Biomarkers in acute coronary syndrome and percutaneous coronary intervention.

The universal definition of myocardial infarction has proved how important the role of biomarkers in the assessment of acute coronary syndrome (ACS) has become. As a result, management of patients with ACS today is more specific and personalized than ever, but there is still a lot of room for improvement. Unmet needs for a faster and more specific rule-in and rule-out of myocardial infarction, for a pronounced risk assessment allowing for standardized guidelines on personalized therapy and for an effective monitoring of our therapeutic efforts to guarantee an optimal risk-benefit turnout still require intensive biomarker research and clinical validation. This review addresses a set of cardiovascular biomarkers with different pathophysiological backgrounds and discusses their diagnostic, prognostic and therapeutic value in the setting of ACS and percutaneous coronary intervention (PCI). The article provides a review of the current knowledge and literature on biomarkers in ACS and PCI, discussing currently used biomarkers like cardiac troponin (cTN), high sensitive cardiac troponin (hscTn), natriuretic peptides (NPs) as well as promising future biomarkers like copeptin, choline and lipoprotein-associated phospholipase A2 (LP-PLA2). The review concentrates on the clinical application of these markers, evaluating not only their diagnostic and prognostic value but also their integrability into routine practice. There are currently a number of new biomarkers and new biomarker assays under investigation which give hope for a much improved diagnostic and risk stratification process. Large diagnostic clinical trials are still needed to evaluate their impact on ACS patient management and subsequent PCI in clinical practice.

Lipoprotein-associated phospholipase A2 for early risk stratification in patients with suspected acute coronary syndrome: a multi-marker approach: the North Wuerttemberg and Berlin Infarction Study-II (NOBIS-II).

AIMS: Numerous markers have been identified as useful predictors of major adverse cardiac events (MACE) in patients with suspected acute coronary syndrome (ACS). However, only little is known about the relative benefit of the single markers in risk stratification and the best combination for optimising prognostic power. The aim of the present study was to define the role of the emerging cardiovascular risk marker lipoprotein-associated phospholipase A2 (Lp-PLA2) in a multi-marker approach in combination with troponin I (TnI), NT-proBNP, high sensitivity (hs)CRP, and D-dimer in patients with ACS. METHODS AND RESULTS: A total of 429 consecutive patients (age 60.5+/-14.1 years, 60.6% male) who were admitted to the emergency room with suspected ACS were analysed in the study. Biochemical markers were measured by immunoassay techniques. All patients underwent point-of-care TnI testing and early coronary angiography if appropriate, in accordance with the current guidelines. Classification and regression trees (CART) and logistic regression techniques were employed to determine the relative predictive power of markers for the primary end-point defined as any of the following events within 42 days after admission: death, non-fatal myocardial infarction, unstable AP requiring admission, admission for decompensated heart failure or shock, percutaneous coronary intervention, coronary artery bypass grafting, life threatening arrhythmias or resuscitation. The incidence of the primary end-point was 13.1%, suggesting a mild to moderate risk population. The best overall risk stratification was obtained using NT-proBNP at a cut-off of 5000 pg/mL (incidence of 40% versus 10.3%, relative risk (RR) 3.9 (95% CI 2.4-6.3)). In the remaining lower risk group with an incidence of 10.3%, further separation was performed using TnI (cut-off 0.14 microg/L; RR=3.1 (95% CI 1.7-5.5) 23.2% versus 7.5%) and again NT-proBNP (at a cut-off of 140 ng/L) in patients with negative TnI (RR=3.2 (95% CI 1.3-7.9), 11.7% versus 3.6%). A final significant stratification in patients with moderately elevated NT-proBNP levels was achieved using Lp-PLA2 at a cut-off of 210 microg/L) (17.9% versus 6.9%; RR=2.6 (95% CI 1.1-6.6)). None of the clinical or ECG variables of the TIMI (Thrombolysis In Myocardial Infarction) risk score provided comparable clinically relevant information for risk stratification. CONCLUSIONS: In the setting of stateof- the-art coronary care for patients with suspected ACS in the emergency room, NT-proBNP, troponin I, and Lp-PLA2 are effective independent markers for risk stratification that proved to be superior to the TIMI risk score. Lp-PLA2 turned out to be a more effective risk marker than hsCRP in these patients.

Reference values for cardiac troponins I and T in a goal-oriented concept of health: cardiac marker values in a series of outpatients without acute coronary syndromes.

BACKGROUND: Cardiac troponins are part of the new definition of acute myocardial infarction (AMI) by the European Society of Cardiology and the American College of Cardiology (ESC/ACC). In the new guidelines, it was suggested to establish reference values for cardiac troponins to calculate the 0.99 quantile (Q99) as cutoff for AMI diagnosis. PATIENTS AND METHODS: We run a prospective series of troponin measurements in unselected outpatients who had no suspicion of cardiac ischemia. The selection of patients as reference population is based on a "goal-oriented concept of health". One hundred and ninety-five patients agreed that 10-ml additional blood was drawn at the occasion of the venous puncture done routinely in the evaluation of their case. Cardiac troponin I was measured using a point of care (POCT) device (Stratus CS, DadeBehring, TNI-PO). Additionally, heparin-plasma was obtained and immediately deep-frozen to -80 degrees C for later batch measurement of cardiac troponin T (Elecsys 2010, Roche Diagnostics, TnT) and troponin I (Centaur, Bayer, TnI-CL). RESULTS: The Q99 values were 0.14 microg/l for TnI-PO, 0.023 microg/l for TnT and 0.07 microg/l for TnI-CL in patients with creatinine levels below 1.5 mg/dl. These values lay above those obtained from people at good health for reference study purposes. On the level of our cutoffs, CVs were 7.5%, 6.4% and 23.7% for TnI-PO, TnT and TnI-CL, respectively. CONCLUSIONS: Only the TnI-PO and TnT tests fulfilled the imprecision criteria in our study. TnI-PO values between 0.10 and 0.14 microg/l and TnT values between 0.01 and 0.03 microg/l have to be interpreted carefully. Patients presenting with chest pain will be possibly true positives, but patients without chest pain and nondiagnostic ECGs should be subjected to repetitive troponin measurements and further noninvasive investigation and maybe not directly sent to the cardiac catheter laboratory.

Mycobacterium xenopi pulmonary infection in an HIV infected patient under highly active antiretroviral treatment.

Highly active antiretroviral therapy (HAART) is responsible for a striking reduction in AIDS related morbidity and mortality by partly restoring immune function. However, HAART can also precipitate the development of clinically apparent opportunistic infections in patients with latent infections. We report a case of an HIV infected patient who developed granulomatous nodular and cavitatory lesions of the lungs due to Mycobacterium xenopi as a manifestation of the immune restoration syndrome.

Mycobacterium xenopi pulmonary infection in an HIV infected patient under highly active antiretroviral treatment.

Highly active antiretroviral therapy (HAART) is responsible for a striking reduction in AIDS related morbidity and mortality by partly restoring immune function. However, HAART can also precipitate the development of clinically apparent opportunistic infections in patients with latent infections. We report a case of an HIV infected patient who developed granulomatous nodular and cavitatory lesions of the lungs due to Mycobacterium xenopi as a manifestation of the immune restoration syndrome.

Validation of NACB and IFCC guidelines for the use of cardiac markers for early diagnosis and risk assessment in patients with acute coronary syndromes.

BACKGROUND: International guidelines have been established for the use of cardiac markers in the early diagnosis and risk assessment of patients with acute coronary syndromes. METHODS: A single center, prospective observational study was conducted in a tertiary care university hospital on 200 consecutive patients with suspected acute myocardial infarction (AMI). Blood was drawn on admission and after 2, 4, 8, 12 and 24 h for the measurement of CK-MB/CK activity, myoglobin, CK-MB mass and troponin I. A 6-week follow-up was undertaken for the combined end point of acute coronary syndrome and death. RESULTS: Myoglobin showed an early diagnostic sensitivity of 0.65 on admission, 0.90 after 2 h and 0.92 after 4 h compared with 0.46, 0.74 and 0.88 for CK-MB/CK activity. The combination of myoglobin and cTnI increased the diagnostic value compared with myoglobin alone on admission, 2 and 4 h later. In multivariate analysis, cTnI and CK-MB/CK mass, but not myoglobin and CK-MB/CK activity, were shown to be independent predictors on the 6-week follow-up. CONCLUSIONS: Repetitive myoglobin measurements within 4 h of admission, combined with at least one early troponin test, was shown to be the strategy of choice in early AMI diagnosis and prognosis assessment.

The acute coronary syndrome diagnosis and prognostic evaluation by troponin I is influenced by the test system affinity to different troponin complexes.

It was suggested recently that cardiac troponins are released as T-I-C complexes and then further degraded to T and I-C. It is not known whether the various affinity to the T-I-C and I-C complex of different troponin I test systems influence the diagnostic and prognostic value of the test results in clinical practice. We studied 162 patients (61.3 S.D. 11.1 years) with suspected acute myocardial infarction (AMI) in a single center study. AMI was confirmed in 109 patients. Blood samples were taken at admission, after 1, 2, 4, 8, 12 and 24 h. Troponin I (TnI) was measured using the OPUS plus (TnI-O, cut-off 1.6 microg/l) and the Stratus II (TnI-S, cut-off 1.5 microg/l) analyzers. TnI-O has high affinity to the binary (I-C) and TnI-S to the ternary (T-I-C) troponin complex. A 6-month follow-up with respect to death and recurrent AMI was performed. The sensitivity (SE) and specificity (SP) for AMI diagnosis were 82.6 and 86.8% for TnI-S; 75.2 and 92.5% for TnI-O 0-2 h after admission. The ROC analysis showed a slightly better curve for TnI-S at 4 h (P<0.05). Logistic regression analysis shows prediction of 6 months outcome by 0-24 h serial TnI-S measurements (odds ratio 5.21, P=0.0356), and serial TnI-O measurements (odds ratio 4.92, P=0.0186). High affinity to the ternary troponin complex enhances the diagnostic but not the prognostic value of a test system. Indeed, the resulting differences are small but underline the need for standardization of biochemical markers.

Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma.

OBJECTIVE: To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma. DESIGN AND SETTING: A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors. PATIENTS AND METHODS: All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction. RESULTS: After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders. CONCLUSION: Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Troponin T in patients with low grade or atypical angina. Identification of a high risk group for short- and long-term cardiovascular events.

AIMS: Cardiac troponin T is an established marker of cardiovascular risk in patients with severe angina pectoris. Data are scarce on patients admitted to a coronary care unit with low grade or atypical angina pectoris to rule out myocardial infarction. METHODS AND RESULTS: We investigated 106 patients (57.4 SD 11.6 years) with low grade (Braunwald class I) or atypical symptoms out of 702 patients admitted to the coronary care unit with suspected acute myocardial infarction. Serum concentrations of troponin T were measured at admission and 4 h later. In hospital cardiovascular events including acute myocardial infarction, life threatening cardiac arrhythmias, congestive heart failure, and death were recorded. Patients were additionally observed after 3 and 6 months post-discharge regarding acute myocardial infarction, unstable angina, rehospitalization for cardiac causes and death. The patients were divided into a troponin T positive (> or =0.2 microg x 1(-1) at admission or 4 h later; n=11) and a troponin T negative group. The mean value of troponin T 4 h after admission in the positive group was 0.58 microg x 1(-1). Of the troponin T positive patients, 0.82 (0.95 CI: 0.48-0.98) had a cardiovascular event during their stay in hospital vs 0.41 (0.95 CI: 0.31-0.52) of troponin T negative patients (P<0.05). In the troponin T positive group 0.64 (0.95 CI: 0.31-0.89) developed myocardial infarction in hospital vs 0.07 (0.95 CI: 0.03-0.15) in the troponin T negative group (P<0.001). Troponin T predicts outcome after 3 and 6 months significantly (P<0.05). CONCLUSION: Troponin T identifies patients with low grade or atypical angina at risk of severe short- and long-term cardiovascular events. Therefore, troponin T adds substantial information in patients with ruled out acute myocardial infarction. Troponin T positive patients have to be observed carefully regardless of their symptom intensity and may have to receive early cardiac catheterization; troponin T negative patients could be released safely from the coronary care unit early.

Early ritonavir-induced maculopapular eruption.

We report 2 cases of maculopapular eruption and fever in patients infected with human immunodeficiency virus (HIV) on the 2nd day of first administration of ritonavir, a protease inhibitor. In the 1st patient, clinical improvement occurred despite continuation of therapy, and in the 2nd the treatment was stopped with remission and rechallenge resulting in recurrence. Ritonavir should be added to the list of drugs that can induce adverse cutaneous reactions in HIV patients.

Mesalamine in Crohn's disease with steroid-induced remission: effect on steroid withdrawal and remission maintenance, Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.

BACKGROUND & AIMS: Steroid dependence and early relapse are frequent after a prednisolone-induces remission in Crohn's disease. The aim of this trial was to test whether mesalamine started at the onset of steroid tapering increases the rate of weaning from prednisolone and reduces the relapse rate after prednisolone cessation. METHODS: One hundred fifty patients with active Crohn's disease were administered oral prednisolone (1 mg.kg(-1). day(-1)) x 3-7 weeks; 129 patients went into clinical remission and were randomized to Pentasa (4 g . day(-1)) or placebo, administered until weaning and for 1 year thereafter. RESULTS: Groups were similar for clinical and biological items collected initially. Weaning failure rate was 30% and 12% in the placebo and mesalamine arms, respectively. At the end of the trial, 9 of 36 patients administered placebo and 14 of 48 administered mesalamine were in remission. Both groups had similar time to relapse curves in the postweaning year; after adjusting for risk factors (high Crohn's Disease Activity Index, white blood cell count of >9 x 10(9) /l-1 at weaning, and use of a medical treatment in the month before inclusion), Pentasa was found to be superior to placebo. CONCLUSIONS: After a prednisolone-induces remission in Crohn's disease, mesalamine facilitates steroid withdrawal and, during the postweaning year, may reduce the relapse rate in certain patient subgroups.

Left ventricular hypertrophy and diastolic dysfunction: their relation to coronary heart disease.

Diastolic dysfunction is an early sign in the temporal sequence of ischemic events in coronary heart disease. The ischemic cascade, beginning with an oxygen demand supply imbalance and metabolic alterations, identifies diastolic disorders of the left ventricle (LV) as an early phenomenon, sometimes before systolic dysfunction, electrocardiographic changes, or chest pain occur. Although the physiology of diastolic function is complex, the factors contributing to diastolic disturbances can be differentiated into intrinsic and extrinsic LV abnormalities. Intrinsic mechanisms include (a) impaired LV relaxation, (b) the complex of LV hypertrophy, and (c) increased LV asynchrony. Myocardial hypertrophy leads to an increase of the myocardial mass/volume ratio, and the degree of hypertrophy is the main determinant of chamber stiffness. The main, if not unique, determinant of myocardial diastolic tissue distensibility is the structure and concentration of the collagen. Consequently, tissue stiffness is increased in coronary disease by reparative interstitial fibrosis or scar following myocardial infarction. In myocardial hypertrophy the LV collagen concentration is elevated due to reactive fibrosis. An increase in regional asynchrony of LV contraction and relaxation is a result of regional ischemia as well as of LV hypertrophy and tissue fibrosis. Factors extrinsic to the LV causing diastolic disorders include (a) increased central blood volume, which will increase left ventricular pressure without altering the LV pressure-volume relation, and (b) ventricular interaction mediated by pericardial restraint, which may cause a parallel upward shift of the diastolic LV pressure-volume relation. Improved insight into the mechanisms of LV relaxation and filling characteristics help in the treatment of LV diastolic dysfunction.

[Stress reduction through listening to music: effects on stress hormones, hemodynamics and mental state in patients with arterial hypertension and in healthy persons]. / Stressreduktion durch Musikhören. Einfluss auf Stresshormone, Hämodynamik und psychisches Befinden bei Patienten mit arterieller Hypertonie und bei Gesunden.

Stress hormones, tissue-plasminogen activator (t-PA) antigen, left-ventricular diastolic function and mood immediately before and after listening to three different kinds of music (a waltz by J. Strauss, a piece of modern classic by H. W. Henze, and meditative music by R. Shankar) were measured in 20 healthy persons (10 women, 10 men; mean age 25 [20-33] years) and 20 hypertensives (8 women, 12 men; mean age 57.5 [25-72] years). To recognise haemodynamic effects, mitral flow by Doppler ultrasound was used as a measure of left-ventricular diastolic function. Atrial filling pressure (AFF) was calculated from the flow integral (VTI) of the early E and the late A waves. The Zerssen scale was used to estimate the immediate mood of the subjects. In hypertensives the levels of cortisol (74 vs 78 ng/ml; P < 0.05) and t-PA antigen (4.3 vs 4.5 ng/ml; P < 0.05) were lower after than before the Strauss waltz. The muscle by Henze lowered the concentrations of cortisol (70 vs 84 ng/ml; P < 0.05), noradrenaline (203 vs 224 ng/l; P < 0.05) and t-PA antigen (4.1 vs 4.6 ng/ml; P < 0.05). After listening to the piece by Shankar the concentrations of cortisol (71 vs 78 ng/ml; P < 0.05), adrenaline 14.5 vs 24.5 ng/ml; P < 0.05) and t-PA antigen (4.2 vs 4.3 ng/ml; P < 0.05) were lower. In healthy subjects AFF (29 vs 26%; P < 0.05) rose after the Strauss music, VTI-E fell (69 vs 73 mm; P < 0.05, while natriuretic peptide rose (63 vs 60 pg/ml; P < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate physiological responses of healthy volunteers to different types of music: cardiovascular, hormonal and mental changes.

A group of 20 healthy volunteers [10 women, 10 men; median age 25 (20-33) years] were examined by means of pulsed wave Doppler echocardiography, blood sample analysis and psychological testing before and after listening to three different examples of music: a waltz by J. Strauss, a modern classic by H. W. Henze, and meditative music by R. Shankar. To assess small haemodynamic changes, mitral flow, which reflects left ventricular diastolic behaviour, was measured by Doppler ultrasound. Heart rate, arterial blood pressure and plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin, adrenaline, noradrenaline, atrial natriuretic peptide (ANP) and tissue plasminogen activator (t-PA) were determined simultaneously. Transmitral flow profile is characterized by early E-wave and late atrial induced A-wave. Velocity-time integrals were measured and the atrial filling fraction was calculated. The mental state was measured by using a psychological score (Zerssen) with low values (minimum 0) for enthusiastic and high values (maximum 56) for depressive patterns. Music by J. Strauss resulted in an increase of atrial filling fraction (AFF; 29% vs 26%; P < 0.05) and ANP (63 pg.ml-1 vs 60 pg.ml-1; P < 0.05). The mental state was improved (Zerssen: 6.5 vs 11 points; P < 0.05). After the music of H. W. Henze prolactin values were lowered (7.7 ng.ml-1 vs 9.1 ng.ml-1; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)