Achim Allroggen

Molecular Imaging with Targeted Contrast Ultrasound

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation.

Influence of inflammation and pump dynamic on cerebral microembolization in patients with Continuous-Flow DeBakey LVAD.

Microembolic signals (MES) have shown to be associated with increased risk of ischemic stroke in patients with pulsatile left ventricular assist devices (LVADs) in contrast to continuous-flow DeBakey LVAD. The pathogenesis of microembolization in LVAD-patients is still not known. We investigated whether systemic markers of inflammation or pump dynamic correlate with cerebral microembolization in nine patients with DeBakey LVAD. We performed transcranial Doppler (TCD) for MES-detection and evaluated parameters of inflammation (i.e. Leukocytes, CRP, Fibrinogen) and pump dynamic (i.e. power, speed, flow). During a mean LVAD duration of 203.7 ± 179 days, thromboembolic events occurred in five patients with an incidence of 0.38% (approximately 0.38 events/100 LVAD-days). We performed 290 TCD monitorings with a MES mean count of 50.4 ± 346 signals/hour (0–5042) and prevalence of 42.8%. There was no association between individual microembolic activity and the markers of inflammation or pump dynamic. In patients with DeBakey LVAD, a high load of clinically silent cerebral microemboli can be detected. However, there is no correlation between markers of inflammation or pump dynamic and the individual amount of microembolization. We hypothesize that a gaseous nature of the majority of detected microemboli in the DeBakey LVAD may be the underlying reason for this discrepancy.

Detektion zirkulierender cerebraler Mikroemboli mittels transkranieller Dopplersonographie

Patienten, z.B. für eine Therapie mit Antikoagulanzien, lassen sich hieraus nicht ableiten. Ein neuer möglicher Ansatz für eine individuell abgestimmte Behandlung besteht in der Detektion zirkulierender Mikroemboli mittels transkranieller Dopplersonographie. Mit dieser Technik lassen sich kleinste gasförmige oder solide Partikel im Blutstrom detektieren, die aufgrund der geringen Größe selbst nicht zu einem klinisch fassbaren thromboembolischen Ereignis führen. Ihr Auftreten korreliert aber nach den Ergebnissen zahlreicher Studien eng mit einem klinisch relevanten Embolierisiko. Zur Untersuchung wird ein Schallkopf am Kopf des Patienten befestigt, der dopplersonographisch Flusssignale der Arteria cerebri media erfasst. Diese werden akustisch und optisch auf zirkulierende Mikroemboli ausgewertet. In der Neurologie wird diese Methode bereits für eine individuelle Risikostratifizierung von Patienten eines Hochrisikokollektivs eingesetzt, z.B. bei der Indikationsstellung zu einer Antikoagulanzientherapie oder Karotisendatherektomie. In der Kardiologie wird die Mikroembolus-Detektion bisher nicht routinemäßig eingesetzt und wurde nur in geringem Maß durch klinische Studien evaluiert. In diesem Überblick sollen die grundlegenden Prinzipien, die methodisch-technischen Voraussetzungen sowie Möglichkeiten und Grenzen der Mikroembolus-Detektion dargestellt werden. Weiterhin werden die wesentlichen Studienergebnisse zum Einsatz dieser Technik bei kardiologischen Erkrankungen und kardiovaskulären Interventionen zusammengefasst.

Can Doppler time domain analysis of microembolic signals discriminate between gaseous and solid microemboli in patients with left ventricular assist device

Abstract Objective: Microembolic signals (MES) can be detected by transcranial Doppler sonography (TCD). To identify gaseous microemboli the inhalation of oxygen is an established method in patients with prosthetic heart valves. Time domain analysis of sample volume length (SVL) and of frequency modulation showed promising results in the discrimination between solid and gaseous microemboli. We investigated whether these time domain analyses allow the discrimination of different types of microemboli in patients with the non-pulsatile DeBakey left ventricular assist device (LVAD). Materials and methods: Repeated unilateral detection of MES was performed by TCD in 20 patients supported with DeBakey LVAD. Each monitoring session consisted of 20 minutes without and 20 minutes with inhalation of 100% oxygen (6 l/min). A total of 500 MES, detected with (n=250) or without (n=250) the supply of oxygen, were randomly chosen for offline analysis. The SVL (in cm) was calculated by duration and velocity of the MES measured in the time domain mode. Additionally, frequency modulation of MES was classified into three main types: Without modulation (type I), with gradual changes (type II) and with rapid changes (type III). Results: With oxygen supply, both prevalence (26.4% versus 36.2%, p<0.01) and mean counts of MES per hour (49±293 versus 108±550, p<0.001) significantly declined compared with the MES load while breathing room air. There was no significant difference in the SVL of MES under oxygen (0.85±0.38 cm) compared with those without oxygen delivery (0.92±0.37 cm, p=0.6). Furthermore, no significant differences were noted for the MES frequency modulation types in time domain analysis with regard to oxygen supply. Conclusions: The reduction of MES under oxygen delivery confirms the gaseous nature in a substantial number of circulating microemboli produced by the DeBakey LVAD. However, SVL and frequency modulation of MES did not appear to provide valuable information regarding the structural nature of the underlying microembolic material.

Absence of circulating microemboli in patients with atrial fibrillation undergoing electric cardioversion.

Electrical cardioversion (CV) of atrial fibrillation (AF) is associated with an increased risk of stroke, and its appropriate prevention is still a matter of debate. It is known that, besides dislodgement of pre-existing intra-atrial thrombi, the ‘stunned’ atrium after CV is an important cause of thrombus formation and subsequent embolism. We investigated whether CV of AF is associated with occurrence of circulating microemboli (ME) representing a sensitive marker of the actual thromboembolic activity. Twenty-nine patients (22 men) aged 54 ± 13 years suffering from valvular (n = 5) or nonvalvular (n = 24) AF were studied. All but 1 patient (with recent-onset AF) had been put on oral anticoagulation (INR >2.0) for at least 3 weeks before and 4 weeks after successful CV. In all patients, exclusion of internal carotid artery stenosis and atrial thrombus was performed prior to CV. Five unilateral 1-hour transcranial Doppler ME monitorings over the middle cerebral artery were performed (1) before CV, and (2) immediately, (3) 4–6 h, (4) 24 h, and (5) 2–4 weeks after CV. Total absence of circulating ME was found before CV as well as during a cumulative monitoring time of 115 h after successful CV. Electrical CV of AF after at least 3 weeks of effective anticoagulation is not associated with occurrence of cerebral circulating ME. This finding requires further investigation including high-risk patients with AF undergoing CV based on different treatment protocols.

Homozygosity for Factor V Leiden mutation and ischemic stroke: two case-reports and review of the literature

Sirs: The factor V Leiden (FVL) mutation is a frequent and accepted risk factor for venous thromboembolism (VE), which occurs at a significantly younger age in homozygous FVL women [12]. Its contribution to arterial ischemic disease (AID) is controversially discussed [4, 14]. While most reports deal with the heterozygous status, only limited data are availale on homozygous FVL patients and AID. We report homozygous FVL-mutation in the patients suffering from ischemic stroke (IS) and provide a survey of so far published cases. A 23-year old man noticed difficulties finding appropriate words and organizing sentences correctly. Neurological examination revealed mild dysphasia and ideomotoric apraxia. Cranial computed tomography (CT) disclosed early infarction signs in the left middle cerebral artery (MCA) territory. Secondly, a 33-year old woman was admitted with reduced consciousness, severe aphasia and rightsided hemiparesis. The initial CT showed two small lacunar infarctions, whereas follow-up imaging revealed extended infarctions in all left-sided cerebral territories with multifocal segmental stenosis on intraarterial digital subtraction angiography. Together with antinuclear antibodies, elevated cell counts and positive oligoclonal bands on lumbar puncture, primary angiitis of the central nervous system was diagnosed. Both patients had negative medical and family histories. Cerebrovascular risk factors including smoking, alcohol consumption, laboratory screening for diabetes, hypercholesterinemia, hyperhomocysteinemia and antiphoshpolipid antibodies were negative. Cardiovascular investigations including 24-hour electrocardiogram monitoring and transesophageal echocardiography with testing for right-to-left shunt was unremarkable. The homozygous FVL mutation was found in both patients. The man was additionally positive for the 4G/4G polymorphism of the plasmin activator inhibitor type 1 genotype (PAI-1) [8], whereas the woman was heterozygous for the prothrombin G 20210A mutation [14]. Screening for C677T mutation in the gene for 5.10-methyl-enetetrahydrofolate reductase (5.10MTHFR) as well as levels of antithrombin, protein C and protein S levels were normal. A Medline search from 1994 to 2004 using the keywords homozygosity, FVL mutation, MI and IS revealed only 17 FVL homozygotes who either suffered from IS (n = 9), MI (n = 7), or other arterial thrombosis (n = 1) (Table 1). The prospective Procare Study including 85 homozygous FVL carriers showed only one patient with AID (1.7 %), whereas 83.3 % suffered from VE [12]. Thus, despite an estimated prevalence of 0.09 % to 5 % in the Caucasian population [1], the small numbers of homozygous FVL patients being symptomatic with AID suggest a more coincidental than causal association. Furthermore, the relatively advanced age (mean 33 ± 5.36 years, Table 1) at disease onset argues against a severe thrombophilia as it is found in patients with protein C, protein S, or AT III deficiency, who experience severe thrombotic disease at a much younger age [13]. Moreover, the frequent coexistence of FVL homozygosity with other prothrombotic factors, which amounts to 42 % in the symptomatic patients reported so far (Table 1) is striking and affects our patients as well. The true coexistence with other conditions could be even higher, as four studies did not exclude them explicitly. Consequently, as in our angiitis patient, other etiologies than FVL homozygosity can more likely be the cause for IS. The increase in prothrombotic risk due to the accompanying conditions (prothrombin and 5.10-MTHFR mutation, polymorphism of the PAI-1 gene and antiphospholipid antibody syndrome) is difficult to assess as they, depending on the metaanalysis performed, turned out to be only weak or non significant risk factors for AID [8, 9, 14]. For all these reasons, the isolated homozygous FVL mutation does not seem to be associated with a significant risk increment for AID. The current literature indicates that most homozygous FVL carriers remain asymptomatic for AID as long as additional trigger mechanisms are absent. Further prospective studies addressing this question are desirable.