Arrangement of the Autonomic Nerves Around the Pulmonary Vein-Left Atrial Junctions —Histologic and Immunohistochemical Analyses—

Introduction: Imbalanced autonomic activity in the area of the pulmonary veins (PVs) can result in spontaneous atrial fibrillation (AF). Histologic characteristics of the PV sleeve musculature and associated autonomic nerve are not fully understood. We investigated the arrangement of autonomic nerve fibers around PV-left atrium (LA) junctional musculature. Methods: Thirteen autopsied adult hearts (9 men and 4 women; mean age at death, 66.2 years were studied. The atria were removed from each heart, along with all PV stalks, and cut longitudinally to each PV myocardial sleeve. After treatment with azan-Mallory stain and immunohistochemical staining for S-100 and tyrosine hydroxylase (TH), autonomic nerve distribution was assessed by counting the numbers of TH-positive (adrenergic and -negative (non-adrenergic) fibers within S-100-positive fibers (>50 mm in diameter) in the anterior, posterior, and septal junctions. Results: TH-positive adrenergic fibers, consisting of sympathetic nerves, were most predominant in the anterior and septal junctions. In the anterior junction, these fibers were packed tightly among myocardial sleeve fascicles. In the posterior junction, the numbers of adrenergic and non-adrenergic fibers were fewer. In the septal junction, the number of THnegative non-adrenergic fibers (predominantly parasympathetic nerves) was greater, concomitant diffuse ganglionic nodule distribution in the interatrial fat pad. Conclusions: In each PV-LA junction, autonomic nerves were localized on the anterior and septal walls. Heterogeneous distribution of TH-positive and TH-negative fibers and ganglion nodules around each PV opening appears to represent the major histologic characteristic in these areas

The Effects of Nicorandil and Nifekalant, Which Were Injected into the Pericardial Space, for Transmural Dispersion of Repolarization in the Pig

Introduction: Some studies have reported that transmural dispersion of repolarization (TDR) is involved in the onset of ventricular arrhythmia. We investigated the effects of nicorandil (NIC) and nifekalant (NIF) injected into the pericardial space, on TDR and T waves in the pig. Methods and Results: We injected NIC 4 or 8 mg and NIF 50 or 100 mg at intervals into the pericardial space for eleven pigs. The effects of these drugs were investigated on the effective refractory period (ERP) between the endocardial and epicardial myocardial cells, as well as on QT time, QT peak-end (QTcpe) as an index of TDR, and T waveforms, respectively. QTcpe increased from 91 ± 21 to 116 ± 19 msec, 2.8 min after injection of NIC (p < 0.01), although corrected QT (QTc) interval did not changed. But 5.5 min after injection, QTc decreased while QTcpe recovered. T wave amplitude significantly increased, and epicardium ERP decreased. When NIF was injected, TDR decreased from 55 ± 10 msec to 44 ± 8 msec (p < 0.01) although QTc did not change. In a later phase, QTc increased (p < 0.01) and QTcpe recovered. T wave amplitude rapidly decreased and became negative. Conclusion: Injected into the pericardial space, NIC and NIF brought about certain changes in ERP, QT and T waveform. Furthermore, NIC increased TDR while NIF decreased TDR

Electrical Remodeling in Persistent Atrial Fibrillation May Be Mediated by Changes in the IKATP Channel

The goal of this study was to measure the effective refractory period (ERP), the conduction velocity (CV) and the wavelength (WL) after cardioversion in patients with persistent atria] fibrillation (AF) and to determine the effects of the adenosine triphosphate sensitive potassium channel (KATP) opening agent, nicorandil, on those parameters in patients with persistent AF. METHODS: Patients with AF underwent elective cardioversion followed by measurement of ERP and CV before and after administration of nicorandil. Parameters were measured again one week later, and the ERP and the CV was used to calculate WL. RESULTS: ERP was significantly shorter immediately after termination of AF than at the 1-week time point (193.4 vs. 228.7 msec p < 0.01). While there was no significant difference in ERP immediately after termination of AF when comparing measurements taken before and after the administration of nicorandil, ERP at the 1-week time point was shorter after nicorandil administration than before nicorandil administration (193.4 vs. 191.4 msec, n.s.; 228.7 vs. 217.2msec, p < 0.01). Further, WL was higher at the 1-week time point after nicorandil administration than before nicorandil administration. CONCLUSIONS: These data indicate that the electrical remodeling that occurs after cardioversion is at least partially mediated by changes in KATP channel behavior. Further, the electrophysiologic properties, that is, nicorandil prolonging the WL, may be of benefit in reducing the recurrence rate of AF

Reproductive Factors and Endometrial Cancer Risk Among Women

Importance: Despite evidence of an association between reproductive factors and endometrial cancer risk, prospective studies have been conducted mainly in non-Asian countries. Objective: To assess the association between reproductive factors, such as number of deliveries, age at menarche, or menopause, and endometrial cancer risk.Design, Setting, and Participants: This cohort study used pooled individual data from 13 prospective cohort studies conducted between 1963 and 2014 in the Asia Cohort Consortium. Participants were Asian women. Data analysis was conducted from September 2019 to April 2023. Exposures: Reproductive factors were assessed using a questionnaire in each cohort.Main Outcomes and Measures: The main outcome was time to incidence of endometrial cancer. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs.Results: A total of 1005 endometrial cancer cases were detected among 332 625 women (mean [SD] age, 54.3 [10.4] years) during a mean (SD) of 16.5 (6.4) years of follow-up. Increasing number of deliveries was associated with a decreased endometrial cancer risk in a dose-response manner (≥5 deliveries vs nulliparous [reference]: HR, 0.37; 95% CI, 0.26-0.53; P for trend Conclusions and Relevance: This large pooled study of individual participant data found that late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These convincing results from Asian prospective studies add to the growing body of evidence for the association between reproductive factors and endometrial cancer.</p

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea

Abstract Background The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. Methods This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. Results Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66–1.13] compared to 0.60 [0.49–0.73], 0.46 [0.38–0.56] and 0.62 [0.51–0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14–1.84] compared to 1.25 [0.99–1.58], 1.06 [0.85–1.32] and 0.86 [0.69–1.08]) and alcohol consumption (1.22 [1.01–1.48] compared to 1.10 [0.90–1.33], 1.15 [0.96–1.38], and 1.07 [0.91–1.26]). Conclusion We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo