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Despite advances in therapy acute myocardial infarction is associated with a mortality rate of up to 30%. Early and complete reperfusion of the infarct related artery (defined as TIMI flow 3 at 90 minutes following therapy) as obtained with thrombolytic therapy in 50 to 80% of patients improves survival and enhances ventricular function. Failure to achieve recanalization should prompt further intervention (second attempt of thrombolysis or rescue-PTCA). Various cardiac markers known from diagnosing acute myocardial infarction or risk stratification in unstable angina pectoris have been assessed in their ability to predict successful reperfusion/failure of therapy. Following reperfusion creatinkinase (CK) and its isoform CK-MB, troponin and myoglobin show an early and rapid rise to a high maximum value with rapid normalization. For creatinkinase time to peak values of less than 9 hours or rates of increase of > 50 U/h (> or = 10 U/h for CK-MB activity) within the first 2.5 hours following thrombolysis have been suggested as useful indicators of successful reperfusion. The same applies for a troponin (T)slope > 0.5 ng/ml/h within the first hour (Table 5). The major limitation in applying either creatinkinase, troponin or even lactatdehydrogenase (LDH) is their comparatively late release (4 to 6 hours) following myocardial infarction. In that respect myoglobin (though not specific for cardiac injury) seems ideal for guidance of intervention after failed thrombolysis. The I.S.A.M. study included 1,741 patients with acute myocardial infarction of less than 6 hours duration being given either streptokinase or placebo. Serial blood samples for measurement of cardiac enzymes were drawn within the first 50 hours. In the streptokinase group the time to peak concentration of CK-MB activity was significantly lower (mean 10.9 hours vs 16.1 hours following initiation of treatment) as was the area under the CK-MB curve indicating reduction of infarct size (Table 2). A substudy investigating the myoglobin release in 120 patients having received streptokinase or placebo demonstrated higher maximum values in the streptokinase group (mean 3008 vs 2097 ng/ml), a shorter time to peak interval following treatment (3.4 vs 6.5 hours) and a reduction in infarct size as suggested by a smaller area under the myoglobin curve (17,377 vs 23,240 ng/ml x h) (Table 3). For LDH/alpha-HBDH the reduction in time to peak intervals was less impressive (Table 4). In angiographic studies with TIMI flow 3 at 90 minutes in the infarct related artery in 22 patients (Figure 5) the maximum myoglobin value was reached in less than 4.2 hours (mean value plus SEM) following treatment (9.5 hours for CK-MB activity). Therefore, myoglobin seems to be the preferred marker in reperfusion assessment.

Early restoration of bloodflow in the infarct-related coronary artery is the principal mechanism by which early reperfusion therapies may improve outcome in patients with acute myocardial infarction. The beneficial effect of reperfusion is independent of the therapy used (thrombolysis or PTCA), but, as shown in many studies, depends very much on the time to reperfusion. The achievement of a normal bloodflow in the infarct vessel, the so called TIMI 3 patency is considered to be the gold standard for the evaluation of the success of reperfusion therapy. However, there is increasing evidence from recent studies, that restoration of epicardial bloodflow does not necessarily indicate perfusion at the myocardial level. As unequivocally shown by contrast echocardiography using intracoronary injections of microbubbles, this is true even for TIMI Grade 3 flow, which correlates most strongly with prognosis and usually is associated with a very low mortality of about 3 to 4%. Angiographic patency not only is a sometimes unreliable indicator of myocardial reperfusion, but also involves an invasive procedure, is expensive and not universally available. A readily available and simple indicator of reperfusion is the early resolution of ST segment elevation. Complete ST resolution at 90 or 180 minutes after the initiation of treatment is associated with an excellent prognosis, even better than TIMI 3 patency. In contrast, no ST resolution indicates an in-hospital mortality which is about 8-fold greater than with complete ST resolution. Since ST resolution may be more closely related with the relief of ischemia than angiographic patency, the prognostic power of the combination of both indicators should be greater than that of either of them alone. Thus, it is evident from many studies that patency of the infarct-related artery is necessary for myocardial salvage in acute myocardial infarction, but it has to be achieved rapidly and has to be complete and sustained. However, even an early and perfect angiographic result achieved by thrombolysis or PTCA, does not consistently indicate myocardial reperfusion, and the mechanisms of the often called no-reflow phenomenon are still poorly understood. The possible contribution of reperfusion injury to poor clinical outcomes after adequate epicardial flow has been restored is also a matter of controversy and deserves further research. Promising results were derived from studies with GP IIb/IIIa inhibitors, in which improved microvascular flow and myocardial reperfusion were observed, when these agents were used as adjunct to thrombolysis and PTCA.

Since reperfusion of the infarct-related coronary artery has been established as a mainstay in the treatment of acute myocardial infarction (AMI) mechanical recanalization by direct angioplasty has been used as an alternative to the standard treatment with thrombolysis. Direct PTCA is more efficient than thrombolysis in terms of reperfusion rates, whereas thrombolysis is more readily available. Thrombolysis reduces mortality from AMI by approximately 25%. The clinical efficacy is strongly time-dependent, and treatment within the first hour of AMI improves survival by nearly 50% by preventing transmural infarction in a significant proportion of the patients. The disadvantage of thrombolysis is its limited efficacy in terms of rapid, complete and sustained patency of the infarct vessel yielding optimal results in only 50% of the patients. Direct PTCA is generally agreed to be more efficient to recanalize the infarct vessel, but its clinical advantage remains controversial. The first randomized studies of direct PTCA in AMI from highly specialized centers in selected patients reported success rates of coronary reperfusion up to 97% resulting in a trend to less death and reinfarction, but the differences were significant only in a metaanalysis of these small studies. The real world of direct PTCA has been depicted by a large registry in Germany of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) now including more than 4,000 direct PTCA-procedures since 1994. In this registry, the success rate of direct PTCA was 87% as defined by a final TIMI-grade 3 perfusion of the infarct vessel which is close to the data of the MITI-registry and the GUSTO IIb study. Failed PTCA was associated with an exceptionally high mortality rate of 36% confirming earlier observational reports. The non-randomized comparison of thrombolysis and direct PTCA in the MITI-registry showed no differene in survival or reinfarction rates, and the randomized GUSTO IIb substudy of direct PTCA versus front-loaded alteplase showed a small advantage in death and reinfarction rates at 30 days which dissipated over time leaving no significant clinical advantage of direct PTCA over thrombolysis at 6 months. Thus, in myocardial infarction in general the advantage of direct PTCA over thrombolysis is at best minimal. The reason is very probably the longer time lag until the procedure is started, the lower success rate as compared to the first reports of some specialized centers, and the clearly negative impact of failed PTCA on survival. Moreover, the immediate success of direct PTCA seems to be overestimated by the operator as demonstrated by comparison of central and local estimates of the TIMI flow rates in GUSTO IIb. Improvements of direct PTCA in AMI might be possible by coronary stenting which has markedly increased to more than 60% during the last year in the ALKK-registry. This was accompanied by a slight decrease in death and reinfarction rates. Further improvements can be expected from GP IIb/IIIa platelet antagonists which are under clinical investigation. It has been claimed, that in cardiogenic shock direct PTCA is more effective than thrombolysis. This hypothesis is based on comparison of failed versus successful PTCA-attempts, but this comparison is not valid since failed procedures clearly increase mortality. In the GUSTO-1 study patients with cardiogenic shock had lower mortality with than without an early coronary angiogram. This survival advantage, however, was independent of revascularization since only half of the patients with an early angiogram had PTCA. The same was observed in the International Shock Registry, reflecting significant selection bias in that patients in relatively better condition will be taken to the cathlab whereas apparently hopeless cases will not. In the ALKK-registry half of the patients in cardiogenic shock died after direct PTCA casting doubt on the presumed high clinical efficacy of this strategy. (ABST

The extent of ST segment elevation resolution (STR) 180 minutes after initiation of streptokinase treatment for acute myocardial infarction within 6 hours after onset of symptoms is an excellent early prognostic indicator that can be easily determined in all patients. This presentation is based on a meta-analysis from 3 thrombolysis studies including 3,912 patients. About 50% of patients had complete STR (> or = 70%). They had small enzymatic infarct sizes and well preserved left ventricular function associated with an excellent chance of survival. Patients with partial STR (< 70 to 30%) developed larger infarcts, but had still a relatively low mortality. To assess the optimal cut-off point that best predicts an increased mortality risk, the squared standardized log odds ratio statistics as a function of the hypothetical cut-off points in STR was used. A cut-off point around 30% STR was associated with an extraordinarily strong predictive power. The 35-day cardiac mortality with STR < 30% was 12.7% as compared to 2.1% for patients who had complete STR and 4.2% for those who had partial STR. Based on STR, age, medical history, and simple parameters at admission, a low risk population can be defined that includes about 50% of all patients aged < or = 70 years, and 20% of older patients. The 35-day and 1-year mortality rates for the group of younger patients was 1.4% and 2.7%, respectively, and for the older age group 5.0% and 7.9%. It appears highly unlikely that aggressive testing and interventions would have any measurable beneficial effect on such a good outcome. In thrombolytic therapy comparative trials STR may perform well as a surrogate endpoint, since it is more powerful than 90 minutes post-thrombolytic patency rates and early mortality, in a statistical sense. This is especially true for Phase-II dose-finding studies and the use as a surrogate or even primary endpoint in phase-III trials. In addition, STR may be very helpful for safety monitoring, interim analyses, and subgroup analyses in megatrials with the endpoint mortality. Use of STR can result in a substantial reduction in the required sample size. However, at least 1 pivotal mortality trial cannot be replaced by STR trials, since STR does not reflect the risk of intracranial hemorrhages and other bleeding complications.

Early treatment with thrombolytic drugs has been shown to reduce mortality in patients with acute myocardial infarction. Thrombolytic therapy with early, complete and sustained patency of the infarct related artery is associated with a low inhospital mortality of 3 to 4% (Figure 1). Even with the most effective thrombolytic regimens this aim at present is achieved in only about 50% of the patients. The optimal thrombolytic drug should be effective (rapid, complete and sustained recanalization of the infarct related artery), safe (low incidence of severe bleedings), easy to administer (e.g. bolus application) and cost effective. Attempts to improve thrombolytic treatment include the search for better fibrinolytic agents and more effective adjunctive therapies. In the field of adjunctive therapy new more specific thrombininhibitors appear promising and are currently under investigation. In dose-finding studies recombinant hirudin reduced reocclusions and reinfarctions after t-PA thrombolysis. There are several approaches for the improvement of plasminogen activation (Table 1). While new improved dose regimens (e.g. "front-loaded" t-PA) and combination therapies are not subject of this article, it will deal with the recombinant production of naturally occurring plasminogen activators and the development of "designer drugs", which were created in the laboratory by altering the natural occurring molecules t-PA and scu-PA. t-PA contains four domains with different functional properties (Figure 3). Of a variety of mutants and variants of t-PA with altered fibrin-affinity half-life or fibrin specificity one recombinant plasminogen activator (r-PA) is under clinical investigation. r-PA, a deletion mutant of t-PA consisting of the kringle-2 and protease domains, in a dose escalation study (GRECO) showed high early patency rates (Table 2), while there was a trend to a higher incidence of very early reocclusions. In a randomised trial (RAPID), comparing three different r-PA regimens with standard t-PA (100 mg/3 h) a double bolus of 10 MU+ 10 MU r-PA was most effective with regard to early patency (Table 3). Chimeric plasminogen activators (Figure 4) consisting of parts of t-PA and the single-chain urokinase-type plasminogen activator (scu-PA) did not significantly improve at the same time fibrin specificity and thrombolytic potency of the natural occurring molecules. Complexes of plasminogen activators and monoclonal antibodies against platelets or fibrin improve the specificity and thrombolytic activity of the plasminogen activators (Figure 5). However, these molecules are potentially antigenic, costly and not in clinical use yet. Recombinant production of naturally occurring plasminogen activators seems at least as promising as the production of the above mentioned socalled designer drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

While percutaneous transluminal valvuloplasty has largely replaced open commissurotomy for congenital pulmonary valve stenosis, the experience with valvuloplasty for congenital aortic stenosis is limited. Between August, 1984 and June, 1987, a total of 27 valvuloplasties were carried out in 25 patients with congenital aortic stenosis; nine infants and 16 patients ranging in age from four to 25 years (mean age 13 +/- 6 years). The indication for valvuloplasty was established on the basis of congestive heart failure or severe stenosis in infants and in the presence of a pressure gradient in excess of 60 mm Hg in those older than one year of age. In eight infants, valvuloplasty reduced the transvalvular pressure gradient from 73 +/- 5 to 36 +/- 9 mm Hg (p less than 0.01; Figure 1). In the 16 patients older than one year of age, the pressure gradient was reduced from 93 +/- 25 to 49 +/- 15 mm Hg (p less than 0.01; Figure 2). The size of the balloon chosen was based on two-dimensional echocardiographic measurements of the aortic ring diameter from inner edge to inner edge. In infants, coronary artery dilating catheters and balloon catheters with an inflated diameter of 4.2 to 8 mm were employed; in children, the balloon diameter selected was 1 to 3 mm less than that of the valve ring diameter, in 15 cases a single-balloon catheter and in one a trefoil catheter. After puncture of the femoral artery and retrograde advancement of a guide-wire into the left ventricle, the balloon catheter was positioned via the guide-wire across the aortic valve.(ABSTRACT TRUNCATED AT 250 WORDS)

With increasing number of noninvasive techniques in clinical cardiology, the question emerges whether it is still justified to continue with cardiac catheterization in the assessment of valvular lesions on a routine basis. Therefore, advantages and disadvantages of invasive and noninvasive procedures are compared with respect to the information they provide in patients with valvular heart disease. Usefulness of invasive criteria in the assessment and quantification of valvular lesions have been analyzed. Limitations of these invasive criteria are derived from a score relating the accuracy obtained to the methodical expense incurred with a given diagnostic parameter. From these analyses and in consideration of findings in the literature, we conclude that cardiac catheterization is not only justified but necessary, particularly in patients prior to valve surgery in order to quantitate the valvular lesion, differentiate between valvular and myocardial dysfunction and screen for associated abnormalities such as concomitant coronary artery disease. Despite the progress in recent years, noninvasive techniques cannot provide this combination of precise information.

Percutaneous balloon valvuloplasty can be considered a therapeutic alternative to surgery for pulmonary valve stenosis. In this analysis, our results will be reported with respect to the various balloon sizes as related to the diameter of the valvular ring as well as differing balloon catheters and the presence of other anomalies in addition to pulmonary valve stenosis. Balloon valvuloplasty was carried out in 23 infants and children ranging in age from one month to eleven years and in two adults at the age of 22 and 50 years, respectively, with a systolic pressure gradient across the pulmonary valve of more than 50 mm Hg or, in the presence of pressure gradients between 40 and 50 mm Hg, in association with a right ventricular pressure of at least 60% of that of the systemic pressure. In all patients echocardiography was carried out prior to the procedure to rule out valve dysplasia and Doppler echocardiographic determination of the pressure gradient was performed before and after dilatation. The diameter of the valvular ring was measured echocardiographically as well as from the right ventriculogram and the size of the balloon chosen accordingly. After diagnostic catheterization, the balloon catheter was advanced to the pulmonary valve with a guidewire. Under fluoroscopy, the balloon was completely inflated then the contrast medium immediately withdrawn, a procedure of seven to 23 seconds with the single-balloon catheter and five to nine seconds with the trefoil catheter. At the first dilatation, the larger portion of the balloon was advanced to the main stem of the pulmonary artery and was placed proximally for subsequent dilatations.(ABSTRACT TRUNCATED AT 250 WORDS)