Thomas Störk

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).

AimsNumerous 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 resultsA 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 µg/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 µg/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.ConclusionsIn 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.

Noninvasive measurement of left ventricular filling pressures by means of transmitral pulsed Doppler ultrasound

In 54 consecutive patients, ages 59 +/- 11 years, the transmitral diastolic flow velocity profile was derived by means of pulsed Doppler echocardiography simultaneously with right-sided heart catheterization. In 30 of them, ages 57 +/- 10 years, left-sided heart catheterization was performed at the same time. The sample volume was positioned exactly in the mitral anulus plane, bisecting the anulus. The ratio of the time-velocity integrals of the A wave (atrial contraction) and E wave (early filling) was calculated (A/E ratio of integrals). Linear regression analysis showed a highly significant linear correlation of the A/E ratio of integrals with regard to left ventricular (LV) end-diastolic pressure (r = 0.98, p less than 0.001) and pulmonary capillary wedge pressure (r = 0.98, p less than 0.001). The A/E ratio of integrals also correlated with other hemodynamic parameters, such as cardiac output (r = -0.73, p less than 0.001), cardiac index (r = -0.74, p less than 0.001) and stroke volume index (r = -0.65, p less than 0.001). For 19 additional patients, ages 55 +/- 8 years, the values of LV end-diastolic pressure and pulmonary capillary wedge pressure were calculated by means of the corresponding formulas from the first data set. The correlation between the calculated and invasively measured LV filling pressures expressed in terms of intraclass correlation coefficients shows highly significant correlations for both LV end-diastolic pressure (intraclass correlation coefficient = 0.99, p less than 0.001) and pulmonary capillary wedge pressure (intraclass correlation coefficient = 0.99, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Development of an optimized multimarker strategy for early risk assessment of patients with acute coronary syndromes

BACKGROUND A multitude of biomarkers have been suggested for early risk-assessment in patients admitted to the emergency department with suspected acute coronary syndromes. We used logistic regression synergistically with classification and regression tree (CART) analysis to define a multimarker strategy and the cut-off values and sequencing needed to optimize risk stratification in a low to moderate risk population of the emergency department. METHODS 432 unselected patients (59.7+/-14.5 y, 60.4% male) admitted to the emergency department (ED) with acute coronary syndromes (ACS) were enrolled. Cardiac troponin I (cTnI), N-terminal pro-B-Type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), placental growth factor (PlGF), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and D-dimers were measured by immunoassay and whole blood choline (WBCHO) and plasma choline (PLCHO) were measured using LC/MS from baseline samples. Logistic regression and CART analysis were used to define the importance of the various biomarkers tested and to define their hierarchy with respect to the prediction of major adverse cardiac events (MACE; cardiac death, non-fatal MI, unstable angina, CHF requiring admission, urgent PCI and CABG) over the 42-day follow-up period. RESULTS A combination of NT-proBNP, WBCHO and Lp-PLA2 with cutoffs identified by CART-analysis was optimal for risk-stratification and superior to all other possible combinations of markers. Increased concentrations of both NT-proBNP (>1400 ng/l) and WBCHO (>21 micromol/l) identified patients with very high risk (RR=2.4, 39% primary endpoint) while low concentrations of NT-proBNP (< or = 1400 ng/l), WBCHO (< or = 17 micromol/l) and LP-PLA2 (< or = 210 microg/l) indicated very low risk (0% primary endpoint). WBCHO > 17 micromol/l additionally identified a subgroup with intermediate risk (RR=3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations < or = 1400 ng/l. Troponin when increased was highly prognostic but was not often positive in this early cohort. CONCLUSIONS A multimarker strategy defined synergistically by logistic regression and by classification and regression tree (CART) analysis can stratify patients into risk groups ranging from very low risk (0% MACE) to very high risk (39.5% MACE) based on admission values.

Diagnostic and Prognostic Role of Myoglobin in Patients With Suspected Acute Coronary Syndrome

diagnostic efficiency of cardiac troponin I and troponin T for acute myocardial infarction. Acad Emerg Med 1997;4:13–21. 15. Zimmerman J, Fromm R, Meyer D, Boudreaux A, Wun CC, Smalling R, Davis R, Habib G, Roberts R. Diagnostic markers cooperative study for the diagnosis of myocardial infarction. Circulation 1999;99:1671–1677. 16. Panteghini M, Apple FS, Christenson RH, Dati F, Mair J, Wu AH. Proposals from IFCC committee on standardization of markers of cardiac damage (C-SMCD): recommendations on use of biochemical markers of cardiac damage in acute coronary syndromes. Scan J Clin Lab Invest 1999; 59(suppl 230):103–112. 17. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 1997;337:1648–1653.

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.

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

SummaryDiastolic 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 intointrinsic andextrinsic 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.

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.

Noninvasive Assessment by Pulsed Doppler Ultrasound of Left Ventricular Filling Behavior in Long Distance Runners During Marathon Race

Abstract The cardiovascular responses to endurance training include an increase in left ventricular (LV) mass and mass index. 1,2 Although a significantly impaired LV diastolic function is known for pathologic hypertrophy, 3,4 LV filling behavior appears unchanged in athletes with exercise-induced hypertrophy as has been demonstrated using M-mode 5 and Doppler 1,2,6,7 eehocardiography or radionuclide scintigraphy. 8 Pulsed Doppler echocardiography of mitral flow has been shown to be a reliable method of assessing LV diastolic filling in healthy 4,9,10 and pathologic 9–11 states. This method has been validated compared with both cineangiographic 12 and radionuclide 13 techniques. We aimed at noninvasively evaluating LV filling behavior in long-distance runners at rest and during a marathon race.

Thrombin activity throughout the acute phase of acute ST-elevation myocardial infarction and the relation to outcome.

Background: Thrombin and plasmin play a central role in ongoing thrombosis and platelet activation in patients with acute ST-elevation myocardial infarction (STEMI). Data of thrombin and plasmin activity in the early course of STEMI and the relation to outcome are scarce. Methods: We included 68 consecutive patients (53 male, 59 ± 11.4 years) with STEMI who underwent acute catheter-based reperfusion therapy within the first 12 h after onset of symptoms. Blood samples were taken at admission and after 4, 8, 12 and 24 h. Thrombin activity and generation was measured by changes in the thrombin/antithrombin-III complex (TAT) and prothrombin fragment (F1.2); plasmin was measured by changes in the plasmin-α2/antiplasmin complex (PAP). A follow-up with respect to the combined primary endpoint consisting of death, acute myocardial infarction or urgent need for revascularization up to 6 weeks post-discharge was carried out. Results: TAT values showed no significant change over time in patients with and without the primary endpoint but there was a borderline difference between these groups at 4 h after admission (event group 9.0 vs no event group 4.7 μg l−1, p = 0.057). F1.2 values were different between groups only after 24 h (event group 1.5 vs no event group 0.9 nmol l−1, p = 0.028) and did not differ in serial sampling of 24 h. PAP values were higher in patients with events after 4 and 8 h and declined over time in the group without events (p <0.001). Odds ratios (OR) with respect to the primary endpoint were highest for TAT >4.8 μg l−1 at 0 h and TAT >8.4 μg l−1 at 4 h (OR 7.1, 95% confidence interval (CI) 1.5–34, p = 0.015 and OR 5.5, 95% CI 1.5–20.0, p = 0.01, respectively). The predictive value of plasmin concentrations were equally high after 4 h (PAP >962 μg l−1; OR 6.8, 95% CI 1.8–26.2, p = 0.005) and 8 h (PAP >495 μg l−1, OR 6.7, 95% CI 1.4–32.9, p = 0.024). Values for F1.2 were only predictive after 24 h (F1.2 >0.85 nmol l−1, OR 13, 95% CI 1.4–117.8, p = 0.023). Conclusions: Markers of thrombin and plasmin activity in acute STEMI are related to outcome. The marker for thrombin generation F1.2 becomes a significant predictor of outcome at 24 h after admission, reflecting the potentially adverse effects of ongoing thrombin generation. This underlines the potential for direct thrombin inhibition and individualization of treatment by thrombin markers in STEMI.

Beneficial effects of fluvastatin on myocardial blood flow at two time-points in hypercholesterolemic patients with coronary artery disease.

Hypercholesterolemia is a major risk factor initiating and accelerating atherosclerosis and leading to severe stages of coronary artery disease (CAD) with a high risk of cardiovascular events. We investigated the impact of lipid lowering in patients with hypercholesterolemia and evident CAD on clinically relevant parameters like myocardial perfusion. Myocardial imaging was performed with thallium-201 single photon-emission computed tomography at rest and after maximal bicycle exercise in 22 patients after a 4-week lead-in period, and after 12 and 24 weeks of therapy with fluvastatin. Perfusion defects occurred in all patients, indicating stress-induced myocardial ischemia. After 12 weeks of therapy, the perfusion of the ischemic segments increased by 26% (277+/-99 to 349+/-96 cpm; p < 0.001), whereas the value of the normal segments was augmented only by 4% (478+/-44 to 497+/-28 cpm; p < 0.05). The results slightly improved further after 24 weeks. Moreover, a subgroup analysis elucidated a more pronounced effect in patients without lipid-lowering premedication. This nonpretreated group (n = 11) revealed an improvement of ischemic segments at stress by 42% at week 24. In contrast, pretreated patients had an increase of only 18% (between groups, p < 0.05), indicating a carryover effect of premedication. In conclusion, short-term therapy with fluvastatin acts beneficially on impaired vascular function in hypercholesterolemic patients with CAD.