Phospholipid hydrolytic enzymes in a 'cesspool' of arterial intimal lipoproteins: a mechanism for atherogenic lipid accumulation.
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Arteriosclerosis↗
Biomedical subjects
J R Guyton
Publications and source records attributed to J R Guyton.
Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group.
OBJECTIVE: To provide a direct comparison of agents that raise plasma levels of high-density lipoprotein cholesterol (HDL-C) to help devise strategies for coronary risk reduction. METHODS: In a multicenter, randomized, double-blind trial, we compared the effects of extended-release niacin (Niaspan), at doses increased sequentially from 1000 to 2000 mg at bedtime, with those of gemfibrozil, 600 mg given twice daily, in raising low levels of HDL-C. Enrollment criteria included an HDL-C level of 1.03 mmol/L or less (< or =40 mg/dL), a low-density lipoprotein cholesterol level of 4.14 mmol/L or less (< or =160 mg/dL) or less than 3.36 mmol/L (<130 mg/dL) with atherosclerotic disease, and a triglyceride level of 4.52 mmol/L or less (< or =400 mg/dL). RESULTS: Among 173 patients, 72 (82%) of the 88 assigned to Niaspan treatment and 68 (80%) of the 85 assigned to gemfibrozil treatment completed the study. Niaspan, at 1500 and 2000 mg, vs gemfibrozil raised the HDL-C level more (21% and 26%, respectively, vs 13%), raised the apolipoprotein A-I level more (9% and 11% vs 4%), reduced the total cholesterol-HDL-C ratio more (-17% and -22% vs -12%), reduced the lipoprotein(a) level (-7% and -20% vs no change), and had no adverse effect on the low-density lipoprotein cholesterol level (2% and 0% change vs a 9% increase). Significance levels for comparisons between medications ranged from P<.001 to P<.02. Gemfibrozil reduced the triglyceride level more than Niaspan (P<.001 to P = .06, -40% for gemfibrozil vs -16% to -29% for Niaspan, 1000 to 2000 mg). Effects on plasma fibrinogen levels were significantly favorable for Niaspan compared with gemfibrozil (P<.02), as gemfibrozil increased the fibrinogen level (from 5% to 9%) and Niaspan tended to decrease the fibrinogen level (from -1% to -6%). CONCLUSIONS: In patients with a low baseline HDL-C level, Niaspan at its higher doses provided up to 2-fold greater HDL-C increases, decreases in lipoprotein(a), improvements in lipoprotein cholesterol ratios, and lower fibrinogen levels compared with gemfibrozil. Gemfibrozil gave a greater triglyceride reduction but also increased the low-density lipoprotein cholesterol level, which did not occur with Niaspan.
Adult↗
Nonpharmacologic and pharmacologic treatment of patients with low levels of high-density lipoprotein cholesterol.
Low levels of high-density lipoprotein cholesterol (HDL-C) constitute a strong risk factor for developing coronary heart disease. This risk can be decreased by even slight improvements in HDL-C levels. This review discusses both pharmacologic and nonpharmacologic treatments of patients with low levels of HDL-C, including lifestyle modifications and the benefits of oral estrogens, niacin, fibrates, statins, and combination drug therapy.
Anticholesteremic Agents↗
Dual hepatic metabolism of cerivastatin--clarifications.
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Aged↗
Combination drug therapy for combined hyperlipidemia.
Combination therapy for hyperlipidemia, especially combined hyperlipidemia, may have advantages over single drug therapy, affording better improvement in lipoprotein risk factors and possibly better prevention of atherothrombotic events. Although preliminary experience has been gained using treatment combinations of niacin with statins, and fibrates with statins, few studies have focused on angiographic or clinical outcomes. Both of these treatment combinations increase the risk of drug-induced myopathy and rhabdomyolysis. Current estimates of myopathy incidence are much lower than original estimates, but the relative safety of combined therapy might depend upon employing low or moderate statin doses. Safety depends critically upon educating the patient to respond appropriately to muscle symptoms, to intercurrent illness, and to concurrent use of certain other medications. Other useful drug combinations include those derived by addition of fish oil, bile acid binding resins, or stanol esters, as well as nonstatin combinations such as niacin-resin or fibrate-niacin.
Arteriosclerosis↗
Treatment of type III hyperlipoproteinemia.
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Apolipoproteins E↗
Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.
Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p <0.001). Niaspan was generally well tolerated, although flushing was common (75%); however, there was a progressive decrease in flushing with time from 3.3 episodes in the first month to < or = 1 episode by week 48. Aspirin was used by one third of patients before Niaspan dosing to minimize flushing episodes. Although serious adverse events occurred in about 10% of patients, none were considered probably or definitely related to Niaspan. Adverse events in general varied widely, but their true relation to the study drug is difficult to ascertain without a placebo (control) group. No deaths occurred. There were statistically significant changes in hepatic transaminases, alkaline phosphatase, direct bilirubin, phosphorus, glucose, amylase, and uric acid. However, these changes were mostly small and are not likely to be biologically or clinically significant (the decrease in phosphorus is a new finding in niacin therapy). No myopathy was observed. Thus, this long-term study confirms the earlier short-term findings that Niaspan is safe and effective as monotherapy in plasma lipoprotein regulation.
Adult↗
A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients.
Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides <9 mmol/L [800 mg/dL]) into 3 treatment groups: (1) Niaspan 1,000 mg/day; (2) Niaspan 2,000 mg/day; and (3) placebo. The primary treatment endpoint was LDL-cholesterol level. This endpoint was not significantly affected by placebo (0.2% increase), but Niaspan decreased LDL cholesterol by 5.8% (1,000 mg/day) and 14.6% (2,000 mg/day) (p <0.001). Likewise, with placebo there were significant changes in total cholesterol, triglycerides, lipoprotein(a), and apoprotein B, whereas both Niaspan 1,000 and 2,000 mg/day significantly (p <0.001) decreased these parameters. In addition, both Niaspan groups showed significant (p <0.001) increases in HDL cholesterol (17% and 23%, respectively), including HDL subfractions. With respect to flushing, 20% of the placebo group reported at least 1 episode, whereas 88% and 83% of the Niaspon 1,000- and 2,000-mg/day groups, respectively, reported episodes. There was no hepatotoxicity as liver enzyme levels remained within clinically accepted limits in all treatment groups. However, Niaspan 2,000 mg/day showed a significant increase in aspartate aminotransferase compared with baseline and placebo. This trial demonstrated a cholesterol-modifying effect of Niaspan consistent with those reported for niacin, but demonstrated a better tolerance for flushing. Moreover, in contrast to sustained-release formulations, Niaspan showed relatively mild hepatic effects.
Cholesterol, LDL↗
Effect of niacin on atherosclerotic cardiovascular disease.
Niacin has been studied in 6 major clinical trials with cardiovascular endpoints. The Coronary Drug Project (CDP) was the largest of these trials and the only one to use niacin monotherapy affecting cardiovascular outcomes: recurrent myocardial infarction and cerebrovascular events were significantly decreased. After long-term (15 years) follow-up, total mortality was also found to be decreased. The other 5 trials used varying combinations of niacin with other pharmacologic agents, examining coronary and total mortality, coronary events, and angiographic progression/regression. Significant benefit was found in all trials except for one in patients with normal cholesterol levels at entry. Thus, the use of niacin to prevent or treat atherosclerotic cardiovascular disease is based on strong and consistent evidence from clinical trials.
Cerebrovascular Disorders↗
Treatment of hyperlipidemia with combined niacin-statin regimens.
Combined use of niacin with a statin is an attractive option, since these types of medication have the best records in clinical trials for reduction in cardiovascular events and improvement in progression/regression of coronary lesions. In early use, the niacin-statin combination generated a few case reports documenting severe myopathy and rhabdomyolysis. Subsequent prospective trials in >400 patients, however, have not encountered myopathy. This experience includes 165 patients who took a statin in combination with Niaspan, a new, extended-release niacin administered once nightly. Hepatic toxicity with immediate-release niacin and with Niaspan used in combination with statins has been minimal. However, substantial transaminase elevations occurred with the use of a sustained-release niacin (Nicobid) given twice daily. The niacin-statin treatment regimens gave augmented low-density lipoprotein (LDL)-cholesterol reduction along with favorable changes in high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and triglycerides. This combination therapy can be used safely as long as (1) careful attention is given to niacin formulation and dosing; (2) liver functions are monitored; and (3) patients are educated to recognize symptoms of myopathy. However, special caution should apply to use of niacin in combination with high doses of statins, or with statins introduced into clinical practice in 1997 or later, since little experience has accumulated in these circumstances.
Anticholesteremic Agents↗
Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia.
We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.
Adult↗
Comparison of proximate composition and fatty acid and cholesterol content of lean and typical commercial pork.
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Animals↗
Novel large apolipoprotein E-containing lipoproteins of density 1.006-1.060 g/ml in human cerebrospinal fluid.
Although the critical role of apolipoprotein E (apoE) allelic variation in Alzheimer's disease and in the outcome of CNS injury is now recognized, the functions of apoE in the CNS remain obscure, particularly with regard to lipid metabolism. We used density gradient ultracentrifugation to identify apoE-containing lipoproteins in human CSF. CSF apoE lipoproteins, previously identified only in the 1.063-1.21 g/ml density range, were also demonstrated in the 1.006-1.060 g/ml density range. Plasma lipoproteins in this density range include low-density lipoprotein and high-density lipoprotein (HDL) subfraction 1 (HDL1). The novel CSF apoE lipoproteins are designated HDL1. No immunoreactive apolipoprotein A-I (apo A-I) or B could be identified in the CSF HDL1 fractions. Large lipoproteins 18.3 +/- 6.6 nm in diameter (mean +/- SD) in the HDL1 density range were demonstrated by electron microscopy. Following fast protein liquid chromatography of CSF at physiologic ionic strength, apoE was demonstrated in particles of average size greater than particles containing apoA-I. The largest lipoproteins separated by this technique contained apoE without apoA-I. Thus, the presence of large apoE-containing lipoproteins was confirmed without ultracentrifugation. Interconversion between the more abundant smaller apoE-HDL subfractions 2 and 3 and the novel larger apoE-HDL1 is postulated to mediate a role in cholesterol redistribution in brain.
Apolipoprotein A-I↗
Lovastatin increases exercise-induced skeletal muscle injury.
This study tested the hypothesis that exercise in combination with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor produces greater creatine kinase (CK) elevations, an index of skeletal muscle injury, than exercise alone, using a double-blind, placebo-controlled design. Fifty-nine healthy men aged 18 to 65 years with low-density lipoprotein cholesterol (LDL-C) levels greater than 3.36 mmol/L (130 mg/dL) despite diet therapy were studied. Subjects were randomly assigned to receive lovastatin (40 mg/d) or placebo for 5 weeks. Subjects completed 45 minutes of downhill treadmill walking (-15% grade) at 65% of their predetermined maximum heart rate after 4 weeks of treatment. During the subsequent week, they completed four 10-repetition sets of one-arm biceps curl exercise using 50% of their maximum capacity. CK levels were measured before exercise and daily for 4 and 5 days after the treadmill and biceps exercises, respectively. Age, body weight, and blood lipid and lipoprotein levels were similar in lovastatin and placebo groups. Resting CK levels were 33% higher in the lovastatin group before treatment (P < .05), but were not significantly altered by lovastatin. CK levels were 62% and 77% higher (P < .05) in the lovastatin group 24 and 48 hours after treadmill exercise after adjusting for initial CK differences. There were no significant CK differences between lovastatin and placebo groups after biceps curl exercise. We conclude that HMG-CoA reductase inhibitors exacerbate exercise-induced skeletal muscle injury.
Adult↗
Dietary fish oil. Influence on lesion regression in the porcine model of atherosclerosis.
We examined the influence of dietary fish oil on lesion regression in a porcine model of atherogenesis. Thirty-two female Yucatan miniature pigs were fed an atherogenic diet for 8 months. A no-regression group (n = 8) was killed to determine the extent of atherosclerosis at 8 months. Three regression groups were switched to normal minipig chow supplemented with either MaxEPA fish oil (FO group, n = 8), a control oil with the ratio of polyunsaturated to monounsaturated to saturated fatty acid matched to that of the fish oil (CO group, n = 8), or no oil supplement (NO group, n = 8) for a further 4 months. Plasma cholesterol levels reached between 15 and 20 mmol/L during the atherogenic phase and returned to normal (2 mmol/L) within 2 months of the beginning of the regression diet. Compared with the NO group, fish oil supplementation during the regression phase caused a decrease in VLDL and HDL cholesterol and an increase in LDL cholesterol. Similarly, the control oil also caused a decrease in VLDL cholesterol; however, in contrast to the FO group, HDL cholesterol increased and LDL cholesterol was unchanged. FO LDL, which had decreased levels of 20:4 (n-6 fatty acid) and increased levels of 18:3, 20:5, and 22:6 (n-3 fatty acids), was shown to be twice as susceptible to copper-mediated oxidation as CO LDL particles. Morphological examination of the major blood vessels revealed a significant reduction in lesion area in the ascending and thoracic aorta as well as the carotid artery after the regression diet; however, there was no significant difference between the fish oil and control oil groups in any of the vessels measured. Therefore, despite increased LDL, decreased HDL, and an increased susceptibility to in vitro oxidation of LDL, fish oil supplementation of a regression diet did not influence lesion regression.
Animals↗
Identification and quantification of regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein.
Oxidation of human LDL is implicated as an initiator of atherosclerosis. Isolated low density lipoprotein (LDL) and high density lipoprotein (HDL2) were exposed to aqueous radicals generated from the thermolabile azo compound 2,2'-azobis(2-amidinopropane) dihydrochloride. The primary nonpolar lipid products formed from the autoxidation of LDL and HDL were the regioisomeric cholesteryl linoleate hydroperoxides. In LDL oxidations, 9- and 13-hydroperoxides with trans,cis conjugated diene were formed as the major oxidation products if endogenous alpha-tocopheral was present in the LDL. After extended oxidation of LDL, at the time when endogenous alpha-tocopherol was consumed, the two trans,cis conjugated diene hydroperoxides began to disappear and the 9- and 13-hydroperoxides with trans,trans conjugated diene appeared. At very long oxidation times, none of the primary products, the conjugated diene hydroperoxides, were present. In HDL2, which has only very low levels of antioxidants, both the 9- and 13-hydroperoxides with trans,cis conjugated diene and the 9- and 13-hydroperoxides with trans,trans conjugated diene were formed at early stages of oxidation. The corresponding alcohols were also formed in the HDL2 oxidations. A mechanistic hypothesis consistent with these observations is presented.
Alcohols↗
Development of the lipid-rich core in human atherosclerosis.
In recent years the role of the atherosclerotic core in promoting plaque rupture has become well recognized. A new insight into core development is its origination early in atherogenesis, before formation of the fibrous plaque. The early core is associated with accumulation of vesicular lipid rich in free cholesterol. Later in core development, lipid deposits become more diverse. The weight of evidence points toward a direct extracellular process, probably lipoprotein aggregation and fusion, as the chief pathway of cholesteryl ester accumulation, although foam cell death may also contribute cholesteryl ester. The mechanism or mechanisms of formation of vesicular, cholesterol-rich deposits are unknown. Since the increase in free cholesterol is likely to have deleterious effects on cells bordering the core, the further elucidation of cellular and biochemical pathways leading to and responding to free cholesterol accumulation is of great importance. Complement activation and cellular stress responses are prominent in the vicinity of core lipids, but their pathogenetic roles remain to be established. Since the core appears so early in atherogenesis, these as well as other, yet to be determined cellular responses to core lipids, oxidized and unoxidized, could have a considerable effect on overall lesion development. Much remains to be learned about macrophage and smooth muscle responses, calcification, capillarization, and matrix protein alterations in the evolution of the core and surrounding arterial intima.
Arteriosclerosis↗
The role of lipoproteins in atherogenesis.
Some of the concepts presented in this review can be recapped as follows: LDL is found in a much higher concentration in arterial intima than in any other connective tissue in the body. One response of the intimal to high LDL levels appears to be a toxic response resulting in atherosclerotic core formation, with eventual breakdown and rupture of the intima causing arterial thrombosis. The core does not develop simply from foam cell necrosis, but from a complex interaction of tissue lipoproteins, cells, and extracellular matrix. Core development is an early event in atherosclerosis progression, since the features of early cores can be found in lesions resembling fatty streaks. Lipoprotein aggregation and fusion may be key processes in extracellular lipid deposition. This is obviously an incomplete summary of the role of lipoproteins in atherosclerosis, but it does point toward new significant areas of research interest. There are several particularly intriguing research questions at the present time. How do the cholesterol-rich extracellular lipid deposits develop? Lipoprotein aggregation and fusion is a partial explanation, but how do deposits with 60% free cholesterol develop when the lipoproteins contributing to them have only 20-30% free cholesterol? Multiple hypotheses have been posed, but little evidence for any one pathway is available. Nevertheless, the extremely high levels of free cholesterol in the atherosclerotic core are likely to have effects on cellular membrane functions. Another intriguing question: How is core development related to the overall process of fatty streak to fibrous plaque conversion? The fibrous plaque has two hallmarks, one of which is a rather massive proliferation of cells and fibrous tissue, and the other is the development of the core. Our recent evidence suggests that core development may occur first (Guyton and Klemp, 1993).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗