Clinical utility of cardiac troponin measurement in COVID-19 infection.

The novel coronavirus SARS-CoV-2 causes the disease COVID-19, a severe acute respiratory syndrome. COVID-19 is now a global pandemic and public health emergency due to rapid human-to-human transmission. The impact is far-reaching, with enforced social distancing and isolation, detrimental effects on individual physical activity and mental wellbeing, education in the young and economic impact to business. Whilst most COVID-19 patients demonstrate mild-to-moderate symptoms, those with severe disease progression are at a higher risk of mortality. As more is learnt about this novel disease, it is becoming evident that comorbid cardiovascular disease is associated with a greater severity and increased mortality. Many patients positive for COVID-19 demonstrate increased concentrations of cardiac troponin, creating confusion in clinical interpretation. While myocardial infarction is associated with acute infectious respiratory disease, the majority of COVID-19 patients demonstrate stable cTn rather than the dynamically changing values indicative of an acute coronary syndrome. Although full understanding of the mechanism of cTn release in COVID-19 is currently lacking, this mini-review assesses the limited published literature with a view to offering insight to pathophysiological mechanisms and reported treatment regimens.

Cardiac troponins: from myocardial infarction to chronic disease.

Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of 'unknown origin'. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.

Investigating the Effect of a Single Infusion of Reconstituted High-Density Lipoprotein in Patients with Symptomatic Carotid Plaques.

BACKGROUND: Elevation of plasma high-density lipoprotein (HDL) cholesterol concentration reduces cardiovascular mortality and morbidity. HDLs have been shown to possess acute anti-inflammatory, antioxidant, and antithrombotic properties. We hypothesize that HDL therapy can acutely alter local and systemic manifestations of plaque instability. METHODS: Forty patients with early symptomatic carotid disease were randomized to either receive reconstituted HDL (rHDL) 40 mg/kg (n = 20) or placebo (n = 20). Carotid endarterectomies were performed 24 hr later. Plaques were obtained intraoperatively and used for measurement of thrombomodulatory genes expression. Plasma samples were collected before the infusion, 24 and 48 hr later to measure changes in systemic markers of plaque instability. RESULTS: No significant differences were noted in thrombomodulatory genes expression between the 2 groups. Systemic levels of tissue factor, matrix metalloproteinase 9 (MMP-9), and monocyte chemotactic factor-1 (MCP-1) were significantly reduced in the rHDL group. However, the effects on MMP-9 and MCP-1 were abolished in the immediate postoperative period. Although rHDL did not affect plasma interleukin-6 levels 24 hr following the infusion, it prevented the significant postoperative elevation seen in the placebo group. CONCLUSIONS: A single infusion of rHDL can acutely alter plasma biomarkers associated with plaque instability and cardiovascular morbidity.

Cardiac troponin I but not cardiac troponin T adheres to polysulfone dialyser membranes in an in vitro haemodialysis model: explanation for lower serum cTnI concentrations following dialysis.

BACKGROUND: Elevated serum cardiac troponin T (cTnT) and I (cTnI) can occur in patients with chronic kidney disease. Differences in cTn concentrations between cTnT and cTnI have been reported but the mechanism of such discrepancy has not been investigated. This study investigates the clearance of cTn with the aid of an in vitro model of haemodialysis (HD). METHODS: Serum was obtained before and after a single session of dialysis from 53 patients receiving HD and assayed for cTnT and cTnI. An in vitro model of the dialysis process was used to investigate the mechanism of clearance of cTn during HD. RESULTS: Serum cTnI was significantly lower (p=0.043) following a session of HD whereas cTnT concentrations were similar to those obtained before HD. Using an in vitro model of dialysis, it was demonstrated that cTnI is not dialysed from the vascular compartment but adheres to the dialyser membrane. CONCLUSIONS: The adherence of cTnI to the dialyser membrane is responsible for the observed decrease in serum cTnI following a session of dialysis. The adherence of cTnT or T-I-C complex to the dialyser membrane could not be demonstrated and supports the observation that pre-HD and post-HD serum concentrations of cTnT are similar.

Analytical evaluation of the automated galectin-3 assay on the Abbott ARCHITECT immunoassay instruments.

BACKGROUND: Galectin-3 is secreted from macrophages and binds and activates fibroblasts forming collagen. Tissue fibrosis is central to the progression of chronic heart failure (CHF). We performed a European multicentered evaluation of the analytical performance of the two-step routine and Short Turn-Around-Time (STAT) galectin-3 immunoassay on the ARCHITECT i1000SR, i2000SR, and i4000SR (Abbott Laboratories). METHODS: We evaluated the assay precision and dilution linearity for both routine and STAT assays and compared serum and plasma, and fresh vs. frozen samples. The reference interval and biological variability were also assessed. Measurable samples were compared between ARCHITECT instruments and between the routine and STAT assays and also to a galectin-3 ELISA (BG Medicine). RESULTS: The total assay coefficient of variation (CV%) was 2.3%-6.2% and 1.7%-7.4% for the routine and STAT assays, respectively. Both assays demonstrated linearity up to 120 ng/mL. Galectin-3 concentrations were higher in plasma samples than in serum samples and correlated well between fresh and frozen samples (R=0.997), between the routine and STAT assays, between the ARCHITECT i1000 and i2000 instruments and with the galectin-3 ELISA. The reference interval on 627 apparently healthy individuals (53% male) yielded upper 95th and 97.5th percentiles of 25.2 and 28.4 ng/mL, respectively. Values were significantly lower in subjects younger than 50 years. CONCLUSIONS: The galectin-3 routine and STAT assays on the Abbott ARCHITECT instruments demonstrated good analytical performance. Further clinical studies are required to demonstrate the diagnostic and prognostic potential of this novel marker in patients with CHF.

Age-dependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cut-point for ruling out suspected systolic dysfunction in primary care.

AIMS: The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards. METHODS AND RESULTS: Data were obtained from 5508 patients from 10 studies in the UK, New Zealand, Europe, and USA. All have had NT-proBNP analysis and echocardiography. The median age was 62 years (range 18-100 years) with a prevalence of reduced left ventricular systolic function (left ventricular ejection fraction < or =40%) of 18%. In a receiver operating characteristic curve analysis, overall area under the curve (AUC) was 0.89. When looking at different age groups, AUC was highest (0.95) for <50 years, intermediate (0.90) for 50-75 years, and lowest (0.82) for >75 years. Using optimized decision limits, sensitivity, specificity, and negative predictive values (NPVs) were: <50 years (50 ng/L): 99.2, 57.2, and 99.7%; 50-75 years (75 ng/L): 95.9, 51.0, and 96.8%; and >75 years (250 ng/L): 87.9, 53.7, and 92.4%, respectively. Using only a single decision value (125 ng/L for all ages) gave sensitivities of 89.1, 91.9, and 94.3%; specificities of 84.0, 69.1, and 29.3% and NPVs of 97.7, 97.6, and 93.4%. A decision value of 400 ng/L for all ages gave much lower sensitivities. CONCLUSION: In a large population of patients in primary care, the use of age-stratified NT-proBNP decision limits considerably improves performance over current standards, with an excellent NPV for exclusion of reduced left ventricular systolic function.

Ischemia modified albumin: a novel biomarker for the detection of cardiac ischemia.

SUMMARY: The diagnosis of cardiac ischemia remains a challenge in contemporary emergency medicine. A blood-borne biomarker is an attractive alternative to cardiac imaging or stress testing as it would be cheaper and logistically faster to obtain. A number of candidate biomarkers have been proposed for the detection of cardiac ischemia; however, only Ischemia Modified Albumin (IMA) has been released for clinical use. IMA is a good discriminator between ischemic and non-ischemic patients. Changes in IMA concentration have shown to occur during coronary angioplasty-induced ischemia. Clinical studies indicate that IMA appears to offer on admission an early test which can be combined with electrocardiographic findings and cardiac troponin measurements for the early exclusion of acute coronary syndrome. IMA is an independent predictor of short and long term adverse outcomes in patients with acute chest pain. However, this test is relatively new and uncertainties remain. Elevations of IMA occur in conditions other than chest pain, thus questioning its specificity. The mechanism of IMA formation and the precise entity being measured are not fully known. Nevertheless, IMA measurement remains the only current clinical biomarker which may be used for the diagnosis of patients suspected of cardiac ischemia.

The diagnostic and prognostic value of tissue Doppler imaging during dobutamine stress echocardiography in end-stage renal disease.

OBJECTIVE: To determine whether a quantitative measurement of peak systolic velocity (PSV) during dobutamine stress echocardiography (DSE) detects severe coronary artery disease (CAD) and predicts mortality in patients with end-stage renal disease. METHODS: One hundred and forty renal transplant candidates had DSE and coronary angiography. DSE analysis was performed using conventional visual wall motion assessment, longitudinal PSV, and combining the two modalities. Failure of PSV to rise by more than 50% predicted an ischemic response. Significant CAD was defined as luminal stenosis greater than 70%. RESULTS: The number of positive DSE studies according to conventional, PSV, and combined criteria was 41 (30%), 42 (31%), and 46 (34%) respectively. Forty patients (29%) had significant CAD at angiography. The sensitivity, specificity, positive and negative predictive values for conventional DSE analysis were 84, 91, 86, and 90% respectively. The same values for PSV analysis were 86, 92, 86, and 91%, respectively. The same values for the combination of visual and PSV analysis were 88, 94, 87, and 92% respectively. The differences between the three methods were not statistically significant. Sensitivity for single-vessel CAD (P=0.05) and circumflex artery disease (P=0.05) diagnosis was higher with PSV compared with conventional DSE analysis. Failure of PSV to rise by more than 50% during DSE was associated with significantly increased mortality (P=0.001). CONCLUSION: A quantitative interpretation of DSE, based on the percentage rise of PSV during stress, accurately detects CAD and predicts prognosis in end-stage renal disease.

Cardiac biomarkers in chronic renal disease.

Cardiac biomarkers have a complex interrelationship with disease pathophysiology in patients with renal dysfunction. The underlying clinical condition results in a direct effect on the normal release and clearance of cardiac troponins and natriuretic peptides. Although initial reports suggested that this might prove a major limitation in the routine clinical use of these markers, a combination of improved assay performance and a better understanding of the underlying biochemistry of these markers in health and disease has clarified the situation. Renal dysfunction does not provide a significant practical limitation to the use of cardiac biomarkers for diagnosis in acute presentation of cardiovascular disease. The direct relationship between cardiac biomarkers and renal dysfunction reflects the high incidence of cardiovascular disease and cardiac death in patients with renal dysfunction and end-stage renal disease. Elevations of the cardiac troponins are prognostic in patients with renal dysfunction and represent global diffuse myocardial injury. Elevations of natriuretic peptides also occur due to abnormalities of ventricular function. In addition, background levels will be affected by fluid and electrolyte abnormalities due to renal dysfunction. This will directly affect vascular volume and fluid distribution altering atrial and ventricular wall tension and hence rates of natriuretic peptide release and production. The challenge is for the renal physician to translate the potential for cardiovascular disease monitoring conferred by these biomarkers into improved patient management.

Multiple molecular forms of circulating cardiac troponin: analytical and clinical significance.

Cardiac troponin T (cTnT) and I (cTnI) are highly specific and sensitive biomarkers of myocardial cell damage and are now accepted as the 'gold standard' diagnostic test for acute coronary syndrome and supersede the classical muscle enzyme biomarkers. While the understanding of the development and structure of the troponins has advanced, detailed biochemistry of the troponin molecules is complex and poorly understood. Many post-translational molecular forms of troponin are known to exist. The diversity of these circulating forms may have a clinical impact and the notion of a disease-specific troponin protein signature has been suggested. However, the effects of these multiple forms on commercial assay performance and their impact clinically are currently unknown and should be the focus of future research and assay design.