[Drugs affect and are affected by body temperature]. / Läkemedel påverkar och påverkas av kroppstemperaturen.

There are several connections between drugs and cold. Drugs can lower body temperature; ambient temperature together with the adaptive capacity of the organism can influence various physiological and also pharmacological processes; furthermore, hypothermia can have an effect on drug pharmacokinetics and pharmacodynamics which is of considerable clinical importance, since the application of hypothermia as a therapeutic adjuvant is on the rise. The present paper discusses different aspects of these problems, concluding with a proposal that it may now be time to ask for the results of a "cold effect test" before a new drug is accepted for common use, especially in hypothermic patients.

[Hibernation--nature's model of resistance to ventricular fibrillation]. / Hibernation--naturens modell för resistens mot kammarflimmer.

During hibernation, animals lower their body temperature to a few degrees above 0 degree C. This means that when entering and emerging from hibernation their body temperature passes through the critical level of +20 degrees C, a temperature region at which non-hibernating mammals develop circulatory arrest, usually due to ventricular fibrillation (VF). The hibernator heart is resistant to VF, not only that caused by hypothermia, but also VF as induced by local application of aconitine on the epicardium, and also by other factors which ordinarily cause VF in non-hibernators. Several mechanisms may explain the resistance to VF observed in the hibernator heart. The factors of greatest importance seem to be contrasting patterns of adrenergic innervation, divergent physico-chemical properties with a lower solidification point of lipids in the hibernator, distinct enzyme temperature activity curves seen in the hibernator, and differences in the handling of intracellular calcium, resulting in protection against calcium overload in the hibernator heart as compared with the non-hibernator heart.

[A history of the electrocardiogram]. / Elektrokardiografins utveckling.

The discoveries by Galvani and Volta of electricity and its effects fascinated the intellectual world, but it was not until 1856 that Köllicker and Müller discovered that the heart muscle could produce electric activity. Muirhead in London recorded the first electrocardiogram (ECG) in man in 1869 or 1870 with a siphon instrument and Waller in 1887 with a capillary electrometer. Einthoven's string galvanometer was a breakthrough. As early as five years after his publication Einthoven introduced "Le Télecardiograme" in 1906 by which a cable connected his instrument to a hospital one and a half kilometres away. The string galvanometer produced precise ECG recordings but it was like the opera primadonnas of the time, voluminous and unpredictable. Rune Elmqvist developed the direct-writing inkjet recorder, first demonstrated at the Congress of Cardiology in Paris, 1950. Ohnell's studies of preexcitation, to which the WPW-syndrome belongs, were important. After the initial focus on arrhythmias, ECG became more and more used in the diagnosis of myocardial ischaemia and coronary heart disease. To refine this diagnosis the hypoxaemia (breathing air with low oxygen content) test, as well as the exercise test and other stress tests were introduced. Vectorcardiography displays the spatial movements of the electrical forces generated by the heart. Long-term ECG registration with a portable tape recorder is important both for the diagnosis of arrhythmias and myocardial ischaemia. Foetal and comparative ECG have provided important clinical and scientific information.

Survival and incidence of myocardial infarction in men with ambulatory ECG-detected frequent and complex ventricular arrhythmias. 10 year follow-up of the 'Men born 1914' study in Malmö, Sweden.

AIM: To assess to what extent do frequent or complex ventricular arrhythmias, detected during 24 h ambulatory electrocardiographic recording (ECG), influence prognosis with regard to survival and incidence of ischaemic heart disease. METHODS AND RESULTS: The study subjects were the 456 randomly selected men born in 1914, the population-based cohort study of 1982-83, in Malmö, Sweden. The main outcome measures were total mortality and incidence of cardiac event (myocardial infarction and death from ischaemic heart disease). Frequent or complex ventricular arrhythmias (Lown classes 2-5) were detected in 49% of the men with (n = 77), and in 35% of those without, a history of myocardial infarction or angina pectoris at baseline, P = 0.019. Independent of clinically evident coronary artery disease at baseline, and after adjustment for traditional atherosclerotic risk factors and use of digitalis or beta-blocker therapy, frequent or complex ventricular arrhythmias were associated with an increased mortality from ischaemic heart disease (relative risk (RR), 2.1; 95% confidence interval (CI), 1.2-3.9) and an increased cardiac event rate (RR, 1.6; 95% CI, 1.0-2.5)). Men free from both ischaemic-type ST depression and frequent or complex ventricular arrhythmias (used as the control group) had the lowest ischaemic heart disease death rate, 5.9 per 1000 person-years. The combination of ST depression and frequent or complex ventricular arrhythmias was associated with an ischaemic heart disease death rate of 20.9 per 1000 person-years. The cardiac event rate in these two groups was 15.6 and 76.1 per 1000 person-years, respectively (adjusted RR, 2.3; CI, 1.1-4.6). CONCLUSIONS: In elderly men without a history of myocardial infarction and angina pectoris, frequent or complex ventricular arrhythmias during ambulatory ECG recording is associated with an increased incidence of myocardial infarction and mortality. Men who, during ambulatory ECG recording, also demonstrate ST-segment depression have an even less favourable prognosis.

The hibernator heart--nature's model of resistance to ventricular fibrillation.

During hibernation animals decrease their body temperature down to a few degrees above 0 degrees C. This means that when entering into and arousing from hibernation their body temperature passes through the critical level of 20 degrees C, a temperature region where nonhibernating mammals develop circulatory arrest, usually ventricular fibrillation (VF). The hibernator heart is resistant to VF, not only induced by hypothermia, but also when induced by local application of aconitine on the epicardium, and other ways of inducing VF in nonhibernators. Several mechanisms may explain this resistance to VF of the hibernator heart. The factors of greatest importance seem to be the different adrenergic innervation pattern, the different physico-chemical properties with a lower melting point of the lipids in the hibernator, the different enzyme temperature activity curves in the hibernator and the different handling of intracellular calcium, which results in protection against calcium overload in the hibernator heart, when compared with the nonhibernator heart.

Effects of carvedilol on the metabolic, hemodynamic, and electrocardiographic responses to increased plasma epinephrine in normal subjects.

To study the effects of the new vasodilating beta-blocking agent carvedilol on a variety of metabolic, hemodynamic, and ECG parameters of importance for the clinical outcome of acute myocardial infarction (AMI), we infused epinephrine (EPI) in healthy male volunteers on two separate occasions to serum concentrations of the same level reached in AMI. Before the EPI infusions, the volunteers were pretreated for 2 weeks with either carvedilol or placebo in randomized order. EPI caused significant decreases in serum levels: S-potassium (0.62 mM), S-magnesium (0.07 mM), S-calcium (0.12 mM), and S-phosphate (0.26 mM). After pretreatment with carvedilol, the decreases in S-calcium and S-phosphate were partly prevented and those in S-potassium and S-magnesium were completely inhibited. Short-term treatment with carvedilol significantly decreased S-insulin and serum C-peptide and significantly attenuated the EPI-induced increase in B-glucose observed after placebo. The EPI infusion significantly increased serum concentrations of free fatty acids and glycerol. These increases were significantly attenuated by carvedilol, whereas carvedilol had no significant affects of a variety of other lipid variables. EPI infusion caused a significant (p < 0.01) increase in systolic blood pressure (SBP) from 124.8 +/- 8.1 to 135.8 +/- 12.5 mm Hg and an increase in heart rate (HR) from 71.0 +/- 11.5 to 77.2 +/- 12.2, resulting in a significant increase in rate-pressure product (RPP). This estimate of cardiac work was significantly (p < 0.05) reduced by pretreatment with carvedilol.(ABSTRACT TRUNCATED AT 250 WORDS)

Microcalorimetric study on myocardial metabolism in a hibernator and two nonhibernators at 20 degrees C and 37 degrees C.

Metabolic activity in cardiac tissue slices from the guinea pig (GP), the rat (RT), the nonhibernating summer and winter hedgehog (SH and WH), respectively, was determined at 20 degrees and at 37 degrees C from their rates of heat production, P, (units, W/g tissue) by direct and indirect calorimetry. Energy-linked transport of Na+ and K+ in the tissues was determined from changes in metabolic rate induced by specific inhibition of the Na/K pump, the functional expression of Na/K-ATPase, the pacemaker enzyme in energy production assigned the role of transporting Na+ and K+ out of and into the cell. The results indicate a higher rate of energy production and utilization in the cardiac tissue of the hedgehog than in that of the nonhibernators, the rat and the guinea pig, at both temperatures. At 37 degrees C the rate at which the cardiac tissue from the hedgehog consumed oxygen was as much as six times that registered for the guinea pig. The temperature coefficients of P and of the Na/K pump in the tissues from the two groups of hedgehogs were significantly higher than in the tissues from the rat and the guinea-pig (P < 0.001). The determined metabolic indices, the basal rate of heat production P, the rate of oxygen consumption, P(O2) in thermal units (W/g tissue), and the Na/K-pump capacity (PC) indicate species-specific differences between the animals. Both PC and its variation with temperature, delta PC/delta T(o)C, were in the order WH > SH > RT > GP. These results indicate that the hedgehog's cardiac tissue, in comparison with that of the nonhibernators, has a greater capacity to generate energy in general and for active transport of Na+ and K+ at 37 degrees C after exposure to a lower temperature. A role is suggested for the Na/K-ATPase and some other unique rate-limiting enzymes in the metabolic pathway for the observed differences in temperature tolerance and cardiac performance between hibernators and nonhibernators.

Anomalous origin of the right coronary artery from the main pulmonary artery. A case report.

A fifty-nine-year-old, asymptomatic woman with anomalous origin of the right coronary artery from the main pulmonary artery is presented. The diagnosis was established by catheterization and angiocardiography. The indications for surgery in this condition are discussed, with special reference to asymptomatic patients. In this patient, surgery was not undertaken, because of the absence of signs of impairment of left ventricular perfusion and function. The patient remains asymptomatic after eight years of observation.

The clinical outcome of acute myocardial infarction is related to the circadian rhythm of myocardial infarction onset.

In order to study whether the circadian rhythm of acute myocardial infarction (AMI) onset has any impact on the clinical outcome, in terms of enzymatically estimated infarct size, circulatory arrest from ventricular tachyarrhythmias, and in-hospital mortality, the authors studied a representative population of 10,791 AMIs treated in the same center between 1973 and 1987. In 6,763 cases (63%) the time of symptom onset was known. In these cases a major peak in AMI incidence was observed between 7:01 AM and 10:00 AM, and minor peaks at 12:01 noon, 3:01 PM-4:00 PM, and 8:01 PM-9:00 PM. In a set of multivariate analyses including several clinical characteristics, symptom onset between 6:00 AM and 12:00 noon significantly predicted a greater infarct size, and symptom onset between 12:00 AM and 6:00 AM was associated with a significantly lower risk of circulatory arrests from ventricular tachyarrhythmias. The time of symptom onset was not significantly associated with in-hospital mortality after adjustment for other clinical characteristics, including infarct size. The authors suggest that the time of day has an impact, not only on the incidence, but also on the severity of AMI and that the ability of beta blockers to blunt the morning increase in AMI incidence may possibly contribute to the beneficial secondary preventive effects of such drugs after AMI.

Benefits of non-selective versus cardioselective beta-blockers in acute myocardial infarction in hypertensive patients.

AIM: To evaluate the effect of current treatment with non-selective or cardioselective beta-blockers on the outcome of a first acute myocardial infarction in hypertensive patients. OUTCOME MEASURES: Peak aspartate aminotransferase was measured as an indirect estimate of infarct size, the occurrence of circulatory arrest from ventricular tachyarrhythmias and in-hospital mortality. DESIGN: A retrospective analysis was performed on data collected in a continuously operating register of all hospitalized acute myocardial infarctions in Malmö, Sweden. PATIENTS: A total of 2114 hypertensive patients were admitted to hospital with a first acute myocardial infarction. Of these patients, 323 were treated with a non-selective beta-blocker on admission and 338 with a cardioselective beta-blocker. RESULTS: In patients given a non-selective beta-blocker the mean peak aspartate aminotransferase was 3.02 +/- 0.15 mukat/l, which was significantly lower than the peak (3.78 +/- 0.35 mukat/l) recorded in the patients given a cardioselective beta-blocker. In a multiple regression analysis, treatment with a non-selective beta-blocker was significantly and inversely related to peak aspartate aminotransferase after adjustment for several clinical characteristics. Age, anterior myocardial infarction, peak aspartate aminotransferase, serum potassium and treatment with a cardioselective beta-blocker were significantly and independently associated with the occurrence of circulatory arrest due to ventricular tachyarrhythmias. The relative risk of circulatory arrest in patients taking cardioselective beta-blockers was 1.73 (95% confidence interval 1.16-2.58) and in patients taking non-selective beta-blockers 1.02 (95% confidence interval 0.64-1.66). Advanced age, a history of diabetes mellitus, a history of stroke, anterior myocardial infarction, a high serum potassium level and a high peak aspartate aminotransferase level significantly predicted in-hospital mortality. The relative risk of in-hospital mortality in patients taking non-selective beta-blockers was 0.92 (95% confidence interval 0.64-1.30), and in patients taking cardioselective beta-blockers 0.84 (95% confidence interval 0.59-1.19). CONCLUSIONS: The study suggests that current treatment with non-selective beta-blockers may have reduced the enzymatically estimated infarct size and the occurrence of circulatory arrest due to ventricular tachyarrhythmias. Both non-selective and cardioselective beta-blockers may also have reduced the in-hospital mortality in this population of hypertensive patients suffering a first acute myocardial infarction. In a clinical study using with adrenaline infusions in healthy volunteers, we found that beta 2-receptor blockade improved potentially arrhythmogenic variables, such as hypokalemia and hypomagnesemia, but the adrenaline-induced reduction in diastolic blood pressure was reversed. Pretreatment with the new beta-blocker carvedilol preserved the beneficial electrolyte effects without increasing blood pressure during the adrenaline infusion.

Effects of hydrochlorothiazide, amiloride, and lisinopril on the metabolic response to adrenaline infusions in normal subjects.

Twelve healthy male volunteers were given adrenaline infusions, 0.05 microgram/kg body weight/min over 120 minutes in order to achieve serum adrenaline concentrations comparable with those seen in acute myocardial infarction. The infusions were given on four occasions, at intervals of at least 4 weeks. Before the infusions the subjects were given, in random order, 14 days of pretreatment with placebo, hydrochlorothiazide 50 mg once daily, amiloride 10 mg once daily, or lisinopril 20 mg once daily. The adrenaline infusion induced a drop in serum potassium of the same magnitude in all four groups, with the lowest absolute value after hydrochlorothiazide because of the lowest pre-adrenaline level. The infusion-induced decreases in serum calcium and magnesium were of the same magnitude in all groups, with the absolute calcium being least low in the hydrochlorothiazide group because of the highest preinfusion value. Preinfusion serum urate was highest after hydrochlorothiazide and fell during the adrenaline infusion in all groups, although not significantly. Blood glucose increased during the adrenaline infusion in all groups, but significantly more after hydrochlorothiazide and amiloride than after lisinopril. Heart rate increased during the adrenaline infusion in all groups but least after lisinopril. QTc preinfusion was longer after hydrochlorothiazide than after amiloride and placebo, but the infusion-induced prolongation of QTc was of the same magnitude in all pretreatment groups. Since our results were obtained in short-term experiments in normal subjects, their clinical relevance is questionable, but they support the view that ACE inhibitors may have certain metabolic advantages over diuretics.

Syncope--brain or heart? A case report.

A 44-year-old man suffered from recurrent episodes of unconsciousness, without any other concomitant manifestations. After routine workup, EEG and CT had proven nondiagnostic, prolonged Holter monitoring revealed a single episode of asystole, lasting 7.6 seconds. A pacemaker was inserted but did not abolish his episodic syncope. Subsequently, long-term EEG recording revealed epileptiform activity with independent foci in both temporal lobes. Antiepileptic treatment relieved the patient of his symptoms. This case illustrates the intimate relationship between the heart and the brain that sometimes lies behind syncope.

Geographical variation and time trends in the attack rate of coronary heart disease in five Swedish cities.

Based upon community myocardial infarction (MI) records in five Swedish cities, geographical variation and time trends in the attack rate of fatal and non-fatal MI have been evaluated. During the study period 1975-1982, a total of 7699 events were registered among men and 1823 events among women. The mean annual mortality was highest in the north, and a declining gradient in mortality was observed from the northern to the southern part of the country. The out-of-hospital death rate was highest in the north, while no difference in in-hospital mortality was observed. However, the geographical variation in the morbidity of MI was less consistent. Changes over time generally followed the same pattern in all cities. The attack rate of fatal and non-fatal MI tended to decline among women and men aged 60-64 years. The pattern was less consistent among younger men. Among women aged 50-59 years the mortality remained unchanged, but the attack rate of non-fatal MI increased in all cities. This increase was not explained by inclusion of less severe infarctions. A considerable proportion, about 85%, were recorded as primary events, emphasizing the possible role of primary prevention in obtaining a decrease in the incidence of the disease. The results of this study support previous findings of an important regional difference in the mortality of MI in Sweden. However, the magnitude of the regional variation in the incidence of coronary heart disease might be overestimated if only the mortality pattern is studied.