Margo A. Denke

Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia.

Purpose To assess cardiovascular risk factors (CVRF) in young adult survivors of childhood acute lymphoblastic leukemia (ALL). Patients and Methods Twenty-six subjects (median age, 20.9 years; median interval since completion of therapy, 13.3 years) were evaluated. Ten participants had received cranial irradiation (CRT), whereas 16 had received only chemotherapy. Primary outcome measures included body mass index (BMI), blood pressure, fasting lipoprotein, glucose, and insulin levels. Secondary measures included insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 levels, physical activity index, a 7-day dietary recall, tobacco product use, and measurement of the intima-media thickness (IMT) of the common carotid artery. Results Sixty-two percent (16/26) of participants had at least one CVRF potentially related to their cancer treatment (obesity, dyslipidemia, increased blood pressure, or insulin resistance), with 30% (7/26) having more than two CVRF. Thirty-one percent (8/26) of subjects were obese (BMI ≥30). Subjects who were treated with CRT (BMI, 30.4 ± 6.7) had an increased BMI (P = 0.039) in comparison with those who received only chemotherapy (BMI, 25.4 ± 5.1). Triglyceride and very low-density lipoprotein C levels were significantly higher in those treated with CRT (P = 0.027 and 0.022, respectively). The IGF-1 was inversely correlated with IMT (total group, −0.514, P = 0.009; females only, −0.729, P = 0.003). Conclusions Young adult survivors of childhood ALL, especially those treated with CRT, are at risk for obesity and dyslipidemia, insulin resistance, hypertension, and cardiovascular disease. Further investigation of these risks is warranted.

Hypercholesterolemia in Elderly Persons: Resolving the Treatment Dilemma

Of all age groups, men and women over 60 years of age have the highest prevalence of elevated serum cholesterol levels. Now that detection and treatment of high serum cholesterol levels are increasing, we need a rational approach to managing elevated cholesterol levels in elderly patients. Recent data indicate that high total cholesterol and low-density lipoprotein levels predict risk for coronary heart disease in patients over 60 years of age. However, selecting appropriate candidates for cholesterol-lowering therapy requires clinical judgment of the relative risks and benefits of each therapy and consideration of each patients overall health status as well as of competing risks. Active medical management of high cholesterol levels, therefore, should be restricted to a limited fraction of elderly patients who are most likely to benefit from long-term therapy. The first line of treatment is diet modification; however, drug therapy for appropriate patients is not contraindicated because of age alone.

Individual responses to a cholesterol-lowering diet in 50 men with moderate hypercholesterolemia

BACKGROUND Dietary modification is the recommended first step in the treatment of hypercholesterolemia. However, the efficacy of the National Cholesterol Education Program Step 1 Diet in outpatients with hypercholesterolemia has been debated. METHODS Fifty normotriglyceridemic men whose ad libitum low-density lipoprotein (LDL) cholesterol levels were 4.14 to 5.69 mmol/L (160 to 220 mg/dL) participated in a two-period outpatient diet counseling study that used a 1-month high-fat, high-saturated fatty acid period (Hi-Sat) and a 4-month low-fat, low-saturated fatty acid period (Step 1 Diet). Lipid, lipoprotein levels, and plasma triglyceride fatty acids were measured five times during the last 2 weeks of each dietary period and averaged for each patient. Dietary intake was assessed by 7-day food records. During the Hi-Sat period, an LDL turnover study was done to determine the fractional catabolic rate of LDL. RESULTS The mean reduction in total and LDL cholesterol levels achieved by diet was 0.54 mmol/L (21 mg/dL) and 0.39 mmol/L (15 mg/dL), respectively. These responses equaled those predicted from metabolic ward investigations. While dietary responsiveness was normally distributed, there was marked individual variation in response. The mean (+/- SD) for quartiles of LDL responsiveness were +0.41 +/- 0.21 mmol/L (+16 +/- 8 mg/dL), -0.16 +/- 0.13 mmol/L (-6 +/- 5 mg/dL), -0.57 +/- 0.16 mmol/L (-22 +/- 6 mg/dL), and -1.16 +/- 0.26 mmol/L (-45 +/- 10 mg/dL). These differences in response were partially explained by dietary adherence, baseline fractional catabolic rates of LDL, and the change in plasma triglyceride palmitate level. CONCLUSIONS The Step 1 Diet is effective in lowering LDL cholesterol levels for many hypercholesterolemic men, and with appropriate counseling, outpatients can achieve results predicted by inpatient metabolic diet studies. Nonetheless, the responsiveness for individuals is highly variable, and this variability is influenced by both compliance and biologic factors. Since many men achieved LDL cholesterol levels low enough to remove the need for drug therapy in primary prevention for coronary heart disease, dietary therapy should remain the initial approach to the treatment of hypercholesterolemia.

Metabolic basis of primary hypercholesterolemia.

BackgroundHypercholesterolemia is a well-established risk factor for coronary heart disease. However, the mechanisms underlying hypercholesterolemia, elevated low density lipoprotein (LDL) in particular, are not well understood. To determine these mechanisms, we studied LDL kinetics in a group of men with primary hypercholesterolemia. Methods and ResultsLDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol, 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol, more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in LDL apolipoprotein (apo) B levels but had abnormally high LDL cholesterol-to-apo B ratios; 14 patients had very low fractional catabolic rates (FCRs) for LDL, similar to FH patients; 35 patients had FCRs for LDL in the borderline range but high production rates for LDL; and 22 patients had a high flux of LDL (high production rates and high FCRs). In general, patients with severe hypercholesterolemia resembled those with moderate LDL elevations, except that their LDL particles were enriched with cholesterol. ConclusionsData from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia. These patterns can serve as the basis for further investigation to determine the molecular defects responsible for each pattern. (Circulation 1991;84:118–128)

Metabolic effects of high-protein, low-carbohydrate diets

Weight-losing diets appeal to the growing population of overweight Americans. Fad diets promise rapid weight loss, easy weight loss, limited restrictions on portion sizes of favorite foods, and above all an enhanced sense of well being. The popularity of fad diets points out the honest promises of traditional weight loss diets. Traditional weight loss diets promise slow weight loss of 0.45 to 0.9 kg/week. The weight loss is nothing but easy, because portion sizes of nearly all foods except low-calorie “free foods” must be continuously evaluated and tracked. Claiming an enhanced sense of well being is hardly appropriate for a traditional diet—most patients report dissatisfaction from the constant vigilance over dietary intake. Through discipline and perseverance, traditional weight loss programs try to teach a patient a new lifestyle of healthy eating. Unfortunately, 70% of successful weight losers return to their old habits and within 2 years regain at least half of the weight lost. These patients typically have little insight into the reasons why the weight was regained, and consider themselves “failures” to traditional diet programs. They become prime targets for diets promising rapid and easy weight loss.

Response to a cholesterol-lowering diet: Efficacy is greater in hypercholesterolemic subjects even after adjustment for regression to the mean

PURPOSE To define how much regression to the mean confounds apparent responsiveness in subgroup analyses, and to test, using techniques that remove regression to the mean, whether hypercholesterolemic subjects are more likely to respond to diet. PATIENTS AND METHODS Data collected on 812 men and women participating in the Minnesota Coronary Survey Dietary Trial who had at least 2 total cholesterol measurements on a high-saturated-fat diet and 1 cholesterol measurement on a low-saturated-fat diet were analyzed for the effects of initial serum cholesterol and regression toward the mean on measurement of diet responsiveness. RESULTS If regression towards the mean is not taken into account, dietary responsiveness in patients with mean cholesterol levels of 280 mg/dL was -25%, whereas dietary responsiveness in subjects with mean serum cholesterol levels of 156 mg/dL was -5%. After regression toward the mean was taken into account, subjects with high initial serum cholesterol levels had an 18% reduction in serum cholesterol levels whereas subjects with lower levels had an 11% reduction. Even after regression toward the mean is accounted for, subjects with high serum cholesterol levels were significantly more diet-responsive (p < 0.005). CONCLUSION The efficacy of a cholesterol-lowering diet for individuals can be overestimated or underestimated if only single measurements are used to determine response. Subjects with hypercholesterolemia, even after adjustment for regression towards the mean, are more diet-responsive than subjects with lower cholesterol levels. Dietary therapy should remain the first step in the treatment of hypercholesterolemia, and should also be effective in reducing cholesterol levels in the population at large.

Prevention Conference VII Obesity, a Worldwide Epidemic Related to Heart Disease and Stroke: Group IV: Prevention/Treatment

Obesity is a worldwide problem, not just an issue for industrialized nations. Therefore, we need to examine opportunities for prevention and treatment from a global perspective.

Role of beef and beef tallow, an enriched source of stearic acid, in a cholesterol-lowering diet.

The effects of stearic acid on metabolism must be evaluated for stearic acid as an isolated dietary constituent and for stearic acid as a component of a natural fat. Beef products are the most common source of dietary stearic acid in the United States. Two components of beef products, beef protein and beef fat, can potentially impart cholesterol-raising properties. Protein has minimal effects on cholesterol concentrations in humans, but studies suggest that beef fat raises serum cholesterol concentrations. Because beef fat is 19% stearic acid, the cholesterol-raising potential of beef is not as great as predicted by its total saturated fatty acid content. However, beef tallow is hypercholesterolemic compared with fats containing less cholesterol-raising saturated fatty acid. Therefore, curtailment of beef tallow in a cholesterol-lowering diet seems appropriate. Data suggest that lean beef is no more hypercholesterolemic than chicken or fish and, therefore, lean beef need not be eliminated from cholesterol-lowering diets.

Hydroxychloroquine Effects on Lipoprotein Profiles (the HELP trial): A Double-Blind, Randomized, Placebo-Controlled, Pilot Study In Patients With Systemic Lupus Erythematosus.

Hydroxychloroquine has been suggested to exert lipid lowering effects. The purpose of this study was to determine the effect of hydroxychloroquine on total cholesterol and on other lipoproteins in a controlled trial involving patients with systemic lupus erythematosus (SLE). Seventeen female patients with SLE were enrolled in a double-blind, randomized, placebo-controlled, multiple-dose pilot study comparing placebo with hydroxychloroquine at daily doses of 400 and 800 mg. The primary endpoint was alteration in total cholesterol. Patients were evaluated at two screening visits pretreatment and at three monthly follow-up visits. At all visits, a fasting panel of lipoproteins, disease activity, and adverse drug effects were assessed. There were no significant alterations in lipoproteins in patients receiving placebo. Treatment with 400 mg/day of hydroxychloroquine resulted in a significant decrease in total cholesterol (mean decrease of 11.6 mg/dL). Treatment with 800 mg/day of hydroxychloroquine resulted in a significant decreases in total cholesterol (mean decrease of 13.4 mg/dL), triglycerides, very low density lipoproteins, cholesterol, and the ratios of total cholesterol/high density lipoprotein cholesterol and low density lipoprotein/high density lipoprotein cholesterol. More adverse effects were noted among patients receiving the high dose (800 mg/day). Hydroxychloroquine affects a significant reduction in total cholesterol in patients with SLE. The findings of this double-blind, placebo-controlled, pilot trial support the conclusions of earlier open trials. This lipid-lowering effect may be an added benefit of hydroxychloroquine treatment in these patients with a high prevalence of atherosclerotic cardiovascular disease.

Efficacy of Low-Dose Cholesterol-Lowering Drug Therapy in Men With Moderate Hypercholesterolemia

OBJECTIVE To test the potency of low-dose cholesterol-lowering drug therapy in patients with moderate hypercholesterolemia and to evaluate the effectiveness for cholesterol lowering of a safe regimen to be used in primary prevention of coronary heart disease. DESIGN The efficacy of three drug regimens (cholestyramine resin, 8 g/d; cholestyramine resin, 8 g/d, plus lovastatin, 5 mg/d; and lovastatin, 20 mg/d) was tested in 26 men aged 31 to 70 years with moderate hypercholesterolemia after a Step-One cholesterol-lowering diet. Each drug period was 3 months in duration, interspersed by a 1-month period of the Step-One diet only. Blood for lipid and lipoprotein measurements was obtained on 5 different days during the last 2 weeks of each drug and diet-only period. RESULTS Cholestyramine resin therapy at 8 g/d achieved a significant reduction in low-density lipoprotein cholesterol levels from 4.47 mmol/L (173 mg/dL) to 3.90 mmol/L (151 mg/dL) (P < .005). The addition of 5 mg of lovastatin to cholestyramine therapy achieved even lower levels, averaging 3.39 mmol/L (131 mg/dL) (P < .005). Lovastatin therapy at 20 mg/d produced lowering of low-density lipoprotein cholesterol levels similar to that of the low-dose combination. CONCLUSIONS Low-dose combination drug therapy for the management of hypercholesterolemia appears to be an effective means of lowering cholesterol levels that remain persistently elevated after dietary therapy, at the same time, it should carry a low risk of toxic effects.