The predictive value of the sFlt-1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study.

BACKGROUND: Internationally, placental growth factor (PlGF)-based tests are used as prognostic markers in suspected preeclampsia. However, Ministry of Health guidelines do not currently endorse PlGF-based tests in New Zealand (NZ). AIMS: To investigate the predictive value of soluble fms-like tyrosine kinase 1 (sFlt-1)/PlGF ratio in suspected preeclampsia in a NZ population. MATERIALS AND METHODS: A prospective cohort study of singleton pregnancies at 20+0 -36+6 weeks gestation with suspected preeclampsia as defined by Society of Obstetric Medicine Australia and NZ (SOMANZ) criteria. PRIMARY OBJECTIVE: to evaluate a sFlt-1/PlGF ratio >38 at ≤35+0 weeks gestation to predict birth ≤14 days. SECONDARY OBJECTIVES: to assess a sFlt-1/PlGF ratio cut-off of 38 at ≤37+0 weeks gestation, to rule out preeclampsia ≤1 week, rule in preeclampsia ≤4 weeks, and to predict perinatal outcome. Clinicians were blinded to sFlt-1/PlGF ratio results. RESULTS: Included were 222 participants, 19.4% Maori and 10.4% Pasifika. A sFlt-1/PlGF >38 predicted birth ≤14 days, positive predictive value (PPV) 51.4% (95% CI, 39.6-63.0) and negative predictive value (NPV) 95.9% (95% CI, 91.4-98.1), median (interquartile range) days to birth 14 (2-27) vs 49 (33-70), P < 0.000. A sFlt-1/PlGF cut-off of 38 ruled out preeclampsia ≤1 week (NPV 96.2% (95% CI, 92.3-98.2)) and ruled in preeclampsia ≤4 weeks (PPV 75.0% (95% CI, 65.0-82.9)). A sFlt-1/PlGF >38 was associated with greater perinatal morbidity. CONCLUSIONS: The predictive value of the sFlt-1/PlGF ratio in NZ is comparable to that reported in international trials. Used in clinical practice the sFlt-1/PlGF ratio may aid risk stratification in suspected preeclampsia, directing limited resources to those pregnancies at highest risk.

Lipoprotein apheresis and PCSK9 inhibitors for severe familial hypercholesterolaemia: Experience from Australia and New Zealand.

INTRODUCTION: Severe familial hypercholesterolaemia (FH) causes premature disability and death due to atherosclerotic cardiovascular disease and is refractory to standard lipid-lowering therapies. Lipoprotein apheresis (LA) has long been a standard of care for patients with severe FH, but is invasive, expensive and time-consuming for patients and their caregivers. Newer drug therapies, including the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, may reduce the need for LA. MATERIALS AND METHODS: We audited the records of 16 patients (eight homozygous, eight heterozygous) treated with LA in Australia and New Zealand, 14 of whom subsequently commenced PCSK9 inhibitor therapy. LA was performed by cascade filtration in all centres. RESULTS: LDL-cholesterol was acutely lowered by 69 ± 7% in patients with homozygous FH and by 72 ± 9% in those with heterozygous FH, representing time-averaged reductions of 36 ± 12% and 34 ± 5%, respectively. LA was well-tolerated, and patients reported comparable quality of life to population and disease-related norms. After commencement of PCSK9 inhibitors, four of seven patients with homozygous FH had meaningful biochemical responses, with a reduction in the frequency of LA permitted in one patient and complete cessation in another. Four of seven patients with heterozygous FH were able to be managed without LA after commencing PCSK9 inhibitors. CONCLUSION: While PCSK9 inhibitors have reduced the need for LA, some patients with severe FH continue to require LA, and will require it for the foreseeable future. However, emerging therapies, including angiopoetin-like 3 inhibitors, may further reduce the need for LA.

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.

Is There a Role for HbA1c in Pregnancy?

Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy.

Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice.

STUDY OBJECTIVE: A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. METHODS: This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. RESULTS: Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference -2.1% [-10.3% to 6.0%], P=.65). CONCLUSION: There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates.

Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Objective: Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. Methods: We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. Results: A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Conclusion: Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Hb Westport [ß121 (GH4) Glu>Asp; HBB:c.366A>C]: A novel ß-globin variant interfering with HbA1c measurement.

OBJECTIVES: To describe a novel ß-globin variant that interferes with HbA1c analysis by cation exchange HPLC. DESIGN AND METHODS: Diabetes screening by HbA1c measurement was assessed using cation exchange HPLC and an immunoassay point-of-care analyzer. Routine hemoglobinopathy screening was performed including CBC, HbF and HbA2 measurement by cation exchange HPLC and capillary electrophoresis (CE). Further variant characterization was undertaken by ESI TOF mass spectrometry and DNA sequencing. RESULTS: Discordant HbA1c results were obtained for our subject, with elevated HbA1c of 52 mmol/mol measured by cation exchange HPLC and a normal level of 34 mmol/mol by immunoassay. Abnormal HbA1c peak shape prompted hemoglobinopathy screening to investigate potential variant interference. Cation exchange HPLC (using ß-thalassemia program) and CE results were apparently normal, with HbF and HbA2 detected within reference intervals. ESI TOF mass spectrometry revealed the presence of a variant ß-globin chain. A novel missense variant was confirmed at codon 121 of the ß-globin gene [ß121 (GH4) Glu>Asp; HBB: c.366A>C], which we have named Hb Westport. CONCLUSIONS: Hb Westport is a novel ß-globin variant that interferes with HbA1c measurement by Bio-Rad D-100 cation exchange HPLC, giving a falsely elevated result. This was clinically significant for our subject because the erroneously elevated HbA1c value was above the diabetes diagnostic threshold. Alternative methods for diabetes assessment should be considered in subjects with Hb Westport.

The performance of high sensitivity troponin for the diagnosis of acute myocardial infarction is underestimated.

BACKGROUND: Many papers evaluating high sensitivity troponin assays make the diagnosis of myocardial infarction based on conventional troponin assays in clinical use at the time of recruitment. Such analyses often do not show superiority of high sensitivity assays compared with contemporary assays meeting precision guidelines. METHODS: Three hundred and twenty-two patients presenting to the emergency department between November 2006 and April 2007 for evaluation for acute coronary syndrome had serial (0 h and >6 h) bloods taken to compare troponin assays (Roche hsTnT, Abbott TnI, Roche TnT and Vitros TnI). The diagnosis of myocardial infarction was made using each troponin assay separately with which that same assay was analysed for diagnostic performance. RESULTS: The rate of myocardial infarction would be 38.9% using serial hsTnT, 31.3% using serial Abbott TnI, 27.1% using serial TnT and 26.4% using serial Vitros TnI. The baseline sensitivities (0 h) are 89.9% (85.2-93.3) for hsTnT, 77.9% (71.0-87.5) for Abbott TnI, 73.0% (65.6-78.7) for TnT and 86.8% (74.6-94.4%) for Vitros TnI. The specificities (peak 0 h and >6 h samples) are 93.1% (91.2-93.1) for hsTnT, 88.3% (86.5-88.3) for Abbott TnI, 92.2% (90.5-92.2) for TnT and 90.6% (70.1-90.6) for Vitros TnI. CONCLUSIONS: hsTnT has superior sensitivity for myocardial infarction than even assays at or near guideline precision requirements (Abbott and Vitros TnI). The specificity of hsTnT assay is not as poor as previous analyses suggest.

Management of co-existing diabetes mellitus and dyslipidemia: defining the role of thiazolidinediones.

The observed reduction in macrovascular outcomes in the United Kingdom Progressive Diabetes Study (UKPDS) trial in patients with type 2 diabetes mellitus (DM), treated intensively with insulin or sulfonylureas, was of borderline significance (p = 0.052). This may be because of the role of factors other than glycemic control in the etiology of macrovascular disease. The UKPDS and other studies have suggested that lipid parameters are potent predictors of adverse outcomes in patients with type 2 DM. In patients with DM, dyslipidemia is characterized by elevated serum triglycerides and low high density lipoprotein-cholesterol (HDL-C) with normal total serum cholesterol levels and usually accompanied by an elevation of atherogenic, small, dense low density lipoprotein-cholesterol (LDL-C) particles. Dyslipidemia is only partly corrected by dietary and lifestyle modifications and pharmacological glycemic control in patients with DM. Several guidelines, including those published by the New Zealand Heart Foundation, suggest that lipid-modifying therapies are appropriate in patients considered to be at high or very high risk of a cardiac event. This includes patients with established vascular disease. Some recent studies suggest that patients with type 2 DM have risk comparable to patients without DM, but have experienced previous myocardial infarction (MI). Subgroup analysis of trials including the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE), which included patients with DM, have shown a significant reduction in adverse outcomes, although many patients with DM and dyslipidemia were excluded. Of lipid-lowering drugs, fibric acid derivatives are probably the most appropriate for patients with DM and dyslipidemia and their role is being evaluated in large, long-term outcome studies such as Fenofibrate Intervention and Event Lowering in Diabetes (FIELD). Thiazolidinediones, a new class of compound for treating patients with type 2 DM, primarily exert their glucose-lowering effect by increasing insulin sensitivity at the level of skeletal muscle, and to a lesser extent, at the liver by decreasing hepatic glucose output. Some of their actions are mediated through binding and activation of the peroxisome proliferator-activated receptor-gamma, a nuclear receptor that has a regulatory role in differentiation of cells, especially adipocytes. The nonhypoglycemic effects of thiazolidinediones, therefore, offer additional potential mechanisms for benefit in patients with type 2 DM and insulin resistance. Thiazolidinediones increase serum HDL-C levels. Troglitazone and pioglitazone have been shown to decrease serum triglyceride levels. Rosiglitazone, conversely has no significant effect on serum triglyceride levels. All of the thiazolidinediones increase serum LDL-C levels (pioglitazone to a lesser extent), although changes in the size of the LDL fraction may render it less susceptible to oxidation and, therefore, less atherogenic. A randomized comparative trial needs to be undertaken to determine whether true differences exist between the thiazolidinediones. Longer studies need to be undertaken to assess their effect on cardiovascular outcomes.

Determination of methylphenidate and its metabolite ritalinic acid in urine by liquid chromatography/tandem mass spectrometry.

Methylphenidate (MPH) is a drug that is licensed for treatment of ADHD and also narcolepsy. Monitoring of the parent drug and its major metabolite ritalinic acid (RA) in urine is considered necessary to ensure compliance with treatment programmes. A rapid, simple and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of MPH and its metabolite RA in human urine. After urine was diluted with water, methylphenidate, the major metabolite ritalinic acid, and d6-amphetamine as the internal standard were resolved on a PFP propyl column using gradient elution of 0.02% ammonium formate and acetonitrile. The total analysis time was 13.5 min. The three compounds were detected using electrospray ionisation in the positive mode. Standard curves were linear over the concentration range 5-5000 µg/L (r>0.997), bias was ≤ ±20%, intra- and inter-day coefficients of variation (imprecision) were <8% and the limit of detection was 5 µg/L. The limit of quantitation was set at 100 µg/L. Matrix effects were up to 140% but these were accounted for by the internal standard. The assay is being used successfully in clinical practice to enhance the safe and effective use of methylphenidate.

Plasma poltergeists: a negative cortisol interference leading to a false diagnosis of adrenal insufficiency.

INTRODUCTION: Adrenal insufficiency is a rare life threatening condition with non-specific clinical signs and symptoms. This necessitates a high level of reliance on laboratory results for making the diagnosis. METHODS: We report a case involving an interference in cortisol measurement leading to spuriously low-cortisol measurements and the incorrect diagnosis and treatment of adrenal insufficiency. We also discuss the testing used to confirm the presence and nature of the interferent. RESULTS: Interference with an IgG antibody was demonstrated, and the patient was found to have a normally functioning adrenal axis. CONCLUSION: Interference in immunoassay is well described but often difficult to detect in clinical practice. Negative interference in cortisol measurement can occur and may lead to inappropriate diagnosis and treatment.

BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency.

The clinical presentation of a neonate with GRACILE-like syndrome, complex III deficiency and BCS1L mutations is discussed. This case is compared and contrasted with the original Finnish reports of GRACILE syndrome and other cases with a similar phenotype. This case confirms the pathogenicity of the BCS1L gene mutation c.166C>T, and provides support for the pathogenicity of a sequence variation, c.-588T>A, previously reported.

High sensitivity troponin outperforms contemporary assays in predicting major adverse cardiac events up to two years in patients with chest pain.

BACKGROUND: Previous studies have shown a risk of subsequent major adverse cardiovascular events (MACEs) in patients with suspected acute coronary syndromes (ACSs) and elevated cardiac troponin. The aim of this study was to compare prognostic utility of high-sensitivity troponin with contemporary troponin assays in such patients. METHODS: In total, 332 patients with suspected ACS were investigated between November 2006 and April 2007; all were followed for two years. Blood samples were analysed to compare Roche Elecsys high-sensitivity troponin T (hsTnT), Abbott Architect troponin I 3rd generation (TnI 3) and Roche Elecsys troponin T (TnT), for the prediction of MACE (composite of cardiovascular death, non-fatal myocardial infarction and revascularization). RESULTS: Sixty-eight patients (20.5%) experienced MACE between discharge and two years. Receiver operating characteristic (ROC) curve derived area under the ROC curve (95% confidence intervals) for baseline hsTnT were 0.70 (0.63-0.76), TnI 3 0.66 (0.59-0.73) and TnT 0.61 (0.53-0.69). hsTnT (P = 0.001) was superior to TnT and TnI 3 trended (P = 0.094) to superiority but were equivalent to each other. hsTnT best stratified patients with cumulative event rates for two-year MACE of 35.6% for levels ≥99th percentile, 17.9% for levels between the limit of detection (LOD) and 99th percentile and 5.4% for levels

Comparison of high sensitivity and contemporary troponin assays for the early detection of acute myocardial infarction in the emergency department.

BACKGROUND: Current guidelines define acute myocardial infarction (AMI) by the rise and/or fall of cardiac troponin with ≥1 value above the 99th percentile. Past troponin assays have been unreliable at the lower end of the range. Highly sensitive assays have therefore been developed to increase the clinical sensitivity for detection of myocardial injury. METHODS: Three hundred and thirty-two patients with chest pain suggestive of AMI were prospectively recruited between November 2006 and April 2007. Serial blood samples were analysed to compare Roche Elecsys high sensitivity troponin T (hsTnT), Abbott Architect troponin I 3rd generation (TnI 3) and Roche Elecsys troponin T (TnT) for the diagnosis of AMI. RESULTS: One hundred and ten (33.1%) patients were diagnosed with AMI. Test performance for the diagnosis of AMI, as quantified by receiver operating characteristic area under the curve (95% confidence intervals) for baseline/follow-up troponins were as follows: hsTnT 0.90 (0.87-0.94)/0.94 (0.91-0.97), TnI 3 0.88 (0.84-0.92)/0.93 (0.90-0.96) and TnT 0.80 (0.74-0.85)/0.89 (0.85-0.94). hsTnT was superior to TnT (P < 0.001/0.013 at baseline/follow-up) but equivalent to TnI 3. For patients with a final diagnosis of AMI, baseline troponins were raised in more patients for hsTnT (83.6%) than TnI 3 (74.5%) and TnT (62.7%). A delta troponin of ≥20% increased the specificity of hsTnT from 80.6% to 93.7% but reduced sensitivity from 90.9% to 71.8%. CONCLUSION: hsTnT was superior to TnT but equivalent to TnI 3 for the diagnosis of AMI. Serial troponin measurement increased test performance. hsTnT was the most likely to be raised at baseline in those with AMI. A delta troponin increases specificity but reduces sensitivity.