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Aims: Atrial Fibrillation (AF) is an arrhythmia of increasing prevalence in the aging populations of developed countries. One of the important indicators of AF is sustained atrial dilatation, highlighting the importance of mechanical overload in the pathophysiology of AF. The mechanisms by which atrial cells, including fibroblasts, sense and react to changing mechanical forces, are not fully elucidated. Here, we characterise stretch-activated ion channels (SAC) in human atrial fibroblasts and changes in SAC- presence and activity associated with AF., Methods and Results: Using primary cultures of human atrial fibroblasts, isolated from patients in sinus rhythm or sustained AF, we combine electrophysiological, molecular and pharmacological tools to identify SAC. Two electrophysiological SAC- signatures were detected, indicative of cation-nonselective and potassium-selective channels. Using siRNA-mediated knockdown, we identified the cation-nonselective SAC as Piezo1. Biophysical properties of the potassium-selective channel, its sensitivity to calcium, paxilline or iberiotoxin (blockers), and NS11021 (activator), indicated presence of calcium-dependent 'big potassium channels' (BK Ca ). In cells from AF patients, Piezo1 activity and mRNA expression levels were higher than in cells from sinus rhythm patients, while BK Ca activity (but not expression) was downregulated. Both Piezo1-knockdown and removal of extracellular calcium from the patch pipette resulted in a significant reduction of BK Ca current during stretch. No co-immunoprecipitation of Piezo1 and BK Ca was detected., Conclusions: Human atrial fibroblasts contain at least two types of ion channels that are activated during stretch: Piezo1 and BK Ca . While Piezo1 is directly stretch-activated, the increase in BK Ca activity during mechanical stimulation appears to be mainly secondary to calcium influx via SAC such as Piezo1. During sustained AF, Piezo1 is increased, while BK Ca activity is reduced, highlighting differential regulation of both channels. Our data support the presence and interplay of Piezo1 and BK Ca in human atrial fibroblasts in the absence of physical links between the two channel proteins., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Recently, long noncoding RNAs (lncRNAs) have caught more attention for their role in the progression of many diseases. Among them, lncRNA GAS5 (Growth Inhibition Specificity 5) was studied in this research to identify how it affects the progression of atrial fibrillation (AF)., Patients and Methods: In 40 patients with AF and 30 patients with sinus rhythm (SR), the GAS5 expression of the right atrial appendage (RAA) tissues was detected by the quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Moreover, the cell proliferation assay was conducted in AC16 cells transfected with GAS5 inhibitor and mimics, respectively. Furthermore, the qRT-PCR was performed to uncover the mechanism., Results: In the research, the expression of GAS5 in RAA tissues was decreased significantly in AF patients than that in SR ones. Moreover, overexpression of GAS5 inhibited cell growth in AC16 cells, while knockdown of GAS5 promoted cell growth in AC16 cells. In addition, further experiments revealed that ALK5 was a target of GAS5 and its expression in AF tissues negatively correlated to GAS5 expression., Conclusions: These results indicate that GAS5 could inhibit cell proliferation of AF via suppressing ALK5, which may offer a new vision for interpreting the mechanism of AF development.

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. We show that local, right atrial delivery of adenoassociated virus vectors encoding a light-gated depolarizing ion channel results in efficient and spatially confined transgene expression. Activation of an implanted intrathoracic light-emitting diode device allows for termination of AF by illuminating part of the atria. Combining this newly obtained antiarrhythmic effector function of the heart with the arrhythmia detector function of a machine-based cardiac rhythm monitor in the closed chest of adult rats allowed automated and rapid arrhythmia detection and termination in a safe, effective, repetitive, yet shock-free manner. These findings hold translational potential for the development of shock-free antiarrhythmic device therapy for ambulatory treatment of AF., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Atrial fibrosis is the fundamental characteristic of the structural pathology associated with atrial fibrillation (AF). Inflammation can contribute to atrial fibrosis, engendering AF. The present study aimed to investigate the role of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, in the regulation of proliferation and function of cardiac fibroblasts (CFs). Biochemical assays were performed to examine the expression of extracellular matrix (ECM) in human atrial tissues, and the proliferation and regulation of ECM induced by MIF in CFs. The expression of ECM, including collage type 3, α1 (Col‑3A1), matrix metalloproteinase (MMP)‑2/-9 and transforming growth factor (TGF)‑β was higher in patients with permanent AF, compared with patients in sinus rhythm (SR), and the expression levels of MIF were also increased in AF. Treatment of CFs with mouse recombinant MIF (rMIF; 40 nM) for 48 h was found to promote the proliferation of CFs. The MIF‑induced CF proliferation was completely inhibited by tyrosine kinase inhibitor‑PP1. rMIF treatment also stimulated the activation of Src kinase in CFs. In addition, MIF treatment upregulated the expression levels of fibrosis‑related proteins, Col‑1, Col‑3, MMP‑2/-9 and TGF‑β, in the CFs. These results suggested that MIF was involved in the structural remodeling that accompanies AF, possibly by promoting the proliferation of CFs and increasing the expression of ECM. These data implicate inflammation as a potential driver of CF.

Background: Atrial fibrillation (AF) is the most common arrhythmia and despite obvious clinical importance remains its pathogenesis only partially explained. A relation between inflammation and AF has been suggested by findings of increased inflammatory markers in AF patients., Objective: The goal of this study was to characterize morphologically and functionally CD45-positive inflammatory cell populations in atrial myocardium of patients with AF as compared to sinus rhythm (SR)., Methods: We examined 46 subjects (19 with AF, and 27 in SR) undergoing coronary bypass or valve surgery. Peroperative bioptic samples of the left and the right atrial tissue were examined using immunohistochemistry., Results: The number of CD3+ T-lymphocytes and CD68-KP1+ cells were elevated in the left atrial myocardium of patients with AF compared to those in SR. Immune cell infiltration of LA was related to the rhythm, but not to age, body size, LA size, mitral regurgitation grade, type of surgery, systemic markers of inflammation or presence of diabetes or hypertension. Most of CD68-KP1+ cells corresponded to dendritic cell population based on their morphology and immunoreactivity for DC-SIGN. The numbers of mast cells and CD20+ B-lymphocytes did not differ between AF and SR patients. No foci of inflammation were detected in any sample., Conclusions: An immunohistochemical analysis of samples from patients undergoing open heart surgery showed moderate and site-specific increase of inflammatory cells in the atrial myocardium of patients with AF compared to those in SR, with prevailing population of monocyte-macrophage lineage. These cells and their cytokine products may play a role in atrial remodeling and AF persistence.

BACKGROUND To examine changes of mRNA and protein expressions of MMP-2, Bcl-2, and BAX in atrial fibrillation (AF) patients, and investigate the correlations among these 3 biomarkers. MATERIAL AND METHODS Rheumatic heart disease patients (n=158) undergoing cardiac surgical procedures for mitral valve repair or replacement were included as the AF group (n=123), containing paroxysmal AF (n=42), persistent AF (n=36), and permanent AF (n=45). Rheumatic heart disease patients with sinus rhythm (SR) (n=35) were enrolled as the SR group (control group). Immunohistochemistry, Western blot, and real-time polymerase chain reaction (PCR) were applied to detect the protein and mRNA expression levels of MMP-2, Bcl-2, and BAX. Apoptosis was observed with light and electron microscopes and detected by TdT-mediated dUTP nick-end labeling (TUNEL). RESULTS Compared with the SR group, the left atrial diameters (LADs), protein and mRNA expression levels of MMP-2 and BAX, apoptotic index (AI), and Bcl-2/BAX ratio were evidently increased in the 3 AF groups, but protein and mRNA expression levels of Bcl-2 decreased in the AF groups (all P<0.05). Correlation analysis found that MMP-2 protein expression levels was positively correlated with BAX expression, but negatively correlated with Bcl-2 expression levels. CONCLUSIONS Our study results suggest that elevated MMP-2 expression and disturbance balance of Bcl-2/BAX expressions may be associated with the development and maintenance of AF. MMP-2 may be involved in the development of AF through promoting BAX expressions and inhibiting Bcl-2.

Background: Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated., Methods: Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting., Results: HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytokines, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3'UTR. In palmitate-stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation., Conclusion: HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Mental stress is a growing problem in our society. In order to deal with this, it is important to understand the underlying stress mechanisms. In this study, we aim to determine how the cardiorespiratory interactions are affected by mental arithmetic stress and attention. We conduct cross time-frequency (TF) analyses to assess the cardiorespiratory coupling. In addition, we introduce partial TF spectra to separate variations in the RR interval series that are linearly related to respiration from RR interval variations (RRV) that are not related to respiration. The performance of partial spectra is evaluated in two simulation studies. Time-varying parameters, such as instantaneous powers and frequencies, are derived from the computed spectra. Statistical analysis is carried out continuously in time to evaluate the dynamic response to mental stress and attention. The results show an increased heart and respiratory rate during stress and attention, compared to a resting condition. Also a fast reduction in vagal activity is noted. The partial TF analysis reveals a faster reduction of RRV power related to (3 s) than unrelated to (30 s) respiration, demonstrating that the autonomic response to mental stress is driven by mechanisms characterized by different temporal scales.

Electroencephalography was performed in 7-8- and 9-10-year-old pupils. Control group consisted of healthy children; experimental group consisted of children without signs of grade IV and V sinus arrhythmia at the age of 7-8 years, but with grade IV and V sinus arrhythmia at the age of 9-10 years. In primary school-aged children (7-8 years), manifestation of marked sinus arrhythmia is associated with disturbances in age-specific dynamics of interhemispheric interaction and with the formation, at the initial stage, of a rigid integrated system primarily due to functional intrahemispheric connections, the major contribution being made by the posterior associative cortical areas.

Background: Respiratory sinus arrhythmia (RSA) has been proposed as a physiological marker of emotion-regulation capacity, and shown to be cross-sectionally associated with depression. Little is known about the role of RSA as a predictor of (subclinical) depressive symptoms over time and as a modifier of the depressogenic effect of stressful life events (SLEs)., Methods: In a longitudinal population-based study with data collected in 1653 adolescents twice (at age 11 and 13.5 years, respectively), RSA was assessed in supine position at the first assessment wave. Depressive symptoms were assessed at both waves and SLEs experienced between the two waves at the last wave., Results: Low levels of RSA were not associated with concurrent or future depressive symptoms, and did not enhance the depressogenic effects of SLEs., Conclusions: In a normal population of young adolescents, a low level of RSA does not identify adolescents at risk for depressive symptoms when confronted with SLEs. In post hoc analyses, among those reporting high exposure to stressful life events, higher RSA tended to predict less self-reported anxiety and more self-reported somatic symptoms as compared to those with lower RSA.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Because heat shock proteins (Hsp) can protect cells from stress, we compared the levels of Hsp60, Hsp72, Hsc73, and Hsp27 in atrial myocardium from 17 patients with AF (8 paroxysmal and 9 persistent) and 7 controls in sinus rhythm (SR). Hsp60, Hsp72, and Hsc73 levels were not significantly different among the 3 groups. Hsp27 expression was slightly higher in paroxysmal AF than in SR and in persistent AF, and a borderline significant difference (P = 0.064) was seen between the paroxysmal and persistent AF subgroups. Hsp60 levels in the moderate, severe, and profound myolysis groups were significantly lower than the light myolysis group, but no differences were found in other Hsps. In summary, the data indicate that expression of Hsp27 and Hsc73 may be associated with different stages of AF and that Hsp60 also may be associated with the degree of atrial myolysis.

Objectives: We sought to compare left atrial (LA) volume to LA area and diameter for the prediction of adverse cardiovascular outcomes., Background: The incremental value of LA volume compared with LA area or diameter as a cardiovascular risk marker has not been evaluated prospectively for patients with sinus rhythm or atrial fibrillation (AF)., Methods: Left atrial size was assessed with biplane LA volume, four-chamber LA area, and M-mode dimension for 423 patients (mean age 71 +/- 8 years, 56% men) who were prospectively followed for development of first AF, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death., Results: Of the 317 subjects in sinus rhythm at baseline, 62 had 90 new events during a mean follow-up of 3.5 +/- 2.3 years. All three LA size parameters were independently predictive of combined outcomes (all p < 0.0001). The overall performance for the prediction of cardiovascular events was greatest for LA volume (area under the receiver operator characteristic curve: indexed LA volume 0.71; LA area 0.64; LA diameter 0.59). A graded association between the degree of LA enlargement and risk of cardiovascular events was only evident for indexed LA volume. For subjects with AF, there was no association between LA size and cardiovascular events., Conclusions: Left atrial volume is a more robust marker of cardiovascular events than LA area or diameter in subjects with sinus rhythm. The predictive utility of LA size for cardiovascular events in AF was poor, irrespective of the method of LA size quantitation.

Introduction: The aim of this study was to assess the safety and feasibility of catheter-based cryothermal ablation lesions in the mid- and distal coronary sinus., Methods and Results: Cryothermal ablation lesions were delivered using a 7-French catheter at the mid- (n = 13) and distal (n = 12) coronary sinus in 14 swine under general anesthesia. Lesions were delivered for 2 or 4 minutes in a 1:2 randomized ratio such that seven 2-minute lesions and eighteen 4-minute lesions were delivered to a maximum negative temperature of -70 degrees C. Integrity of the circumflex artery was assessed by angiography before and after each lesion application. In five animals, arterial Doppler flow velocity was continuously monitored and coronary flow reserve assessed. Histologic assessment of the left AV ring was made after a 48-hour survival period and lesions graded for depth and transmurality. Eighteen of 25 lesions were >3 mm deep: five of seven 2-minute lesions and thirteen of eighteen 4-minute lesions. Lesions were transmural in 18 of 25 cases. Two transmural lesions were limited in depth due to their epicardial position. One 2-minute mid-coronary sinus lesion was not found. Adherent thrombus was seen grossly in the coronary sinus at one site and only on microscopic examination in three other lesions. Angiography demonstrated no arterial spasm or thrombosis. Continuous-flow Doppler remained unchanged throughout lesion production. Coronary flow reserve was unchanged (1.7 +/- 0.8 preablation vs 1.7 +/- 1.0 postablation, P = 0.6). The media and intima were preserved in all cases. Necrosis of the adventitia was seen in one arterial segment., Conclusion: Catheter-based cryoablation can produce lesions in the musculature of the adjacent atrium and ventricle when accessed from the coronary sinus without significant injury to the coronary sinus or adjacent artery. This method has potential application as the ablation method of choice when such lesions are required.

Introduction: Striated myocardial connections between the venous wall of the coronary sinus (CS) and the left atrium have been described in humans. This aim of this study was to investigate the conduction properties and potential arrhythmogenicity of CS and left atrial myocardial connections in patients with and patients without paroxysmal atrial fibrillation (PAF)., Methods and Results: Thirty-eight patients with PAF, 52 patients with other arrhythmias, and 44 patients without arrhythmia underwent catheter mapping of the CS from the distal superoposterior part to the ostium. Catheterization of the superoposterior CS was feasible in 21, 32, and 25 subjects in the three groups, respectively (P = 0.82). Discrete double potentials or fractionated electrograms were recorded during proximal CS or right atrial pacing in 14 (66.7%), 11 (34.4%), and 5 (20.0%) patients, respectively (P = 0.004). In 29 patients, double or fractionated potentials were recorded at the distal superoposterior CS, in 3 at the mid-CS, and in 4 at the ostium. Spontaneous or induced atrial ectopy and/or tachyarrhythmias were recorded in 18 (85.7%), 12 (37.5%), and 2 (8.0%) patients in the three groups, respectively (P < 0.001) and originated from the CS in 6, 3, and 0 patients, respectively (P = 0.010)., Conclusion: Recording of double potentials is possible within the CS, particularly at its distal superoposterior part, near the left superior pulmonary vein. Their prevalence is higher in patients with PAF than in subjects with other or no arrhythmias, and their presence denotes possible sources or substrate for atrial arrhythmia.

Background: Respiratory sinus arrhythmia (RSA) is a noninvasive measure of parasympathetic tone that has been related to emotion regulatory capacity. While some previous work indicates that clinically depressed persons exhibit lower levels of RSA than do normal controls, there is nevertheless considerable between-subject variation in RSA among depressed persons. The current study evaluated the significance of variation in RSA among depressed persons by examining whether levels of RSA predicted concurrent symptomatology and the course of depressive illness., Methods: The RSA levels of 55 diagnosed depressed individuals were assessed during a paced breathing procedure at Time 1. Six months later (Time 2), participants were interviewed again to determine whether or not each had fully recovered from depression. Multinomial regression analyses were conducted to examine whether RSA predicted Time 2 clinical status., Results: Although RSA levels were not related to overall depression severity, they were associated with specific symptoms of depression: RSA was positively associated with the report of sadness and negatively associated with the report of suicidality. More strikingly, however, higher levels of RSA at Time 1 predicted non-recovery from depression at Time 2, even when statistically controlling for initial depression severity, age and medication use., Limitations: Treatment and medication use were not controlled during the follow-up period and a group of nonpsychiatric controls was not included in this study., Conclusions: A relatively high level of RSA among depressed individuals predicts a more pernicious course of illness than do lower RSA levels.

The arterial supply to the region of the coronary sinus and the interatrial septum was examined in 18 normal canine hearts. In 13 of a further 18 dogs, coronary sinus rhythm was evoked by the ligation of atrial arteries, subsequent to which the arteries were visualized by injection of latex. A stable coronary sinus rhythm is evoked by producing ischaemia in an extensive area of the right atrium, including the sinus node, the interatrial septum and Bachmann's bundle, but preserving from ischaemia the posteroinferior part of the right atrium. Microscopical examination of the hearts with coronary sinus rhythm, and comparison with 9 control hearts, failed to demonstrate any morphological centre, in the form of nodal cells, which might have been responsible for the abnormal rhythm. In the posterior part of the right atrium, the ischaemic changes failed to affect the approaches of the atrioventricular node. The approaches were predominantly composed of cells poor in myofibrils mixed to a variable degree with cells of the working myocardium. We discuss the possibilities of the development of coronary sinus rhythm and "circus movement" with regard to the participation of the approaches to the atrioventricular node.

Patterns of arterial supply to the atria were studied with respect to the coronary sinus region in 60 human hearts obtained from patients with a negative cardiac history and in 2 hearts with ECG-demonstrated coronary sinus rhythm. The atria, including the interatrial septum, were supplied by the right (40%) or left (30%) or both (30%) sinuatrial arteries which, however, did not reach as far as the posterior margin of the oval fossa and the coronary sinus. The region of the coronary sinus with the Eustachian ridge received direct branches from the trunk of the right (41%) or left (11%) coronary artery or both (48%) in the adjacent part of the coronary sulcus. Possible development of the 'coronary sinus rhythm' on the basis of multifocal damage of the sinuatrial arteries is discussed.

Six hearts from patients suffering from rhythm disorders consistent with the diagnosis of sinoatrial disease were histologically examined. Four of the patients had shown a tachycardia-bradycardia syndrome, and the remaining two patients episodes of sinus arrest or sinoatrial block with a slow junctional escape rhythm. The rhythm disorders had occurred in the setting of chronic sinoatrial disease (3 cases), acute myocardial infarction (2 cases), and diphtheritic myocarditis (1 case). The abnormalities which were more consistently observed consisted of (1) total or subtotal destruction of the sinus node (6 cases); (2) total or subtotal destruction of the areas of nodal atrial continuity (5 cases); (3) inflammatory or degenerative changes of the nerves and ganglia surrounding the node (6 cases); (4) pathological changes in the atrial wall (5 cases). Chronic or acute lesions involving the AV node, the bundle of His, and its branches or their distal subdivisions were also found in all 6 hearts. The relationship between the observed pathological changes and the physiological disorders are discussed.

This is a case report of a 63-year-old man with myotonic dystrophy in whom an ECG showed atrial flutter, complete A-V block, idioventricular rhythm with image of left bundle branch block and giant, wide and negative "T-U" waves. The microscopic study of the conduction system showed slight fibrosis of the SAN, fatty infiltration and cellular atrophy of the AVN and bundle of HIS, as wells ad basophilic degeneration of a cell at the begining of the left branch and diffuse sclerosis of the left subendocardial ramifications. Advanced coronary atherosclerosis was also found. Since only two complete pathologic descriptions of the heart in myotonic dystrophy have been reported, no definitive specificity could be atributed to this findings. It is suggested that in the present case both coronary atherosclerosis and an intrinsic myocellular dystrophy could have contributed to the final lesions of the conducting system.

Report on a systematical histological investigation of sinu-atrial nodes in strongly suspected cases of cardiac death in which no pertinent myocardial or coronary changes were found. In over 40% of the cases studied there were histopathological changes in the mixed tissue components of the sinu-atrial node which were highly suggestive of severe or fatal functional impairment.