Voluntary exercise does not affect stress-induced tachycardia, but improves resistance to cardiac arrhythmias in rats

1. It is currently unknown whether long-term voluntary exercise has enduring cardioprotective effects in animal models.

2. The present study was conducted in three groups of rats: (i) sedentary controls (n = 6); (ii) 24 h runners (n = 8; unlimited access to running wheels); and (iii) 2 h runners (n = 8; access to running wheels limited to 2 h daily). After termination of the 6 week exercise protocol, all rats were implanted with the telemetric electrocardiogram transmitters and were studied 1 week later.

3. Resting heart rate (HR) values in the control rats, 24 h runners and 2 h runners were 372 ± 7, 361 ± 9 and 298 ± 5 b.p.m., respectively (P < 0.05 for 2 h runners vs controls). The high-frequency spectral power in the control rats, 24 h runners and 2 h runners was 3.9 ± 0.2, 4.3 ± 0.3 and 5.3 ± 0.3 s2, respectively (P < 0.05 for 2 h runners vs controls), whereas intrinsic HR was 383 ± 3, 377 ± 2 and 346 ± 3 b.p.m., respectively (P < 0.001 for 2 h runners vs controls). Restraint stress provoked tachycardia of similar magnitude in all groups.

4. After completion of telemetric studies, haemodynamic indices and susceptibility to cardiac arrhythmias were assessed in anaesthetized animals, there were no major between-group differences in HR, arterial pressure, contractility indices or sensitivity to β-adrenoceptor stimulation (dobutamine) or blockade (atenolol). The effective refractory period in the control rats, 24 h runners and 2 h runners was 49 ± 2, 55 ± 2 and 60 ± 4 ms, respectively (P = 0.054 for 2 h runners vs controls). A significantly higher dose of aconitine was required to provoke ventricular arrhythmias in the 24 h and 2 h running groups compared with controls (489 ± 76, 505 ± 88 and 173 ± 33 μg, respectively; P < 0.05).

5. We conclude that, in rats, long-term voluntary exercise has enduring cardioprotective effects mediated at the level of both the central nervous system and the heart.

Benchmarking ventricular arrhythmias in the mouse—revisiting the ‘Lambeth Conventions’ 20 years on

The isolated Langendorff-mode perfused heart has become a valuable experimental model, used extensively to examine cardiac function, pathophysiology and pharmacology. For the clinical cardiologist an ECG is often a simple practicality, however in experimental circumstances, particularly with ex vivo murine hearts it is not always possible to obtain an ECG due to experimental recording constraints. However, the mechanical record of ventricular contractile function can be highly informative in relation to electrical state. It is difficult though to achieve consistency in these evaluations of arrhythmia as a validated common reference framework is lacking. In 1988, a group of investigators developed the ‘Lambeth Conventions’—a standardised reference for the definition and classification of arrhythmias in animal experimental models of ischaemia, infarction and reperfusion in vivo. Now, two decades later it is timely to revisit the Lambeth Conventions, and to update the guidelines in the context of the marked increase in murine heart study in experimental cardiac pathophysiology. Here we describe an adjunct to the Lambeth Conventions for the reporting of ventricular arrhythmias post-ischaemia in ex vivo mouse hearts when ECG recordings are not employed. Of seven discrete and identifiable patterns of mechanical dysrhythmia observed in reperfusion, five could be classified using conventional ECG terminology: ventricular premature beat, bigeminy, trigeminy, ventricular tachycardia and ventricular fibrillation. Two additional rhythm variations detected from the pressure record are described (potentiated contraction and alternans).

The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses.

The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients.

Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic ‘co-morbidity’ perhaps underlies the clinical concordance.

Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

A genetic and epigenetic analysis of the noradrenaline transporter

In this study the importance of epigenetic control of the NET gene was demonstrated using mouse and human tissues. Differences in the state of the NET gene were identified between healthy individuals and patients with postural orthostatic tachycardia syndrome (POTS), potentially leading to new treatment possibilities.

Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats

The aim of this study was to determine whether 5-HT2A receptors mediate cardiovascular and thermogenic responses to acute psychological stresses. For this purpose, adult male Wistar hooded rats instrumented for telemetric recordings of either electrocardiogram (ECG) (n=12) or arterial pressure (n=12) were subjected, on different days, to four 15-min episodes of social defeat. Prior to stress, animals received s.c. injection of the selective 5-HT2A receptor antagonist SR-46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate) (at doses of 0.3, 1.0 and 3.0 mg/kg) or vehicle. The drug had no effect on basal heart rate or heart rate variability indexes, arterial pressure, and core body temperature. Social defeat elicited significant and substantial tachycardic (347±7 to 500±7 bpm), pressor (77±4 to 97±4 mm Hg) and hyperthermic (37.0±0.3 to 38.5±0.1 °C) responses. Blockade of 5-HT2A receptors, at all doses of the antagonist, completely prevented stress-induced hyperthermia. In contrast, stress-induced cardiovascular responses were not affected by the blockade (except small reduction of tachycardia by the highest dose of the drug). We conclude that in rats, 5-HT2A receptors mediate stress-induced hyperthermic responses, but are not involved in the genesis of stress-induced rises in heart rate or arterial pressure, and do not participate in cardiovascular control at rest.

The uptake of an early warning system in an Australian emergency department : a pilot study

Objectives: To evaluate the uptake of an emergency department early warning system (ED EWS) for recognition of, and response to, clinical deterioration.

Design, setting and participants: A descriptive exploratory study conducted in an urban district hospital in Melbourne, Australia. Systematic sampling was used to identify every 10th patient for whom the ED EWS was activated from May 2009 to May 2011.

Main outcome measures: Patient characteristics, ED system data and ED EWS activation characteristics.

Results: ED EWS activation occurred in 1.5% of ED patients; 204 patients were included in this pilot study. The median age was 65.1 years (interquartile range [IQR], 47.8-77.5 years), 89.2% of patients were classified as triage category 2 or 3, and 82.4% of patients were seen by medical staff before ED EWS activation. Hypotension (27.7%) and tachycardia (23.7%) were the most common reasons for ED EWS activation. Median duration of clinical instability was 39 minutes (IQR, 5- 129 minutes). Nurses made 93.1% of ED EWS activations. Median time between documenting physiological abnormalities and ED EWS activation was 5 minutes (IQR, 0- 20). Most patients (57.8%) required hospital admission: 4.4% of patients required intensive care unit admission.

Conclusions: The ED EWS resulted in at least two formal reports of clinical deterioration in ED patients per day, indicating reasonable uptake by clinicians. A greater understanding of clinical deterioration in ED patients is warranted to inform an evidence-based approach to recognition of, and response to, clinical deterioration in ED patients.

Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity

In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n¼23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP p80mmHg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2mmHg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4mmHg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline 480mmHg. Plasma concentrations of leptin and insulin increased during the first 3–6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertensionand tachycardia in the rabbit model of obesity.

Short term fat feeding rapidly increases plasma insulin but does not result in dyslipidaemia

Although the association between obesity and hypertension is well known, the underlying mechanism remains elusive. Previously, we have shown that 3 week fat feeding in rabbits produces greater visceral adiposity, hypertension, tachycardia and elevated renal sympathetic nerve activity compared to rabbits on a normal diet. Because hyperinsulinaemia, hyperleptinemia and dyslipidaemia are independent cardiovascular risk factors associated with hypertension we compared plasma insulin, leptin and lipid profiles in male New Zealand White rabbits fed a normal fat diet (NFD 4.3% fat, n = 11) or high fat diet (HFD 13.4% fat, n = 13) at days 1, 2, 3 and weeks 1, 2, 3 of the diet. Plasma concentrations of diacylglyceride (DG), triacylglyceride (TG), ceramide and cholesteryl esters (CE) were obtained after analysis by liquid chromatography mass spectrometry. Plasma insulin and glucose increased within the first 3 days of the diet in HFD rabbits (P <0.05) and remained elevated at week 1 (P <0.05). Blood pressure and heart rate followed a similar pattern. By contrast, in both groups, plasma leptin levels remained unchanged during the first few days (P >0.05), increasing by week 3 in fat fed animals alone (P <0.05). Concentrations of total DG, TG, CE and Ceramide at week 3 did not differ between groups (P >0.05). Our data show plasma insulin increases rapidly following consumption of a HFD and suggests that it may play a role in the rapid rise of blood pressure. Dyslipidaemia does not appear to contribute to the hypertension in this animal model.

Prevalence of cardiovascular and metabolic events in patients prescribed clozapine: a retrospective observational, clinical cohort study

BACKGROUND: The efficacy of clozapine for the treatment of schizophrenia has been demonstrated. However, a range of adverse events have been associated with its use. To date, there remains a paucity of data regarding the prevalence of clozapine-induced cardiovascular (CV) and parameters associated with the development of metabolic syndrome, alongside associated risk factors for their development. METHODS: An observational, clinical cohort study design of 355 clozapine patients who were enrolled in the Barwon Health Clozapine Program at Geelong Hospital, Victoria, Australia, between 2008-12. Medical records were accessed retrospectively. Multivariate logistic regression was used to determine associations with adverse event(s). RESULTS: Older age of commencement with clozapine was consistently associated with increased risk of CV abnormalities, with the exception of tachycardia where older age was protective (Odds Ratio [OR]: 0.97; 95% Confidence Intervals [CI]: 0.95, 0.99). Males had significantly greater odds of most metabolic disturbances with the exception of being obese (BMI: ≥30 OR: 0.45; 95% CIs: 0.24, 0.85). Older age of commencement was a significantly associated variable with High- Density Lipoprotein-cholesterol (OR: 1.03; 95% CIs: 1.01, 1.07) and fasting glucose (OR:1.04; 95% CIs: 1.02, 1.07). An increase in BMI was consistently and significantly associated with all metabolic events. CONCLUSION: Male patients who are obese at any point during treatment and older at treatment commencement may be the most vulnerable to adverse CV and metabolic events. While future studies using a matched case-control design may be required to verify these findings, we recommend that treating clinicians consider these risks when assessing patient suitability to clozapine therapy.

Epidemiology of early Rapid Response Team activation after emergency department admission

BACKGROUND: Rapid Response Team (RRT) calls can often occur within 24h of hospital admission to a general ward. We seek to determine whether it is possible to identify these patients before there is a significant clinical deterioration. METHODS: Retrospective case-controlled study comparing patient characteristics, vital signs, and hospital outcomes in patients triggering RRT activation within 24h of ED admission (cases) with matched ED admissions not receiving a RRT call (controls). RESULTS: Over 12 months, there were 154 early RRT calls. Compared with controls, cases had a higher heart rate (HR) at triage (92 vs. 84beats/min; p=0.008); after 3h in the ED (91 vs. 80beats/min; p=0.0007); and at ED discharge (91 vs. 81beats/min; p=0.0005). Respiratory rate (RR) was also higher at triage (21.2 vs. 19.2breaths/min; p=0.001). On multiple variable analysis, RR at triage and HR before ward transfer predicted early RRT activation: OR 1.07 [95% CI 1.02-1.12] for each 1breath/min increase in RR; and 1.02 [95% CI 1.002-1.030] for each beat/minute increase in HR, respectively. Study patients required transfer to the intensive care in approximately 20% of cases and also had a greater mortality: (21% vs. 6%; OR 4.65 [95% CI 1.86-11.65]; p=0.0003) compared with controls. CONCLUSIONS: Patients that trigger RRT calls within 24h of admission have a fourfold increase in risk of in-hospital mortality. Such patients may be identified by greater tachycardia and tachypnoea in the ED.

If a trauma patient is tachycardic, should we call for a counsellor?

BACKGROUND: It has been suggested in the literature that raised heart rate in the early period after trauma is associated with the development of post-traumatic psychopathology, but little account has been taken of the potential confounding effect of injury severity.

MATERIALS AND METHODS: A cohort of 154 patients, studied as part of a wider investigation of trauma outcomes, was included. Initial heart rate in the accident & emergency department, and injury severity score and new injury severity scores were recorded. Patients completed the General Health Questionnaire (GHQ-28) as a measure of psychopathology at presentation and again at two- and six-month follow-up.

RESULTS: There was no relationship between psychopathology at presentation and initial heart rate or injury severity. Raised heart rate was associated with post-traumatic psychopathology at two months but not at six months. When the potential confounding effect of injury severity was controlled for, there was no independent correlation between heart rate and post-traumatic psychopathology. Injury severity score and new injury severity scores were strongly associated with GHQ-28 caseness.

CONCLUSION: Post-traumatic tachycardia is not associated with development of psychopathology, but injury severity is. Previous studies that have suggested a link between tachycardia and development of psychopathology are flawed because they have not considered the confounding effect of severity of injury.

A novel technique for analysing beat-to-beat dynamical changes of QT-RR distribution for arrhythmia prediction

Ventricular tachycardia (VT) leading to ventricular fibrillation (VF) is the major cause of sudden cardiac death (SCD) with subjects with or without any history of cardiac disease. Prediction of the initiation of ventricular fibrillation is crucial for both successful preventive measure and effective defibrillation therapy. A lot of studies have been done based on electrocardiogram (ECG) waveform analysis for VF detection but this field still needs more perfection. Both HRV and QTV related parameters were reported to be analysed for VT/VF detection and prediction with inconsistent results in different populations. In this study, we propose a novel time domain measurement tool to detect the pattern of dynamical changes of both RR and QT intervals in subjects having sustained VT/VF episodes form VFDB and AHA database (www.physionet.org). We also analyse the same pattern in some healthy subjects from Fantasia database and compare the distribution of patterns between healthy and VT/VF subjects. Our findings showed that the distribution of QT-RR dynamics are statistically significantly different (p<0.05) in healthy subjects from VT/VF in particular before the start of VF episode. Therefore, distribution of change in QT-RR dynamics may provide insight of the underlying instability before VF events and can be used for better prediction of arhythmogenesis.