, aVL, AVF and V3-V6, changes suggesting peri- and myocarditis. The Widal test gave a raised antibody titre (1:800) against Yersinia enterocolitica serotype O:3. Seven days later the immunoblot test demonstrated antibodies against the same organism, which was finally isolated from stool after 11 days. Treatment consisted of ciprofloxacin (500 mg twice daily for 14 days). All symptoms, as well as the biochemical and ECG abnormalities, quickly improved. The patient was discharged free of symptoms after 34 days.

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.

Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Anglo-Scandinavian Study of Early Thrombolysis.

In a randomised, controlled trial 2514 patients with suspected acute myocardial infarction received 100 mg intravenous alteplase (recombinant tissue plasminogen activator [rt-PA]) plus heparin within 5 h of onset of symptoms, and 2499 similar controls received placebo plus heparin. At 1 month the overall mortality rates were 7.2% and 9.8%, respectively, a relative reduction of 26% (95% confidence interval [CI] 11-39%). At 6 months the mortality rates were 10.4% (alteplase) and 13.1% (placebo), a relative reduction of 21% (95% Cl 8%-32%, p = 0.0026). 6-month mortality rates in patients with proven myocardial infarction were 12.6% and 17.1%, respectively (relative reduction 26%; 95% Cl 14-37%); this effect was similar for anterior (15.6% vs 21.2%) and inferior (7.7% vs 12.8%) myocardial infarction. 6-month mortality rates were lower in those treated with alteplase irrespective of other recognised cardiac risk factors. However, treatment with alteplase made no difference to subsequent cardiac events after one month (readmissions, reinfarctions, death) nor to treatment for angina or heart failure. Product limit estimates of one year mortality are 13.2% with alteplase and 15.1% with placebo. The corresponding figures for patients with an index diagnosis of myocardial infarction are 15.7% and 18.9%, a relative reduction of 16.9%.

Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET).

13,318 patients admitted to fifty-two coronary care units with suspected acute myocardial infarction were considered for inclusion in a double-blind study comparing recombinant tissue-type plasminogen activator (rt-PA) 100 mg plus heparin with placebo plus heparin. 8307 (62%) were excluded, mainly because their symptoms had begun more than 5 h previously, but all excluded patients were followed up at least until hospital discharge. 2516 patients were randomly allocated to rt-PA and 2495 to placebo. At one month the overall case fatality rates were 7.2% and 9.8%, respectively, a relative reduction of 26% (95% confidence interval 11-39%). 6.3% of patients given rt-PA had a bleeding complication (1.4% major) compared with 0.8% given placebo (0.4% major). However, the incidence of stroke was similar--1.1% in the rt-PA group and 1.0% in the placebo group. Subset analysis showed that patients who had a normal electrocardiogram (ECG) at the time of randomisation (17.5% of the whole trial population) had a low case fatality rate (1.6% in those given rt-PA compared with 3.0% in those given placebo). In those with an abnormal ECG at entry, rt-PA was associated with a 24.5% relative reduction in 1 month fatality (95% confidence interval 9-37%).

Risk factors for embolisation in patients with left ventricular thrombi and acute myocardial infarction.

Risk factors for systemic embolisation in patients with ventricular thrombi caused by an acute myocardial infarction were studied in 150 consecutive patients with an infarction of the anterior wall. Serial echocardiograms were performed 2-10 days after the acute event and patients were followed up for three months. Anticoagulation treatment was started only after the detection of thrombi. Of the 55 patients in whom a thrombus developed, 15 (27%) had peripheral emboli between 6-62 days; but only two (2%) of 95 patients without thrombus had emboli. Among 15 variables, the best single predictors of embolisation were age greater than 68 years (80% sensitive, 85% specific), pendulous thrombus (60%, 93%), and independent thrombus mobility (60%, 85%). Logistic regression analysis showed that a formula that included patient age, thrombus area, and the length of thrombus in the ventricular lumen predicted embolisation (sensitivity 87%, specificity 88%). There was no correlation between age and the thrombus variables. The risk of embolisation from left ventricular thrombi in acute anterior myocardial infarction can be accurately assessed from patient age and echocardiographic features. The risk of peripheral emboli is high in patients with left ventricular thrombi and those aged greater than 68.

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.

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.

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.