Should we be evaluating the ventricle or the myocardium? Advances in tissue characterization

The assessment of left ventricular (LV) dysfunction has become the most frequent indication for echocardiography, a growth that has been driven by the epidemic of heart failure. The value of echocardiography for assessing LV dysfunction is unquestionable, the quantification of both LV systolic and diastolic dysfunction being a reliable indicator of mortality. 1,2 Nonetheless, whereas the ejection fraction and diastolic assessment are important clinical parameters, they are highly dependent on loading and may produce abnormal results under unusual loading conditions. Moreover, in a number of situations where the LV is evaluated, although the overall function is an important finding, the referring clinician is really requesting an assessment of the nature of the underlying myocardial tissue (Table 1). Indeed, in some situations (eg, among family members of patients with a cardiomyopathy) questions arise about the presence of pathology despite the presence of normal ventricular function. Traditionally, it has been difficult to obtain this information because of the lack of sufficiently sensitive parameters, but a number of new developments have shown such success in this area that the clinical application of tools to assess the myocardium in routine practice appears finally to be a realistic proposition.

Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT4 receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT4 receptors in porcine and human ventricle. 5-HT4 mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT4 receptor mRNA. Ventricular 5-HT4(b) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC50=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 muM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC50=60 nM) and PKA activity by 39% of (-)-iso-proterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca2+ and 1.2 mM Mg2+ followed by a switch to 2.5 mM Ca2+ and 1 mM Mg2+, 5-HT (1-100 muM, 3-isobutyl-1-melhylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of I I patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT4 receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT4 receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Dietary supplementation of vitamin E and -lipoic acid upregulates cell growth and signaling genes in rat myocardium

The efficacy of antioxidant supplementation in the prevention of cardiovascular disease appears equivocal, however the use of more potent antioxidant combinations than those traditionally used may exert a more positive effect. We have shown previously that supplementation of vitamin E and α-lipoic acid increases cardiac performance during post-ischemia reperfusion in older rats and increases Bcl-2 levels in endothelial cells. The purpose of this study was to examine the effects of vitamin E and α-lipoic acid supplementation on myocardial gene expression with a view to determine their mechanism of action. Young male rats received either a control (n=7) or vitamin E and α-lipoic acid supplemented diet (n=8) for 14 weeks. RNA from myocardial tissue was then amplified and samples were pooled within groups and competitively hybridized to 5K oligonucleotide rat microarrays. The relative expression of each gene was then compared to the control sample. Animals that received the antioxidant-supplemented diet exhibited upregulation (>1.5×) of 13 genes in the myocardium with 2 genes downregulated.� �Upregulated genes include those involved in cell growth and maintenance (LynB, Csf1r, Akt2, Tp53), cell signaling (LynB, Csf1r) and signal transduction (Pacsin2, Csf1r). Downregulated genes encode thyroid (Thrsp) and F-actin binding proteins (Nexilin).

The relative impact of scar and viable tissue in predicting global left ventricular remodeling in medically treated patients

We sought to determine the relative impact of myocardial scar and viability on post-infarct left ventricular (LV) remodeling in medically-treated patients with LV dysfunction. Forty patients with chronic ischemic heart disease (age 64±9, EF 40±11%) underwent rest-redistribution Tl201 SPECT (scar = 50% transmural extent), A global index of scarring for each patient (CMR scar score) was calculated as the sum of transmural extent scores in all segts. LV end diastolic volumes (LVEDV) and LV end systolic volumes (LVESV) were measured by real-time threedimensional echo at baseline and median of 12 months follow-up. There was a significant positive correlation between change in LVEDV with number of scar segts by all three imaging techniques (LVEDV: SPECT scar, r = 0.62, p < 0.001; DbE scar, r = 0.57, p < 0.001; CMR scar, r = 0.52, p < 0.001) but change in LV volumes did not the correlate with number of viable segments. ROC curve analysis showed that remodeling (LVEDV> 15%) was predicted bySPECTscars(AUC= 0.79),DbEscars(AUC= 0.76),CMR scars (AUC= 0.70), and CMR scar score (AUC 0.72). There were no significant differences between any of the ROC curves (Z score

Information management for viable organisations

The recent global „credit crunch? has brought sharply into focus the need for better understanding of what it takes for organisations to survive. This research seeks to help organisations maintain their „viability? – the ability to maintain a separate existence and survive on their own. Whilst there are a multitude of factors that contribute to organisational viability, information can be viewed as the lifeblood of organisations. This research increases our understanding of how organisations can manage information effectively to help maintain their viability. The viable systems model (VSM) is an established modelling technique that enables the detailed analysis of organisational activity to examine how the structure and functions performed in an organisation contribute to its „viability?. The VSM has been widely applied, in small/large companies, industries and governments. However, whilst the VSM concentrates on the structure and functions necessary for an organisation to be viable, it pays much less attention to information deployment in organisations. Indeed, the VSM is criticised in the literature for being unable to provide much help with detailed information and communication structures and new theories are called for to explore the way people interact and what information they need in the VSM. This research analyses qualitative data collected from four case studies to contribute to our understanding of the role that information plays in organisational viability, making three key contributions to the academic literature. In the information management literature, this research provides new insight into the roles that specific information plays in organisations. In the systems thinking literature, this research extends our understanding of the VSM and builds on its powerful diagnostic capability to provide further criteria to aid in the diagnosis of viable organisations. In the information systems literature, this research develops a framework that can be used to help organisations design more effective information systems.