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The pharmacodynamics of several tin compounds were studied in healthy rabbits, rabbits with myocardial infarcts, and isolated myocardial tissue. The results showed that tin chelates of pyrophosphate, HEDP, DTPA, and glucoheptonate are very unstable in vivo, giving rise to free stannous ions. These ions localize mainly in bone, with the rest being primarily excreted in the urine. They also concentrate more in infarcted than in normal myocardium; there they enter the mitochondria. The supernatant of homogenates contains bound and free fractions, demonstrating a subcellular distribution pattern similar to that of calcium ions. Tin chelates have different pharmacodynamics from the corresponding 99mTc chelates.

Plasma concentrations and urinary excretions of various hormones and hormone metabolites were measured in four groups. Group 1 was composed of 13 men with prior myocardial infarction; Group 2 contained 35 clinically normal men; Group 3 consisted of 44 men with normal coronary arteriograms; and Group 4 was composed of 25 men with severe coronary artery disease shown on arteriogram but no infarction. There were four major findings: Group 1 had significantly higher 24-hour mean plasma concentrations of estrone (E1), dehydroisoandrosterone (DHA), and dehydroisoandrosterone sulfate (DHAS) than Group 2, while Group 3 had the same levels as Group 4; Group 4 had significantly lower urinary excretion of androsterone glucuronide (AG) than Group 3, while Group 1 excreted normal amounts. There are three possible explanations for these findings: 1) myocardial infarction occurring in men with coronary artery disease may elevate the plasma levels of E1, DHA, and DHAS and eliminate the preinfarction depression of urinary AG levels; 2) higher than average levels of E1, DHA, DHAS, and AG may favor the development of infarction in men with coronary artery disease; 3) higher than average levels of E1, DHA, DHAS, and AG may favor survival from any infarction that occurs in men with coronary artery disease. Experimental and epidemiological evidence seems to favor the third possibility.

Thirty-five patients with suspected acute myocardial infarction were studied in a randomised controlled trial to determine whether the catecholamine response to myocardial infarction was altered by administration of the beta blocker, sotalol, given within six hours of the onset of chest pain. Myocardial infarction evolved in 30 patients (15 placebo-treated, 15 sotalol-treated) and was associated with markedly increased plasma and urine noradrenaline and adrenaline levels. Intravenously administered sotalol was well tolerated and produced significant acute falls in blood pressure and heart rate. The reduction in heart rate was maintained in the sotalol group with once-daily therapy. Plasma levels of both catecholamines showed slow but very similar falls in the two groups, the decline being evident earlier for adrenaline than for noradrenaline. This was also reflected in the pattern of catecholamine excretion: significant falls in adrenaline but not noradrenaline excretion were seen on day 2 in both groups. Although mean plasma and urinary catecholamine levels tended to be higher in the sotalol group throughout the study, the differences between the sotalol and placebo groups for the changes in plasma or urinary catecholamines with time were not statistically significant. Episodes of ventricular tachycardia occurred in 68% of the patients on day 1 and 27% of patients on day 2. More patients in the sotalol group experienced episodes of ventricular tachycardia (sotalol 89% placebo 54%) but this difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between norepinephrine and stress caused by life changes was assessed using urinary norepinephrine levels and responses to a 57-item stress questionnaire interview obtained from 21 post-myocardial infarction and 27 healthy control male and female subjects. High correlations between norepinephrine and duration of present stress and duration and severity of life changes, and moderate correlations between norepinephrine and anxiety and depression were found among the post-infarction group. No significant correlations were found in the control group. Post-infarction subjects with elevated norepinephrine had significantly higher scores on duration of present stress and duration and severity of life changes than did post-infarction subjects with normal norepinephrine levels. Control subjects with normal and elevated norepinephrine did not differ significantly on any of the comparison variables. Standard risk factors failed to add significantly to the prediction of norepinephrine in either group. However, 68.3 percent of the variance in norepinephrine was accounted for by a single predictor, the duration of present stress.

A clinical study of some biological and biochemical factors was carried out on patients with acute myocardial infarction. It was shown that: (i) the plasma viscosity was highly correlated to the clinical evolution of myocardial infarction; (ii) the variations of plasma viscosity were related to changes in the connection of fibrinogen and globulin; (iii) the highest correlation was between the plasma viscosity and alpha2-globulin concentration. The monitoring of these may be useful in the clinical evaluation of myocardial infarction.

Adenylate kinase was purified in pooled urinary samples from patients with uncomplicated myocardial infarction. The purification procedure included ammonium sulfate precipitation and column chromatographic steps. It was necessary to stabilize the enzyme during purification with 2-mercaptoethanol and AMP. Polyacrylamidgelelectrophoresis in sodium dodecanyl sulfate revealed the release of 4 different isoenzymes of AK into urine from patients with myocardial infarction. The molecular weights of these isoenzymes were estimated to be 21,000; 24,000; 33,000 and 36,000, respectively.

Urinary fpA excretion and fpA in plasma were studied in patients with peripheral artery disease, aortic aneurysm, severe coronary artery disease, acute myocardial infarction and in normal controls. Mean urinary fpA was significantly higher in all groups of patients than in normal controls whose excretion was 1.9 +/- 1.2 micrograms/24 hours (mean +/- SD). We found a good correlation between urinary fpA excretion and plasma fpA (r = 0.68, p less than 0.01, n = 81). The highest levels of urinary fpA were found in 9 patients with aortic aneurysm (11.9 +/- 6.1 micrograms/24 hours). The 10 patients with acute myocardial infarction had also abnormally elevated values (4.3 +/- 1.8 micrograms/24 hours) which were only slightly higher than the levels found in another 10 patients with myocardial infarction receiving subcutaneous heparin in a dosage of 2 X 5000 IU daily (2.9 +/- 1.7 micrograms/24 hours). The 13 patients with peripheral artery disease showed an increase in urinary fpA excretion from 4.0 +/- 1.7 to 10.5 +/- 2.3 micrograms/24 hours after percutaneous angioplasty (p less than 0.001). These data demonstrate that urinary fpA excretion may represent a valid means to detect the cumulative effect of thrombin action on fibrinogen in patients with atherosclerotic vascular disease and after therapeutic intervention.

Although statistically significant, the relation between certain life changes and imminent myocardial infarction appears to be quantitatively weak. Of particular importance are events connected with employment. However, the summation of life changes has not proved to be of use in the prediction of imminent myocardial infarction. For patients with ischemic heart disease, variations in life change measures have proved to be of use in the prediction of changes in catecholamine output and in prognosis. When genetic factors are held constant, as in monozygotic twin pairs vulnerable to ischemic heart disease, more life changes in one partner may indicate a greater risk of unexpected sudden cardiac death in this partner than in the other twin. The self-rating of the severity of each experienced event has proved more useful than "standard weights" in the retrospective discrimination of myocardial infarction patients. Further clinical and epidemiological studies are needed in this field. For the future, the following recommendations are made: The studies should be prospective. The individual's habitual level and actual level of the change should be recorded. The severity of events should be self-rated. Risk variables, known to be of importance to the development of MI should be recorded. They are for instance smoking habits, blood pressure, serum lipids and genetic predisposition. Psychological variables should be mentioned separately in this connection.

The concentration of vanyl-mandelic acid is analysed in the urine collected within 24 hours from normal subjects, from those with painful ischemic cardiopathy, infarction and post-infarction sequelae. Statistically significant results have been obtained only in infarction patients. The study of the concentration of vanyl-mandelic acid by age decades points to the increase of average values throughout life.

ADP-induced and whole blood platelet adhesiveness have been studied by repeated measurements during the acute stage of the disease and the following two months in 86 randomly selected patients admitted to a coronary care unit because of acute central chest pain. In the patients who developed ECG and enzyme changes typical of infarction (group 1), platelet adhesiveness was significantly increased on admission compared with the rest of the patients (group 2) and controls (group 3). Patients in groups 1 and 2 showed a secondary increase during the first week, but two months after admission the means had returned to values within the normal range. No correlation was found between platelet adhesiveness and infarction size or fatal outcome of the disease. Platelet adhesiveness did not differ between patients with ECG changes indicating a transmural infarct and those with mainly subendocardial infarction.

Urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), noradrenaline, adrenaline and vanillylmandelic acid (VMA) was studied in 30 patients with acute myocardial infarction. The excretion of MHPG was higher in patients with myocardial infarction than in the control group, with no difference between uncomplicated and complicated courses of the disease. The excretion of MHPG showed a negative although not significant correlation with noradrenaline and VMA during the first days of infarction and a statistically significant positive correlation on the 5th day of the disease. The possible causes of the changes observed are discussed.

In 17 hospitalized patients affected by acute myocardial infarction (AMI) PGE2 urinary excretion, renal function and, furthermore, cortisol urinary excretion were tested during a 21 days trial. In 12 patients all the parameters under consideration underwent a similar trend: PGE2 urinary excretion exactly like glomerular filtration rate, Na+ excretion and diuresis tended to be reduced during the first 5 days and they rapidly recovered the normality after this period. Cortisol urinary excretion displayed a characteristic pattern: i.e. the highest values were observed in the first days, followed by a progressive decrease towards physiological levels since the 4th day. Different findings were obtained in 5 cases treated with an antiinflammatory drug (Indoprophen i.m. 200 mg x2 die). In fact the low levels of urinary PGE2 on the first days did not display any increasing and GFR, urinary flow, and Na+ tubular balance underwent irregular and not significant variations. These data suggest that an impaired Prostaglandin synthesis may be related to a compromised renal function often occurring in AMI.

Urinary concentrations of nicotine and its major metabolite cotinine were measured in volunteers whose smoking habits were known to test the reliability of the measurements as indicators of current smoking. In the non-smokers detectable concentrations were always below the confidence limits set for the method, while in smokers the concentrations were always above these limits. After subjects stopped smoking cotinine appeared in the urine for longer than nicotine and was still detectable at least 36 hours after the last cigarette had been smoked. When this method was used to verify the smoking histories given by patients attending an infarction clinic it was estimated that 46-53% of previous smokers had actually stopped smoking compared with the 63% who said that they had done so. It is suggested that simultaneous assays of urinary nicotine and cotinine may be a useful means of verifying patients' current smoking habits.

Quantitation of 2,3-dinor-thromboxane B2 (2,3-dinor-TxB2) was performed by gas chromatography-mass spectrometry. Under normal conditions the urinary excretion of 2,3-dinor-TxB2 was relatively constant in the same individual from day to day but during a 24-hour period a somewhat higher excretion rate was found during the first few hours after awakening. A pronounced reduction of the urinary excretion of 2,3-dinor-TxB2 was found after oral administration of 500 mg of aspirin or 50 mg of indomethacin, while 500 mg of paracetamol did not affect the urinary excretion. Increased excretion of 2,3-dinor-TxB2 was found in normal pregnancies and in diseases such as diabetes mellitus and homocysteinuria in comparison to the urinary excretion in normal healthy subjects. We also report one case, where the urinary excretion of 2,3-dinor-TxB2 was increased for a short period following the first symptoms of a myocardial infarction and those data indicate that thromboxane A2 (TxA2) may be of pathophysiological importance in human myocardial infarction. The results strongly indicate that measurements of the urinary excretion of 2,3-dinor-TxB2 should be meaningful as a tool for investigation of the involvement of thromboxane in various pathophysiological processes in vivo in man.

The in vivo production of prostacyclin and thromboxane was monitored by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in ten patients with acute myocardial infarction, five on standard treatment and five receiving prostacyclin infusion. During acute myocardial infarction excretion of 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, measured by a gas chromatography-mass spectrometry method with deuterated internal standards, was significantly increased. This indicates that thromboxane and prostacyclin synthesis are increased during the development of acute myocardial infarction. The excretion data for 2,3-dinor-thromboxane B2 showed that after administration of aspirin there was less pronounced and more variable inhibition than expected. Prostacyclin infusion did not markedly affect the excretion of the thromboxane metabolite.

A solid-phase immunoassay was developed for quantitative estimation of myoglobin in human biological fluids. This technique was used for analyses of blood serum and plasma from patients with acute myocardium infarction. The method developed was similar to radioimmunoassay by its diagnostic characteristics but more simple and available. The immunoassay might be used in diagnosis of myocardium infarction as well as in estimation of the disease severity at least in clinics.

In chronic cardiac failure, various neurohumoral mechanisms are activated to sustain blood volume, blood pressure, and organ perfusion. Using the coronary artery ligation model of heart failure in the rat, we have measured changes in vasoactive hormone secretion and related these changes to salt and water status during a 1-month period. When compared with controls, rats with infarction had a marked rise in plasma atrial natriuretic peptide (294 +/- 59 vs. 79 +/- 10 pg/ml, p less than 0.001) although there was no increase in total exchangeable body sodium. Plasma renin activity and plasma aldosterone concentrations were the same for both rats with infarction and controls. Similarly, there were no significant differences in plasma arginine vasopressin, plasma osmolality, or plasma sodium concentration in rats with infarction. Ventricular norepinephrine levels were reduced in animals with infarction (p less than 0.01). Plasma atrial natriuretic peptide levels were raised in this model of chronic left ventricular failure. However, there was no salt retention and little stimulation of the renin-angiotensin-aldosterone system or vasopressin. The results suggest that high circulating atrial natriuretic peptide levels may prevent or limit salt and water retention, either directly or indirectly, by inhibiting the renin-angiotensin-aldosterone system.

Using a specific quantitative method based on gas chromatography-mass spectrometry the urinary excretion of 2,3-dinor-TxB2 was measured in five patients with acute myocardial infarction shortly after the onset of symptoms. The urinary excretion of 2,3-dinor-TxB2 was markedly higher than seen in normals in three of the five patients. This increased excretion of 2,3-dinor-TxB2 during and after the development of myocardial necrosis indicates an involvement of thromboxane A2 in the pathogenesis of at least some cases of acute myocardial infarction.

Immunoreactive thromboxane B2 (i-TXB2) was measured by radio-immunoassay (RIA) in urines collected over eight hours on the day of admission in 25 patients who were admitted with the diagnosis of myocardial infarction. In 16 of the patients myocardial infarction was confirmed by ECG and plasma enzymes. Another patient presented with pulmonary embolism and the remaining eight patients had angina pectoris. A further eight hour urine collection was obtained 24 hours later from eleven of the sixteen patients with myocardial infarction. In these eleven patients myocardial infarction was associated with five fold higher urine i-TXB2 (2.72 +/- 0.48 ng/ml) at the day of admission when compared to patients admitted under the same diagnosis but found to have angina only (0.51 +/- 0.08 ng/ml, p less than 0.001). In patients with myocardial infarction the urine i-TXB2 values were reduced 24 hours later (1.58 +/- 0.27 ng/ml, p less than 0.01). One patient was followed with urine i-TXB2 from three days prior to diagnosis of myocardial infarction and to one day prior to a second infarction. In this patient i-TXB2 was highest three days prior to infarction. We conclude that this early elevation of urine i-TXB2 three days prior to diagnosis of infarction and the increased i-TXB2 in patients with myocardial infarction when compared to patients with angina suggest thromboxane is probably released from activated platelets prior to infarction. We suggest that urine i-TXB2 may be of value in the differential diagnosis between myocardial infarction and angina.

The effect of acute physical exercise and a four-month conditioning program on cardiovascular risk factors was investigated in patients with myocardial infarction. The bicycle exercise testing caused a moderate rise in urinary epinephrine, serum cholesterol and HDL cholesterol levels. The changes in platelet aggregation and urinary catecholamines were markedly greater in the group with exercise induced ischaemic changes. Under the effect of the conditioning program a significant improvement in the performance capacity and circulatory response could be observed. The direction of changes in platelet aggregation and in the lipid parameters were favourable too.

Kinin has been hypothesized to be involved in the mechanism of the procordialgia, collapse, and shock in myocardial infarction. In spontaneous and experimental animal infarction, the long-lasting lowering of plasma kininogen is perhaps the expression of kinin release from the plasma precursor. More recently, a durable reduction of plasma prekallikrein and of the plasma inhibitor of kallikrein, both evaluated with the kaolin contact method, has been demonstrated to support the implication of the kinin system in the course of myocardial infarction. In the present study, the dialy urinary excretion of kallikrein, according to the Porcelli and Croxatto method, has been studied in a group of patients with acute myocardial infarction and in a group of control patients, Differences between the two groups have been observed. They consist mainly in strong daily oscillations in the amount of urinary kallikrein excretion during the 24 hour period in the group of patients with myocardial infaction. At this moment, however, it is not possible to give a definite interpretation of these results.

Several studies conducted by the authors' group have shown that urinary steroid measurements are a valuable aid in differentiating the normal aging process, the pronounced aging associated with increased risk to coronary heart disease, and the deviations associated with myocardial infarction. Data are presented on 428 men in the age range of 30-70 years. The study design most effective in elucidating aging and disease patterns involves selection of subjects from a wide age range. Data on persons identified as clinically normal can be used to describe physiologic aging. Once this is determined, data on persons with disease can be used to identify abnormalities of aging associated with the clinical conditions studied. This approach offers a potential method for differentiating between aging effects and disease effects. The foregoing findings led to the development of an Index of Aging in males, based on combined serum lipid and urinary steroid values. This Index may be a means of differentiating between normal aging and the deviations seen in atherosclerosis and myocardial infarction. Current studies are directed toward extending these observations.