Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9 (HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes.
Apoptosis and necrosis are two distinctly different forms of cell death, and both occur in the human heart. In contrast to necrosis, apoptosis is not associated with inflammation for two reasons. First, the apoptotic cell does not swell or rupture before it is engulfed by either a macrophage or even a neighboring like cell. Second, the phagocytosis occurs with unusual rapidity. Apoptosis, also thought of as cell suicide, is a tidy way of removing cells no longer useful, in essence a form of selective deletion. These features make apoptosis a valuable component of morphogenesis, mediation of hormonal and immunologic responses, and the homeostatic balance between hypertrophy and atrophy or involution. In the human heart apoptosis has been found in the sinus node of patients with the long QT syndrome. It most likely participates in the important postnatal morphogenesis of the sinus node, AV node, and His bundle. Apoptosis may also participate in the genesis and pathophysiology of cardiomyopathy, paroxysmal arrhythmias, or conduction disturbances (some of which may be responsible for sudden death), focal fibromuscular dysplasia of small coronary arteries, hereditary medial degeneration of the tunica media of coronary arteries, and arrhythmogenic right ventricular dysplasia. The possible role apoptosis in numerous other changes in the human heart, among them the pathogenesis of atherosclerosis and mechanisms of aging in the myocardium, merits future investigation.
The nature of localized atrial activation during atrial fibrillation was characterized in 34 patients following open heart surgery. Bipolar atrial electrograms (AEG) recorded in each patient with atrial fibrillation exhibited a myriad of sizes, shapes, polarities, amplitudes, and beat-to-beat intervals. On the basis of the AEG morphology and the nature of its baseline, we have classified the recordings into four Types. Type I was characterized by discrete AEG complexes separated by an isoelectric baseline free of perturbation, Type II by discrete AEG complexes but with perturbations of the baseline between complexes, Type III by AEGs which failed to demonstrate either discrete complexes or isoelectric intervals, and Type IV in which AEGs of Type III alternated with periods characteristic of Type I and/or Type II. In 22 patients, the AEGs were recorded a second time, and in 11 of these patients the type of atrial fibrillation changed between the first and second recording period. An atrial flutter-fibrillation pattern in the ECG was associated with a relatively ordered atrial activation pattern and a relatively slow atrial rate. Human atrial fibrillation is not an electrophysiologically homogeneous process when compared among different patients or ad seriatim in the same patient.
SummaryBackgroundResults of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.MethodsFOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.FindingsBetween Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.InterpretationFluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.FundingUK Stroke Association and NIHR Health Technology Assessment Programme.
The relationships among the His bundle, the origin of both bundle branches, and the interventricular (IV) septum were examined histologically in 32 human hearts, and the entire bundle branch systems were delineated in 13 of these. The His bundle in five hearts traversed the right IV septal crest, and the LBB origin was a very narrow stem (maximum 1.5 mm in cross-section) crossing from right to left through the inferior margin of the membranous septum. Proximal LBB anatomy was extremely variable, demonstrating multiple fiber groups which fanned out over the entire left septal surface. The LBB did not divide into two discrete divisions without multiple interconnections. The RBB formed an obtuse angle with the His bundle in 27 of 32 hearts. In those five hearts with "right-sided His bundles," the right bundle branch was a direct continuation. The clinical, electrophysiologic, and electrocardiographic implications of these anatomical observations are discussed.
To examine the question of why the pacing rate and duration of atrial pacing are crucial factors in the successful interruption of atrial flutter, studies were performed on 30 patients in the period following open heart surgery. In each patient the diagnosis of atrial flutter was made using a pair of wire electrodes placed on the right atrial epicardium at the time of operation and brought out through the anterior chest wall. The same electrodes were used for atrial pacing. Pacing faster than the spontaneous rate of the atrial flutter which failed to interrupt the atrial flutter was associated with transient entrainment of the atrial flutter up to the atrial pacing rate. Atrial flutter was interrupted successfully when the atria were paced at a rate which was too fast for the atrial flutter to follow. This was heralded by the conversion of previously negative flutter waves to positive atrial complexes in ECG lead II. When pacing the atria at a constant rate, 2-22 seconds with a mean of 10 seconds were required to interrupt the atrial flutter.
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