Age-related changes in cardiac adenosine receptor expression

Adenosine is an important cardioprotective agent that works via several adenosine receptor (ADOR) subtypes to regulate cardiovascular activity. It is well established that functional responses to adenosine decline with age. What is unclear, though, is whether these changes occur at the receptor, second messenger or translational level. In this study we determined the effect of age on cardiac adenosine receptor expression using the housekeeping gene 18S rRNA versus the adenosine A2B receptor gene as internal controls. Absolute quantification showed that no age-related changes occurred in the expression of 18S rRNA or adenosine A2B receptor internal control genes. Subsequently, relative analysis of the adenosine receptor subtypes using 18S rRNA found a significant age-related reduction in the expression of the adenosine A1 receptor (5.5-fold), with no changes in the expression of the adenosine A2A, A2B and A3 receptors. When using the expression of the adenosine A2B receptor as the internal control gene, a significant down regulation of both the adenosine A1 (5.4-fold) and A2A (2.2-fold) receptors with no change in the expression of adenosine A3 receptor was found. Therefore, the high level of expression of the 18S rRNA housekeeping gene was found to mask a significant change in expression of the adenosine A2A receptor with age. Ultimately, these findings show an age-related reduction in adenosine A1 and A2A receptor expression in rat heart.

Cardiac parasympathetic reactivation following exercise : implications for training prescription

The objective of exercise training is to initiate desirable physiological adaptations that ultimately enhance physical work capacity. Optimal training prescription requires an individualized approach, with an appropriate balance of training stimulus and recovery and optimal periodization. Recovery from exercise involves integrated physiological responses. The cardiovascular system plays a fundamental role in facilitating many of these responses, including thermoregulation and delivery/removal of nutrients and waste products. As a marker of cardiovascular recovery, cardiac parasympathetic reactivation following a training session is highly individualized. It appears to parallel the acute/intermediate recovery of the thermoregulatory and vascular systems, as described by the supercompensation theory. The physiological mechanisms underlying cardiac parasympathetic reactivation are not completely understood. However, changes in cardiac autonomic activity may provide a proxy measure of the changes in autonomic input into organs and (by default) the blood flow requirements to restore homeostasis. Metaboreflex stimulation (e.g. muscle and blood acidosis) is likely a key determinant of parasympathetic reactivation in the short term (0–90 min post-exercise), whereas baroreflex stimulation (e.g. exercise-induced changes in plasma volume) probably mediates parasympathetic reactivation in the intermediate term (1–48 h post-exercise). Cardiac parasympathetic reactivation does not appear to coincide with the recovery of all physiological systems (e.g. energy stores or the neuromuscular system). However, this may reflect the limited data currently available on parasympathetic reactivation following strength/resistance-based exercise of variable intensity. In this review, we quantitatively analyse post-exercise cardiac parasympathetic reactivation in athletes and healthy individuals following aerobic exercise, with respect to exercise intensity and duration, and fitness/training status. Our results demonstrate that the time required for complete cardiac autonomic recovery after a single aerobic-based training session is up to 24 h following low-intensity exercise, 24–48 h following threshold-intensity exercise and at least 48 h following high-intensity exercise. Based on limited data, exercise duration is unlikely to be the greatest determinant of cardiac parasympathetic reactivation. Cardiac autonomic recovery occurs more rapidly in individuals with greater aerobic fitness. Our data lend support to the concept that in conjunction with daily training logs, data on cardiac parasympathetic activity are useful for individualizing training programmes. In the final sections of this review, we provide recommendations for structuring training microcycles with reference to cardiac parasympathetic recovery kinetics. Ultimately, coaches should structure training programmes tailored to the unique recovery kinetics of each individual.

Incidence of hypotony and sympathetic ophthalmia following trans scleral cyclophotocoagulation for glaucoma and a report of risk factors

Background: To report the incidence and risk factors for hypotony and estimate the risk of sympathetic ophthalmia following diode laser trans-scleral cyclophotocoagulation (TSCPC). Design: Retrospective study using data from a private tertiary glaucoma clinic and review of the literature. Participants: Seventy eyes of 70 patients with refractory glaucoma who received TSCPC treatment. Methods: Review of the records of consecutive patients who underwent TSCPC by a single ophthalmic surgeon and review of the literature. Main Outcome Measures: Hypotony (including phthisis bulbi), sympathetic ophthalmia. Results: Seven eyes (10%; CI 5-19%) developed hypotony and included 4 eyes that developed phthisis. Higher total energy delivered during TSCPC treatment was associated with an increased risk of hypotony: eyes that developed hypotony received a mean total energy of 192.5 ± 73.2 joules, compared to a mean of 152.9 ± 83.2 joules in hypotony-free cases. The difference in mean energy delivered between the hypotony and non-hypotony group was 38.53 (95% CI: -27.57 to 104.63). The risk of sympathetic ophthalmia estimated from a review of the published literature and current series was one in 1512, or 0.07% (CI 0.03% - 0.17%). Conclusions: Total laser energy is one of several risk factors that act in a sufficient component cause-model to produce hypotony in an individual patient. The small sample size precluded inference for other individual putative risk factors but titrating laser energy may help decrease the occurrence of hypotony. The risk of sympathetic ophthalmia calculated from the literature is likely an overestimate caused by publication bias.

Protocol for a randomised blocked design study using telephone and text-messaging to support cardiac patients with diabetes : a cross cultural international collaborative project

Background The prevalence of type 2 diabetes is rising internationally. Patients with diabetes have a higher risk of cardiovascular events accounting for substantial premature morbidity and mortality, and health care expenditure. Given healthcare workforce limitations, there is a need to improve interventions that promote positive self-management behaviours that enable patients to manage their chronic conditions effectively, across different cultural contexts. Previous studies have evaluated the feasibility of including telephone and Short Message Service (SMS) follow up in chronic disease self-management programs, but only for single diseases or in one specific population. Therefore, the aim of this study is to evaluate the feasibility and short-term efficacy of incorporating telephone and text messaging to support the care of patients with diabetes and cardiac disease, in Australia and in Taiwan. Methods/design A randomised controlled trial design will be used to evaluate a self-management program for people with diabetes and cardiac disease that incorporates the use of simple remote-access communication technologies. A sample size of 180 participants from Australia and Taiwan will be recruited and randomised in a one-to-one ratio to receive either the intervention in addition to usual care (intervention) or usual care alone (control). The intervention will consist of in-hospital education as well as follow up utilising personal telephone calls and SMS reminders. Primary short term outcomes of interest include self-care behaviours and self-efficacy assessed at baseline and four weeks. Discussion If the results of this investigation substantiate the feasibility and efficacy of the telephone and SMS intervention for promoting self management among patients with diabetes and cardiac disease in Australia and Taiwan, it will support the external validity of the intervention. It is anticipated that empirical data from this investigation will provide valuable information to inform future international collaborations, while providing a platform for further enhancements of the program, which has potential to benefit patients internationally.

Clinical practice guidelines for nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory : A modified Delphi study

Aim To develop clinical practice guidelines for nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory. Background Numerous studies have reported that nurse-administered procedural sedation and analgesia is safe. However, the broad scope of existing guidelines for the administration and monitoring of patients who receive sedation during medical procedures without an anaesthetist presents means there is a lack of specific guidance regarding optimal nursing practices for the unique circumstances in which nurse-administered procedural sedation and analgesia is used in the cardiac catheterisation laboratory. Methods A sequential mixed methods design was utilised. Initial recommendations were produced from three studies conducted by the authors: an integrative review; a qualitative study; and a cross-sectional survey. The recommendations were revised in accordance with responses from a modified Delphi study. The first Delphi round was completed by nine senior cardiac catheterisation laboratory nurses. All but one of the draft recommendations met the pre-determined cut-off point for inclusion. There were a total of 59 responses to the second round. Consensus was reached on all recommendations. Implications for nursing The guidelines that were derived from the Delphi study offer twenty four recommendations within six domains of nursing practice: Pre-procedural assessment; Pre-procedural patient and family education; Pre-procedural patient comfort; Intra-procedural patient comfort; Intra-procedural patient assessment and monitoring; and Post-procedural patient assessment and monitoring. Conclusion These guidelines provide an important foundation towards the delivery of safe, consistent and evidence-based nursing care for the many patients who receive sedation in the cardiac catheterisation laboratory setting.

Regulation of the Fear Network by Mediators of Stress: Norepinephrine Alters the Balance between Cortical and Subcortical Afferent Excitation of the Lateral Amygdala

Pavlovian auditory fear conditioning involves the integration of information about an acoustic conditioned stimulus (CS) and an aversive unconditioned stimulus in the lateral nucleus of the amygdala (LA). The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE), regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased toward the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance toward the faster but more primitive subcortical input

A review of sedation scales for the cardiac catheterization laboratory

Sedation scales have the potential to facilitate effective procedural sedation and analgesia in the cardiac catheterization laboratory (CCL). For this potential to become realised, a scale that is suitable for use in the CCL either needs to be identified or developed. To identify sedation scales, a review of Medline and CINHAL was conducted. One sedation scale for the CCL, the NASPE SED, and 15 Intensive Care Unit (ICU) scales met the inclusion and exclusion criteria. Analysis of the scale’s item structures and psychometric properties was then performed. None of these scales were deemed suitable for use in the CCL. As such, further research is required to develop a new scale. The new scale should consist of more than one item because it will be the most effective for tracking the patient’s response to medications. Specific tests required to conduct a rigorous evaluation of the new scale’s psychometric properties are outlined in this paper.

Cardiac safety concerns for ondansetron, an antiemetic commonly used for nausea linked to cancer treatment and following anaesthesia

Introduction: Ondansetron is a 5-HT3 receptor antagonist commonly used as an anti-emetic to prevent the nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy, or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes. Areas covered: We undertook a review of the cardiac safety of ondansetron. Our primary sources of information were PubMed (with downloading of full articles), and the internet. Expert opinion: The dose of ondansetron that the FDA has concerns about is 32 mg iv (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in the lower doses used to prevent the nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken of the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of pro-arrhythmic risk when introducing warnings for this.

Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine

Introduction: Domperidone is a dopamine D2-receptor antagonist developed as an antiemetic and prokinetic agents. Oral domperidone is not approved in the US, but is used in many countries to treat nausea and vomiting, gastroparesis, and as a galactogogue (to promote lactation). The US Food and Drug Administration (FDA) have issued a warning about the cardiac safety of domperidone. Areas covered: The authors undertook a review of the cardiac safety of oral domperidone. Expert opinion: The data from preclinical studies are unambiguous in identifying domperidone as able to produce marked hERG channel inhibition and action potential prolongation at clinically relevant concentrations. The compound’s propensity to augment instability of action potential duration and action potential triangulation are also indicative of proarrhythmic potential. Domperidone should not be administered to subjects with pre-existing QT prolongation/LQTS, subjects receiving drugs that inhibit CYP3A4, subjects with electrolyte abnormalities or with other risk factors for QT-prolongation. With these provisos, it is possible that domperidone may be used as a galactogogue without direct risk to healthy breast feeding women but more safety information should be sought in this situation. Also, more safety information is required regarding risk to breast feeding infants or before domperidone is routinely used in gastroparesis or gastroesphageal reflux in children.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.

Nurse-led chest drain removal in a cardiac high dependency unit

Within the cardiac high dependency unit it is currently a member of the surgical team who makes the decision for a patient's chest drain to be removed after cardiac surgery. This has often resulted in delays in discharging one patient and therefore in admitting the next. A pilot study was carried out using a working standard that had been developed, incorporating an algorithmic model. The results have enabled nursing staff in a cardiac high dependency unit to undertake this responsibility independently.

Functional independence following subacute inpatient rehabilitation was not affected by age among older patients recovering from cardiac-related hospital admissions

Introduction Older people recovering from cardiac events requiring an acute hospital admission may experience a decline in physical function limiting their ability to return home to their previous accommodation. Subacute inpatient rehabilitation therapies have potential to assist recovery of physical functioning. However, it is unknown whether age influences the length of stay or physical functioning at discharge from subacute inpatient rehabilitation for this population. Objectives This study examined the outcomes of a cohort of older patients recovering from a cardiac event requiring hospitalisation to investigate the association between age and physical function at discharge, as well as age and length of rehabilitation stay. Methods Participants included 145 consecutive inpatient admissions to a subacute geriatric assessment and rehabilitation unit with a cardiac condition as their primary reason for hospital admission. Participants were required to complete a multi-disciplinary physical functioning assessment within 72 hours of admission to the unit, and again within 72 hours prior to discharge from the unit. The primary outcome measure was the Functional Independence Measure motor score. Demographic and clinical information, including length of stay and discharge destination, were also recorded. Results A total n=126 (87%) participants, with a mean (standard deviation) age of 79 (10) years, had both assessments completed and were included in analyses. Participants who had passed away (n=4, 3%), or did not have both assessments completed per protocol were excluded from analyses. Discharge destinations included home (n=101, 80%), residential aged care (n=17, 13%) and another hospital (n=8, 6%). The (median, interquartile range) Functional Independence Measure motor score was higher at discharge (79, 71 to 84) than admission (61, 48 to 71); z=7.75 p<0.001. Age was not associated with Functional Independence Measure motor score at discharge (t= -0.18, p=0.86), or length of stay in the rehabilitation unit (t= -0.52, 0.60). Conclusion Any perception that age may be associated with longer lengths of stay and reduced physical function outcomes among patients with cardiac conditions admitted for subacute inpatient rehabilitation for older adults is not supported data from this investigation. Older age should not be considered a disincentive when considering the suitability of patients with cardiac diagnoses for this type of inpatient rehabilitation or their potential physical functioning outcome.

Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment

Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

A review of the effects of sedation on thermoregulation : insights for the cardiac catheterisation laboratory

Purpose To examine the effects that the sedative and analgesic medications which are commonly used in the cardiac catheterisation laboratory have on thermoregulation. Design A structured review strategy was used. Methods Medline and CINAHL were searched for published studies and reference lists of retrieved studies were scrutinized for further research. Data were extracted using a standardised extraction tool. Results A total of nine studies examined the effect that sedative and analgesic medications have on thermoregulation. Midazolam has minimal impact on thermoregulation while opioids, dexmedetomidine and propofol markedly decrease vasoconstriction and shivering thresholds. Conclusions Patients who receive sedation in the cardiac catheterisation laboratory may be at risk of hypothermia, due to the use of medications that impair thermoregulation. Further research is required to identify the prevalence of unplanned hypothermia during sedation in the cardiac catheterisation laboratory.

Bridging experiments, models and simulations : an integrative approach to validation in computational cardiac electrophysiology

Computational models in physiology often integrate functional and structural information from a large range of spatio-temporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and scepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace and refine animal experiments. A fundamental requirement to fulfil these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations between experiments, models and simulations in cardiac electrophysiology. We describe the processes, data and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. Validation must therefore take into account the complex interplay between models, simulations and experiments. Key points for developing strategies for validation are: 1) understanding sources of bio-variability is crucial to the comparison between simulation and experimental results; 2) robustness of techniques and tools is a pre-requisite to conducting physiological investigations using the MSE system; 3) definition and adoption of standards facilitates interoperability of experiments, models and simulations; 4) physiological validation must be understood as an iterative process that defines the specific aspects of electrophysiology the MSE system targets, and is driven by advancements in experimental and computational methods and the combination of both.