Jeffrey W. Meeusen

Validation of a proposed novel equation for estimating LDL cholesterol.

BACKGROUND Aggressive LDL cholesterol (LDL-C)-lowering strategies are recommended for primary and secondary prevention of cardiovascular events. A newly derived equation for LDL-C estimation was recently published that addressed limitations in the commonly used Friedewald LDL-C calculation method. The novel method was reported to classify patients with superior concordance to measured LDL-C compared to the Friedewald method, particularly in patients with LDL-C <70 mg/dL. METHODS We evaluated the performance of the novel method within an independent cohort of 23 055 patients with LDL-C measured by the gold standard β-quantification reference method. RESULTS Overall Friedewald underestimated and the novel method overestimated measured LDL-C. Both estimations significantly deviated from the reference method when LDL-C was <70 mg/dL. Overall, the Friedewald and novel calculations correctly classified 77% and 78% of patients, respectively. The largest discrepancy in classification was observed in individuals with measured LDL-C <70 mg/dL. For this group the novel calculation would reclassify 8.7% of patients as >70 mg/dL compared to the Friedewald equation. CONCLUSIONS We compared both novel and Friedewald estimated LDL-C against the LDL-C reference method; in contrast, the prior study relied on validation of a subset of samples by β-quantification to allow the use of the vertical autoprofile method for LDL-C measurement. We conclude that the novel method has some benefits but it is unclear whether improvements over the Friedewald calculation are substantive enough to justify making the change in routine clinical practice and to improve patient outcomes.

Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol

To test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory‐predominant polyradiculoneuropathy among swine abattoir employees in the Midwestern United States.

Performance of Cystatin C– and Creatinine-Based Estimated Glomerular Filtration Rate Equations Depends on Patient Characteristics

BACKGROUND The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends use of a cystatin C-based estimated glomerular filtration rate (eGFR) to confirm creatinine-based eGFR between 45 and 59 mL · min(-1) · (1.73 m(2))(-1). Prior studies have demonstrated that comorbidities such as solid-organ transplant strongly influence the relationship between measured GFR, creatinine, and cystatin C. Our objective was to evaluate the performance of cystatin C-based eGFR equations compared with creatinine-based eGFR and measured GFR across different clinical presentations. METHODS We compared the performance of the CKD-EPI 2009 creatinine-based estimated GFR equation (eGFRCr) and the newer CKD-EPI 2012 cystatin C-based equations (eGFRCys and eGFRCr-Cys) with measured GFR (iothalamate renal clearance) across defined patient populations. Patients (n = 1652) were categorized as transplant recipients (n = 568 kidney; n = 319 other organ), known chronic kidney disease (CKD) patients (n = 618), or potential kidney donors (n = 147). RESULTS eGFRCr-Cys showed the most consistent performance across different clinical populations. Among potential kidney donors without CKD [stage 2 or higher; eGFR >60 mL · min(-1) · (1.73 m(2))(-1)], eGFRCys and eGFRCr-Cys demonstrated significantly less bias than eGFRCr; however, all 3 equations substantially underestimated GFR when eGFR was <60 mL · min(-1) · (1.73 m(2))(-1). Among transplant recipients with CKD stage 3B or greater [eGFR <45 mL · min(-1) · (1.73 m(2))(-1)], eGFRCys was significantly more biased than eGFRCr. No clear differences in eGFR bias between equations were observed among known CKD patients regardless of eGFR range or in any patient group with a GFR between 45 and 59 mL · min(-1) · (1.73 m(2))(-1). CONCLUSIONS The performance of eGFR equations depends on patient characteristics that are readily apparent on presentation. Among the 3 CKD-EPI equations, eGFRCr-Cys performed most consistently across the studied patient populations.

Advantages of the lipoprotein-associated phospholipase A2 activity assay

OBJECTIVES Lipoprotein-associated phospholipase A2 (Lp-PLA2) is increased in circulation in patients at higher risk of coronary heart disease (CHD) events and stroke. Therefore, measurement of Lp-PLA2 can be used as an adjunct to traditional cardiovascular risk factors for identifying individuals at higher risk of cardiovascular events. Recently, a reagent for measuring Lp-PLA2 activity (diaDexus, San Francisco, CA) received FDA approval. Here we evaluate the assay performance of the Lp-PLA2 activity assay. METHODS Lp-PLA2 activity assay reagent performance was evaluated on an open user-defined channel on a Cobas 6000/c501 (Roche Diagnostics, Indianapolis, IN) using a 5-point calibration curve (0-400nmol/min/mL). Analytical performance was established for the following parameters: precision, linearity, accuracy, analytical sensitivity, analytical specificity, reference interval, reagent lot-to-lot comparison, specimen type, on-board reagent stability, and sample stability. RESULTS Assay limit of detection was determined to be 7.8nmol/min/mL with an average %CV of 2.8%. Precision studies revealed a coefficient of variation ≤1.6% between 79 and 307nmol/min/mL and accuracy was demonstrated between 4.8-368.7nmol/min/mL. Comparable results were generated in paired SST serum and EDTA plasma. No age association was found with Lp-PLA2 activity at the 95th percentile however a gender association was identified resulting in gender-specific 95th percentile limits in a healthy reference population. No bias was found when comparing results from several different lots of assay reagent. Lp-PLA2 activity results are extremely stable in both serum and EDTA plasma under refrigerate and frozen storage conditions up to 31days. CONCLUSIONS Lp-PLA2 activity assay displays accurate and precise performance characteristics on the Cobas c501 platform. The assay performance is significantly improved over the predecessor immunoassay allowing for adoption of Lp-PLA2 activity in clinical practice.

Impact of Glucose Meter Error on Glycemic Variability and Time in Target Range During Glycemic Control After Cardiovascular Surgery.

Background: We retrospectively studied the impact of glucose meter error on the efficacy of glycemic control after cardiovascular surgery. Method: Adult patients undergoing intravenous insulin glycemic control therapy after cardiovascular surgery, with 12-24 consecutive glucose meter measurements used to make insulin dosing decisions, had glucose values analyzed to determine glycemic variability by both standard deviation (SD) and continuous overall net glycemic action (CONGA), and percentage glucose values in target glucose range (110-150 mg/dL). Information was recorded for 70 patients during each of 2 periods, with different glucose meters used to measure glucose and dose insulin during each period but no other changes to the glycemic control protocol. Accuracy and precision of each meter were also compared using whole blood specimens from ICU patients. Results: Glucose meter 1 (GM1) had median bias of 11 mg/dL compared to a laboratory reference method, while glucose meter 2 (GM2) had a median bias of 1 mg/dL. GM1 and GM2 differed little in precision (CV = 2.0% and 2.7%, respectively). Compared to the period when GM1 was used to make insulin dosing decisions, patients whose insulin dose was managed by GM2 demonstrated reduced glycemic variability as measured by both SD (13.7 vs 21.6 mg/dL, P < .0001) and CONGA (13.5 vs 19.4 mg/dL, P < .0001) and increased percentage glucose values in target range (74.5 vs 66.7%, P = .002). Conclusions: Decreasing glucose meter error (bias) was associated with decreased glycemic variability and increased percentage of values in target glucose range for patients placed on intravenous insulin therapy following cardiovascular surgery.

Soluble ST2 and galectin-3 in pediatric patients without heart failure.

OBJECTIVES Soluble ST2 (ST2) and galectin-3 (Gal3) are biomarkers of myocardial fibrosis and remodeling. This study provides a foundation for the use of ST2 and Gal3 in pediatric patients by assessing values of these biomarkers among children without heart failure. DESIGN AND METHODS Sera from 240 children, 40 males and 40 females from each of three age groups, (2-6 years, 7-11 years, and 12-17 years) without heart failure were identified from residual clinical testing. Serum ST2 and Gal3 were measured by ELISA. RESULTS Serum ST2 increased with age among males, but not females. However, the difference was not statistically significant at the 95th or 97.5th percentiles. No relationship was found between serum Gal3 concentrations and age or gender. Central 95th percentiles (2.5th to 97.5th) were 9-50 ng/mL for ST2 and 7-33 ng/mL for Gal3. CONCLUSIONS We have presented baseline, normative data for ST2 and Gal3 in children. This will allow for study of the utility of these biomarkers in children with heart disease.

Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: Active immunization model in mice

Background  Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic‐acetylcholine receptors containing α3 subunits [α3*‐ nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant α3‐polypeptide produce α3*‐nAChR autoantibodies, and profound AGID ensues. Human and rabbit α3*‐nAChR‐specific‐IgGs induce transient hypomotility when injected into mice. Here, we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization.

Looking for a Better Creatinine

Our kidneys maintain a constant internal environment and circulatory volume through a combination of filtration, selective reabsorption and secretion, and production of several key hormones. Young, healthy individuals filter >100 L of blood each day; however, their kidneys then reabsorb most of this for a mean urine output of only 1.5 L/day. This filtration process is necessary to eliminate byproducts of ongoing metabolism (so-called uremic toxins). Indeed, a minimum amount of kidney function is essential for life, and one can demonstrate increased morbidity and mortality when the glomerular filtration rate (GFR)3 chronically dips low enough. Thus, GFR is widely considered the single most important and useful indicator of overall kidney function. It is possible to directly measure GFR by administration of small molecules that are freely filtered by the kidneys and neither metabolized, secreted, nor reabsorbed. Examples include inulin, iothalamate, and iohexol, for which the renal clearance of these molecules equals GFR. However, protocols that use these exogenous agents to measure GFR require some combination of intravenous or subcutaneous administration of the marker, multiple blood draws, and carefully timed urine collections. Thus, direct measurement of GFR is not practical for most routine situations. For these reasons, several methods of GFR estimation have been developed on the basis of endogenous molecules. The best example is creatinine, a byproduct of muscle metabolism that is freely filtered, produced in a relatively consistent manner, and not reabsorbed. Although some creatinine is secreted, this amount is usually small enough that creatinine remains a useful marker of GFR. A bigger problem, however, is that muscle mass (and consequently serum creatinine) varies widely between individuals. Thus, although serum creatinine goes up as GFR goes down, the GFR for a given serum creatinine can vary widely between individuals. For example, a “normal” serum creatinine of 1.0 mg/dL …

Immunotherapy-responsive pain in an abattoir worker with fluctuating potassium channel-complex IgG.

In late 2007, a neurologic disorder was identified in the midwestern United States among swine abattoir workers who were exposed to aerosolized brain tissue.1,2 All patients reported positive sensory symptoms with pain. Neurologic signs and electrophysiologic testing abnormalities were limited and compatible with a sensory-predominant painful polyradiculoneuropathy.1 Serologic analysis revealed an unusual profile of neural-specific autoantibodies.1,3 Here we describe an early presenting case from this outbreak who was followed longitudinally with pain-predominant symptomatology, a newly recognized manifestation of voltage-gated potassium channel (VGKC)-complex autoimmunity.4 In the course of IV immune globulin therapy, the patients pain symptoms paralleled fluctuating levels of VGKC-complex autoantibodies.

Should apolipoprotein B replace LDL cholesterol as therapeutic targets are lowered

Purpose of review The success of LDL cholesterol (LDL-C) as a predictor of atherosclerotic cardiovascular disease and a therapeutic target is indisputable. Apolipoprotein B (apoB) is a more contemporary and physiologically relevant measure of atherogenic lipoproteins. This report summarizes recent comparisons of apoB and LDL-C as biomarkers of cardiovascular risk. Recent findings Multiple recent reports have found that LDL-C methods perform poorly at low concentrations (<70 mg/dl). Several meta-analyses from randomized controlled trials and large prospective observational studies have found that apoB and LDL-C provide equivalent information on risk of cardiovascular disease. More innovative analyses have asserted that apoB is a superior indicator of actual risk when apoB and LDL-C disagree. Summary ApoB is more analytically robust and standardized biomarker than LDL-C. Large population studies have found that apoB is at worst clinically equivalent to LDL-C and likely superior when disagreement exists. Realistically, many obstacles prevent the wide spread adoption of apoB and for now providers and their patients must weigh the costs and benefits of apoB.