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Assessment of Myocardial Reperfusion by Intravenous Myocardial Contrast Echocardiography and Coronary Flow Reserve After Primary Percutaneous Transluminal Coronary Angiography in Patients With Acute Myocardial Infarction

Background—This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery. Methods and Results—Twenty-five patients with first AMI underwent intravenous MCE with NC100100 with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the “no-reflow” region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR ≥1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. M...

Relation of Stent Design and Stent Surface Material to Subsequent In-Stent Intimal Hyperplasia in Coronary Arteries Determined by Intravascular Ultrasound

A variety of different stent designs and coatings have become available. This study sought to determine the impact of stent design and gold-coating of stents on intimal hyperplasia (IH) in human atherosclerotic coronary arteries in relation to known predictors of restenosis. Angiographic and intravascular ultrasound (IVUS) studies were performed at 6-month follow-up on 311 native coronary lesions of 311 patients treated with 99 Multi-Link stents, 74 InFlow steel stents, 73 InFlow gold-coated stents, 41 Palmaz-Schatz stents, 12 NIR steel stents, and 12 gold-coated NIR Royal stents. Lumen and stent cross-sectional area (CSA) were measured at 1-mm axial increments. Mean IH CSA (stent CSA - lumen CSA) and mean IH thickness were calculated and averaged over the total stent length. IVUS demonstrated different levels of IH for the 6 stents. Mean IH thickness ranged from 0.20 +/- 0.13 mm for Multi-Link stents to 0.43 +/- 0.14 mm for InFlow goal-coated stents (p <0.001). Multivariate analysis proved non-Multi-Link stent design (odds ratio 3.45, 95% confidence intervals 1.13 to 11.11, p <0.034) and gold coating (odds ratio 3.78, 95% confidence intervals 1.88 to 7.54, p <0.001) to be the only independent predictors of IH thickness >0.3 mm. In conclusion, stent design and surface material have an important impact on the IH response to stents implanted in human coronary arteries. However, the differences in IH thickness between the analyzed stents were relatively small compared with the absolute lumen dimensions.

Characterization of Differential Gene Expression in Quiescent and Invasive Human Arterial Smooth Muscle Cells

Proliferation, migration and invasion of smooth muscle cells (SMCs) are essential pathogenic processes in the development of a broad spectrum of cardiovascular disorders, like arteriosclerosis, restenosis after percutaneous transluminal angioplasty and stent implantation as well as transplant vessel disease. As an in vitro model mimicking these processes, the Boyden chamber was employed to characterize the diverging migratory and invasive potentials of proliferating and nonproliferating human arterial SMCs (haSMCs). Using this model, differential gene expression of both phenotypes was analyzed by a cDNA array system (Clontech human cardiovascular array). With these arrays, 558 cardiovascular-associated genes could be compared. Further, gene expression was exactly quantified by real-time RT-PCR. Protein expression was analyzed by ELISA and Western blotting. In total, 47 genes were differentially expressed more than 1.5 times. Most of the differentially regulated genes in this study were associated with the extracellular matrix (ECM) and cell motility. In detail, the respective groups were matrix-organizing proteins, ECM proteins, cell adhesion proteins, extracellular communication and cytoskeleton motility proteins. Genes known to be differentially regulated during haSMC migration and invasion, like TIMP 2, TIMP 3, and MMP 3, were confirmed by the array data. Reduced expression of several cytoskeletal proteins, like vimentin, fibronectin, cytokeratins and β1 integrin, was shown in the invasive phenotype. Further, angio-associated protein, alpha E-catenin and atrial brain natriuretic peptide receptor were downregulated whereas TFPI 2 was strongly upregulated in invasive haSMCs. In conclusion, several relevant potential candidate genes for the quiescent and the invasive SMC phenotype were identified and genes already known to be differentially regulated by previous analysis were confirmed.

Activation of IP and EP3 receptors alters cAMP-dependent cell migration

Migration of vascular smooth cells from the media to the intima essentially contributes to neointima formation after percutaneous transluminal angioplasty and stent implantation. The stable prostacyclin mimetic iloprost has been shown to inhibit neointima formation in experimental restenosis, but it is currently unknown whether this may be caused by an antimigratory effect. Hence, the present study analyses (i) the influence of G(s)-coupled prostacyclin (IP) receptors on cell migration and (ii) verifies whether EP(3) receptors with opposite (i.e., G(i)) coupling may conversely stimulate cell migration. In a modified Boyden chamber model, it was shown that iloprost dose-dependently inhibits the migration of primary human arterial smooth muscle cells, which constitutively express the IP receptor. On the other hand, human arterial smooth muscle cell migration was stimulated by the EP(3) receptor agonist M&B 28.767. To independently study the effects of these receptors, IP or EP(3) receptors were stably overexpressed in chinese hamster ovary cells (CHO-IP and CHO-EP(3)). Chemotaxis of CHO cells transfected with G(s)-coupled IP receptors was concentration-dependently inhibited by iloprost (2-100 nM), while there was no effect of iloprost on mock-transfected CHO. By contrast, CHO-cells that overexpressed EP(3) receptors showed a significant, concentration dependent (1-100 nM) increase of cell migration in presence of the selective EP(3) agonist M&B 28.767. It is concluded that the prostacyclin mimetic iloprost inhibits vascular cell migration, which probably depends on a G(s)-mediated increase of intracellular cAMP. EP(3) receptors conversely stimulate CHO migration.

Upregulation of the cytoskeletal-associated protein Moesin in the neointima of coronary arteries after balloon angioplasty: a new marker of smooth muscle cell migration?

Migrating cells like coronary smooth muscle cells in restenosis change their cell shape and form cellular protrusions called filopodia. A prerequisite for filopodia formation is the rearrangement of the actin cytoskeleton. An essential role of the 78-kDa protein Moesin is described for Rho- and Rac-dependent assembly of actin filaments. In vivo Moesin is not observed in mature smooth muscle cells. The objective of this study was to demonstrate that Moesin is upregulated in migrating coronary smooth muscle cells during restenosis development. In vivo expression of Moesin was upregulated in neointimal coronary smooth muscle cells of dilated porcine coronary arteries compared to the undilated left circumflex coronary artery of the same swine. Concordant to these results Moesin expression was upregulated in migrating and invading human arterial smooth muscle cells in vitro analyzed by FACS, Western blotting and RT-PCR. In addition, the invasive potential of Moesin-positive Mel Im cells transfected with Moesin sense DNA increased by 28% as compared to mock-transfected control, whereas antisense transfected cells had a decreased invasive potential of 32%. Transfection of Moesin-negative HepG2 with Moesin sense cDNA increased the invasive potential by 43%. Finally, transfection of human arterial smooth muscle cells with Moesin sense cDNA caused an increased invasive potential of 30%. Transfection of haSMCs with antisense cDNA decreased the invasive potential by 37% in comparison to mock-transfected control. These results demonstrate for the first time an upregulation of Moesin expression in coronary smooth muscle cells of the neointima after arterial injury. The increased migrative and invasive potential of cells transfected with Moesin confirmed the functional role of Moesin in cell migration. This indicates an important role of Moesin during restenosis development.

Cardiac stress-rest single-photon emission computed tomography with technetium 99m-labeled tetrofosmin: Influence of washout kinetics on regional myocardial uptake values of the rest study with a 1-day protocol

BackgroundThe purpose of this study was to evaluate (1) the washout kinetics of99mTc-labeled tetrofosmin, separately for myocardium with normal and reduced perfusion, and (2) its influence on quantitative analysis in a 1-day stress-rest protocol.Methods and ResultsTwenty-five patients with angiographically proved coronary artery disease underwent bicycle exercise stress testing with injection of 200 MBq99mTc-labeled tetrofosmin and first single-photon emission computed tomographic (SPECT) imaging 40 minutes after injection. A second SPECT was acquired 2.3±0.4 hours after the first one immediately before rest injection of 800 MBq99mTc-labeled tetrofosmin. The rest (third) SPECT was acquired 15 minutes thereafter. The relative washout fraction per time (WOFt) was calculated assuming linear washout kinetics. Thirty-three regional uptake values per study were calculated, normalized to the perfusion maximum (100%) in either the postexercise SPECT and the rest SPECT, for the latter with and without correction of remaining counts from stress injection. In regions with normal perfusion, WOFt was 11.5%±3.5% per hour. In regions with markedly reduced perfusion (relative uptake <50%, WOFt was 8.3%±9.9% per hour. The highest variation of the relative uptake values between rest SPECT with and without correction of remaining counts from stress injection was 5.4%±3.5% in regions with stress-induced ischemia.ConclusionTo use a 1-day protocol with a stress-rest radioactivity ratio of 1∶4 and an interval of more than 2 hours between the examinations, a correction for remaining counts from stress injection seems not to be necessary for the quantitative analysis of rest SPECT.

Gastric tonometry in patients with cardiogenic shock and intra-aortic balloon counterpulsation.

ObjectiveTo study the course of gastric regional Pco2 (Prco2) in patients with cardiogenic shock requiring intra-aortic balloon (IAB) counterpulsation and the prognostic value of Prco2 in this patient population. DesignA prospective, observational clinical study. SettingMedical intensive care unit in a university hospital. PatientsTwenty-six consecutive patients with cardiogenic shock requiring mechanical support with an IAB counterpulsation undergoing mechanical ventilation InterventionsNone. Measurements and Main ResultHemodynamic variables, tonometric variables, arterial blood gases, and arterial lactate were assessed before insertion of IAB (baseline), and 1, 2, 3, 8, 16, 24, and 48 hrs thereafter. A subset of these patients (n = 14) were studied just before and 1, 8, 24, and 32 hrs after IAB removal; 12/26 patients (46.2%) died. Cardiac index increased from baseline to 1 hr after insertion of IAB (1.7 ± 0.3 to 2.6 ± 0.8 L/min/m2, p < .05). Prco2 did not change between admission (47 ± 13 torr [6.3 ± 1.7 kPa]) and 8 hrs after placement of IAB but increased to 63 ± 22 torr (8.4 ± 2.9 kPa) at 16 hrs (p < .05) without any further alteration until 48 hrs. CO2 gap showed a similar pattern with 15 ± 11 torr (2.0 ± 1.5 kPa) at baseline and an increase to 28 ± 22 torr (3.7 ± 2.9 kPa) 16 hrs later. Prco2 and CO2 gap remained at high levels (59 ± 11 torr [7.7 ± 1.5 kPa] and 22 ± 10 torr [2.9 ± 1.3 kPa], respectively), before IAB removal without further improvement or deterioration thereafter. Prco2values showed no difference between survivors and nonsurvivors at any time point. ConclusionPatients with cardiogenic shock developed high Prco2 within the first 24 hrs, which reflects gastric mucosal ischemia. Persistently high levels of Prco2 were indicative for prolonged hypoperfusion of the gut. Gastric tonometry failed to discriminate between survivors and nonsurvivors.

Untersuchung der Myokardperfusion mit der Positronen-Emissions-Tomographie

Positron emission tomography (PET) of the heart has gained widespread scientific and clinical acceptance with regard to two indications: 1) The detection of perfusion abnormalities by qualitative and semiquantitative analyses of perfusion images at rest and during physical or pharmacological stress using well-validated perfusion tracers, such as N-13 ammonia, Rb-82 rubidium chloride, or O-15 labeled water. ¶2) Viability imaging of myocardial regions with reduced contractility by combining perfusion measurements with substrate metabolism as assessed from F-18 deoxyglucose utilization.¶   This overview summarizes the use of PET as a perfusion imaging method. With a sensitivity >90% in combination with high specificity, PET is today the best-validated available nuclear imaging technique for the diagnosis of coronary artery disease (CAD). The short half-life of the perfusion tracers in combination with highly sophisticated hard- and software enables rapid PET studies with high patient throughput. The high diagnostic accuracy and the methological advantages as compared to conventional scintigraphy allows one to use PET perfusion imaging to detect subtle changes in the perfusion reserve for the detection of CAD in high risk but asymptomatic patients as well as in patients with proven CAD undergoing various treatment forms such as risk factor reduction or coronary revascularization. In patients following orthotopic heart transplantation, evolving transplant vasculopathy can be detected at an early stage. Quantitative PET imaging at rest allows for detection of myocardial viability since cellular survival is based on maintenance of a minimal perfusion and structural changes correlate to the degree of perfusion reduction. Furthermore, quantitative assessment of the myocardial perfusion reserve detects the magnitude and competence of collaterals in regions with occluded epicardial collaterals and, thus, imaging of several coronary distribution territories in one noninvasive study.¶   The cost of PET in combination with the cost of a cyclotron facility together with the demanding methological problems have limited the availability of perfusion PET to a few sophisticated centers. Therefore, quantitative PET investigations of myocardial perfusion have been performed predominantly for scientific purposes, and the cost-effectiveness of PET in the everyday clinical setting is not yet finally proven. However, the unique possibilities of PET to study non-invasively and quantitatively myocardial perfusion and metabolism as well as cardiac innervation and pharmacokinetics of cardiac drugs have established cardiac PET as a scientific tool of the highest quality for the future. Die Positronen-Emissions-Tomographie (PET) hat sich in den letzten Jahren vor allem in zwei Indikationsbereichen einen festen Platz in der Diagnostik und Therapiekontrolle der koronaren Herzkrankheit (KHK) erworben: einerseits im Rahmen der Perfusionsuntersuchungen bei der Diagnostik der KHK und zur Schweregradbeurteilung von Koronarstenosen, andererseits bei der Vitalitätsbeurteilung zur Frage der Reversibilität von ischämisch bedingten Kontraktilitätsstörungen.¶   Perfusionsuntersuchungen sind im klinischen Alltag vor allem als qualitativer und semiquantitativer Vergleich von gesunden und erkrankten Regionen als Untersuchungsprotokolle in Verbindung mit körperlicher oder medikamentöser Belastung üblich. Die Erkennung des Vorliegens einer KHK ist mit einer Sensitivität von >90% bei hoher Spezifität möglich. Bedingt durch die methodischen Vorteile gegenüber der konventionellen Szintigraphie ist die diagnostische Genauigkeit höher einzustufen, was allerdings durch die Kosten relativiert wird. Semiquantitative und v.a. quantitative Untersuchungen sind in der Lage, bereits relativ geringe Einschränkungen der myokardialen Perfusionsreserve zu diagnostizieren und somit für die nichtinvasive Diagnostik im Rahmen der Primär- und Sekundärprophylaxe sowie der Verlaufskontrolle bei manifester KHK und zur Erfolgsbeurteilung bei revaskularisierenden Maßnahmen hervorragend geeignet. Insbesondere ein Monitoring von asymptomatischen Risiko-Patienten für eine KHK (Diabetiker, familiäre Hypercholesterinämie, Raucher etc.) aber auch die Früherkennung einer Transplantatvakulopathie sind mit der PET hervorragend nicht-invasiv möglich. Quantitative Perfusionsmessungen haben zunehmende Bedeutung auch im Rahmen der Vitalitätsdiagnostik bekommen. Dennoch sind, v.a. aus logistischen und Kostengründen, quantitative Perfusionsuntersuchungen überwiegend wissenschaftlichen Fragestellungen vorbehalten. Quantitative Untersuchungen mit regionalen Messungen der Perfusion sowie des Myokardstoffwechsels ermöglichen aber ebenso wie die Untersuchungen zur kardialen Innervation und zur Pharmakotherapie des Herzens einzigartige nichtinvasive Einblicke in die Physiologie und Pathophysiologie bei verschiedenen Erkrankungen des Herzens.

THE HETEROGENEOUS AND DELAYED COURSE OF BLOOD PRESSURE NORMALIZATION IN HYPERTENSIVE PATIENTS AFTER BILATERAL NEPHRECTOMY WITH AND WITHOUT SUBSEQUENT RENAL TRANSPLANTATION

CONDENSED ABSTRACT Controversy exists about the time course of blood pressure normalization in hypertensive patients after bilateral nephrectomy. The course of blood pressure was retrospectively assessed in 14 hypertensive patients. Bilateral nephrectomy resulted in a decrease of blood pressure within 6 months following surgery. Combined antihypertensive medication was necessary in most patients with renovascular hypertension even after bilateral nephrectomy. Subsequent renal transplantation following bilateral nephrectomy caused de novo increase in blood pressure in formerly hypertensive patients. Background. Controversy exists about the time course of blood pressure normalization following bilateral nephrectomy. We sought to evaluate the time course of blood pressure normalization following bilateral nephrectomy and after subsequent kidney transplantation. Methods and Results. Clinical data from 14 hypertensive patients were retrospectively assessed. Baseline blood pressure was 175 ± 33/109 ± 9 mmHg. Ten patients firstly underwent unilateral nephrectomy, which resulted in a slight increase of blood pressure (185 ± 22/110 ± 5 mmHg). One month following bilateral nephrectomy, blood pressure was 167 ± 23/104 ± 17 mmHg, at 3 months 159 ± 42/104 ± 25 mmHg, and at 6 months 149 ± 41/96 ± 30 mmHg. Antihypertensive medication was necessary in 9/14 patients at a 2 year follow-up. Eight patients remained anephric (group I), 6 patients had subsequent kidney transplantation (group II). In group I, blood pressure was 159 ± 42/93 ± 17 mmHg and 129 ± 34/75 ± 14 mmHg at 3 and 6 months, respectively (p < 0.05 vs. baseline). In group II, blood pressure decreased from 188 ± 42/128 ± 46 mmHg to 167 ± 48/113 ± 32 mmHg at 3 months, but increased after tansplantation to 186 ± 39/118 ± 33 mmHg. Antihypertensive medication was still necessary in 5 transplanted patients (83%) and in 3 anephric patients (38%). Conclusion. Adaptation of the blood pressure response following bilateral nephrectomy is a time requiring process, and long-term antihypertensive medication may still be necessary.

The IST Registry

Die intrakoronare Brachytherapie hat sich in Europa und in den USA als evidenzbasierte Behandlungsmethode der In-stent-Restenose etabliert. Ziel des IST-Registers ist es, möglichst vollständig alle in Deutschland intrakoronar bestrahlten Patienten zu erfassen und ihren klinischen Verlauf über fünf Jahre zu beobachten. Um die Mitarbeit zu erleichtern, ist der zu erhebende Datensatz knapp gehalten. Sämtliche Daten werde online eingegeben. Jedes teilnehmende Zentrum kann die wichtigsten Paramenter jederzeit im Vergleich zur Gesamtheit aller Zentren über das Internet abrufen. Derzeit wird das Novoste™-System in 58 Katheterlabors und das Guidant™-System in 16 Labors angewendet, einige Zentren benutzen beide Systeme. Da in Deutschland die Anforderungen an den Strahlenschutz für die intrakoronare Anwendung von Gammastrahlen sehr streng sind, wird das Cordis™-Gamma-System in Deutschland lediglich in einem Labor verwendet. In einer ersten Analyse von 332 bestrahlten Stenosen war zu beobachten, dass es selbst nach sechsmonatiger Einnahme von Clopidogrel (zusätzlich zu ASS) zu späten Gefäßverschlüssen kommen kann – ohne dass neue Stents im Rahmen der Brachytherapie implantiert wurden. Somit sollte Clopidogrel für mindestens ein Jahr zusätzlich zu ASS eingenommen werden. Bei derzeit ca. 270 intrakoronar bestrahlten Patienten pro Monat in Deutschland wird das IST-Register wichtige Daten zur Langzeitbeobachtung liefern und eine Grundlage für zukünftige Verhandlungen mit den Kostenträgern sein. Derzeit werden weder die ärztliche Leistung noch die Materialkosten für die intrakoronare Brachytherapie separat bzw. adäquat erstattet. Ferner kann das IST-Register als vergleichende Datenbank für den Langzeitverlauf nach Implantation von antiproliferativ beschichteten Stents herangezogen werden. Intracoronary brachytherapy has been established in Europe and the US as an evidence-based treatment of in-stent restenoses. The objective of the IST Registry is to register all patients treated in Germany with intracoronary radiation and to observe the clinical outcome for a duration of 5 years. The required set of data for each patient is kept to a minimum to encourage participation. All data are entered online. In the internet, each participating site can, at any time, check their most important parameters and compare them with those of other sites. Presently, the Novoste™ System is used in 58 catheter labs and the Guidant™ System in 16, while several sites use both. The requirements regarding radiation safety in intracoronary application of gamma radiation are very strict in Germany, so the Cordis™-Gamma System is used in only one German lab. In a first analysis of 332 radiated stenoses, it was observed that late vessel occlusion could occur even after 6-month administration of clopidogrel (in addition to ASA) – without new stents being implanted within the brachytherapy session. Clopidogrel should thus be administered in addition to aspirin for at least a year. Ca. 270 patients per month receive intracoronary radiation in Germany, so the IST Registry will provide important data regarding long-term observation and a foundation for future negotiations with insurance companies potentially bearing the costs. At present, neither the physicians service nor the material costs are reimbursed. The IST Registry can furthermore be used as a comparative database regarding long-term outcome following implantation of antiproliferative-coated stents.