Combined measurement of N-terminal pro-B-type natriuretic peptide and highly sensitive cardiac troponin T for diagnosis and monitoring of heart injury in chronic Chagas' disease.

OBJECTIVE: Chronic Chagas disease afflicts millions of patients in Latin America of which 70% remain asymptomatic but 30% develop fatal heart injury. To evaluate the impact of laboratory medicine for diagnosis and guiding of patients with Chagas' heart disease, we measured N-terminal B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). DESIGN AND METHODS: NT-proBNP and cTnT using the highly sensitive assay (hs-cTnT) were measured in 48 asymptomatic Chagas' patients (control group; (-) CM), and in symptomatic patients who suffered from mild/moderate (group (+/++) CM, n=62) or severe cardiomyopathy (group (+++) CM, n=27). RESULTS: Both markers were higher in (+/++) CM and (+++) CM vs. (-) CM and increased in the cardiomyopathy severity. Values of 3 ng/L cTnT and 160 ng/L NT-proBNP were calculated as optimal cut-offs to distinguish (-) CM vs. CM. The NT-proBNP cut-off of 125ng/L, as recommended by international guidelines, was additionally incorporated in the analysis. Cardiomyopathy was most successfully predicted by dual positivity of both markers (positive predictive value=1.0). Negativity of both markers effectively excluded cardiomyopathy (negative predictive value of 0.85). Positivity for at least one of the markers is the best for overall correct classification. CONCLUSIONS: Combined measurement of hs-cTnT and NT-proBNP can be used for diagnosis and monitoring of cardiomyopathy in chronic Chagas' patients. In this way, laboratory medicine increases the pre-test probability of the cardiologic diagnostics, which would reduce its time, cost, and logistical problems.

Chronic Chagas disease: from basics to laboratory medicine.

Chagas disease, caused by Trypanosoma cruzi infection, is ranked as the most serious parasitic disease in Latin America and has huge potential to become a worldwide problem, due to increasing migration, and international tourism, as well as infectant transfer by blood contact and transfusion, intrauterine transfer, and organ transplantation. Nearly 30% of chronically-infected patients become symptomatic, often with a latency of 10-30 years, developing life-threatening complications. Of those, nearly 90% develop Chagas heart disease, while the others manifest gastrointestinal disease and neuronal disorders. Besides interrupting the infection cycle and chemo therapeutic infectant elimination, starting therapy early in symptomatic patients is important for counteracting the disease. This would be essentially supported by optimized patient management, involving risk assessment, early diagnosis and monitoring of the disease and its treatment. From economic and logistic viewpoints, the tools of laboratory medicine should be especially able to guarantee this. After summarizing the basics of chronic Chagas disease, such as the epidemiological data, the pathogenetic mechanisms thought to drive symptomatic Chagas disease and also treatment options, we present tools of laboratory medicine that address patient diagnosis, risk assessment for becoming symptomatic and guidance, focusing on autoantibody estimation for risk assessment and heart marker measurement for patient guidance. In addition, increases in levels of inflammation and oxidative stress markers in chronic Chagas disease are discussed.

Two novel equations to estimate kidney function in persons aged 70 years or older.

BACKGROUND: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease. OBJECTIVE: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. DESIGN: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. SETTING: Random community-based population of a large insurance company. PARTICIPANTS: 610 participants aged 70 years or older (mean age, 78.5 years). INTERVENTION: Iohexol plasma clearance measurement as gold standard. MEASUREMENTS: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample. RESULTS: The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). LIMITATION: There was no validation by an external data set. CONCLUSION: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative. PRIMARY FUNDING SOURCE: Kuratorium für Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine.

Evaluation of the iChem® Velocity™ urine chemistry analyzer in a hospital routine laboratory.

BACKGROUND: The novel urine chemistry analyzer iChem Velocity (IRIS Diagnostics) offers improved urinalysis automation options through integration with the well-established iQ200 urine microscopy analyzer. In the course of optimizing the workflow in our hospital routine laboratory, we evaluated the performance of the iChem Velocity. METHODS: A total of 257 random urine samples were analyzed with the iChem Velocity, iQ200, Clinitek Atlas (Siemens Healthcare Diagnostics) and by manual microscopy. RESULTS: Depending on the parameter, 93% (hemoglobin) to 100% (urobilinogen), the iChem Velocity and Clinitek Atlas results agreed within the same rank or within one level of difference. The Clinitek Atlas featured a higher sensitivity for hemoglobin (area under the curve 0.86) and leukocyte esterase (area under the curve 0.85) compared with the iChem Velocity (area under the curve for hemoglobin 0.73, leukocytes 0.78). Imprecision was highest for hemoglobin and leukocytes in a pathological sample pool. While the precision of the Clinitek Atlas for hemoglobin measurements was superior, the iChem Velocity was more precise in analyzing protein and pH. CONCLUSIONS: Through urinalysis automation with the iChem Velocity and iQ200, we achieved a reduction of hands-on time by 89%. The sensitivity of this new system should be further improved through ongoing development.

Cardiac troponin T release and inflammation demonstrated in marathon runners.

BACKGROUND: As shown on the basis of highly sensitive assays, cardiac troponin release is now observed after physiological heart stress and in mild heart pathologies: both are [corrected] considered unrelated to the irreversible cardiac alteration that is typically the source of release. Transitory cardiac membrane leakage was suggested as the basis. In our view, mild inflammation may drive this type of cardiac troponin release. To verify this hypothesis, marathon runners who demonstrated post-run inflammation were used as a model to correlate cTnT release and inflammation intensity. METHODS: In 78 male marathon runners who participated in the BERLIN-MARATHON 2006, cardiac troponin T (cTnT) was monitored [corrected] at three time points (pre-race, post-race, and after two weeks of rest). [corrected] Measurements were done with the highly sensitive assay (hs cTnT assay) and the conventional fourth-generation cTnT assay for comparison. Concurrently, [corrected] the inflammation markers (leukocyte and neutrophil counts, CRP, IL-6) were measured. RESULTS: Pre-race, the fourth-generation assay failed to demonstrate cTnT positivity (> test specific LLD). In contrast, with the [corrected] use of the highly sensitive assay, 28% of the participants were positive for cTnT (> LLD of hs cTnT assay). Post-race, cTnT as measured with the fourth-generation assay was observed to be detectable in 43% of the runners (> LLD = 99(th) percentile cut off), but all runners had detectable cTnT values (> LLD) when measured with the highly sensitive assay. Even in 94% of these cTnT-positive runners, the value exceeded the 99(th) percentile cut off determined for the highly sensitive assay (13 ng/L). cTnT release correlated significantly with inflammation intensity. Faster runners demonstrated significantly stronger cTnT releases and inflammation signs. CONCLUSIONS: As demonstrated after physiological heart stress such as marathon running, transitory inflammation is evidently one of the events contributing to the cardiac troponin release under conditions suggested as unrelated to irreversible cardiac alteration.

Gender-dependent impact of risk factors for cardiovascular and non-cardiovascular mortality in end-stage renal disease patients on haemodialysis.

We investigated whether mortality risk factors are gender dependent in haemodialysis patients. Patients (n = 230; 118 women, 112 men) on haemodialysis were followed for 52 months to assess the incidence of death due to cardiovascular or non-cardiovascular causes. Survival was compared by Cox regression analysis using age, diabetes, pre-existing coronary disease, troponin T and C-reactive protein as covariates. In total, 120 participants (52.2%) died within the 52 months of follow-up: 57 patients died of cardiovascular disease, 35 patients died of infectious diseases. Cox regression revealed that age, pre-existing coronary heart disease and troponin T were independent all-cause mortality risk factors for both sexes. Analyzing men and women separately revealed that diabetes and C-reactive protein seemed to be a stronger risk factors for all-cause mortality in women. Cardiovascular mortality was predicted by troponin T in women (relative risk = 5.16, 95% CI: 1.67-15.88; p = 0.004), but not in men (relative risk = 1.69; 95% CI: 0.72-3.96; p = 0.23). Our study showed for the first time that the impact of risk factors in predicting death due to cardiovascular disease is clearly gender dependent.

Reliability of different expert systems for profiling proteinuria in children with kidney diseases.

This study was designed to compare three urinary protein expert systems for profiling proteinuria in children with kidney diseases. Freshly voided urine specimens were collected from 61 children with glomerular diseases, 19 children with tubular diseases and 25 healthy children aged 3-16 years. The urinary protein expert systems were: (1) albumin/total protein ratio (APR), (2) alpha-1-microglobulin/alpha-1-microglobulin + albumin algorithm (AAA), and (3) the complex urine protein expert system (UPES, PROTIS) algorithm. APR correctly identified glomerular proteinuria in 47/61 children, tubular proteinuria in 16/19 children and normal proteinuria in 23/25 healthy children. AAA correctly identified glomerular proteinuria in 61/61 children and tubular proteinuria in 18/19 children, and 25/25 healthy children were characterized as having no abnormal proteinuria. AAA was not influenced by the stage of chronic kidney disease. UPES differentiated the type of proteinuria in children with glomerular diseases into glomerular (50/61 patients) and mixed glomerulo-tubular (6/61 patients). Tubular proteinuria was identified in 16/19 patients and described as mixed glomerulo-tubular proteinuria in 3/19 patients. Mixed glomerulo-tubular proteinuria was found only in children with chronic kidney disease stages 2-5 of glomerular and tubular diseases. In conclusion, the AAA and UPES had the highest accuracy levels.

Impact of kidney function on plasma troponin concentrations after coronary artery bypass grafting.

BACKGROUND: To date, there have been no studies reliably showing an influence of the kidney on the concentration of troponins. We therefore analysed the concentration curves in patients after coronary artery bypass grafting (CABG) according to their dependence on renal function. METHODS: We determined cardiac troponin I (cTnI), cardiac troponin T (cTnT) and creatinine in plasma in 28 patients after CABG. Discrimination into patients with normal (n=13) and impaired (n=15) renal function was based on creatinine clearance (Crea-Clear). The curves for cTnI and cTnT, as recorded by post-operative measurements, were approximated using mathematical functions. The curve parameters peak maximum (P(max)), peak position (P(pos)), half-height breadth (HHB) and area under the curve (AUC) were established after this. Assuming an exponential function, the half-life (t(1/2)) of cTnI was determined from the declining part of the curve. RESULTS: For both, cTnI and cTnT, significant differences in P(max), P(pos), HHB and AUC were detected after curve approximation. The t(1/2) values of cTnI were 25.1 h (22.0-35.3) for the group with normal renal function and 38.4 h (35.9-51.9) for patients with impaired renal function (P=0.001). An influence of diabetes mellitus (Dm), renal replacement therapy or the age of the patients could not be verified. CONCLUSION: The results of this study clearly demonstrate that kidney function has an impact on plasma troponin concentrations. In everyday clinical practice this has to be considered when interpreting elevated plasma troponin concentration in patients with impaired renal function.

Soluble CD154 is a unique predictor of nonfatal and fatal atherothrombotic events in patients who have end-stage renal disease and are on hemodialysis.

Cardiovascular mortality is remarkably high in patients who are on hemodialysis. Soluble CD154 (sCD154), a protein that belongs to the TNF receptor superfamily, has been implicated in the pathogenesis of atheromatous plaque destabilization and thrombotic events. The predictive value of sCD154 as a marker for clinical outcome in patients with ESRD was investigated. A total of 232 patients were prospectively followed for 52 mo. At study entry, clinical characteristics were documented and plasma concentrations of sCD154 and those of conventional risk predictors were analyzed. The time and cause of any hospitalization and death were documented during the entire follow-up. Survival rates were compared by Kaplan-Meier and Cox regression analyses. A total of 122 patients died, 64 of cardiovascular disease, including 20 cases of fatal atherothrombotic diseases (myocardial infarction, stroke, mesenteric ischemia). All 20 cases of fatal atherothrombotic events had high sCD154 plasma levels (cutoff >6.42 ng/ml) at study entry. The total number of fatal and nonfatal atherothrombotic events was 66. Only five atherothrombotic nonfatal events occurred in patients with sCD154 <6.42 ng/ml, whereas 61 fatal and nonfatal events were seen in patients with sCD154 > or =6.42 ng/ml (P < 0.005). This was confirmed by Kaplan-Meier curves for fatal atherothrombotic events (P = 0.0214) and the combined end point fatal and nonfatal atherothrombotic events (P = 0.0039). Cox regression analysis revealed that high sCD154 is an independent predictor (relative risk 6.80; 95% confidence interval 1.64 to 28.26; P = 0.008) for the combined end point death or hospitalization as a result of atherothrombotic events. Death or hospitalizations as a result of any other reason (arrhythmia, heart failure, infectious diseases, and cancer) were not linked to sCD154 plasma concentrations. In conclusion, sCD154 predicts nonfatal and fatal atherothrombotic events (myocardial infarction, stroke, mesenteric ischemia) but not death and hospitalization as a result of any other reason in stable patients who have ESRD and are on hemodialysis.

Does contrast echocardiography induce increases in markers of myocardial necrosis, inflammation and oxidative stress suggesting myocardial injury?

BACKGROUND: Contrast echocardiography is a precise tool for the non-invasive assessment of myocardial function and perfusion. Side effects of contrast echocardiography resulting from contrast-agent induced myocardial micro-lesions have been found in animals. The goal of this study is to measure markers of myocardial necrosis, inflammation and oxidative stress in humans to evaluate potential side-effects of contrast echocardiography. METHODS: 20 patients who underwent contrast echocardiography with Optison as the contrast medium were investigated. To evaluate myocardial micro-necrosis, inflammation and oxidative stress, cardiac troponin I (cTnI), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, -8 and thiobarbituric acid reactive substances (TBARS) were measured at baseline and at 2, 4, 8 and 24 hours after contrast echocardiography. RESULTS: At baseline, 50% of the patients had cTnI and TBARS values outside the reference range. TNF-alpha, IL-6, IL-8 levels were within the reference range. Patients with cTnI above the RR clustered to significantly higher levels of TNF-alpha and IL-6. After contrast echocardiography, no statistically significant increase of cTnI, cytokines and TBARS was found. However, for nearly 50% of the patients, the intra-individual cTnI kinetics crossed the critical difference (threefold of methodical variation) which indicates a marker increase. This was neither predicted by the baseline levels of the cytokines nor the markers of oxidative stress. CONCLUSION: There are no clinically relevant increases in serum markers for micro-necrosis, inflammation and oxidative stress in humans after contrast echocardiography. Future studies have to address whether cTnI increase in some patients represent a subset with increased risk for side effects after contrast echocardiography.

Relaxin is an independent risk factor predicting death in male patients with end-stage kidney disease.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have a reduced life expectancy mainly as the result of cardiovascular diseases. Relaxin has been implicated in the pathogenesis of cardiovascular diseases. We analyzed the impact of relaxin on death in patients with ESKD. METHODS AND RESULTS: Patients (n =245; 122 women, 123 men) on long-term hemodialysis were followed for 1140 days for death. Blood samples for analysis of relaxin, C-reactive protein, Troponin T, cholesterol, HDL, brain natriuretic peptide, and albumin were taken at study entry. Survival was compared by the Kaplan-Meier method and Cox regression analysis. One hundred seven patients died during the observation period; 66 died of cardiovascular diseases and 28 died of infectious diseases. Elevated serum relaxin concentrations (greater than median) predicted death in male but not in female patients with ESKD: All-cause death (men: relative risk, 2.63; 95% CI, 1.34 to 5.12; P=0.005; women: relative risk, 0.671; 95% CI, 0.33 to 1.35; P=0.262) and cardiovascular death (men: relative risk, 2.95; 95% CI, 1.20 to 7.21; P=0.018; women: relative risk, 0.639; 95% CI, 0.26 to 1.56; P=0.324). CONCLUSIONS: Relaxin is an independent risk factor predicting death in male patients with ESKD on chronic hemodialysis.

Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis.

Diabetic patients undergoing hemodialysis demonstrate much worse survival rates than do nondiabetic patients undergoing hemodialysis. To search for risk predictors, a prospective cohort study was performed with 245 hemodialysis patients, including 84 with diabetes mellitus, for 2 yr. C-reactive protein, troponin T (TnT), total, HDL, LDL, and lipoprotein(a) cholesterol, apoA2, apoB, triglyceride, fibrinogen, D-dimer, albumin, and creatinine levels and clinical characteristics at the time of entry were recorded. Survival rates were compared with Kaplan-Meier and Cox regression analyses. Forty-three diabetic patients and 30 nondiabetic patients died. Among diabetic patients, oliguria (<200 ml/d) (relative risk, 3.24; 95% confidence interval, 1.63 to 6.41; P = 0.001), elevated C-reactive protein levels (relative risk, 2.57; 95% confidence interval, 1.06 to 6.18; P = 0.035), and elevated D-dimer levels (relative risk, 2.36; 95% confidence interval, 1.11 to 5.01; P = 0.025) predicted all-cause mortality rates. Oliguria was by far the most important predictor, particularly for infectious disease-related death (relative risk, 23.35; 95% confidence interval, 2.60 to 209.97; P = 0.005). Among nondiabetic patients, elevated TnT levels (relative risk, 4.00; 95% confidence interval, 1.58 to 10.10; P = 0.003), elevated D-dimer levels (relative risk, 3.45; 95% confidence interval, 1.27 to 9.33; P = 0.015), and low cholesterol levels (relative risk, 3.61; 95% confidence interval, 1.34 to 9.71; P = 0.011) predicted all-cause mortality rates. Subdivision of the causes of death among nondiabetic patients revealed that TnT levels predicted cardiovascular mortality rates (relative risk, 5.38; 95% confidence interval, 1.11 to 26.10; P = 0.037) and infectious disease-related mortality rates (relative risk, 12.02; 95% confidence interval, 1.42 to 191.96; P = 0.023). In conclusion, mortality predictors among patients undergoing hemodialysis differed substantially between diabetic and nondiabetic patients. Strategies to reduce mortality rates should consider these differences.

Does contrast echocardiography with Optison induce myocardial necrosis in humans?

Myocardial contrast echocardiography is a promising diagnostic tool for detecting microvascular integrity. Multiple experimental laboratories have shown that diagnostic combined microbubble contrast and ultrasound exposure can cause vessel rupture and myocardial damage in laboratory animals. This study investigated the phenomenon of contrast ultrasonically induced myocardial damage in human beings. Twenty consecutive patients (mean age of 60 +/- 12 years, 14 men) underwent contrast echocardiography with intravenous Optison using a mechanical index of at least 1.4 (Vivid Five System (GE, Vingmed Ultrasound, Horton, Norway). Creatine kinase (CK), creatine kinase-isoenzyme MB (CK-MB); CK-MB mass, myoglobin, and troponin I were measured before and 2, 4, 8, and 24 hours after contrast echocardiography. There was no significant correlation concerning the response to contrast echocardiography for any pair of parameters at any time after the intervention. Only in 2 patients were there higher values for troponin I before and after contrast echocardiography without an increase of myoglobin, CK, or CK-MB mass and activity. These values were therefore interpreted as false positive because of renal failure and severe heart failure. The use of contrast echocardiography is without demonstrated risk of myocardial damage even in patients with different cardiologic entities.