Association of cardiac biomarkers with long-term cardiovascular events in a community cohort.

MATERIALS AND METHODS: The study assessed major adverse cardiac events (MACE) (myocardial infarction, coronary artery bypass graft, percutaneous intervention, stroke, and death. Cox proportional hazards models assessed apolipoprotein AI (ApoA1), apolipoprotein B (ApoB), ceramide score, cystatin C, galectin-3 (Gal3), LDL-C, Non-HDL-C, total cholesterol (TC), N-terminal B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin (HscTnI) and soluble interleukin 1 receptor-like 1. In adjusted models, Ceramide score was defined by from N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)] and N-lignoceroyl-sphingosine [Cer(24:0)]. Multi-biomarker models were compared with C-statistics and Integrated Discrimination Index (IDI). RESULTS: A total of 1131 patients were included. Adjusted NT proBNP per 1 SD resulted in a 31% increased risk of MACE/death (HR = 1.31) and a 31% increased risk for stroke/MI (HR = 1.31). Adjusted Ceramide per 1 SD showed a 13% increased risk of MACE/death (HR = 1.13) and a 29% increased risk for stroke/MI (HR = 1.29). These markers added to clinical factors for both MACE/death (p = 0.003) and stroke/MI (p = 0.034). HscTnI was not a predictor of outcomes when added to the models. DISCUSSION: Ceramide score and NT proBNP improve the prediction of MACE and stroke/MI in a community primary prevention cohort.

In a community cohort, where a wide range of biomarkers were evaluated, Ceramide score provided additive value over traditional cardiac risk factors alone for predicting stroke/MI. NT ProBNP provided additive value in prediction of MACE/death. Other biomarkers failed to improve the discrimination of these models.

The Elevated High-Sensitivity Cardiac Troponin T Pilot: Diagnoses and Outcomes.

OBJECTIVE: To identify the diagnoses and outcomes associated with elevated high sensitivity cardiac troponin T (hs-cTnT) compared with the 4th-generation troponin T and to validate the Mayo Clinic hs-cTnT myocardial infarction algorithm cutoff values. PATIENTS AND METHODS: Consecutive blood samples of patients presenting to the emergency department between July 2017 and August 2017, who had 4th-generation troponin T, were also analyzed using the hs-cTnT assay. Troponin T values, discharge diagnoses, comorbidities, and outcomes were assessed. In addition, analyses of sex-specific and hs-cTnT cutoff values were assessed. RESULTS: Of 830 patients, 32% had an elevated 4th-generation troponin T, whereas 64% had elevated hs-cTnT. With serial sampling, 4th-generation troponin missed a chronic myocardial injury pattern and acute myocardial injury pattern in 64% and 16% of patients identified with hs-cTnT, respectively. Many of these "missed" patients had discharge diagnoses associated with cardiovascular disease, infection, or were postoperative. Five of the 6 patients with unstable angina ruled in for myocardial infarction. CONCLUSION: There were many increases in hs-cTnT that were missed by the 4th-generation cTnT assay. Most new increases are not related to acute cardiac causes. They were more consistent with chronic myocardial injury. High-sensitivity cTnT did reclassify most patients with unstable angina as having non-ST-elevation myocardial infarction. Older age, more comorbidities, and lower hemoglobin were associated with elevated hs-cTnT. Our data also support the use of our sex-specific cutoff values.

Ceramide Scores Predict Cardiovascular Risk in the Community.

[Figure: see text].

Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification.

Ceramides are bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. During the past decade emerging clinical data have shown that ceramides are not only of great biochemical interest but may also have diagnostic utility. Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. Currently serum ceramides are used clinically as efficient risk stratifiers for primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). A direct cause-effect relationship between CVD and ceramide has not been established to date. As ceramide-specific medications are being developed, conventional strategies such as lipid lowering agents and lifestyle interventions can be used to reduce overall risk. Ceramides can identify a very high-risk coronary heart disease category of patients in need for more intense medical attention, specifically those patients at higher risk as highlighted in the 2019 European Society of Cardiology guidelines for stable chronic coronary syndrome patients. In addition, the ceramide risk score may be used as a decision-making tool in primary prevention patients with moderate CVD risk. Finally, the ceramide risk score may have a unique utility as a motivational tool to increase patient's adherence to medical therapy and lifestyle changes.

Ceramides improve atherosclerotic cardiovascular disease risk assessment beyond standard risk factors.

Ceramides are bioactive lipids that act as secondary messengers for both intra- and inter-cellular signaling. Elevated plasma concentrations of ceramides are associated with multiple risk factors of atherosclerotic cardiovascular diseases and comorbidities including obesity, insulin resistance and diabetes mellitus. Furthermore, atherosclerotic plaques have been shown to be highly enriched with ceramides. Increases in ceramide content may accelerate atherosclerosis development by promoting LDL infiltration to the endothelium and aggregation within the intima of artery walls. Thus, ceramides appear to play a key role in the development of cardiometabolic disease due to their central location in major metabolic pathways that intersect lipid and glucose metabolism. Recently published data have shown that ceramides are not only of scientific interest but may also have diagnostic value. Their independent prognostic value for future cardiovascular outcomes over and above LDL cholesterol and other traditional risk factors have consistently been shown in numerous clinical studies. Thus, ceramide testing with a mass spectrometer offers a simple, reproducible and cost-effective blood test for risk stratification in atherosclerotic cardiovascular diseases.

Measuring the contribution of Lp(a) cholesterol towards LDL-C interpretation.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a pro-atherogenic and pro-thrombotic LDL-like particle recognized as an independent risk factor for cardiovascular disease (CVD). The cholesterol within Lp(a) (Lp(a)-C) contributes to the reported LDL-cholesterol (LDL-C) concentration by nearly all available methods. Accurate LDL-C measurements are critical for identification of genetic dyslipidemias such as familial hypercholesterolemia (FH). FH diagnostic criteria, such as the Dutch Lipid Clinic Network (DLCN) criteria, utilize LDL-C concentration cut-offs to assess the likelihood of FH. Therefore, failure to adjust for Lp(a)-C can impact accurate FH diagnosis and classification, appropriate follow-up testing and treatments, and interpretation of cholesterol-lowering treatment efficacy. OBJECTIVE: In this study, we use direct Lp(a)-C measurements to assess the potential misclassification of FH from contributions of Lp(a)-C to reported LDL-C in patient samples submitted for advanced lipoprotein profiling. METHODS: A total of 31,215 samples submitted for lipoprotein profiling were included. LDL-C was measured by beta quantification or calculated by one of three equations. Lp(a)-C was measured by quantitative lipoprotein electrophoresis. DLCN LDL-C cut-offs were applied to LDL-C results before and after accounting for Lp(a)-C contribution. RESULTS: Lp(a)-C was detected in 8665 (28%) samples. A total of 940 subjects were reclassified to a lower DLCN LDL-C categories; this represents 3% of the total patient series or 11% of subjects with measurable Lp(a)-C. CONCLUSION: Lp(a)-C is present in a significant portion of samples submitted for advanced lipid testing and could cause patient misclassification when using FH diagnostic criteria. These misclassifications could trigger inappropriate follow-up, treatment, and cascade testing for suspected FH.

High-Sensitivity Cardiac Troponin for the Diagnosis of Patients with Acute Coronary Syndromes.

PURPOSE OF REVIEW: High-sensitivity cardiac troponin (hscTn) assays are replacing the older-generation assays used to detect myocardial injury because they have improved analytical sensitivity and lead to a more rapid diagnosis of acute myocardial infarction (AMI) and enhanced risk stratification in patients with non-ST elevation acute coronary syndromes (NSTE-ACS). This review focuses on advantages and difficulties of using hscTn as diagnostic and prognostic tools in acute coronary syndromes (ACS). RECENT FINDINGS: The newer assays have a lower specificity for AMI as compared to conventional assays, potentially leading to an increased number of unwarranted hospitalizations and amplified cost unless how to use these assays appropriately is appreciated. Several approaches can increase the specificity of the high sensitivity assays. This review will present the current literature data regarding the use of hscTn assays and will focus on modalities used to increase the specificity, as well as the advantages and pitfalls of using the high sensitivity approach in clinical practice.

Natriuretic Peptides and Analytical Barriers.

BACKGROUND: The natriuretic peptide system is an endocrine, autocrine and paracrine system that plays an important role in the maintenance of cardiovascular homeostasis. Biomarkers based on these peptides are important diagnostic and prognostic tools for myocardial function. CONTENT: Although natriuretic peptides were discovered more than 2 decades ago, their intricate and complex biology is associated with important questions not yet elucidated. The diversity of circulating forms of natriuretic peptides, the distinct expression of these forms in particular patients, and the heterogeneity of heart failure forms, along with specific assay-related and preanalytic issues, cause assays to be poorly harmonized. SUMMARY: This review presents the relevant issues related to the biology of natriuretic peptides and differences between assays with immediate implications for clinical practice.

Does cardiac rhythm monitoring in patients with elevated troponin levels lead to changes in management?

BACKGROUND: We sought to identify the frequency of arrhythmias in patients with elevated cardiac troponin levels and without ST-segment elevation myocardial infarction or a primary arrhythmia, and to determine whether detection of an arrhythmia leads to management changes. METHODS: A review of 1381 consecutive patients admitted from the emergency department for rhythm monitoring with an elevated cardiac troponin T (cTnT) level was performed. Patients admitted to an intensive care unit and those with an initial primary arrhythmia were excluded. Troponin values were obtained on admission, at 3 hours and at 6 hours. Electronic medical records and all rhythm recordings were reviewed for documentation of an arrhythmia and any changes in management. RESULTS: An arrhythmia was detected in 26% of the 330 patients who met the inclusion criteria. Those with arrhythmias had higher rates of coronary artery disease and prior percutaneous coronary intervention ( p = 0.02 and p = 0.01, respectively). Those with arrhythmias had higher mean cTnT values compared to those without arrhythmias ( p = 0.02 at 3 hours and p = 0.006 at 6 hours) even after controlling for a discharge diagnosis of acute coronary syndrome. Changes in management in response to the detection of arrhythmias were infrequent (6.3%) and usually included only changes in medication doses. CONCLUSIONS: Patients admitted with an elevated cTnT level to a non-intensive care unit rhythm-monitored bed without ST-segment elevation myocardial infarction or primary arrhythmia have a high incidence of arrhythmias; however, changes in management are infrequent.

Emerging biomarkers for acute heart conditions.

PURPOSE OF REVIEW: Acute cardiac conditions such as acute myocardial infarction and heart failure are associated with significant morbidity and mortality. Rapid diagnosis allows risk stratification and initiation of treatment in a timely manner. Numerous novel biomarkers have been identified to predict outcomes. These may assist in tailoring of appropriate therapy to high-risk patients. RECENT FINDINGS: This study reviews several novel biomarkers - galectin-3, ST2 and copeptin. The scope of this review is to identify and underline the clinical aspects of these emerging biomarkers. SUMMARY: Galectin-3 is an active biomarker found in inflammatory and fibrotic processes, and is a marker of mortality. ST2 is released by stressed cardiac myocytes and also predicts mortality in heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor associated with increased risk of heart failure. It may also be useful to exclude acute myocardial infarction.

Elevated cardiac troponin T levels in critically ill patients with sepsis.

BACKGROUND: It is known that troponin elevations have prognostic importance in critically ill patients. We examined whether cardiac troponin T elevations are independently associated with in-hospital, short-term (30 days), and long-term (3 years) mortality in intensive care unit (ICU) patients admitted with sepsis, severe sepsis, and septic shock after adjusting for the severity of disease with the Acute Physiology, Age and Chronic Health Evaluation III system. METHODS: We studied the Mayo Clinic's Acute Physiology, Age and Chronic Health Evaluation III database and cardiac troponin T levels from patients admitted consecutively to the medical ICU. Between January 2001 and December 2006, 926 patients with sepsis had cardiac troponin T measured at ICU admission. In-hospital, short-term, and long-term all-cause mortality were determined. RESULTS: Among study patients, 645 (69.7%) had elevated cardiac troponin T levels and 281 (30.3%) had undetectable cardiac troponin T. During hospitalization, 15% of the patients with troponin T <0.01 ng/mL died compared with 31.9% of those with troponin T ≥ 0.01 ng/mL (P < .0001). At 30 days, mortality was 31% and 17% in patients with and without elevations, respectively (P < .0001). The Kaplan-Meier probability of survival at 1-, 2-, and 3-year follow-ups was 68.1%, 56.3%, and 46.8% with troponin T ≥ 0.01 ng/mL, respectively, and 76.4%, 69.1%, and 62.0% with troponin T <0.01 µg/L, respectively (P < .0001). After adjustment for severity of disease and baseline characteristics, cardiac troponin T levels remained associated with in-hospital and short-term mortality but not with long-term mortality. CONCLUSIONS: In patients with sepsis who are admitted to an ICU, cardiac troponin T elevations are independently associated with in-hospital and short-term mortality but not long-term mortality.

Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T.

OBJECTIVES: The purpose of this study was to determine whether there is immunoreactive cardiac troponin T (cTnT) expression in diseased skeletal muscle that might cause possible false-positive increases in cTnT. BACKGROUND: Cardiac troponin (I or T) is the biomarker of choice for the diagnosis of cardiac injury. Recently, we were presented with a case that challenged the specificity of cTnT. METHODS: Patients with myopathies seen in the Neuromuscular Clinic at the Mayo Clinic were screened for increases in cTnT. If present, an assay for cTnI was performed. If normal, skeletal biopsy tissue was obtained for Western blot analysis using the capture and detection antibodies from both the fourth-generation and high-sensitivity cTnT assays. Results were compared with findings in normal cardiac tissue. RESULTS: Sixteen patients had increases in cTnT but not cTnI. All had a myopathy by clinical evaluation, clinical testing, and biopsy. Four residual biopsy samples were obtained. All 3 antibodies used in the cTnT (M11.7, M7) and high-sensitivity cTnT (5D8, M7) assays were immunoreactive with a 37- to 39-kDa protein in all 4 diseased skeletal muscle biopsy specimens and in cardiac tissue. A second immunoreactive isoform (34 to 36 kDa) was also found in 1 patient. None of the noncardiac control tissues expressed immunoreactive protein. CONCLUSIONS: These results document that there are forms in diseased skeletal muscle that could cause increases in circulating levels of cTnT. These increases could reflect re-expressed isoforms. Clinicians need to be aware of the possibility that noncardiac increases in cTnT may occur and lead to a possible false-positive diagnosis of cardiac injury when skeletal muscle pathology is present.

Significance of elevated cardiac troponin T levels in critically ill patients with acute respiratory disease.

BACKGROUND: Elevations in cardiac troponin have prognostic importance in critically ill patients. However, there are no data addressing the independent association between troponin levels and mortality, adjusted for the severity of the underlying disease, in patients hospitalized for acute respiratory disorders. We investigated whether troponin T (cTnT) elevations are independently associated with in-hospital mortality in patients in the intensive care unit (ICU) admitted for severe and acute respiratory conditions. After adjusting for the severity of disease measured by the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III prognostic system, we evaluated short-term (30 days) and long-term (3 years) mortality. METHODS: We studied the APACHE III database and cTnT levels from patients admitted consecutively to the ICU at Mayo Clinic, Rochester, Minnesota. Between January 2001 and December 2005, 2078 patients with respiratory conditions had cTnT measured at ICU admission. In-hospital, short-term (30 days) and long-term (3 years) all-cause mortality were determined. RESULTS: Of the study patients, 878 (42.3%) had elevated cTnT and 1200 patients (57.7%) had undetectable cTnT. During hospitalization, 1.1% of the patients with troponin T <0.01 ng/mL died compared to 21% of those with troponin T ≥0.01 ng/mL (P <.0001). At 30 days, mortality was 18.6% in patients with elevations of cTnT and 1.5% in patients without elevations of cTnT (P <.0001). The Kaplan-Meier probability of survival at 1-year follow-up was 71.0%, at 2-year follow-up was 48.3%, and 3-year follow-up was 39.4% with troponin T ≥0.01 ng/mL and at 1-year follow-up was 98.8%, at 2-year follow-up was 97.2%, and at 3-year follow-up was 95.5% with troponin T <0.01 µg/L (P <.0001). After adjustment for severity of disease and baseline characteristics, cTnT levels remained associated with in-hospital, short-term and long-term mortality (P <.0001). CONCLUSIONS: In patients admitted to the ICU for respiratory disorders, cTnT elevations are independently associated with in-hospital, short-term and long-term mortality.

Biological and analytical variability of a novel high-sensitivity cardiac troponin T assay.

BACKGROUND: High-sensitivity cardiac troponin assays will augment the frequency of increased results, making important the determination of reference change values to distinguish acute from chronic increases. We assessed short- and long-term biological variability of cardiac troponin T (cTnT) in healthy subjects with a novel high-sensitivity (hs) assay. METHODS: We collected blood from 20 healthy volunteers at 5 time points for short-term study and biweekly at 4 times from the same volunteers for long-term study. We analyzed serum samples in duplicate with a hscTnT assay on the Roche Modular E170 and computed reference change values (RCVs) for analytical, intraindividual, interindividual, and total change values (CV(A), CV(I), CV(G), and CV(T), respectively) and the index of individuality (II). We calculated RCVs by using a log-normal approach, owing to the skewed results of the data. RESULTS: Short- and long-term CV(A) values were 53.5% and 98%. CV(I) and CV(G) were 48.2% and 85.9%, respectively, for short-term studies and 94% and 94% for long-term studies. Mean delta values for the within-day study were 58% and -57.5%, and between-day mean delta values were 103.4% and -87%. Within- and between-day IIs were 0.8 and 0.14, respectively. CONCLUSIONS: The biological variation demonstrated with the hscTnT assay is higher than prior data for cardiac troponin I. This may be attributed to differences in biology or assay imprecision at low concentrations. A short-term change (RCV log normal) of 85% and a long-term change of 315% is necessary to define a changing pattern.

Aborted myocardial infarction: is it real in the troponin era?

BACKGROUND: Cardiac troponins are the markers of choice for the diagnosis of acute myocardial infarction. The objective of this study was to compare the frequency of "aborted myocardial infarction" (no detectable myocardial injury) determined by measurement of troponin versus that determined by creatine kinase (CK) and creatine kinase-muscle brain (CK-MB) measurement criteria among patients with ST-elevation myocardial infarction (STEMI) who received reperfusion therapy. METHODS: Since 2004, the Mayo Clinic (Rochester, MN) has had a standard reperfusion protocol for the treatment of patients with STEMI. During the study period, 767 patients presented with new or presumed new ST elevation or left bundle block. RESULTS: The diagnosis of STEMI was confirmed in 765 (99.7%) patients. Using the 99th percentile cutoff value, troponin T elevations occurred in 765 (100%) of 765 patients when serial samples were available. Creatine kinase-MB levels of twice or more the upper limit of normal occurred in 681 (90.1%) of 749 patients with serial samples for CK-MB, and CK equal or greater than twice the gender-specific upper limits of normal occurred in 521 (78.8%) of 661 patients with serial samples for CK available. CONCLUSION: The frequency of aborted myocardial infarction is 0% when using troponin at the 99th percentile cutoff as recommended by contemporary guidelines from the European Society of Cardiology (Nice, France) and American College of Cardiology (Washington, DC).

Long-term prognostic significance of elevated cardiac troponin levels in critically ill patients with acute gastrointestinal bleeding.

BACKGROUND: Elevations in troponin level have prognostic importance in critically ill patients, including those with gastrointestinal (GI) bleeding. However, there are no data addressing the independent association of troponin levels and mortality, adjusted for the severity of the underlying disease, in patients with GI bleeding. OBJECTIVE: This study was designed to determine whether troponin T elevations are independently associated with in-hospital, short-term (30 days), and long-term mortality in medical intensive care unit patients with GI bleeding after adjusting for the severity of disease measured by the Acute Physiology, Age, and Chronic Health Evaluation score prognostic system. DESIGN: Retrospective study. SETTING: We examined the Acute Physiology, Age, and Chronic Health Evaluation III database and cardiac troponin T levels from patients consecutively admitted to the medical intensive care unit at Mayo Clinic, Rochester, MN, with acute GI bleeding. PATIENTS: Between August 2000 and July 2005, 1076 patients with acute GI bleeding consecutively admitted to the medical intensive care units. MEASUREMENTS: In-hospital, short-term (30 days), and long-term all-cause mortality. RESULTS: During hospitalization, 8.0% of deaths occurred in patients with troponin T < 0.01% and 11.9% with troponin T > or = 0.01 (p = 0.083). At 30 days, mortality was 10.1% and 18.8% in patients without and with elevations of troponins, respectively (p < 0.001). The Kaplan-Meier expected probability of survival at 1-, 2-, and 3-yr follow-up was 54.2%, 40.8%, and 30.4% with troponin T > or = 0.01 microg/L and 78.3%, 69.3%, and 61.5% with troponin T < 0.01 microg/L (p < 0.001). After adjustment for severity of disease and baseline characteristics, cardiac troponin levels were associated only with long-term mortality (p < 0.001). LIMITATIONS: This is a retrospective, single-center study which included only patients in whom troponin level was determined upon admission. CONCLUSIONS: In patients with GI bleeding severe enough to require admission to the medical intensive care unit, admission troponin T elevations are associated with long-term but not short-term mortality.