Laboratory Test Predictors for Major Bleeding in Elderly (≥80 Years) Patients With Nonvalvular Atrial Fibrillation Treated With Edoxaban 15 mg: Sub-Analysis of the ELDERCARE-AF Trial.

Background We investigated the predictors related to major bleeding events during treatment with edoxaban 15 mg in patients aged ≥80 years with nonvalvular atrial fibrillation and high bleeding risk, for whom standard oral anticoagulants are inappropriate, focusing on standard laboratory tests related to bleeding. Methods and Results This was a prespecified subanalysis of the on-treatment analysis set of the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Major bleeding was the primary safety end point. The event rates were calculated according to prespecified characteristics at baseline. A total of 984 Japanese patients were randomly assigned to edoxaban 15 mg or placebo (n=492, each). During the study period, 20 and 11 major bleeding events occurred in the edoxaban and placebo groups, respectively. The adjusted analysis revealed that hemoglobin <12.3 g/dL (adjusted hazard ratio [aHR], 3.57 [95% CI, 1.10-11.55]) and prothrombin time ≥12.7 seconds; (aHR, 2.89 [95% CI, 1.05-8.02]) independently predicted major bleeding, while creatinine clearance <30 mL/min showed a tendency towards an increase in major bleeding (aHR, 2.68; 95% CI, 0.96-7.46). In patients treated with edoxaban lacking these 3 risk factors, no major bleeding occurred; major bleeding event rates increased with each risk factor. Patients with 3 risk factors were significantly more likely to have a major bleeding event at 11.05%/year (HR, 7.15 [95% CI, 1.92-26.71]). Conclusions In elderly patients with nonvalvular atrial fibrillation with high bleeding risk, baseline hemoglobin <12.3 g/dL, prothrombin time ≥12.7 seconds, and creatinine clearance <30 mL/min may predict major bleeding during treatment with edoxaban 15 mg. Registration URL: ELDERCARE-AF https://www.clinicaltrials.gov; Unique number: NCT02801669.

Reliability of measurement using Image J for reach distance and movement angles in the functional reach test.

[Purpose] The purpose of this study was to examine the test-retest reliability and minimal detectable change (MDC) of reach distance and movement angle analyses using Image J. [Participants and Methods] Thirty-eight healthy young males performed the functional reach test (FRT) twice, and their reach movements were recorded using a digital video camera. Image J was used to combine the digital photographs taken at the start position and maximum reach and to measure each movement. The measurements recorded were the movement distance of the third metacarpal bone (reach distance), anterior-superior iliac spine, and trochanter major, and the angles recorded were the acromion-malleolus lateralis, acromion-trochanter major, and trochanter major-malleolus lateralis. The reliability of all the measurements was analyzed using intraclass correlation coefficients (ICCs), Bland-Altman plots, and MDCs. [Results] The ICCs (1, 1) were >0.80 for all the outcomes. The Bland-Altman analysis revealed no systematic bias in any outcome. The MDC of reach distance was 18.3 mm. [Conclusion] Measurement using Image J for reach distance and movement angles in the FRT showed acceptable high test-retest reliability. Measurement of the FRT and the MDC calculated in this study could be used as a reference for further research.

Isolated cardiac sarcoidosis requiring open-chest myocardial biopsy for differentiation from malignant lymphoma.

A 68-year-old woman with a history of hypertension was admitted to our hospital because of dyspnea during physical exertion. Echocardiography demonstrated impaired left ventricular systolic function, and her ejection fraction was reduced to 30%. Coronary angiography did not show significant stenosis. Endomyocardial biopsy showed only nonspecific findings without noncaseating granulomas. Cardiac magnetic resonance (CMR) imaging showed transmural late gadolinium enhancement on the basal part of the left ventricle. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) showed abnormal focal uptake specific to the left ventricle; no abnormal manifestations in other organs were observed. The CMR and 18F-FDG PET features could not rule out either sarcoidosis or malignant lymphoma. Therefore, we conducted open-chest myocardial biopsy to differentiate between the two possible diseases. Histopathological findings showed noncaseating epithelioid cell granuloma, confirming isolated cardiac sarcoidosis. This is an example of a challenging case of diagnosing isolated cardiac sarcoidosis. .

False tendon-related polymorphic ventricular tachycardia.

A 39-year-old woman showed nonsustained polymorphic ventricular tachycardia (PVT) during light physical activity. Cardiac multidetector row computed tomography demonstrated false tendons, one of which proved to be the focus triggering premature ventricular contraction (PVC) in electrophysiological studies. The triggered PVC arose during the diastolic period, which might have caused tension in the false tendon. Radiofrequency catheter ablation targeting the triggered PVC by pace mapping was performed and proved partially effective against PVT.

Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo.

Electrophysiological remodeling involving gap junctions has been demonstrated in failing hearts and may contribute to intercellular uncoupling, delayed conduction, enhanced arrhythmias, and vulnerability to sudden death in patients with heart failure. Recently, we showed that failing human hearts exhibit marked increases in connexin45 (Cx45) expression in addition to previously documented decreases in connexin43 (Cx43) expression. Each of these changes results in reduced gap junction coupling. The objective of the present study was to examine functional consequences of increased Cx45 in cardiac gap junctions. Transgenic mice with cardiac-selective overexpression of the developmentally downregulated cardiac connexin, connexin45 (Cx45OE mice) were subjected to in vivo electrophysiology studies in which an intracardiac catheter was used to induce ventricular arrhythmias in anesthetized mice, and in which ambulatory ECG monitoring was used to detect spontaneous arrhythmias in unanesthetized mice. Hearts were analyzed by TaqMan RT-PCR, immunostaining, immunoblotting, and echocardiography. Lucifer yellow and neurobiotin dye transfer was used to assess coupling in transgenic and control myocyte cultures. Cx45 mRNA was two orders of magnitude greater in Cx45OE mice. Cx45-immunoreactive signal at gap junctions increased twofold and total Cx45 protein by immunoblotting increased 25% in Cx45OE mice compared with nontransgenic littermate controls. Functionally, Cx45OE mice exhibited more inducible ventricular tachycardia than controls but did not exhibit any other functional or structural derangements as assessed by echocardiography. Ventricular myocytes isolated from Cx45OE mice exhibited diminished intercellular transfer of Lucifer yellow dye and increased transfer of neurobiotin, consistent with altered cell-to-cell communication. Thus increased myocardial expression of Cx45 results in remodeling of intercellular coupling and greater susceptibility to ventricular arrhythmias in vivo.

Positional ventricular tachycardia.

A 60-year-old man showed nonsustained repetitive monomorphic VT in the left lateral position, but this was terminated by deep inspiration. Echocardiography and MRI demonstrated a false tendon extending from the apex to the basal septum where the VT could have originated. Spontaneous remission occurred during the 16-year follow-up.

Spontaneous and inducible ventricular arrhythmias after myocardial infarction in mice.

INTRODUCTION: Remodeling of gap junctions has been implicated in development of ventricular arrhythmias following myocardial infarction (MI) but the specific contribution of reduced electrical coupling is not known. We addressed this question using hearts from mice heterozygous for a connexin43 null allele (Cx43(+/-)). METHODS: To determine whether Cx43-deficient mice exhibit increased spontaneous ventricular arrhythmias in the setting of chronic ischemic heart disease, radiofrequency transmitters were implanted in wild-type and Cx43(+/-) mice 2 days or 9 weeks after left anterior descending coronary artery ligation or sham operations. ECGs were recorded from unanesthetized, unrestrained mice 1 and 10 weeks after MI. Isolated, perfused hearts excised 1 and 10 weeks after MI were subjected to programmed electrical stimulation to induce arrhythmias. RESULTS AND CONCLUSIONS: Hearts with infarcts exhibited more spontaneous and inducible arrhythmias, but there was no significant difference between wild-type and Cx43-deficient mice. Fewer hearts exhibited spontaneous ventricular tachycardia (VT) in vivo than were inducible in vitro, suggesting that structural and functional substrates for inducible VT in isolated hearts may not be sufficient for initiation and maintenance of sustained VT in vivo. Previous studies have shown that Cx43-deficient mice exhibit more VT than wild-type mice during acute regional ischemia. Mice with MI exhibit increased arrhythmias. However, reduced coupling in Cx43-deficient mice does not significantly enhance spontaneous or inducible VT after MI.

Percutaneous coronary intervention for central sleep apnoea with ischaemic cardiomyopathy.

Central sleep apnoea is often recognized in patients with heart failure. Although the medical treatment to improve cardiac function is effective for sleep apnoea, direct evidence that improved cardiac function ameliorates sleep apnoea has not been reported due to the fact that a particular drug may affect a multitude of organs. We present a chronic heart failure patient with central sleep apnoea whose nocturnal desaturation was improved by percutaneous coronary intervention that resulted in improved cardiac function. This is the first case where percutaneous coronary intervention improved sleep apnoea, suggesting that the improved cardiac function led to amelioration of sleep apnoea.

Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction.

Gene-targeting in mice is a powerful tool to define molecular mechanisms of ischemic heart disease that determine infarct size, postinfarct left ventricular (LV) remodeling, and arrhythmogenesis. Coronary ligation in mice is becoming a widely used model of myocardial infarction (MI), but the pathophysiologic consequences of MI in mice and its relevance to human MI have not been fully elucidated. To characterize structural and functional changes during evolving MI, we analyzed 2-dimensional-based reconstruction of the left ventricle by noninvasive echocardiography obtained 1 day and 1 week after surgical ligation of the left anterior descending coronary artery in mice. Sequential 2-dimensional short-axis cineloops of the left ventricle were used to measure LV mass, and LV volumes at end-diastole and end-systole. Echocardiographic infarct size was estimated by measuring the volume of akinetic LV segments. Histologic infarct size was measured by planimetry of 9 transverse sections of each heart. There was close correlation between the 2 methods (31% +/- 20% of LV mass and 34% +/- 17% of LV area, respectively; y =.83x + 7.9, r = 0.96, P <.01). LV volumes at end diastole increased significantly between 1 day and 1 week (51 +/- 17 microL vs 78 +/- 46 microL, respectively, P <.05). The relative change in LV volumes at end diastole varied as a function of infarct size (r = 0.93, P <.01). LV mass and the extent of hypertrophy of noninfarcted segments also varied with infarct size (r = 0.92, P <.01; r = 0.90, P <.01, respectively). Thus, echocardiography is an accurate noninvasive tool for determination of infarct size and quantitative characterization of postinfarct remodeling in the mouse model of MI. Alterations in cardiac structure and function after coronary ligation in mice closely resemble pathophysiologic changes in human ischemic heart disease.

Redistribution of connexin45 in gap junctions of connexin43-deficient hearts.

OBJECTIVE: Adult ventricular myocytes express two gap junction channel proteins: connexin43 (Cx43) and connexin45 (Cx45). Cx43-deficient mice exhibit slow ventricular epicardial conduction, suggesting that Cx43 plays an important role in intercellular coupling in the ventricle. Cx45 is much less abundant than Cx43 in working ventricular myocytes. Its role in ventricular conduction has not been defined, nor is it known whether expression or distribution of Cx45 is altered in Cx43-deficient mice. The present study was undertaken to determine (1) whether expression of Cx45 is upregulated and (2) whether gap junction structure and distribution are altered in Cx43-deficient mice. METHODS: Ventricular tissue from neonatal Cx43(+/+), Cx43(+/-) and Cx43(-/-) and adult Cx43(+/+) and Cx43(+/-) mice was analyzed by immunoblotting and confocal immunofluorescence microscopy. RESULTS: Total Cx45 protein abundance measured by immunoblotting was not different in Cx43-deficient or null hearts compared to wild-type control hearts. However, the amount and distribution of Cx45 immunoreactive signal measured by quantitative confocal analysis were markedly reduced in both Cx43(+/-) and Cx43(-/-) hearts. CONCLUSION: Although the total content of Cx45 is not upregulated in Cx43-deficient hearts, the localization of Cx45 to cardiac gap junctions depends on the expression level of Cx43 and is dramatically altered in mice that express no Cx43.

Cardiac structure and function in young and senescent mice heterozygous for a connexin43 null mutation.

Downregulation of connexin43 (Cx43) in the failing heart has been implicated not only in arrhythmogenesis but in contractile dysfunction as well. Cx43-deficient mice exhibit reduced baseline conduction velocity and increased arrhythmias in response to ischemia. However, it is not known whether Cx43-deficient mice have any abnormalities in contractile function or, furthermore, whether cardiac dysfunction may be manifested in Cx43-deficient mice with advancing age. Therefore, we analyzed echocardiographic images from young and senescent Cx43-deficient C57BL/6Jx129 mice compared to wild-type littermate controls. Only a few, modest genotype-related differences were observed. LV wall thickness during systole and % fractional shortening were diminished by 8-10% in Cx43-deficient v wild-type mice. Aging alone had a greater effect on cardiac structure and function. LV mass and relative wall thickness were significantly increased in senescent v young mice independent of genotype. Percent fractional shortening and LV internal chamber dimension were significantly reduced in senescent v young mice. Thus, aging in mice, as in humans, is associated with concentric remodeling, mild systolic dysfunction and fibrosis. Although diminished Cx43 expression could contribute to contractile dysfunction in patients with advanced heart failure, genetic deficiency in Cx43 does not appear significantly to alter cardiac structure or function even in aged mice.