Verapamil versus propranolol for angina at rest

We previously showed that verapamil is highly effective in the treatment of patients with angina at rest, in whom coronary vasospasm likely represents the primary underlying pathophysiologic mechanism. Beta-adrenergic blocking drugs, on the other hand, do not exert any vasodilating effect on large coronary arteries, and hence do not represent a rational therapeutic approach to the treatment of patients with this syndrome.The present report reviews the results of three clinical trials comparing the effectiveness of verapamil and propranolol in patients with angina at rest. In 17 patients enrolled in a randomized triplecrossover study, verapamil was superior to propranolol in preventing ergonovine-induced coronary artery spasm (p < 0.001). In 18 patients with rest angina evaluated in a double-blind crossover study, both verapamil and propranolol reduced the number of episodes of angina at rest (from 3.0/day to 1.7/day with propranolol, p < 0.05, and to 0.2/day with verapamil, p < 0.001); the degree of improvement with verapamil was superior to that seen with propranolol (p < 0.005). In 10 patients with rest angina evaluated in a single-blind multiple crossover trial which assessed symptomatic and asymptomatic ischemia, the number of ischemic events was reduced significantly only by verapamil (5 ± 1 episodes/48 hours) but not by placebo or propranolol (25 ± 3 and 23 ± 3 episodes/48 hours, respectively).These studies confirm the effectiveness of verapamil in the management of patients with angina at rest; in contrast, the effectiveness of propranolol in this syndrome appears comparable to that of placebo.     

Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate. A double crossover study in a coronary care unit.

Twelve patients were studied who had frequent transient ischemic episodes at rest with a variable degree of coronary atherosclerosis and vasospastic origin of angina as evidenced by good exercise tolerance and results of thallium-201 scintigraphy during angina at rest, ergonovine maleate provocative test and coronary angiography. With the aim of keeping a constant blood drug level, the trial consisted of a continuous intravenous infusion of isosorbide dinitrate (1.25 to 5.0 mg/hour) during two periods (T₁ and T₂) of 24 hours (four patients) or 12 hours (eight patients) alternating with two equal periods (P₁ and P₂) of infusion of saline solution with a double crossover design (T₁, P₁, T₂ and P₂).Continuous electrocardiographic monitoring revealed that the total number of transient ischemic attacks at rest characterized by S-T segment elevation (four patients), S-T depression (two patients) and either S-T depression or elevation (six patients), with or without pain, was 100, 104 and 91, respectively, during the introductory control period and during P₁ and P₂, but was reduced to 13 and 20, respectively, during periods T₁ and T₂ (P = 0.002). Transient ischemic attacks at rest were completely prevented during both T₁ and T₂ in four patients and during T₁ or T₂ in three patients, and were not abolished but significantly reduced in T₁ and T₂ in the other five patients. The reduction in ischemic attacks was similar for episodes characterized by S-T segment elevation or depression and with or without pain. Side effects were negligible. Therefore, infusion of isosorbide dinitrate appears to be a very effective treatment for patients with vasospastic angina at rest.     

“Variant” angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia: Pathogenetic Mechanisms, Estimated Incidence and Clinical and Coronary Arteriographic Findings in 138 Patients

From January 1970 to December 1977, transient reversible episodes of S-T segment elevation were documented in 138 patients (80 with angina only at rest, 58 with angina both on exertion and at rest). Electrocardiographic monitoring in 33 patients with hemodynamic monitoring revealed that (1) during 6,009 transient episodes of myocardial ischemia, pain was always a late phenomenon and, in some patients, often did not occur; (2) during such transient episodes, ST-T wave behavior was often variable in the same patient with alternation of elevation, depression or only T wave changes with or without pain; (3) independent of the direction of the S-T segment and T wave changes, the episodes were never preceded by an increase of the hemodynamic determinants of myocardial demand but were associated with obvious impairment of left ventricular function. Thallium scintigraphy in 32 patients revealed a regional massive and localized reduction of myocardial perfusion during S-T segment elevation and pseudonormalization of T waves. During S-T segment depression the reduction of thallium uptake was diffuse with fuzzy limits. Coronary angiography revealed no significant stenosis in 8 patients and single, double and triple vessel disease in 38, 34 and 26 patients, respectively. Angiography in all 37 patients studied during angina revealed a severe coronary vasospasm involving vessels with extremely variable extent of atherosclerosis. Severe arrhythmias were recorded in 27 patients, and a myocardial infarction occurred in 28. A total of five patients died within 1 month of hospital admission. Thus, variable intensity and extension of coronary vasospasm and the presence of collateral vessels may result in different degrees of ischemia and various electrocardiographic patterns with or without anginal pain. Vasospastic angina can occur in the presence of extremely variable degrees of coronary atherosclerosis and in any phase of ischemie heart disease. It may evolve into acute myocardial infarction and sudden death: Variant angina appears to be only its most striking electrocardiographic manifestation. When vasospastic angina is appropriately searched for, its incidence rate appears to be high.     

Significance of spasm in the pathogenesis of ischemic heart disease.

The role of coronary arterial vasospasm in the pathogenesis of ischemic heart disease is reviewed on the basis of investigations carried out in our laboratory. Patients were selected because they had angina either at rest or both at rest and during exercise. With continuous hemodynamic and electrocardiographic monitoring of these patients, as well as thallium-201 scintigraphy and coronary arteriography during ischemic episodes, we were able to demonstrate a vasospastic origin for the attacks. During anginal episodes, electrocardiographic changes were variable, with S-T segment elevation, S-T segment depression, a rise in T wave potential and pseudonormalization of inverted T waves corresponding to various distributions of myocardial ischemia in different patients and even in the same patient at different times. Increases in hemodynamic variables that control myocardial oxygen consumption never preceded the onset of ischemic episodes, which challenges the theory that the limitation of a possible increase in flow caused by critical organic stenosis is the only cause of myocardial ischemia. In some patients in whom myocardial infarction developed, the lesion was always found in the same area in which the vasospastic phenomena had been seen angiographically. Vasospasm led to serious arrhythmias in some patients. We therefore believe that independent of atherosclerosis or superimposed on it, vasospasm plays an important role in producing myocardial ischemia—angina, myocardial infarction and possibly sudden death. Elucidation of its mechanisms will lead to more appropriate therapy.     

Long-term prognosis of “variant” angina with medical treatment

One hundred thirty-eight patients with “variant angina” were followed up for periods of 2 to 8 years. All patients had a history of angina at rest, and 42 percent also had exertional angina. Normal coronary arteries were found in 9 of the 107 patients who underwent coronary arteriography; the remainder had stenosis greater than 50 percent in diameter of at least one major vessel. Coronary vasospasm was demonstrated in all 37 patients studied with coronary arteriography during angina at rest. Twenty-eight patients had acute myocardial infarction and five patients died within 1 month of admission to hospital. Of the 133 surviving patients, 120 were treated medically and 13 underwent coronary arterial surgery. In the medically treated group, only seven patients died and only four had acute myocardial infarction during the remainder of the follow-up period. Symptoms became less frequent and less severe; approximately 50 percent of the patients remained completely asymptomatic for at least 12 months by the end of the 4th year. Death, acute myocardial infarction and persistence of symptoms were more frequent in those patients with more severe coronary atherosclerotic disease although, even in this group, the overall incidence of death and acute myocardial infarction was small. It is concluded that the prognosis of patients with “variant” angina receiving appropriate medical therapy is reasonably good after the acute phase, even in the presence of severe coronary atherosclerosis.     

Pathophysiologic studies of the pulmonary and coronary circulations in man

Studies of the pulmonary circulation in normal man, performed with external radiation detectors, have shown that pulmonary blood volume is about 10 percent of total blood volume. Pulmonary blood volume was unchanged in patients with acute or chronic left atria I hypertension and in normal persons during expansion of total blood volume in spite of marked increases in pulmonary vascular pressures. However, pulmonary blood volume was greatly increased in patients with polycythemia rubra vera and a large total blood volume and in patients with a left to right shunt but normal pulmonary intravascular pressure.Studies of regional myocardial perfusion with injection of xenon-133 solution into the left coronary artery revealed localized areas of ischemia distal to stenotic lesions even when the patient was at rest. During angina produced by pacing, more severe ischemia occurred, thus suggesting that functional factors reduce local perfusion below resting levels.In patients with “variant” angina, intravenous injection of thallium-201 chloride during spontaneous attacks has revealed large cold areas in myocardial scintigrams not present under control conditions, thus suggesting severe transmural reduction of perfusion in heart muscle corresponding to S-T segment elevation in the electrocardiogram.     

The response to intravenous glucose of patients on maintenance hemodialysis: Effects of dialysis

To learn whether a single dialysis can acutely improve the intravenous glucose tolerance (i.v.GTT) of chronically dialyzed patients, a standard i.v.GTT was performed on 10 nonobese uremic subjects on maintenance hemodialysis for 27 ± 9 (mean ± SEM) mo, and on a control group of 13 normal subjects. The uremic patients were tested first 0.2–17 (range) hr, and then 65–109 hr, from last dialysis. In the uremic sera, plasma glucose was analyzed by 4 methods; 2 reducing (neocuproine and ferricyanide) and 2 enzymatic (hexokinase and glucose oxidase). The reducing methods markedly overestimated plasma glucose concentration because of the presence of nonglucose, reducing substances (notably, creatinine). This interference was significantly cut down by dialysis. A single dialysis, on the other hand, failed to improve the glucose fractional decay rate (KG) computed from the glucose oxidase data (1.69 ± 0.2%/min before and 1.35 ± 0.1 after dialysis, versus 1.47 ± 0.1 of the normal subjects). The same conclusion was derived from the data measured by the other 3 methods of glucose assay. Fasting plasma insulin concentrations were, on average, above normal (5.5 ± 0.6 μU/ml) both before (12.3 ± 2.7, p < 0.05) and after (17.2 ± 3.5, p < 0.01) a single dialysis. Likewise, the area under the glucose-induced plasma insulin curve was significantly greater than normal (1.46 ± 0.21 mU/ml·min) both before (2.26 ± 0.34, p < 0.05), and after (2.86 ± 0.43, p < 0.01) dialysis. A single dialysis had little effect on either basal or glucose-stimulated insulin release, and no significant difference in the insulinogenic index (insulin area/glucose area) was found between the control and the uremic group in either test. Insulin response was not correlated with KG, whereas it was significantly associated with higher triglyceride levels. Creatinine, urea or methylguanidine did not appear to have any influence on KG, but lower serum potassium levels were significantly associated with poorer i.v.GTT's. Plasma calcium bore a reciprocal relation to the insulinogenic index. Chronically dialyzed subjects show some degree of tissue insulin resistance, which a single dialysis fails to correct. Electrolyte disturbances may play a role in this metabolic derangement.     

Effects of dilazep on coronary and systemic hemodynamics in humans

The cardiovascular effects of dilazep, a new antianginal drug, were investigated in 18 patients, who underwent cardiac catheterization and coronary angiography for the evaluation of chest pain. Dilazep, 0.2 mg/kg, was injected intravenously over 1 to 2 minutes. The changes induced by dilazep in coronary tone were assessed by quantitative angiography in four patients, changes in systemic and coronary hemodynamics and blood gases in eight patients, and changes in systemic and pulmonary hemodynamics and blood gases in six. In 6 of the 18 patients the effects on hemoglobin-O2 oxygen binding were also investigated. Following dilazep administration, we observed a marked reduction of coronary resistance (six patients) (0.5 vs 1.0 mm Hg X min X ml-1, p less than 0.01) and of aortic-coronary sinus oxygen difference (seven patients) (4.6 vs 12.3 vol%, p less than 0.01), and a 23% increase in coronary diameter (four patients) (p less than 0.001). Total systemic resistance was also reduced by dilazep (six patients). Conversely, only minimal or insignificant changes were observed in heart rate (14 patients), aortic pressure (14 patients), total pulmonary resistance (six patients), myocardial oxygen consumption (six patients), double product (14 patients), blood gases (seven patients), and hemoglobin-oxygen affinity (six patients). We conclude that dilazep exerts a powerful dilating action on coronary vasculature without appreciable increase of myocardial oxygen consumption and cardiac work simultaneously with a reduction of peripheral resistance.     

Impaired insulin degradation in a patient with insulin resistance and acanthosis nigricans

The kinetics of plasma insulin were studied in a 14 year old girl with the syndrome of insulin resistance and acanthosis nigricans. The clearance of plasma insulin was found to be strikingly reduced (135 ml/min·m² versus 456 ± 22 in 17 normal control subjects), whereas the basal systemic insulin delivery rate was increased about 10-fold (25.5 mU/mim·m² versus 2.6 ± 0.3 in normal subjects). Thus, reduced insulin clearance and excessive posthepatic delivery of the hormone both contributed to the severe fasting hyperinsulinemia (218 μU/ml) associated with the other clinical features of the syndrome (glucose intolerance, primary amenorrhea, polycystic ovaries, hirsutism). Following ovarian wedge resection, insulin clearance rose to 264 ml/min·m², and insulin delivery fell to 9.8 mU/ min·m². The resulting abatement of the patient's hyperinsulinism (fasting plasma insulin = 37 μU/ml) was accompanied by the appearance of menses, normalization of glucose tolerance, and amelioration of the acanthosis. The improvement in menstrual function and acanthosis, however, was not sustained. This case provides evidence for interdependence of insulin action and insulin degradation in humans.     

Uric acid metabolism in normal subjects and in gouty patients by chromatographic measurement of 14C-uric acid in plasma and urine.

The turnover kinetics of uric acid were determined in a group of 25 subjects, including 6 controls, 17 gouty patients, and 2 subjects with asymptomatic hyperuricemia. According to their daily urate excretion while on a purine-free diet, the gouty patients (none of whom had evidence of tophi at the time of the study) were classified as follows: five overexcretor patients (“metabolic” gout), six normo-excretor patients (“renal” gout), and six borderline patients. Uric acid-2-¹⁴C was used as the tracer, and the uric acid radioactivity in plasma and urine samples was measured after column chromatography through a polyacrylamide gel that specifically adsorbs uric acid. The experimental data of plasma disappearance curves and urine radioactivities of ¹⁴C-uric acid (followed up to 3 days after injection) were analyzed by the noncompartmental approach and by the urine/plasma ratio method, in order to calculate the total removal rate of uric acid, its distribution volumes, and the removal rate of uric acid through the renal route. The monocompartmental approach and the urine specific radioactivity methods were also employed to compute the uric acid turnover data, and the results were compared with those of noncompartmental analysis. The overexcretor patients were found to have normal metabolic clearance rate and fractional catabolic rate values, but significantly higher-than-normal total turnover rate values (p < 0.005), whereas the normo-excretors had normal total turnover rate values but significantly lower metabolic clearance rate and fractional catabolic rate values compared to the controls (p < 0.001). Uric acid excretion through the kidneys was found to be about two-thirds of the total removal both in the control subjects and in the gouty patients. The results obtained allowed the exclusion of any significant delay in the excretion of uric acid through the kidneys. The use of monocompartmental analysis led to a significant overestimation of both the total turnover rate (p < 0.005) and the total pool of uric acid (p < 0.001), and the urine specific radioactivity approach implied a significant overestimation of the total turnover rate (p < 0.001). The gouty patients as a whole had a significantly larger-than-normal (p < 0.001) total pool of uric acid, however determined. On the basis of the results obtained, a metabolic differentiation was made possible for the two pathophysiologic types of gout. In fact, the metabolic gout patients were all characterized by normal metabolic clearance rate values and increased total pool values, whereas the renal gout patients were all characterized by reduced metabolic clearance rate values and increased total pool values.     

Sudden coronary death. A postmortem study in 208 selected cases compared to 97 "control" subjects.

Two hundred eight witnessed subjects dying suddenly (SD) (151 in 10 minutes, 47 in one hour, and 10 in three hours) and 97 dying by accident (AD) were studied. All these subjects had no clinical history of CHD. They were at the time of death in their normal, usual activity, and not under medical care. No therapy before and resuscitation attempts after death were done. The unique postmortem findings were coronary atherosclerosis, and/or myocardial necrosis or fibrosis. Coronary stenosis was absent or insignificant (< 50 per cent) in 28, median in 23, and severe (≥ 70 per cent) in 157 (53 monovessel, 60 double vessel, 44 triple vessel or more) SD cases. In AD the figures were 28, 31, 38 (26, nine, and three), respectively. Thirty-two (15.3 per cent) SD subjects showed an acute occlusive thrombus located in a severe, long, concentric stenosis. An infarct was demonstrable in 35 SD cases (11 plus occlusive thrombus). A necrosis resembling that induced by catecholamines was the unique acute myocardial lesion found in 149 SD subjects (72 per cent). This lesion was also present in 29 out of 35 subjects with an infarct (total 178 = 85.5 per cent), in 22 out of 28 SD cases with insignificant coronary damage, and in 19 AD cases. One hundred two SD cases with prodroma had a significant lower frequency of thrombi and a higher frequency of stenosis ≥ 90 per cent, triple vessel involvement, myocardial fibrosis, and pathologic heart weight (≥ 500 gm.). These data suggest that: (1) there is no proof that SD is due to a morphologic occlusive cause, the thrombus being likely to be an ineffective event secondary to regional increased peripheral resistance in the presence of functioning collaterals; (2) there is no linear cause-effect relation between the degree of coronary damage and SD; (3) a primitive sympathetic disorder may be responsible for ventricular fibrillation, myocardial necrosis/fibrosis, and cardiac hypertrophy—SD being not necessarily synonymous with infarct.     

Labeled metabolites appearing in human serum after 125I-triiodothyronine (T3) administration: A quantitative reappraisal

The appearance in human serum of labeled iodothyronines arising from 3,5,3′-triiodothyronine (T₃) catabolism was measured after bolus administration of ¹²⁵I-T₃. The use of column chromatography made it possible to separate in the plasma samples iodoproteins, iodide, T₃ and a fourth peak (“pre-T₃”) eluting just before T₃. The radioactivity associated with this pre-T₃ peak was found to be 0.5% of T₃ activity 30 min after injection, and reached a plateau value of 5.6% ± 1.2 (mean ± SD) from the 10th hr onward. From these data, we calculated that a maximal 5% underestimation in T₃ metabolic clearance rate is inherent in those analytical methods that do not completely separate pre-T₃ from T₃ radioactivity. The MCR of 3,3′-diiodothyronine (T₂) was also measured from the plasma disappearance curve after single injection of ¹²⁵I-3,3′-T₂. From these data and the mean disappearance curve of T₃, the appearance curve of 3,3′-T₂ in plasma was reconstructed by convolution under the assumption of a 100% conversion of T₃ to 3,3′-T₂. A plateau value of 4.6% of T₃ activity was computed, very comparable to the experimentally determined 5.6%. This suggest that, if labeled 3,3′-T₂ is the main component of the pre-T₃ peak, the conversion into 3,3′-T₂ represents a major pathway of T₃ metabolism in man.     

Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected unstable angina patients

Asymptomatic episodes of ST segment and/or T wave changes are often reported during Holter monitoring in patients with angina pectoris. However, the interpretation of such changes is debated relative to silent myocardial ischemia. We studied 11 patients admitted to the CCU because of frequent episodes of unstable anginal attacks who had undergone repeated periods of Holter monitoring, characterized by predominantly occurring asymptomatic episodes of ST segment and/or T wave changes associated with less frequent typical anginal attacks. In a total of 89 days of Holter monitoring, the patients evidenced 520 episodes of transient ECG changes including 180 of ST elevation, 73 of ST depression, and 267 of T wave alterations. Only 12% of episodes were symptomatic. Coronary injection during asymptomatic ST-T changes was performed in eight patients. In six it was possible to document spontaneous coronary spasm. In seven patients ergonovine administration induced anginal pain, ST-T changes, and coronary spasm. In all patients the anginal attacks completely disappeared with medical treatment and the asymptomatic episodes were abolished in six and reduced in four. Our findings support the hypothesis that in certain selected unstable anginal patients, transient asymptomatic ECG changes are caused by acute myocardial ischemia.     

Factors affecting regional pulmonary blood flow in left heart valvular disease

The base to apex distribution of blood flow per unit of lung volume was assessed by pulmonary scintigraphy in 99 patients with rheumatic heart disease. The prevalent valvular lesion was mitral stenosis in 56, mitral regurgitation in 14, aortic stenosis in 11 and aortic insufficiency in 18. Each patient underwent hemodynamic assessment by cardiac catheterization within a few days of scintigraphic study. Some hemodynamic parameters were then correlated with the ratio between upper and lower third of lung scan (U:L ratio) taken as a numerical index of the base to apex distribution of lung blood flow.The U:L ratio had a positive correlation coefficient with the mean pulmonary wedge pressure (MPWP) but the dispersion of individual data was wide. Dividing the patients into groups according to the level of MPWP and to the location of U:L ratio either above or below the regression line, variance analysis showed that a highly significant part of this dispersion can be accounted for by pulmonary vascular resistance (PVR). The same conclusion was reached using different statistical approaches. These findings suggest that inversion of pulmonary blood flow is not only associated with elevation of MPWP and increase of vascular resistance in the dependent lung zones but also with a rise in the general PVR. Furthermore, the cardiothoracic ratio, as index of the heart size relative to the chest cage and, therefore, of the parenchymal compression in the lower lung zones, also proved statistically and at the individual level responsible at least in part for this dispersion.Considering these multiple influences on the regional distribution of lung blood flow in these cardiac patients, a very close correlation between U:L ratio and MPWP is not to be expected. Consequently, an estimate of MPWP from U:L ratio is open to great uncertainties. Furthermore, our data show that, at the same level of MPWP, U:L ratio is higher when PVR is higher. This observation means that PVR increases and pulmonary perfusion inversion develops to some extent independently from the actual value of MPWP. We then suggest that water filtration in the lung interstitium may be ruled out as a factor responsible per se for these changes and can only be retained as a mechanism initiating them. We postulate that functional and pathologic changes in the lung vessels and interstitium may develop on the basis of a different individual response to a given stimulus.     

Triiodothyronine turnover studies in euthyroid patients with autonomous thyroid nodules

Triiodothyronine (T₃) kinetic studies were carried out using ¹²⁵I-T₃ and the single injection technique in eight clinically euthyroid patients with autonomous thyroid nodules and the metabolic results were compared to those obtained in a group of 12 healthy control subjects. Plasma labeled T₃ concentration was measured by a chromatographic method based on the extraction of the hormone on Sephadex G-25 columns, followed by its elution with a specific anti-T₃ antiserum. The analysis of the experimental plasma disappearance curves of the labeled hormone was performed using the noncompartmental method. The results obtained showed a significantly increased metabolic clearance rate of T₃ in the patients with autonomous thyroid nodules, as compared to the control group. On the average, the T₃ production rates were increased more significantly than the corresponding circulating levels of the hormone, therefore, suggesting that the significant TSH inhibition observed in the euthyroid patients with autonomous thyroid nodules could be related with an increased peripheral utilization of triiodothyronine.     

Transient changes in left ventricular mechanics during attacks of Prinzmetal's angina: an M-mode echocardiographic study

M-mode echocardiograms were recorded in 12 patients with Prinzmetal's angina during 29 episodes of transient myocardial ischemia at rest (18 spontaneous and 11 ergonovine-induced). At peak ST segment elevation a regional mechanical impairment was observed in the interventricular septum during 23 episodes of angina and in the posterior wall during six episodes. In the 18 spontaneous episodes the left ventricular ischemic wall, when compared to the basal state, was found to have a significant reduction in motion (-76.3 +/- 9.1%) (mean +/- SEM), in diastolic thickness (-11.7 +/- 2.5%), and in percent systolic thickening (-88.0 +/- 5.6%). Increase in left ventricular end-diastolic diameter (+13.1 +/- 2.1%) and decrease in percent fractional shortening (-38.1 +/- 3.7%) were also observed. When ST segment was back to the isoelectric line, a transient overshoot in regional left ventricular function was observed. In induced episodes statistically significant changes could be detected by M-mode echocardiography even before appearance of ST segment elevation and anginal pain. No significant difference was found in type or degree of mechanical impairment between induced and spontaneous episodes. Therefore, in patients with Prinzmetal's angina: (1) M-mode echocardiography allows detection of mechanical changes due to transient myocardial ischemia; and (2) mechanical impairment occurs earlier than clinical (pain) and electrocardiographic (ST segment elevation) signs of transmural ischemia.     

Effect of captopril on renal function in patients with essential hypertension

The glomerular filtration rate (creatinine clearance), glomerular permeability (qualitative and quantitative proteinuria), tubular reabsorption (k-λ chains of immunoglobulins and lysozyme) and indexes of tubular cell lysis (alpha-glucosidase and gamma-glutamyltranspeptidase) were measured in the urine of 10 patients with moderate, uncomplicated essential hypertension during placebo therapy and after captopril given at increasing doses of 25, 50, 100 and 200 mg twice daily, the first three doses being given for 3 days and the last one for 4 weeks in all patients and for an additional 6 months in 5 patients. During placebo therapy, proteinuria was absent in eight patients and detectable (glomerular and selective) in two; selective proteinuria appeared in two and a decrease in selectivity was observed in two patients with previous proteinuria after 4 weeks of captopril therapy. No proteinuria was detectable in the five patients followed up for 6 months, not even in the one in whom a decrease in glomerular selectivity had occurred after 4 weeks. The glomerular filtration rate was unchanged as were lysozyme and gamma-glutamyltranspeptidase values, while light chains were always undetectable. Alpha-glucosidase showed some increase; however, increments were transient and always much lower than those observed with known tubular toxic drugs. These data show that under our experimental conditions captopril caused no evident changes in glomerular and tubular function.     

Different types of myocardial necrosis in coronary heart disease: A pathophysiologic review of their functional significance

The different histologic types of myocardial necrosis have been investigated in 100 acute cardiac infarction, in 200 sudden coronary deaths, and in 100 control cases. The incidence as well as the frequent association of three different morphologic patterns of myocardial necrosis suggest that various pathogenetic mechanisms with different biochemical derangements may interact in the natural history of the coronary heart disease.     

A kinetic analysis of plasma insulin disappearance and glucose-induced insulin delivery rate in diabetic and nondiabetic acromegalics.

Derangements of insulin metabolism may have a role in the pathophysiology of diabetes in acromegaly. To investigate this point, we employed a technique that allows the measurement of the degradation rate, the distribution volumes of the hormone, and the posthepatic insulin delivery rate both in the fasting state and after intravenous (i.v.) glucose. ¹²⁵I-insulin was injected i.v. as a single bolus and the plasma disappearance curve of the immunoprecipitable radioactivity was sampled for 120 min. Immediately afterwards, an i.v. glucose tolerance test (GTT) was performed and both glucose and IRI levels were measured from samples taken for 90 min. By noncompartmental analysis of the plasma ¹²⁵I-insulin curves were computed: (1) the initial distribution volume of insulin (IDV); (2) metabolic clearance rate (MCR); (3) basal posthepatic delivery rate (IDR); and (4) total plasma equivalent distribution volume (TDV). By deconvolution analysis of glucose-induced immunoreactive insulin (IRI) curve and plasma disappearance curve of tracer insulin, the posthepatic secretion curve of the hormone was reconstructed. Nine acromegalic patients were studied; 4 had a normal glucose tolerance (NA), and 5 were diabetic (DA). Seven normals (N) were taken as a control group. In the acromegalics the IDV was enlarged compared to normals (2.6 ± 0.2 versus 1.8 ± 0.1 liter/sq m; p < 0.01) and MCR was also greater (564 ± 24 versus 473 ± 24 ml/min × sq m; p < 0.05). In the DA the TDV was larger than in N (17.1 ± 3.4 versus 8.4 ± 0.7 liters/sq m; p < 0.05). In both NA (4.8 ± 0.7 mU/min × sq m) and DA (8.6 ± 1.9) the IDR was greater (p < 0.01) than N (2.3 ± 0.9). Glucose-stimulated posthepatic insulin secretion showed, both in N and acromegalics, a first rapid burst secretion (Secr), which had its peak at 2–3 min and lasted for 6–10 min, and a more sustained second phase. Secr (6–90), which returned to the basal levels by the end of 90 min. In NA, Secr (0–6) was greater than in N (500 ± 93 versus 232 ± 39 mU/sq m; p < 0.05) and DA (174 ± 39; p < 0.01). Secr (6–90) was significantly greater in both NA (1707 ± 205) and DA (1752 ± 391) than N (615 ± 167 mU/sq m). When glucose-induced insulin secretion was expressed as a multiple of the basal insulin delivery the first phase of insulin secretion was superimposable in N and NA (17.7 ± 2.7 versus 17.8 ± 3.9) while it was reduced in DA (3.5 ± 0.8; p < 0.01). The second phase was not significantly different in the 3 groups. All acromegalic patients showed: (1) an enlarged IDV, (2) an increased MCR, and (3) a higher secretion rate, both in the fasting state and after i.v. glucose. These alterations of insulin kinetics and secretion seem therefore to be caused by acromegaly itself. On the other hand, an enlarged TDV, a marked decrease of the early phase of insulin secretion, and an additional factor of insulin resistance independent from GH were found in DA only, therefore they are more related to diabetes than to acromegaly.     

Humoral and hemodynamic effects of increasing doses of captopril in patients with essential hypertension

To compare the hemodynamic and humoral effects of increasing doses of captopril, blood pressure, heart rate, plasma renin activity, plasma aldosterone and angiotensin-converting enzyme activity were measured in 10 patients with mild uncomplicated essential hypertension before and after captopril given in an increasing dose of 25, 50 and 100 mg twice a day, with each dose given for 3 days. The maximal decrease in blood pressure, which was predicted both by basal plasma renin activity values and by the hypotensive response to the first dose, was found after the lowest (25 mg) dose; this effect was detectable for 12 hours independently of the dose administered. Similarly, plasma renin activity was already maximally increased and plasma aldosterone maximally decreased at the lowest dose, while angiotensin-converting enzyme activity showed a dose-dependent inhibition. These data suggest that (1) neither the magnitude nor the duration of the hypotensive effect nor the resin-stimulating and aldosterone-inhibiting actions of captopril are enhanced by drug doses above 25 mg (at least up to 100 mg), and (2) there was no apparent correlation between the degree of angiotensin-converting enzyme inhibition with increasing doses of captopril and the hypotensive effects of the drug.