The treatment of low-renin ("primary") hyperaldosteronism

Sixty-four patients with low-renin (“primary”) hyperaldosteronism underwent adrenal surgery. A unilateral adrenocortical adenoma was found in 48; no tumor was identified in 14, the adrenal glands then usually showing hyperplasia of the zona glomerulosa. The adrenal lesion in two further patients was difficult to classify. There was a significant fall in systolic and diastolic blood pressure after operation in both the adenoma and hyperplasia groups, although the fall in diastolic pressure was significantly greater in the adenoma group. Blood pressure fell to an arbitrary normal level in 56 per cent of patients with adenoma and in 15 per cent of patients in the hyperplasia group.Ninety-five patients with primary hyperaldosteronism received spironolactone for a minimum period of four weeks. There was a significant fall in mean systolic and diastolic pressure during treatment in both the adenoma and hyperplasia groups. However, the fall in diastolic pressure was again significantly greater in the adenoma group. There was a significant positive correlation between the fall in blood pressure during spironolactone and following adrenal surgery.Eighteen patients also received amiloride preoperatively and again there was a significant fall in systolic and diastolic blood pressure, although levels were slightly higher than during spironolactone or after subsequent adrenal surgery. Nineteen patients received a two week course of dexamethasone, without effect on blood pressure or the electrolyte abnormalities.It is suggested that removal of the tumor-bearing gland is usually the treatment of choice for patients with an aldosterone producing adenoma, provided preoperative spironolactone has reduced blood pressure to normal or near normal. However, long-term spironolactone is an acceptable alternative. For patients in the hyperplasia group, long-term spironolactone is usually the treatment of choice. If this drug is not tolerated, amiloride may be substituted. If preoperative spironolactone does not produce a satisfactory hypotensive response, adrenal surgery is unlikely to do so and hypertension should be controlled with other conventional hypotensive drugs. All patients with primary hyperaldosteronism in whom an adrenocortical adenoma is not identified preoperatively should be screened for the rare glucocorticoid-remediable variant. Dexamethasone 1 to 2 mg. daily for two to four weeks will reverse the biochemical abnormalities and reduce blood pressure. When an adrenocortical carcinoma is suspected, prompt surgical excision is required.     

Clinical, biochemical and pathological features of low-renin ("primary") hyperaldosteronism

The clinical and biochemical findings in 136 patients with low-renin (“primary”) hyperaldosteronism are described. A pathological diagnosis was made in 82 cases and a unilateral adrenocortical adenoma was found in 62. However, a tumor was not identified in 17, the adrenal glands then usually showing hyperplasia of the zona glomerulosa, often with nodular changes. The adrenal lesion in a further three cases proved fifficult to classify.Patients with an adrenocortical adenoma were significantly younger than those in whom a tumor was not found. The female/male ratio was greater than 2:1 in the adenoma group, but no sex difference was observed in the group without tumor. Vascular complications of hypertension occurred in 23 per cent and there was histologic evidence of malignant-phase hypertension in four. It is concluded that this condition is not a benign form of hypertension.Biochemical abnormalities were more marked among patients with an adrenocortical adenoma, compared with those in whom a tumor was not found. Mean plasma concentrations of aldosterone, sodium and tCO₂, and mean exchangeable sodium were significantly higher, while plasma potassium and renin concentrations and mean exchangeable potassium were significantly lower. Although plasma aldosterone was above normal at least once in all, levels were often only intermittently raised. Hypokalemia occurred in all patients with a proved adenoma and was usually persistent. Among patients in whom a tumor was not found, hypokalemia was less severe and usually intermittent, while plasma potassium was persistently normal in three of 17 patients in this group.In addition to the aldosterone excess, plasma deoxycorticosterone was raised in 13 of 26 patients, plasma corticosterone was marginally raised in two and plasma 18-OH-DOC in four of 15. There was a significant inverse correlation between plasma renin concentration and age in the non-adenoma group but not among patients with an aldosterone-producing adenoma. Weak positive correlations were observed in the adenoma group between total exchangeable sodium and both systolic and diastolic blood pressure and between exchangeable sodium and plasma aldosterone concentrations. Such correlations were not seen in the non-tumor group. The hypertension may have a different basis in these two groups.     

Angiotensin- and norepinephrine-induced myocardial lesions: experimental and clinical studies in rabbits and man.

The ability of large doses of exogenous angiotensin II to cause widespread multifocal microscopic myocardial necrosis in the rabbit has been confirmed. Angiotensin II also consistently produced acute renal failure with, less consistently, renal tubular necrosis. Norepinephrine infusions caused histologically indistinguishable myocardial lesions, but did not detectably affect renal function or histology. Severe renal failure, induced by bilateral nephrectomy (with or without concurrent glycerol administration) was not associated with similar cardiac lesions. Acute renal failure of comparable or greater severity to that induced by angiotensin II was produced by intramuscular cephaloridine, and was not associated with cardiac lesions. Rabbits infused with saline intravenously or "sham"-operated by simply opening and closing the peritoneal cavity did not develop renal failure and showed no cardiac or renal lesions histologically. Myocardial lesions, apparently identical to those seen in the rabbits, were observed postmortem in three patients known to have had high circulating levels of angiotensin II before death, although in all three cases alternative explanations are possible. Unexplained arrhythmia, cardiac arrest, and central chest pain without clear cardiographic or serum enzyme evidence of myocardial infarction occurred in two other subjects with very high plasma levels of angiotensin II. These attacks ceased after bilateral nephrectomy and a consequent fall in plasma angiotensin II. The cardiac attacks in these five patients all occurred during or shortly after procedures, such as sodium-depleting dialysis, renal artery surgery, or diazoxide administration, known to cause increase in plasma concentrations of renin and angiotensin II.     

Captopril in the management of hypertension with renal artery stenosis: Its long-term effect as a predictor of surgical outcome

Fifteen patients with hypertension and unilateral renal artery disease were treated with captopril alone; 10 came to operation and were later assessed postoperatively with no drug treatment. Captopril caused both immediate and sustained decreases in plasma angiotensin II and aldosterone, with increases in plasma active renin and blood angiotensin I concentrations. Decrements in systolic and diastolic pressure 2 hours after the first dose of captopril were closely correlated with the initial decreases in plasma angiotensin II. Blood pressure was decreased by long-term captopril therapy irrespective of whether plasma angiotensin II was abnormally high before treatment. The long-term response of both systolic and diastolic pressure correlated well with the response to surgery. By contrast, the blood pressure decrease 2 hours after the initial dose of captopril variously underestimated and overestimated the decrease during prolonged use of the drug and did not relate to surgical outcome. In patients who, before treatment, had secondary aldosteronism, hyponatremia, hypokalemia and sodium and potassium deficiency, captopril corrected these abnormalities. In the remaining patients, long-term captopril therapy did not alter exchangeable sodium, plasma sodium or total body potassium, although plasma potassium levels increased.     

Angiotensin II levels, hemodynamics, and sympathoadrenal function after low-dose captopril in heart failure

The angiotensin converting enzyme inhibitor captopril improves the altered hemodynamics in many patients with chronic heart failure, but the first dose may precipitate hypotension. Ten patients with chronic heart failure were studied, nine with high plasma concentrations of renin and one with a low concentration. Frequent measurements of plasma concentrations of angiotensin II, renin, and catecholamines were made over 60 minutes after a small dose (6.25 mg) of captopril and related to concurrently measured hemodynamic variables. Captopril caused a decrease in systemic and pulmonary artery pressure and an increase in cardiac index, and these changes coincided with reductions in the plasma concentrations of angiotensin II and increases in plasma concentrations of renin. The hemodynamic changes were accompanied by reductions in the plasma concentrations of norepinephrine but transient increases in plasma concentrations of epinephrine in patients in whom vasomotor syncope developed. The patient with a low plasma renin concentration showed little hemodynamic response to the drug. It is concluded that vasomotor syncope occurs quite frequently in patients with severe chronic heart failure after captopril in a small dose and is associated with a selective increase in epinephrine secretion from the adrenal medulla.     

Hypertension in chronic renal failure. An abnormal relation between sodium and the renin-angiotensin system

Hypertensive patients with chronic renal failure show evidence of an abnormal relationship between sodium and the reninangiotensin system in that circulating levels of renin and angiotensin II are abnormally high in relation to exchangeable sodium. The abnormality may well contribute to the hypertension in this syndrome. In a minority of cases blood pressure cannot be controlled by dialysis. In these, renin levels are particularly high and rise even further in response to therapeutic sodium depletion. It is suggested that this may perpetuate the hypertension.In most patients, however, blood pressure can be controlled by dialysis and, in these, renin and angiotensin II levels are lower, but, again, their relation to exchangeable sodium is abnormal. It is suggested that the rise in arterial pressure in this group results from a failure of renin to suppress normally with sodium retention. This would also explain the fall in blood pressure with sodium depletion at hemodialysis. The inflexibility of the renin-angiotensin system in its relation to sodium may be the cause of hypertension as well as the basis for its cure.     

Effect of infused captopril on blood pressure and the renin-angiotensin-aldosterone system in normal dogs subjected to varying sodium balance

Infusion of captopril at 20, 200, 2,000 and 6,000 μg/kg/hour into sodium-depleted conscious dogs produced a rapid, dose-dependent decrease in blood pressure and plasma angiotensin II and III, maximal suppression being achieved at 200 μg/kg/hour (97 ± 14 to 65 ± 8 [standard deviation]mm Hg, 38 ± 10.6 to 3.2 ± 1.5 pmol/liter and 7.0 ± 4.8 to 1 ± 0.5 pmol/liter, respectively). Angiotensin I concentration increased with each infusion rate to a maximal 16-fold increase at 6,000 μg/kg/hour (26 to 416 pmol/liter). For all infusion rates the percentage decrease in blood pressure correlated with the percentage decrease in plasma angiotensin II (r = 0.65, p < 0.001). Infusion of captopril at 6,000 μg/kg/hour into sodium-loaded dogs also produced a decrease in both blood pressure (117 ± 9 to 96.6 ± 11 mm Hg) and plasma angiotension II (11.0 ± 3 to 1.6 ± 1.3 pmol/liter). Plasma aldosterone concentrations decreased whereas both blood angiotensin I and renin concentration increased. In another experiment angiotensin II was infused at 2, 6, 18 and 54 ng/kg/min into sodium-depleted dogs firstly without modification and secondly combined with captopril (6,000 μg/kg/hour) given for 1 hour before the angiotensin dose-response study and continued throughout. Angiotensin II infusion raised mean arterial pressure and plasma angiotensin II in each animal. However, the angiotensin II blood pressure dose-response curve was shifted downwards and to the right in the captopril-treated animals.These results suggest that arterial pressure and aldosterone secretion in normal dogs are partly dependent on the renin-angiotensin system but that not all of the acute decrease in blood pressure produced by captopril can be explained by the suppression of the acute vasoconstrictor effect of circulating angiotensin II.     

Control of renal and adrenocortical function by the renin-angiotensin system in two euryhaline teleost fishes

Plasma ions and cortisol levels were measured sequentially during the adaptation of European eels (Anguilla anguilla) from fresh water (FW) to sea water (SW). The importance of the renin-angiotensin system in the regulation of this adaptation was assessed using captopril (SQ14225, an inhibitor of angiotensin I-converting enzyme). The effects of captopril on renal function in FW- and SW-adapted trout were also examined. During the first 5 hr in sea water, plasma levels of cortisol in eels increased threefold, plasma sodium rose steadily from 137 to 156 mmol/l and plasma potassium fell from 2.1 to 1.6 mmol/l. In contrast, captopril-treated eels when adapted to sea water had plasma cortisol levels twice those of controls. Captopril treatment did not affect the electrolyte responses to seawater adaptation. Captopril injected into eels which were fully adapted to and wholly maintained in sea water had no effect on plasma levels of cortisol, sodium, and potassium. Plasma cortisol was 30% lower in freshwater eels 2 hr after an injection of captopril but plasma sodium and potassium levels were unchanged. In both FW- and SW-adapted trout, captopril infusions doubled the glomerular filtration and urine production rates and the tubular transport maxima for glucose without changes in plasma composition.     

An in vivo study of muscle phosphate metabolism in Becker's dystrophy by 31P NMR spectroscopy

The forearm flexor muscles of five patients with Becker's dystrophy were examined by the painless and noninvasive technique of high resolution phosphorus nuclear magnetic resonance spectroscopy. In the mildly affected cases, the ratios of the signals of phosphocreatine to ATP and to inorganic phosphate were normal but they were reduced in the patients with advanced disease. Absolute quantitation under the conditions of the study was not feasible, but it was probable that whereas in advanced Becker's dystrophy the intramyocellular concentration of phosphocreatine was reduced, that of ATP was unchanged. The intramyocellular pH was normal in three of the four patients in whom this could be measured and an additional unidentified signal between those of phosphocreatine and inorganic phosphate was recorded in two patients. This study emphasizes some metabolic similarities between Becker's and Duchenne type muscular dystrophy and suggests that nuclear magnetic resonance spectroscopy may be a useful and objective technique with which to investigate the biochemistry of these and other muscle diseases.     

Metabolism of apolipoprotein A-I in healthy young adults.

The metabolism of 125I-labeled apolipoprotein A-I bound to high-density lipoproteins by an in vitro transfer procedure was studied in 10 healthy young adults (5 males and 5 females). Both sexes handled the labeled apolipoprotein similarly, and no statistically significant differences were found in the derived kinetic data. The mean (+/- 1 SD) plasma apolipoprotein A-I concentrations (males, 105 +/- 19 mg/dl; females, 111 +/- 13.8 mg/dl) and half-lives (males, 4.46 +/- 0.45 days; females, 4.64 +/- 0.70 days) were similar, as were the fractional rates of catabolism (FCR) of the apoprotein derived from the above data (FCR in males, 27% of intravascular pool/day; FCR in females, 25% of intravascular pool/day). The absolute catabolic rate of the apoprotein, equivalent under steady-state conditions to the synthetic rate, was 12.1 +/- 1.6 mg/kg/day in males and 11.9 +/- 2.4 mg/kg/day in females.     

The effect of noradrenaline on blood flow and oxygen consumption in normal and ischemic areas of myocardium

The effects of infusions of noradrenaline (1.0 μg/Kg./min.) were studied in dogs 2 to 3 hr. after acute ligation of the anterior descending branch of the left coronary artery. The model allowed blood flow to be simultaneously measured in the ischemic (infarcting) region and in the normal myocardium. Sampling blood from a local vein (draining the ischemic region) and from the coronary sinus (draining the normal myocardium) allowed comparisons to be made of oxygen consumption by the two regions.Coronary artery ligation resulted in a marked decrease in cardiac output and external cardiac work and an increase in left ventricular end-diastolic pressure with an unchanged LV $\text{dP}\text{dt}$. This is indicative of reduced myocardial contractility. Blood flow in the area supplied by the ligated vessel fell to a mean of 17.6 ± 2.7 ml./100 Gm./min., which is about 20 per cent of the normal flow in this region.Infusing noradrenaline 2 to 3 hr. after ligation increased systemic arterial pressure, LV $\text{dP}\text{dt}$ max, external cardiac work, and blood flow and oxygen consumption in normal areas of the myocardium. There was some evidence that pulmonary shunting was increased by the drug.Noradrenaline also markedly increased peripheral coronary pressure and blood flow in the ischemic region, as assessed by ¹³³Xenon clearance and by retrograde flow from the ligated vessel. Oxygen consumption in the ischemic region was also increased by noradrenaline. It is suggested that part of the increase in flow occurs in the endocardial region since the effective subendocardial perfusion pressure is increased by noradrenaline. This increase in flow would account for the reduction in infarct size which has been observed by other workers when the systemic arterial pressure is raised.     

Editorial: Observations on the diagnosis of isolated rheumatic carditis.

There are many similarities between the clinical features of viral heart disease and of rheumatic carditis, as defined in the revised Jones criteria for the diagnosis of rheumatic fever. Because of this, it is likely that viral heart disease has been, and still is, diagnosed as rheumatic. This situation can be avoided if isolated rheumatic carditis is diagnosed only when a viral etiology has been definitely excluded, and when there is unequivocal evidence of recent infection with an appropriate strain of streptococcus.     

An analysis of electrocardiographic,radiographic, and vectorcardiographic findings in patients with implanted cardiac pacemakers

In patients with implanted cardiac pacemakers, the radiological appearances, and the configuration of the 12-lead ECG have been conventionally used both to locate the site of the electrode implantation and to diagnose electrode placement errors. These techniques have limitations, and in the present study vectorcardiographic data derived from the pacemaker stimulus and the spread to ventricular depolarization has been added to improve accuracy. Three hundred patients with implanted cardiac pacemakers were studied. Unusual QRS complexes as determined from the 12-lead ECG were found in 37 (12%) and the position of the pacemaker electrodes determined from the lateral chest x-ray was outside normal (R.V. apex) in 61 patients (20.3%). A combined interpretation of the ECG, chest x-ray, and the vectorcardiogram agreed on positioning (correct or incorrect) in all but 17 patients (5.6%). Three patients had a perforated right ventricle, while further study of the other 14 suggested malpositioning of the catheter electrode in the right ventricle or in the coronary venous system. An analysis of the ECG patterns, x-ray appearances, and vectorcardiograms is presented with respect to the diagnosis of pacemaker electrode placement errors and a logical tree for establishing the position of the pacemaker is introduced.     

Peritoneoscopy in the diagnosis of liver abscess. Experience with 108 cases during a 10-year period

Among 4569 cases of peritoneoscopy performed in a period of 10 years (1972-1981), 108 patients with liver abscesses were encountered. The diagnosis of hepatic abscess was made on the basis of gross liver inspection and confirmed or disproved by needle puncture biopsy, histopathologic study, or surgery. Peritoneoscopy is a valuable procedure for the diagnosis of liver abscess. Liver aspiration under direct vision during peritoneoscopy yields more dependable material for the diagnosis of liver abscess than blind liver aspiration. Moreover, during peritoneoscopy one can choose more accurately the site for the insertion of the aspirating needle.     

Evidence for the early reduction of the 24,25 double bond in the conversion of lanosterol to cholesterol in cerebrotendinous xanthomatosis

The metabolism of lanosterol and 24,25-dihydrolanosterol (DL) was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse labeling with a mixture of DL-2-¹⁴C and 3S,4S,3R, 4R-(4-³H)mevalonate. Sterols were isolated from the feces and purified by silver nitrate thin-layer chromatography, and their identities were confirmed by gasliquid chromatography and mass spectrometry. Their specific activities were then determined and plotted as a function of time. These isotope ratio measurements and specific activity decay curves were consistent with 24,25-dihydrolanosterol and Δ⁷-cholestenol being intermediates in the synthesis of cholesterol from mevalonate and lanosterol, and they suggested that reduction of the lanosterol side chain may occur as an early step in the synthesis of cholesterol. These results are in contrast to the results reported after the administration of triparanol, a Δ²⁴-reductase inhibitor.     

Relative insesitivity of isovolumic phase indices in the assessment of left ventricular function.

1. The authors compared the sensitivity of the isovolumic phase indices (contractility indices) against LV function curves ("pump-function" indices) in assessing ventricular performance. 2. Certain modifications of the usual isovolumic phase indices, especially those introducing the concept of comparison of exercise with rest, seemed to us to be slightly more helpful in separating normal subjects from the patient with coronary artery disease or cardiomyopathies, but these differences were not striking when statistically evaluated, and could not be utilized in assessment of left ventricular function in individual patients. 3. The construction of left ventricular function curves, in our hands, yielded equally as satisfactory information and, in addition, was much simpler to perform. 4. It is concluded that contractility indices are relatively insensitive in the assessment of left ventricular function, and that they offer little advantage over "pump-function" indices for this purpose.     

Atherosclerotic ulcerative disease and associated aneurysms of the coronary arteries.

Abnormal cardiac muscle function has been reported in experimental diabetes mellitus from this laboratory. To examine left ventricular performance in diabetic patients without clinical evidence of myocardial ischemia or other cardiovascular disease, a noninvasive measurement of the systolic time intervals was carried out. Simultaneous recordings of the electrocardiogram, heart sounds, and carotid pulse were made in 25 diabetic subjects, 20 to 56 years of age, and compared with 37 normal subjects. The diabetic subjects had a shorter left ventricular ejection time, longer pre-ejection period, and a higher ratio of pre-ejection period/left ventricular ejection time (P < 0.001). The isovolumic time was prolonged (P < 0.001), while heart rate and arterial pressure were within normal limits. Abnormal function was independent of apparent duration and treatment by diet alone, insulin, or hypoglycemic agents. On the basis of available morphologic data in human and canine diabetes, an alteration of the myocardial interstitium may be the basis for this preclinical abnormality in diabetic patients.