Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

The impact of front-of-pack nutrition labels on consumer product evaluation and choice: an experimental study.

OBJECTIVE: The present research was an experimental test that aimed to quantify the impact of two dominant front-of-pack (FOP) nutritional label formats on consumer evaluations of food products that carried them. The two FOP label types tested were the traffic light label and the Percentage Daily Intake. DESIGN: A 4×5 partially replicated Latin square design was used that allowed the impact of the FOP labels to be isolated from the effects of the product and the consumers who were performing the evaluations. SETTING: The experiment was conducted on campus at the University of Otago, New Zealand. SUBJECTS: The participants were 250 university students selected at random who met qualifying criteria of independent living and regular purchase of the products used in the research. They were not aware of the purpose of the research. RESULTS: The presence of FOP labels led to significant and positive changes in consumer purchase intentions towards the products that carried them. These changes were not affected by the nature of FOP labels used, their size or the product nutritional status (good/bad) that they were reporting. CONCLUSIONS: The result is consistent with the participants paying attention to the FOP label and then using it as an adimensional cue indicating product desirability. As such, it represents a complete functional failure of both of these FOP label types in this specific instance. This result supports calls for further research on the performance of these FOP labels before any move to compulsory deployment is made.

Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in aerobic- and resistance-trained subjects.

PURPOSE: Increased arterial stiffness is associated with an impairment of ventricular-vascular coupling efficiency and increased risk of cardiovascular mortality. Recently, it has been suggested that an increase in arterial stiffness is associated with resistance exercise training. Therefore, the aims of this study were to compare augmentation index (AIx) and left ventricular wasted pressure energy (LVEW) as markers of arterial stiffness and ventricular-vascular coupling efficiency in young aerobic-trained (AT) and resistance (RT)-trained subjects. We also investigated the relationship of muscle sympathetic nerve activity (MSNA) and flow-mediated dilation (FMD) to AIx in both sets of subjects to determine if endothelial function or sympathetic outflow could explain any differences in arterial stiffness. METHOD: To achieve our aims, we measured MSNA in 15 male subjects (8 RT, 7 AT) using microneurography. We also used applanation tonometry of the radial pressure waveform to noninvasively synthesize aortic pressure waveforms. FMD was calculated as percent dilation of the radial artery from baseline following a 5 min occlusion. RESULT: RT subjects had an increased AIx (12 ± 3 vs. -7 ± 2; P < 0.01), LVEW (429 ± 111 vs. -360 ± 77; P < 0.01) and MSNA burst incidence (34 ± 4 vs. 26 ± 4; P < 0.01) when compared with AT subjects. There was no difference in FMD between groups. MSNA burst incidence was also significantly related to AIx in subjects (R (2) = 0.61; P < 0.01) with a distinct demarcation between RT and AT subjects. CONCLUSION: These results confirm previous reports of a positive association between MSNA and AIx in young male resistance-trained subjects. Furthermore, RT is associated with increased arterial stiffness and elevated sympathetic outflow.

Ibandronate and ventricular arrhythmia risk.

INTRODUCTION: Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis. METHODS AND RESULTS: We report a case of suspected ibandronate-associated arrhythmia, following a single dose of ibandronate in a 55-year-old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow-up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced Ito (P < 0.05), with no change in IKr . Ibandronate-induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in Ito alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca(2+) load consistent with observed experimental results. CONCLUSION: Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced Ito combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug-induced proarrhythmia.

At-risk but viable myocardium in a large animal model of non ST-segment elevation acute coronary syndrome: cardiovascular magnetic resonance with ex vivo validation.

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees of salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces acute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant necrosis by late gadolinium enhancement (LGE). METHODS: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium. Myocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing. RESULTS: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 ± 0.72 ng/mL in model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote myocardium (53.2 ± 4.9 vs. 43.6 ± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant irreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly lower in model vs. sham animals (0.72 ± 0.07 vs. 1.04 ± 0.07, p < 0.001). Lower RRR corresponded to higher final TnI levels (R(2) = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression. CONCLUSIONS: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the human syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage. Reduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased myocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium warrants further consideration in preclinical and clinical studies of NSTE-ACS.

Toward a universalistic behavioural model of perceived managerial and leadership effectiveness for the health services sector.

Much management and leadership development provision for healthcare professionals has been the subject of considerable criticism, and there have been numerous calls for training programmes explicitly focused on the specific managerial (manager/leader) behaviours healthcare managers, physician leaders and nurse managers need to exhibit to be perceived effective. The aim of our multiple cross-case/cross-nation comparative study has been to: i) identify similarities and differences between the findings of published qualitative critical incident studies of effective and ineffective managerial behaviour observed within British, Egyptian, Mexican and Romanian public hospitals, respectively, and ii) if possible, deduce from the identified commonalities a healthcare-related behavioural model of perceived managerial and leadership effectiveness. Adopting a philosophical stance informed by pragmatism, epistemological instrumentalism and abduction, we used realist qualitative analytic methods to code and classify into a maximum number of discrete behavioural categories empirical source data obtained from five previous studies. We found high degrees of empirical generalization which resulted in the identification of five positive (effective) and four negative (ineffective) behavioural dimensions (BDs) derived, respectively, from 14 positive and 9 negative deduced behavioural categories (BCs). These BDs and underpinning BCs are expressed in the form of an emergent two-factor universalistic behavioural model of perceived managerial and leadership effectiveness. We suggest the model could be used to critically evaluate the relevance and appropriateness of existing training provision for physician leaders, nurse managers and other healthcare managers/leaders in public hospitals or to design new explicit training programmes informed and shaped by healthcare-specific management research, as called for in the literature.

Retailer branding of consumer sales promotions. A major development in food marketing?

This article examines retailer branding of consumer price promotions. It discusses the mechanics of price promotions, consumers' reactions to them and the benefits that accrue to those that use them. It describes how large food retailers can now deploy branded price promotion systems that are fundamentally different to 'traditional' price promotions in both their mechanics and their effects on consumer decision processes. The article describes a field experiment that compared the performance of a food retailer's branded price promotion system with that of a generic (manufacturer) price promotion. The research involved three experiments that covered two food categories (sliced bread and margarine) and two levels of discount (10% and 20%). The results indicate that food retailers are able to attach powerful brands to their price promotion systems, and these brand heuristics can significantly increase consumer purchase intent relative to an equivalent generic/manufacturer promotion. This incremental heuristic effect was stable in both categories and for both levels of price discount studied. These results are consistent with the predictions of alternative, non-cognitive and heuristic based models of food consumer choice that have been published recently in 'Appetite'.

The Relative Merits of Observational and Experimental Research: Four Key Principles for Optimising Observational Research Designs.

The main barrier to the publication of observational research is a perceived inferiority to randomised designs with regard to the reliability of their conclusions. This commentary addresses this issue and makes a set of recommendations. It analyses the issue of research reliability in detail and fully describes the three sources of research unreliability (certainty, risk and uncertainty). Two of these (certainty and uncertainty) are not adequately addressed in most research texts. It establishes that randomised designs are vulnerable as observation studies to these two sources of unreliability, and are therefore not automatically superior to observational research in all research situations. Two key principles for reducing research unreliability are taken from R.A. Fisher's early work on agricultural research. These principles and their application are described in detail. The principles are then developed into four key principles that observational researchers should follow when they are designing observational research exercises in nutrition. It notes that there is an optimal sample size for any particular research exercise that should not be exceeded. It concludes that best practice in observational research is to replicate this optimal sized observational exercise multiple times in order to establish reliability and credibility.

Food neophobia, food choice and the details of cultured meat acceptance.

This study focuses on the details of consumer response to lab grown 'cultured meat (CM)', compared to meat derived from insects, plants and animals. A sample of 254 New Zealanders were interviewed. A word association exercise revealed that consumer reaction to CM was dominated by affective, rather than cognitive factors. The linkages between a general food neophobia scale, a specific CM evaluation scale and purchase intent were studied. The general neophobia scale performed poorly as a predictor, while the 19-point CM evaluation scale performed well. Reducing this scale to its seven affective components, and then to just the two key affective components did not significantly reduce the scale's predictive performance. Overall, the results of this research reveal very significant differences in preference for meat products based upon their origins. Insect protein was strongly disfavoured over all alternatives, while cultured meat was significantly disfavoured compared to more established alternatives. The implications of this for the commercialisation of CM are discussed.

Bioenhancing effects of piperine and curcumin on triterpenoid pharmacokinetics and neurodegenerative metabolomes from Centella asiatica extract in beagle dogs.

Centell-S is a water-soluble extract of Centella asiatica containing more than 80% w/w triterpenoid glycosides. Madecassoside and asiaticoside are two major components of the extract and can be converted into active metabolites, triterpenic acids in large mammal species. In this study, the pharmacokinetic profiles and metabolomic changes generated by the bioactive triterpenoids of Centell-S alone, and in combination with the bioenhancers piperine and curcumin, were investigated in beagle dogs. The test substances were orally administered over multiple doses for 7 consecutive days. At day 1 and 7 after receiving the test compounds, the level of major bioactive triterpenoids and related metabolites were measured using triple quadrupole and high-resolution accurate mass orbitrap models of LCMS to determine pharmacokinetic and metabolomic profiles, respectively. Centell-S was well tolerated, alone and in all combination groups. The combination of Centell-S and piperine significantly increased (p < 0.05) the systemic exposure of madecassoside on day 1 and asiatic acid on day 7, by approximately 1.5 to 3.0-fold of Cmax and AUC values as compared to the Centell-S alone, while the addition of curcumin did not provide a significant improvement. Several metabolomic changes were observed from pre-dose to 4 h post-dose, with some biomarkers of neurodegenerative diseases including L-glutamine, lysophosphatidylcholine (17:0), taurochenodeoxycholic acid, uric acid, stearic acid, palmitic acid, and lactic acid showing good correlation with the systemic exposure of the bioactive triterpenoids (asiatic acid). Thus, the combining of piperine to Centell-S exhibits the improvement of bioactive triterpenoids which are related to the biomarkers of neurodegenerative diseases. These promising results might be useful for the development of this standardised extract to become a more effective phytomedicine for neurodegenerative diseases.

Dynamic detection and reversal of myocardial ischemia using an artificially intelligent bioelectronic medicine.

Myocardial ischemia is spontaneous, frequently asymptomatic, and contributes to fatal cardiovascular consequences. Importantly, myocardial sensory networks cannot reliably detect and correct myocardial ischemia on their own. Here, we demonstrate an artificially intelligent and responsive bioelectronic medicine, where an artificial neural network (ANN) supplements myocardial sensory networks, enabling reliable detection and correction of myocardial ischemia. ANNs were first trained to decode spontaneous cardiovascular stress and myocardial ischemia with an overall accuracy of ~92%. ANN-controlled vagus nerve stimulation (VNS) significantly mitigated major physiological features of myocardial ischemia, including ST depression and arrhythmias. In contrast, open-loop VNS or ANN-controlled VNS following a caudal vagotomy essentially failed to reverse cardiovascular pathophysiology. Last, variants of ANNs were used to meet clinically relevant needs, including interpretable visualizations and unsupervised detection of emerging cardiovascular stress. Overall, these preclinical results suggest that ANNs can potentially supplement deficient myocardial sensory networks via an artificially intelligent bioelectronic medicine system.

Acute Effects of Pimobendan on Cardiac Function in Dogs With Tachycardia Induced Dilated Cardiomyopathy: A Randomized, Placebo-Controlled, Crossover Study.

Background: Pimobendan provides a significant survival benefit in dogs with cardiac disease, including degenerative mitral valve disease and dilated cardiomyopathy (DCM). Its positive inotropic effect is well-known, however, it has complex effects and the mechanisms behind the survival benefit are not fully characterized. Secondary hemodynamic effects may decrease mitral regurgitation (MR) in DCM, and the benefits of pimobendan may extend to improved cardiac relaxation and improved atrial function. Hypothesis/Objectives: Our objective was to investigate the acute cardiac effects of pimobendan in dogs with a DCM phenotype. We hypothesized that pimobendan would increase left atrial (LA) contractility, reduce mitral regurgitation, improve diastolic function, and lower circulating NT-ProBNP levels. Animals: Seven purpose-bred Beagles were studied from a research colony with tachycardia induced DCM phenotype. Methods: The effects of pimobendan were studied under a placebo-controlled single-blinded cross-over design. In short, dogs underwent baseline and 3 h post-dose examinations 7 days apart with echocardiography and a blood draw. Dogs were randomized to receive oral placebo or 0.25 mg/kg pimobendan after their baseline exam. Investigators were blinded to treatments until all measurements were compiled. Results: When treated with pimobendan, the dogs had significant increases in systolic function and decreases in MR, compared to when treated with placebo. There were no detectable differences in left atrial measures, including LA size, LA emptying fraction, LA functional index or mitral A wave velocity. Heart rate decreased significantly with pimobendan compared to placebo. There was also a decrease in isovolumetric relaxation time normalized to heart rate. NT-proBNP levels had a high degree of variability. Conclusions: Improved mitral regurgitation severity and improved lusitropic function may contribute to the reported survival benefit for dogs with cardiac disease administered pimobendan. Pimobendan did not overtly improve LA function as assessed by echocardiography, and NT-proBNP was not significantly changed with a single dose of this medication. Further studies are needed to better characterize LA effects with other imaging modalities, to better quantify the total improvement of MR severity, and to assess chronic use of pimobendan on diastolic function in DCM.

Direct Interstitial Decongestion in an Animal Model of Acute-on-Chronic Ischemic Heart Failure.

Removal of excess fluid in acute decompensated heart failure (ADHF) targets the intravascular space, whereas most fluid resides in the interstitial space. The authors evaluated an approach to interstitial decongestion using a device to enhance lymph flow. The device was deployed in sheep with induced heart failure (HF) and acute volume overload to create a low-pressure zone at the thoracic duct outlet. Treatment decreased extravascular lung water (EVLW) volume (mL/kg) (-32% ± 9%, P = 0.029) compared to controls (+46% ± 9%, P = 0.003). Device-mediated thoracic duct decompression effectively reduced EVLW. Human studies may establish device-based interstitial decongestion as a new ADHF treatment.

Cue-based decision making. A new framework for understanding the uninvolved food consumer.

This article examines the processes that occur within the consumer's head as they make a choice between alternative market offers at a low level of involvement. It discusses recent research that indicates that the Theory of Planned Behaviour and its derivatives have restricted validity as a predictor of food consumers' evaluations and purchase patterns. This has significant implications as Planned Behaviour is the dominant paradigm within food industry research. The article demonstrates that Planned Behaviour has acquired this status more by default than by proven merit. The specific reasons for the failure of Planned Behaviour are discussed. An alternative paradigm, Cue-Based Decision Making is developed from an existing literature, and is proposed as a basis for increasing our understanding of the uninvolved food consumer in order to predict and influence their behaviour.

An Experimental Comparison of the Impact of 'Warning' and 'Health Star Rating' FoP Labels on Adolescents' Choice of Breakfast Cereals in New Zealand.

This research investigated the performance of the red, octagonal Vienna Convention traffic 'STOP' sign as a front of pack (FoP) warning nutritional label. While the Vienna Convention traffic light system is an established FoP label, the potential of the 'STOP' sign in the role has not been investigated. The performance of the 'STOP' label was compared with that of a single star (low nutritional value) Australasian Health Star Rating (HSR) label using a fractionally replicated Latin square design. The labels were presented on choice diads of cold breakfast cereal packets. The sample of 240 adolescents aged 16-18 was drawn from a secondary school in the South Island of New Zealand. A large and significant main effect was observed at the p < 0.01 level for the difference between the 'STOP' sign and the control condition (no nutritional FoP label), and at p < 0.05 for the difference between the HSR and the 'STOP' label. There was no significant difference between the HSR FoP and the control condition. A significant non-additivity (interaction) (p < 0.01) was also observed via the fractional replication. The results indicate that the Vienna Convention 'STOP' sign is worthy of further research with regard to its potential as an FoP nutritional label.

Myocardial Contractility: Historical and Contemporary Considerations.

The term myocardial contractility is thought to have originated more than 125 years ago and has remained and enigma ever since. Although the term is frequently used in textbooks, editorials and contemporary manuscripts its definition remains illusive often being conflated with cardiac performance or inotropy. The absence of a universally accepted definition has led to confusion, disagreement and misconceptions among physiologists, cardiologists and safety pharmacologists regarding its definition particularly in light of new discoveries regarding the load dependent kinetics of cardiac contraction and their translation to cardiac force-velocity and ventricular pressure-volume measurements. Importantly, the Starling interpretation of force development is length-dependent while contractility is length independent. Most historical definitions employ an operational approach and define cardiac contractility in terms of the hearts mechanical properties independent of loading conditions. Literally defined the term contract infers that something has become smaller, shrunk or shortened. The addition of the suffix "ility" implies the quality of this process. The discovery and clinical investigation of small molecules that bind to sarcomeric proteins independently altering force or velocity requires that a modern definition of the term myocardial contractility be developed if the term is to persist. This review reconsiders the historical and contemporary interpretations of the terms cardiac performance and inotropy and recommends a modern definition of myocardial contractility as the preload, afterload and length-independent intrinsic kinetically controlled, chemo-mechanical processes responsible for the development of force and velocity.

Hyperbaric oxygenation enhances transplanted cell graft and functional recovery in the infarct heart.

A major limitation to the application of stem-cell therapy to repair ischemic heart damage is the low survival of transplanted cells in the heart, possibly due to poor oxygenation. We hypothesized that hyperbaric oxygenation (HBO) can be used as an adjuvant treatment to augment stem-cell therapy. Therefore, the goal of this study was to evaluate the effect of HBO on the engraftment of rat bone marrow-derived mesenchymal stem cells (MSCs) transplanted in infarct rat hearts. Myocardial infarction (MI) was induced in Fisher-344 rats by permanently ligating the left-anterior-descending coronary artery. MSCs, labeled with fluorescent superparamagnetic iron oxide (SPIO) particles, were transplanted in the infarct and peri-infarct regions of the MI hearts. HBO (100% oxygen at 2 ATA for 90 min) was administered daily for 2 weeks. Four MI groups were used: untreated (MI); HBO; MSC; MSC+HBO. Echocardiography, electro-vectorcardiography, and magnetic resonance imaging were used for functional evaluations. The engraftment of transplanted MSCs in the heart was confirmed by SPIO fluorescence and Prussian-blue staining. Immunohistochemical staining was used to identify key cellular and molecular markers including CD29, troponin-T, connexin-43, VEGF, alpha-smooth-muscle actin, and von Willebrand factor in the tissue. Compared to MI and MSC groups, the MSC+HBO group showed a significantly increased recovery of cardiac function including left-ventricular (LV) ejection fraction, fraction shortening, LV wall thickness, and QRS vector. Further, HBO treatment significantly increased the engraftment of CD29-positive cells, expression of connexin-43, troponin-T and VEGF, and angiogenesis in the infarct tissue. Thus, HBO appears to be a potential and clinically-viable adjuvant treatment for myocardial stem-cell therapy.

Use of the rabbit with a failing heart to test for torsadogenicity.

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades de pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades de pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades de pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts.

Animal models of ventricular arrhythmias.

Limitations in understanding of arrhythmias stem from lack of animal models which serve as surrogates for man. The purpose of this review is to discuss iatrogenic and naturally occurring animal models that are useful in our understanding of the mechanisms of ventricular arrhythmia and of antiarrhythmic and proarrhythmic agents. It is not surprising however that some information obtained from studies on infrahuman mammals may not be extrapolated to man. Need for anesthesia affects profoundly the electrophysiology of the heart, including autonomic affects. Most of the animal are modification of the Harris' 2-stage model. A model proposed by Schwartz, Billman and Stone has evolved as one that produces arguably the most information on the pathophysiology of arrhythmia production, including the role of the autonomic nervous system and the interaction with pharmacological agents. Intoxication with digitalis and escalating doses of epinephrine are commonly used models for production of ventricular arrhythmias. No matter what model of ventricular arrhythmias is used, programmed electrical stimulation can be useful to uncover increased tendency for arrhythmia, even if no arrhythmia occurs spontaneously. Models of spontaneous ventricular arrhythmia occur in German shepherd puppies, Boxer dogs, Doberman pinchers with dilated cardiomyopathy, and in large dogs with gastric dilatation or splenic torsion. Models are necessary because they allow for controlled studies and methods of exploration impossible, for legal and ethical reasons, in humans. Nonetheless, ethical considerations in using animal models are still important, and there is a continual search for non-animal models to explore ventricular arrhythmias.