Exchange of phospholipids between unilamellar vesicles of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and plasma very low density lipoproteins.

Purified phosphatidylcholine exchange protein from bovine liver was used to exchange [14C]dipalmitoyl phosphatidylcholine from sonicated vesicles to human plasma very low density lipoproteins (VLDL). The exchange of [14C]-dipalmitoyl phosphatidylcholine for VLDL phospholipids was temperature dependent and linear with respect to time and amount of exchange protein. In the absence of the exchange protein, less than 10% of the [14C]dipalmitoyl phosphatidylcholine was transferred. At an initial weight ratio of [14C]-dipalmitoyl phosphatidylcholine vesicles to VLDL phospholipid (1.2 mg) of 2.2, the exchange protein (14 microgram) replaced 55% of the VLDL phospholipids with [14C]dipalmitoyl phosphatidylcholine in 15 min; VLDL protein and cholesterol content were unaltered. From these studies we conclude that the exchange protein is a useful method to alter the phospholipid composition of VLDL under conditions such that there is minimal perturbation of the lipoprotein.

Dietary and other correlates of changes in total and low density lipoprotein cholesterol in hypercholesterolemic men: the lipid research clinics coronary primary prevention trial.

Correlates of changes in total (TOTAL-C) and low density lipoprotein cholesterol (LDL-C) were examined in the 3806 hypercholesterolemic men of the Lipid Research Clinics Coronary Primary Prevention Trial. These correlates included changes in weight, dietary and alcohol intake, plasma glucose and thyroxine, cigarette smoking, packet count, lipid-lowering drugs other than cholestyramine, and antihypertensive drugs. In both placebo plus diet and cholestyramine plus diet treatment groups, decreases in Quetelet index and in saturated fat and cholesterol intake and increases in polyunsaturated fat intake were consistently associated with reductions in TOTAL-C and in LDL-C. In the cholestyramine group, plasma glucose and smoking were predictors of increased TOTAL-C and LDL-C; age and packet count were predictors of decreased TOTAL-C and LDL-C. Diuretic use was associated with increases in TOTAL-C in both groups and with increases in LDL-C in the cholestyramine group.

Therapy of familial hypercholesterolemia in childhood: diet and cholestyramine resin for 24 to 36 months.

In 16 children heterozygous for familial hypercholesterolemia, two- to three-year therapy with diet and cholestyramine resin (16 gm/day) was assessed in terms of effectiveness, practicality, and safety. All 16 children had previously taken a low-cholesterol (less than 300 mg/day), polyunsaturate-rich (P/S ratio, 1.5:1) diet and choeltyramine resin (12 gm/day) for 12 months. In this study, the cholestyramine resin dose was increased to 16 gm/day, and follow-up was maintained through months 13 through 18, 19 through 24, 25 through 30, and 31 through 36. Eleven children had good drug adherence (four packs of cholestyramine per day) and five children had fair adherence (two to three packs per day). Plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not significantly lowered on the drug-plus-diet regimen as compared to diet alone in five children with fair drug adherence. For children with good drug adherence, mean plasma cholesterol level was lowered below levels achieved on diet alone by 13% (months 13 through 18), 12% (months 19 through 24), 12% (months 25 through 30), and 11% (months 31 through 36) (P less than .05). Reduction in plasma cholesterol level was no greater with 16 than with 12 gm of cholestyramine per day. There were no group changes in mean plasma triglyceride levels. Cholestyramine resin, when added to diet and maintained for two to three years effects a significant reduction in total and LDL cholesterol levels in about 60% of children heterozygous for familial hypercholesterolemia. Continued reinforcement of both diet and drug adherence is necessary in the face of gradual increments in plasma cholesterol level with time.

Pediatric familial type II hyperlipoproteinemia: therapy with diet and colestipol resin.

Effects of a low-cholesterol, polyunsaturate-rich diet and a synthetic organic bile sequestrant polymer (U26,597A, colestipol) were studied in 21 children, heterozygous for familial hypercholesterolemia. Total cholesterol, beta-lipoprotein cholesterol, and triglyceride were measured twice on habitual diet, monthly for six months on a low-cholesterol diet, and monthly for six months on low-cholesterol diet plus 10 gm of colestipol per day. Total cholesterol (mean +/- 1 SD) was 295 +/- 37 on habitual diet, 278 +/- 29 on low-cholesterol diet, and fell significantly to 242 +/- 29 mg/100 ml on diet plus colestipol. Low-density lipoprotein (LDL) cholesterol was 234 +/- 37 on habitual diet, 220 +/- 28 on low-cholesterol diet, and fell significantly to 179 +/- 26 mg/100 ml on diet plus drug. Plasma triglyceride levels on habitual diet were 79 +/- 31, remained unchanged on low-cholesterol diet, 86 +/- 22, and were unaffected by low-cholesterol diet plus drug, 85 +/- 17 mg/100 ml. On diet alone, plasma LDL was not normalized (less than 170 mg/100 ml) in any of the 21 children, and cholesterol fell to within normal limits (less than 230 mg/100 ml) in only one child. The combination of diet plus colestipol resin normalized total and LDL cholesterol in 52% of the children. Cholesterol was lowered to a "moderately elevated" range of 230 to 250 mg/100 ml in an additional 14% of the children and LDL was lowered to a range of 170 to 190 mg/100 ml in an additional 29%. In 33% of the children, cholesterol remained greater than 250 mg/100 ml despite diet plus colestipol, while LDL was greater than 190 mg/100 ml in 19%. Colestipol is an effective and well-tolerated cholesterol lowering compound which, in conjunction with diet, may prove to be very useful in the treatment of children heterozygous for familial hypercholesterolemia.

Safety and efficacy of long-term diet and diet plus bile acid-binding resin cholesterol-lowering therapy in 73 children heterozygous for familial hypercholesterolemia.

Our specific aim was to examine the efficacy and safety of long-term cholesterol-lowering diet and bile acid-binding resin therapy in 73 children heterozygous for familial hypercholesterolemia (FH). We prospectively followed accretion of height and weight in 40 FH children for 5.8 years on diet alone and in 33 FH children for 4.3 years on diet and bile acid-binding resins (8 to 20 g/d). In 67 of these 73 children, sequential data on plasma cholesterol lowering was obtained, including 32 children on diet plus bile acid-binding resins and 35 on diet alone. For all 73 children, median age, sex, and race-specific percentiles for height and weight at entry were 50 and 50, respectively, and 5.7 years later, were unchanged at 50 and 50. Initial and final percentiles for height (r = .76, P less than .001) and weight (r = .70, P less than .001) were closely correlated. Percentile distributions for height and weight at entry into the study did not differ from those at the end of follow-up (P greater than .1), in both the 40 FH children on diet alone and the 33 on diet plus bile acid-binding resins. Tracking of height and weight did not differ in the 40 children on diet alone v the 33 on diet plus bile acid-binding resins (P greater than .1). During 6 years of follow-up there were no significant differences in the percentage of serial, postbaseline measurements for height which were either less than or greater than or equal to baseline percentiles, comparing 40 FH children on diet alone, 33 FH children on diet plus resin, and 39 normal children (on ad libitum diet). FH children on diet or plus resin had a smaller percentage of weight measurements equal to or more than baseline percentiles than normals on follow-up (P less than .01), probably reflecting restriction of total fat intake to less than 35% of calories. On diet alone, 32 FH children had total plasma cholesterol of 307 +/- 8 mg/dL (mean +/- SE); bile acid-binding resins were added to diet in these children at an average age of 11.5 years, with this regimen maintained for 4.6 +/- 0.4 years, leading to a mean reduction in total plasma cholesterol of 12.5% +/- 2% beyond the effects of diet alone (P less than .01).(ABSTRACT TRUNCATED AT 400 WORDS)

Nonprogression of coronary artery atherosclerosis in homozygous familial hypercholesterolemia after 31 months of repetitive plasma exchange.

The effects of plasma exchange performed every two weeks for 31 months in combination with diet and drug therapy were studied in a patient with receptor-defective homozygous familial hypercholesterolemia. Coronary angiography performed three years prior to commencing plasma exchange was compared to angiography 31 months after starting the program. Comparison of the angiograms taken six years apart showed no progression of coronary atheroma in the main left coronary artery in which a 30% narrowing was originally seen. An internal mammary artery-coronary artery bypass remained widely patent and showed no development of atherosclerosis. Plasma cholesterol levels were reduced 46% by plasma exchange, diet and drug compared to diet and drug alone. Achilles tendon xanthoma diminished significantly. It appears that plasma exchange combined with diet and drug therapy, while not producing regression of existing atheromatous lesions, does retard or prevent further progression.

Thrombophilia, hypofibrinolysis, and alveolar osteonecrosis of the jaws.

OBJECTIVES: Our specific aim in 49 patients (42 women, 7 men) with osteonecrosis of the jaw was to determine whether thrombophilia (increased tendency to intravascular thrombosis) or hypofibrinolysis (reduced ability to lyse thrombi) were associated with this regional avascular necrosis. STUDY DESIGN: Determinants of thrombosis and fibrinolysis were compared in healthy controls and in 42 women and 7 men who had biopsy-proven idiopathic osteonecrosis of the jaw with severe chronic jaw or facial pain syndromes and failure to respond to conventional medical and dental treatments. RESULTS: Of the 49 patients, 35 (71%) had thrombophilia or hypofibrinolysis and only 14 were normal. Thrombophilia as a sole coagulation defect was found in 10 patients, 7 with resistance to activated protein C and 3 with low protein C (deficiency of an antithrombotic protein). Hypofibrinolysis with low stimulated tissue plasminogen activator activity and high lipoprotein (a) (an atherogenic, hypofibrinolytic lipoprotein) were found as sole coagulation defects in seven and eight patients, respectively. Ten patients had mixed defects; 7 of these 10 had thrombophilia with resistance to activated protein C. Sinusoidal dilatation was a constant feature in maxillary and mandibular bone biopsies, suggesting venous occlusion with intramedullary hypertension. Marrow fibrosis and occasional fibrin plugs were additional microscopic features believed to impair venous drainage and to contribute to ischemic necrosis of the alveolar bone. CONCLUSIONS: Primary thrombophilia and hypofibrinolysis appear to be common, heritable, pathophysiologic risk factors for idiopathic osteonecrosis of the jaws. These coagulation defects may also contribute to alveolar neuralgia, atypical odontalgia and facial neuralgia, idiopathic trigeminal neuralgia, and to treatment failures so often encountered in patients with alveolar osteonecrosis and disabling chronic facial and jawbone pain syndromes.

A preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws.

OBJECTIVES: In a preliminary pilot study of 30 treatments in 26 patients with osteonecrosis of the jaws and chronic disabling facial pain, our specific aim was to determine whether, to what degree, and how safely therapy of hypofibrinolysis and thrombophilia would ameliorate the chronic pain associated with osteonecrosis of the mandible and maxilla. STUDY DESIGN: Thrombophilia was treated with Coumadin (DuPont) in 10 patients; hypofibrinolysis was treated with Winstrol (Sanofi-Winthrop) in 20 patients, including 4 who had mixed thrombophilia and hypofibrinolysis and had previously been treated with Coumadin. The initial treatment period was targeted to be 4 months. Each patient was asked to keep a daily written pain-relief numeric rating score and side-effects diary and to provide a summary pain-relief numeric rating score and side effects compilation for the total treatment period. RESULTS: There were 4 men and 22 women in the study group; their mean age was 49 +/- 11 years. The mean onset of their osteonecrosis pain was at age 45 +/- 12 years, and the mean duration of their facial pain prior to therapy was 4.5 +/- 4.2 years. Ten patients had one or more thrombophilic traits (there were two patients with protein C deficiency, five with resistance to activated protein C and/or the mutant Factor V Leiden gene, and four with high anticardiolipin antibodies). The 10 patients who were thrombophilic were treated with Coumadin (the international normalized ratio was targeted to 2.5-3.0) for 22 +/- 9 weeks. By self-reported pain-relief numeric rating scores, 6 of the 10 patients with thrombophilia (60%) had > or = 40% pain relief, 2 (20%) had no change, and 2 (20%) had increased pain (30% and 80% worse). Nine of the 10 patients with thrombophilia (90%) had no Coumadin-related side effects; 1 patient (10%) stopped Coumadin therapy (after 28 weeks) because of nosebleeds. Winstrol (6 mg per day) was used for 16 +/- 9 weeks in 20 patients with hypofibrinolysis, some of whom had one or more hypofibrinolytic traits (10 had high levels of plasminogen activator/inhibitor activity, usually accompanied by low stimulated tissue plasminogen activator activity; 13 had high Lp[a] lipoprotein). Of these 20 patients with hypofibrinolysis, 9 patients (45%) had > or = 40% pain relief, 3 patients (15%) had 20% to 30% relief, 5 patients (25%) had no improvement, and 3 patients (15%) had increased pain (30% worse, 60% worse, and 70% worse). Six of the 20 patients with hypofibrinolysis (30%) had no Winstrol-related side effects, while 14 (70%) had side effects that could be attributed to Winstrol, including weight gain, peripheral edema, increased facial and body hair, and acne--all of which were reversed within 6 weeks of stopping Winstrol therapy. CONCLUSIONS: We postulate that thrombophilia and hypofibrinolysis lead to impaired venous circulation and venous hypertension of the mandible/maxilla with subsequent development of osteonecrosis and chronic facial pain. In many patients, facial pain can be ameliorated by treating the pathogenetic coagulation defects with Coumadin or Winstrol. Large, double-blind, placebo-controlled crossover studies will be required in the future to validate these preliminary results and to determine whether pain relief with Coumadin or Winstrol justifies the risks and side effects associated with these medications, especially for long-term use, in osteonecrosis of the jaws.

Exogenous estrogen may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain.

A 32 year old white female, in apparently good health, failed to respond to conservative wound care for alveolar osteitis after a routine mandibular first molar extraction. Curettage and biopsy of necrotic alveolar bone from the #30 socket escalated her pain such that hospitalization was necessary for pain management with intravenous morphine. Twelve months prior to admission she had been placed on exogenous estrogen (Premarin, 0.625 mg/day) after a partial oophorectomy. While hospitalized, she was found to have resistance to activated protein C (APCR). Premarin was discontinued. After discharge, weekly changes of an antibiotic impregnated dressing allowed for progressive regeneration of bone and epithelium with gradual reduction in her pain. She was found to be heterozygous for the mutant Factor V Leiden, a heritable factor for increased tendency to form thrombi, so-called thrombophilia. We speculate that the exogenous estrogen administration exacerbated the thrombophilia associated with the Factor V Leiden mutation by compounding the patient's resistance to activated protein C thereby contributing to her development of osteonecrosis and severe alveolar neuralgia.

Colestipol and probucol: treatment of primary and familial hypercholesterolemia and amelioration of atherosclerosis.

Colestipol is a safe, effective, cholesterol-lowering, bile-acid sequestrant that lowers low-density-lipoprotein (LDL) and total plasma cholesterol levels without consistently affecting high-density-lipoprotein (HDL) cholesterol levels. Long-term colestipol therapy in conjunction with diet may reduce xanthoma size, arrest progression of coronary artery atherosclerosis, and may reduce mortality from coronary heart disease. Probucol, a bisphenol cholesterol-lowering drug, is an effective cholesterol-lowering agent that reduces levels of HDL cholesterol, HDL cholesterol, and apoprotein A-1, the major apolipoprotein of HDL. Because HDL cholesterol is independently and inversely associated with development of coronary heart disease, the ramifications of simultaneous lowering of LDL and HDL cholesterol levels by probucol treatment need further study. Long-term, placebo-controlled studies of repetitive coronary arteriography, coronary heart disease morbidity and mortality, or both are needed to ascertain the efficacy of long-term probucol use in relation to development of atherosclerosis.

Role of thrombosis in osteonecrosis.

We think that osteonecrosis, to a large degree, develops because of familial and acquired thrombophilia and hypofibrinolysis causing venous thrombosis in the femoral head. We postulate that venous thrombosis leads to increased intraosseus venous pressure, reduced arterial flow, and hypoxic bone death. Many studies suggest that familial and acquired thrombophilia and hypofibrinolysis may play an important etiologic role in adults with osteonecrosis of the hip and jaw and in children with Legg-Perthes disease (pediatric osteonecrosis). We have limited pilot data in adults with osteonecrosis associated with familial thrombophilia and hypofibrinolysis that suggest that 12 weeks of therapy with enoxaparin, if started early (Ficat stages I/II) before femoral head collapse (Ficat stages III/IV), may interrupt the progression of osteonecrosis of the hip. Placebo-controlled trials with a 2-year follow-up or longer in adults will be required to assess the promise of the pilot anticoagulant studies in osteonecrosis.

Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens.

We assessed whether heterozygosity for the thrombophilic Leiden mutation of the factor V gene (MFV) was pathogenetic for alveolar osteonecrosis of the jaw and chronic facial pain (neuralgia-inducing cavitational osteonecrosis (NICO)) in 89 patients with NICO. A second specific aim was to assess for thrombophilic synergism between exogenous estrogens and MFV for development of osteonecrosis of the jaw. MFV was found in 24% of the patients, 16 (21%) of 76 women and 5 (39%) of 13 men. The mutation was much less common in healthy normal controls: 3 (3%) of 101 women (chi2 = 14.8, p = 0.001) and 4 (3.7%) of 108 men (chi2 = 20.4, p = 0.001). Patients with and without MFV did not differ in tissue plasminogen activator activity, plasminogen activator inhibitor activity, proteins C and S, lipoprotein (a), or anticardiolipin antibodies (p > 0.05). Use of standard-dose oral contraceptives and/or postmenopausal estrogens before the development of NICO was more common in female patients with MFV (13 (81%) of 16) than in those without it (23 (38%) of 60; chi2 = 9.33, p = 0.002). When the thrombophilic effects of such exogenous estrogens were superimposed on the familial resistance to activated protein C associated with MFV, thrombophilia was augmented and the risk of osteonecrosis was increased. Since heterozygosity for this mutation occurs in at least 3% of unselected, healthy women, measurement of resistance to activated protein C and MFV would identify women at high risk for venous thrombosis and osteonecrosis, in whom use of oral contraceptives or postmenopausal estrogens might be contraindicated, while identifying a much larger group of women (approximately 97%) without the mutation whose risk from exogenous estrogens would be low.

The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis.

We studied 55 patients (50 women, 5 men) with severe facial pain and biopsy-proven neuralgia-inducing cavitational osteonecrosis (NICO) of the alveolar bone of the jaws. Our aim was to assess the pathophysiologic contributions to NICO of anticardiolipin antibodies (aCLA), thrombophilia (increased tendency to intravascular thrombi), and hypofibrinolysis (reduced ability to lyse thrombi). Of the 55 patients, 43 (78%) had one or more tests positive for thrombophilia or hypofibrinolysis (or both), and only 12 (22%) were normal. Eighteen of 55 (33%) patients had high aCLA (> 2 SD above mean value for control subjects); immunoglobulin G (IgG) (p = 0.01) and immunoglobulin A (IgA)(p = 0.001) levels were higher in patients than in controls. The distribution of elevated aCLA immunoglobulin classes among patients was as follows: IgG alone, 5 (9%); IgA alone, 7 (13%); and IgM alone, 3 (5%). Three patients (5%) had high levels of both IgG and IgA aCLA. Other defects of the thrombotic or fibrinolytic systems in the 55 patients included high lipoprotein(a) in 36% (vs 20% in control subjects (p = 0.03)), low stimulated tissue plasminogen activator activity (tPA-Fx) in 22% (vs 7% in control subjects (p = 0.08)), high plasminogen activator inhibitor activity (PAI-Fx) in 18% (vs 8% in control subjects (p = 0.03)), resistance to activated protein C in 16% (vs 0% in control subjects (p = 0.007)), low antigenic protein C in 4+ (vs 0% in control subjects (p > 0.2)), and low antigenic protein S in 4% (vs 0% in control subjects (p > 0.2)). Anticardiolipin antibodies and other defects of the thrombotic and fibrinolytic systems appear to be common, potentially reversible pathogenetic risk factors associated with osteonecrosis of the jaw.