Juergen R. Schaefer

Delayed catabolism of high density lipoprotein apolipoproteins A-I and A-II in human cholesteryl ester transfer protein deficiency.

Deficiency of the cholesteryl ester transfer protein (CETP) in humans is characterized by markedly elevated plasma concentrations of HDL cholesterol and apoA-I. To assess the metabolism of HDL apolipoproteins in CETP deficiency, in vivo apolipoprotein kinetic studies were performed using endogenous and exogenous labeling techniques in two unrelated homozygotes with CETP deficiency, one heterozygote, and four control subjects. All study subjects were administered 13C6-labeled phenylalanine by primed constant infusion for up to 16 h. The fractional synthetic rates (FSRs) of apoA-I in two homozygotes with CETP deficiency (0.135, 0.134/d) were found to be significantly lower than those in controls (0.196 +/- 0.041/d, P < 0.01). Delayed apoA-I catabolism was confirmed by an exogenous radiotracer study in one CETP-deficient homozygote, in whom the fractional catabolic rate of 125I-apoA-I was 0.139/d (normal 0.216 +/- 0.018/d). The FSRs of apoA-II were also significantly lower in the homozygous CETP-deficient subjects (0.104, 0.112/d) than in the controls (0.170 +/- 0.023/d, P < 0.01). The production rates of apoA-I and apoA-II were normal in both homozygous CETP-deficient subjects. The turnover of apoA-I and apoA-II was substantially slower in both HDL2 and HDL3 in the CETP-deficient homozygotes than in controls. The kinetics of apoA-I and apoA-II in the CETP-deficient heterozygote were not different from those in controls. These data establish that homozygous CETP deficiency causes markedly delayed catabolism of apoA-I and apoA-II without affecting the production rates of these apolipoproteins.

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule

Background: Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. Methods: We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). Results: The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83–0.91) for the derivation cohort and 0.90 (95% CI 0.87–0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3–5 points; negative result ≤ 2 points), which had a sensitivity of 87.1% (95% CI 79.9%–94.2%) and a specificity of 80.8% (77.6%–83.9%). Interpretation: The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care.

Chest pain in primary care: Epidemiology and pre-work-up probabilities

Abstract Background/objective: Chest pain is a common complaint and reason for consultation. We aimed to study the epidemiology of chest pain with respect to underlying aetiologies and to establish pre-work-up probabilities for the primary care setting. Methods: We included 1212 consecutive patients with chest pain, aged 35 years and older, attending 74 general practitioners (GPs). GPs recorded symptoms and findings of each patient and provided follow-up information. An independent interdisciplinary reference panel reviewed clinical data of every patient and decided on the aetiology of chest pain at the time of patient recruitment. Results: The prevalence of chest pain among all attending patients was 0.7%. The majority (55.9%) of patients were women. Mean age was 59 (35–93) years. Of these patients, 53.2% had chest pains at the time of consultation and 29.6% presented with acute (<48 hours’ duration) chest pain. Pain originating from the chest wall was diagnosed in 46.6% of all patients, stable ischaemic heart disease (IHD) in 11.1%, and psychogenic disorders in 9.5%; 3.6% had acute coronary syndrome (ACS). Conclusion: The study adds important information about the epidemiology of chest pain as a frequent reason for consulting primary care practitioners. We provide updated pre-work-up probabilities for IHD for each age and sex category.

Homozygous Familial Defective Apolipoprotein B-100: Enhanced Removal of Apolipoprotein E–Containing VLDLs and Decreased Production of LDLs

Familial defective apolipoprotein B-100 (FDB) is a frequently inherited disorder of lipoprotein metabolism. The glutamine-for-arginine substitution at position 3500 of apolipoprotein (apo) B-100 leads to defective binding of apo B-100 to the low density lipoprotein (LDL) receptor and accumulation of LDL in the plasma. We recently identified a patient homozygous for this mutation. His LDL cholesterol and apo B concentrations were approximately twice normal, whereas his apo E plasma level was low. Using a stable-isotope labeling technique ([2H3]leucine-primed constant infusion), we studied lipoprotein turnover in vivo in the fasting state in this patient and three clinically healthy, normolipidemic individuals not carrying the FDB mutation. The residence time of LDL apo B-100 was prolonged 3.6-fold in the FDB homozygote (8.3 vs 2.3 days). The production rate of LDL apo B-100 was decreased (7.4 vs 15 mg per kg per day). In FDB the residence time of very low density lipoprotein (VLDL) apo B-100 was longer (2.6 vs 1.3 hours), whereas the residence time of VLDL apo E was shorter (2.6 vs 4.5 hours) than normal. These data show that the in vivo metabolism of apo B-100-containing lipoproteins in FDB is different from that in familial hypercholesterolemia, in which LDL receptors are defective. In both conditions the residence times of LDL apo B-100 appear to be increased to approximately the same degree. This contrasts with the LDL apo B-100 synthetic rate, which is increased in familial hypercholesterolemia and decreased in FDB. The decreased production of LDL apo B-100 in FDB may originate from enhanced removal of apo E-containing LDL precursors by LDL receptors, which may be upregulated in response to the decreased flux of LDL-derived cholesterol into hepatocytes.

Delayed In Vivo Catabolism of Intermediate-Density Lipoprotein and Low-Density Lipoprotein in Hemodialysis Patients as Potential Cause of Premature Atherosclerosis

Objective—Premature cardiovascular disease is the leading cause of death in patients with end-stage renal disease treated by hemodialysis (HD). Low-density lipoprotein (LDL) levels are not generally increased in HD patients, but their LDL metabolism is still poorly understood. We therefore investigated the in vivo metabolism of apoB-containing lipoproteins in two different ethnic populations of HD patients and controls. Methods and Results—We performed stable isotope kinetic studies using a primed constant infusion of deuterated leucine in 12 HD patients and 13 healthy controls. Tracer/tracee ratio of apoB was determined by means of gas chromatography/mass spectrometry, and the modeling program SAAMII was used to estimate the fractional catabolic rate (FCR) of apoB. Mean LDL-apoB plasma concentrations were almost identical in both groups (HD: 95±30 mg/dL, controls: 91±40 mg/dL), whereas LDL-apoB FCR was 50% lower in HD patients as compared with controls (0.22±0.12 days−1 versus 0.46±0.20 days−1, P=0.001) with concomitantly decreased production rates of LDL. Compared with controls, intermediate-density lipoprotein (IDL)-apoB FCR was 65% lower (2.87±1.02 days−1 versus 8.89±4.94 days−1, P=0.014), accompanied by 1.5-fold higher IDL-apoB levels in HD. Very low-density lipoprotein metabolism was similar in both study groups. Conclusions—In vivo catabolism of LDL and IDL is severely impaired in HD patients but misleadingly masked by normal plasma cholesterol levels. The resulting markedly prolonged residence times of both IDL and LDL particles might thus significantly contribute to the well-documented high risk for premature cardiovascular disease in HD patients.

In vivo metabolism of apolipoprotein A-I in a patient with homozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH), caused by a defect in the low density lipoprotein (LDL) receptor, results in high plasma concentrations of LDL cholesterol due to both overproduction and delayed catabolism of LDL. FH is also associated with significantly lower levels of plasma high density lipoprotein cholesterol and apolipoprotein (apo) A-I in both heterozygous and homozygous patients. However, the metabolic basis of the hypoalphalipoproteinemia in FH has not been elucidated. We investigated the kinetics of apo A-I in a homozygous FH patient and two normal control subjects by using endogenous labeling with a stable isotopically labeled amino acid. Study subjects were administered a primed constant infusion of 13C6-phenylalanine for 12 hours. Apolipoproteins were isolated from plasma drawn at selected time points and analyzed for their isotopic enrichment by gas chromatography-mass spectrometry. The fractional catabolic rate of apo A-I in the FH subject was found to be substantially increased (0.38 day-1) compared with that of the normal subjects (mean, 0.26 day-1). In addition, the apo A-I production rate was decreased in the FH subject (6.5 mg/kg.day-1) compared with the normal subjects (mean, 11.1 mg/kg.day-1). In conclusion, the low levels of high density lipoprotein cholesterol and apo A-I in this homozygous FH patient are due to the combined metabolic defects of increased apo A-I catabolism and decreased apo A-I production.

Cobalt intoxication diagnosed with the help of Dr House

Medical examinations ruled out coronary artery disease, a common cause of heart failure, but the medics working on the case noticed some striking similarities between the patients symptoms and those of a fictional patient in the TV Series House [1], ultimately diagnosed by lead character Gregory House, M.D. (played by British actor Hugh Laurie) as cobalt poisoning caused by debris from a metal hip replacement.

In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a)

OBJECTIVE Lipoprotein(a) [Lp(a)] consists of apolipoprotein B-100 (apoB-100) as part of an LDL-like particle and the covalently linked glycoprotein apolipoprotein(a) [apo(a)]. Detailed mechanisms of its biosynthesis, assembly, secretion and catabolism are still poorly understood. To address the Lp(a) assembly mechanism, we studied the in vivo kinetics of apo(a) and apoB-100 from Lp(a) and LDL apoB-100 in nine healthy probands using stable-isotope methodology. METHODS The level of isotope enrichment was used to calculate the fractional synthesis rate (FSR), production rate (PR) and retention time (RT) using SAAMII software and multicompartmental modeling. RESULTS We observed a similar mean PR for apo(a) (1.15 nmol/kg/d) and apoB-100 (1.31 nmol/kg/d) from Lp(a), which differed significantly from the PR for apoB-100 from LDL (32.6 nmol/kg/d). Accordingly, mean FSR and RT values for Lp(a)-apo(a) were similar to those of Lp(a)-apoB and different from those for LDL-apoB. CONCLUSION Two different kinetic apoB pools within Lp(a) and LDL suggest intracellular Lp(a) assembly from apo(a) and newly synthesized LDL.

Gender differences in presentation and diagnosis of chest pain in primary care.

BackgroundChest pain is a common complaint and reason for consultation in primary care. Research related to gender differences in regard to Coronary Heart Disease (CHD) has been mainly conducted in hospital but not in primary care settings. We aimed to analyse gender differences in aetiology and clinical characteristics of chest pain and to provide gender related symptoms and signs associated with CHD.MethodsWe included 1212 consecutive patients with chest pain aged 35 years and older attending 74 general practitioners (GPs). GPs recorded symptoms and findings of each patient and provided follow up information. An independent interdisciplinary reference panel reviewed clinical data of every patient and decided about the aetiology of chest pain at the time of patient recruitment. Multivariable regression analysis was performed to identify clinical predictors that help to rule in or out CHD in women and men.ResultsWomen showed more psychogenic disorders (women 11,2%, men 7.3%, p = 0.02), men suffered more from CHD (women 13.0%, men 17.2%, p = 0.04), trauma (women 1.8%, men 5.1%, p < 0.001) and pneumonia/pleurisy (women 1.3%, men 3.0%, p = 0.04) Men showed significantly more often chest pain localised on the right side of the chest (women 9.1%, men 25.0%, p = 0.01). For both genders known clinical vascular disease, pain worse with exercise and age were associated positively with CHD. In women pain duration above one hour was associated positively with CHD, while shorter pain durations showed an association with CHD in men. In women negative associations were found for stinging pain and in men for pain depending on inspiration and localised muscle tension.ConclusionsWe found gender differences in regard to aetiology, selected clinical characteristics and association of symptoms and signs with CHD in patients presenting with chest pain in a primary care setting. Further research is necessary to elucidate whether these differences would support recommendations for different diagnostic approaches for CHD according to a patients gender.

Accuracy of symptoms and signs for coronary heart disease assessed in primary care

BACKGROUND Diagnosing the aetiology of chest pain is challenging. There is still a lack of data on the diagnostic accuracy of signs and symptoms for acute coronary events in low-prevalence settings. AIM To evaluate the diagnostic accuracy of symptoms and signs in patients presenting to general practice with chest pain. DESIGN OF STUDY Cross-sectional diagnostic study with delayed-type reference standard. SETTING Seventy-four general practices in Germany. METHOD The study included 1249 consecutive patients presenting with chest pain. Data were reviewed by an independent reference panel, with coronary heart disease (CHD) and an indication for urgent hospital admission as reference conditions. Main outcome measures were sensitivity, specificity, likelihood ratio, predictive value, and odds ratio (OR) for non-trauma patients with a reference diagnosis. RESULTS Several signs and symptoms showed strong associations with CHD, including known vascular disease (OR = 5.13; 95% confidence interval [CI] = 2.83 to 9.30), pain worse on exercise (OR = 4.27; 95% CI = 2.31 to 7.88), patient assumes cardiac origin of pain (OR = 3.20; 95% CI = 1.53 to 6.60), cough present (OR = 0.08; 95% CI = 0.01 to 0.77), and pain reproducible on palpation (OR = 0.27; 95% CI = 0.13 to 0.56). For urgent hospital admission, effective criteria included pain radiating to the left arm (OR = 8.81; 95% CI = 2.58 to 30.05), known clinical vascular disease (OR = 7.50; 95% CI = 2.88 to 19.55), home visit requested (OR = 7.31; 95% CI = 2.27 to 23.57), and known heart failure (OR = 3.53; 95% CI = 1.14 to 10.96). CONCLUSION Although individual criteria were only moderately effective, in combination they can help to decide about further management of patients with chest pain in primary care.