Mathias Grebe

Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study.

BackgroundSeveral case reports have linked iron deficiency anemia with the occurrence of cerebral venous thrombosis (CVT) or stroke, yet, it is unclear whether this is a chance association.MethodsIn a case-control design data of whole blood count and screening for thrombophilic coagulation abnormalities of 121 prospectively identified patients with CVT and 120 healthy controls were compared. Anemia was defined as a hemoglobin (Hb) concentration of <120 g/l in females, and <130 g/l in males, severe anemia as a Hb <90 g/l. Adjusted odds ratios (OR) were calculated based on a logistic regression model treating variables with a level of significance of p ≤0.2 on univariate analysis as potential confounders.ResultsThrombophilia (OR 1.22, 95% CI 1.07-1.76, p < 0.01), severe anemia (OR 1.10, 95% CI 1.01-2.22, p < 0.05), and hypercholesterinemia (OR 1.21, 95% CI 1.04-2.57, p < 0.05) were the only independent variables associated with CVT on multivariate analysis.ConclusionSevere anemia is significantly and independently associated with CVT.

Insulin Stabilizes Microvascular Endothelial Barrier Function via Phosphatidylinositol 3-Kinase/Akt-Mediated Rac1 Activation

Objective—Insulin is a key regulator of metabolism, but it also confers protective effects on the cardiovascular system. Here, we analyze the mechanism by which insulin stabilizes endothelial barrier function. Methods and Results—Insulin reduced basal and antagonized tumor necrosis factor-&agr;-induced macromolecule permeability of rat coronary microvascular endothelial monolayers. It also abolished reperfusion-induced vascular leakage in isolated-perfused rat hearts. Insulin induced dephosphorylation of the regulatory myosin light chains, as well as translocation of actin and vascular endothelial (VE)-cadherin to cell borders, indicating a reduction in contractile activation and stabilization of cell adhesion structures. These protective effects were blocked by genistein or Hydroxy-2-naphthalenylmethylphosphonic acid tris acetoxymethyl ester (HNMPA-[AM]3), a pan-tyrosine-kinase or specific insulin-receptor-kinase inhibitor, respectively. Insulin stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and NO production, and it activated Rac1. Inhibition of PI3K/Akt abrogated Rac1 activation and insulin-induced barrier protection, whereas inhibition of the endothelial nitric oxide synthase/soluble guanylyl cyclase pathway partially inhibited them. Inhibition of Rac1 abrogated the assembly of actin at cell borders. Accordingly, it abolished the protective effect of insulin on barrier function of the cultured endothelial monolayer, as well as the intact coronary system of ischemic-reperfused hearts. Conclusion—Insulin stabilizes endothelial barrier via inactivation of the endothelial contractile machinery and enhancement of cell-cell adhesions. These effects are mediated via PI3K/Akt- and NO/cGMP-induced Rac1 activation.

High Frequency of Silent Pulmonary Embolism in Patients With Cryptogenic Stroke and Patent Foramen Ovale

Background and Purpose— Deep vein thrombosis and pulmonary embolism (PE) prove venous embolic activity and enforce the suspicion of paradoxical embolism in patients with stroke with patent foramen ovale. Because it has implications in secondary prevention, we investigated the frequency of silent PE in such a cohort of patients. Methods— Patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale who underwent a ventilation perfusion scintigraphy were identified from a stroke registry. Blinded from clinical data, ventilation perfusion scintigraphy scans were re-evaluated independently by 2 experts. Patients showing at least a subsegmental defect were considered as having silent PE. Factors potentially associated with PE were analyzed. Results— The evaluation included 151 patients. Median age was 55.2 years and 59.9% were male. In 56 (37%) patients, silent PE was found; a deep vein thrombosis was evident in 11 (7%) patients. Atrial septal aneurysm was identified in 39 patients and hypermobile atrial septum in 37 patients. Atrial septal aneurysm and hypermobile atrial septum were independently associated with PE. In females, intake of oral contraceptives showed certain association with PE (6 of 25 versus 3 of 40; P=0.07). Conclusions— Silent PE frequently occurs in patients with cryptogenic stroke and patent foramen ovale, particularly when atrial septal aneurysm or hypermobile atrial septum are present.

[Obstructive sleep apnea-related cardiovascular disease].

ZusammenfassungDie vaskulären Folgeerkrankungen der obstruktiven Schlafapnoe (OSA) umfassen die systemarterielle Hypertonie (Prävalenz: 40–60%), die pulmonalarterielle Hypertonie (20–30%), die koronare Herzerkrankung (20–30%), die Linksherzinsuffizienz (5–10%) sowie Schlaganfälle (5–10%). Während der Nacht können durch die OSA verschiedene Herzrhythmusstörungen induziert werden (u. a. Vorhofflimmern und Sinusarreste/AV-Blöcke). Diese Erkrankungen betreffen in erster Linie Patienten mit höhergradiger OSA (Apnoe-Hypopnoe-Index > 30/h) und führen zu einer erhöhten Mortalität im Vergleich zu Patienten ohne schlafbezogene Atmungsstörungen. Epidemiologische Studien belegen, dass das Risiko kardio- und zerebrovaskulärer Erkrankungen bei der OSA unabhängig von „confounding factors“ wie Adipositas und metabolischen Erkrankungen erhöht ist. Die Pathophysiologie der OSA-assoziierten kardiovaskulären Erkrankungen konnte in den letzten Jahren zunehmend aufgeklärt werden, wobei neben der seit längerem bekannten Sympathikusaktivierung Hinweise für einen erhöhten oxidativen Stress und proinflammatorische Veränderungen gefunden wurden. Des Weiteren konnte durch hochauflösende Ultraschallverfahren der Nachweis einer endothelialen Dysfunktion und einer akzelerierten Atherosklerose bei diesen Patienten erbracht werden. Ergänzt werden diese Befunde durch Tiermodelle der OSA, die bisher vor allem die Entwicklung einer systemarteriellen Hypertonie im Rahmen der OSA-assoziierten chronischen intermittierenden Hypoxie gezeigt haben. Die Behandlung der OSA mittels „continuous positive airway pressure„-(CPAP-)Therapie wirkt kardioprotektiv. So sind u. a. günstige Effekte auf kardiovaskuläre Biomarker, die Vasoreaktivität, den 24-h-Blutdruck, die nächtlichen Herzrhythmusstörungen und die linksventrikuläre Funktion beschrieben. Auch kardiovaskuläre Endpunkte wie die Rate an Myokardinfarkten und Schlaganfällen werden positiv beeinflusst.AbstractThe clinical spectrum of obstructive sleep apnea-(OSA-)related cardiovascular disease (CVD) comprises systemic arterial hypertension (prevalence: 40–60%), pulmonary hypertension (20–30%), coronary artery disease (20–30%), congestive heart failure (5–10%), and stroke (5–10%). During sleep, heart rhythm disorders such as atrioventricular blocks, sinus arrests and atrial fibrillation can be induced by OSA. OSA-related CVD mainly affects those patients with an apnea-hypopnea index > 30/h and, if left untreated, is linked to increased mortality. Epidemiologic data have clearly shown that cardiovascular risk is increased in OSA independent of confounding factors such as obesity and concomitant metabolic disease. In recent years, the pathophysiology of OSA-related CVD has been further elucidated showing that apart from the well-known sympathetic activation, increased oxidative stress and pro-inflammatory changes seem to play major roles. Furthermore, studies using highresolution ultrasonography have demonstrated endothelial dysfunction and enhanced atherosclerosis in these patients. Finally, animal models of OSA have delineated that daytime arterial hypertension is the consequence of the OSA-associated chronic intermittent hypoxia. Therapy of OSA by continuous positive airway pressure (CPAP) ventilation exerts cardioprotective effects. It has been shown to rectify the vascular micromilieu, restore endothelium-dependent vasodilation, lower 24-h blood pressure, eliminate nocturnal heart rhythm disorders, and improve left ventricular function. Furthermore, long-term CPAP therapy leads to a reduction in important clinical endpoints such as the rates of myocardial infarction and stroke.

Use of gadobutrol in coronary angiography

Gadobutrol was used in coronary angiography in three patients. All three patients had a substantially increased risk of developing renal complications with iodinated contrast agents. Gadobutrol was well tolerated in all three patients without any complications. The quality of the coronary angiograms was good. Catheter Cardiovasc Interv 2004;63:319–322.

Severity of Coronary Artery Disease but Not Degree of Coronary Stenosis Is Correlated to Cerebrovascular Reactivity

Background: A decade difference in peak incidences of coronary and cerebral ischemia assumes a protection of the brain vasculature. Therefore, we hypothesize that early indicators of cerebrovascular disease such as parameters of the neurovascular coupling show a higher correlation to coronary artery disease than morphologic parameters. Methods: Stenotic degree (%) of coronary arteries (RCA, LCA, LAD, RCX) was determined together with the Gensini score by angiography in 96 patients (80 men; 62 ± 10 years), which were grouped according to disease severity (sclerosis, 1-vessel disease (VD), 2-VD, 3-VD). Presence of internal carotid artery stenosis and left ventricular ejection fraction (LVEF) were established with duplex sonography. Resting and visually evoked hemodynamic responses were measured with transcranial Doppler ultrasound in both posterior cerebral arteries and expressed in terms of control system parameters. These were gain, natural frequency, attenuation, and rate time. Group differences and correlations between stenosis and parameters of vasoreactivity were tested. Results: Groups differed in stenotic degree of coronary arteries, Gensini score, LVEF, carotid artery stenosis, resting flow velocity, and evoked responses (gain, p < 0.005; attenuation, p < 0.05). Stenosis of each coronary artery and LVEF were correlated to carotid artery stenosis but no association was found to cerebrovascular parameters. Only severity of coronary artery disease and the Gensini score were associated with disturbed cerebrovascular reactivity. Carotid artery stenosis was associated with decreased cerebrovascular parameters (attenuation, p < 0.05; rate time, p < 0.01). Conclusions: Although atherosclerosis is a systemic disease our data support concepts of a heterogeneous distribution of the disease indicating protection of brain vessels.

Decrease in shunt volume in patients with cryptogenic stroke and patent foramen ovale

BackgroundIn patients with patent foramen ovale (PFO) there is evidence supporting the hypothesis of a change in right-to-left shunt (RLS) over time. Proven, this could have implications for the care of patients with PFO and a history of stroke. The following study addressed this hypothesis in a cohort of patients with stroke and PFO.MethodsThe RLS volume assessed during hospitalisation for stroke (index event/T0) was compared with the RLS volume on follow-up (T1) (median time between T0 and T1 was 10 months). In 102 patients with a history of stroke and PFO the RLS volume was re-assessed on follow-up using contrast-enhanced transcranial Doppler/duplex (ce-TCD) ultrasound. A change in RLS volume was defined as a difference of ≥20 microembolic signals (MES) or no evidence of RLS during ce-TCD ultrasound on follow-up.ResultsThere was evidence of a marked reduction in RLS volume in 31/102 patients; in 14/31 patients a PFO was no longer detectable. An index event classified as cryptogenic stroke (P < 0.001; OD = 39.2, 95% confidence interval 6.0 to 258.2) and the time interval to the follow-up visit (P = 0.03) were independently associated with a change in RLS volume over time.ConclusionsRLS volume across a PFO decreases over time, especially in patients with cryptogenic stroke. These may determine the development of new strategies for the management in the secondary stroke prevention.

Combined computed tomographic (CT)-angiography and indirect CT-venography for the diagnosis of pulmonary embolism: is more scanning better?

Combined computed tomographic (CT)-angiography and indirect CT-venography for the diagnosis of pulmonary embolism: Is more scanning better? -

Risk Factors for Pulmonary Embolism in Patients with Stroke and Patent Foramen Ovale

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Vaskuläre Folgeerkrankungen bei obstruktiver Schlafapnoe

ZusammenfassungDie vaskulären Folgeerkrankungen der obstruktiven Schlafapnoe (OSA) umfassen die systemarterielle Hypertonie (Prävalenz: 40–60%), die pulmonalarterielle Hypertonie (20–30%), die koronare Herzerkrankung (20–30%), die Linksherzinsuffizienz (5–10%) sowie Schlaganfälle (5–10%). Während der Nacht können durch die OSA verschiedene Herzrhythmusstörungen induziert werden (u. a. Vorhofflimmern und Sinusarreste/AV-Blöcke). Diese Erkrankungen betreffen in erster Linie Patienten mit höhergradiger OSA (Apnoe-Hypopnoe-Index > 30/h) und führen zu einer erhöhten Mortalität im Vergleich zu Patienten ohne schlafbezogene Atmungsstörungen. Epidemiologische Studien belegen, dass das Risiko kardio- und zerebrovaskulärer Erkrankungen bei der OSA unabhängig von „confounding factors“ wie Adipositas und metabolischen Erkrankungen erhöht ist. Die Pathophysiologie der OSA-assoziierten kardiovaskulären Erkrankungen konnte in den letzten Jahren zunehmend aufgeklärt werden, wobei neben der seit längerem bekannten Sympathikusaktivierung Hinweise für einen erhöhten oxidativen Stress und proinflammatorische Veränderungen gefunden wurden. Des Weiteren konnte durch hochauflösende Ultraschallverfahren der Nachweis einer endothelialen Dysfunktion und einer akzelerierten Atherosklerose bei diesen Patienten erbracht werden. Ergänzt werden diese Befunde durch Tiermodelle der OSA, die bisher vor allem die Entwicklung einer systemarteriellen Hypertonie im Rahmen der OSA-assoziierten chronischen intermittierenden Hypoxie gezeigt haben. Die Behandlung der OSA mittels „continuous positive airway pressure„-(CPAP-)Therapie wirkt kardioprotektiv. So sind u. a. günstige Effekte auf kardiovaskuläre Biomarker, die Vasoreaktivität, den 24-h-Blutdruck, die nächtlichen Herzrhythmusstörungen und die linksventrikuläre Funktion beschrieben. Auch kardiovaskuläre Endpunkte wie die Rate an Myokardinfarkten und Schlaganfällen werden positiv beeinflusst.AbstractThe clinical spectrum of obstructive sleep apnea-(OSA-)related cardiovascular disease (CVD) comprises systemic arterial hypertension (prevalence: 40–60%), pulmonary hypertension (20–30%), coronary artery disease (20–30%), congestive heart failure (5–10%), and stroke (5–10%). During sleep, heart rhythm disorders such as atrioventricular blocks, sinus arrests and atrial fibrillation can be induced by OSA. OSA-related CVD mainly affects those patients with an apnea-hypopnea index > 30/h and, if left untreated, is linked to increased mortality. Epidemiologic data have clearly shown that cardiovascular risk is increased in OSA independent of confounding factors such as obesity and concomitant metabolic disease. In recent years, the pathophysiology of OSA-related CVD has been further elucidated showing that apart from the well-known sympathetic activation, increased oxidative stress and pro-inflammatory changes seem to play major roles. Furthermore, studies using highresolution ultrasonography have demonstrated endothelial dysfunction and enhanced atherosclerosis in these patients. Finally, animal models of OSA have delineated that daytime arterial hypertension is the consequence of the OSA-associated chronic intermittent hypoxia. Therapy of OSA by continuous positive airway pressure (CPAP) ventilation exerts cardioprotective effects. It has been shown to rectify the vascular micromilieu, restore endothelium-dependent vasodilation, lower 24-h blood pressure, eliminate nocturnal heart rhythm disorders, and improve left ventricular function. Furthermore, long-term CPAP therapy leads to a reduction in important clinical endpoints such as the rates of myocardial infarction and stroke.