Uwe Helber

Atrial Septal Defect in Adults: Cardiopulmonary Exercise Capacity Before and 4 Months and 10 Years After Defect Closure

OBJECTIVES The purpose of the study was to evaluate the cardiopulmonary exercise capacity and ventilatory function in adults with atrial septal defect (ASD) preoperatively and 4 months and 10 years postoperatively. BACKGROUND Only few data are available on cardiopulmonary exercise tolerance after ASD closure, but detailed knowledge might be helpful for indication for defect closure in certain patients. METHODS The study was performed in adult patients (mean [+/-SD] age at operation 39.9 +/- 11.5 years; left-right shunt 9.6 +/- 5.6 liters/min; pulmonary/systemic flow ratio 2.8 +/- 1.2; mean pulmonary artery pressure 18.2 +/- 6.2 mm Hg). Cardiopulmonary exercise testing was performed with a bicycle ergometer. We determined peak oxygen uptake, anaerobic threshold, performance at anaerobic threshold and maximal performance in relation to these variables in a normal group. Ventilatory function at rest was expressed by vital capacity, maximal voluntary ventilation and forced expiratory volume in 1 s. RESULTS Preoperatively, ventilatory function at rest was only moderately reduced to approximately 75% to 85%. Four months postoperatively we found no significant improvement, but 10 years postoperatively ventilatory function at rest was normalized. Preoperative cardiopulmonary exercise capacity was markedly reduced to 50% to 60%; early postoperatively it was only slightly higher, but late postoperatively exercise capacity significantly improved and was completely normalized. CONCLUSIONS Although preoperative cardiopulmonary capacity in adult patients with nonrestrictive ASD was significantly decreased, some improvement was seen at 4 months postoperatively, with complete restitution to normal at 10 years after shunt closure.

Thrombolytic therapy in acute myocardial infarction : Comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the Kallikrein system and plasmin

BACKGROUND Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein-contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI. METHODS AND RESULTS Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Moderate thrombin (initial thrombin-antithrombin [TAT] complex 18+/-5 versus 4+/-0.3 microg/L, P<0.05) and kallikrein (up to 45+/-4 versus 30+/-1 U/L at 3 hours, P<0.01) activation occurs in patients with AMI. D-Dimers are increased (P<0.01), and plasmin is stimulated (P<0.01). Streptokinase and alteplase increase TAT to 50+/-17 and 51+/-18 microg/L at 3 hours and to 50+/-17 and 33+/-14 microg/L at 6 hours, respectively (P<0.01). Kallikrein activity is elevated (P<0. 01) to 76+/-5 and 71+/-7 U/L at 3 hours and 64+/-6 and 47+/-5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in D-dimers and plasmin-antiplasmin complexes are more marked (P<0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (P<0.01). CONCLUSIONS The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.

Assessment of myocardial viability using delayed enhancement magnetic resonance imaging at 3.0 Tesla.

Objective:Cardiac magnetic resonance imaging (MRI) at 3.0 T has recently become available and potentially provides a significant improvement of tissue contrast in T1-weighted imaging techniques relying on Gd-based contrast enhancement. Imaging at high-field strength may be especially advantageous for methods relying on strong T1-weighting and imaging after contrast material administration. The aim of this study was to compare cardiac delayed enhancement (DE) MRI at 3.0 T and 1.5 T with respect to image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) between infarcted and normal myocardium. Materials and Methods:Forty consecutive patients with history of myocardial infarction were examined at 3.0 T (n = 20) or at 1.5 T (n = 20). Myocardial function was assessed using cine steady-state-free-precession (SSFP) sequences (TR 3.1 milliseconds, TE 1.6 milliseconds, flip angle 70°, and a matrix of 168 × 256 at 1.5 T and TR 3.4 milliseconds, TE 1.7 milliseconds, flip angle 50° and a matrix of 168 × 256 at 3.0 T), acquired in long- and short-axes views. DE images were obtained 15 minutes after the administration of 0.15 mmol of Gd-DTPA/kg body weight using a segmented inversion recovery prepared gradient echo sequence at 1.5 T (TR 9.6 milliseconds, TE 4.4 milliseconds, flip angle 25°, matrix 160 × 256, bandwidth 140 Hertz/pixel) and at 3.0 T (TR 9.8 milliseconds, TE 4.3 milliseconds, flip angle 30°, matrix 150 × 256, bandwidth 140 Hertz/pixel). For image analysis, standardized SNR and CNR measurements were performed in infarcted and remote myocardial regions. Two independent observers rated image quality on a 4-point scale (0 = poor image quality, 1 = sufficient image quality, 2 = good image quality, 3 = excellent image quality). Results:High diagnostic image quality was obtained in all patients. Rating of mean image quality was 2.2 ± 0.8 at 1.5 T and 2.5 ± 0.6 at 3.0 T (P = 0.012) for observer 1 and 2.2 ± 0.7 at 1.5 T and 2.6 ± 0.6 at 3.0 T (P = 0.003) for observer 2, respectively. Interobserver agreement was good (κ = 0.68 at 1.5 T and 0.78 at 3.0 T). SNR measurements yielded a mean SNR of 37.8 ± 13.9/22.9 ± 6.0 in infarcted myocardium (P < 0.001) and 5.6 ± 2.2/5.9 ± 2.4 in normal myocardium (P = 0.45) at 3.0 T/1.5 T, respectively. CNR measurements revealed mean values of 32.4 ± 13.0/16.7 ± 5.4 (P<0.001) at 3.0 T/1.5 T, respectively. Conclusions:Delayed enhancement MRI at 3.0 T is feasible and provides superior image quality compared with 1.5 T. Furthermore, using identical contrast doses, increased SNR and CNR values were recorded at 3.0 T.

Endothelial tissue-type plasminogen activator release in coronary heart disease : Transient reduction in endothelial fibrinolytic reserve in patients with unstable angina pectoris or acute myocardial infarction

OBJECTIVES We sought to examine whether the disturbed fibrinolytic system in patients with an acute coronary syndrome is associated with a reduced endothelial fibrinolytic capacity. BACKGROUND Intracoronary thrombus formation is a frequent finding in acute coronary syndromes. Systemic alterations of coagulation and fibrinolysis are known to occur, but possible disturbances of endothelial fibrinolytic function have not been investigated. METHODS We compared 42 patients with an acute coronary syndrome (acute myocardial infarction in 11 and unstable angina pectoris in 31) with 25 patients with stable angina. Venous blood was sampled serially for determination of markers of the fibrinolytic system and of hypercoagulability from admission to day 10. An occlusion test to determine the maximal endothelial tissue-type plasminogen activator (t-PA) release was also performed. RESULTS Both on day 0 and day 10, patients with an acute coronary syndrome had a marked elevation of t-PA mass concentration (mean value +/- SEM 14.4 +/- 1.6 [day 0], 18.9 +/- 2.5 ng/ml [day 10]) and of plasminogen activator inhibitor (PAI) (9.4 +/- 2.2 [day 0], 11.3 +/- 2.6 AU/liter [day 10], p < 0.05 vs. patients with stable angina). There was also a hypercoagulative state with elevated thrombin activity and increased D-dimers (p < 0.05 vs. patients with stable angina). Maximal endothelial t-PA release was initially reduced (p < 0.05 vs. patients with stable angina) to 2.3 +/- 0.9 ng/ml, but levels recovered during follow-up to 4.4 +/- 1.4 ng/ml (vs. 5.7 +/- 1.5 ng/ml in patients with stable angina). CONCLUSIONS Despite the known prolonged systemic alteration of fibrinolysis in acute coronary syndromes, endothelial fibrinolytic capacity is reduced only during the acute phase and becomes normalized during follow-up, and thus is linked more to intravascular thrombus formation than to steady state levels of markers of the fibrinolytic system.

Subacute myocardial infarction: assessment by STIR T2-weighted MR imaging in comparison to regional function

PurposeIncreased T2 signal intensity (SI) can be regularly observed in myocardial infarction. However, there are controversial reports about the relationship of elevated T2 SI to myocardial viability and some authors propose that high T2 SI serves as a sign of irreversible myocardial injury. This study investigates increased T2 SI compared to myocardial function in patients with reperfused subacute myocardial infarction. Preserved function was used as criterion for viability.MethodsTen healthy volunteers and 17 patients with myocardial infarction and patent inlarct related coronary artery were examined on a 1.5 T Magnetom Vision system (Siemens). For T2-weighted MR imaging a breath-hold STIR sequence with dark-blood preparation was used. Cine FLASH 2D imaging was applied to assess myocardial function. Signal-to-noise (S/N) in STIR T2 images was measured in normal and infarcted regions and subsequently identified by two independent observers. Based on a 20 segment model of the left ventricle findings were compared to regional myocardial function.ResultsElevated STIR T2 SI was found in all 17 patients and observed in 27% (204/754) of segments. S/N of normal myocardium was 5.1 ±0.7 in volunteers and 4.9 ± 0.8 in patients(P=NS). Infarcted myocardium presented with significantly-increased S/N 12.8 ± 1.9 (P < 0.0001). Significant transmural elevation of T2 SI was noted in 32% of segments with preserved systolic function.ConclusionIncreased STIR T2 SI can be observed transmurally in post-ischemic myocardial regions with preserved function. It therefore cannot be used as an exclusive marker for the non-viable region.

Correlation between coronary morphology and molecular markers of fibrinolysis in unstable angina pectoris

BACKGROUND In acute coronary syndromes, marked alterations of coagulation and fibrinolysis have been observed, but no data are available concerning a possible relation to coronary stenosis morphology. METHODS Thirty one patients with unstable angina pectoris were included. Culprit stenosis morphology judged from coronary angiography was graded using the modified ACC/AHA classification. Molecular and functional markers of hemostasis and fibrinolysis were determined from venous plasma samples obtained at admission. RESULTS Patients with unstable angina pectoris had a moderate procoagulant state, especially a contact phase activation compared with age-matched controls (factor XII 93.9 +/- 5.6 vs 112.8 +/- 5.4%; P < 0.05; high molecular weight kininogen 55.3 +/- 5.4 vs 86.1 +/- 6.5%; P < 0.01). Thrombin-antithrombin (TAT) was not significantly elevated (7.6 +/- 1.9 vs 4.0 +/- 0.5 microg/l). Elevated plasminogen activator mass concentration (16.6 +/- 2.1 vs 5.4 +/- 0.6 ng/ml; P < 0.01) and plasminogen activator inhibitor (PAI) activity (9.9 +/- 3.0 vs 5.6 +/- 3.0 AU/ml; P < 0.05) indicated an alteration of the fibrinolysis. Complexity of coronary stenosis was positively correlated with tissue-type plasminogen activator (TPA) mass concentration (P < 0.01) and PAI activity (P < 0.05). No association was found to markers of a hypercoagulative state. CONCLUSION These findings indicate a relation between alterations of the fibrinolytic system and coronary morphology, whereas the acute changes of coagulation occur independently of culprit stenosis complexity.

Evaluation of K-Space Segmented Cine Sequences for Fast Functional Cardiac Imaging

RATIONALE AND OBJECTIVES In functional cardiac magnetic resonance imaging, reduction of measuring time is very important for many patients who are not able to rest motionless for long-lasting examinations. In this study, the image quality of sequences with k-space segmented data recording was compared with conventional gradient-echo sequences for cine imaging with flow compensation in applications on patients with normal and reduced ejection fractions. METHODS Thirty-one subjects (4 volunteers and 27 patients with cardiac diseases) were examined using different techniques for cine imaging of the left and right ventricles. The ejection fraction in the patients was calculated based on images of a conventional two-dimensional gradient-echo technique using a biplane ellipsoid model. The results from k-space segmented methods (3 to 9 Fourier lines per cardiac cycle for each phase image) were compared with the conventional images of the same short-axis view separately for groups of subjects with normal and reduced ejection fraction. The contrast between blood and myocardium at several sites of the heart and the homogeneity of the blood signal in the ventricle were evaluated for several phases of the heart cycle. RESULTS The segmentation in the acquisition of raw data allows reduction of measuring time to approximately 20% to 40% of the time required for conventional sequences in cine imaging of the heart. In patients with normal or only slightly reduced heart function (ejection fraction > or = 60%) the image quality of k-space segmented sequences was not significantly different from the conventionally recorded images. In contrast, patients with markedly lowered ejection fraction (< 60%) showed degraded results of the k-space segmented sequences compared with the conventional sequence (P < 0.001). The anterolateral border and the right ventricle especially were not sufficiently delineated by the k-space segmented sequences in these patients. CONCLUSION The k-space segmentation for the reduction of examination time is suitable for measuring heart volumes and functional parameters of patients expected to have a nearly normal ejection fraction, whereas for patients with markedly reduced cardiac function further technical improvements of segmented techniques are necessary.

Fibrin specificity and procoagulant effect related to the kallikrein-contact phase system and to plasmin generation with double-bolus reteplase and front-loaded alteplase thrombolysis in acute myocardial infarction.

This study was undertaken to compare the effects of reteplase and alteplase regimens on hemostasis and fibrinolysis in acute myocardial infarction (AMI). Thrombolytic treatment in patients with AMI is hampered by paradoxical procoagulant effects that favor early reocclusion. In vivo data comparing this effect and the fibrin specificity of double-bolus reteplase and front-loaded alteplase regimens are not available. In a prospective, randomized study, 50 patients with AMI were either treated with double bolus (10 + 10 U) reteplase or with front-loaded alteplase (up to 100 mg) within 6 hours of symptom onset. Thirty apparently healthy persons served as controls. Molecular markers of coagulation and fibrinolysis were serially examined for up to 5 days. Paradoxical thrombin activation at 3 hours after initiation of therapy was comparable between reteplase and alteplase. Reteplase (65 +/- 5 U/L) and alteplase (72 +/- 8 U/L) caused significantly elevated kallikrein activity at 3 hours after adminstration (p <0.01 vs controls 30 +/- 1 U/L). Fibrin specificity was less for reteplase (p <0.05) with a decrease in fibrinogen at 3 hours to 122 +/- 27 mg/dl versus 224 +/- 28 mg/dl for alteplase (p <0.01 and p <0.05 vs controls). D-Dimer levels at 3 hours were higher (p <0.05) after reteplase (5,459 +/- 611 ng/ml) versus alteplase (3,445 +/- 679 ng/ml) (both p <0.01 vs controls 243 +/- 17 ng/ml). Plasmin generation (plasmin-antiplasmin complexes) was significantly (p <0.01) increased at 3 hours with both regimens to 27,079 +/- 3,964 microg/L (reteplase) and 19,522 +/- 2,381 microg/L (alteplase). The data from 3 hours after start of thrombolytic therapy proved less marked fibrin specificity of the reteplase regimen (in vivo) compared with front-loaded alteplase. Both regimens have a moderate procoagulant effect without differences in activation of the kallikrein system.

Fat- and water-selective MR cine imaging of the human heart: assessment of right ventricular dysplasia.

RATIONALE AND OBJECTIVES The purpose of this study was to develop and implement MR sequences for chemical shift-selective breath-hold cine imaging of the heart. Fibroadipose conversion of myocardium in cases suspected of right ventricular dysplasia should be revealed in fat- and water-selective MR images of high quality. METHODS Frequency-selective saturation of one chemical shift component was applied in modified k-space-segmented, electrocardiography-gated sequences, allowing high-quality cine imaging of the human heart in a single breath-hold. Phantom studies and human examinations in eight normal subjects (aged 24-62 years) and in seven patients (aged 31-47 years) with suspected right ventricular dysplasia were performed. The patients showed suspicious findings, such as a dyskinetic and dilated right ventricle combined with ventricular arrhythmia, and underwent MR imaging after exclusion of other possible reasons (eg, coronary artery disease or pulmonary hypertension). RESULTS High selectivity to the desired chemical shift component was confirmed by test measurements in a phantom containing water and lipids. In the human subjects, minor problems with magnetic field inhomogeneities appeared in the thoracic walls only. Four patients with suspected right ventricular dysplasia showed clearly abnormal signal behavior of the right myocardial wall in both fat- and water-selective cine images. Bright transmural structures were exhibited in fat-selective images, but the origin of the fat (epicardium or infiltrated myocardium) was often difficult to assess. CONCLUSIONS Right ventricular areas with fibrosis and fatty degeneration often show normal signal intensity in standard T1-weighted images but can be differentiated from normal tissue by the new chemical shift-selective breath-hold cine techniques.

Absence of paradoxical thrombin activation by fibrin-specific thrombolytics in acute myocardial infarction: comparison of single-bolus tenecteplase and front-loaded alteplase.

OBJECTIVES Thrombolytic therapy in patients with acute myocardial infarction is hampered by bleeding complications and procoagulant effects favoring early reocclusion. TNK-tPA was shown in vitro to have considerable fibrin specificity. We investigated the effects of tenecteplase (TNK-tPA) and alteplase (rt-PA) on the haemostasis and fibrinolytic system. METHODS AND RESULTS We enrolled 30 patients with AMI into the study. Twenty patients received front-loaded rt-PA up to 100 mg; 10 patients were given TNK-tPA in a single bolus up to 50 mg. All patients received aspirin and intravenous heparin. During the first 2 days, the following parameters were repetitively determined: thrombin-antithrombin III complexes (TAT), antithrombin III (ATIII), prothrombin fragment F 1 + 2 (F 1 + 2), kallikrein-like activity (KK), activated factor XII (FXIIa), plasmin alpha 2-antiplasmin complexes (PAP), fibrinogen, D-dimers (DD), tissue-type plasminogen activator (t-PA). A total of 75 healthy persons served as control group. TAT increased significantly after rt-PA but not after TNK-tPA (3 h: 38.1 +/- 29.4 versus 10.5 +/- 4.2 microg/l; p < 0.01), indicating paradoxical thrombin activation. F 1 + 2 increased transiently after rt-PA but not after TNK-tPA. Fibrinogen was significantly lower after rt-PA versus TNK-tPA (3 h: 163 +/- 27 versus 380 +/- 54 mg/dl; p < 0.05). KK activities in the rt-PA group were significantly (p < 0.01) increased over 48 h versus TNK-tPA. PAP and D-dimers were lower over the time course of 48 h in the tenecteplase group versus rt-PA. CONCLUSIONS This study indicates that tenecteplase has higher fibrin specificity not only in vitro but also in vivo versus alteplase. TNK-tPA consecutively has no paradoxical systemic procoagulant effect due to the lower extent of activation of the kallikrein-factor XII system than alteplase.