Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

Pharmacokinetics of felodipine and effect on digoxin plasma levels in patients with heart failure.

Some calcium antagonist drugs used in hypertension and cardiac diseases have been shown to increase plasma digoxin levels mainly as a result of reduced renal clearance. Felodipine is a new dihydropyridine calcium antagonist drug with cardiovascular effects, whose pharmacokinetics and effects on plasma digoxin levels have been studied in patients with left ventricular failure. 12 patients (11 men) on long term digoxin therapy were given 2.5 or 5 mg felodipine bid for 7 days followed by 1 week on 10mg bid. Plasma levels of digoxin and felodipine were measured before dosage and 30, 60 and 90 minutes and 2, 3, 4, 6, 8, 10 and 24 hours after the first dose and after 1 week of therapy (steady state). The area under plasma concentration versus time curve was calculated after the first dose and in steady state both for digoxin and felodipine. The absorption characteristics Cmax and Tmax were calculated both for felodipine and digoxin on the different felodipine doses. There was a linear relationship between dose and plasma level of felodipine. Plasma half-life in the 4- to 10-hour period of felodipine was 5.5 hours after a 10mg single dose, and 12 hours after 10mg bid. Felodipine 2.5mg, 5mg and 10mg all transiently increased peak plasma digoxin concentrations (by about 40%) at 1 hour after intake. Urinary excretion of digoxin during the day was unchanged, but impaired renal clearance may account for the transient increase in digoxin plasma level after felodipine.

Unexpected death in patients suffering from eating disorders. A medico-legal study.

Medico-legal investigation into causes of unexpected death of five persons who suffered from eating disorders did not give distinct pathoanatomical explanations. The analysis disclosed a number of risk factors whose interplay may have resulted in a circulatory catastrophy. These factors were of organisational and ideological character: simultaneous treatment at different departments, lack of contact with psychiatrists, or unclear criteria for admission to hospital; or somatic: circulatory and electrocardiographic S-T and T wave abnormalities, hypopotassemia and hypoglycemia, as well as anergy of the emaciated patient which may have led to symptoms of bronchopneumonia being overlooked. Morphological investigation revealed heart atrophy as well as recent lesions such as haemorrhages, fragmentation and contraction bands of the myofibres. In two extremely emaciated patients there was a disproportion between the size of the mitral valves and the atrophic ventricular wall, an appearance similar to "floppy valves". In one instance an erroneously inserted gastric tube contributed to vomiting, hypopotassemia and sudden death.

The effect of isosorbide-5-mononitrate (5-ISMN) Durules on exercise tolerance in patients with exertional angina pectoris. A placebo controlled study.

Twenty-four patients with stable exercise-induced angina pectoris entered a double-blind cross-over study. Isosorbide-5-mononitrate (5-ISMN) 60 mg in a controlled release formulation (Durules) given once daily was compared with identical placebo. The exercise tolerance was determined by bicycle ergometry before and 3 h after a single dose of 5-ISMN and following one week's treatment with 5-ISMN and placebo. Nineteen patients completed the study. Exercise tolerance until the onset of chest pain and until 1 mm ST segment depression increased significantly 3 h after dose. The same increase was seen both after a single dose and the same dose under steady-state conditions. No increase was seen with placebo. The heart rate and systolic blood pressure reactions in the standing position were less pronounced 3 h after dose in steady-state than after a single dose of 5-ISMN. Headache was the only bothersome side-effect reported. The study demonstrates that 60 mg 5-ISMN in a Durules formulation given once daily has a significant anti-anginal effect and that tolerance does not develop.

Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity.

The effects of metoprolol treatment in patients surviving acute myocardial infarction have been investigated in a double-blind randomized study. The patients were stratified according to age, infarct size and type of ventricular arrhythmias before administration of metoprolol, 100 mg twice daily (n = 154), or placebo (n = 147). All patients were followed up for 36 months. There were 31 (29 cardiac) and 25 (20 cardiac) deaths in the placebo and metoprolol groups, respectively. Subgroup analyses showed a significant reduction of cardiac death in patients with a large infarct (32.1% with placebo versus 12.5% with metoprolol, p less than 0.05) as a result of active treatment. Sudden death rates were 14.7% in the placebo versus 5.8% in the metoprolol group (p less than 0.05). The incidence of nonfatal reinfarction was 21.1% in the placebo versus 11.7% in the metoprolol group (p less than 0.05). The reduction in nonfatal reinfarction was similar in all pretreatment risk strata. The difference between the two groups in cumulative number of cardiac deaths and patients experiencing nonfatal reinfarction increased throughout the study. Furthermore, cerebrovascular events (p less than 0.05) and coronary bypass surgery (p = 0.058) were more frequent in the placebo group. In conclusion, after 36 months of metoprolol treatment after myocardial infarction, there was a significant reduction of nonfatal reinfarction and sudden death in all patients and a reduction of cardiac death in those with a large infarct.

Genetic and environmental determinants of cholesterol and HDL-cholesterol concentrations in blood.

Serum cholesterol and HDL-cholesterol have been studied in 274 Swedish nuclear families. The families were ascertained through the Swedish twin registry and consisted of married mono- and dizygous twins, their spouses and with at least one adult child. Total cholesterol was determined using an enzymatic colorimetric method and HDL-cholesterol by the heparin-manganese chloride precipitation method. The genetic analysis was performed using a path analytic model to resolve genetic and cultural heritability, marital correlations and maternal effects. Genetic heritability was 0.50 and 0.37 for total cholesterol and HDL-cholesterol, respectively. Cultural heritability was small, 0.04, for cholesterol but substantial 0.22, for HDL-cholesterol. A maternal effect was evident for cultural inheritance for HDL-cholesterol but not for cholesterol.

Ventricular arrhythmias and left ventricular dysfunction in familial cardiomyopathy.

In familial cardiomyopathy (CM), different forms of myocardial abnormalities including asymmetric and symmetric hypertrophy and dilated left ventricles are presented, mostly showing varying hereditary penetrance. This study presents a family with CM including three major clinical manifestations: severe ventricular arrhythmias, repolarization abnormalities and left ventricular hypertrophy. This triad was strikingly consistent in the two generations examined. The familial pattern with an autosomal dominant inheritance did not show any linkage to the HLA region.

Pre-beta 1-lipoprotein in patients with ischemic heart disease. Genetic determination and relation to early insulin response.

The genetic determination of pre-beta 1-lipoprotein and its relation to insulin response was studied in 18 male monozygotic and 13 male dizygotic twin pairs, aged 51-74. They had been selected from the Swedish Twin Registry by means of an angina pectoris questionnaire. Results revealed a heritability index for the pre-beta 1-lipoprotein, determined quantitatively, to be as high as 0.94. The subjects in whom pre-beta 1-lipoprotein was present exhibited a significantly delayed early insulin response compared to subjects without this lipoprotein fraction. Our data seem to justify the use of pre-beta 1-lipoprotein as a genetic marker. Data also indicate that important metabolic differences may exist between pre-beta 1+ and pre-beta 1- individuals, and it is possible that such differences may explain in part an increased susceptibility to ischemic heart disease for those possessing the pre-beta 1 fraction.

Metoprolol treatment after acute myocardial infarction. Effects on ventricular arrhythmias and exercise tests during 6 months.

One hundred and six patients on double-blind treatment with placebo or metoprolol, 100 mg b.i.d., during the first 6 months after an acute myocardial infarction were investigated. The patients were stratified and randomized to treatment according to type of ventricular arrhythmias on a six-hour ECG registration, size of infarct estimated by enzyme maximum and age. During the follow-up period, a further three six-hour ECG recordings and three exercise tests were performed. In the metoprolol group the incidence of malignant ventricular ectopic beats decreased significantly (p less than 0.05) after three days' treatment. This decrease lasted for one month but was not observed at the six-month registration. No difference in working capacity was seen between the two groups, nor were there any differences in ischemic ST depressions on ECG during exercise. The proportion of patients terminating exercise because of angina pectoris was similar, but significantly more patients in the metoprolol group (p less than 0.05) discontinued exercise at six months because of fatigue. Large heart volumes were observed somewhat more often in the metoprolol group but there was no extended need of treatment for cardiac failure.

QTc intervals in acute myocardial infarction: first-year prognostic implications.

Corrected QT (QTc) intervals were measured retrospectively in 160 consecutive survivors of acute myocardial infarction under 66 years of age. Calculations were made the first 2 d in the coronary care unit (CCU), the first post-CCU day, at discharge, and at 1-3, 6, and 12 months after discharge. All patients were in sinus rhythm and without bundle branch block at discharge from the hospital. Sixteen patients died during the first follow-up year. Twenty patients suffered a reinfarction, five of whom died. The highest QTc values were registered in the CCU and the lowest at the 1-year control. Patients with subendocardial infarcts had longer QTc intervals than those with transmural infarcts, especially during the acute phase. Patients with inferior infarcts had shorter QTc intervals during the CCU period. Those who reinfarcted or died a cardiac death (particularly when sudden) during the follow-up year had longer QTc intervals during the post-CCU phase. A multivariate analysis of risk factors revealed that the QTc interval at discharge was of significant independent value for predicting major cardiac events after discharge from the hospital. It is concluded that repeated measurements of QTc may be of value when assessing prognosis after acute myocardial infarction.

QTc intervals at discharge after acute myocardial infarction and long-term prognosis.

QTc intervals were measured retrospectively in 46.3 survivors of AMI with a mean age of 65 years. The measurement was made one at discharge from hospital. Patients with anterior infarcts had significantly longer QTc intervals than those with inferior or uncertain infact localization. A weak but significant correlation was found between S-GOT maximum and QTc interval. Patients with ventricular arrhythmias in the CCU had longer QTc intervals. Patients with a poor long-term prognosis had significantly shorter QTc intervals. This finding was explained by digitalis therapy. Among patients without bundle branch block, digitalis and quinidine, those below 66 years of age who died within the first six months tended to have longer QTc intervals than the survivors. It is concluded that measurements of QTc interval at discharge have no long-term predictive value. This factor may, however, have some bearing on the short-term prognosis in younger patients without therapy which affects the QTc interval.

Effect of metoprolol on QTc intervals after acute myocardial infarction.

The effect of metoprolol on corrected QT interval (QTc) was studied retrospectively in 111 survivors of AMI below 70 years of age. Prior to discharge the patients were stratified by age, infarction size and ventricular arrhythmias and randomized. Metoprolol, 100 mg b.i.d., or placebo were given double-blindly to 59 and 52 patients, respectively. QTc intervals were measured four times prior to randomization and three times during the follow-up year. The highest QTc mean was registered on the second day in the CCU. QTc intervals subsequently decreased significantly in both groups between discharge and the three-month control (p < 0.001). Patients on metoprolol had significantly shorter QTc intervals during the follow-up year than those on placebo (0.394 +/- 0.028 vs. 0.406 +/- 0.034 sec, p < 0.001). The QTc-shortening effect of beta-receptor blockade was most marked in patients with prolonged QTc intervals at discharge. Patients who died suddenly had prolonged QTc intervals prior to discharge. In this group the proposed beneficial effect of beta-receptor blockade on QTc interval cannot be evaluated as most of these patients had died before the first control.

Early mobilization and discharge of patients with acute myocardial infarction. A prospective study using risk indicators and early exercise tests.

Consecutive patients (n=184) surviving 48 hours in a coronary care unit were divided into one rapidly (RM) (n=55, 30%) and one conventionally mobilized (CM) group (n=129, 70%). The selection of RM patients was based on the absence of five early risk indicators (RI), reflecting electrical and mechanical heart dysfunction. During after-care, five late RIs were evaluated, including a submaximal bicycle exercise test to 50 W, which excluded nine (16%) additional patients from the RM group. After excluding four patients for non-cardiac reasons, the remaining 42 RM patients were rapidly mobilized and discharged after a mean of nine days, in contrast to a mean of 19 days in the CM group, comprising 121 patients. No RM patient dies in hospital and only one patient died during a six-month follow-up, compared to 17 (p less than 0.01) and 28 (p less than 0.01) patients respectively, in the CM group. Both reinfarction and mortality increased with the number of positive RIs. The early exercise test excluded four patients from the RM group. Altogether 22 of 45 patients showed some abnormality during exercise. Half of these 22 patients were readmitted due to cardiac complications during the follow-up period. These findings indicate that it is possible to identify a group of patients with AMI suitable for early discharge, and that an early exercise test in selected good risk patients is safe and identifies a group prone to complications during the early follow-up period.