Loci affecting gamma-glutamyl transferase in adults and adolescents show age x SNP interaction and cardiometabolic disease associations

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 x 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 x 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 x 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 x 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

P2 purinergic receptor mRNA in rat and human sinoatrial node and other heart regions.

It is known that adenosine 5'-triphosphate (ATP) is a cotransmitter in the heart. Additionally, ATP is released from ischemic and hypoxic myocytes. Therefore, cardiac-derived sources of ATP have the potential to modify cardiac function. ATP activates P2X(1-7) and P2Y(1-14) receptors; however, the presence of P2X and P2Y receptor subtypes in strategic cardiac locations such as the sinoatrial node has not been determined. An understanding of P2X and P2Y receptor localization would facilitate investigation of purine receptor function in the heart. Therefore, we used quantitative PCR and in situ hybridization to measure the expression of mRNA of all known purine receptors in rat left ventricle, right atrium and sinoatrial node (SAN), and human right atrium and SAN. Expression of mRNA for all the cloned P2 receptors was observed in the ventricles, atria, and SAN of the rat. However, their abundance varied in different regions of the heart. P2X(5) was the most abundant of the P2X receptors in all three regions of the rat heart. In rat left ventricle, P2Y(1), P2Y(2), and P2Y(14) mRNA levels were highest for P2Y receptors, while in right atrium and SAN, P2Y(2) and P2Y(14) levels were highest, respectively. We extended these studies to investigate P2X(4) receptor mRNA in heart from rats with coronary artery ligation-induced heart failure. P2X(4) receptor mRNA was upregulated by 93% in SAN (P < 0.05), while a trend towards an increase was also observed in the right atrium and left ventricle (not significant). Thus, P2X(4)-mediated effects might be modulated in heart failure. mRNA for P2X(4-7) and P2Y(1,2,4,6,12-14), but not P2X(2,3) and P2Y(11), was detected in human right atrium and SAN. In addition, mRNA for P2X(1) was detected in human SAN but not human right atrium. In human right atrium and SAN, P2X(4) and P2X(7) mRNA was the highest for P2X receptors. P2Y(1) and P2Y(2) mRNA were the most abundant for P2Y receptors in the right atrium, while P2Y(1), P2Y(2), and P2Y(14) were the most abundant P2Y receptor subtypes in human SAN. This study shows a widespread distribution of P2 receptor mRNA in rat heart tissues but a more restricted presence and distribution of P2 receptor mRNA in human atrium and SAN. This study provides further direction for the elucidation of P2 receptor modulation of heart rate and contractility.

The intra-aortic balloon pump in heart failure management : implications for nursing practice

Management of acute heart failure is an important consideration in critical care. Mechanical support of the failing heart is crucial for improving health outcomes. The most common Australasian application of intraaortic balloon counterpulsation (IABP) is in the setting of cardiogenic shock. High end users of IABP (>37/annum) demonstrate significantly lower mortality for cardiogenic shock managed with IABP (p <0.001) in contrast to hospitals which employ limited IABP (<4/annum). This underscores the importance of proficiency in managing patient receiving IABP support. Nurses play a crucial role in carding for patients with acute heart failure. This paper summarises care considerations for management of the IABP.

Caveat Anicula! Beware of the Quiet Little Old Ladies : Demographics, Pharmacotherapy, Survival and Readmissions in a 10 Year Cohort of Heart Failure Patients with Preserved Systolic Function

Objective--To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD). Design and setting--A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital.Main outcome measures-- Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival.Results--Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912). Conclusions--Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

Ryanodine receptor phosphorylation in human heart failure

Heart failure is a complex disorder, characterized by activation of the sympathetic nervous system, leading to dysregulated Ca2+ homeostasis in cardiac myocytes and tissue remodeling. In a variety of diseases, cardiac malfunction is associated with aberrant fluxes of Ca2+ across both the surface membrane and the internal Ca2+ store, the sarcoplasmic reticulum (SR). One prominent hypothesis residues is that in heart failure, the activity of the ryanodine receptor (RyR2) Ca2+ release channel in the SR is increased due to excess phosphorylation and that this contributes to excess SR Ca2+ leak in diastole, reduced SR Ca2+ load and decreased contractility (Huke & Bers, 2008). There is controversy over which serine residues in RyR2 are hyperphosphorylated in animal models of heart failure and whether this is via the CaMKII or the PKA-linked signaling pathway. S2808, S2814 and S2030 in RyR2 have been variously claimed to be hyperphosphorylated. Our aim was to examine the degree of phosphorylation of these residues in RyR2 from failing human hearts. The use of human tissue was approved by the Human Research Ethics Committee, The Prince Charles Hospital, EC28114. Left ventricular tissue samples were obtained from an explanted heart of a patient with endstage heart failure (Emery Dreifuss Muscular Dystrophy with cardiomyopathy) and non-failing tissue was from a patient with cystic fibrosis undergoing heart-lung transplantation with no history of heart disease. SR vesicles were prepared as described by Laver et al. (1995) and examined with SDS-Page and Western Blot. Transferred proteins were probed with antibodies to detect total protein phosphorylation, phosphorylation of RyR2 serine residues S2808, S2814, S2030 and for the key proteins calsequestrin, triadin, junctin and FKBP12.6. To avoid membrane stripping artifact, each membrane was exposed to one phosphorylation-specific antibody and signal densities quantified using Bio-Rad Quantity One software. We found no distinguishable difference between failing and healthy hearts in the protein expression levels of RyR2, triadin, junctin or calsequestrin. We found an expected upregulation of total RyR2 phosphorylation in the failing heart sample, compared to a matched amount of RyR2 (quantified using densiometry) in healthy heart. Probing with antibodies detecting only the phosphorylated form of the specific RyR2 residues showed that the increase in total RyR2 phosphorylation in the failing heart was due to hyperphosphorylation of S2808 and S2814. We found that S2030 phosphorylation levels were unchanged in human heart failure. Interestingly, we found that S2030 has a basal level of phosphorylation in the healthy human heart, different from the absence of basal phosphorylation recently reported in rodent heart (Huke & Bers, 2008). Finally, preliminary results indicate that less FKBP 12.6 is associated with RyR2 in the failing heart, possibly as a consequence of PKA activation. In conclusion, residues S2808 and S2814 are hyperphosphorylated in human heart failure, presumably due to upregulation of the CaMKII and/or PKA signaling pathway as a result of chronic activation of the sympathetic nervous system. Such changes in RyR2 phosphorylation are believed to contribute to the leaky RyR2 phenotype associated with heart failure, which increases the incidence of arrhythmia and contributes to the severely impaired contractile performance of the failing heart. Huke S & Bers DM. (2008). Ryanodine receptor phosphorylation at serine 2030, 2808 and 2814 in rat cardiomyocytes. Biochemical and Biophysical Research Communications 376, 80-85. Laver DR, Roden LD, Ahern GP, Eager KR, Junankar PR & Dulhunty AF. (1995). Cytoplasmic Ca2+ inhibits the ryanodine receptor from cardiac muscle. Journal of Membrane Biology 147, 7-22. Proceedings

The Chronic Heart-Failure Assistance by Telephone (CHAT) Study: Assessment of Telephone Support for Vulnerable Patients with Chronic Disease

Aim: To determine whether telephone support using an evidence-based protocol for chronic heart failure (CHF) management will improve patient outcomes and will reduce hospital readmission rates in patients without access to hospital-based management programs. Methods: The rationale and protocol for a cluster-design randomised controlled trial (RCT) of a semi-automated telephone intervention for the management of CHF, the Chronic Heart-failure Assistance by Telephone (CHAT) Study is described. Care is coordinated by trained cardiac nurses located in Heartline, the national call center of the National Heart Foundation of Australia in partnership with patients’ general practitioners (GPs). Conclusions: The CHAT Study model represents a potentially cost-effective and accessible model for the Australian health system in caring for CHF patients in rural and remote areas. The system of care could also be readily adapted for a range of chronic diseases and health systems. Key words: chronic disease management; chronic heart failure; integrated health care systems; nursing care, rural health services; telemedicine; telenursing

Striving to achieve best practice in heart failure disease management

Based on a national audit of chronic heart failure (CHF) management programmes (CHF-MPs) conducted in 2006, Driscoll et al identified a disproportionate distribution ranging from 0 to 4.2 programmes/million population in the various states of Australia with many programmes not following best practice.1 We welcome their proposal to develop national benchmarks for CHF management and acknowledge the contributions of the Heart Foundation and health professionals in finalising these recommendations.2 We would like to share the Queensland experience in striving towards best practice with the number of CHF-MPs increasing from four (at the time of the 2006 survey) to 23, equating to 5.0 programmes/million population. Queensland now has a state-wide heart failure service steering committee with a focus on the development of CHF-MPs supported by a central coordinator...

The effect of exercise on sleep quality in heart failure

Purpose The primary objective of this study was to examine the effect of exercise on subjective sleep quality in heart failure patients. Methods This study used a randomised, controlled trial design with blinded end-point analysis. Participants were randomly assigned to a 12-week programme of education and self-management support (control) or to the same programme with the addition of a tailored physical activity programme designed and supervised by an exercise specialist (intervention). The intervention consisted of 1 hour of aerobic and resistance exercise twice a week. Participants included 108 patients referred to three hospital heart failure services in Queensland, Australia. Results Patients who participated in supervised exercise classes showed significant improvement in subjective sleep quality, sleep latency, sleep disturbance and global sleep quality scores after 12 weeks of supervised hospital based exercise. Secondary analysis showed that improvements in sleep quality were correlated with improvements in geriatric depression score (p=0.00) and exercise performance (p=0.03). General linear models were used to examine whether the changes in sleep quality following intervention occurred independently of changes in depression, exercise performance and weight. Separate models adjusting for each covariate were performed. Results suggest that exercise significantly improved sleep quality independent of changes in depression, exercise performance and weight. Conclusion This study supports the hypothesis that a 12 week program of aerobic and resistance exercise improves subjective sleep quality in patients with heart failure. This is the first randomised controlled trial to examine the role of exercise in the improvement of sleep quality for patients with this disease. While this study establishes exercise as a therapy for poor sleep quality, further research is needed to investigate exercise as a treatment for other parameters of sleep in this population. Study investigators plan to undertake a more in-depth examination within the next 12 months

Development and testing of an iPad application for teaching self-management to heart failure patients. (Nursing/Allied Health Professional Investigator Award)- Abstract

Purpose: Heart failure (HF) is the leading cause of hospitalization and significant burden to the health care system in Australia. To reduce hospitalizations, multidisciplinary approaches and enhance self-management programs have been strongly advocated for HF patients globally. HF patients who can effectively manage their symptoms and adhere to complex medicine regimes will experience fewer hospitalizations. Research indicates that information technologies (IT) have a significant role in providing support to promote patients' self-management skills. The iPad utilizes user-friendly interfaces and to date an application for HF patient education has not been developed. This project aimed to develop the HF iPad teaching application in the way that would be engaging, interactive and simple to follow and usable for patients' carers and health care workers within both the hospital and community setting. Methods: The design for the development and evaluation of the application consisted of two action research cycles. Each cycle included 3 phases of testing and feedback from three groups comprising IT team, HF experts and patients. All patient education materials of the application were derived from national and international evidence based practice guidelines and patient self-care recommendations. Results: The iPad application has animated anatomy and physiology that simply and clearly teaches the concepts of the normal heart and the heart in failure. Patient Avatars throughout the application can be changed to reflect the sex and culture of the patient. There is voice-over presenting a script developed by the heart failure expert panel. Additional engagement processes included points of interaction throughout the application with touch screen responses and the ability of the patient to enter their weight and this data is secured and transferred to the clinic nurse and/or research data set. The application has been used independently, for instance, at home or using headphones in a clinic waiting room or most commonly to aid a nurse-led HF consultation. Conclusion: This project utilized iPad as an educational tool to standardize HF education from nurses who are not always heart failure specialists. Furthermore, study is currently ongoing to evaluate of the effectiveness of this tool on patient outcomes and to develop several specifically designed cultural adaptations [Hispanic (USA), Aboriginal (Australia), and Maori (New Zealand)].

Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.

Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart

G protein-coupled receptors (GPCRs) are critical for cardiovascular physiology. Cardiac cells express >100 nonchemosensory GPCRs, indicating that important physiological and potential therapeutic targets remain to be discovered. Moreover, there is a growing appreciation that members of the large, distinct taste and odorant GPCR families have specific functions in tissues beyond the oronasal cavity, including in the brain, gastrointestinal tract and respiratory system. To date, these chemosensory GPCRs have not been systematically studied in the heart. We performed RT-qPCR taste receptor screens in rodent and human heart tissues that revealed discrete subsets of type 2 taste receptors (TAS2/Tas2) as well as Tas1r1 and Tas1r3 (comprising the umami receptor) are expressed. These taste GPCRs are present in cultured cardiac myocytes and fibroblasts, and are enriched in myocytes, which we corroborated using in situ hybridization. Tas1r1 gene-targeted mice (Tas1r1Cre/Rosa26tdRFP) strikingly recapitulated these data. In vivo taste receptor expression levels were developmentally regulated in the postnatal period. Intriguingly, several Tas2rs were upregulated in cultured rat myocytes and in mouse heart in vivo following starvation. The discovery of taste GPCRs in the heart opens an exciting new field of cardiac research. We predict that these taste receptors may function as nutrient sensors in the heart.

A sonographer's guide to the assessment of heart disease

The book is mostly designed for students of echocardiography, teachers of echocardiography and cardiac sonographers working in routine clinical practice, but will also be very useful to echocardiologists and cardiac registrars. The goal of the text is to provide a comprehensive review of transthoracic echocardiography in the assessment of various cardiac pathologies. Refresher notes on cardiac anatomy and the relevant cardiac physiology and pathophysiology are included to expand the cardiac sonographer’s knowledge in this area and further their understanding of various diseases, disease processes and associated findings.

Burden of non-communicable diseases (NCDs) in Nepal and the availability and affordability of NCD medicines

Background: Traditionally communicable diseases were the main causes of burden in developing countries like Nepal. In recent years non-communicable diseases (NCDs), mainly cardiovascular diseases (CVDs), cancer, chronic respiratory diseases and diabetes mellitus, impose a larger disease burden compared to communicable diseases. Most elements of health and medicine policies in Nepal are still focused on communicable diseases. There is limited evidence about NCDs and NCD medicines in Nepal. Aim: To explore the gap between the burden of NCDs and the availability and affordability of NCD medicines in Nepal. Methods: Biomedical databases like Medline, Scopus, Web of Science and other online sources (including Global Burden of Diseases data) were searched for data on the burden of NCDs in term of Disability Adjusted Life Years (DALYs). The Essential Medicines List (EML) of Nepal was compared with World Health Organisation (EML) for inclusion of NCD medicines. Results: In Nepal, NCDs caused nearly 45% of the total 10.5 million DALYs in 2010. CVDs (15.2%), were the leading cause of NCDs burden followed by chronic respiratory diseases (14.7%), cancer (7.3%) and diabetes mellitus (3.2%). One hospital based national survey found that 37% of hospitalised patients had NCDs. Among them, 38% had heart disease followed by COPD (33%) , and diabetes (10%). Most (23 out of 28) non-cancer NCD medicines recommended in WHO-EML were present in Nepal's EML, theoretically indicating good availability. However, it is difficult to say whether they are accessible and affordable due to the lack of adequate data on access and pricing. Conclusion: This study gives some insight into the burden of NCDs. Although NCD medicines are available in Nepal, further research is required to determine whether they are accessible and affordable to the general population.