[Portable X-ray devices: technique, image quality and regulations]. / Draagbare röntgentoestellen: techniek, beeldkwaliteit en regelgeving.

Portable intraoral X-ray devices are marketed as an alternative for conventional wall mounted devices. On the basis of a recent clinical trial the diagnostic quality of portables appears to measure up to the conventional devices. When CE-certified portable devices are used with rectangular collimation and a backshatter radiation shield with adapted technique resulting in a beam parallel to the ground, operator exposure stays well within dose limits. However, the dose to the operator is higher than when using conventional devices. Therefore, in the Netherlands, guidelines restrict the use of portable devices to ambulant use outside the dental clinic while deploying additional radiation protection measures. If presumed advantages of increased control over the exposure due to proximity to the patient would be substantiated by research, this restricted use could be reconsidered. Dentists should be aware of online availability of non-CE-certified portable intra-oral X-ray devices that are potentially unsafe.

[Is thyroid shielding recommendable during upper anterior radioagraphy in young patients?] / Röntgenopnamen bij jongeren in het bovenfront: is afscherming schildklier wenselijk?

During intraoral radiography of the upper anterior teeth, the dose the patient is exposed to can be reduced by shielding the thyroid area by using a thyroid shield or collar. However, the dose to the patient is already low and it is questionable whether efforts to reduce this even further are sensible. A cost-utility analysis demonstrated that thyroid shielding is utile when it is used at least 24 times per year for upper anterior exposures in children.

Determination of intra-oral surface areas by cone-beam computed tomography analysis and their relation with anthrometric measurements of the head.

PURPOSE: Determination of intra-oral surface areas might contribute to our understanding of the physiology of the oral cavity and oral diseases. In previous studies, the intra-oral surface area was determined using a laborious and technically challenging method. Our aim was to develop an easy and non-invasive method to determine the intra-oral surface areas. METHODS: In this study, we used cone-beam computed tomography (CBCT) and digital analysis in 20 human cadavers to determine various intra-oral surface areas, based on digital segmentation. Next, we explored whether there was a relationship between various intra-oral surface areas and anthropometric measurements of the head using Pearson correlation coefficient. RESULTS: Using CBCT and digital analysis, it was possible to determine various intra-oral surface areas. On average, the total intra-oral surface area was 173 ± 19 cm2. Moderate, statistical significant correlations were observed between (1) the length of the head and the palatal surface area, as well as (2) the depth of the head and the surface area of the tongue. These correlations suggest the feasibility of estimating intra-oral surface areas without relying on CBCT imaging. CONCLUSIONS: This study presents a technique for measuring the intra-oral surface areas by CBCT imaging in combination with digital analysis. The results of this study suggest that anthropometric measurements of the head might be used to estimate the surface areas of the palate and tongue.

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

Cardiovascular risk prediction in HIV-infected patients: comparing the Framingham, atherosclerotic cardiovascular disease risk score (ASCVD), Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models.

OBJECTIVES: The aim of the study was to compare the predictions of five popular cardiovascular disease (CVD) risk prediction models, namely the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, the Framingham Heart Study (FHS) coronary heart disease (FHS-CHD) and general CVD (FHS-CVD) models, the American Heart Association (AHA) atherosclerotic cardiovascular disease risk score (ASCVD) model and the Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) model. METHODS: A cross-sectional design was used to compare the cumulative CVD risk predictions of the models. Furthermore, the predictions of the general CVD models were compared with those of the HIV-specific D:A:D model using three categories (< 10%, 10-20% and > 20%) to categorize the risk and to determine the degree to which patients were categorized similarly or in a higher/lower category. RESULTS: A total of 997 HIV-infected patients were included in the study: 81% were male and they had a median age of 46 [interquartile range (IQR) 40-52] years, a known duration of HIV infection of 6.8 (IQR 3.7-10.9) years, and a median time on ART of 6.4 (IQR 3.0-11.5) years. The D:A:D, ASCVD and SCORE-NL models gave a lower cumulative CVD risk, compared with that of the FHS-CVD and FHS-CHD models. Comparing the general CVD models with the D:A:D model, the FHS-CVD and FHS-CHD models only classified 65% and 79% of patients, respectively, in the same category as did the D:A:D model. However, for the ASCVD and SCORE-NL models, this percentage was 89% and 87%, respectively. Furthermore, FHS-CVD and FHS-CHD attributed a higher CVD risk to 33% and 16% of patients, respectively, while this percentage was < 6% for ASCVD and SCORE-NL. CONCLUSIONS: When using FHS-CVD and FHS-CHD, a higher overall CVD risk was attributed to the HIV-infected patients than when using the D:A:D, ASCVD and SCORE-NL models. This could have consequences regarding overtreatment, drug-related adverse events and drug-drug interactions.

GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study.

AIM: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. METHODS: We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. RESULTS: The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele ß=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele ß=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). CONCLUSIONS: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.

Carboxymethyl lysine, an advanced glycation end product, and incident diabetes: a case-cohort analysis of the ARIC Study.

AIMS: To verify whether elevated fasting levels of circulating carboxymethyl lysine (CML), an advanced glycation end product, predict the development of diabetes in middle-age adults. METHODS: Using a stratified case-cohort design, we followed 543 middle-aged individuals who developed diabetes and 514 who did not over a median 9 years in the Atherosclerosis Risk in Communities Study. Weighted Cox proportional hazards analyses were used to account for the design. RESULTS: In weighted analyses, correlation between CML levels and anthropometric, inflammatory or metabolic variables was minimal (Pearson correlations usually < 0.10). CML, when modelled as a continuous variable and after adjustment for age, sex, race, centre, parental history of diabetes, BMI, waist-to-hip ratio, non-esterified fatty acids, oxidized LDL-cholesterol, GFR, smoking, an inflammation score, adiponectin, leptin, insulin and glucose levels, was associated with an increased risk of diabetes [Hazard ratio (HR) = 1.35; 95% confidence interval (CI) 1.09-1.67, for each 100 ng/ml CML increment]. Baseline glucose level and race each modified the association (P < 0.05 for interaction), which was present only among those with impaired fasting glucose (≥ 5.6 mmol/l, HR = 1.61, 95% CI 1.26-2.05) and among white participants (HR = 1.50, 95% CI 1.13-1.99). CONCLUSIONS: Elevated fasting CML, after adjustment for multiple risk factors for diabetes, predicts the development of incident diabetes, the association being present among those with impaired fasting glucose and in white participants. These prospective findings suggest that advanced glycation end products might play a role in the development of diabetes.

[Radiobiological aspects of diagnostic X-ray use in dentistry]. / Radiobiologische aspecten van tandheelkundige röntgendiagnostiek.

Soon after the discovery of X-rays, it became clear that their use can cause detrimental effects. The field of radiobiology deals with these detrimental effects. In this article, the theoretical concepts of radiobiology relevant to diagnostic X-ray use are presented. The effects of radiation on living tissues, the relationship between dose and effect, and a translation of these effects into the dental application are discussed. X-rays cannot be considered to be harmless even when used at the relatively low doses as in dentistry. If applied with justification and optimization, the risk to the patient will, however, be small.

Reducing an already low dental diagnostic X-ray dose: does it make sense? Comparison of three cost-utility analysis methods used to assess two dental dose-reduction measures.

OBJECTIVES: To find a method that is suitable for providing an objective assessment of the cost effectiveness of a dose-reducing measure used for diagnostic dental X-ray exposures. METHODS: Three cost-utility analysis (CUA) methods were evaluated by comparing their assessments of two dose-reduction measures, a rectangular collimator and the combination of two devices that reduce the radiation dose received during orthodontic lateral cephalography. The following CUA methods were used: (1) the alpha value (AV), a monetary valuation of dose reduction used in the nuclear industry; (2) the value of a statistical life for valuation of the reduction in stochastic adverse effects; and (3) the time-for-time method, based on the postulate that risk reduction is effective when the number of years of life gained is more than the years that an average worker must work to earn the costs of the risk-reducing measure. The CUA methods were used to determine the minimum number of uses that was required for the dose-reducing device to be cost effective. The methods were assessed for coherence (are comparable results achieved for comparable countries?) and adaptability (can the method be adjusted for age and gender of specific patient groups?). RESULTS: The performance of the time-for-time method was superior to the other methods. Both types of dose-reduction devices tested were assessed as cost effective after a realistic number of uses with all three methods except low AVs. CONCLUSIONS: CUA for the methods of X-ray dose reduction can be performed to determine if investment in low dose reduction is cost effective. The time-for-time method proved to be a coherent and versatile method for performing CUA.

Dose reduction in orthodontic lateral cephalography: dosimetric evaluation of a novel cephalographic thyroid protector (CTP) and anatomical cranial collimation (ACC).

OBJECTIVES: To test the dose-reducing capabilities of a novel thyroid protection device and a recently introduced cranial collimator to be used in orthodontic lateral cephalography. METHODS: Cephalographic thyroid protector (CTP) was designed to shield the thyroid while leaving the cervical vertebrae depicted. Using a RANDO(®) head phantom (The Phantom Laboratory, Salem, NY) equipped with dosemeters and a Proline XC (Planmeca, Helsinki, Finland) cephalograph, lateral cephalograms were taken, and the effective dose (ED) was calculated for four protocols: (1) without shielding; (2) with CTP; (3) with CTP and anatomical cranial collimator (ACC); and (4) with a thyroid collar (TC). RESULTS: The ED for the respective protocols was (1) 8.51; (2) 5.39; (3) 3.50; and (4) 4.97 µSv. The organ dose for the thyroid was reduced from 30.17 to 4.50 µSv in Protocols 2 and 3 and to 3.33 µSv in Protocol 4. CONCLUSIONS: The use of just the CTP (Protocol 2) resulted in a 36.8% reduction of the ED of a lateral cephalogram. This was comparable to the classical TC (Protocol 4). A 58.8% reduction of the ED was obtained when combining CTP and ACC (Protocol 3). The dose to the radiosensitive thyroid gland was reduced by 85% in Protocols 2 and 3 and by 89% in Protocol 4.

Assessment of Random Error in Phantom Dosimetry with the Use of Error Simulation in Statistical Software.

OBJECTIVE: To investigate if software simulation is practical for quantifying random error (RE) in phantom dosimetry. MATERIALS AND METHODS: We applied software error simulation to an existing dosimetry study. The specifications and the measurement values of this study were brought into the software (R version 3.0.2) together with the algorithm of the calculation of the effective dose (E). Four sources of RE were specified: (1) the calibration factor; (2) the background radiation correction; (3) the read-out process of the dosimeters; and (4) the fluctuation of the X-ray generator. RESULTS: The amount of RE introduced by these sources was calculated on the basis of the experimental values and the mathematical rules of error propagation. The software repeated the calculations of E multiple times (n = 10,000) while attributing the applicable RE to the experimental values. A distribution of E emerged as a confidence interval around an expected value. CONCLUSIONS: Credible confidence intervals around E in phantom dose studies can be calculated by using software modelling of the experiment. With credible confidence intervals, the statistical significance of differences between protocols can be substantiated or rejected. This modelling software can also be used for a power analysis when planning phantom dose experiments.

Validation of anatomically shaped cranial collimation (ACC) in orthodontic lateral cephalography.

The use of an anatomically shaped cranial collimator (ACC) to reduce patient dose in orthodontic lateral cephalography was investigated in this study. The aim was to evaluate the potential interference of the ACC on landmark identification for orthodontic cephalometry. Consecutive orthodontic patients underwent a total of 100 cephalograms using an ACC mounted on a Veraviewepocs(®) 3D X550 (J. Morita Co., Kyoto, Japan) X-ray unit. 10 observers were asked whether the identification of 5 landmarks close to the collimated area was hindered or rendered impossible by the presence of the collimator. Of the 500 landmarks that were judged by the 10 observers, 496 (99.2%) were reported to lack hindrance. In three landmarks, a minority of the observers reported hindrance. In 1 landmark, 8 of the 10 observers reported hindrance by the collimator. In no instance did the observers state that the identification of landmarks was impossible as a result of the collimation. Application of the ACC on the cephalostat of the X-ray unit is a viable way of reducing patient dose, as it only marginally interferes with the diagnostic yield of the exposure. The need to retake images when the ACC is applied was found to be extremely low.

Anatomically shaped cranial collimation (ACC) for lateral cephalometric radiography: a technical report.

Lateral cephalograms in orthodontic practice display an area cranial of the base of the skull that is not required for diagnostic evaluation. Attempts have been made to reduce the radiation dose to the patient using collimators combining the shielding of the areas above the base of the skull and below the mandible. These so-called "wedge-shaped" collimators have not become standard equipment in orthodontic offices, possibly because these collimators were not designed for today's combination panoramic-cephalometric imaging systems. It also may be that the anatomical variability of the area below the mandible makes this area unsuitable for standardized collimation. In addition, a wedge-shaped collimator shields the cervical vertebrae; therefore, assessment of skeletal maturation, which is based on the stage of development of the cervical vertebrae, cannot be performed. In this report, we describe our investigations into constructing a collimator to be attached to the cephalostat and shield the cranial area of the skull, while allowing the visualization of diagnostically relevant structures and markedly reducing the size of the irradiated area. The shape of the area shielded by this "anatomically shaped cranial collimator" (ACC) was based on mean measurements of cephalometric landmarks of 100 orthodontic patients. It appeared that this collimator reduced the area of irradiation by almost one-third without interfering with the imaging system or affecting the quality of the image. Further research is needed to validate the clinical efficacy of the collimator.

Effect of head position on cephalometric evaluation of the soft-tissue facial profile.

OBJECTIVES: During a cone beam CT scan, the patient is in an upright or supine position. This position depends on the brand and type of the scanner. The aims of this study are: (1) to investigate if the head position has an effect on cephalometric evaluation of the soft-tissue facial profile, comparing the recordings in natural head position (NHP) and supine head position (SHP) and (2) to investigate if age, gender and body mass index (BMI) are contributing factors to the effect of the head position. METHODS: 90 subjects were photographed in profile both in NHP and in SHP. 12 soft-tissue angular and linear cephalometric values were calculated. Two-way random intraclass correlation coefficients were calculated to determine observer reliability. Paired t-tests and linear regression analyses were performed to investigate the differences between the head positions and the influence of age, gender and BMI. RESULTS: Intraobserver reliability was generally high. Paired t-tests showed significant changes as a result of head positioning (p < 0.0001) in 9 of the 12 measurements. These differences were small and clinically not relevant, except for the "lower face-throat angle". Regression analysis revealed no relevant influence of age, gender and BMI. CONCLUSIONS: Cephalometric soft-tissue evaluation from a recording in SHP is generally reliable, except for the throat-chin area where a clinically relevant difference was found. The contour of the submandibular tissues in SHP causes the chin to appear more prominently. This can cause incorrect orthodontic diagnosis and treatment planning.

Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study.

OBJECTIVE: The metabolic syndrome is associated with increased risk for cardiovascular disease and diabetes. Several analyses from the Atherosclerosis Risk in Communities (ARIC) study have been performed to examine the role of the metabolic syndrome and its components in predicting risk for cardiovascular disease and diabetes. DESIGN AND SUBJECTS: The large, biracial, population-based ARIC study enrolled 15792 middle-aged Americans in four communities in the United States and has followed them for the development of cardiovascular disease and diabetes. MEASUREMENTS: Outcome parameters included prevalence of the metabolic syndrome and its individual components, carotid intima-media thickness, incident coronary heart disease, incident ischemic stroke and incident diabetes. RESULTS AND CONCLUSION: Several analyses from the ARIC study have shown that the metabolic syndrome, as well as individual metabolic syndrome components, is predictive of the prevalence and incidence of coronary heart disease, ischemic stroke, carotid artery disease and diabetes.

Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study.

AIMS/HYPOTHESIS: To evaluate the role of oxidative stress and inflammation in the aetiology of type 2 diabetes, we examined the association of oxidised LDL (ox-LDL) and soluble intercellular adhesion molecule-1 (sICAM-1) levels with type 2 diabetes incidence over 9 years in the Atherosclerosis Risk in Communities Study. MATERIALS AND METHODS: In a large, prospective, case-cohort design, ox-LDL and sICAM-1 were measured in stored plasma samples collected at baseline in stratified samples of 581 diabetes cases and 572 non-cases selected from 10,275 middle-aged men and women without prevalent diabetes at baseline. RESULTS: Compared with non-cases, diabetes cases had significantly higher mean baseline levels of ox-LDL and sICAM-1. Elevated ox-LDL and sICAM-1 were both associated with increased risk of incident diabetes after adjustment for age, sex, race and centre, with hazard ratios for the highest vs lowest tertiles of 1.68 (95% CI 1.25-2.24) and 1.91 (95% CI 1.45-2.50), respectively. After additional adjustment for fasting glucose, waist circumference, HDL-cholesterol, triacylglycerol, hypertension and C-reactive protein, only sICAM-1 remained an independent predictor of incident diabetes (hazard ratio 1.50; 95% CI 1.02-2.23). CONCLUSIONS/INTERPRETATION: In this community-based cohort of middle-aged US adults, elevated plasma ox-LDL and sICAM-1 levels were associated with increased risk of type 2 diabetes. Measurement of ICAM-1 or ox-LDL, or other measures related to inflammation or oxidative stress, may be helpful in identifying those patient populations in which to test whether novel therapies that inhibit specific pathways related to inflammation or oxidative stress are beneficial in the prevention of diabetes in humans.

Leptin and incident type 2 diabetes: risk or protection?

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance. SUBJECTS AND METHODS: We conducted a case-cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA. RESULTS: In proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6-5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23-0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32-1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both). CONCLUSIONS/INTERPRETATION: High leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin's described protective effects against diabetes.

Isolation, quantitation, and characterization of a stable complex formed by Lp[a] binding to triglyceride-rich lipoproteins.

Lipoprotein [a] (Lp[a]) is a cholesterol-rich lipoprotein resembling LDL to which a large polymorphic glycoprotein, apolipoprotein [a] (apo[a]), is covalently coupled. Lp[a] usually exists as a free-standing particle in normolipidemic subjects; however, it can associate noncovalently with triglyceride-rich lipoproteins in hypertriglyceridemic (HTG) subjects. In this study, 10-78% of the Lp[a] present in five HTG subjects was found in the triglyceride-rich lipoprotein (TRL) fraction. The Lp[a]-TRL complex was resistant to dissociation by ultracentrifugation (UCF) alone, but was quantitatively dissociated by UCF in the presence of 100 mM proline. Of this dissociated Lp[a], 70-88% was in the form of a lipoprotein resembling conventional Lp[a]. Incubation of Lp[a]-depleted TRL with native Lp[a] resulted in a reconstituted Lp[a]-TRL complex that closely resembled the native isolates in all examined properties. Complex formation was inhibited by several compounds in the order proline > tranexamate > epsilon-aminocaproate >> arginine > lysine. Neither plasminogen nor LDL inhibited binding of Lp[a] to TRL. We observed the preferential binding of Lp[a] containing higher apparent molecular weight apo[a] polymorphs to TRL both in native and reconstituted Lp[a]-TRL complexes. A disproportionate amount of Lp[a] was bound to the larger TRL particles. Although most apo[a] bound to TRL was in the form of conventional Lp[a] particles, lipid-free recombinant apo[a] was observed to bind TRL. These results provide unequivocal evidence of the existence of an Lp[a]-TRL complex under pathophysiologic conditions. The metabolic fate of the Lp[a]-TRL complex, which is more abundant in hypertriglyceridemia, may be different from that of conventional Lp[a], and may contribute uniquely to the progression or severity of cardiovascular disease.

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients.

BACKGROUND: Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. METHODS: To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. RESULTS: Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. CONCLUSIONS: This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins.