Cardiac Autonomic Stress Responsivity in rodents

La risposta di stress coinvolge un insieme di attivazioni fisiologiche e comportamentali adottate dall’organismo per reagire adeguatamente ai cambiamenti ambientali di varia natura e intensità. In situazioni in cui un animale eserciti un limitato controllo sugli stimoli stressanti, alcuni cambiamenti fisiologici e comportamentali possono aumentare la possibilità di sviluppare disturbi psicosomatici, come le patologie cardiovascolari. In particolare, lo stress sociale è stato indicato indurre una consistente attivazione, a breve e lungo termine, del sistema simpatico-adrenomidollare del surrene (SAM) e dell’asse ipotalamo-cipofisi-corticosurrene (HPA). Gli esperimenti inclusi in questa tesi sono legati da una caratteristica comune, che è quella di studiare ed evidenziare maggiormente le conseguenze pato-fisiologiche dello stress sociale in modelli animali di topo e ratto. In particolare, sono stati valutati gli effetti cardiovascolari, neuroendocrini, e comportamentali dell’esposizione a stress acuti o cronici, sociali o non sociali. Inizialmente, sono state analizzate le conseguenze a lungo termine dello stress prenatale, più specificatamente, è stato esaminato se l’esposizione a stress durante la terza settimana di gravidanza poteva predisporre allo sviluppo di patologie, come la depressione, in età adulta. In seguito, è stato studiato se, nell’adulto, il ruolo di un episodio sociale avverso, come la sconfitta sociale, associato ad un prolungato periodo di isolamento sociale poteva produrre effetti simili alla sintomatologia depressiva. Successivamente, si sono studiati i meccanismi centrali coinvolti nell’aumento della componente simpatica durante lo stress, e per questo fine, è stato somministato sistemicamente l’8-OH-DPAT, un’agonista dei recettori 5-HT1A dotato di proprietà simpatolitiche centrali. Infine, ho studiato il ruolo che questi recettori hanno nella risposta cardiovascolare di stress in un ceppo di topo modificato geneticamente. Nel capitolo 2 ho esaminato gli effetti a lungo termine della manipolazione fetale, in particolare utilizzando un paradigma sperimentale di stress psicologico, che prevedeva di stressare le madri durente la terza settimana di gravidanza. Esperienze stressanti subite dalla madre in questa finestra temporale, possono avere profondi effetti a lungo-termine sulla fisiologia e sul comportamento della prole. I dati riportati in questa tesi, suggeriscono che lo stress prenatale induceva un’aumentata sensibilità agli stress durante l’età adulta. In particolare, quando i ratti stressati prenatalmente erano esposti a stress ambientali, emozionali e fisici in età adulta, mostravano sintomi di depressione. Nel capitolo 3 ho esplorato gli effetti a carico della bilancia simpatovagale cardiaca, dell’andamento dei ritmi circadiani di frequenza cardiaca, temperatura corporea e attività motoria, e della morfologia cardiaca, dovuti all’esposizione ad un episodio sociale avverso seguito da un lungo periodo di isolamento sociale. I risultati supportano l’idea che lo stress psicosociale può indurre depressione, infatti, questo tipo di manipolazione produce nei ratti effetti strutturali, fisiologici e comportamentali analoghi a quelli riscontrati nei pazienti depressi. Nel capitolo 4 è stato utilizzato ancora una volta il modello della sconfitta sociale per studiare i meccanismi neurali alla base dell’aritmogenesi indotta dall’esposizione allo stress. L’iniezione dell’agonista serotonergico attenuava la tachicardia e l’ipertermia indotte dallo stress sociale, e la zatebradina, un bloccante della corrente pacemaker, causava un prolungamento dell’intervallo RR. Questo studio mette in evidenza il potenziale ruolo dell’8-OH-DPAT nell’abolire gli eventi aritmici, probabilmente sopprimendo la componente simpatica attivata in risposta ad uno stress. Infine, nel capitolo 5 ho utilizzato un modello di topo knockout per il recettore 5-HT1A della serotonina per valutare lo stato della bilancia simpatovagale cardiaca in topi esposti a stress psicosociale cronico. I risultati confermano il ruolo di questi recettori nel controllo cardiovascolare durante l’esposizione allo stress. In particolare, i dati riportati nella tesi propongono che la delezione di questi recettori comporti un’aumentata tachicardia e una ridotta modulazione della componente vagale.Stress response is a set of functional and behavioral activations adopted by an organism to cope adequately with environmental challenges of varying nature and intensity. In situations in which an animal exerts limited control over environmental stimuli, such physiological and behavioral changes may ultimately produce increased susceptibility to psychosomatic disorders such as cardiovascular diseases. In particular, social stressors have been shown to induce robust short and long-term activations of the sympathetic-adrenomedullary system and the pituitary-adrenocortical axis (HPA). The experiments included in this thesis are linked by a common threat, that is that they were all aimed at providing further insights on cardiovascular (patho)physiological consequences of social stressors in rodents. In particular, I studied cardiovascular, neuroendocrine, and behavioral effects of exposure to acute or chronic, social or non-social stress in rats and mice. In the first time, I chosed to investigate the long-term consequences of foetal manipulation, more specifically, I examined if exposition to stress during the last week of pregnancy can predispose to develop pathologies as depression in adult life. Subsequently, I studied, in adulthood, the role of an adverse stress episode such as social defeat followed by a prolonged period of isolation in producing effects which resemble some of the symptoms of depression in humans. The next step was tried the central mechanisms generating increases in cardiac sympathetic activity during stress, and for this aim I used systemic administration of 8-OH-DPAT, a 5-HT1A agonist possessing central sympatholytic properties. Finally, I chosed to study the role of these receptors in cardiovascular stress response using mouse knockout for serotonin 1A receptors. In Chapter 2 I examined the long-term effects of foetal manipulation, in particular I used an appropriate experimental paradigms of psychological prenatal stress, like the repeated restraint test on mothers in the last week of pregnancy. There is a growing body of evidences that demonstated that adverse life events experienced by the pregnant mother and her reactions to them can produce alterations in the foetal environment, which in turn may have profound, long-term effects on the offspring physiology and behaviour. The new data reported in this thesis suggested that prenatal stress induced heightened sensitivity to acute stressors occurring in adulthood. In particular, when exposed to environmental, emotional, and physical challenges in adult age, prenatally stressed rats showed depressive-like symptoms. Specifically, theses rats exhibited longer-lasting adrenocortical stress responsivity, disturbances of circadian rhythmicity of heart rate, body temperature and physical activity, and increased adrenal weight as compared to controls. The successive step was study the role of stress in the development of depression syndrome. In contrast with the Chapter 2 where I applied a model of prenatal stress in order to study long-lasting changes, in Chapter 3 I implemented an animal model of depression in adulthood. In particular, the study in this chapter, made use of the exposure to an adverse stress episode (social defeat) followed by prolonged social isolation. I explored the effects of these manipulations on acute adrenocortical and cardiac sympathovagal stress reactivity, sucrose intake, circadian rhythmicity of heart rate, body temperature, and physical activity, myocardial and adrenal structure. These results support the current view that the psychosocial stress can induce depression, in fact, social defeat and a prolonged period of isolation produces some structural, physiological, and behavioral effects in rats, which resemble those observe in depresse and chronically stressed subjects. These effects mainly consisted in HPA axis negative feedback dysfunction, adrenal gland enlargement, biological rhythm alterations, and the establishment of an anhedonic condition. In Chapter 4 I applied a behavioral stress paradigm, social defeat, for studying the neural mechanisms underlying stress induced arrthythmias, and I tested whether such arrthythmias could be suppressed by systemic administration of 8-OH-DPAT, a 5-HT1A agonist possessing central sympatholytic properties. Successively, before the administration of 8-OH-DPAT, the male rats were pre-treated with zatebradine, a blocker of the pacemaker current. The injection of the serotonergic agonist, attenuated the tachycardia and hyperthermia induced by social stress, and zatebradine caused prolongation of RR interval. This study further delineates the potential role of 8-OH-DPAT, in fact systemic administration of agonist abolishes arrhythmic events, likely by suppressing stress-induced cardiac sympathetic outflow. As suggested by previous studies and by results reported in Chapter 4, the activation of central 5-HT1A receptors has sympatholytic effects, with attenuation of stress-induced heart rate and blood pressure raises. In Chapter 5 I evaluated cardiac sympathovagal modulation in mice lacking 5-HT1A receptors and exposed to chronic psychosocial stress. Again, the result confirmed the role of these receptors in the cardiovascular control during stress conditions. In particular, data presented in this section propose that the deletion of 5-HT1A receptors enhances stress-induced tachycardia and reduces vagal modulation of heart rate

Sweat Rate Monitoring During Maximal Exercise in Healthy Soccer Players: A Close Relationship with Anaerobic Threshold

Purpose: Sweating is a homeostatic phenomenon regulated by both thermal and non-thermal factors during exercise. There are no evidences whether anaerobic metabolism induced during isotonic maximal exercise can modify sweating rate. Aim of the study was to investigate the relationship between sweating and the anaerobic threshold (AT). Methods: The sweat rate in thirteen soccer players was measured by a sensor providing a continuous monitoring of sweating, whereas the anaerobic threshold was assessed with ergospirometry during maximal isotonic stress test. During stress test, cardio respiratory, metabolic and galvanic skin response (GSR) were also monitored. Results: At AT, stroke volume, heart rate and systolic blood pressure significantly increased (p<0.001), as well as GSR (p=0.04). Sweat rate abruptly increased at AT compared with rest (p<0.001). AT-to-rest changes in sweating rate were associated with concomitant changes in VO2 max (r=0.82, p<0.001), heart rate (r=0.73, p=0.04) and GSR (r=0.79, p=0.001). Conclusion: We suggest that aerobic-to-anaerobic switch is associated with a sudden increase in sweating likely induced by sympathetic activation. Considering the role of hydration in preserving the health status and optimizing the physical performance, we believe that this finding may have relevant practical implication in particular in soccer, which is characterized by an alternation of aerobic and anaerobic phases

Mind-body relationships in elite apnea divers during breath holding: a study of autonomic responses to acute hypoxemia

The mental control of ventilation with all associated phenomena, from relaxation to modulation of emotions, from cardiovascular to metabolic adaptations, constitutes a psychophysiological condition characterizing voluntary breath-holding (BH). BH induces several autonomic responses, involving both autonomic cardiovascular and cutaneous pathways, whose characterization is the main aim of this study. Electrocardiogram and skin conductance (SC) recordings were collected from 14 elite divers during three conditions: free breathing (FB), normoxic phase of BH (NPBH) and hypoxic phase of BH (HPBH). Thus, we compared a set of features describing signal dynamics between the three experimental conditions: from heart rate variability (HRV) features (in time and frequency-domains and by using nonlinear methods) to rate and shape of spontaneous SC responses (SCRs). The main result of the study rises by applying a Factor Analysis to the subset of features significantly changed in the two BH phases. Indeed, the Factor Analysis allowed to uncover the structure of latent factors which modeled the autonomic response: a factor describing the autonomic balance (AB), one the information increase rate (IIR), and a latter the central nervous system driver (CNSD). The BH did not disrupt the FB factorial structure, and only few features moved among factors. Factor Analysis indicates that during BH (1) only the SC described the emotional output, (2) the sympathetic tone on heart did not change, (3) the dynamics of interbeats intervals showed an increase of long-range correlation that anticipates the HPBH, followed by a drop to a random behavior. In conclusion, data show that the autonomic control on heart rate and SC are differentially modulated during BH, which could be related to a more pronounced effect on emotional control induced by the mental training to BH

A New Web Score to Predict Health Status in Paediatric Patients with Chronic Diseases: Design and Development of the PENSAMI Study

Paediatric chronic diseases (CD) are characterised by their ongoing duration and the fact that they are often managed throughout the lifespan, with the need to adjust lifestyle and expectations with the limitations coming from the CD. The aim of the PENSAMI study is to not only cure the disease, but to also care for the person from a clinical and psychosocial perspective. Data will be collected from 150 paediatric patients affected by heart disease, diabetes, and asthma admitted during in-hospital stay or outpatient visits, and from 200 healthy control subjects. The protocol will consist of two phases. The first one will aim at elaborating the predictive model by detecting (clinical, anthropometric at birth, environmental, lifestyle, social context, emotional state, and mental abilities) in order to develop a model predictive of the events considered: (1) re-hospitalisation; (2) severity and progression of the disease; (3) adherence to therapy; (4) HRQoL; (5) obesity and metabolic syndrome; (6) illness-stress related; (7) school drop-out; (8) school performance. The second one will address validating the previous predictive model. This model will aim to: (1) understand, prevent, and halt the progression of childhood CD; (2) develop new and improved diagnostic tools; (3) pave the way for innovative treatments and additional therapies to traditional clinical practice; and (4) create truly personalised therapeutic and preventive strategies in various sectors, such as cardiology, diabetes, and respiratory diseases

Gender Differences for Health Indicators in a Sample of School Dropout Adolescents: A Pilot Study

Background: The ever-increasing prevalence of school dropout (SD) highlights the need to gain insight into risk factors for dropout causes and consequences. The aim of this study was to evaluate the gender differences for health indicators in a sample of school dropout adolescents. Methods: Data were collected regarding 450 adolescent&rsquo;s SD (19 &plusmn; 2 years; 308 males), and health-related quality-of-life (HRQoL) and risk behaviors were assessed by means of a standardized questionnaire. Results: The results revealed that the female population was characterized by a compromised health indicator profile in terms of both risk behaviors and HRQoL dimensions. Conclusion: These findings indicate that SD is a multidimensional phenomenon, for which the implementation of multiple educational, social, and psychological policies aimed at mitigating the issue are recommended

A New Web Score to Predict Health Status in Paediatric Patients with Chronic Diseases: Design and Development of the PENSAMI Study

Paediatric chronic diseases (CD) are characterised by their ongoing duration and the fact that they are often managed throughout the lifespan, with the need to adjust lifestyle and expectations with the limitations coming from the CD. The aim of the PENSAMI study is to not only cure the disease, but to also care for the person from a clinical and psychosocial perspective. Data will be collected from 150 paediatric patients affected by heart disease, diabetes, and asthma admitted during in-hospital stay or outpatient visits, and from 200 healthy control subjects. The protocol will consist of two phases. The first one will aim at elaborating the predictive model by detecting (clinical, anthropometric at birth, environmental, lifestyle, social context, emotional state, and mental abilities) in order to develop a model predictive of the events considered: (1) re-hospitalisation; (2) severity and progression of the disease; (3) adherence to therapy; (4) HRQoL; (5) obesity and metabolic syndrome; (6) illness-stress related; (7) school drop-out; (8) school performance. The second one will address validating the previous predictive model. This model will aim to: (1) understand, prevent, and halt the progression of childhood CD; (2) develop new and improved diagnostic tools; (3) pave the way for innovative treatments and additional therapies to traditional clinical practice; and (4) create truly personalised therapeutic and preventive strategies in various sectors, such as cardiology, diabetes, and respiratory diseases

Relationship between Weight Status and Health-Related Quality of Life in a Sample of Early Adolescents from Central and Northern Italy: A Cross-Sectional Study of the AVATAR Project Participants

Among the various factors that could influence health-related quality of life (HRQoL) in adolescence, body mass index (BMI) seems to play a key role as a main anthropometric parameter. The aim of this cross-sectional study was to determine, in a sample of Italian adolescents, whether HRQoL is associated with the different weight status categories (underweight, normal weight, overweight, obese), according to BMI cut-off points for children, even considering sex differences. Data were collected from 1707 adolescents (n = 828 males) in seven schools. HRQoL was analyzed using the Italian version of KIDSCREEN-52. Males were more overweight and obese than females (13% vs. 10% and 4% vs. 2%, p &lt; 0.05, respectively). In females, BMI categories are associated with physical well-being (p &lt; 0.05), emotion/mood (p &lt; 0.05), self-perception (p &lt; 0.001), financial resources (p &lt; 0.05), and bullying behavior (p &lt; 0.05). In males, weight status is linked to physical well-being dimension (p &lt; 0.001) and perception of self (p &lt; 0.05). Our results may suggest that there is an association between weight status categories and HRQoL, more pronounced in females than in males. Interestingly, the weight status correlated more with the psychological dimension mainly in females, whereas in males, a stronger association between weight and physical status was observed, suggesting that given the complex, multifaceted, and dynamic nature of relationship between health-related quality of life and weight status in adolescents, multiple factors must be considered

Undernutrition and Overnutrition Burden for Diseases in Developing Countries: The Role of Oxidative Stress Biomarkers to Assess Disease Risk and Interventional Strategies

The increased life expectancy, urbanization, and unhealthy lifestyle characterized by a shift towards a sedentary lifestyle and decreased energy expenditure are considered the main drivers of epidemiological transition. In particular, developing countries are facing a double burden caused by coexisting under- and over-nutrition, which causes a change in the disease profile from infectious diseases to a chronic degenerative pattern. This review discusses the under- and over-nutrition context in Mauritania and India, two countries that are experiencing a nutritional transition, and where we began a collaboration with local medical staff to integrate interventional and diagnostic guidelines. If many studies about diet and its relationship to non-communicable diseases are available for India, very few nutrition and cardiovascular risk studies have been conducted in Mauritania. Presently, with the exponential increase of nutrition-related diseases, targeted approaches are needed to provide balanced diets in parallel with the development of national preventive health systems and screening programs adapted to local needs. In this context, the measurement of oxidative stress biomarkers could be promising as an additive tool to assess cardiovascular (CV) risk in general population, and ameliorating prevention in patients at CV risk or with overt CV disease. Moreover, the possibility of improving the outcome by the direct employment of antioxidant remains plausible. Moreover, studies on the content of antioxidant in different foods may be helpful to develop a balanced diet, and achieve the maximal nutritional and functional properties of cultivars with benefits for human health

8-OH-DPAT prevents cardiac arrhythmias and attenuates tachycardia during social stress in rats

The aim of this study was to apply a behavioural stress paradigm for studying the neural mechanisms underlying stress-induced arrhythmias, and to test whether such arrhythmias could be suppressed by systemic administration of 8-OH-DPAT, a 5-HT1A agonist possessing central sympatholytic properties. The study was conducted on adult male rats instrumented for telemetric recordings of ECG, body temperature and locomotor activity. In the first experiment, rats were subjected to social defeat after either 8-OH-DPAT (100 µg/kg s.c.) or vehicle injection. In the second experiment, prior to vehicle/8-OH-DPAT administration, animals were pre-treated with zatebradine, a blocker of the pacemaker current. 8-OH-DPAT caused prolongation of basal RR interval, increase in locomotion and hypothermia. Subjecting vehicle-treated animals to social defeat caused shortening in RR interval, increase in locomotor activity and hyperthermia, and provoked the occurrence of premature ventricular and supraventricular beats; all these effects were substantially attenuated by 8-OH-DPAT. Zatebradine caused prolongation of RR interval. In zatebradine/vehicle-treated rats, the incidence of ventricular and supraventricular premature beats during defeat increased 2.5-fold and 3.5-fold, respectively. 8-OH-DPAT administered after zatebradine significantly reduced these stress-induced arrhythmias. We conclude that: i) pharmacologically induced prolongation of RR interval may contribute to an increased susceptibility to stress-induced cardiac arrhythmias, possibly due to the prolongation of the ventricular diastolic period with restored excitability; and ii) systemic administration of 8-OH-DPAT abolishes these arrhythmic events, likely by suppressing stress-induced cardiac sympathetic outflow