Catheter-based septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: follow-up results of the TASH-registry of the German Cardiac Society.

INTRODUCTION: In late 1997, the German Cardiac Society set up a multicenter registry to evaluate the acute and mid-term course of all patients (pts.) treated with septal ablation for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). An analysis of the acute results has already been published. We now report on the mid-term course (3-6 months) of 242 pts. registered through September 1999. RESULTS: Follow-up was 92% complete (n=222). During follow-up (mean: 4.9+/-2.3 months), an additional 3 pts. died (in-hospital mortality: 3 pts.). A satisfactory clinical effect was reported by 195 pts. (88%); 27 pts. (12%) remained in NYHA classes III and IV. Overall symptomatic improvement (NYHA class: from 2.8+/-0.7 to 1.7+/-0.7) paralleled the outflow gradient (LVOTG) reduction which was further accentuated as compared with the acute result (Doppler measurement at rest: from 57+/-31 to 25+/-25 mmHg to 20+/-21 mmHg; with provocation: from 107+/-53 to 49+/-40, to 44+/-40 mmHg, p<0.001, resp.). Left atrial (LA) diameter (from 46+/-8 to 44+/-7 mm) and septal thickness (from 20+/-5 to 15+/-5 mm; p<0.001, resp.) were also reduced. Comparing the methods for target vessel selection (i.e., with contrast echo monitoring vs pressurefluoroscopy guidance), at followup clinical improvement and hemodynamic measurements were comparable. CONCLUSION: Clinical success can be achieved by septal ablation, both with the echocontrast guided and gradient-fluoroscopy guided method, in 88% of highly symptomatic HOCM pts. At mid-term follow-up, symptoms, left atrial size and septal thickness are reduced, and outflow gradients are further improved as compared to the acute result.

[The clinical value of Holter ECG recording]. / Klinische Bedeutung der Langzeit-Elektrokardiographie.

The Holter ECG is a well established clinical tool to document intermittent arrhythmias. The main indications are palpitations and syncope. However, the occurrence of these events during 24 h recording is very rare. So, it is often a matter of definition, what findings can speculatively "explain" a syncope. Therefore, an event recorder is often more successful. In addition, in patients with organic heart disease and reduced left ventricular function invasive electrophysiologic testing may be more appropriate. In these cases prophylactic implantation of an ICD may be indicated to prevent sudden death. So, in many instances the clinical value of Holter recording is overestimated.

Catheter-based therapy for hypertrophic obstructive cardiomyopathy. First in-hospital outcome analysis of the German TASH Registry.

BACKGROUND: Registry results of the new catheter-based method in the treatment for HOCM are missing so far. In 1997, the Transcoronary Ablation of Septal Hypertrophy Registry (TASH Registry) was established by the German Cardiac Society (GCS) as a multicenter, national registry of patients with HOCM undergoing the new catheter interventional therapy. This is the report of the in-hospital outcome of patients who underwent the procedure during the first two years of data collection in the registry. METHODS AND RESULTS: Information was based on three standard forms for each patient, with a total of 86 variables. Information was collected on an "intention to treat" basis. The TASH Registry includes the establishment of a data base in the data collecting center. Ten centers participated. Enrollment forms were received for 264 patients out of 279 patients registered up to January 2000. There was a history of medical treatment of 3.6+/-3.9 years. The vast majority of patients (91%) were treated in three centers. The Vasalva maneuver and the exercise Doppler echocardiography were used for noninvasive stress testing. Exercise Doppler echocardiography induced a significantly higher augmentation of the baseline gradient (70.1% vs 133.4%; p<0.01). The echo-contrast guided technique was used for the intervention in 50.8% and the pressure angiography guided technique in 49.2%. On the average 2.8+/-1.3 ml of alcohol were injected. Before the procedure, the gradient measured by catheterization was 60.4+/-38.6 mmHg at baseline and 142.7+/-46.2 mmHg following the extrasystolic beat. At the end of the session it was reduced significantly by 75% and 67%. The peak phosphocreatine kinase activity was 482.5+/-246.4 U/L. Major complications occurred in 15.6% including a mortality rate of 1.2% and a permanent pacemaker implantation rate because of total heart block in 9.6%. There was an early in-hospital improvement of dyspnoe corresponding to a significant decrease of NYHA functional class from 2.8+/-0.7 to 1.8+/-0.6 (p<0.001). Similar hemodynamic and clinical benefit was found in patients with and without resting gradient at baseline. CONCLUSION: This analysis for the first time gives a comprehensive overview of clinical characteristics, technique, procedural data, in-hospital outcome and complications in a large number of patients with HOCM who were treated by the new catheter-based method and prospectively enrolled in a registry. The results contribute considerably to critical evaluation and validation of the new technique. This analysis supports the catheter-based method to constitute a new therapeutic option for very symptomatic patients, to be effective both in patients with and without intraventricular pressure gradient at rest and to be an alternative to surgical treatment, as has been stated recently.

The thrombolytic paradox.

Thrombolytic drugs do not only stimulate the plasmin system but also induce thrombin activation additionally to the preexisting hypercoagulative state in patients with acute myocardial infarction. Testing the in vitro-derived hypothesis of a plasmin-mediated activation of the contact phase of the coagulation leading to the procoagulant effect, several thrombolytic regimen have been evaluated. Paradoxical thrombin activation (referred to as "thrombolytic paradox") was related to absence of fibrin specificity. Highly fibrin-specific drugs like tenecteplase did not cause additional thrombin activation, while non-fibrin-specific drugs like streptokinase caused a marked additional activation of the contact phase and of thrombin. It could be shown that the thrombolytic paradox was related to the extent of systemic plasmin activation confirming the hypothesis of a plasmin-mediated factor XII/kallikrein system activation as cause of the thrombolytic paradox.

Percutaneous coronary interventions using a new 5 French guiding catheter: results of a prospective study.

The aim of this prospective study was to analyze the technical feasibility, the success rate, and the special complications of percutaneous coronary interventions (PCIs) using a newly released 5 Fr guiding catheter with an inner diameter of 0.058". The study was performed in 150 consecutive patients subjected to coronary angioplasty. In 89% of the patients, the intervention was started with a 5 Fr catheter (JR4 or JL4); in 16 patients a 6 or 7 Fr catheter was used because of unstable clinical conditions according to the decision of the interventional cardiologist. In 12 out of 134 patients, the guiding catheter had to be changed during the intervention from 5 Fr to a 6 or 7 Fr catheter due to poor backup support. In 112 out of 118 patients, the intervention was successfully performed using a 5 Fr catheter (95%); in 12 out of 16 patients, after changing the guiding catheter, the overall success rate was 93%. In patients with type A and B lesions who were initially treated using a 5 Fr catheter, the procedural success rate was 100% (81 out of 81), whereas in patients with type C lesions the procedural success rate was 83% (43 out of 53; P = 0.000053, Fisher's exact test). Furthermore, in patients with a diameter stenosis < 90%, the procedural success rate was 100% (57 out of 57), whereas in patients with a diameter stenosis of 90%-100%, the procedural success rate was 87% (67 out of 77; P = 0.0050). Stent implantation was performed successfully in 24 patients (18%) using the 5 Fr guiding catheter. This study confirms that PCI was technically feasible using a 5 Fr guiding catheter in the majority of consecutive patients with a success rate of 95%. There were significant differences in the success rate depending on the lesion type and the diameter stenosis. Complications were very rare and were not related to the guiding catheter. Limitations of the 5 Fr guiding catheters arose mainly from a poor backup support in long lesions and severe stenosis. Cathet Cardiovasc Intervent 2001;53:308-312.

Comparison of the efficacy of a subcutaneous array electrode with a subcutaneous patch electrode, a prospective randomized study.

The patch electrode and the array electrode are the two types of subcutaneous leads available as an adjunct to a transvenous lead system in patients with high defibrillation thresholds. A prospective randomized study was conducted in 30 consecutive patients comparing the efficacy and the long-term performance of a patch electrode with an array electrode. After determination of the defibrillation threshold for the transvenous lead alone, a subcutaneous patch or an array electrode was implanted in random order. Adding a patch electrode decreased the defibrillation threshold in seven out of 15 patients (47%) from 13.2+/-6.6 to 10.5+/-5.1 J (P<0.05). In 13 out of 15 patients (87%), the implantation of an array electrode caused a significant lowering of the defibrillation threshold from 15.4+/-6.6 to 8.2+/-5.0 J (P<0.0001). The array electrode was significantly more effective in lowering the defibrillation threshold than the patch electrode (P<0.01). Complications during follow-up associated with the subcutaneous patch electrode were observed in four patients whereas no complications were associated with the array electrode (P<0.01). The additional implantation of an array electrode is more effective and associated with fewer complications compared to a patch electrode.

Variable responsiveness of anterograde and retrograde fast pathway conduction to adenosine in patients with typical AV-nodal reentry tachycardia.

Adenosine is known as a substance which depresses predominantly the slow pathway of the av-node. However, the effect of adenosine on the anterograde and retrograde fast pathway (FP) has not been studied in a large patient population. Ninety-one patients with inducible typical av-nodal reentrant tachycardias (AVNRT) were included. The clinically used dosage of 12 mg adenosine was administered subsequently as bolus injection during a constant atrial and ventricular pacing (500 ms) in all patients. Electrophysiological av-nodal parameters were determined. A higher responsiveness of the anterograde compared to the retrograde FP was observed: the majority of patients (76%) blocked anterogradely and 55% blocked retrogradely within the FP after the administration of 12 mg adenosine. Thirty-six percent of all patients revealed a differential behaviour to adenosine. Sixteen percent of all patients were completely resistant to adenosine (P=0.012). Electrophysiological parameters did not predict the responsiveness of the FP to adenosine. In patients with typical AVNRT the anterograde FP shows a higher sensitivity than the retrograde FP to adenosine. This might reflect an anatomical and/or functional distinction between anterograde and retrograde FP. The variable response to adenosine could be due to individual anatomical and electrophysiological heterogenity of the perinodal tissue and the av-node.

[Electrical remodeling in atrial fibrillation--cellular and molecular mechanisms]. / Elektrisches Remodeling bei Vorhofflimmern--Zelluläre und molekulare Mechanismen.

Atrial fibrillation is associated with changes in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. The underlying cellular and molecular mechanisms are diverse; they have intensively been investigated over the past few years. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation are reviewed. On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa,L) and of potassium channels (Ito, IK1, IKACh). The molecular mechanisms of intraatrial conduction slowing are less well understood; changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) seem to be involved. A trigger for many of the observations is an overload of the myocyte cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. In the last part, the clinical relevance and potential new therapeutic approaches are discussed.

High variability of retrograde fast pathway sensitivity to adenosine.

BACKGROUND: Adenosine is widely used as a tool to assess the effectiveness of radiofrequency ablation of concealed accessory pathways. HYPOTHESIS: The goal of this study was to determine the reliability of this test by studying the retrograde fast pathway sensibility in a large patient population with typical atrioventricular (AV) nodal reentry tachycardias. We sought also to determine whether AV nodal properties were predictive of a retrograde fast pathway sensitivity to adenosine. METHODS: In all, 124 patients with inducible AV nodal reentrant tachycardia were included in this study. All patients received a clinically used standard dose of 12 mg adenosine during ventricular pacing, with 500 ms and a constant ventriculoatrial (VA) conduction via the fast pathway. Electrophysiologic parameters of the AV node were determined in all patients in order to correlate them with the adenosine sensitivity of the retrograde pathway. RESULTS: In 74 patients, the injection of 12 mg adenosine resulted in a transient VA block, whereas no VA block occurred in the remaining 50 patients. In two patients, concealed accessory pathways were unmasked after the injection of adenosine. The adenosine sensitivity of the retrograde fast pathway was associated with longer retrograde conduction times and cycle lengths during AV nodal reentrant tachycardias. CONCLUSION: This study shows a high variability of retrograde fast pathway sensitivity to adenosine. Thus, in 40% of patients the lack of VA block after adenosine injection is not specific for persistent accessory pathway function after radiofrequency ablation. Electrophysiologic properties of patients with AV nodal reentrant tachycardias were different in patients with and without adenosine-sensitive retrograde fast pathways, possibly indicating differential patterns of penetration of the retrograde fast pathway into the compact AV node.

Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with important alterations in cardiac ion channels that cause shortening and impaired rate adaptation of atrial repolarization. The mechanisms underlying potassium current remodeling in human AF are not clear. We investigated the effects of AF on the gene expression of the Kv4.3, Kv1.4, and Kv1.5 potassium channel subunits and correlated the findings with the transient outward (Ito) and the sustained outward (Isus or I(Kur)) potassium current. METHODS AND RESULTS: Semiquantitative reverse transcription-polymerase chain reaction was used to evaluate mRNA expression, and ion currents were studied with the patch clamp technique in right atrial appendages from patients in AF and compared with those from patients in stable sinus rhythm (SR). The presence of AF was associated with a 61% reduction in Kv4.3 mRNA expression (P < 0.001 vs SR), which was paralleled by a reduction in Ito current densities in this group of patients (i.e., at +50 mV: 7.44+/-0.76 pA/pF in SR and 1.24+/-0.28 pA/pF in AF; P < 0.001 vs SR). mRNA levels of Kv1.4 were identical in the two groups. AF did not affect either the gene expression of Kv1.5 or the current densities of Isus. CONCLUSION: Chronic AF in humans reduces Ito by transcriptional down-regulation of the Kv4.3 potassium channel. Altered gene expression is an important component of the electrical remodeling process and may contribute to repolarization abnormalities in AF.

Molecular and electrophysiological evidence for "remodeling" of the L-type Ca2+ channel in persistent atrial fibrillation in humans.

Persistent atrial fibrillation (AF) is associated with shortened action potential duration (APD) and reduced atrial refractoriness. Remodeling of ion currents responsible for AP morphology has been proposed as a major mechanism in persistent AF. In the present study we investigated the activity of the cardiac L-type Ca2+ channel and the mRNA transcription of the cardiac L-type Ca2+ channel subunits in patients with persistent AF compared to patients in sinus rhythm (SR). Right atrial appendages of 10 patients in SR and of 5 patients with AF were used for myocyte isolations to record L-type Ca2+ currents (ICa,L) by the patch-clamp technique. Right atrial appendages of 16 patients in Sr and of 5 patients with AF served as sources for determining the mRNA expression of the L-type Ca2+ channel alpha 1c-, alpha 2/delta-, beta a-, and beta b/beta c-subunits by semiquantitative RT-PCR. ICa,L density was reduced by 70% (p < 0.001) in AF patients compared to the sinus rhythm group. Cell sizes, expressed as cell capacitance, were identical in both groups. mRNA expressions of the alpha 1c-subunit and the beta b/beta c-subunits were reduced in AF patients by 18.9% (p < 0.05) and 77.7% (p < 0.005), respectively, while mRNA transcriptions of the alpha 2/delta- and the beta a-subunits were not significantly different between SR and AF patients. A decrease in the availability of functional L-type Ca2+ channels in AF patients, due to reduced alpha 1c-subunit and substantial lack of beta b/beta c-subunit transcription seems to contribute to the shortening of APD and refractory periods in AF, thereby favoring increased atrial excitation rate and perpetuation of AF.

[Improved assessment of the left ventricular endocardial border by intravenous injection of a left heart contrast agent]. / Verbesserung der linksventrikulären Endokarddarstellung durch intravenöse Gabe eines Linksherzechokontrastmittels.

PURPOSE: The purpose of this study was to find out whether intravenous injection of a phospholipid-based left heart echo contrast agent improves the delineation of the left ventricular endocardial border. The influence of echo contrast on the quantification of left ventricular volumes, ejection fraction, regional wall function and interobserver variability was also assessed. METHOD: Prospectively, the apical 4-chamber view was recorded in 20 adult patients before and after intravenous injection of the contrast agent. Left ventricular endocardial border resolution was assessed in 5 segments and left ventricular volumes, ejection fraction, regional wall motion and interobserver variability were measured. RESULTS: After contrast injection a diagnostically useful left ventricular opacification was present in 18 patients (90%) and an optimal opacification in 14 patients (70%). Without contrast 1.05 endocardial segments could be delineated at end diastole and 1.8 segments at end systole. After contrast injection 3.65 endocardial segments were recognizable at end diastole (p < 0.01), 2.5 segments at end systole (p < 0.02). Left heart contrast improves interobserver-variability of end diastolic volume (p < 0.006), end systolic volume (p < 0.004), ejection fraction (p < 0.0002) and regional wall motion assessment (p < 0.03). Side effects did not occur. CONCLUSIONS: The intravenous injection of the investigated phospholipid-based echo contrast agent improves left ventricular endocardial border delineation and reproducibility of left ventricular volumes, ejection fraction and regional wall motion assessment.

[Clinical utility of contrast echocardiography for quantification of left ventricular volumes and function in patients with suboptimal echocardiograms]. / Klinische Wertigkeit der intravenösen Kontrastmittelechokardiographie zur Quantifizierung der linksventrikulären Volumina und Funktion bei Patienten mit reduzierter echokardiographischer Bildqualität.

In the present study, we investigated whether the intravenous injection of air-filled albumin microspheres (Infoson) as a contrast medium improves the echocardiographic quantification of left ventricular enddiastolic and endsystolic volumes, stroke volume, ejection fraction, and regional wall motion in patients with suboptimal endocardial border definition on echocardiography. In 30 adult patients, apical two and four chamber views were performed. In comparison to biplane cineventriculography enddiastolic and endsystolic volumes, stroke volume, ejection fraction, and regional wall function were assessed for heart cycles with and without left ventricular contrast. In comparison to biplane cineventriculography echocardiography underestimates enddiastolic (167+/-64 ml, 111+/-43; p<0.0001) and endsystolic volumes (77+/-63 ml, 54+/-40 ml; p<0.0002), stroke volume (90+/-25 ml, 57+/-17 ml; p<0.0001), and ejection fraction (58+/-16%, 55+/-14%; p<0.03). By contrast echocardiography ejection fraction (58+/-16%) agreed with the angiocardiographically measured ejection fraction. Furthermore, after contrast injection correlations improved between cineventriculography and echocardiography for the assessment of left ventricular enddiastolic volumes (without contrast r = 0.90, SEE = 19 ml; with contrast r = 0.93, SEE = 19 ml), endsystolic volumes (without contrast r = 0.94, SEE = 14 ml; with contrast r = 0.95, SEE = 15 ml), stroke volume (without contrast r = 0.63, SEE = 14 ml; with contrast r = 0.67, SEE = 14 ml), ejection fraction (without contrast r = 0.84, SEE = 8%; with contrast r = 0.88, SEE = 7%), regional wall motion (p<0.01) and its reproducibility (p<0.02). In adult patients with suboptimal endocardial border delineation intravenous contrast echocardiography improves the assessment of left ventricular ejection fraction, regional wall motion, and its reproducibility without severe side effects.

Clinical experience with the new detection algorithms for atrial fibrillation of a defibrillator with dual chamber sensing and pacing.

INTRODUCTION: A major drawback of therapy with an implantable defibrillator is the nonspecificity of detection. Theoretically, adding atrial sensing information to a decision algorithm could improve specificity of detection. METHODS AND RESULTS: This open-label nonrandomized study compares the detection algorithm of the Ventak AV and the Ventak Mini implantable defibrillators. The Ventak AV (n = 39) uses dual chamber detection as opposed to single chamber detection (with rate stability) in the Ventak Mini (n = 55). Programmed zone configurations, rate thresholds, and stability criteria were identical in all patients. In the Ventak AV group, 235 ventricular tachyarrhythmias were adequately detected and treated by the device. In the Mini group, 699 episodes of ventricular fibrillation/tachycardia occurred. All but six of the latter episodes were correctly identified and treated: one patient with incessant ventricular tachycardia had five episodes not terminated by the device, another episode occurred in a patient with a device/lead defect. In the Ventak AV group, 33 episodes of sinus tachycardia and 166 episodes of atrial fibrillation/flutter activated the device; inappropriate therapy was applied to 41% of atrial fibrillation/flutter episodes. In the Ventak Mini group, 226 supraventricular tachyarrhythmias activated the device, eight of which were sinus tachycardia and 218 were atrial fibrillation or flutter; of the atrial fibrillation/ flutter episodes 24% were treated inappropriately (fewer vs Ventak AV, P < 0.001). CONCLUSION: The new detection algorithm incorporated in the Ventak AV did not inadvertently withhold therapy for ventricular tachyarrhythmias, but at the same time the number of inappropriate therapies for atrial fibrillation was not decreased in comparison to a single chamber device.

Effect of amiodarone and sotalol on the defibrillation threshold in comparison to patients without antiarrhythmic drug treatment.

AIM OF THE STUDY: It is generally accepted that chronic therapy with antiarrhythmic drugs might increase the defibrillation threshold at implantation of an implantable cardioverter defibrillator. A recently published animal study showed a minor effect of the class 1 antiarrhythmic drug lidocaine on the defibrillation threshold if biphasic shocks were used. METHODS AND RESULTS: We therefore performed a retrospective analysis in 89 patients who received an ICD capable of monophasic (n=18) or biphasic (n=71) shocks with a transvenous lead system. In all patients the defibrillation threshold was determined according to the same step down protocol. In the 18 patients with a monophasic device the effects of chronic therapy with amiodarone (n=7) on the defibrillation threshold were evaluated in comparison to a group without antiarrhythmic treatment (n=11). In those patients receiving a biphasic device the effects of chronic therapy with amiodarone (n=29), sotalol (n=20) or no antiarrhythmic medication (n=22) on the defibrillation threshold were evaluated. The groups receiving a monophasic device did not differ in respect to age, sex, underlying cardiac disease, clinical arrhythmia (VT/VF), clinical functional status, left ventricular ejection fraction and the number of patients with additional subcutaneous electrodes. These parameters as well as the type of implanted device were not different between patient groups receiving a biphasic device. Patients on chronic amiodarone therapy receiving a monophasic device had a significantly higher defibrillation threshold (29.1 +/- 8.8 J) than patients without antiarrhythmic treatment (19.1 +/- 5.1 J, P = 0.021). The groups did not differ significantly in respect to the impedance measured at the shocking lead (P = 0.13). In three patients on chronic amiodarone an epicardiac lead system had to be implanted due to an inadequate monophasic defibrillation threshold compared to no patient without antiarrhythmic drug treatment (P = 0.043). In the patients with a biphasic device the intraoperative defibrillation threshold was not significantly different between the three study groups (P = 0.44). No patient received an epicardiac lead system. The defibrillation threshold in the amiodarone group was 15.3 +/- 7.3 J, in the sotalol group 14.4 +/- 7.2 J and in the patients without antiarrhythmic drug treatment 17 +/- 6.1 J. As well, no significant difference was seen between the groups in respect of the impedance of the high voltage electrode (P = 0.2). CONCLUSION: With the use of a biphasic device in combination with a transvenous lead system the intraoperative defibrillation threshold is not significantly different between patients on chronic amiodarone in comparison to patients without antiarrhythmic drug treatment or patients on chronic oral sotalol. This is in contrast to our findings with a monophasic device.

[Blood coagulation and fibrinolysis in arteriosclerosis]. / Gerinnung und Fibrinolyse bei Arteriosklerose.

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.

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.

Long-term reproducibility of electrophysiologically guided therapy with sotalol in patients with ventricular tachyarrhythmias.

OBJECTIVES: Goal of this study was to assess the long-term reproducibility of electrophysiologic drug testing in patients with ventricular tachyarrhythmias (VT/VF). BACKGROUND: Programmed ventricular stimulation (PVS) is still widely used to guide antiarrhythmic therapy in patients with sustained ventricular tachycardia/fibrillation (VT/VF). Sotalol is considered as one of the most effective drugs for VT/VF. Because there is no proof of long-term reproducibility of a successful drug test with sotalol, we investigated the long-term reproducibility of drug testing with sotalol. METHODS: Thirty patients with VT/VF (age: 57+/-11 years, 20 patients with coronary heart disease, 7 patients with no structural heart disease, 3 with others) and reproducible induction of VT/VF (28 patients VT, two patients VF) in a baseline PVS, were suppressible with sotalol (mean dosage 395+/-137 mg) in a subsequent PVS. After a mean follow-up of 13+/-10 months a PVS was again performed in patients, who had no evidence of progressive cardiac disease, who did not experience any arrhythmia recurrences or who were drug compliant. Irrespective of the inducibility after long-term therapy with sotalol, all patients were kept on the initial sotalol regimen. All 30 patients had a stable cardiac condition, were free of VT/VF recurrences and were drug compliant. RESULTS: Despite the clinical efficacy of sotalol, in 12 patients (40%) VT/VF could again be induced after 13+/-10.2 months. Inducibility was independent of age, heart disease, ejection fraction and follow-up time. During a further follow-up of 22.1+/-10.9 months, five patients experienced nonfatal VT recurrences independently of the prior inducibility. CONCLUSIONS: This study shows a lacking long-term reproducibility of an initial effective PVS with sotalol. Despite an uneventful clinical follow-up, late electrophysiologic testing showed a VT/VF inducibility in a high portion of patients. Hence, electrophysiologic testing performed late after the initial drug test may no longer be predictive of outcome.

Action of aprotinin in myocardial ischemia - an investigation using a plasma-free model.

BACKGROUND: The protease inhibitor aprotinin has been reported to have an anti-ischemic effect on left-ventricular myocardium in patients undergoing cardiopulmonary bypass operation. To examine the anti-ischemic properties beside its antifibrinolytic and inhibitory action on the kallikrein-bradykinin system, we investigated this substance in buffer-perfused rat hearts. METHODS: 24 isolated isovolumically contracting rat hearts received a 10-minute infusion of either 10000 units aprotinin or pure saline followed by 30 minutes of no-flow global ischemia and 45 minutes of reperfusion. Hemodynamics, high-energy phosphates, and troponin T as molecular marker of cardiac injury were studied. RESULTS: During 15 minutes of reperfusion steady state function was identical in both groups, with a recovery of the developed left-ventricular pressure to 81.9+/-1.5% after protease inhibition and 83.0+/-2.6% in the controls. Coronary flow, myocardial oxygen consumption, and contractile reserve after maximum Ca++ stimulation were also identical. High-energy phosphates were comparably reduced in both groups (adenine nucleotides: 3.1+/-0.3 micromol/g ww after aprotinin vs. controls 2.7+/-0.4 micromol/g ww and creatine phosphate: 6.5+/-0.9 micromol/g ww vs. controls 4.7+/-1.1 micromol/g ww). However, release of the cardiac specific marker troponin T was lower after ischemia at several measurements (p<0.05). The total release of troponin T was 44+/-10 ng in the aprotinin treated hearts vs. 90+/-17 ng in the postischemic control hearts (p<0.05). CONCLUSIONS: The findings demonstrate that aprotinin in a moderate dose is effective in reducing postischemic troponin release in a non-blood perfused system. Measurement of myocardial high-energy phosphates after aprotinin use was performed for the first time and indicates that not a reduction in severity of direct myocardial ischemic intensity but a beneficial action on processes causing release of troponin is the mode of action of this effect.