Ralph D. Ellefson

Predictive Value of Electrophoretically Detected Lipoprotein(a) for Coronary Heart Disease and Cerebrovascular Disease in a Community-Based Cohort of 9936 Men and Women

BACKGROUND Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory. METHODS AND RESULTS From 1968 through 1982, lipoprotein analysis was performed in 11,335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131,330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women. CONCLUSIONS In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.

Association of risk factor variables and coronary artery disease documented with angiography.

Stepwise linear discrimination was used to analyze risk factors in 431 consecutive patients who underwent coronary angiography to determine which variables were most closely associated with coronary artery disease. Twenty-one risk factors were considered: total plasma cholesterol and triglycerides; the cholesterol and triglyceride content of high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very low density lipoproteins (VLDL); and the percentage of total cholesterol and triglycerides in each fraction. Age, smoking history, family history, hypertension, diabetes mellitus and relative weight were also considered. Coronary artery disease was assessed using three standard grading scores. There were significant differences in risk factors between males and females. In males, LDL cholesterol and age were selected by multivariate analysis. In females, the ratio of HDL cholesterol to total cholesterol, as well as relative weight, family history, age and smoking were selected. The discriminating value of HDL cholesterol as the percentage of total cholesterol was significantly greater than that of HDL cholesterol itself. Despite highly significant associations between risk factors and the presence of coronary artery disease, the discrimination did not provide sufficient separation of the groups to give results that are useful diagnostically in individual patients.

Total cholesterol and lipoproteins in school children: prediction of coronary heart disease in adult relatives.

The distribution of risk factors and the prevalence of coronary heart disease (CHD) were studied in 850 first- and second-degree relatives of 98 healthy index cases selected from 3666 school children surveyed for lipid levels in Rochester, Minnesota. Three groups of families were based on an index childs total plasma cholesterol level: 18 families with a child in less than the fifth percentile (low-cholesterol group), 47 with a child in the fifth to ninety-fifth percentiles (middle-cholesterol group) and 33 with a child in greater than the ninety-fifth percentile (high-cholesterol group). The childrens cholesterol levels clustered with those of their relatives; mortality due to CHD before age 65 was increased by 2.5 times in grandfathers of index cases in the high-cholesterol group compared with those of the middle-cholesterol group (p < 0.016). The prevalence of CHD in all the grandfathers was associated with an index childs total cholesterol, more strongly associated with an index childs low-density lipoprotein cholesterol level and most strongly associated with an index childs high-density lipoprotein cholesterol level as a fraction of total cholesterol. This study establishes that childhood lipid and lipoprotein levels from a single cross-sectional survey identify families at elevated risk for CHD.

Comparison of serum cholesterol in children fed high, moderate, or low cholesterol milk diets during neonatal period.

The long-term effects of milk diets in infancy on the blood serum cholesterol concentrations were studied in 97 school children 7-12 yr of age. Detailed histories were available for these children with respect to their diets during infancy. The major criterion for inclusion in the study was milk (human milk, cows milk, or commercial formula) as the exclusive source of diet cholesterol during the first 3 mo of life. Fasting blood cholesterol and triglycerides were measured in these 97 school children, and the current diets of 29 of the 97 were evaluated for daily cholesterol intake. A 7-day diet diary was recorded, the food intake was measured and analyzed for nutrients, and validity of the diets was verified by determination of urinary nitrogen excretion. Results of the study showed that the school children fed a low cholesterol formula during infancy had a mean serum cholesterol value 7-12 yr later that was lower than the mean values of the groups fed greater amounts of cholesterol in infancy. Analysis of current diets of 29 of the 97 school children showed that their current dietary intake of cholesterol was low. Dietary intake of cholesterol did not have a noticeable effect on the serum cholesterol levels of the 29 children.

Adult-Onset of Tangier Disease: 1. Morphometric and Pathologic Studies Suggesting Delayed Degradation of Neutral Lipids after Fiber Degeneration

A 67-year-old woman, with the typical biochemical features of Tangier disease, had a syringomyelia-like syndrome which has now been observed in several patients with symptomatic onset in adult life. She developed progressive facial diplegia, bilateral wasting of hand muscles and loss of sensation over cranial, cervical and brachial dermatomes over 17 years. Nociception alone was first affected, then nociception and thermal discrimination and finally all modalities of sensation. Quantified tests of cutaneous sensation confirmed that sensation was normal in lower limbs but markedly abnormal in upper limbs. Biopsied fascicles of cutaneous nerves from clinically affected (forearm) and from clinically unaffected (leg) regions permitted a comparison of welladvanced and early pathologic lesions, respectively. The selective vulnerability of unmyelinated and small myelinated fibers in affected regions in this disorder has been confirmed. The earliest morphologic abnormalities of myelinated fibers, but seen infrequently, were mitochondrial enlargement and structural abnormality, aggregation of mitochondria and dense bodies and clusters of neurofilaments. Increased numbers of sudanophilic lipid droplets did not seem to form in Schwann cell cytoplasm prior to fiber degeneration. On the contrary, for myelinated fibers there appeared to be an altered process of axonal degeneration from that seen in Wallerian degeneration and in other axonal degenerations. Distinctive linear bands of closelypacked, minute, osmiophilic and clear lipid droplets formed and their further degradation appeared delayed. Although less clearly demonstrated, lipid droplets in Schwann cells of unmyelinated fibers also appeared to form following their degeneration. We would propose that in Tangier disease, the degradation of myelin ovoids to neutral lipid in Schwann cells does not appear to be delayed. However, further degradation of neutral lipid or its transport away from Schwann cells appears to be retarded.

Lipid abnormalities in hereditary neuropathy: Part 1. Serum non-polar lipids☆

The non-polar lipids from sera of 54 patients, with various types of hereditary motor and sensory neuropathies, and from 72 healthy subjects were evaluated. A small but highly significant decrease in the percentage of linoleate to total fatty acids in both cholesteryl ester and triglyceride fractions was found in the sera of the neuropathy patients, except in those who had dominantly inherited sensory neuropathy (HSN-I) and who had spinocerebellar degeneration with retinitis pigmentosa and other features (SpC+). A significant decrease of serum lecithin-cholesterol acyltransferase activity was also found in those patients with hereditary motor and sensory neuropathies, Type I and Type II (two types of peroneal muscular atrophy). The biochemical basis of these abnormalities is not apparent. The biochemical abnormalities reported here have been found in several neurologic disorders and hence are unlikely to be disease-specific.

Glycerol metabolism in the hibernating black bear

SummaryThe contribution of glycerol to protein, carbohydrate, and lipid metabolism was studied in black bears. Special attention was directed at the role of glycerol in preventing uremia. In summer and winter, U-14C glycerol, as well asl(U14C)-alanine andd(U-14C)-glucose were injected intravenously; timed sampling of venous blood and expiratory gases was made.In winter, during hibernation,14C-label from glycerol was found in alanine and other free amino acids and plasma proteins, pyruvate, lactate, glucose and lipid esters. After 48 h, most of the14C-label in plasma was found in proteins. However, during the four days of study, no label was found in serum urea. Similar results occurred in summer except, in marked contrast to winter,14C-labeled urea was continually detected in blood. Expired14C-CO2 was considerably lower in winter than summer and winter respiratory quotient was 0.69.In both summer and winter,14C-labeled alanine also entered plasma proteins and generated pyruvate, lactate and glucose. Once again the marked difference between active and dormant phases was demonstrated: There was no labeled plasma urea in winter while it was continually detected in summer. 14C-labeled glucose experiments revealed very slow carbohydrate metabolism in winter.These findings suggest that in winter, glycerol helps prevent uremia by serving as a carbon source for amino acid formation. The nitrogen involved in these reactions is thus diverted from urea synthesis into protein synthetic pathways. Further, glycerol also appears to serve as an active substrate for gluconeogenesis and lipogenesis in hibernation.

Influence of Aspirin and Ethanol on Fecal Blood Levels As Determined by Using the HemoQuant Assay

We sought to determine the short-term effects of use of aspirin and ethanol on fecal occult blood levels measured with the HemoQuant assay. A factorial design was used to study 68 healthy volunteers randomized to receive various doses of aspirin, ethanol, or a combination of both for either 1 or 3 days. Fecal hemoglobin concentrations were measured before and after drug ingestions. Moderate quantities of ethanol (300 ml of 5% or 30 ml of 50% three times nightly) did not cause significant fecal blood elevation unless aspirin was administered concomitantly (P = 0.05). High-dose aspirin alone, 975 mg three times daily, induced abnormal blood loss (P less than 0.01). The highest HemoQuant levels were usually noted after concomitant administration of aspirin and ethanol at maximal doses for 3 days (P less than 0.005), some HemoQuant levels approaching 5 times the normal value. We conclude that, in a short-term analysis, social consumption of ethanol is unlikely to interfere with fecal blood testing but therapeutic doses of aspirin will.

Colorectal cancer detection in the practice setting. Impact of fecal blood testing

To assess the contribution of fecal blood testing to cancer detection in a clinical practice setting, we studied records from 160 patients with both a new tissue diagnosis of colorectal adenocarcinoma and a preceding stool blood test (HemoQuant, Mayo Medical Laboratories, Rochester, Minn) determination. In this group, 71% had suggestive colorectal symptoms (particularly stool changes, overt bleeding, and abdominal pain) or anemia at presentation, and 29% were asymptomatic. Fecal blood levels remained normal in more than 40% of both symptomatic and asymptomatic patients. In only 26 patients (16% overall) was an abnormal fecal blood level the sole heralding feature, but this subset of patients had a more favorable stage. Fecal blood levels were higher with advanced, larger, and more proximal tumors and with stools collected before purgation. We conclude that, in the practice setting, fecal blood level elevation alone is an uncommon but important manner of colorectal cancer presentation, most cancers present with symptoms, and fecal blood levels are often normal in both symptomatic and asymptomatic patients.

Measurement of degraded fecal hemoglobin-heme to estimate gastrointestinal site of occult bleeding appraisal of its clinical utility

Hemoglobin-heme is variably converted to porphyrin during enterocolic transit. This intestinal converted fraction, as measured by HemoQuant, was elevated as a predictor of the occult bleeding site in 152 patients with discrete lesions. The intestinal converted fraction, expressed as the percentage of total fecal hemoglobin, was similar with upper gastrointestinal and proximal colon lesions. Within the colon, values trended downward with more distal location: means ± standard deviations were 18±14 proximal colon, 16 ±15 sigmoid, and 10±10 rectum. The amount of fecal blood also affected the intestinal converted fraction; correcting for hemoglobin concentration improved separation by site. Corrected intestinal converted fraction values were significantly lower with rectal (P< 0.0005) and sigmoid (P<0.02) lesions than with proximal colon lesions. Unfortunately, large within-site variation caused considerable overlap between sites. We conclude that the intestinal converted fraction is influenced by the site and amount of bleeding. However, its clinical utility is compromised by substantial individual differences in luminal hemoglobin metabolism.