Can a single low-intensity premature stimulus induce ventricular arrhythmias in the normal heart?

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

Vaiabilità della frequenza cardiaca in modelli animali di comorbilità tra psicopatologie e disfunzione cardiovascolare

Le patologie cardiovascolari e le psicopatologie rappresentano rispettivamente la prima e la seconda causa di morbilità, disabilità e morte nei Paesi industrializzati. Inoltre, studi clinici e sperimentali hanno evidenziato un’associazione bidirezionale tra queste due classi di patologie. Gli eventi stressanti possono essere considerati un elemento comune nello sviluppo sia dei problemi psichiatrici che delle patologie cardiovascolari. Ad oggi, i substrati neurobiologici alla base di questa relazione non sono ancora stati completamente compresi. Uno dei principali meccanismi patofisiologici responsabili di questa associazione è l’alterazione del controllo neurovegetativo della frequenza cardiaca, che può portare a elevata frequenza cardiaca, ridotto tono vagale, iperattività simpatica, diminuita variabilità della frequenza cardiaca, aumento del rilascio di catecolamine e ridotta sensibilità del riflesso barocettivo. I modelli animali che riproducono le caratteristiche fisiologiche e comportamentali delle patologie psichiatriche rappresentano un utile strumento per meglio studiare le alterazioni alla base della comorbilità tra depressione/ansia e patologie cardiovascolari. L’obiettivo principale di questa tesi è quello di indagare le eventuali alterazioni del controllo neurovegetativo cardiaco nell’ambito di differenti modelli di psicopatologie (depressione e ansia) nel ratto utilizzando le metodiche di analisi della variabilità della frequenza cardiaca. I risultati ottenuti hanno consentito di ampliare le informazioni già presenti in letteratura sui meccanismi coinvolti nell’associazione bidirezionale tra psicopatologie e disfunzione cardiovascolare.Cardiovascular disease and psychopathologies, including depression and anxiety, represent respectively the first and second leading cause of serious illnesses, reduced quality of life, and mortality among the population of the Western countries. Interestingly, epidemiological and clinical studies highlighted a bidirectional association between cardiovascular dysfunction and psychiatric illnesses. The presence of environmental stressors represents a common factor in the development of both psychopathologies and cardiovascular disease. However, the precise neurobiological mechanisms linking cardiovascular dysfunction and altered mood or anxiety are not completely clarified. The alteration of autonomic neural regulation of the heart has been proposed as one of the most important pathophysiological mechanisms underlying this link. Cardiac autonomic dysfunction includes increased heart rate, decreased vagal tone, sympathetic hyperactivity, reduced heart rate variability, augmented catecholamine release, and reduced sensitivity of the baroreceptor reflex. Reliable animal models that mimic human psychiatric illnesses may provide further insights into the alterations that characterize comorbid depression/anxiety and cardiovascular dysfunction. In this thesis the possible alterations of cardiac autonomic control were investigated via heart rate variability analysis in rat models of psychopathology (depression and anxiety). The findings obtained in these studies clarify and extend the knowledge about the mechanistic links between psychological and cardiovascular pathologies

Different patterns of respiration in rat lines selectively bred for high or low anxiety

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<0.05). During initial testing into the plethysmograph and during a restraint test, HAB rats spent less time at high-frequency sniffing compared to LAB rats. In addition, HAB rats did not habituate in terms of respiratory response to repetitive acoustic stressful stimuli. Finally, HAB rats exhibited a larger incidence of sighs during free exploration of the plethysmograph and under stress conditions. We conclude that: i) HAB rats showed respiratory changes (elevated resting respiratory rate, reduced sniffing in novel environment, increased incidence of sighs, and no habituation of the respiratory response to repetitive stimuli) that resemble those observed in anxious and panic patients, and ii) respiratory patterns may represent a promising way for assessing anxiety states in preclinical studies

Vagal withdrawal and susceptibility to cardiac arrhythmias in rats with high trait aggressiveness

Personality characteristics, e.g. aggressiveness, have long been associated with an increased risk of cardiac disease. However, the underlying mechanisms remain unclear. In this study we used a rodent model for characterizing cardiac autonomic modulation in rats that differ widely in their level of aggressive behavior. To reach this goal, high-aggressive (HA, n = 10) and non-aggressive (NA, n = 10) rats were selected from a population (n = 121) of adult male Wild-type Groningen rats on the basis of their latency time to attack (ALT, s) a male intruder in a resident-intruder test lasting 600 s. In order to obtain information on their cardiac autonomic modulation, ECG recordings were subsequently obtained via radiotelemetry at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HA rats (ALT600 s). Exposure to stressful stimuli (i.e. restraint and psychosocial stress) provoked similar tachycardic responses between the two groups. However, under stress conditions HA rats displayed a reduced vagal antagonism and an increased incidence of tachyarrhythmias compared to NA rats. In addition, beta-adrenergic pharmacological stimulation induced a much larger incidence of ventricular tachyarrhythmias in HA rats compared to NA counterparts. These findings are consistent with the view that high levels of aggressive behavior in rats are associated to signs of cardiac autonomic impairment and increased arrhythmogenic susceptibility that may predict vulnerability to cardiac morbidity and mortality

Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high increased susceptibility anxiety

In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease

Raw data records of respiratory signal, respiratory rate and motor movements.

<p>These data were obtained from a representative high-anxiety behavior rat during free exploration of the plethysmographic chamber. The respiratory signal (top trace) indicates: i) slow regular breathing (referred in the text as “dominant respiratory rate”), ii) sniffing behavior, and iii) a sigh. The movement signal (bottom trace) is from a piezoelectric sensor positioned under the plethysmographic chamber. Note that only small movements occurred during episodes of sniffing (for comparison, the effect of locomotion is shown at the end of the bottom trace (asterisk)).</p

Respiratory patterns before and during the restraint test.

<p>Panels (A) and (B) show how much time high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats spent at a given respiratory rate during: (A) 5-min pre-restraint recording and (B) first 5-min test recording. Panel (C) depicts the time course of changes in the time spent by the animals at high-frequency sniffing mode before and during the restraint test, expressed as % of total time (5-min epochs). Panel (D) illustrates the time course of changes in the dominant respiratory rate (i.e. the mode of the low-frequency peaks). Results of ANOVA: (i) significant effect of ‘group’ (F = 5.6, p<0.05) for values relative to the % of time spent at high-frequency sniffing (Panel C); (ii) significant effect of ‘time’ (F = 13.2, p<0.01), of ‘group’ (F = 18.8, p<0.01) and a ‘time x group’ interaction (F = 5.4, p<0.05) for respiratory rate values (Panel D). * indicates a significant difference between HAB and LAB rats (Student ‘t’ test, p<0.01).</p

Behavior on the elevated plus maze.

<p>For high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats, data are expressed as means (±SEM) of: (A) time spent in the open arms (% of total time), (B) number of entries in the open arms (% of total entries), and (C) latency to enter an open arm (s). * indicates a significant difference between HAB and LAB rats (p<0.01).</p

Respiratory rate changes during predator calls.

<p>For high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats, data are expressed as means (±SEM). Baseline reference value is the mean of the 60 s prior to stimulus onset. During the first (A) and second (B) predator call, each point represents the mean of 5-s intervals. Inner graphs in (A) and (B) represent the area under the response curve (AUC) of respiratory rate during predator calls. Two-way ANOVA yielded a tendency for a group difference in respiratory rate values between HABs and LABs during the second predator call (F = 3.7, p = 0.07). * indicates a significant difference between HAB and LAB rats (Student ‘t’ test, p<0.05). ^# indicates a significant difference in AUC values between the first and second predator call in LAB rats (Student ‘t’ test, p<0.05).</p

Radiotelemetric and HRV parameters during the restraint test.

<p>Values are reported as means ± SEM of data obtained by averaging multiple 5-min segments acquired in baseline conditions (30 min), during the restraint (15 min) and the recovery phase (45 min), in high-aggressive (HA, n = 10) and non-aggressive (NA, n = 10) rats. Abbreviations: HRV = heart rate variability; HR = heart rate; RMSSD = square root of the mean squared differences of successive RR intervals; LF = low-frequency; HF = high-frequency; T = body temperature; LOC = locomotor activity. * and ^# indicate a significant difference between HA and NA rats (p<0.05 and p<0.01, respectively).</p