Samir M. Said

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUND The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

Influence of Enzyme-Inducing Antiepileptic Drugs on Trough Level of Imatinib in Glioblastoma Patients

Background: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine - as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine - are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). Methods: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). Results: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%) , 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). Conclusion: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.

Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia : Diagnosis and treatment

SummaryThrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte aggregation. The inhibition of thrombocyte activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI).Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without thrombocytopenia.Advanced age (> 65 years), low BMI and a low initial thrombocyte count (<180 000/µl) are independent risk factors of thrombocytopenia. The risk of bleeding is higher with this form of thrombocytopenia not only due to the low thrombocyte count but also to the impaired function of the remaining thrombocytes.It is important to closely monitor platelet count during GP IIb/IIIa antagonist treatment. Platelet count monitoring two, six, twelve and 24 hour after starting the treatment reveals most cases of acute thrombocytopenia. Side effects can be avoided by the early discontinuation of the GP IIb/IIIa antagonist treatment.This article reviews the diagnosis and treatment of glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia and summarizes the differential diagnosis from heparin-induced thrombocytopenia and laboratory-related pseudothrombocytopenia.

Efficacy and safety profile of dronedarone in clinical practice. Results of the Magdeburg Dronedarone Registry (MADRE study)

BACKGROUND Dronedarone is a new antiarrhythmic agent that has only recently been approved for the therapy of atrial fibrillation (AF). Results regarding a broader spectrum of patients and experience accumulated in clinical practice are still very scarce. Therefore, we prospectively investigated the efficacy and tolerance of dronedarone in a real life setting. METHODS AND RESULTS The study included 191 patients (85 women) aged 63 ± 9.9 years with a history of paroxysmal or persistent AF. Follow-up time was 14.3 ± 4.9 months. In patients with persistent AF, sinus rhythm was restored using electrical cardioversion prior to dronedarone administration. Each patient underwent standard ECG on a daily basis during the first 4 days of treatment, and on days 7, 30 and 90, resp. After that, the patients had a follow-up visit every three months. Creatinine, creatine kinase, and hepatic enzymes were closely monitored. Clinical history was meticulously taken at multiple follow-up visits. Dronedarone maintained sinus rhythm in 33.5% (95% CI: 27%-40%), and AF recurrence rate was high: 66.5% (95% CI: 60%-73%). Adverse effects occurred in 31.9% (95% CI: 27%-38%) of the patients and necessitated permanent discontinuation of dronedarone in 22% (95% CI: 17%-27%). CONCLUSIONS The results suggest that dronedarone may not be superior to available antiarrhythmic agents and caution against its use as a first line therapy in AF.

Ultrasound guided thrombin injection of pseudoaneurysm of the radial artery after percutaneous coronary intervention.

Thrombin injection is frequently used to occlude iatrogenic pseudoaneurysms in larger vessels, but has never successfully been used in the radial artery location. Here we report the use of this treatment in a patient with radial artery pseudoaneurysm following coronary intervention. After Doppler sonographic visualization of the pseudoaneurysm cavity and its neck, an ultrasound-guided transcutaneous injection of thrombin was carried out. Immediately after the injection, the pseudoaneurysm was completely clotted and Doppler measurement confirmed the stop of blood flow. The result suggests that ultrasound-guided injection of thrombin into a radial artery pseudoaneurysm following coronary intervention is a feasible alternative to surgical intervention.

Efficacy and safety profile of dronedarone in clinical practice. Preliminary results of the Magdeburg Dronedarone Registry

threshold by gas exchange. J Appl Physiol 1986;60(6):2020–7. [12] Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis 1984;129(2 Pt 2):S49–55. [13] Ingle L, Witte KK, Cleland JG, Clark AL. The prognostic value of cardiopulmonary exercise testing with a peak respiratory exchange ratio of b1.0 in patients with chronic heart failure. Int J Cardiol 2008;127(1):88–92. [14] Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894:i–xii 1–253. [15] Witte KKA, NikitinNP, Cleland JGF, Clark AL. Excessive breathlessness inpatientswith diastolic heart failure. Heart 2006;92(10):1425–9.

Das Takotsubo-Syndrom von der Erstbeschreibung bis heute

ZusammenfassungDie stressinduzierte Kardiomyopathie, auch als Takotsubo-Syndrom bekannt, ähnelt einem akuten ST-Hebungsinfarkt bzw. einem akuten Koronarsyndrom in Abwesenheit einer relevanten koronaren Herzerkrankung. Exakte epidemiologische Daten liegen bisher nicht vor, jedoch befällt das Takotsubo-Syndrom vorzugsweise Frauen in der Menopause. Auch die genaue Pathogenese ist noch nicht gesichert. Als häufigster beschriebener Auslöser wird plötzlich einsetzender emotionaler Stress genannt. Es gibt bis dato keine offiziellen Leitlinien für die Therapie des Takotsubo-Syndroms. Eine symptomatische Behandlung mit Aspirin, β-Blockern und Angiotensin-converting-Enzym-Hemmern wird empfohlen. Die ventrikuläre Kinetikstörung bildet sich normalerweise innerhalb von 4–5 Wochen zurück. Das Takotsubo-Syndrom hat im Vergleich zum akuten Herzinfarkt eine günstigere Prognose, allerdings können alle Komplikationen des akuten Herzinfarkts bis hin zum kardiogenen Schock auftreten.AbstractStress-induced cardiomyopathy, also known as takotsubo syndrome, imitates an acute ST elevation myocardial infarction or an acute coronary syndrome, but without concomitant coronary artery disease. It mainly affects postmenopausal women, but no established epidemiologic data of this syndrome are available to date. Furthermore, the underlying etiologies are still largely unknown. The most frequently described trigger is strong emotional stress. Supportive therapy with aspirin, β-blockers and angiotensin-converting enzyme inhibitors is recommended. The abnormal kinetics usually reverse or improve within 4–5 weeks. Compared with acute myocardial infarction, takotsubo cardiomyopathy carries a favorable prognosis. However, severe complications, including ventricular fibrillation and cardiogenic shock, may still occur.Stress-induced cardiomyopathy, also known as takotsubo syndrome, imitates an acute ST elevation myocardial infarction or an acute coronary syndrome, but without concomitant coronary artery disease. It mainly affects postmenopausal women, but no established epidemiologic data of this syndrome are available to date. Furthermore, the underlying etiologies are still largely unknown. The most frequently described trigger is strong emotional stress. Supportive therapy with aspirin, beta-blockers and angiotensin-converting enzyme inhibitors is recommended. The abnormal kinetics usually reverse or improve within 4-5 weeks. Compared with acute myocardial infarction, takotsubo cardiomyopathy carries a favorable prognosis. However, severe complications, including ventricular fibrillation and cardiogenic shock, may still occur.

Relation of impaired interorgan communication and parasympathetic activity in chronic heart failure and multiple-organ dysfunction syndrome

BACKGROUND We investigated the relationship of impaired autonomic function and severity of illness in chronic heart failure (CHF) and multiple-organ dysfunction syndrome (MODS) as an end stage of CHF. Furthermore, we assessed the link of parasympathetic modulation of the heart rate and inflammatory activation in CHF and MODS. METHODS Sixty-five patients admitted for worsening of CHF were retrospectively enrolled in this study. In addition, 65 age- and sex-matched patients with pronounced MODS were assigned for comparison of autonomic function and C-reactive protein in patients with CHF or MODS, respectively. Heart rate variability (HRV) parameters of the time and frequency domain as markers of autonomic function were analyzed from 24-hour Holter electrocardiograms. RESULTS The more pronounced the severity of illness as expressed by the Acute Physiology and Chronic Health Evaluation score, the more the HRV was impaired. This effect was particularly seen for overall variability (SD of RR intervals) and HRV parameters characterizing the parasympathetic modulations of the heart rate (high, very low frequency power). C-reactive protein levels as markers of inflammation were inversely related to high and very low frequencies. CONCLUSION Our results allow for speculation that autonomic dysfunction in CHF indicates a beginning of uncoupled interorgan communication potentially leading to MODS as characterized by disruption of communication between the organs.

Comment on the European guidelines for the management of atrial fibrillation

Atrial fibrillation (AF) is an important cause of ischaemic stroke and systemic embolism [1]. Stroke in AF patients is associated with greater morbidity and mortality and costlier medical care than in patients with stroke but without AF [2–4]. Therefore, the recently published guidelines for the management of AF emphasized the risk stratification for stroke and thrombo-embolism [5]. Increasing life expectancy in industrialized societies has resulted in a high population of older adults with AF and other cardiovascular diseases. Hence, it is important to find simple means that enable general practitioners to evaluate the stroke risk factors and decide on the antithrombotic therapy. In the recently published guidelines, a new and more detailed stroke risk assessment scheme is introduced as CHA2DS2VASc score. Similar to the CHADS2 score (maximum 6 points), the CHA2DS2-VASc score is also based on a point system (maximum 9 points), but the age score has been categorized differently. Two points are assigned for age [75 years and 1 point for age 65–74 years, while in the CHADS2 score, 1 point is given for age [75 years only. Additionally, 1 point each is assigned for female sex and vascular disease. Of note, the recommended antithrombotic therapy according to the point system remained unchanged (oral anticoagulation is recommended at CHA2DS2-VASc score of C2). As a result, chronic oral anticoagulation (OAC) therapy with vitamin K antagonists (VKA) is recommended in male patients over the age of 75 and female patients over the age of 65 years, even in the absence of other risk factors for stroke. In other words, except for female patients less than 65 years and male patients less than 75 years, who exhibit no other stroke risk factors, OAC is recommended for all AF patients. The expected increased use of OAC therapy is more relevant to the elderly patients who represent an increasing population in industrialized societies. Two studies in elderly patients (BAFTA and WASPO) that were cited in the guidelines showed VKA superiority to aspirin in reducing stroke and arterial embolism, with no difference in the risk of major haemorrhage [6, 7]. Both studies included only patients with intact memory and cognitive function and excluded those with history of or risk for falls or syncope. The exclusion of high risk patients and the optimal anticoagulation monitoring in these two studies could have underestimated the haemorrhage rate that occurs in practice in patients on OAC. Moreover, the WASPO study cohort was too small to reach statistical significance. Hylek et al. [8] found a higher rate of major haemorrhage in elderly patients on OAC (13.08 and 4.75% for patients C80 years and patients \80 years, respectively, P = 0.010). In our opinion, OAC with VKA in elderly AF patients should be tailored individually based on a careful assessment of risk–benefit ratio, domestic situation and concomitant diseases, and this remains challenging in the real-world practice. Direct thrombin inhibitors do not require anticoagulation monitoring, have no drug–food interactions and will become a good alternative to VKA in elderly AF patients, although randomized studies of the major haemorrhage and tolerability of direct thrombin inhibitors among elderly patients are still missing. S. M. Said (&) R. C. Braun-Dullaeus Cardiology, Otto-von-Guericke University, Leipzigerstrasse 44, 39120 Magdeburg, Germany e-mail: samir.said@med.ovgu.de

Takotsubo syndrome from original description up to now

ZusammenfassungDie stressinduzierte Kardiomyopathie, auch als Takotsubo-Syndrom bekannt, ähnelt einem akuten ST-Hebungsinfarkt bzw. einem akuten Koronarsyndrom in Abwesenheit einer relevanten koronaren Herzerkrankung. Exakte epidemiologische Daten liegen bisher nicht vor, jedoch befällt das Takotsubo-Syndrom vorzugsweise Frauen in der Menopause. Auch die genaue Pathogenese ist noch nicht gesichert. Als häufigster beschriebener Auslöser wird plötzlich einsetzender emotionaler Stress genannt. Es gibt bis dato keine offiziellen Leitlinien für die Therapie des Takotsubo-Syndroms. Eine symptomatische Behandlung mit Aspirin, β-Blockern und Angiotensin-converting-Enzym-Hemmern wird empfohlen. Die ventrikuläre Kinetikstörung bildet sich normalerweise innerhalb von 4–5 Wochen zurück. Das Takotsubo-Syndrom hat im Vergleich zum akuten Herzinfarkt eine günstigere Prognose, allerdings können alle Komplikationen des akuten Herzinfarkts bis hin zum kardiogenen Schock auftreten.AbstractStress-induced cardiomyopathy, also known as takotsubo syndrome, imitates an acute ST elevation myocardial infarction or an acute coronary syndrome, but without concomitant coronary artery disease. It mainly affects postmenopausal women, but no established epidemiologic data of this syndrome are available to date. Furthermore, the underlying etiologies are still largely unknown. The most frequently described trigger is strong emotional stress. Supportive therapy with aspirin, β-blockers and angiotensin-converting enzyme inhibitors is recommended. The abnormal kinetics usually reverse or improve within 4–5 weeks. Compared with acute myocardial infarction, takotsubo cardiomyopathy carries a favorable prognosis. However, severe complications, including ventricular fibrillation and cardiogenic shock, may still occur.Stress-induced cardiomyopathy, also known as takotsubo syndrome, imitates an acute ST elevation myocardial infarction or an acute coronary syndrome, but without concomitant coronary artery disease. It mainly affects postmenopausal women, but no established epidemiologic data of this syndrome are available to date. Furthermore, the underlying etiologies are still largely unknown. The most frequently described trigger is strong emotional stress. Supportive therapy with aspirin, beta-blockers and angiotensin-converting enzyme inhibitors is recommended. The abnormal kinetics usually reverse or improve within 4-5 weeks. Compared with acute myocardial infarction, takotsubo cardiomyopathy carries a favorable prognosis. However, severe complications, including ventricular fibrillation and cardiogenic shock, may still occur.