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The standardized and constant fixed-dose rate, no necessity for a close and regular blood monitoring as well as the small number of interactions with other drugs and daily food make therapy with the new oral anticoagulants dabigatran and rivaroxaban and in future presumably apixaban much easier and more feasible than the standard therapy with vitamin K antagonists (VKA). In summary the trials focusing on patients with non-valvular atrial fibrillation show that the new substances are at least non-inferior or even coequal to the well-known VKAs regarding prevention of thromboembolism. In addition the risk of fatal and especially intracranial hemorrhage can be considered even lower. Furthermore, the trials indicate a trend in reduction of death from any cause in treating these patients with the new drugs. There was no inferiority or even superiority in patient-outcome in extended prevention of venous thrombosis and pulmonary embolism after knee or hip arthroplasty when treating patients with the new substances by oral administration versus subcutaneous administration of low molecular weight heparin. Comparable results were demonstrated in the therapy of patients with acute deep vein thrombosis compared with the standard therapy of low molecular weight heparin and VKAs while there was a similar safety profile. Concerning the specific treatment of coronary heart disease and a combined antiplatelet therapy, profound data are still missing. The lack of specific antidotes the as yet limited experience with these substances over a longer period of time and last but not least the emerging costs have inhibited a broad use of these new agents up until now.

Holter-monitoring and exercise-ECG can be employed for the detection of myocardial ischemia. Exercise-ECG is capable of detecting ischemias caused by physical activity. In contrast, Holter monitoring can detect episodes of myocardial ischemia independent of exertion, but possibly connected with other factors such as mental stress. In 60 patients (49 male, 11 female, mean age 55.1 years) with angiographically documented coronary artery disease (26 x 1-vessel, 21 x 2-vessel, 13 x 3-vessel diseases) exercise-ECG and ambulatory 24-h monitoring were performed (3-channel recordings, ST-segment analysis). The assessment of the exercise-ECG showed 31 out of 60 patients with pathological results. 34 patients had pathological ST-segment changes during Holter monitoring (56%). Since both methods detected different patients, a combination of these techniques is useful. The combination of Holter monitoring and exercise-ECG raised the sensitivity to 78% (47/60 patients). Different heart rates were found at the point of maximal ST-segment changes in exercise-ECG as compared to the episodes of ST-segment changes recorded by Holter monitoring. This finding clearly illustrates the fact that different pathophysiological mechanisms are causing myocardial ischemia in respective cases. Using the coronary arteriogram as standard, the sensitivity of the two methods was different. While both techniques could detect multi-vessel disease at a similar level, Holter monitoring was significantly more sensitive in detecting patients with single-vessel disease. Thus, exercise-ECG and Holter monitoring supplement each other in detecting myocardial ischemia. In the future, larger clinical trials will have to confirm these results.

The effect of endocardial cardioversion was investigated in 17 patients (aged 26-76 years), ten of them with ventricular tachycardia, either spontaneous or initiated by programmable stimulation. During a total of 14 days of observation there were 33 episodes of spontaneous or induced ventricular tachycardia. A special cardioverter catheter had been placed into the right ventricle and endocardial microshocks were given ranging from 0.05-2.0 J. All patients could feel the shock, but in most instances it was mild to moderate, in only one painful. The tachycardia was slowed in 20% of all microshocks, moderate acceleration occurred in 6%, while in 71% the tachycardia rate remained unchanged. In 7 out of 65 microshocks sinus rhythm occurred spontaneously, after an interval in which the tachycardia slowed. Atrial fibrillation was induced in 6% of cases, but there was no instance of ventricular fibrillation. Reversion directly to sinus rhythm after endocardial cardioversion occurred in 26 of 33 episodes of ventricular tachycardia, while in 7 episodes the tachycardia rate slowed. In no case was it necessary to use external DC cardioversion to terminate a ventricular tachycardia. Threshold values for successful cardioversion of ventricular tachycardia averaged 0.77 (+/- 0.63) J. In one patient, atrial flutter with a relatively high A-V conduction rate was converted into atrial fibrillation by an intra-atrial microshock of 5.0 J. Thus endocardial cardioversion proved effective and safe in terminating ventricular tachycardia, even in patients in whom anti-tachycardic ventricular pacemaker stimulation had failed. The method is apparently not suitable for the conversion of supraventricular tachy-arrhythmias to sinus rhythm.

Ventricular late potentials are regarded as an expression of delayed impulse conduction in an area of myocardial ischemia and, accordingly, indicative of a preformed reentry circuit. Late potentials can be detected in chronic, stable coronary artery disease and their presence correlates closely with impairment of ventricular function and with the probability of future occurrence of tachyarrhythmic events or sudden cardiac death. While repetitive ventricular arrhythmias in the chronic stage of coronary artery disease result almost invariably from circling intraventricular wavefronts, tachyarrhythmias associated with acute myocardial infarction appear attributable to differing pathomechanisms. According to experimental studies, in acute myocardial infarction, three phases of arrhythmogenesis can be differentiated: phase 1 encompasses the first hours after vessel occlusion which generally corresponds with the prehospital phase. Due to the difference in potential of up to 25 mV between ischemic and nonischemic cardiac muscle areas, an injury current is called into existence which leads to depolarization of normal cardiac muscle tissue. The ectopic impulses so precipitated, the conduction of which is supported by the functional inhomogeneity of the infarcted region, are capable of initiating reentry tachycardia. During phase 2, a few hours to days after the ischemic event, only the subendocardial Purkinje fibers in the infarcted region exhibit focal arrhythmogenicity. In contrast to the working myocardial cells, the latter survive due to their immediate proximity to the cardiac chamber and show, ischemia-induced, a propensity to high-frequency impulse formation in terms of abnormal automaticity. Similar to the experimental findings, the cause of the frequently-observed ventricular arrhythmias in the early hospital phase appears predominantly attributable to a focal arrhythmia mechanism. During phase 3, several days to weeks after the acute myocardial ischemic event, reentry mechanisms again are in the foreground in which the electrophysiologic changes in the Purkinje fibers, in terms of increasing desynchronization, together with conduction barriers arising through the infarct scar, pave the way for reentry phenomenon. After abrupt restoration of patency of a previously occluded vessel the very frequent "reperfusion arrhythmias" are also attributable primarily to reentry mechanisms due to inhomogeneous improvement of the conduction properties in the region of the reperfused myocardium. Ventricular late potentials can be registered both invasively by means of epi- or endocardial leads as well as noninvasively from the body surface.(ABSTRACT TRUNCATED AT 400 WORDS)

In a population of 40 patients with coronary artery disease the overall incidence of spontaneous ischemic episodes during 24-h Holter monitoring could be significantly reduced with ISDN 120 mg ret. and ISDN 120 mg plus Diltiazem 120 mg ret. However, the intraindividual day-to-day variability of ischemic episodes on three consecutive days of Holter monitoring is taken into consideration, an intraindividual reduction of ischemic episodes of at least 97% is required to separate a true therapeutic effect from the considerable spontaneous variability.

Recognition of patients at risk of sudden cardiac death and prevention of such lethal events represent important and, for the most part, unresolved problems in clinical cardiology. From pathologic-anatomical and clinical studies of instances of sudden death it is known that in more than 80% the lethal electrical events, that is ventricular fibrillation, are attributable to myocardial ischemia, usually due to coronary artery disease. Experience in experimental studies as well as in treatment of patients with myocardial infarction on coronary care units has shown that certain types of arrhythmias such as frequent, multiform, repetitive and early-occurring (R-on-T) ventricular premature beats, in particular, may be associated with sudden arrhythmic cardiac death. Accordingly, in 1971, Lown and Wolf proposed a system for grading of ventricular arrhythmias and their severity which assumed world-wide importance for clinical and prognostic studies. This system of classification contains quantitative and qualitative criteria and is ordered in part on exclusion and in part on hierarchy, in which it is implied that the hierarchy of ventricular premature beats corresponds with that of the risk of death. Since the system enables only semiquantitative delineation of ventricular arrhythmias whose absolute number, however, within a given observation period appears to be of prognostic relevance and, additionally, since the Lown system is encumbered by the fact that classification is based only on the most severe arrhythmia with subsequent loss of information regarding concurrent arrhythmias of lesser severity, Bigger and his associates, in 1978, suggested a modification to provide quantification of all ventricular premature beats. In addition to the problems inherent to grading ventricular premature beats, further problems are also incurred with respect to spontaneous variability of ventricular arrhythmias. Based on statistical considerations and clinical studies accordingly, adequate assessment of complex ventricular arrhythmias prerequisites continuous monitoring for a period of 24 to 48 hours. Furthermore, for the exact recognition and quantitative detection of ventricular arrhythmias, the reliability of the individual systems for continuous ECG monitoring plays an important role since, by no means, have they all been validated in arrhythmia-detection capabilities. Since 1971, a number of clinical studies have shown, in particular, that complex ventricular arrhythmias are of important prognostic relevance in characterization of patients at risk of sudden cardiac death. The results may be summarized as follows: Ventricular premature beats can be found frequently in

To evaluate spontaneous variability of ST-segment changes within the Holter ECG, in 20 patients with documented coronary heart disease (CHD) long-term ambulatory ECG recordings were performed over 3 consecutive days, when the patients were only receiving short-acting nitrates. ST-segment alterations per day were measured as the area beneath the baseline (mV x min), and were compared day-to-day intraindividually. The intra-day variations of ST-segment area alterations were a factor of about 10, when compared with the baseline values. Following administrations of 120 mg ISDN ret. at the beginning of day 4, the number of anginal attacks was reduced, as was the acute medication with short-acting nitrates. There was also a trend to reduction of ischemic ST-segment changes, but these reductions could not be confirmed statistically. In studies on the course and therapeutic interventions of patients with CHD, the phenomenon of spontaneous variability of ST-segment alterations must be taken into account--as applies also to the arrhythmia analysis within the Holter ECG--and the recording period must probably be prolonged beyond the 24-h limit presently used.

The haemodynamic and antianginous efficacy of percutaneous nitroglycerin was evaluated in 24 patients with coronary heart disease. Groups of 8 patients each received one, two or four patches (nitroglycerin liberation 5 mg per patch within 24 hours). Prior to application and after 1 and 2 hours cardiac frequency, arterial and pulmonary arterial pressures and exercise tolerance were assessed. Cardiac frequency and arterial pressure showed no relevant changes after application of patches. The mean pulmonary arterial pressure decreased after application of one or two plasters by 18.5 and 22.2% at rest and by 12.7 and 21.1%, respectively, during exercise. The working capacity showed a trend towards improvement only. With four nitroglycerin patches the mean pulmonary arterial pressure at rest was lower by 26.2% and during exercise by 39.1%. The working capacity rose significantly by 48.7%. Comparison of these effects with oral single dosage of 20 mg 5-isosorbide mononitrate (ISMN) showed that two simultaneously administered plasters did not achieve efficacy of 20 mg 5-ISMN, four plasters, however, were more effective.

In 56 patients with angiographically-documented coronary artery disease, the longterm effects of isosorbide dinitrate (ISDN) and isosorbide 5-mononitrate (5-ISMN) on exercise hemodynamics and exercise capacity were assessed. The hemodynamic and antianginal acute and longterm effects of the respective agents were objectively analyzed on the basis of the tested parameters of mean pulmonary artery pressure and work capacity (watts X minutes). These parameters are unaffected by placebo and show reproducible changes at rest and during exercise after drug administration. After the standard 20 mg dose of ISDN or 5-ISMN, both at rest and during exercise, there was a marked decrease in pulmonary artery pressure as well as an increase in exercise capacity. The acute effects of 60 mg ISDN or 50 mg 5-ISMN were not substantially more marked than those of the 20 mg doses. During longterm treatment with 20 mg ISDN or 5-ISMN three times daily there was no attenuation of the hemodynamic effects, that is, no tolerance development; the increase in exercise capacity was maintained. In contrast, at the end of the four-week treatment period with 60 mg ISDN or 50 mg 5-ISMN three times daily there was a marked attenuation of the hemodynamic effects as well as the associated exercise capacity. The results of this study do not enable delineation of the mechanism responsible for the attenuated effect during high-dose treatment. Most probably, it is due to a complex process, in which, in addition to pharmacokinetics and pharmacodynamics, alterations in various reflex and adaptive mechanisms also play a role.

Patients suffering from long QT syndrome are threatened by torsade de pointes tachycardias and sudden arrhythmic cardiac death. An inhomogenic sympathetic innervation of the heart with dominance of the left cervicothoracic sympathetic nerves has been considered to be a major cause of life threatening cardiac arrhythmias. This study presents the electrocardiographic and electrophysiologic results of 7 patients with long QT syndrome. In agreement with data published earlier our results of Holter monitoring, exercise testing and programmed electrical right ventricular stimulation were of no diagnostic or prognostic significance in predicting syncopal attacks or sudden arrhythmic cardiac death. Thus, the high resolution ECG methods played an important role in this study. During noninvasive recordings of signal averaged ECGs and high resolution surface ECGs with beat to beat registration, diastolic microvolt potentials could be detected in 6/7 patients within the ST segment and in 5/7 patients after the T wave. Our results evidently show that the signal averaged ECG and the high resolution surface ECG could be of diagnostic significance in patients with long QT syndrome.

An automatic, implantable cardioverter-defibrillator (AICD) which generates a high-energy current impulse is now available for the management of treatment-resistant malignant ventricular arrhythmias. Such a device (manufactured by Intec/CPI) was implanted into eight patients with coronary heart disease or dilated cardiomyopathy, and in four after surgery for postinfarction ventricular arrhythmias. All patients had had life-threatening episodes of ventricular fibrillation or tachycardia: the arrhythmias were refractory to multiple drug therapy (mean of 6.8 antiarrhythmia drugs per patient). The threshold energy for converting ventricular fibrillation was 9.6 Joules +/- 5.7. Except for one bacterial infection of the electrodes, there were no serious complications. During a mean observation period of 13.6 months 21 electrophysiologically induced and 105 spontaneous tachyarrhythmias were successfully terminated by the AICD. No malfunctions occurred and there was no death due to an arrhythmia.

Haemodynamic effects of 5-isosorbide mononitrate (5-ISMN) were studied at rest and on exercise in 31 patients with angiographically confirmed coronary heart disease. A decrease in arterial blood pressure and mean pulmonary artery pressure without significant change in heart rate, cardiac output and stroke volume occurred both at rest and on exercise after 20 mg of 5-ISMN to 12 patients. Administration of 50 mg 5-ISMN to 19 patients achieved greater decrease in mean pulmonary artery pressure; cardiac output and stroke volume were highly significantly reduced at rest, while on exercise both cardiac output and stroke volume remained unchanged. Ten patients, in whom after a single dose of 50 mg 5-ISMN the mean pulmonary artery pressure at rest and on exercise had decreased 28% and 45%, respectively, with a definite rise in exercise tolerance, repeat acute administration of a single dose of 50 kmg 5-ISMN produced a fall in mean pulmonary artery pressure at rest by 20% after 50 mg three times daily for four weeks. On exercise the fall was only 14% below the control levels before treatment. In addition, exercise tolerance was reduced. These results indicate that acute administration of 5-ISMN at rest and on exercise decreases cardiac work load. But on chronic administration of high doses, tolerance to the drug may develop.

100 healthy medical students were studied with 24-h Holter monitoring for ST-segment evaluation. Six recordings (1.8% of males and 11.6% of females) contained at least one episode of horizontal or downsloping ST-segment depression of at least 0.1 mV or more and 1 min duration in the V-5-like lead. Since ST-segment elevations (in 73% of the recordings in the V-5-like lead, and in 40% in the V-2-like lead) and discordant (negative) T-waves associated with ST-segment depressions (in 31% of the recordings in the V-2-like lead) were commonly seen, these ECG findings have to be considered as nonspecific. During exercise tests using a protocol of maximal work load, not one of these healthy individuals displayed typical ST-segment depressions indicative of myocardial ischemia. Therefore, typical documented ST-segment alterations in Holter-ECG recordings should be used with caution when observed in individuals with suspected coronary heart disease, particularly when they are female.

In a prospective study of 23 patients the clinical effects of rate-adapted activity-sensed (by mechanical resonance oscillations) pacing (Activitrax system) were tested over a mean period of 8.1 +/- 3.8 months. This form of pacemaker treatment was used when, after exercise and on long-term ECG monitoring, the spontaneous heart rate had not exceeded 85 beats per min and there had been symptoms of decreased exercise tolerance. Lasting improvement in physical exercise tolerance was achieved in 11 of 17 patients after changing from fixed-rate to rate-adapted pacing. Treadmill ergometry, randomised in the fixed-rate or rate-adapted mode, brought about a significant rise in exercise tolerance (P greater than 0.01). Contrary to results after external influences, insufficient rate increases in five patients in the course of static stress was of clinical significance and thus narrow the indications for this type of pacing.

In 500 patients suffering from angina pectoris (454 males, 46 females) in whom coronary angiography had been performed a dipyridamole test was carried out. The test was positive in 319 of 396 patients with stenosing coronary heart disease (sensitivity 80%); ECG changes typical of ischaemia were demonstrated in 51%. The exercise ECG test was positive in only 68% of 229 patients with coronary heart disease. Among 104 patients without stenosing coronary heart disease the dipyridamole test was false-positive in 47, giving a specificity of 55%, while in 17 (16%) there were false-positive ECG-changes. The exercise test was falsely positive in 20 of 38 patients without stenosing coronary heart disease (specificity of 47%). Coronary blood flow was measured with the argon technique in 19 of 47 with a false-positive dipyridamole test and three with a false-positive exercise ECG. Maximal pharmacologically induced coronary blood flow was significantly reduced in all so that the diagnosis of "atypical coronary heart disease" or "small vessel disease" was made. The dipyridamole test or the exercise ECG test were falsely positive in these patients only with regard to the coronary arteriogram, correctly positive, however, in relation to angiographically non-demonstrable coronary blood flow abnormalities. The dipyridamole test is complementary to the exercise ECG test and has comparable accuracy. The same precautions must be observed for both tests.