The effect of hypoglycemia on hypothalamic thyrotropin-releasing hormone (HRH) in the rat.

A rapid radioimmunoassay for TRH with a high degree of specificity and sensitivity is described. The procedure is capable of measuring TRH in amounts less than 15 pg/tube. Such an assay system has enabled us to study the effect of hypoglycemia on hypothalamic TRH content. Forty-eight female, adult Holtzman rats were divided into 8 groups of 6. Regular insulin was injected intraperitoneally into each rat except for the basal group. A separate batch of similar rats was studied in the same fashion except that saline was injected instead of insulin. Each group of rats was decapitated and the trunk blood collected at 0, 15, 30, 45, 60, 90, 120 and 180 min post-injection. Appropriate tissues were rapidly taken and immediately extracted in ice-cold methanol. Hypothalamic TRH, pituitary TSH, serum TSH and serum triiodothyronine (T3) and thyroxine (T4) were serially determined. In the insulin-treated group, a rapid fall in blood sugar was observed reaching a nadir in 15 min. Hypothalamic TRH fell from a basal mean +/- SE value of 3.25 +/- 0.31 ng to 1.54 +/- 0.14 ng/hypothalamus (P less than 0.01). Pituitary TSH decreased from 10.0 +/- 0.9 mug to a low of 2.6 +/- 0,8 mug/pituitary (P less than 0.02) at 30 min postinsulin. Serum TSH increased from a basal level of 42.5 +/- 20.5 muU/mo to a peak of 102.1 +/- 10.0 muU/ml 45 min (P less than 0.05) after insulin administration. The incremental change in serum T3 occurred at 90 min when T3 levels increased from a baseline of 107.5 +/- 53.7 ng/100 ml to a peak of 711.7 +/- 20.2 ng/100 ml (P less than 0.01). No changes in T4 were observed. The control group of rats did not show significant changes in hypothalamic TRH. The results of the study indicate that hypoglycemia can induce depletion (presumably release) of hypothalamic TRH with a consequent cascade stimulation of the pituitary-thyroid axis.

Sustained coronary-risk-factor reduction after gastric bypass for morbid obesity.

Lipids and clinical changes including diabetes and hypertension were monitored in morbidly obese patients after Roux-Y gastric bypass. Total cholesterol (Chol), high-density-lipoprotein (HDL) cholesterol, and triglycerides at 1 and at 5-7 y postoperatively in 33 patients and at 1 y in 23 patients (including apolipoproteins A-I and B) were compared with preoperative concentrations. Mean concentrations of Chol and both apolipoproteins were unchanged. Elevated serum triglycerides became normal, and reduced concentrations persisted at 5-7 y in men (p less than 0.025). HDL-cholesterol concentrations increased at 1 y (p less than 0.01) and remained higher at 5-7 y in women. Ratios of Chol to HDL cholesterol were lower at 1 y (p less than 0.01) in both men and women. Diabetes (9 patients) and hypertension (22 patients) also were reduced at 1 y (p less than 0.01) and remained lower at 5-7 y. A mean 61% of excess weight was lost in 1 y whereas a 12% weight gain occurred by 5-7 y. The beneficial changes in most coronary risk factors lasted 5-7 y after surgery.

Calcium intake and the relationship of dietary sodium and potassium to blood pressure.

Using First National Health and Nutrition Examination Survey (NHANES I) data, we studied the relationships of dietary sodium, potassium, and alcohol to blood pressure in relation to levels of dietary calcium intake. At low Ca intakes (less than 400 mg/d for men and less than 800 mg/d for women) the ratio of Na to K (Na:K) was significantly related to blood pressure (p less than 0.01) after controlling for age, body mass index (BMI), race, and gender. At higher Ca intakes neither Na:K nor any other nutrient (with the exception of alcohol) was related to either systolic or diastolic blood pressures. Na:K was more strongly related to blood pressure than either nutrient alone and low Ca intakes were necessary for the Na:K-blood pressure relationship to be evident. Interaction of these three dietary factors in relation to blood pressure was evident in all race and gender groups. Associations of age, BMI, gender, and alcohol with blood pressure were not affected by Ca levels.

Alcohol consumption, nutrient intake and relative body weight among US adults.

Data from the first National Health and Nutrition Examination Survey (HANES I) were analyzed for differences in nutrient intakes based on the amounts of alcohol consumed by US adults, and for relationships between alcohol consumption, calorie intake, and relative body weight. Drinkers had significantly higher intakes of total calories than nondrinkers, but only because of their intakes of alcoholic calories. Among drinkers, the intakes of nonalcoholic calories decreased as alcohol intakes increased, and it was estimated that between 15 and 41% of the alcoholic calories replaced nonalcoholic calories. Despite their higher caloric intakes, drinkers were not more obese than nondrinkers, suggesting that alcoholic calories may be less efficiently utilized than nonalcoholic calories, or may interfere with utilization of nonalcoholic calories. The most salient difference in nutrient intake between drinkers and nondrinkers was the substantially lower carbohydrate intake of drinkers.

Preprandial drinking and plasma lipids in man.

A group of normolipemic subjects who consumed alcoholic drinks before their evening meals for a period of 7 consecutive days demonstrated a significant increase in their fasting plasma triglyceride levels. On cessation of alcohol consumption, the fasting triglyceride levels reverted to their pre-experimental levels. The plasma cholesterol levels did not show any consistent changes.

Smoking, alcohol and coronary artery occlusion.

The effects of smoking and alcohol intake on the extent of coronary artery occlusion were studied in 2989 men undergoing a diagnostic coronary arteriography. Smoking showed an exposure-related enhancing effect on the extent of coronary artery occlusion. Conversely, alcohol consumption demonstrated an attenuating dose-related effect, offsetting the increased coronary occlusion associated with smoking. Alcohol intake should be considered in studies evaluating the risk factors--coronary artery disease interaction.

Apolipoprotein B (Apo B) in vein graft atherosclerosis. An immunoperoxidase study.

An immunoperoxidase procedure was used to localize the apolipoprotein B in the atherosclerotic lesions of vein grafts removed 5 years after an aortocoronary bypass operation and preserved by embedding in paraffin. Apolipoprotein B was mainly found at the cell-rich interface of the lesion proper and the underlying fibrous tissue. The findings of this study indicate that the immunoperoxidase procedure can be used to investigate the localization of immunoactive components in paraffin-embedded tissue sections.

Pathologic findings in the aortocoronary vein grafts. A scanning electron microscope study.

Examination of totally or partially obstructed human aortocoronary vein grafts, obtained at different time intervals after the bypass operation, has shown that the initial occlusive process is due to thrombosis and may appear a few hours or days after surgery. The cellular phase of intimal proliferation affecting most of the grafts becomes apparent about 4 weeks after the operation. After 1 year the intimal hyperplasia acquires a cell-poor, fibrotic character; the graft usually remains patent. About one-half of the vein grafts obtained 3 or more years after the operation show complicated atherosclerotic lesions. These findings indicate that most of the vein grafts undergo extensive structural changes and some may show similar degenerative lesions as they develop in the coronary arteries.

Effects of drinking patterns on the relationship between alcohol an coronary occlusion.

Previous reports have described an inverse relationship between alcohol consumption and the prevalence of myocardial infarction or the extent of coronary artery occlusion. The study reported here explored the relationship between patterns of alcohol intake and coronary occlusion in 526 patients who have had coronary arteriography. Patients were characterized as regular drinkers, occasional drinkers and non-drinkers. Regular drinkers were further characterized as drinking relatively consistent amounts or variable amounts. The inverse correlation between amounts of alcohol consumed and coronary occlusion found in previous studies was reaffirmed. It was also observed that the pattern of alcohol intake was related to the degree of occlusion. Higher levels of occlusion were found among non-drinkers, occasional drinkers, and regular drinkers with patterns of variable intake, while significantly lower levels of occlusion were observed for regular drinkers who drank relatively consistent amounts (P = 0.014). Furthermore, while occlusion scores were inversely correlated with amounts consumed by regular drinkers with consistent intake (P = 0.019), drinkers with variable drinking patterns had higher occlusion scores regardless of amounts consumed. Analyses of serum lipids according to drinking patterns showed a significant association between the total/HDL cholesterol ratio and drinking patterns. These findings suggest that whatever attenuating effect alcohol consumption might exert on coronary occlusion, it appears to be reversed by a variable or sporadic pattern of alcohol intake.

Correlation of the extent of coronary occlusion with Apo B levels. Application of a new enzyme immunoassay technique for Apo B.

A new rapid and sensitive method for measurement of apolipoprotein B (Apo B) in plasma has been developed. This method, based on a Competitive Enzyme-Linked Immunoassay (CELIA), has been used to study the association between the extent of coronary artery occlusion as measured by coronary arteriography and the levels of plasma Apo B. The correlation between Apo B levels and some other plasma lipids was also determined. Significant relationship was found between the extent of coronary artery occlusion and Apo B, as well as between Apo B and plasma total cholesterol and plasma triglyceride levels.

Risk factors and the anatomic distribution of coronary artery disease.

Differences in the importance of risk factors according to the anatomic location of coronary artery disease (CAD) were assessed in 4722 men and 1069 women who underwent arteriography. Examined characteristics included total and high-density lipoprotein (HDL)-cholesterol, triglycerides, obesity, smoking, alcohol consumption, diabetes, and hypertension. Of these risk factors, the ratio of total to HDL-cholesterol showed the highest correlation with the overall severity of CAD (r = 0.24, men; r = 0.38, women); in contrast, its relation to left main (LM) disease was much lower (r = 0.10, men; r = 0.08 women) than were correlations with stenotic disease in the left anterior descending, circumflex, and right coronary arteries. Other risk factors also showed weaker associations with LM disease than with stenoses in other vessels, and none was related to increased LM disease after controlling for disease in other vessels. For example, as compared with men who had no significant CAD, those with 1-, 2-, and 3-vessel disease had mean increases in total cholesterol of 12, 18, and 19 mg/dl, respectively. In contrast, after adjusting for disease in other vessels, LM disease (present in 293 men) was associated with only a 4 mg/dl increase in mean cholesterol levels (P = 0.20). These results indicate that the relation of risk factors to CAD differs according to the location of the stenotic disease, and that LM disease is poorly predicted by the standard risk factors.

Effect of drinking pattern on plasma lipoproteins and body weight.

The effect of drinking pattern on plasma lipoproteins and body weight was examined in three groups of squirrel monkeys: (1) controls fed isocaloric liquid diet; (2) regular drinkers given liquid diet containing ethanol (EtOH) substituted isocalorically for carbohydrate at 12% of calories daily; and (3) binge drinkers fed 6% EtOH calories daily for a four-day period followed by three days of 20% EtOH to mimic a weekend bout drinking cycle. The number of calories offered per day was the same for all groups, and the average weekly EtOH consumption (12% calories) was identical for the two alcohol treatments. The entire study lasted six months. There were no significant differences in plasma cholesterol, triglyceride or liver function tests. Regular drinkers had the highest high density lipoprotein2/high density lipoprotein3 (HDL2/HDL3) protein and apolipoprotein A-I/B ratios of any group and exhibited a significant elevation in the molar plasma lecithin:cholesterol acyltransferase (LCAT) rate (nmol/min/ml). Binge drinking produced a selective increase in low density lipoprotein (LDL) cholesterol and apolipoprotein B, and a depression in the fractional LCAT rate (% esterified/min). During the course of the study, controls ate 92% of their diet while the alcohol groups each consumed 95% of the liquid diet. Despite this difference, body weight and Quetelet index (weight/height2) decreased progressively in the order controls greater than regular drinkers greater than binge drinkers. Results from our study indicate that moderate, regular daily consumption of EtOH at 12% of calories causes a modest reduction in body weight and produces a coronary protective lipoprotein profile (increases HDL2/HDL3, increases apolipoprotein A-I/B, low LDL cholesterol). By contrast, when this same average weekly dose is concentrated in a binge cycle, unfavorable alterations in lipoprotein composition (increases LDL cholesterol, increases apolipoprotein B) and metabolism (decreases LCAT activity) occur along with weight loss and depletion of body fat. These studies point to the value of the squirrel monkey model in evaluating both favorable and pathophysiological effects of chronic EtOH intake.

Plasma lipoprotein alterations in squirrel monkeys (Saimiri sciureus) during ethanol administration and abstinence.

The time course of lipoprotein changes during ethanol (EtOH) consumption followed by abstinence was examined in 3 groups of male squirrel monkeys: 1) controls fed isocaloric liquid diet; 2) low EtOH monkeys given liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) high EtOH animals fed diet plus vodka at 24% of calories. After 2 weeks, high EtOH monkeys showed significant elevations in total plasma cholesterol which continued to increase at 4 weeks and then declined at 8 weeks. These elevations were the result of increases in both low density (LDL)- and high density lipoprotein (HDL)-cholesterol. Low EtOH monkeys had a modest increase in total cholesterol throughout 8 weeks which was attributed to increments in HDL-cholesterol alone. During abstinence, total, HDL- and LDL-cholesterol concentrations decreased rapidly in the high EtOH group and were similar to control values after 4 days. HDL-cholesterol showed a more gradual decline in animals fed 12% EtOH while LDL-cholesterol remained low and not significantly different from controls. Liver function tests were normal for all animals. Our results indicate that low-dose EtOH favors a coronary protective lipoprotein profile (increases HDL, decreases LDL) in squirrel monkeys while the higher alcohol regimen causes both favorable and unfavorable alterations in plasma lipids which quickly revert to control levels during abstinence.

Early detection of hypersensitivity pneumonitis in office workers.

Symptoms of hypersensitivity pneumonitis in three employees in an office building led to an investigation of their work environment. An open spray water air cooling system was implicated when inhalation challenge with the spray water caused acute illness in one of them. A questionnaire survey of the 4,023 co-workers identified 48 other suspect cases, and laboaratory studies confirmed hypersensitivity pneumonitis in three additional workers of this group. A significant change in pulmonary function, occurring only after exposure to the work environment, was the most useful laboratory finding and was found in five workers with no other pulmonary abnormalities, but not is asymptomatic workers or controls, since five of the six patients with hypersensitivy pneumonitis worked in offices cooled by the spray water system and since three had positive responses to inhalation challenge, use of the spray water system was discontinued. The affected workers improved after they were removed from the office complex.

Black/white differences in risk factors for arteriographically documented coronary artery disease in men.

Although the leading cause of death among black men in the United States is coronary artery disease (CAD), risk factors have not been well documented in black populations. Therefore, possible racial differences in the relation of several characteristics to the extent of CAD were assessed in 4,722 white and 169 black men who underwent arteriography. Associations between an occlusion score (ranging from 0 to 300), reflecting the severity of CAD, and levels of total and high-density lipoprotein (HDL) cholesterol, triglycerides, cigarette smoking, alcohol intake, relative weight, systemic hypertension and diabetes mellitus were examined. Most risk factors were significantly related to the extent of CAD in both races, but lipid levels showed stronger associations with CAD among blacks: correlations between CAD and total cholesterol were 0.16 (whites) vs 0.29 (blacks) and associations with HDL cholesterol were -0.22 (whites) vs -0.49 (blacks). In addition, at adverse levels of certain risk factors, blacks had more extensive CAD than did whites: mean occlusion scores were 148 (whites) and 238 (blacks) at HDL cholesterol levels less than 30 mg/dl. As assessed by multiple linear regression, however, only triglyceride levels were differentially related to CAD between whites (beta = 0) and blacks (beta = 0.47), p less than 0.01 for racial contrast. These results document the importance of risk factors in black men and indicate black/white differences in the relation of triglycerides to CAD.

Correlates of leukocyte counts in men.

Because of previously reported associations between a high leukocyte count and risk of ischemic heart disease (IHD), we examined the relation of leukocyte counts to various characteristics among 3591 white and 506 black 31- to 45-year-old men. The mean leukocyte count was approximately 1000 cells/microL higher among whites than among blacks, and approximately 1900 cells/microL higher among current smokers than among nonsmokers. The leukocyte count was also higher among men who had recently stopped smoking and among men who reported their general health as poor or fair. Independent of these relations, the leukocyte count was associated positively with the platelet count (r = 0.29), triglyceride level (r = 0.21), heart rate (r = 0.15), and use of corticosteroids and beta-blockers; and inversely with alcohol consumption and prothrombin time (r = -0.10). The examined characteristics could together account for 37% of the variability in leukocyte counts. These relatively strong associations indicate that it may be difficult to disentangle the relation of the leukocyte count to IHD from that of other risk factors.

Cigarette smoking and leukocyte subpopulations in men.

Because of previously reported associations among the total leukocyte count, cigarette smoking, and risk of cardiovascular disease, we examined the relation of cigarette smoking to various leukocyte subpopulations among 3467 men aged 31 to 45 years. The median total leukocyte count was 36% higher (7840 vs. 5760 cells/mL) among current cigarette smokers than among men who had never smoked, and both stratification and regression analyses were used to examine independent associations with leukocyte subpopulations. At equivalent counts of other subpopulations, CD4+ lymphocytes and neutrophils were the cell types most strongly associated with cigarette smoking; each standard deviation change in counts of these subpopulations increased the odds of current (vs. never) smoking by approximately threefold. Furthermore, whereas 15% of the 238 men with relatively low (< 25 percentile) counts of both neutrophils and CD4+ lymphocytes were cigarette smokers, 96% of the 249 men with relatively high counts of both subpopulations were current smokers. Counts of T lymphocytes also tended to be higher among the 32 men with self-reported ischemic heart disease than among other men. These results, along with previous reports of immunologically active T lymphocytes in atherosclerotic plaques, suggest that this subpopulation may be of particular interest in studies examining the relation of leukocytes to cardiovascular disease.

Diabetes mellitus and arteriographically-documented coronary artery disease.

Diabetics are at increased risk for coronary heart disease even after accounting for other risk factors, and the impact of diabetes mellitus may be particularly strong among females and at adverse levels of other risk factors. Therefore, the independent relation of diabetes to arteriographically-documented coronary artery disease (CAD) was examined in 5620 patients (18% female) referred to two Milwaukee hospitals from 1972 to 1986. As assessed by questionnaire, the prevalence of diabetes mellitus among these patients was 8% (n = 466). Diabetics had increased CAD (assessed by the number and severity of stenoses) even after accounting for levels of total and high-density lipoprotein cholesterol, triglycerides, hypertension, obesity, smoking, and alcohol consumption. In addition, regression analyses indicated that as compared with nondiabetics, female diabetics tended to have a greater increase in CAD than did male diabetics (p = 0.06 for sex x diabetes interaction). Although adverse levels of other risk factors did not increase the association between diabetes and CAD, female diabetics who were using oral hypoglycemics or insulin showed almost a two-fold increase in CAD severity (p less than 0.01). Results suggest that the higher relative risk of coronary heart disease among female (vs male) diabetics may be due to a proportionately greater increase in atherosclerosis.

Cholesterol and coronary artery disease: age as an effect modifier.

An elevation of serum cholesterol has been one of the more frequently cited risk factors for coronary heart disease, found in both case-control and cohort studies. As a result, this country has undertaken massive screening of adults older than 20 years of age in an attempt to identify those persons with cholesterol levels greater than 200 mg/dl, and follow up with an active approach for intervention. The suggested cutpoints for borderline (200-240 mg/dl), and definite (> or = 240 mg/dl) hypercholesterolemia have been applied to all age groups despite suggestions of a diminution of risk conferred by cholesterol in the elderly. This study of 2544 white men undergoing coronary angiography shows that for all men, aged 25-84 years, plasma cholesterol levels were associated with an increase in coronary artery occlusion (rs = 0.15, p < 0.01). However, when stratified by age, this association held only for the younger men, the association diminishing to near zero in the oldest age group. The negative interaction between cholesterol levels and age in predicting coronary artery disease proved highly significant (p < 0.001) in multivariable linear regression analysis, suggesting that cholesterol levels are much less predictive of coronary artery disease in the elderly as compared to the young. These results point to the need for a more finely tuned set of criteria for the evaluation of hypercholesterolemia, one that takes into account the age of the screenee.

Scanning electron microscope study of human veins and aorta-coronary artery vein grafts.

Scanning electron microscope study of two vein grafts which were removed after 50 months of implantation as aorta-coronary artery vein grafts showed considerable subendothelial thickening, which consisted of relatively cell-poor fibrous layer. In one of the grafts the endothelial surface was intact; the second graft showed focal loss of endothelial cells. Sections of two fresh human veins, studied prior to their insertion as aorta-coronary artery vein grafts, have shown that they retained an intact endothelial layer. A third fresh vein, however, showed focal damage with missing endothelial cells and adherent fibrin.