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R S Lees

Publications and source records attributed to R S Lees.

At least 19 recordsLinked to original sources
PubMed2001

The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function.

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.

Adult↗
PubMed2001

Reversible and irreversible non-internalized LDL and methyl LDL accumulation by human fibroblasts.

In previous in vivo animal studies, we showed that low density lipoprotein (LDL) accumulated irreversibly at the edges of healing arterial lesions rather than being internalized and degraded. To see if similar LDL accumulation occurs in vitro, fibroblasts from normal and homozygous familial hypercholesterolemic (FH) subjects were incubated at 37 degrees C with 125I-LDL and 125I-methyl LDL; the latter is not recognized by any known LDL receptor. Normal fibroblast accumulation of LDL and methyl LDL (5 microg/ml) plateaued within 1 h at 200 and 100 ng/mg, respectively. With FH cells, both LDL and methyl LDL accumulation plateaued at 100 ng/mg. Lipoprotein accumulation by both cell types rose steeply at concentrations up to 15-25 microg/ml, and less so at higher concentrations. Except for degradation of LDL by normal cells, degradation was minimal, which indicated that much of the lipoprotein accumulation was unaccompanied by internalization. The accumulation of both lipoproteins by both cell types was greater at 37 degrees C than at 4 degrees C, and was inhibited between 43 and 75% by homologous unlabeled lipoprotein. To see if any accumulation was irreversible, cells were incubated with radiolabeled lipoproteins for 3 h (pulse), then with homologous unlabeled lipoproteins for up to 20 h (chase). About 50% of intact radiolabeled lipoprotein rapidly dissociated from cells into the medium in the first 4 h of the chase period. In contrast, between 4 and 20 h, most of the remaining intact LDL and methyl LDL appeared to be irreversibly bound, because it was released at a rate of only 0-1%/h. Thus, we conclude that, under the conditions studied, both reversible and irreversible non-internalized LDL binding play a major role in LDL accumulation by cultured cells.

Binding, Competitive↗
PubMed2000

Low-density lipoprotein apheresis therapy during pregnancy.

Pregnancy in patients with severe hypercholesterolemia and coronary artery disease results in multiple problems both for mother and fetus; the most potent agents for low-density lipoprotein (LDL) cholesterol reduction, the HMG-CoA reductase inhibitors (statins) cannot be used during pregnancy. We present a case in which LDL apheresis via heparin-induced extracorporeal LDL precipitation was employed safely and efficaciously during pregnancy in a woman with heterozygous familial hypercholesterolemia and stable coronary artery disease.

Adult↗
PubMed2000

A new model-based technique for enhanced small-vessel measurements in X-ray ciné-angiograms.

Arterial diameter estimation from X-ray ciné angiograms is important for quantifying coronary artery disease (CAD) and for evaluating therapy. However, diameter measurement in vessel cross sections < or =1.0 mm is associated with large measurement errors. We present a novel diameter estimator which reduces both magnitude and variability of measurement error. We use a parametric nonlinear imaging model for X-ray ciné angiography and estimate unknown model parameters directly from the image data. Our technique allows us to exploit additional diameter information contained within the intensity profile amplitude, a feature which is overlooked by existing methods. This method uses a two-step procedure: the first step estimates the imaging model parameters directly from the angiographic frame and the second step uses these measurements to estimate the diameter of vessels in the same image. In Monte-Carlo simulation over a range of imaging conditions, our approach consistently produced lower estimation error and variability than conventional methods. With actual X-ray images, our estimator is also better than existing methods for the diameters examined (0.4-4.0 mm). These improvements are most significant in the range of narrow vessel widths associated with severe coronary artery disease.

Arterial Occlusive Diseases↗
PubMed1999

Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. QUIET Investigators. QUinapril Ischemic Event Trial.

Angiotensin-converting enzyme inhibitors have proven to be of clinical benefit in congestive heart failure. Whether they also provide benefit to patients with coronary artery disease in the absence of congestive heart failure via an antiatherosclerotic mechanism is a question the QUinapril Ischemic Event Trial quantitative coronary angiography (QCA) study attempted to answer: 1,750 patients with normal left ventricular function who were undergoing coronary angiography and angioplasty were randomized to 20 mg/day of quinapril versus placebo and followed for 3 years for cardiac end points. A randomly selected subgroup of the total cohort underwent follow-up angiography. The primary QCA end point was the categorical designation of progression versus nonprogression, defined either by QCA or by a cardiac event in patients selected for the QCA trial who had no usable follow-up x-ray film. Secondary end points in patients with 2 angiograms were: new stenosis development, change in minimum lumen diameter index, and change in percent diameter stenosis index. There were 119 progressors among 243 placebo-treated patients (49%) and 111 progressors among 234 quinapril-treated patients (47%) (p = NS). There were 44 patients with new stenosis development in the placebo group (19%) and 50 (22%) in the quinapril group (p = NS). Change in minimum lumen diameter index was -0.21+/-0.03 mm in the placebo group and -0.18+/-0.03 mm in the quinapril group (p = NS). Finally, change in percent diameter stenosis index was +5.1+/-1.0 in the placebo group and +3.5+/-1.0 in the quinapril group (p = NS). Potential confounders of this trial are presented and discussed.

Adult↗
PubMed1999

Non-pharmacological lowering of low-density lipoprotein by apheresis and surgical techniques.

In the past year, new data have appeared on the long-term benefits of low-density lipoprotein apheresis in severely hypercholesterolemic patients who are refractory to lipid-lowering drug therapy. Such data are critical for clinical decision-making, because they confirm the hypothesis that the dramatic reduction in low-density lipoprotein made possible by this technique produces clear-cut clinical benefits. Because of its efficacy and low incidence of side-effects, apheresis for severe drug-refractory hypercholesterolemia has superseded surgical approaches, such as liver transplantation or ileal bypass.

Animals↗
PubMed1998

Histopathology of human coronary atherosclerosis by quantifying its chemical composition with Raman spectroscopy.

BACKGROUND: Lesion composition, rather than size or volume, determines whether an atherosclerotic plaque will progress, regress, or rupture, but current techniques cannot provide precise quantitative information about lesion composition. We have developed a technique to assess the pathological state of human coronary artery samples by quantifying their chemical composition with near-infrared Raman spectroscopy. METHODS AND RESULTS: Coronary artery samples (n=165) obtained from explanted recipient hearts were illuminated with 830-nm infrared light. Raman spectra were collected from the tissue and processed to quantify the relative weights of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts in the examined artery location. The artery locations were then classified by a pathologist and grouped as either nonatherosclerotic tissue, noncalcified plaque, or calcified plaque. Nonatherosclerotic tissue, which included normal artery and intimal fibroplasia, contained an average of approximately 4+/-3% cholesterol, whereas noncalcified plaques had approximately 26+/-10% and calcified plaques approximately 19+/-10% cholesterol in the noncalcified regions. The average relative weight of calcium salts was 1+/-2% in noncalcified plaques and 41+/-21% in calcified plaques. To make this quantitative chemical information clinically useful, we developed a diagnostic algorithm, based on a first set of 97 samples, that demonstrated a strong correlation of the relative weights of cholesterol and calcium salts with histological diagnoses of the same locations. This algorithm was then prospectively tested on a second set of 68 samples. The algorithm correctly classified 64 of these new samples, thus demonstrating the accuracy and robustness of the method. CONCLUSIONS: The pathological state of a given human coronary artery may be assessed by quantifying its chemical composition, which can be done rapidly with Raman spectroscopic techniques. When Raman spectra are obtained clinically via optical fibers, Raman spectroscopy may be useful in monitoring the progression and regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic intervention.

Algorithms↗
PubMed1998

Measurement of the time course of peripheral vasoactivity: results in cigarette smokers.

The brachial artery response to flow was assessed non-invasively by ultrasonic measurement of arterial diameter before and 1 min after 5 min of cuff-induced ischemia. It was hypothesized that continuous measurement of arterial diameter and flow velocity would provide a more complete and accurate evaluation of the response to change in blood flow. Therefore, a system to provide this data was developed and its utility in exploring the acute and chronic effects of smoking on arterial function was demonstrated. Brachial artery diameter and flow velocity were measured before, during and for at least 3 min after 5-min of forearm cuff occlusion. Measurements were acquired from 12 habitual smokers (mean 18.3 pack years), after at least 2 h (mean 6.5 h) without smoking ('pre-cigarette') and immediately after smoking one cigarette ('post-cigarette'), as well as from 12 age- and sex-matched lifelong non-smokers. The slope of brachial artery diameter versus time during the occlusion period and the maximum dilation after cuff release relative to the pre-occlusion diameter were significantly decreased in pre-cigarette smokers compared with non-smokers (P < 0.0001 for both comparisons). Importantly, the absolute arterial dilation during the period of increased flow (i.e. reactive hyperemia) was equal for the pre-cigarette smokers and non-smokers (0.31 +/- 0.03 vs. 0.32 +/- 0.04 mm, respectively). Immediately after smoking, the flow response parameters in chronic smokers changed toward non-smoker values (P < 0.001 for post-cigarette vs. pre-cigarette comparisons of the diameter slope during occlusion and the maximum dilation after cuff release relative to pre-occlusion diameter). Thus, continuous diameter measurements in smokers who refrained from smoking demonstrated abnormal constriction of the brachial artery during the low flow period of cuff occlusion, but normal absolute dilation during the period of increased flow. Immediately after smoking, the artery no longer constricted during occlusion. These findings demonstrate the potential value of continuous monitoring of arterial diameter and flow velocity before, during and after application of a vasoactive stimulus.

Adult↗
PubMed1997

Determination of human coronary artery composition by Raman spectroscopy.

BACKGROUND: We present a method for in situ chemical analysis of human coronary artery using near-infrared Raman spectroscopy. It is rapid and accurate and does not require tissue removal; small volumes, approximately 1 mm3, can be sampled. This methodology is likely to be useful as a tool for intravascular diagnosis of artery disease. METHODS AND RESULTS: Human coronary artery segments were obtained from nine explanted recipient hearts within 1 hour of heart transplantation. Minces from one or more segments were obtained through grinding in a mortar and pestle containing liquid nitrogen. Artery segments and minces were excited with 830 nm near-infrared light, and Raman spectra were collected with a specially designed spectrometer. A model was developed to analyze the spectra and quantify the amounts of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts present. The model provided excellent fits to spectra from the artery segments, indicating its applicability to intact tissue. In addition, the minces were assayed chemically for lipid and calcium salt content, and the results were compared. The relative weights obtained using the Raman technique agreed with those of the standard assays within a few percentage points. CONCLUSIONS: The chemical composition of coronary artery can be quantified accurately with Raman spectroscopy. This opens the possibility of using histochemical analysis to predict acute events such as plaque rupture, to follow the progression of disease, and to select appropriate therapeutic interventions.

Calcium↗
PubMed1997

Peripheral vasoactivity in familial hypercholesterolemic subjects treated with heparin-induced extracorporeal LDL precipitation (HELP).

Hypercholesterolemia is associated with abnormalities in arterial vasoactivity which can be reversed with cholesterol-reducing therapies. Heparin-induced extracorporeal LDL precipitation (HELP), an invasive method for treating refractory hypercholesterolemia, causes regression of both xanthomas and atherosclerosis, but its effect on vasoactivity has not been investigated. We tested the effects of HELP on vasoactivity with an ultrasound system for continuous measurement of arterial flow velocity and end-diastolic diameter. We measured brachial artery vasoactivity before, during, and after a 5 min forearm vascular occlusion. Vasoactivity measurements were acquired from 6 subjects with familial hypercholesterolemia (FH) who had been treated chronically with HELP, immediately before and after each of 4 treatments, and from 12 age- and sex-matched normocholesterolemic subjects (2 matched with each HELP subject). Peak arterial dilation after cuff release, relative to the pre-occlusion diameter, was similar for the pre-treatment, post-treatment, and normocholesterolemic groups (0.29 mm pre-treatment, 0.30 mm post-treatment and 0.33 mm normocholesterolemic, P = NS). The slope of arterial diameter during occlusion was also similar for the three groups (-0.10 microm/s pre-treatment, 0.02 microm/s post-treatment, and 0.06 microm/s normocholesterolemic, P = NS). These two parameters are known to be decreased in hypercholesterolemic subjects to an extent which could be readily detected by the power of this study. Interestingly, one homozygous FH subject consistently demonstrated significant improvement in these two parameters immediately after HELP, suggesting an individual difference in arterial physiology. On average, FH patients treated chronically with HELP have similar vasoactivity to age- and sex-matched subjects with low risk for atherosclerosis. This result, in light of the many studies that have associated hypercholesterolemia with abnormal vasoactivity, suggests that chronic HELP therapy improves vasoactivity in patients with severe hypercholesterolemia.

Adult↗
PubMed1997

Comparison of B-mode, M-mode and echo-tracking methods for measurement of the arterial distension waveform.

Measurements of arterial diameter throughout the cardiac cycle (i.e., the arterial distension waveform) are conducted increasingly to study mechanical properties of the arterial wall and changes associated with disease. The distension waveform of peripheral arteries can be measured noninvasively via ultrasonic echo tracking. M-mode imaging, and B-mode imaging. Of these, echo tracking is the most popular method because of its single micrometer resolution during continuous measurements under ideal conditions. However, high resolution within continuous measurements does not imply high reproducibility between measurements. Therefore, we compared repeated measurements of the amplitude of common carotid artery distension in 26 subjects, obtained sequentially in random order by: 1. Off-line echo tracking of digitized radiofrequency ultrasound; 2. M-mode imaging with automated edge detection; and 3. 30-Hz B-mode imaging with automated edge detection and model-based diameter estimation. In each case, the transducer was hand-held and was removed from the neck between repeated measurements. The amplitude of arterial distension was estimated from the serial diameter measurements by maximum likelihood (ML) estimation, by least-squares fit of a Fourier series model, and by application of a cubic smoothing spline. Within continuous measurements, the standard deviation of the ML distension amplitude for neighboring cardiac cycles was significantly smaller (p > 0.05) with echo-tracking (0.023 mm) than with the B-mode (0.036 mm) or M-mode (0.074 mm) methods. However, between discontinuous measurements on the same subject, the standard deviation of the ML distension amplitude was similar for the echo-tracking (0.076 mm) and B-mode (0.073 mm) methods. The Fourier series model and the cubic smoothing spline slightly reduced the standard deviation of the B-mode and M-mode distension amplitudes, but also reduced the mean amplitude estimate. On the basis of this relative comparison of methods, we conclude that, although echo tracking offers high resolution for continuous measurements, the reproducibility of discontinuous measurements of carotid artery distension is no better with echo tracking than can be obtained from 30-Hz B-mode images.

Adult↗
PubMed1996

Baseline clinical and angiographic data in the Quinapril Ischemic Event (QUIET) Trial.

The QUinapril Ischemic Event Trial (QUIET) is the first prospective, double-blind, placebo-controlled trial to investigate the long-term antiatherosclerotic effects of angiotensin-converting enzyme inhibition. Normotensive, nonhyperlipidemic subjects (1,750) with normal left ventricular systolic function were randomly assigned to treatment or placebo at percutaneous transluminal coronary angioplasty (PTCA). The primary end point is time to first cardiac ischemic event. Baseline clinical characteristics are (mean +/- SD): age 58 +/- 9 years; blood pressure 123 +/- 15/74 +/- 10 mm Hg; low density lipoprotein cholesterol 124 +/- 27 mg/dL; high density lipoprotein cholesterol 37 +/- 10 mg/dL; and triglycerides 167 +/- 91 mg/dL. In addition, 81% are men; 22% are current smokers; 49% give a history of myocardial infarction. Baseline angiographic characteristics are (mean +/- SD): left ventricular ejection fraction 59% +/- 11%; per patient diameter stenosis (excluding the PTCA segment) 49% +/- 31%; 8.9 +/- 3.5 analyzable segments per patient (excluding the PTCA segment), 3.8 +/- 2.3 of which have visible stenosis. Including the PTCA segment, 52% have single vessel disease and 48% have multivessel disease. Baseline angiographic data for non-PTCA segments will be correlated with cardiac ischemic events which occur after 6 months. Up to 500 subjects will undergo follow-up angiography with quantitative coronary angiographic analysis (QCA) of baseline and follow-up films. The primary QCA end point will be per-patient categorical designation as progressor or nonprogressor based on the presence or absence of > or = 400 microns narrowing in > or = 1 vessels that did not undergo PTCA.

Adult↗
PubMed1996

Treatment of hypercholesterolemia with heparin-induced extracorporeal low-density lipoprotein precipitation (HELP).

Familial hypercholesterolemia (FH) can cause early disability and death from premature atherosclerotic cardiovascular disease. Patients homozygous for the disease have very high plasma cholesterol, extensive xanthomatosis, and die from atherosclerosis in childhood or early adulthood. Past attempts to improve the prognosis included removal of cholesterol from the circulation by ileal bypass or biliary diversion. Neither treatment was successful. Direct removal by plasmapheresis of low-density lipoprotein (LDL), the primary carrier of cholesterol in plasma, was first performed on an FH homozygous patient in 1966. The treatment was well tolerated and led to rapid diminution of xanthomas. Other experimental treatments included selective LDL apheresis with monoclonal or polyclonal antibody affinity columns. A method for selective LDL apheresis was developed in 1983 by Armstrong, Seidel, and colleagues based on heparin precipitation of LDL at low pH. This method, called HELP, removes all apolipoprotein B-containing lipoproteins including LDL and lipoprotein (a), as well as some fibrinogen. LDL apheresis by HELP is well tolerated; the incidence of side effects is low, and the treatment has been associated with regression of cardiovascular disease. LDL apheresis, rather than liver transplantation, is the treatment of choice for patients with severe, life-threatening hypercholesterolemia which does not respond to diet and drug therapy.

Adult↗
PubMed1996

New methods for arterial diameter measurement from B-mode images.

Arterial diameter is an important parameter of vascular physiology in vivo. Noninvasive measurements of arterial diameter can be used in the assessment of endothelium-dependent vasoreactivity (EDV) and arterial compliance. Measurements of EDV may serve for assessment of early atherosclerosis. The potential value of EDV measurements with specificity for individual subjects is a strong motivation for improvements in the ultrasonic measurement of arterial diameter. This article presents and evaluates new methods for the measurement and tracking of arterial diameter from B-mode images. B-mode images acquired in planes longitudinal to the vessel and in planes rotated slightly off of the vessel axis ("skew") are considered. The cross-sections of arteries in these planes are modeled as parabola pairs or as ellipses. For the brachial artery, the variance of caliper-based diameter estimates (0.0139 mm2) is twice as large as that of elliptical-model-based diameter estimates (0.0072 mm2) and five times as large as parabolic-model-based diameter estimates (0.0027 mm2). Diameter estimates from the skew and longitudinal planes perform equivalently in limited-motion quantitative comparisons. However, diameter estimates from skew planes are less sensitive to translational motions of the artery. Also, translational motions are unambiguously represented in the skew image, thus facilitating compensatory motions of the transducer. The methods described here are relatively simple to implement and may provide adequate resolution for noninvasive assessment of EDV with individual specificity.

Algorithms↗
PubMed1996

The application of echo-tracking methods to endothelium-dependent vasoreactivity and arterial compliance measurements.

Measurements of endothelium-dependent vasoreactivity and arterial compliance are important metrics of vascular pathophysiology which may be used for the development and evaluation of therapeutic methods. The technique of ultrasonic echo tracking is applicable to measurements of endothelium-dependent vasoreactivity and arterial compliance. To evaluate the application of echo tracking to these measurements, we constructed a system based upon analog-to-digital conversion and storage of the radio frequency (RF) ultrasound signals. Off-line analysis of the RF data with various echo-tracking algorithms demonstrated two potential sources of error: tracking drift and RF transition regions. The tracking drift resulted from the slow accumulation of tracking error. The RF transition regions were associated with disparate motions of neighboring reflectors or the insonation of a new series of tissue layers. As a result of these sources of error, the application of echo tracking to endothelium-dependent vasoreactivity measurements is unlikely to outperform duplex ultrasound methods. The application of echo tracking to arterial compliance measurements via the arterial pressure/diameter relationship may produce variable results due to RF transition regions. Finally, the application of echo tracking to arterial compliance measurements via the pulse wave velocity is relatively insensitive to these sources of error because the pulse-wave velocity measurement depends upon the timing of the peak arterial distension, not on the absolute value of the distension.

Algorithms↗
PubMed1995

Selective removal of plasma low density lipoprotein with the HELP system: biweekly versus weekly therapy.

PURPOSE: Biweekly (once every 2 weeks) heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels compared with weekly HELP therapy. PATIENTS AND METHODS: Biweekly treatments were given to high-risk, diet/drug resistant hypercholesterolemic patients (n = 23) after 6 months of weekly HELP therapy. Lipids, lipoprotein cholesterol, apolipoproteins A-I and B, and fibrinogen were measured on plasma samples before and after treatment. RESULTS: Mean plasma volume treated was 2.8 l and mean treatment duration 1.7 h. Therapy complications were minimal. In 98% of 268 biweekly HELP treatments, LDL cholesterol levels were reduced by > 30%. For patients completing 6 months of biweekly therapy following 6 months' weekly therapy (n = 23), mean LDL cholesterol levels were reduced 138.5 mg/dl (111.2 mg/dl weekly) with a time-averaged decrease from mean pre-apheresis levels of 33% for biweekly therapy (39% weekly). Mean total cholesterol (161.2 mg/dl biweekly versus 132.9 weekly) and apolipoprotein B (104.6 mg/dl versus 92.6) levels were also reduced with each treatment. Mean HDL cholesterol was reduced only 6.1 mg/dl (6.3 mg/dl weekly). CONCLUSIONS: Biweekly HELP treatments can safely reduce LDL cholesterol levels as consistently as weekly HELP treatments. However, the higher pre-treatment LDL cholesterol levels with biweekly treatments may produce less therapeutic benefit than with weekly therapy.

Blood Component Removal↗
PubMed1994

Homozygous Tangier disease and cardiovascular disease.

Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (+/- S.D.) lipid values of all cases were as follows: total cholesterol 68 +/- 30 mg/dl (32% of normal), triglycerides 201 +/- 118 mg/dl (162% of normal), HDL cholesterol 3 +/- 3 mg/dl (6% of normal) and LDL cholesterol 50 +/- 38 mg/dl (37% of normal). The most common clinical finding in these subjects (n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects (n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls (P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group (P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗