Jaffe, Allan S.

Abstract Background β-Quantification (BQ) is the reference method for low-density lipoprotein cholesterol (LDL-C) determination. It is not widely available, making it challenging for laboratories to assess the accuracy of LDL-C methods. Our goal was to develop an indirect graphical approach for comparing LDL-C test results to the BQ reference method. Methods BQ results from Mayo Medical Laboratories (n = 39 969) and the National Institutes of Health (n = 17 825) were used to investigate the interrelationships between lipid panel tests. A plot of LDL-C/non high-density lipoprotein cholesterol (nonHDL-C) vs (triglyceride (TG)/nonHDL-C)0.5 (lipid ratio plot) resulted in a negative linear regression line (y = −34.2x + 115). Based on simulation analysis, the minimum sample size for calculating its slope and intercept with a coefficient of variation of about 7.5% was 80. Results The regression lines for the lipid ratio plot of LDL-C calculated by the Sampson–NIH (y = −37.6x + 118) and enhanced Sampson–NIH (y = −33.1x + 116) equations closely overlapped with the BQ method. In contrast, the Martin–Hopkins equation showed a positive bias with an increasing TG/nonHDL-C ratio and exceeded the recommended bias limit of 4% on hypertriglyceridemic samples (y = −25.5x + 107). The Friedewald equation showed an even larger negative bias with hypertriglyceridemia (y = −47.5x + 126). Lipid ratio plots of the Roche direct assay revealed a fixed positive bias of approximately 4% (y = −33.9x + 120), whereas a much larger proportional positive bias was observed with increasing triglycerides for the Beckman direct assay (y = −14.6x + 97.8). Conclusions The lipid ratio plot is a simple graphical approach that can be readily performed by clinical laboratories for investigating the accuracy of LDL-C assays by calculation methods or direct assays.

Abstract Background Cardiovascular guidelines have long recommended low-density lipoprotein-cholesterol (LDL-C) as the primary target for lipid-lowering therapy. Recent guidelines have emphasized the importance of achieving low LDL-C levels; hence, the accurate measurement of low LDL-C is increasingly clinically relevant. Methods Using lipid panel test results from the Mayo Clinic (n = 24 590) and the FOURIER clinical trial of evolocumab (n = 9605), the following modified Sampson equation was developed by least-squares regression to match LDL-C (mg/dL) by the β-quantification reference method, by combining terms into non High Density Lipoprotein Cholesterol (nonHDLC = Total Cholesterol – High Density Lipoprotein Cholesterol) and forcing the coefficient to be one: Results The modified Sampson equation demonstrated significant improvement in its concordance to the reference method compared to other equations (the Lin Concordance Correlation Coefficient 0.992, P < 0.001). By overall kappa analysis, it showed the best agreement to the reference method at the 55 mg/dL cutpoint (1.4 mmol/L, 0.98 [P < 0.001], Sampson–NIH: 0.96, Martin–Hopkins: 0.96, Friedewald: 0.94) and the 70 mg/dL cutpoint (1.8 mmol/L, 0.97 [P < 0.001], Sampson–NIH: 0.94, Martin–Hopkins: 0.95, Friedewald: 0.92). The false classification rate of the modified Sampson equation was also significantly lower compared to the other equations at 55 mg/dL (15%, [P < 0.001], Sampson–NIH: 29%, Martin–Hopkins: 28%, Friedewald: 37%) and 70 mg/dL (18%, [P < 0.001]; Sampson–NIH: 30%, Martin–Hopkins: 28.%, Friedewald: 34%). The new equation increases the percentage of correctly classified patients with low LDL-C by approximately 10% to 20% over the other equations based on its net reclassification index. Conclusions The modified Sampson equation shows improved accuracy compared to other equations for low LDL-C. It more accurately identifies high-risk patients, who are not at their LDL-C goals and could benefit from more intensive lipid-lowering therapy.

Abstract New technologies enabling access to high-sensitivity cardiac troponin (hs-cTn) assays at the point of care (POC) are available for routine use. POC technology can accelerate cardiac troponin testing within the hospital setting and support testing in other healthcare environments. Pre-analytical and analytical issues unique to POC testing are discussed. The opportunities and the evidence needed to support the routine use of hs-cTn POC assays in clinical care are outlined. Based on recent developments, the potential impact of hs-cTn at the POC in multiple clinical settings is described, and a roadmap of the steps required for successful implementation is provided.

Abstract Background Cardiac troponin (cTn) levels exceeding the 99th percentile upper reference limit and a rise/fall pattern are key for diagnosing myocardial injury and infarction. Macrotroponins, formed by patient anti-cTn antibodies targeting cTn, can cause persistently elevated cTn levels without ongoing myocardial injury. The frequency and impact of macrotroponin interference on cTn 99th percentiles are unclear. This study compares sex-specific 99th percentiles for 2 cTn assays, before and after excluding macrotroponin-positive samples, focusing on the top 10% of cTn levels. Methods We examined 1058 plasma samples from healthy individuals previously used for Danish cTn 99th percentiles. Following International Federation of Clinical Chemistry and Laboratory Medicine educational recommendations, macrotroponin presence was assessed in the top 10% cTn samples using immunoglobulin G (IgG) depletion screening and a reference sucrose gradient, confirming macrotroponin when both methods concurred. Due to analytical dilution constraints, [the highest] 88 of 135 Siemens Atellica high-sensitivity cTnI (hs-cTnI) samples were analyzed with both methods. All 106 Roche hs-cTnT samples were negative using IgG depletion, and sucrose analysis was limited to the highest 70 samples. Results Macrotroponin was found in 76% (67/88) of Siemens samples but in none of the Roche samples (0/70). Excluding macrotroponin-affected samples lowered the Siemens 99th percentiles from 117 ng/L to 22 ng/L in men and from 37 ng/L to 9 ng/L in women. The 99th/50th percentile ratio for Siemens decreased from 12- to 29-fold to 3- to 7-fold, approaching the Roche ratios. Conclusions Macrotroponin significantly influenced the Siemens Atellica hs-cTnI 99th percentiles, suggesting important clinical implications that warrant further prospective studies. The 99th/50th percentile ratio may help evaluate macrotroponin interference in troponin assays.

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Abstract Background Cardiac troponin is the gold-standard biomarker for the evaluation of patients with suspected acute myocardial infarction (MI). Improvements in assay technology have led to high-sensitivity cardiac troponin assays that, when incorporated into accelerated diagnostic pathways, may rapidly diagnose or exclude acute MI more efficiently than conventional troponin assays. Content In this narrative review, we provide practical suggestions for implementing high-sensitivity cardiac troponin assays, review accelerated diagnostic pathways incorporating these assays, and review the impact of these assays on resource utilization and cost-effectiveness in relation to the evaluation of individuals with possible acute MI. Summary An increasing number of hospitals are transitioning to high-sensitivity cardiac troponin assays. This narrative review provides an overview of the potential benefits of this transition.

Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10–20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents.

Background: With demographic trends transitioning towards older adults, dementia and cognitive impairment are predicted to increase dramatically. We aim to elucidate the relationship between subclinical myocardial injury, as indicated by asymptomatic increased levels of high-sensitivity cardiac Troponin (hs-cTnT), and cognitive performance. Methods: We studied MESA participants from Exam 1 (2000-02) to Exam 6 (2016-18), categorizing them based on baseline hs-cTnT at Exam 1. Cognitive decline was defined as a decrease of ≥5 units in CASI between Exam 5&6. We used Pearson correlation and linear regression to analyze the association of hs-cTnT levels with CASI scores, and logistic regression to examine the association with cognitive decline. We also explored the relationship between different hs-cTnT categories and cognitive measures. Models were adjusted for demographics, lifestyle, APOE status, comorbidities, and medication use ( Figure ). Results: 4445 participants had both baseline hs-cTnT and valid Exam 5 CASI scores while only 1776 participants had valid Exam 6 CASI scores. Cohort was predominantly female (53%), mean age of 60 years, and 27% had at least one APOE e4 allele. Median hs-cTnT was 6.32 ng/L, and median CASI scores were 89 at Exam 5 and 91.5 at Exam 6. We found a negative correlation between the log-hs-cTnT at Exam 1 and Exam 5 with CASI scores at Exam 5. An increase of one unit in log-hs-cTnT level was associated with a decrease of 0.67 (CI -1.17, -0.17) in CASI and corresponded to higher odds (OR: 1.44; CI 1.05-1.95) of cognitive decline, after adjusting for covariates. When comparing various categories of hs-cTnT with category 1, we observe that the odd of cognitive decline increases as the category increases. However, this trend does not hold for category 5 with significantly lower sample size ( Figure ). Conclusion: Our findings indicate an inverse relationship between hs-cTnT and cognitive function years later, which is significantly attenuated by known risk factors for cognitive decline. Further research is needed to determine hs-cTnT as a predictor of future global cognitive functions.