Remote Ischemic Preconditioning induces Cardioprotective Autophagy and Signals through the IL-6-Dependent JAK-STAT Pathway.

: Autophagy is a cellular process by which mammalian cells degrade and assist in recycling damaged organelles and proteins. This study aimed to ascertain the role of autophagy in remote ischemic preconditioning (RIPC)-induced cardioprotection. Sprague Dawley rats were subjected to RIPC at the hindlimb followed by a 30-min transient blockade of the left coronary artery to simulate ischemia reperfusion (I/R) injury. Hindlimb muscle and the heart were excised 24 h post reperfusion. RIPC prior to I/R upregulated autophagy in the rat heart at 24 h post reperfusion. In vitro, autophagy inhibition or stimulation prior to RIPC, respectively, either ameliorated or stimulated the cardioprotective effect, measured as improved cell viability to mimic the preconditioning effect. Recombinant interleukin-6 (IL-6) treatment prior to I/R increased in vitro autophagy in a dose-dependent manner, activating the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway without affecting the other kinase pathways, such as p38 mitogen-activated protein kinases (MAPK), and glycogen synthase kinase 3 Beta (GSK-3ß) pathways. Prior to I/R, in vitro inhibition of the JAK-STAT pathway reduced autophagy upregulation despite recombinant IL-6 pre-treatment. Autophagy is an essential component of RIPC-induced cardioprotection that may upregulate autophagy through an IL-6/JAK-STAT-dependent mechanism, thus identifying a potentially new therapeutic option for the treatment of ischemic heart disease.

Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection.

Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.

Environmental stress and vestibular inputs modulate cardiovascular responses to orthostasis in hypertensive rats.

The frequent accompaniment of hypertension by orthostatic circulatory disorders prompted us to investigate the effect of repeated and sustained head-up and head-down tilt positions on cardiovascular responses in spontaneously hypertensive rats vs. Wistar rats using radiotelemetric implants. Repeated orthostasis caused a transient elevation in blood pressure (7.3±1.7 mmHg) and heart rate (39.7±10.5 BPM), while repeated antiorthostasis led only to reversible tachycardia (85.6±11.7-54.3±16.8 BPM) in spontaneously hypertensive rats. In contrast to the Wistar rats, sustained tilt failed to affect the blood pressure or heart rate in spontaneously hypertensive rats because the environmental stress of being placed in horizontal tilt cages prior to the sustained tilt test induced marked changes in cardiovascular parameters. Non-specific stress responses were eliminated both by the anxiolytic diazepam and a sub-anesthetic dose of chloralose. Unlike diazepam, chloralose amplified the orthostatic pressor responses in the Wistar rats. In contrast to diazepam preventing the pressor response and associated tachycardia in spontaneously hypertensive rats, chloralose elicited this effect during both sustained orthostasis (36.0±7.3 mmHg, 63.7±21.8 BPM) and antiorthostasis (42.9±10.9 mmHg, 82.8±25.4 BPM), with a reduced baroreflex sensitivity. However, during sustained orthostasis, removal of the vestibular input led to a depressor response with bradycardia (12.5±3.2 mmHg, 59.3±17.3 BPM), whereas antiorthostasis only reduced blood pressure (20.5±7.1 mmHg) in the spontaneously hypertensive rats. We conclude that repeated tilts induce a transient pressor response and/or tachycardia in spontaneously hypertensive rats. Cardiovascular parameters are suppressed by diazepam, whereas chloralose evokes both blood pressure and heart rate responses during sustained tilts, which are primarily elicited by baroreflex suppression in hypertension. Vestibular inputs support cardiovascular tolerance to sustained postural changes in a rat model of human 'essential' hypertension.

Arrhythmogenicity of hypothermia - a large animal model of hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) is used to mitigate cerebral injury after an out of hospital cardiac arrest. There is a perceived risk of increased arrhythmias with temperatures lower than the current target of 32-34°C for TH. This study sought to develop and investigate the electrophysiological changes in a sheep model of systemic hypothermia regarding the susceptibility to ventricular arrhythmias. METHODS: Ten sheep underwent systemic hypothermia using a venous-venous extra-corporeal circuit whilst instrumented with a 12 lead ECG. An epicardial sock recorded potentials to 30°C (N=10) or 26°C (N=6). Activation times (AT) and Activation Recovery Intervals (ARI) were calculated using custom software. RESULTS: The AT and ARI were significantly prolonged with increased heterogeneity during hypothermia. This effect was most pronounced between normothermia and 34°C during sinus rhythm (SR). For ventricular pacing (VP) however heterogeneity continued to increase with progressive hypothermia. CONCLUSIONS: Hypothermia causes a significant increase in the heterogeneity of depolarisation and repolarisation. There is evidence to suggest that SR is protective with most of the increase in heterogeneity occurring with cooling to 34°C. This raises the possibility that the current target temperatures for therapeutic hypothermia may be safely lowered to provide a gain in cerebral protection.

Selective inhibition of the master regulator transcription factor Egr-1 with catalytic oligonucleotides reduces myocardial injury and improves left ventricular systolic function in a preclinical model of myocardial infarction.

BACKGROUND: Egr-1 is implicated in the pathogenesis of myocardial ischemia-reperfusion injury. The aim of this study was to ascertain the effectiveness of intracoronary delivery of DNAzyme targeting the transcription factor Egr-1 at reperfusion following experimental myocardial ischemia. METHODS AND RESULTS: Functional DNAzyme targeting Egr-1 or a size-matched scrambled control were delivered via the intracoronary route immediately on reperfusion after 60 minutes' balloon occlusion of the left anterior descending coronary artery in a pig model of myocardial I/R injury (n=7 per treatment group). Heart function and extent of myocardial infarction were determined following intervention by echocardiography and cardiac magnetic resonance imaging, respectively. Hearts were removed and examined for molecular and histological markers of inflammation and apoptosis. Administration of functional DNAzyme led to an overall decrease in the expression of inflammatory markers including intracellular adhesion molecule-1, tissue factor, and complement 3, with associated decreases in the extent of neutrophil infiltration, oxidative damage, and subsequent apoptosis within the infarct border zone. Functional significance was indicated by an increase in salvaged left ventricular myocardium (P=0.012), ejection fraction (P=0.002), and fractional area change (P=0.039) in the functional DNAzyme-treated group compared with the control. CONCLUSIONS: Egr-1 silencing through intracoronary delivery of a targeting DNAzyme at the time of reperfusion following acute myocardial ischemia decreases myocardial inflammation and apoptosis leading to improved cardiac function.

Translation of Methodology Used In Human Myocardial Imaging to a Sheep Model of Acute Myocardial Infarction.

INTRODUCTION: Pre-clinical investigation of stem cells for repairing damaged myocardium predominantly uses rodents, however large animals have cardiac circulation closely resembling the human heart. The aim of this study was to evaluate whether SPECT/CT myocardial perfusion imaging (MPI) could be used for assessing sheep myocardium following an acute myocardial infarction (MI) and response to intervention. METHODS: Eighteen sheep were enrolled in a pilot study to evaluate [(99m)Tc]-sestamibi MPI at baseline, post-MI and after therapy. Modifications to the standard MPI protocols were developed. All data was reconstructed with OSEM using CT-derived attenuation and scatter correction. Standard analyses were performed and inter-observer agreement was measured using Kappa (κ). Power determined the sample sizes needed to show statistically significant changes due to intervention. RESULTS: Ten sheep completed the full protocol. Data processed was performed with pre-existing hardware and software used in human MPI scanning. No improvement in perfusion was seen in the control group, however improvements of 15%-35% were seen after intra-myocardial stem cell administration. Inter-observer agreement was excellent (К=0.89). Using a target power of 0.9, 28 sheep were required to detect a 10-12% change in perfusion. CONCLUSION: This study demonstrates the suitability of large animal models for imaging with standard MPI protocols and its feasibility with a manageable number of animals. These protocols could be translated into humans to study the efficacy of stem cell therapy in heart regeneration and repair.

Nonsurround, nonuniform, biventricular-capable direct cardiac compression provides Frank-Starling recruitment independent of left ventricular septal damage.

OBJECTIVES: Right ventricular (RV) function is compromised in 25% of left ventricular (LV) assist device recipients despite effective LV support. The risk of such dysfunction has been enhanced by an ischemic or undamaged interventricular septum; however, we found septal infarction to be paradoxically protective. We, therefore, evaluated the potential of nonsurround, nonuniform, biventricular-capable direct cardiac compression (DCC) (using the HeartPatch DCC) to overcome RV dysfunction in hearts with a normal or infarcted interventricular septum. METHODS: Ethanol ablation was used to create an interventricular septal infarction in 6 sheep, and 6 others served as the control sheep. The load-independent and in-series RV response to DCC was assessed using sonomicrometer heart dimension sensors. Triphenyltetrazolium perfusion delineated the septal damage. RESULTS: LV DCC caused a greater increase of the RV preload recruitable stroke work in the control sheep than in the study sheep (190.6 ± 23.5 and 135.0 ± 40.8 erg*10^3, respectively, P < .001). In contrast, RV end-systolic elastance increased more in the septal-ablated sheep with RV DCC (17.29 ± 3.40 vs 9.88 ± 2.01 mm Hg/mL in the control sheep, P < .001). Abnormal RV diastolic function before device insertion in the septal-ablated sheep was normalized with both passive DCC placement and after activation (RV diastolic relaxation constant 23.5 ± 2.3 and 20.0 ± 2.1 ms, respectively, P < .001). Both biventricular and RV DCC actuation increased the RV systolic pressure more in the septal-ablated sheep than in the control sheep (37.9 ± 6.3 and 47.7 ± 4.6 mm Hg vs 29.7% ± 4.8% and 40.3% ± 8.3%, respectively, P < .001). In contrast, the RV end-systolic diameter decreased more during LV DCC (70.1% ± 15.9% vs 90.5% ± 5.0%, P < .001). CONCLUSIONS: The HeartPatch DCC support of LV and RV function results from improvement of the systolic septal-lateral fractional change that is not influenced by septal infarction. The latter attenuated LV to RV device energy delivery during LV patch actuation but enhanced RV energy delivery during RV patch actuation. This DCC technique can provide effective support in high-risk RV failure situations arising from left ventricular assist device use.

ß(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification.

BACKGROUND: inhibition of L-type Ca(2+) current contributes to negative inotropy of ß(3) adrenergic receptor (ß(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na(+) levels and upregulation of the ß(3) AR in heart failure. METHODS AND RESULTS: we voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (I(p)) as the shift in holding current induced by ouabain. The synthetic ß(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the ß(1)/ß(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the ß(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to ß(3) AR agonists decreased ß(1) Na(+)-K(+) pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial ß(1) pump subunit glutathionylation with elimination of ß(3) AR-mediated signaling in ß(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na(+)-K(+) pump stimulation in heart failure. CONCLUSIONS: the ß(3) AR mediates decreased ß(1) subunit glutathionylation and Na(+)-K(+) pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na(+).

Chronic septal infarction confers right ventricular protection during mechanical left ventricular unloading.

OBJECTIVE: Right ventricular failure manifests in 25% of left ventricular assist device recipients because of ventricular coupling mechanism disruption. Septal ischemia accentuates this process, but the effect of septal infarction has not been elucidated. Right ventricular response to incremental left ventricular unloading was studied in sheep with septal infarction. METHODS: Septal infarction was induced in 6 sheep using ethanol delivery into the main septal perforating artery. Six shams avoided ethanol. Load-independent and in-series right ventricular response to incremental (0%-100%) left ventricular unloading was measured 4 weeks later. Dimensions of whole heart, wall thickness, and chamber volumes were obtained using sonomicrometers. Selective perfusion with triphenyltetrazolium quantified septal damage. RESULTS: Right ventricular preload-recruitable-stroke-work, contractility, and ejection fraction were lower at 75% and 100% left ventricular unloading in sham compared with infarcted animals (75%: 26.3 +/- 3.4, 0.70 +/- 0.15, and 23.9 +/- 4.6 vs 37 +/- 2.6 erg *10;3, 0.99 +/- 0.18 mm Hg/mL, and 35.5% +/- 3.4%, all P < . 01, 100%: 24.8 +/- 4.5, 0.67 +/- 0.14, and 23.8 +/- 5.8 vs 36.0 +/- 4.6 erg *10;3, 0.90 +/- 0.09 mm Hg/mL, and 32.7% +/- 11.0%, all P < . 01). Central venous pressure was higher at 75% and 100% unloading in sham compared with infarcted animals (75%: 8.6 +/- 1.0 vs 4.5 +/- 1.0, 100%: 12.4 +/- 0.8 vs 3.4 +/- 1.0 mm Hg, all P < . 01). Right ventricular cardiac output was less in shams with 100% unloading (1.2 +/- 0.2 L/min vs 2.1 +/- 0.3 L/min, P < . 01). End-diastolic and end-systolic right ventricular short-axis dimension at 75% and 100% unloading was greater in sham compared with infarcted animals (75%: 34.4 +/- 5.5 mm and 29.1 +/- 5.5 mm vs 25.6 +/- 4.7 mm and 20.5 +/- 4.0 mm; 100%: 37.6 +/- 6.6 mm and 29.9 +/- 5.9 mm vs 25.5 +/- 3.9 mm and 21.1 +/- 3.8 mm, all P < .01). Prolonged diastolic relaxation (Tau) in infarcted animals was normalized with 75% and 100% unloading. CONCLUSION: High-level (>or=75%) left ventricular unloading causes right ventricular dilatation and compromised function. Chronic septal damage, however, confers protection by preserving right ventricular dimensions.

Mesenchymal stem cells: isolation, characterisation and in vivo fluorescent dye tracking.

Cell therapies have been used to regenerate the heart by direct myocardial delivery, by coronary infusion and by surface attached scaffolds. Multipotent mesenchymal stem cells (MSC) with capacity to differentiate into cardiomyocytes and other cell lines have been predominantly trialled in rodents. However, large animal models are increasingly needed to translate basic research into new, safe regenerative therapies. Understanding the mode of action of cell therapies in the mammalian heart has been limited by cell tracking capability. This study examined the ability to track the fate of allogeneic MSC in sheep using various fluorescent dyes. MSC isolated from sheep bone marrow were grown in culture following extraction and flow cytometric characterisation. After labelling with fluorescent tracking dyes (e.g. CFSE and DiI) cells were tested for in vitro and in vivo signal up to six weeks. Labelling effect on cell division and differentiation was studied. Several dyes lost fluorescence and slowed cell division. However, the thiol reactive dye CM-DiI showed detectable in vivo fluorescence in labelled MSC six weeks after injection into sheep skeletal muscle and two weeks after implantation of an MSC coated biomaterial scaffold. CM-DiI labelled MSC differentiated in vitro showed label retention over four weeks. The fluorescent membrane dye CM-DiI tracks implanted sheep MSC and provides an alternative to traditional cell markers such as gene modified GFP.

The Royal North Shore Hospital inquiry: an analysis of the recommendations and the implications for quality and safety in Australian public hospitals.

In October 2007, the New South Wales Parliament appointed a Joint Select Committee to inquire into the quality of patient care at Royal North Shore Hospital (RNSH). The inquiry was initiated in response to the publicity and complaints surrounding a patient who had a miscarriage in the toilets of the RNSH emergency department waiting area. The Committee held four public hearings and received 103 submissions. It handed down 45 recommendations in its report on 20 December 2007. There has been criticism from clinicians and others that the recommendations are too general and will not effect significant change for the severe systemic problems affecting the hospital. This article represents the view of some of the clinicians who work at RNSH, and who gave evidence at the inquiry, on the recommendations and some possible solutions for the health system in general.

Time-dependent response of both ventricles after septal ablation: implications for biventricular support after left ventricular assist device placement.

OBJECTIVES: An ovine model of septal ablation was studied to elucidate the mechanisms involved in right ventricular failure when commencing left ventricular mechanical assistance. The disruption of ventricular interdependence after acute and chronic septal injury was examined. METHODS: Twelve sheep underwent percutaneous transluminal septal myocardial ablation using 0.6 mL ethanol. Twelve other sheep underwent a sham procedure. Left ventricular and right ventricular pressure and volume (conductance) response 15 minutes and 4 weeks postinjury were measured. Ultrasonic crystals measured chamber dimensions and wall movement. Areas at risk and infarct zones were quantified. RESULTS: Compared with sham, ablation chronically reduced systolic interventricular septal thickening (18.4% +/- 5.8% vs 7.3% +/- 3.1%; P < .001) and acutely increased right ventricular ejection fraction (37.6% +/- 8.5% vs 69.9% +/- 7.2%; P < .001), preload recruitable stroke work (42.0 +/- 4.4 erg x 10(3) vs 48.7 +/- 2.0 erg x 10(3), P < .001), end-systolic elastance (1.03 +/- 0.19 mm Hg mL(-1) vs 1.31 +/- 0.18 mm Hg mL(-1); P < .001), and Tau (24.9 +/- 3.8 ms vs 29.6 +/- 8.2 ms; P < .001). In contrast, for left ventricular ejection fraction (55.5% +/- 5.9% vs 38.9% +/- 7.7%; P < .001), preload recruitable stroke work (85.9 +/- 10.6 mm Hg vs 66.5 +/- 9.6 mm Hg; P < .001) and elastance (2.13 +/- 0.51 mm Hg mL(-1) vs 1.81 +/- 0.44 mm Hg mL(-1); P < .001) were reduced, but Tau increased (22.0 +/- 3.5 ms vs 28.9 +/- 5.8 ms; P < .001) and remained elevated at 4 weeks compared with sham. The area at risk was the same between groups, and injury was limited to the septum (17.2% +/- 2.7% vs 2.9% +/- 5.8%; P < .001). CONCLUSIONS: Acute and chronic hemodynamic responses are distinctly different after septal injury; the acute response demonstrates a paradoxical motion. Resolution of this motion at 4 weeks is suggestive of reduced septal compliance and buttressing. Ventricular interactions after placement of a left ventricular assist device will vary depending on the injury duration.

Effect of direct cardiac compression on left ventricular axial dynamics in sheep.

The HeartPatch direct cardiac compression device consists of two separate, nonsurround patches placed on the left and right ventricular free walls. Although the device has been shown to effectively restore circulatory parameters in acute heart failure sheep, the impact of device inflation on left ventricular geometry is yet to be elucidated. This study used sonomicrometer crystal transducers to examine three orthogonal left ventricular dimensions under various cardiac states and assessed the feasibility of determining stroke volume from these dimensions. Seven sheep (weight, 51 +/- 5 kg) were implanted with six sonomicrometer crystals, and a heart patch was placed on each of the ventricles. The crystals were positioned to measure anterior-posterior, septal-lateral, and apex-base (long-axis) dimensions. Sheep were studied under both awake and anesthetized conditions. Septal-lateral shortening was increased with direct cardiac compression assist, whereas anterior-posterior and long-axis dimensions were either unchanged (awake) or decreased (anesthetized). Estimation of stroke volume, using the ellipsoid volume model, correlated well with stroke volume measured from an aortic flow probe; however, absolute stroke volumes were lacking in agreement.

Efficacy and mechanisms of biventricular and left/right direct cardiac compression in acute heart failure sheep.

Direct cardiac compression (DCC) with implanted heart patches has previously demonstrated efficacy of biventricular (BiV) support in acute heart failure (HF) sheep. We hypothesized that this was primarily due to a left ventricular (LV) effect. This study compared BiV, LV, and right ventricular (RV) assists in terms of hemodynamic and energetic response. Ten sheep underwent instrumentation and device implantation at least 1 week prior to study. HF (50% reduction in cardiac output) was maintained with intravenous esmolol infusion. BiV, LV, and RV assists were activated randomly with intervening stable HF periods. BiV assist was more effective than either LV or RV assist in restoring hemodynamic parameters; however, there was no difference in efficacy of LV and RV support. RV assist preserved left coronary flow patterns and chamber geometry compared to other assist conditions, but increased LV preload. These results suggest that LV and RV support each make a significant contribution to the efficacy of BiV assist, albeit through different mechanisms.

Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheep.

Cardiac remodeling following myocardial infarction (MI) is a maladaptive process, fundamental to the progression of ischemic heart failure. The extent of remodeling is influenced by mechanical stress, inflammatory response and activation of matrix metalloproteinases (MMPs). This study examined regional association between these parameters in response to acute MI. Coronary ligation was performed in ten sheep. Sonomicrometer transducers measured segmental length in the infarcted, border and non-infarcted region. Regional tissue samples obtained 3 h post MI from six sheep were analysed using RT-PCR, gelatin zymography and Western blot. Six sham-operated sheep served as controls.Region-specific dilation and reduced contraction was associated with corresponding alterations in matrix molecules.IL-6 and MMP-9 mRNA were increased in the infarcted and border regions compared to controls.MMP-2 and TIMP-1 mRNA increased in non-infarcted myocardium and both correlated positively with segmental shortening. IL-6 mRNA levels, in contrast, were negatively associated with segmental shortening. In summary, inflammatory cytokines and MMPs are altered early after MI in a region-specific manner, and these changes correspond to acute regional myocardial dysfunction. Therapies for LV remodeling from the time of reperfusion may benefit from further understanding this portfolio of acute alterations.

Myocardial extracellular matrix remodeling in ischemic heart failure.

Left ventricular (LV) remodeling is a process whereby structural alterations attempt to compensate altered hemodynamic load. In the chronic setting this process becomes maladaptive, self-sustaining and is associated with worsened survival. The extracellular matrix (ECM) of the heart, once believed an inert scaffold for cardiomyocytes, is now known to play an important role in LV remodeling. The enzyme system primarily responsible for ECM turnover is the matrix metalloproteinases (MMPs), and these enzymes are robustly altered in cardiovascular pathologies, including myocardial infarction (MI) and ischemic heart failure. A cause-and-effect relationship has been established between MMPs and LV remodeling post MI, as MMP inhibition prevents LV dilation and preserves cardiac function in animal models of infarction. In spite of this, initial clinical experience with MMP inhibition post MI has been disappointing. This review examines the structural and functional roles of the myocardial ECM, the evidence for MMP involvement in LV remodeling, and recent investigations into MMPs as prognostic markers and therapeutic targets.

Postural effects when cycling in late pregnancy.

AIM: This study assessed if upright cycling is preferable to semi-recumbent cycling during pregnancy. METHOD: Healthy women with low risk singleton pregnancies were tested at 34-38 weeks gestation. They cycled for 12 min, either semi-recumbent (45 degrees, n = 27) or upright (n = 23), at 135-145 beats min(-1). RESULTS: When semi-recumbent, minute ventilation was greater (p<0.03) at rest and systolic blood pressure and pulse pressure were greater during exercise (p<0.05). Exercise maternal heart rate, oxygen consumption, oxygen consumption per kilogram, minute ventilation, cardiac output, stroke volume, mean and diastolic blood pressures and arterio-venous oxygen difference were posture-independent. All increased with exercise (p<0.01), except stroke volume when semi-recumbent (p>0.05). Small post-exercise fetal heart rate increases (by 8 beats min(-1), p<0.05) were similar in both postures (n = 11 in each sub-group), with no adverse changes. Fetal heart rate accelerations and uterine activity (n = 11 in each sub-group) were not influenced by posture or exercise. CONCLUSIONS: (1) Neither posture had a distinct advantage. (2) Both postures were safe for short duration cycling. (3) The same target maternal heart rates are suitable for both postures because they resulted in similar oxygen consumptions and fetal heart rates.

Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses.

The mandatory use of pharmacotherapy in human heart failure (HF) impedes further study of natural history and remodeling mechanisms. We created a sheep model of chronic, severe, ischemic HF [left ventricular (LV) ejection fraction (LVEF) <35% stable over 4 wk] by selective coronary microembolization under general anesthesia and followed hemodynamic, energetic, neurohumoral, structural, and cellular responses over 6 mo. Thirty-eight sheep were induced into HF (58% success), with 23 sheep followed for 6 mo (21 sheep with sufficient data for analysis) after the LVEF stabilized (median of 3 embolizations). Early doubling of LV end-diastolic pressure persisted, as did increases in LV end-diastolic volume, LV wall stress, and LV wall thinning. Contractile impairment (LV end-systolic elastance, LV preload recruitable stroke work, and dobutamine-responsive contractile reserve) and diastolic dysfunction also remained stable. Cardiac mechanical energy efficiency did not recover. Plasma atrial natriuretic peptide levels remained elevated, but rises in plasma aldosterone and renin activity were transient. Collagen content increased 170%, the type I-to-III phenotype ratio doubled in the LV, but right ventricular collagen remained unaltered. Fas ligand cytokine levels correlated with expression of both caspase-3 and -2, suggesting a link in the apoptotic "death cascade." Caspase-3 activity also bore a close relationship to LV meridional wall stress calculated from echocardiographic and intraventricular pressure measurements. We concluded that the stability of chronic untreated severe ischemic HF depends on the recruitment of myocardial remodeling mechanisms that involve an interaction among hemodynamic load, contractile efficiency/energetics, neurohumoral activation, response of the extracellular matrix, wall stress, and the myocyte apoptotic pathway.