Angelika Hammerer-Lercher

The impact of cardiac natriuretic peptide determination on the diagnosis and management of heart failure.

Abstract The long-predicted endocrine function of the heart has been proven by the discovery of atrial natriuretic peptide (atrial natriuretic factor, A-type natriuretic peptide; ANP) 20 years ago. This subsequently led to the description of a whole family of structurally similar but genetically distinct peptides, the natriuretic peptide family, which contributes to cardiovascular homeostasis. These looped peptides promote natriuresis and diuresis, act as vasodilators, and exert antimitogenic effects on cardiovascular tissues. Two members, ANP and brain natriuretic peptide (B-type natriuretic peptide; BNP) are secreted by the heart mainly in response to myocardial stretch induced by volume load. The natriuretic peptides are synthesized as preprohormones. The C-terminal endocrinological active peptides (ANP, BNP) and their N-terminal prohormone fragments are found in plasma. The natriuretic peptide system is activated to its highest degree in ventricular dysfunction. However, natriuretic peptides are increased in all patients with edematous disorders which lead to an increase in atrial tension or central blood volume, such as renal failure or ascitic liver cirrhosis. It could be demonstrated that in chronic heart failure patients and during the subacute phase of myocardial infarction, of all tested neurohormones, the cardiac natriuretic peptides were best markers to identify heart failure and the most powerful predictors of morbidity and mortality. Natriuretic peptides are independent markers for risk assessment. In comparative studies BNP was superior to ANP and its N-terminal prohormone fragments in myocardial infarction as well as in chronic heart failure patients. Less data on N-terminal proBNP (NT-proBNP) is available, but BNP and NT-proBNP appear to be equivalent markers. For primary care physicians natriuretic peptide measurement is useful to decide which patient with suspected heart failure warrants further investigation, particularly when assessment of left ventricular function is not readily available. Natriuretic peptides have an excellent negative predictive value, particularly in high risk patients. An increase in BNP is serious enough to warrant follow-up examinations. For the cardiologists the natriuretic peptides are helpful for guidance of therapy and monitoring disease course in heart failure patients and for risk stratification in heart failure and myocardial infarction.

Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction

Brain natriuretic peptide (BNP), NT-proBNP and NT-pro-atrial natriuretic peptide (NT-proANP) were measured in blood samples from 57 patients using immunoassays and immunoradiometric assays to evaluate the usefulness as diagnostic markers for the detection of heart failure. For the detection of impaired left ventricular ejection fraction (LVEF), receiver operating characteristic curves showed that BNP had the best diagnostic performance with an area under curve (AUC) of 0.75+/-0.06. However, NT-proBNP (AUC: 0.67+/-0.07) and NT-proANP (AUC: 0.69+/-0.08) showed no significant difference to BNP. In a further analysis for the detection of resting LVEF <40%, BNP again was the best marker with an AUC of 0.83+/-0.06. NT-proBNP showed only a slightly smaller AUC (0.79+/-0.07). The AUC for NT-proANP was significantly smaller (0.65+/-0.08) compared to BNP. Additionally, BNP and NT-proBNP correlated negatively with the resting LVEF (BNP: -0.472, p<0.001; NT-proBNP: -0.306, p=0.026), whereas NT-proANP showed no significant correlation. In summary, BNP was the best marker to detect patients with impaired LVEF compared to NT-proBNP and NT-proANP. However, NT-proBNP showed no significant differences to BNP and it is therefore a new promising alternative marker for the detection of left ventricular dysfunction.

Plasma cardiac troponin T closely correlates with infarct size in a mouse model of acute myocardial infarction

BACKGROUND Cardiac troponins replaced creatine kinase and lactate dehydrogenase isoenzymes as criterion standards for the laboratory diagnosis of myocardial damage. However, there are only few publications on correlations of cardiac troponin T (cTnT) with pathologically determined infarct size which are flawed by insufficient sample size. METHODS In 38 anesthetized wildtype mice, the chest and pericardium were opened and the left descending artery was ligated. After sham operation, all mice recovered. Twenty-four hours after surgical induction of acute myocardial infarction heparinized blood samples were collected, the animals sacrificed and hearts harvested. Plasma cTnT was measured by a quantitative rapid assay using the Cardiac Reader (Roche Diagnostics). The hearts were cut into four transverse sections which were stained with 1.5% triphenyltetrazolium chloride for evaluation of necrosis by computerized planimetry. Pearson correlation coefficients were calculated between histological infarct size and cardiac markers. RESULTS Infarct sizes ranged from 14% to 55% of left ventricle and cTnT concentrations from 3.9 to 14.1 microg/l. cTnT correlated closely with histological infarct size (r = 0.84, p < 0.001). CONCLUSIONS This study for the first time demonstrates a close correlation of cTnT release with pathological infarct size in a suitable experimental model with a sufficient sample size.

Hypoxia induces heat shock protein expression in human coronary artery bypass grafts

OBJECTIVE Heat shock proteins (HSPs) are molecular chaperones which are essential for cell survival. Heat shock and hypoxia markedly increase the expression of several HSPs in various tissues, i.e. heart. In our in vitro study, we investigated whether HSPs are inducible in human vessels which are used as coronary artery bypass grafts. METHODS We used remnants of the saphenous vein and the internal mammary artery from 34 patients undergoing coronary artery bypass surgery. Each vessel was divided into segments, one for control conditions at 37 degrees C (5% CO(2)-95% air), the remaining ones for thermal (30 min at 42 degrees C) or hypoxic treatment (6 h oxygen deprivation with nitrogen). The expression of Hsp60, Hsp72 and Hsp73 was investigated by immunohistochemistry and Western-blot analysis. RESULTS Compared to controls, segments of the saphenous vein undergoing heat treatment showed significantly increased expression of Hsp72 in the intima (P=0.035) and Hsp73 in the media (P=0.003). In the internal mammary artery, Hsp72 and Hsp73 were expressed in the intima at significantly higher levels (P=0.042 each). A 6 h oxygen deprivation with nitrogen resulted in elevated levels of Hsp60 (media: P=0.048), of Hsp72 (intima: P<0.001 and media: P=0.004) and of Hsp73 (intima: P=0.029) in the saphenous vein. In the internal mammary artery, Hsp73 expression was significantly enhanced (intima: P=0.048 and media: P=0.017). The results were confirmed by Western-blot analysis in representative veins. CONCLUSIONS These findings demonstrate the common cellular defense mechanism of HSP expression in response to stress in coronary artery bypass grafts. Hypoxia and heat treatment strongly induce Hsp72 and Hsp73 expression in human coronary artery bypass grafts.

Serum levels of ischemia-modified albumin in healthy volunteers after exercise-induced calf-muscle ischemia.

Abstract Background: Ischemia-modified albumin (IMA) is an emerging marker of ischemia. To investigate the applicability of IMA for the diagnosis of skeletal muscle ischemia, we examined IMA changes as measured by the albumin-cobalt binding test, in a group of healthy volunteers after standardized exercise-induced calf muscle ischemia. Methods: A total of 12 healthy volunteers underwent standardized exercise on a plantar flexion pedal. Ischemic conditions were achieved by inflating a femoral blood pressure cuff at incremental pressures of 0, 60, 90, 120 and 150 mm Hg. Calf muscle ischemia was identified by synchronous 31P magnetic resonance spectroscopy, measuring intracellular concentrations of phosphocreatine (PCr) and inorganic phosphate (Pi). In addition, IMA, serum albumin, lactate, troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and at 5, 10, 30, 360 and 720 min after cuff release. Results: Magnetic resonance spectroscopy showed calf muscle ischemia in all participants upon exercise and cuff inflation. Circulating IMA concentrations increased significantly after cuff release (p=0.03) and returned to baseline within 30 min. While we found a significant negative correlation with albumin, there was no association of IMA levels with lactate or intracellular levels of PCr or Pi in samples obtained at baseline and post-ischemia. TnT and NT-proBNP remained within the normal range throughout the observation period in all participants. Conclusions: IMA may represent a clinical marker for skeletal muscle ischemia, although its lack of specificity requires careful clinical interpretation of data. The short period of IMA elevation after ischemic exercise requires standardized conditions for use as a diagnostic tool and hints at IMA applicability as a marker of prolonged or chronic ischemia. Clin Chem Lab Med 2007;45:535–40.

Association of copeptin with myocardial infarct size and myocardial function after ST segment elevation myocardial infarction

Objective To investigate the relationship between circulating plasma copeptin values and infarct size as well as myocardial function at baseline and 4 months after mechanical reperfusion for ST segment elevation myocardial infarction (STEMI). Design Prospective observational cohort study. Setting University Hospital of Innsbruck. Patients 54 patients with acute STEMI. Main outcome measures Correlation of plasma copeptin with infarct size as well as left ventricular ejection fraction (LVEF) and remodelling. Methods Participants underwent contrast enhanced cardiac MRI at baseline and 4 months thereafter. Blood samples were drawn 2 days after the onset of symptoms. Copeptin values were determined by an immunofluorescent assay. Results Copeptin concentrations (median 10.4 pmol/l, IQR 6.0–14.4) were associated with early and chronic infarct size (r=0.388, p=0.004 at baseline; r=0.385, p=0.011 at follow-up) and inversely related to LVEF at both times (r=−0.484, p<0.001 at baseline; r=−0.461, p<0.001 at follow-up). Patients with adverse remodelling showed higher baseline copeptin values compared to patients without remodelling (p=0.02). Receiver operating characteristic analysis indicated a cut-off value of 16.7 pmol/l for copeptin to best identify patients with future adverse remodelling. Conclusions Increased copeptin values 2 days after STEMI are associated with larger acute and chronic infarct sizes. Moreover, elevated copeptin concentrations at baseline were associated with myocardial function and remodelling 4 months post-STEMI. These findings strengthen the role of copeptin as a biomarker of adverse outcome after STEMI.

Evidence-Based Laboratory Medicine: How Well Do Laboratories Follow Recommendations and Guidelines? The Cardiac Marker Guideline Uptake in Europe (CARMAGUE) Study

To the Editor: The original Cardiac Marker Guideline Uptake in Europe (CARMAGUE) study (1) surveyed laboratory practice against the then current clinical practice recommendations (2). The survey was repeated after the publication of the universal definition to see if newer recommendations were being followed (3, 4). An updated version of the questionnaire was implemented as a Web-based form linked to a database and was tested and validated. Data extraction to a spreadsheet allowed direct tabulation of the numbers of responses and combinations of responses for each question. A link to this form was sent via local representatives to a representative sample of laboratories in each country surveyed. The survey is available on the website http://www.carmague.fi/2/. Responses were obtained from 303 laboratories in 28 countries. The responders were from a full range of laboratories: 34% university hospital laboratories, 36% district hospitals, 25% central hospitals, and 5% primary care facilities. Ninety-five percent of the laboratories used troponin as the preferred marker for routine diagnosis of suspected acute coronary syndromes. Fifty percent of the laboratories use troponin T, and 45% used troponin …

High-sensitivity cardiac troponin T compared with standard troponin T testing on emergency department admission: how much does it add in everyday clinical practice?

Background We compared high‐sensitivity cardiac troponin T (hs‐cTnT) and standard cTnT for acute myocardial infarction (AMI) diagnosis in everyday clinical practice of an emergency department (ED). Methods and Results cTnT was measured in 2384 consecutive patients (60±21 years, 52% female) on ED admission. Readmissions to the ED (n=720) and mortality (n=101) were followed for an average period of 239±49 days. There were 53 AMIs (delay, 1 to 96 hours; median, 3 hours), 440 chest pain patients, 286 dyspnea patients, 785 acute or chronic cardiac diseases, and 540 neurological diseases, with the remaining having various internal diseases. The diagnostic performances of hs‐ and standard cTnT were comparable for AMI diagnosis (area under receiver operating characteristics curves [ROC AUC], 0.91±0.02 versus 0.90±0.03; P=0.31). Using the 99th‐percentile cutoff, the sensitivities and specificities for AMI in the whole population were 91% and 74% for hs‐cTnT and 89% and 80% for standard cTnT. hs‐cTnT detected significantly more patients with cardiac diseases (ROC AUC, 0.77±0.01 versus 0.67±0.01; P<0.001). hs‐cTnT and standard cTnT were significant predictors of ED readmissions but not of mortality, but both were not independent predictors of ED readmissions or the combined end point of readmission or mortality in binary logistic regression analysis. Conclusions In unselected ED patients the diagnostic performances of hs‐cTnT and standard cTnT for AMI diagnosis did not differ significantly. hs‐cTnT detected significantly more cardiac diseases. hs‐cTnT and standard cTnT were not independent predictors of ED readmissions and mortality from all causes.

How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE).

BACKGROUND We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS In 2013-2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA).

The association of relative telomere length with symptomatic peripheral arterial disease: Results from the CAVASIC study

BACKGROUND AND OBJECTIVES Short telomere length has been described to be associated with biological aging including atherosclerosis phenotypes. However, information in patients with symptomatic peripheral arterial disease (PAD) is sparse. We therefore aimed to investigate whether inter-individual differences in relative telomere length (RTL) are associated with symptomatic PAD. DESIGN We measured RTL by a quantitative PCR method in the CAVASIC Study, a cohort of 241 male Caucasian patients diagnosed with intermittent claudication and 249 age- and diabetes-matched controls. RESULTS We observed significantly shorter mean RTL in patients than in controls (1.24 ± 0.19 vs. 1.32 ± 0.23, p < 0.001). Each shortening of RTL by one standard deviation significantly increased the odds for PAD by 44%: age-adjusted OR = 1.44 (95%CI 1.19-1.75, p < 0.001). This association remained significant after additional adjustment for log-C-reactive protein, glomerular filtration rate, HDL cholesterol, current smoking and log N-terminal pro-B-type natriuretic peptide (NT-proBNP). Excluding patients with prevalent cardiovascular disease revealed very similar results. When we compared the model fit of the various adjustment models including cardiac risk factors and/or NT-proBNP the addition of RTL significantly improved discrimination between patients and controls. CONCLUSION This study in a male cohort of patients with intermittent claudication and age- and diabetes-matched controls indicates a significant association of shorter relative telomere length with PAD. Our results reinforce RTL as a marker for PAD that reflects the influence of genetic and environmental risk factors. Moreover, the association remains significant after excluding patients and controls free from prevalent cardiovascular disease.