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Objective The purpose of this study was to investigate the effects of osteopathic manipulative treatment (OMT) on cardiovascular autonomic parameters after a rugby match. Methods Resting and reactivity (ie, response to orthostasis) measures of mean arterial pressure, heart rate, and heart rate variability were assessed in 23 male players after a single session of OMT, both 18 to 20 hours after a rugby match and in a corresponding no-match condition, in a randomized, sham-controlled, crossover design. Results Signs of reduced heart rate variability and elevated mean arterial pressure and heart rate were found 18 to 20 hours after a rugby match compared with the no-match condition. A significant increase in heart rate variability and a significant reduction in mean arterial pressure were observed after OMT in both the after-match and no-match conditions. Heart rate and heart rate variability responses to orthostasis were not affected by previous match competition, but were significantly larger after OMT compared with sham treatment. Conclusion This study suggests the presence of cardiovascular autonomic alterations in rugby players after a competitive match, which may be indicative of prolonged fatigue and incomplete recovery. In these players, favorable changes in cardiovascular autonomic parameters were observed following a single session of OMT.

Depression is a well-established stress-related risk factor for several diseases, mainly for those with cardiovascular outcomes. The mechanisms that link depression disorders with cardiovascular diseases (CVD) include dysfunctions of the autonomic nervous system. Heart rate variability analysis is a widely-used non-invasive method that can simultaneously quantify the activity of the two branches of cardiac autonomic neural control and provide insights about their pathophysiological alterations. Recent scientific literature suggests that sex influences the relationship between depressive symptoms and cardiac autonomic dysfunction. Moreover, a few studies highlight a possible sex paradox: depressed women, despite a greater vagal tone, experience a higher risk of adverse cardiovascular events than depressed men. Although there are striking sex differences in the incidence of depression, scanty data on this topic are available. Lastly, studies on the heart-brain axis bidirectionality and the role of sex are fundamental not only to clarify the biological bases of depression-CVD comorbidity, but also to develop alternative therapies, where vagus nerve appears to be a promising target of non-invasive neuromodulation techniques.

Background The flow-diverter devices (FDDs) safety and effectiveness have been demonstrated by large series and meta-analyses. Due to the high occlusion rates and the acceptable morbidity rates of FDDs, the indications for their use are continuously expanding. We presented our Italian multicentric experience using the second generation of DERIVO® Embolization Device (DED®; Acandis, Pforzheim, Germany) to cure cerebral aneurysms, evaluating both middle and long-term safety and efficacy of this device. Methods Between July 2016 and September 2017 we collected 109 consecutive aneurysms in 108 patients treated using DED® during 109 endovascular procedures in 34 Italian centers (100/109 aneurysms were unruptured, 9/109 were ruptured). The collected data included patient demographics, aneurysm location and characteristics, baseline angiography, adverse event and serious adverse event information, morbidity and mortality rates, and pre- and post-treatment modified Rankin Scale scores. Midterm and long-term clinical, angiographic and cross-sectional CT/MR follow-up were recorded and collected until December 2018. Results In 2/109 cases, DED® placement was classified as technical failures. The overall mortality and morbidity rates were respectively 6.5% and 5.5%. Overall DERIVO® related mortality and morbidity rates were respectively 0% and 4.6% (5 out of 108 patients). Midterm neuroimaging follow-up showed the complete or nearly complete occlusion of the aneurysm in 90% cases, which became 93% at long-term follow-up. Aneurysmal sac shrinking was observed in 65% of assessable aneurysms. Conclusions Our multicentric experience using DED® for endovascular treatment of unruptured and ruptured aneurysms showed a high safety and efficacy profile, substantially equivalent or better compared to the other FDDs.

The inflammatory reflex is known as the body's primary defense against infection and has been implicated in a number of diseases. The magnitude of the inflammatory response is important, as an extreme or insufficient response can be differentially harmful to the individual. Converging evidence suggests that the autonomic nervous system (ANS) regulates the inflammatory reflex. Heart rate variability (HRV) can be separated into components that primarily reflect parasympathetic (PNS) or vagal activity (i.e., indices of vagally mediated HRV) and a combination of both sympathetic (SNS) and PNS influences. Given the physiological relation between the vagus and inflammatory processes, one would expect to find higher HRV, especially indices of vagally-mediated HRV, to be associated with decreased levels of inflammation via the cholinergic anti-inflammatory pathway. However, existing findings here are mixed, such that studies have also shown a positive association between indices of HRV and markers of inflammation. Therefore, the present meta-analysis aimed to synthesize existing studies, estimating the general direction and strength of the relationship between different indices of HRV and inflammatory markers. A systematic search of the literature yielded 2283 studies that were screened for inclusion eligibility (159 studies eligible for inclusion); in sum, 51 studies reported/provided adequate information for inclusion in meta-analyses. Results generally showed negative associations between indices of HRV and markers of inflammation. In this regard, the standard deviation of R-R intervals (SDNN) and power in the high frequency band of HRV (HF-HRV) showed the strongest and most robust associations with inflammatory markers compared to other time- and frequency-domain measures of HRV. Overall, we propose that indices of HRV can be used to index activity of the neurophysiological pathway responsible for adaptively regulating inflammatory processes in humans.

Stress related to parenting a child with autism spectrum disorder can differently affect caregiver's physiological reactivity to acute stress. Here, parental stress levels, psychological characteristics, and coping strategies were assessed alongside measures of heart rate, heart rate variability, and cortisol during a psychosocial stress test in mothers of children with ASD (M-ASD, n = 15) and mothers of typically developing children (n = 15). M-ASD reported significantly higher levels of parental stress, anxiety, negative affectivity, social inhibition, and a larger preference for avoidance strategies. M-ASD showed larger heart rate and cortisol responses to the psychosocial stress test. A positive relationship was found between parental stress levels and the magnitude of the cortisol stress response in both groups. The present findings indicate exaggerated physiological reactivity to acute psychosocial stress in M-ASD and prompt further research to explore the role of individual differences in mediating the effects of parental stress on physiological stress responses.

Many factors acting during the neonatal period can affect neurological development of the infant. Neonatal seizures (NS) that frequently occur in the immature brain may influence autonomic maturation and lead to detectable cardiovascular signs. These autonomic manifestations can also have significant diagnostic and prognostic value. The analysis of Heart Rate Variability (HRV) represents the most used and feasible method to evaluate cardiac autonomic regulation. This narrative review summarizes studies investigating HRV dynamics in newborns with seizures, with the aim of highlighting the potential utility of HRV measures for seizure detection and management. While HRV analysis in critically ill newborns is influenced by many potential confounders, we suggest that it can enhance the ability to better diagnose seizures in the clinical setting. We present potential applications of the analysis of HRV, which could have a useful future role, beyond the research setting.

This study investigated epigenetic risk factors that may contribute to stress-related cardiac disease in a rodent model. Experiment 1 was designed to evaluate the expression of microRNA-34a (miR-34a), a known modulator of both stress responses and cardiac pathophysiology, in the heart of male adult rats exposed to a single or repeated episodes of social defeat stress. Moreover, RNA sequencing was conducted to identify transcriptomic profile changes in the heart of repeatedly stressed rats. Experiment 2 was designed to assess cardiac electromechanical changes induced by repeated social defeat stress that may predispose rats to cardiac dysfunction. Results indicated a larger cardiac miR-34a expression after repeated social defeat stress compared to a control condition. This molecular modification was associated with increased vulnerability to pharmacologically induced arrhythmias and signs of systolic left ventricular dysfunction. Gene expression analysis identified clusters of differentially expressed genes in the heart of repeatedly stressed rats that are mainly associated with morphological and functional properties of the mitochondria and may be directly regulated by miR-34a. These results suggest the presence of an association between miR-34a overexpression and signs of adverse electromechanical remodeling in the heart of rats exposed to repeated social defeat stress, and point to compromised mitochondria efficiency as a potential mediator of this link. This rat model may provide a useful tool for investigating the causal relationship between miR-34a expression, mitochondrial (dys)function, and cardiac alterations under stressful conditions, which could have important implications in the context of stress-related cardiac disease.

The QT interval (QT) variability has been recently computed to infer cardiac control of rats. It has been suggested that QT variability markers in rats have the same physiological meaning as in humans. However, some evidences indicate a different dependence of QT on the previous RR interval (RR). Thus, the aim of this study was to compare the relation of the QT to the preceding RR in humans and in rats. Electrocardiogram was recorded in supine position (REST) and during tilt test (T90) in 23 healthy subjects and in 9 Wistar (WI) and 14 wild-type Groningen (WT) rats during the dark period. Pearson product moment correlation coefficient r computed between RR and QT was calculated for each subject or animal within each experimental condition. In humans we found that r was positive and decreased from REST to T90. Conversely, r was negative in rats and did not differ between WI and WT. The r absolute value was significantly higher in humans than in rats. Our results showed that trends toward longer RRs lead to longer QTs in humans but shorter QTs in rats and that the strength of the QT-RR association is lower in rats. We conclude that attention should be paid when using the rat model in translational studies assessing the QT-RR relation.

The osteopathic community has long hypothesized that the autonomic nervous system (ANS) represents one of the putative substrates through which osteopathic manipulative treatment (OMT) can improve body functions that have been altered by musculoskeletal alterations. Heart rate variability (HRV) is an important physiological measure of cardiac ANS activity. Emerging evidence suggests that OMT is associated with HRV changes that (i) are indicative of a larger cardiac vagal modulation, (ii) are independent from the part of the body needing treatment, (iii) occur even in the absence of musculoskeletal alterations. Yet, many questions remain unanswered, the duration of these effects and the specificity of HRV responses to different OMT techniques being perhaps the most critical. Therefore, this paper discusses prospects for future applications of HRV for the study of the influence of OMT on ANS function. Moreover, based on existing studies and preliminary data on the effects of OMT on HRV in specific pathological (hypertension) and physiological (stress exposure and recovery from sport competition) conditions that are commonly associated with increased sympathetic and/or decreased vagal activity, we propose that HRV analysis could be exploited to evaluate the effectiveness of OMT as a preventive or complementary strategy in clinical and non-clinical conditions characterized by ANS imbalance.

Context The efficacy of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) is supported by observational data and patient feedback, but there is still a need for objective, quantitative biomarkers that allow measurement of the underlying mechanisms. No study exploring the protective potential of OMTh for mental stress has been published, to the authors’ knowledge. Objectives To explore the modulating effect of OMTh on autonomic neural regulation of the heart and verifiy its ability to influence the activity of the hypothalmic-pituitary-adrenocortical axis. Methods Healthy young adult men who had never received OMTh were exposed to either a brief protocol using craniosacral techniques or sham therapy (control) involving the same anatomical areas. A laboratory stress episode consisting of a 5-minute arithmetic task participants were required to perform in front of a committee preceded the therapy sessions. Continuous electrocardiograph recordings were done before, during, and after the stress episode. Heart rate and frequency-domain parameters of heart rate variability (specifically, high-frequency component power in normalized units and the ratio of low-frequency to high-frequency power) were measured to quantify the activity of the parasympathetic nervous system and the state of sympathovagal balance at the level of the heart, respectively. Saliva samples were also collected at points throughout the study to determine cortisol levels. Results Osteopathic manipulative therapy reduced the overall chronotropic effect of the stressor (t=−2.9, Pt=−2.8, Pt=−2.3, Pt=2.7, PP=.83). Conclusion The application of a single OMTh session to healthy participants induced a faster recovery of heart rate and sympathovagal balance after an acute mental stressor by substantially dampening parasympathetic withdrawal and sympathetic prevalence. The OMTh session also prevented the typical increase in cortisol levels observed immediately after a brief mental challenge.

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges.

Background Tennis is an open-skill dynamic sport in which players over a limited period of time have to process and integrate complex visual information. Therefore, the aim of this study was to assess the effects of 12 weeks visual training (VT) in junior tennis players. Methods This was a two-arm parallel-group randomized-controlled trial in which 20 male junior players were randomized to either an experimental group (EG: N.=10; age: 15±1 year; height: 1.67±0.01 m; body mass: 52±11 kg) that performed VT or a control group (CG: N.=10; age: 15±1 year; height: 1.70±0.01 m; body mass: 52±12 kg) that was involved in a standard training for 3 sessions a week for 12 weeks. Players were tested at baseline (T0) and after 12 weeks of training (T12) for evaluate sweet spot, speed and time course between split steep and shoulder rotation during forehand, backhand, 1st and 2nd serve and return to serve. Results At T12 two-way Anova with Tuckey multiple comparison test showed significant improvements in sweet spot (P=0.032; ES: 2.1±0.3, most likely) and speed (P=0.002; ES: 1.8±0.4, very likely) during second serve were found. Moreover, the time course between the split step and shoulder rotation in forehand (P=0.0008; ES: ≥2.0±0.3, most likely), backhand (P=0.001; ES: ≥2.0±0.5, most likely), and return to serve (P=0.001; ES: 1.7±0.2, very likely) improved significantly. Conclusions These results suggest that VT was effective to improve on-court tennis performance in junior tennis players.

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats.

The variability of heart period, measured as the time distance between two consecutive QRS complexes from the electrocardiogram (RR), was exploited to infer cardiac vagal control, while the variability of the duration of the electrical activity of the heart, measured as the time interval from Q-wave onset to T-wave end (QT), was proposed as an indirect index of cardiac sympathetic modulation. This study tests the utility of the concomitant evaluation of RR variability (RRV) and QT variability (QTV) markers in typifying cardiac autonomic control of humans under different experimental conditions and of rat groups featuring documented differences in resting sympatho-vagal balance. We considered: (i) 23 healthy young subjects in resting supine position (REST) undergoing head-up tilt at 45° (T45) and 90° (T90) followed by recovery to the supine position; (ii) 9 Wistar (WI) and 14 wild-type Groningen (WT) rats in unstressed conditions, where the WT animals were classified as non-aggressive (non-AGG, n = 9) and aggressive (AGG, n = 5) according to the resident intruder test. In humans, spectral analysis of RRV and QTV was performed over a single stationary sequence of 250 consecutive values. In rats, spectral analysis was iterated over 10-min recordings with a frame length of 250 beats with 80% overlap and the median of the distribution of the spectral markers was extracted. Over RRV and QTV we computed the power in the low frequency (LF, from 0.04 to 0.15 Hz in humans and from 0.2 to 0.75 Hz in rats) band (LFRR and LFQT) and the power in the high frequency (HF, from 0.15 to 0.5 Hz in humans and from 0.75 to 2.5 Hz in rats) band (HFRR and HFQT). In humans the HFRR power was lower during T90 and higher during recovery compared to REST, while the LFQT power was higher during T90. In rats the HFRR power was lower in WT rats compared to WI rats and the LFQT power was higher in AGG than in non-AGG animals. We concluded that RRV and QTV provide complementary information in describing the functioning of vagal and sympathetic limbs of the autonomic nervous system in humans and rats.

The electrical stability of the myocardium is dependent on the dynamic balance between sympathetic and parasympathetic influences on the heart, which is reflected by heart rate variability (HRV). Reduced HRV is a proposed predictor of sudden death caused by ventricular tachyarrhythmias in cardiac patients. However, the link between individual differences in HRV and ventricular tachyarrhythmic risk in populations without known pre-existing cardiac conditions is less well explored. In this study we investigated the extent to which individual differences in resting state HRV predict susceptibility to spontaneous and pharmacologically-induced ventricular arrhythmias in healthy rats. Radiotelemetric transmitters were implanted in 42 adult male Wild-type Groningen rats. ECG signals were recorded during 24-h resting conditions and under &beta, adrenoceptor pharmacological stimulation with isoproterenol and analyzed by means of time- and frequency-domain indexes of HRV. No significant association was found between individual differences in resting measures of HRV and spontaneous incidence of ventricular arrhythmias. However, lower resting values of HRV predicted a higher number of ventricular ectopic beats following &beta, adrenergic pharmacological stimulation with isoproterenol (0.02 mg/kg). Moreover, after isoproterenol administration, one rat with low resting HRV developed sustained ventricular tachycardia that led to death. The present results might be indicative of the potential utility of HRV measures of resting cardiac autonomic function for the prediction of ventricular arrhythmias, particularly during conditions of strong sympathetic activation, in populations without known cardiac disease.

Context European beef production is facing fresh challenges on various fronts: increasing public concern on animal welfare; declining EU meat consumption; and, conversely, expected growth in global demand for meat. The Italian National Reference Centre for Animal Welfare (CReNBA) has developed an assessment protocol for collecting information about beef cattle welfare and biosecurity conditions, with the intention of better understanding animal needs and disseminating best practices. Aims The protocol was applied on Italian and Irish farms, and the results were used as a starting point for a specific statistical analysis for comparing animal welfare and biosecurity levels in the two countries. Methods The protocol consists of animal-based measures and non-animal-based measures (management-based and resource-based indicators) and has been designed to determine the major hazards and benefits that can influence cattle health and welfare, including the presence of biosecurity issues. The outcomes of welfare and biosecurity assessments conducted during November 2016–July 2017 of 40 Irish beef herds reared indoors were compared with those of 85 Italian beef units assessed over the same period. Differences obtained within each beef-unit distribution were calculated by the VARNC index (diversity index), and a distance estimate of the beef-unit distribution from a hypothetical ideal condition was calculated by using the distance from ideal (dfi) index. Key results The dfi index revealed that Irish farms were closer to the ideal condition for the measures ‘experience and training of stockpersons’, ‘water provision’, ‘handling facilities’, ‘restraint facilities’, and ‘temperature, humidity and ventilations conditions’. Italian farms were closer to the ideal condition for ‘diet calculation and feed quality’, ‘feeding management’, ‘feeding place dimension’, ‘cleanliness of water points’, ‘cleanliness of floors’, ‘type of floors’, ‘cleanliness of animals’, and ‘integument alterations’. In contrast to the Italian farms, there was particular awareness of the importance of biosecurity on Irish farms. Conclusions The results revealed intrinsic management and housing differences between the two rearing systems, although only few dissimilarities were found in the animal outcomes: in fact, the assessment of the animal-based measures gave very similar results for the two countries, except for ‘cleanliness of the animals’ and ‘integument alterations’. Implications In the face of global challenges affecting the pursuit of farming sustainability, farmers should be encouraged to improve safeguards for animal welfare and reduce the spread of animal diseases. This can be achieved by facilitating knowledge exchange internationally.

Prolonged or repeated activation of the stress response can have negative psychological and physical consequences. The prefrontal cortex (PFC) is thought to exert an inhibitory influence on the activity of autonomic and neuroendocrine stress response systems. In this study, we further investigated this hypothesis by increasing PFC excitability using transcranial direct current stimulation (tDCS). Healthy male participants were randomized to receive either anodal (excitatory) tDCS (

This review offers a perspective of the utility of rodent models of stress for identifying sources of individual vulnerability to depression and cardiovascular disease comorbidity. Differential stress susceptibility is found in rodents exposed to repeated social defeat as a function of their coping style. Specifically, passive coping rodents show an increase in inflammatory processes within the brain that favour the development of depressive-like symptoms and cardiovascular abnormalities. Similarly, only a sub-group of rats develops depressive-like symptoms following chronic mild stress exposure. Cardiovascular changes differ depending on individual stress susceptibility and may be related to an imbalance in the autonomic regulation of cardiac function in stress vulnerable subjects. Rodent models of stress that take into account individual phenotypic variations are useful for a better understanding of the role of neuroinflammatory and autonomic processes in the development of comorbid depression and cardiovascular disease under stressful conditions.

Sleep is altered in response to an immune challenge: non-rapid eye movement (NREM) sleep is increased and fragmented, REM sleep is inhibited. Sleep and immune response are affected by stress: several stressors inhibit sleep and increase waking time; stress-induced cortisol secretion affects the immune response, with immunosuppressive effects. Different levels of trait aggressiveness are associated with specific patterns of neuroendocrine and autonomic stress responsiveness. Aim of this study was to test the hypothesis that trait aggressiveness, by affecting response to stressors, modifies sleep alterations induced by the activation of the immune response. To this aim, rats were selected on the basis of their latency time to attack a male intruder in the resident-intruder test. Animals were instrumented for chronic recordings of sleep-wake activity and injected, intraperitoneally, with an immune challenge (250 μg/kg lipopolysaccharide – LPS, a component of gram-negative bacterial cell wall). Here we report that high aggressive (HA) rats responded to an immune challenge with a 24-h long increase in cortical brain temperature. During the first 12 post-injection hours, HA rats also responded with a prolonged increase in NREM sleep amount, and a 5-h long and continuous inhibition of REM sleep. In HA rats, the LPS-induced increase in the amount of time spent in NREM sleep was due to an increase in the number of episodes of this sleep phase, without any change in the bout duration. The LPS-induced REM sleep inhibition observed in HA rats was due to a decrease in both the number and duration of REM sleep bouts. In HA rats, during REM sleep, LPS administration significantly reduced the power of the EEG theta band. In non-aggressive (NA) rats, in response to LPS administration, cortical brain temperature was increased only for two hours, NREM sleep was unaffected, and REM sleep inhibition was scattered along the first 8 post-injection hours. The LPS-induced changes in the number of NREM sleep bouts of NA rats were limited to few and scattered hours, with a change in bout duration only in a single hour. A combination of decreases, in few hours, in both REM sleep bouts and their duration contributed to the REM sleep inhibition observed in NA rats. In NA rats, the power of EEG theta band was not modified, during REM sleep, by LPS administration. Gross motor activity was inhibited in both HA and NA rats. Results of this study show that trait aggressiveness affects febrile and sleep responses to an immune challenge.

Objective Seizures are frequently observed in neurological conditions affecting newborns. Since autonomic alterations are commonly associated with neonatal seizures (NS), we investigated the utility of heart rate variability (HRV) indexes of cardiac autonomic regulation for NS detection. Methods HRV analysis was conducted on ECG tracings recorded during video-EEG monitoring in newborns with NS and matched-controls. The effects of gestational age on HRV were also evaluated. Results Newborns with NS showed lower resting state HRV compared to controls. Moreover, seizure episodes were characterized by a short-lasting increase in vagal indexes of HRV. Pre-term newborns with NS had a lower HRV than full-term at rest. In pre-term newborns, no changes in HRV were observed before and during NS. On the contrary, full-term newborns showed significantly higher HRV before and during NS compared to the respective baseline values. Conclusion Our data point to resting autonomic impairment in newborns with NS. In addition, an increment in HRV has been observed during NS only in full term newborns. Significance Although these findings do not allow validation of HRV measures for NS prediction and detection, they suggest that a putative protective vagal mechanism might be adopted when an advanced maturation of autonomic nervous system is achieved.

Introduction Fatigue is a frequent, disabling, and difficult to treat symptom in neurological disease and in other stress-related conditions; Integrated Imaginative Distention (IID) is a therapy combining muscular and imaginative relaxation, feasible also in disabled subjects; the DIMMI SI trial was planned to evaluate IID efficacy on fatigue. Methods The design was a parallel, randomised 1:1 (intervention:waiting list), controlled, open-label trial. Participants were persons with multiple sclerosis (pwMS), persons with insomnia (pwINS), and health professionals (HP) as conditions related to fatigue and stress. The primary outcome was the post-intervention change of fatigue; secondary outcomes were changes in insomnia, stress, and quality of life (QoL). Eight IID weekly training group sessions were delivered by a skilled psychotherapist. The study lasted 12 months. Results One hundred and forty-four subjects were enrolled, 48 for each condition. The mean change in Modified Fatigue Impact Scale (MFIS) score among exposed was 7.7 [95% CI 1.1, 14.4] (P = 0.023) in pwMS; 7.1 [1.9, 12.3] (P = 0.007) among pwINS, and 11.3 [4.3, 18.2] among HP (P = 0.002). At the last follow-up, the benefit was confirmed on physical fatigue for pwMS, on total fatigue for pwINS and HP. Conclusions DIMMI SI is the first randomized controlled trial evaluating the efficacy of IID on fatigue. IID resulted a complementary intervention to reduce fatigue in stress-related conditions, in both health and disease status. NCT02290990ClinicalTrials.gov. Electronic supplementary material The online version of this article (doi:10.1007/s40120-017-0081-9) contains supplementary material, which is available to authorized users.

Objective: Despite a well-documented association between stress and depression with cardiac morbidity and mortality, there is no satisfactory explanation for the mechanisms linking affective and cardiac disorders. This study investigated cardiac electrophysiological properties in an animal model of depression. Methods: Depression-relevant physiological and behavioral parameters were measured in adult male wild-type rats during and after a period of intermittent social defeat stress (n = 12) or empty cage exposure (control, n = 11). Nine days after the last defeat/empty cage exposure, high-definition epicardial mapping was performed under anesthesia. Results: Stressed animals versus controls displayed a larger reduction in the circadian amplitude of heart rate (-32% [3%] versus 13 [2%]; p = .001) and body temperature (-33% [4%] versus -5% [2%]; p = .001) rhythms, had smaller body weight gain (+11% [1%] versus +17% [1%]; p

Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's “pinwheel experiment,” usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites ( n = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: 1) along fiber direction, on right and left ventricular free walls ( n = 23), initiating figure-eight reentry ( n = 17) and tachycardia ( n = 12), and 2) across fiber direction, on lower interventricular septum ( n = 3), initiating spiral wave reentry ( n = 2) and tachycardia ( n = 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response ( n = 13) characterized by focal activations. NEW & NOTEWORTHY We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations.

Our aim was to assess the impact of motor activity and of arousing stimuli on respiratory rate in the awake rats. The study was performed in male adult Sprague–Dawley (SD, n = 5) and Hooded Wistar (HW, n = 5) rats instrumented for ECG telemetry. Respiratory rate was recorded using whole-body plethysmograph, with a piezoelectric sensor attached for the simultaneous assessment of motor activity. All motor activity was found to be associated with an immediate increase in respiratory rate that remained elevated for the whole duration of movement; this was reflected by: i) bimodal distribution of respiratory intervals (modes for slow peak: 336 ± 19 and 532 ± 80 ms for HW and SD, p

In patients with ischemic stroke, endovascular treatment results in a higher rate of recanalization of the affected cerebral artery than systemic intravenous thrombolytic therapy. However, comparison of the clinical efficacy of the two approaches is needed.We randomly assigned 362 patients with acute ischemic stroke, within 4.5 hours after onset, to endovascular therapy (intraarterial thrombolysis with recombinant tissue plasminogen activator [t-PA], mechanical clot disruption or retrieval, or a combination of these approaches) or intravenous t-PA. Treatments were to be given as soon as possible after randomization. The primary outcome was survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms, and 6 death) at 3 months.A total of 181 patients were assigned to receive endovascular therapy, and 181 intravenous t-PA. The median time from stroke onset to the start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P0.001). At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence interval, 0.44 to 1.14; P=0.16). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rate.The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA. (Funded by the Italian Medicines Agency, ClinicalTrials.gov number, NCT00640367.).

In humans, depression is often triggered by prolonged exposure to psychosocial stressors and is often associated with cardiovascular comorbidity. Mounting evidence suggests a role for endocannabinoid signaling in the regulation of both emotional behavior and cardiovascular function. Here, we examined cardiac activity in a rodent model of social stress-induced depression and investigated whether pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid anandamide, exerts antidepressant-like and cardioprotective effects. Male Wistar Kyoto rats were exposed to five weeks of repeated social stress or control procedure. Starting from the third week, they received daily administration of the selective FAAH inhibitor URB694 (0.1 mg/kg, i.p.) or vehicle. Cardiac electrical activity was recorded by radiotelemetry. Repeated social stress triggered biological and behavioral changes that mirror symptoms of human depression, such as (i) reductions in body weight gain and sucrose solution preference, (ii) hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and (iii) increased immobility in the forced swim test. Moreover, stressed rats showed (i) alterations in heart rate daily rhythm and cardiac autonomic neural regulation, (ii) a larger incidence of spontaneous arrhythmias, and (iii) signs of cardiac hypertrophy. Daily treatment with URB694 (i) increased central and peripheral anandamide levels, (ii) corrected stress-induced alterations of biological and behavioral parameters, and (iii) protected the heart against the adverse effects of social stress. Repeated social stress in Wistar Kyoto rats reproduces aspects of human depression/cardiovascular comorbidity. Pharmacological enhancement of anandamide signaling might be a promising strategy for the treatment of these comorbid conditions.

European Directive 96/22/EC, which controls veterinary residues in animals, does not permit the presence of synthetic growth promoters in products of animal origin or in livestock. Boldenone is categorized in class A3 (growth promoters -- steroids) and is thus a banned substance. Testing of veal urine for banned substances is part of the European Union statutory programme for animals going into the food chain. In relation to this monitoring, three studies were conducted to investigate the apparent presence of the banned growth promoter boldenone in veal urine, which was suspected as being caused by interference from faecal contamination of the sample. In the first study, urine samples were collected at different times (time 0 and after 30 min) using (1) a conventional zoonotechnical apron and (2) a technique designed specifically to avoid faecal contamination ('kettle'). This resulted in samples that were, respectively, positive and negative for the presence of alpha-boldenone (alpha-BOL). In a second study, urine samples negative to alpha-BOL were collected from eight veal calves, but became positive after deliberate faecal contamination. In a third study, data obtained from the Italian RNP (Residual National Program) indicated that 18.1% of 3295 urine samples collected using the zootechnical apron were positive for alpha-BOL and 2.1% for beta-boldenone (beta-BOL), whilst of 902 samples collected using the kettle, beta-BOL was not detected in any samples and only 0.2% were positive to alpha-BOL, in concentrations lower than 2 ng ml(-1). These results further support the supposition that faecal contamination of the urine during sample collection can lead to false-positive results during boldenone analysis.

In normal rats, we analysed the arrhythmogenic role of intrinsic action potential duration (APD) heterogeneity. In each animal, ventricular arrhythmic events (VAEs) occurring spontaneously and during the exposure to an acute social challenge were telemetrically recorded. Action potentials were recorded from isolated left ventricular myocytes, at a pacing rate of 5 Hz (patch clamp: current-clamp mode). APDs were measured at -20 mV, -30 mV, -40 mV, -50 mV and -60 mV. The difference between the shortest and the longest APD was also computed, as an index of individual APD heterogeneity. Animals predisposed to stress-induced arrhythmias showed higher values of APD and APD heterogeneity as compared with the remaining rats. We concluded that, in the normal heart, a large intrinsic APD heterogeneity resulting from specific electrophysiological properties of ventricular myocytes is not in itself arrhythmogenic, but can predispose towards arrhythmia development under certain conditions, such as autonomic activation.

In humans, there are large individual differences in the levels of vagal modulation of resting heart rate. High levels are a recognized index of cardiac health, whereas low levels are considered an important risk factor for cardiovascular morbidity and mortality. Several factors are thought to contribute significantly to this inter-individual variability. While regular physical exercise seems to induce an increase in resting vagal tone, chronic life stress and psychosocial factors such as negative moods and personality traits appear associated with vagal withdrawal. Preclinical research has been attempting to clarify such relationships and to provide insights into the neurobiological mechanisms underlying vagal tone impairment/enhancement. This paper focuses on rat studies that have explored the effects of stress, psychosocial factors and physical exercise on vagal modulation of resting heart rate. Results are discussed with regard to: (i) individual differences in resting vagal tone, cardiac stress reactivity and arrhythmia vulnerability; (ii) elucidation of the neurobiological determinants of resting vagal tone.

An increased activity of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias. Changes in average R-R interval, R-R interval variability (indirect measure of sympathovagal balance), occurrence of arrhythmias, and plasma norepinephrine concentrations were measured during a social stress episode (defeat) in two strains of rats, Wistar and wild type, which were supposed to differ in their autonomic stress responsiveness. Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from healthy, freely moving animals. R-R interval variability was estimated by the following time-domain parameters: the standard deviation of the mean R-R interval, the coefficient of variance, and the root mean square of successive differences in R-R interval. Average R-R interval and R-R interval variability measures, as well as plasma norepinephrine concentrations, indicated a higher sympathetic tone, a larger sympathetic responsiveness, and a lower parasympathetic antagonism after sympathetic activation in wild-type animals, which also showed a much higher incidence of arrhythmias (ventricular premature beats), compared with Wistar rats. These two strains might represent a valuable experimental model for studying the mechanisms (cellular/electrophysiological) responsible for the susceptibility to arrhythmias in healthy individuals exposed to stressful situations.

In humans, variants of the fat mass and obesity associated (FTO) gene have recently been associated with obesity. However, the physiological function of FTO is not well defined. Previous investigations in mice have linked FTO deficiency to growth retardation, loss of white adipose tissue, increased energy metabolism and enhanced systemic sympathetic activation. In this study we investigated for the first time the effects of global knockout of the mouse FTO gene on cardiac function and its autonomic neural regulation. ECG recordings were acquired via radiotelemetry in homozygous knockout (n = 12) and wild-type (n = 8) mice during resting and stress conditions, and analyzed by means of time- and frequency-domain indexes of heart rate variability. In the same animals, cardiac electrophysiological properties (assessed by epicardial mapping) and structural characteristics were investigated. Our data indicate that FTO knockout mice were characterized by (i) higher heart rate values during resting and stress conditions, (ii) heart rate variability changes (increased LF to HF ratio), (iii) larger vulnerability to stress-induced tachyarrhythmias, (iv) altered ventricular repolarization, and (v) cardiac hypertrophy compared to wild-type counterparts. We conclude that FTO deficiency in mice leads to an imbalance of the autonomic neural modulation of cardiac function in the sympathetic direction and to a potentially proarrhythmic remodeling of electrical and structural properties of the heart.

Cardiovascular disease increases with age as well as alterations of cardiac electrophysiological properties, but a detailed knowledge about changes in cardiac electrophysiology relevant to arrhythmogenesis in the elderly is relatively lacking. The aim of this study was to determine specific age-related changes in electrophysiological properties of the ventricles which can be related to a structural-functional arrhythmogenic substrate. Multiple epicardial electrograms were recorded on the ventricular surface of in vivo control and aged rats, while arrhythmia vulnerability was investigated by premature stimulation protocols. Single or multiple ectopic beats and sustained ventricular arrhythmias were frequently induced in aged but not in control hearts. Abnormal ventricular activation patterns during sinus rhythm and unchanged conduction velocity during point stimulation in aged hearts suggest the occurrence of impaired impulse conduction through the distal Purkinje system that might create a potential reentry substrate.

Previously, we observed that a single low-intensity premature ventricular stimulation could occasionally induce spontaneous ectopic beats in normal rat hearts. Possible hypothesis for the arrhythmia is that a premature beat can encounter a zone of conduction block to initiate reentry. However, enhanced dispersion of repolarization, a necessary condition for initiation of reentry, is unlikely to be present in normal myocardium. Thus, the main objective of the present study was to perform detailed pace mapping measurements in normal ventricular myocardium with a view to identify pacing sites and critical coupling intervals which could induce spontaneous ectopic beats and to characterize the reentrant circuits.

In humans, there is unequivocal evidence of an association between anxiety states and altered respiratory function. Despite this, the link between anxiety and respiration has been poorly evaluated in experimental animals. The primary objective of the present study was to investigate the hypothesis that genetic lines of rats that differ largely in their anxiety level would display matching alterations in respiration. To reach this goal, respiration was recorded in high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) male rats using whole-body plethysmography. In resting state, respiratory rate was higher in HABs (85 ± 2 cycles per minute, cpm) than LABs (67 ± 2 cpm, p

Plasma concentrations of noradrenaline (NA), adrenaline (A) and corticosterone (CORT) were determined in male rats before, during and after 15-min exposure to social stress (defeat experience), novelty stress (presentation of a novel object) and conditioned emotional stress (presentation of a known noxious stimulus). Blood was frequently sampled from freely moving animals via a jugular vein catheter externalized on top of the skull. All three stressful events provoked significant, rapid rises of plasma NA, A and CORT levels over baseline values. However, social stress produced a markedly higher neuroendocrine response as compared to novelty and conditioned emotional stress, both in terms of intensity and duration of the effects. These differences are presumably due to the higher degree of emotional arousal and somatomotor activation provoked by the social challenge.

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= −23 ± 3 beats per minute (bpm)] and light/inactive (Δ= −20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= −54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= −16 ± 3 bpm, inactive phase Δ= −19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.

Ventricular arrhythmias are frequently observed in the elderly population secondary to alterations of electrophysiological properties that occur with the normal aging process of the heart. However, the underlying mechanisms remain poorly understood. The aim of the present study was to determine specific age-related changes in electrophysiological properties and myocardial structure in the ventricles that can be related to a structural-functional arrhythmogenic substrate. Multiple unipolar electrograms were recorded in vivo on the anterior ventricular surface of four control and seven aged rats during normal sinus rhythm and ventricular pacing. Electrical data were related to morphometric and immunohistochemical parameters of the underlying ventricular myocardium. In aged hearts total ventricular activation time was significantly delayed (QRS duration: +69%), while ventricular conduction velocity did not change significantly compared with control hearts. Moreover, ventricular activation patterns displayed variable numbers of epicardial breakthrough points whose appearance could change with time. Morphological analysis in aged rats revealed that heart weight and myocyte transverse diameter increased significantly, scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium, and gap junction connexin expression decreased significantly in ventricular myocardium compared with control rats. Our results show that in aged hearts delayed total ventricular activation time and abnormal activation patterns are not due to delayed myocardial conduction and suggest the occurrence of impaired impulse propagation through the conduction system leading to uncoordinated myocardial excitation. Impaired interaction between the conduction system and ventricular myocardium might create a potential reentry substrate, contributing to a higher incidence of ventricular arrhythmias in the elderly population.

Cardiac arrhythmias are frequent in the elderly population, perhaps secondary to an increased prevalence of hypertension and coronary artery disease as well as aging related changes resulting in loss of pacemaker cells and degenerative alteration of the conduction system. Independent from underlying structural heart disease, advanced age alone appears to be a risk factor for increased susceptibility to ventricular arrhythmia. However, the electrophysiological basis of this phenomenon is still unclear. Thus, it is important to assess and to define the underlying arrhythmogenic substrate. The aim of the present study was to identify a likely structural-functional ventricular arrhythmogenic substrate in aged hearts. For this purpose ventricular activation patterns were measured in control (n = 4) and aged (n = 10) in vivo rat hearts by recording unipolar electrograms with an epicardial, 1 mm resolution, 8 times 8 electrode array, during pacing and spontaneous or induced ventricular ectopic beats. Our results in aged hearts suggest that peripheral conduction system might be involved in perpetuating sequences of ventricular ectopic beats, regardless of their origin.

Methods The study was conducted in Umbria (Italy) on three adult populations affected by disabling neurological diseases: Epilepsy, Stroke and Dementia. It was structured through the use of Focus Groups. Patients and carers were recruited by telephone calls from the patients lists maintained by hospital wards, outpatients clinics and charities. From the respondents, two groups of patients and two groups of carers were formed for each level of severity of the disease based on the modified Rankin Scale (0-2; 3; 4-5). Two psychologists conducted recruitment, used predetermined semi-structured questions to interview attendees, and moderated group discussions. These were digitally recorded and transcribed into text-files, blindly analyzed and elaborated into key semantic meanings expressing perceived needs and emotions. Codes were analyzed using «Concordance» software, to identify the key semantic significants expressing the perceived needs and emotions in relation to the disease and its consequences. Results Preliminary results of focus groups in Epilepsy are presented: 61 patients and carers participated (40% of people contacted), organized into 5 groups of patients, and 6 groups of Caregivers. Most frequently expressed needs were “assistance”, expressed 3 times more frequently by carers than patients, “Experience sharing” and “need for knowledge” expressed 2 times more frequently by patients. The need for assistance was directly proportional with disease severity, while the need for knowledge inversely proportional with disease severity. Emotions most frequently expressed were anger and fear, proportional with disease severity, but also hope, resignation and acceptance. These two were 2 and 5 times each more frequently expressed by patients. Anger and hope were equally distributed among patients and carers.

Methods Stroke, dementia and epilepsy are the greater and most common disabling neurological diseases and were considered in this study. For each mentioned disease we will perform a Systematic reviews of all randomized clinical trials published in any language over the last 5 years with the aim of identifying and analyzing the outcome measures used in the evaluation of any kind of intervention. Fifteen Neurologists are filling out a single computerized form for each single trial assigned. The form has the following information: Characteristics of the trial with relevance on quality, Extent of variability in end points selected and their domains, Scales or techniques used to make the measurement, type of analysis applied and time of measurement, Presence of attrition bias in terms of fraction of patients reported by end points on the number enrolled in the study, Presence of outcome reporting bias in terms of end points declared and non-reported, end points not declared but reported, Source of funding. The valuation of patient and career needs and emotions will be performed with focus group discussions in a parallel section of the study.

In rat models of cardiac hypertrophy (moderate aortic coarctation: ACm, n =18; severe aortic coarctation: ACs, n =27; aging: OLD, n =25; spontaneous chronic hypertension: SHR, n =18) and properly matched control animals (C ACm , n =17; C ACs , n =19; C OLD , n =24; C SHR , n =22), we investigated the relative contribution of intense autonomic activity and cardiac structural damage to ventricular arrhythmogenesis. We used an “in vivo” to tissue level approach, by correlating in the same animal: (i) social stress-induced ventricular arrhythmias, telemetrically recorded, and (ii) left ventricular weights (LVW) and amount and geometrical properties of myocardial fibrosis (MF). Arterial blood pressure was significantly higher in ACm (+11%), ACs (+28%) and SHR (+34%) than in controls. LVW were approximately 20% greater in ACm, ACs and OLD and 50% greater in SHR. MF was about twice as great and characterized by more frequent occurrence of microscopic scarring in ACm and ACs, and eight times greater and associated with both a higher number and a larger size of fibrotic foci in OLD and SHR compared to controls. Social stress increased ventricular arrhythmia vulnerability in all models of cardiac hypertrophy, as well as in controls. The arrhythmogenic action of stress was facilitated in ACs, OLD and SHR. A correlation between structural cardiac remodeling and ventricular arrhythmias was found only in SHR and OLD, which exhibited the greatest increase in LVW and/or MF. Social stress proved to be a valuable tool for analyzing the combined effects of autonomic stimulation and altered myocardial substrate on the genesis of potentially life-threatening arrhythmias in social animals.