Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Das Leib-Seele-Problem im medizinhistorischen Kontext : ein kritischer Vergleich von René Descartes und António Damásio

This doctoral thesis compares the theories of both René Descartes and António Damásio regarding their examination of the mind-body problem. The pivotal question of the mind-body problem is how mental states behave to physical states. René Descartes represents an interactional dualism looking at body and mind as different entities on the one hand, but also positing a relationship between body and mind on the other. Damásio criticizes Descartes’ dualism based on his knowledge of modern neuroscience. He militates against a disjunction of body and mind: according to Damásio the body forms a frame of reference for all neuronal processes, which in conjunction produce consciousness. Whereas both scientists differ in their personal and professional background, they resemble each other in their critical attitude towards the science of their time, their reforming efforts, and their habit of publishing for both a professional and popular audience. As regards objective targets, theoretical parameters and manner of reasoning both scientists vary considerably from each other: Descartes intends to revolutionize all sciences by creating a methodic, universally valid fundamental concept. Damásios aim is changes in therapeutic concepts in western medicine. In his investigations Descartes works on a metaphysical and epistemological level and stands for an exclusive and hypothetic dualism, which should be considered as ideal and hypothetic. Damásio in contrast works on an empirical and experimental level. Damásio does not engage in a direct discussion of Descartes’ argument; Damásio instead limits his reasoning to a criticism of dualism and does not observe the supplement “interactional”. He directs his criticism not only at Descartes, but also at society, especially the medical fraternity. Damásio does not appropriately correct the “error”, furthermore he steps out of his own scientific field by using neurobiological determinism of the human mind to falsify Descartes’ experiment of fundamental principles. Complex questions as the mind-body problem cannot be resolved by an accusation of error based on weak reasoning. They cannot be resolved through one discipline alone. Therefore their development is in need of an interdisciplinary, constructive collaboration following universal standards

Das Leib-Seele-Problem im medizinhistorischen Kontext : ein kritischer Vergleich von René Descartes und António Damásio

This doctoral thesis compares the theories of both René Descartes and António Damásio regarding their examination of the mind-body problem. The pivotal question of the mind-body problem is how mental states behave to physical states. René Descartes represents an interactional dualism looking at body and mind as different entities on the one hand, but also positing a relationship between body and mind on the other. Damásio criticizes Descartes’ dualism based on his knowledge of modern neuroscience. He militates against a disjunction of body and mind: according to Damásio the body forms a frame of reference for all neuronal processes, which in conjunction produce consciousness. Whereas both scientists differ in their personal and professional background, they resemble each other in their critical attitude towards the science of their time, their reforming efforts, and their habit of publishing for both a professional and popular audience. As regards objective targets, theoretical parameters and manner of reasoning both scientists vary considerably from each other: Descartes intends to revolutionize all sciences by creating a methodic, universally valid fundamental concept. Damásios aim is changes in therapeutic concepts in western medicine. In his investigations Descartes works on a metaphysical and epistemological level and stands for an exclusive and hypothetic dualism, which should be considered as ideal and hypothetic. Damásio in contrast works on an empirical and experimental level. Damásio does not engage in a direct discussion of Descartes’ argument; Damásio instead limits his reasoning to a criticism of dualism and does not observe the supplement “interactional”. He directs his criticism not only at Descartes, but also at society, especially the medical fraternity. Damásio does not appropriately correct the “error”, furthermore he steps out of his own scientific field by using neurobiological determinism of the human mind to falsify Descartes’ experiment of fundamental principles. Complex questions as the mind-body problem cannot be resolved by an accusation of error based on weak reasoning. They cannot be resolved through one discipline alone. Therefore their development is in need of an interdisciplinary, constructive collaboration following universal standards

Extended Second Window of Protection of Sevoflurane-induced Preconditioning

Late preconditioning (LPC) can be induced by volatile anesthetics and initiates cardioprotection against ischemia/reperfusion injury for 3-4 days. We investigated the possibility to extend the time window of sevoflurane-induced LPC by repeated sevoflurane administration. An in vivo rat model of regional myocardial ischemia/reperfusion injury was used. Myocardial infarct size was determined by triphenyltetrazolium chloride staining at the end of the experiment. In the first series of experiments, male Wistar rats were randomized to 5 groups (each n = 8). Control animals were not treated further. Animals in the preconditioning groups inhaled sevoflurane for 60 minutes (1 MAC) 24, 48, 72, and 96 hours, respectively, before myocardial ischemia. Based on the findings of the first experimental series, another 6 groups of animals were investigated. Again, control animals were left untreated; all other animals received a second sevoflurane stimulus 72 hours after the first sevoflurane treatment, and myocardial ischemia was induced 24, 48, 72, and 96 hours, respectively, after the second sevoflurane treatment to investigate, whether the cardioprotective effect could be extended. Sevoflurane reduced infarct size after 24, 48, and 72 hours (each P <0.05 vs. control) but not after 96 hours. The repeated administration of sevoflurane 72 hours after the first stimulus extended the time window of protection for additional 72 hours (each P <0.05 vs. control). There was no myocardial protection 4 days after the second preconditioning stimulus. The time window of sevoflurane-induced LPC can be extended by an additional sevoflurane stimulus up to 72 hours after the initial sevoflurane exposur

Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats

Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro. Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate. In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P <0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P <0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups. This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotectio

Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore.

BACKGROUND:Morphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway. METHODS:Male Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition. RESULTS:Morphine reduced infarct size from 64±5% to 39±9% (P0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P0.05 vs. Con). In isolated hearts STAT3 inhibitor Stattic completely abolished morphine-induced preconditioning. Administration of Stattic and mPTP inhibitor cyclosporine A reduced infarct size to 31±6% (Stat+CsA, P<0.05 vs. Con). Cyclosporine A alone reduced infarct size to 26±7% (CsA P<0.05 vs. Con). In cardiomyocytes, PKA activity was increased by morphine. CONCLUSION:Our data suggest that morphine-induced cardioprotection is mediated by STAT3-activation and inhibition of mPTP, with STA3 located upstream of mPTP. There is some evidence that protein kinase A is involved within the signalling pathway

Tranexamic Acid Does Not Influence Cardioprotection by Ischemic Preconditioning and Remote Ischemic Preconditioning

Prior studies have suggested that the antifibrinolytic drug aprotinin increases the infarct size after ischemia and reperfusion (I/R) and attenuates the effect of ischemic preconditioning (IPC). Aprotinin was replaced by tranexamic acid (TXA) in clinical practice. Here, we investigated whether TXA influences I/R injury and/or cardioprotection initiated by IPC and/or remote ischemic preconditioning (RIPC). Anesthetized male Wistar rats were randomized to 6 groups. Control animals were not further treated. Administration of TXA was combined with and without IPC and RIPC. Estimated treatment effect was 20%. Compared to control group (56% ± 11%), IPC reduced infarct size by 46% (30% ± 6%; mean difference, 26%; 95% confidence interval, 19-33; P < .0001), and RIPC reduced infarct size by 29% (40% ± 8%; mean difference, 16%; 95% confidence interval, 9-24; P < .011). Additional application of TXA had no effect on I/R injury and cardioprotection by IPC or RIPC. TXA does not abolish infarct size reduction by IPC or RIP