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The blood pressure (BP) effect and modes of action of a twice daily regimen of labetalol (mean 450 mg/day) were assessed in ten mild to moderate hypertensives using continuous ambulatory BP monitoring. The reflex control of BP during physiological interventions was examined just prior to the next dose of medication to estimate the residual alpha- and beta-adrenoceptor blockade. Global 24 h BP was reduced by 15/9 mm Hg, and home pressures by 13/11 mm Hg. The predominant antihypertensive effect was noted during the waking hours. During dynamic exercise significant inhibition of the heart rate and blood pressure rise occurred. Coupled with a reduction of the post-release BP 'overshoot' in Valsalva's manoeuvre, the response resembles that seen with beta-adrenoceptor blockade. A small alpha-adrenoceptor blocking action was evident in one patient's response to the Valsalva manoeuvre. [ABSTRACT FROM AUTHOR]

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.

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., (Copyright © 2013. Published by Elsevier B.V.)

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.

Background: inhibition of L-type Ca(2+) current contributes to negative inotropy of β(3) adrenergic receptor (β(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 β(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 β(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the β(1)/β(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the β(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 β(3) AR agonists decreased β(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 β(1) pump subunit glutathionylation with elimination of β(3) AR-mediated signaling in β(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 β(3) AR mediates decreased β(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(+).

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.

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.

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.

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.

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.

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.

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.

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.

Background: Therapeutic modulation of myocardial metabolism improves outcomes in diabetic patients following myocardial infarction and coronary artery surgery. However, the mechanism of this beneficial effect has not been fully elucidated. This study evaluated the effect of glucose-insulin-potassium solution (GIK) on left ventricular (LV) energetics and oxygen utilization efficiency in a chronic ovine model of diabetes., Methods: Diabetes was induced in sheep with streptozotocin. Experiments were performed following 12 months untreated diabetes (n = 6) and in controls (n = 6). Open-chest anesthetized sheep were instrumented to determine the LV pressure-volume relationship, oxygen consumption, and free fatty acid uptake. Glucose-insulin-potassium was infused at 1.5 mL x kg(-1) x h(-1) for 60 minutes and assessment repeated., Results: Glucose-insulin-potassium decreased LV free fatty acid uptake in control: 0.090 +/- 0.047 microg/beat/100 g to 0.024 +/- 0.022 microg/beat/100 g, p = 0.02 and diabetes: 0.33 +/- 0.32 microg/beat/100 g to 0.11 +/- 0.13 microg/beat/100 g, p = 0.04. Similarly, GIK decreased unloaded left ventricular oxygen consumption (LVVO(2)) in both control (0.42 +/- 0.05 to 0.37 +/- 0.13J/beat/100 g, p < 0.001) and diabetic sheep (0.40 +/- 0.24 to 0.23 +/- 0.23J/beat/100 g, p < 0.001). The slope of the LVVO(2)-pressure-volume area relation (contractile efficiency) was unchanged in either group. Glucose-insulin-potassium improved LV contractility 58% +/- 37% (p = 0.005) and stroke work efficiency 18% +/- 10% (p = 0.009) in diabetic animals but not controls. Therefore, oxygen utilization efficiency (stroke work-LVVO(2)) increased only in diabetic animals (16.6% +/- 4.8% to 26.9% +/- 3.6%, p = 0.002) following GIK., Conclusions: This study provides in vivo evidence that GIK improves LV energetics in diabetes. Oxygen utilization efficiency is improved as a result of improved stroke work efficiency and decreased unloaded LVVO(2). Improved efficiency of oxygen utilization provides a physiologic rationale for the beneficial effect of GIK in diabetic patients.

A novel HeartPatch direct cardiac compression (DCC) device has been shown to effectively restore circulatory parameters in sheep with acute heart failure (HF). Its effect on the coronary circulation and myocardial perfusion, however, remains uncertain. The effect of DCC assist on coronary artery blood flow (CABF) and its patterns in acute HF sheep were examined in this study. Ten sheep (51 +/- 6 kg) were implanted with a heart patch on each of the left ventricular and right ventricular free walls 1 week before study. Stable HF [cardiac output (CO) at 51 +/- 8% of baseline] induced by intravenous esmolol resulted in CABF decreasing to 53 +/- 16% of baseline (p < 0.001). DCC device activation did not alter CABF (54 +/- 15% of baseline, N.S.) but was accompanied by increases in both peak antegrade and retrograde flow velocity (161 +/- 75%, p < 0.001 and 413 +/- 377%, p < 0.001). A shift in the proportion of flow occurring in diastole (%DF) also was observed: baseline, 81 +/- 9%; HF, 82 +/- 6%; DCC assist, 121 +/- 16% (p < 0.001). Despite significant changes in coronary artery flow pattern resulting from DCC of the failing heart, total antegrade coronary flow was maintained. These findings suggest that myocardial perfusion is not compromised by DCC.

Background: In failing hearts, homeostatic mechanisms contrive to maximize stroke work and maintain normal arterial blood pressure at the expense of energetic efficiency. In contrast dobutamine reestablishes maximal mechanical efficiency by promoting energetically optimal loading conditions. However, dobutamine also wastefully increases nonmechanical oxygen consumption. We investigated whether direct mechanical cardiac compression would reestablish maximal mechanical efficiency without the oxygen-wasting effect., Methods: The pressure-volume relationship and myocardial oxygen consumption were derived in sheep using left ventricular pressure and volume from manometer-tipped and conductance catheters, and coronary flow from Transonics flow probe., Results: Propranolol hydrochloride and atropine sulfate were administered to reduce ejection fraction to 21% when ventricular elastance fell to 1.35 mm Hg/mL and mechanical efficiency to 79% of maximal. Low-pressure direct mechanical compression of the failing heart restored mechanical efficiency to 94% of maximal and realigned optimal left ventricular end-systolic pressure with operating left ventricular end-systolic pressure without altering nonmechanical oxygen consumption., Conclusions: We conclude that direct cardiac compression restores mechanical efficiency to normal maximum without wasting energy on additional nonmechanical activity.

Background: This study investigates the possibility of reducing myocardial oxygen consumption by dynamic cardiomyoplasty in chronic heart failure. The sheep model used is relevant for cardiac assist using direct mechanical cardiac compression., Methods: In 7 sheep, heart failure was induced by staged intracoronary microembolization followed by dynamic cardiomyoplasty. Six months later, the effect of latissimus dorsi muscle stimulation in the 2:1 mode (on, cardiomyoplasty; off, control) was studied. Left ventricular pressure-volume loops were obtained by conductance, micromanometer, and inferior vena cava occlusion catheter. Myocardial oxygen consumption was derived from left main coronary artery blood flow and oxygen content of arterial and coronary sinus blood., Results: Cardiomyoplasty had no significant effect on left ventricular hemodynamic variables such as end-systolic pressure. However, cardiomyoplasty increased stroke volume and ejection fraction significantly by 11% +/- 12% and 11% +/- 10%, respectively. Although pressure-volume area and external work did not increase with cardiomyoplasty, myocardial oxygen consumption decreased by 21% +/- 11%. Therefore, cardiomyoplasty increased myocardial efficiency (external work/myocardial oxygen consumption) by 16% +/- 13%., Conclusions: Despite limited hemodynamic improvement from dynamic cardiac compression by cardiomyoplasty in sheep with chronic heart failure, myocardial oxygen consumption was significantly reduced. These findings provide a rationale for reverse remodeling of the failing heart using direct mechanical compression.

Background: Dynamic cardiomyoplasty (d-CMP) encourages reverse remodeling and improved contractility and stroke work (SW) efficiency of the failing native heart. This contrasts with passive cardiomyoplasty (p-CMP), which provides "passive girdling." To further evaluate pump recovery we assessed native left ventricular performance (without assist) 6 months after dynamic and passive CMP in sheep with heart failure with acute volume loading., Methods: Heart failure (left ventricular ejection fraction 26%+/-8%) induced by coronary microembolization was followed by CMP in 11 sheep. After 8 weeks of muscle "training," paced cardiac assist was undertaken in the d-CMP group (n = 6). Five sheep with heart failure served as controls. Six months later the pressure-volume relationship was derived before and after volume loading by colloid solution. Latissimus dorsi muscle pacing was previously ceased in the d-CMP group., Results: Volume loading increased left ventricular end-diastolic volume and pressure in all groups. After volume loading in d-CMP, the SW and pressure-volume area were increased, and SW efficiency remained unchanged. In p-CMP neither variable changed, whereas in control heart failure SW efficiency decreased due to a rise in pressure-volume area with stable SW., Conclusions: Based on response to volume loading, the failing native heart after 6 months of d-CMP showed functional recovery from "active girdling," whereas p-CMP prevented functional deterioration through passive girdling. The failing control heart progressively deteriorated.

Background: The mechanism by which glucose-insulin-potassium solutions enhance recovery of left ventricular function after myocardial ischemia in diabetic patients is not well understood. We evaluated the effect of glucose-insulin-potassium on ventriculoarterial coupling and left ventricular mechanics in a chronic ovine model of diabetes., Methods: Diabetes was induced in 6 sheep with streptozotocin. After 6 months of diabetes, the response of the left ventricular pressure-volume relationship to 60 minutes of intravenous glucose-insulin-potassium solution (1,000 mL of 5% dextrose in water, 100 IU of regular insulin, 90 mmol of KCl at 1.5 mL x kg(-1) x h(-1)) was determined., Results: Glucose-insulin-potassium solution increased end-systolic elastance 68% (p = 0.01) and improved ventriculoarterial coupling (1.7+/-0.3 to 1.0+/-0.1; p < 0.01). Potential energy decreased 35% (p = 0.01), and pressure-volume area decreased 20% (p = 0.01). However, stroke work did not change; therefore stroke work efficiency increased from 50.1%+/-3.5% to 60.2%+/-5.1% (p = 0.01)., Conclusions: Glucose-insulin-potassium solution improves left ventricular contractility and ventriculoarterial coupling in diabetes. Left ventricular mechanics is improved by decreasing total mechanical work without significantly affecting stroke work, resulting in improved stroke work efficiency. Improved efficiency facilitates understanding of the enhanced tolerance to myocardial ischemia afforded by glucose-insulin-potassium solution.

Staged coronary embolization, causing myocardial microinfarctions, has been shown in dogs and sheep to cause chronic ischemic heart failure (HF) that resembles the hemodynamics of the human condition. However, its histopathological basis remains unclear. We examined the hypothesis that the ventricular remodeling seen in such sheep resembles the histopathology of human ischemic cardiomyopathy (ICM). Understanding the pathophysiology of this model will determine its place in the development of treatment strategies for HF. Global left ventricular (LV) damage resulting in HF was induced by staged coronary embolization in 11 sheep. Six others served as controls (normal control, NC). In HF sheep, the heart was harvested 6 months after LV ejection fraction (EF) had stabilized at <35%. Histopathological profiles were compared in biventricular transverse sections at midpapillary level using computed image analysis. LV end-diastolic volume increased in the HF group from 84.9+/-29 to 122.4+/-30.3 ml (n=11, P<.05), but myocytes across the LV wall in noninfarcted zones decreased (435.7+/-38.2 NC; 297.8+/-48.4/unit area HF; n=11, P<.0001) as did myocyte nuclear density (990.5+/-51.5 NC; 677.5+/-121.1/mm(2) HF, n=11, P<.0001). In contrast, LV replacement and interstitial fibrosis increased as did myocyte diameter in noninfarcted zones: 0.1+/-0.1 to 6.2+/-4.5% (P=.0049); 2.0+/-1.0 to 7.6+/-4.9% (P=.0149); and 10.0+/-0.5 to 15.9+/-2.2 microm (P<.0001), respectively. Although LV myocyte nuclear length increased (10.2+/-1.0 NC; 12.2+/-0.9 microm HF, n=11, P=.0006), right ventricular (RV) myocyte nuclear density and length did not alter. In this ovine chronic HF model, LV dilation and interstitial and myocyte remodeling resemble human ICM.

Background: Recent reports claim that cardiomyoplasty (CMP) has a girdling effect on the left ventricle, to prevent dilatation and functional deterioration, but the mechanism of its long-term effects on the native heart is not known. We compared the relative role of CMP's active squeezing and passive girdling in chronically failing hearts., Methods: After induction of stable heart failure (left ventricular ejection fraction = 27% +/- 7%) by staged coronary microembolization, CMP was performed in 11 of 18 sheep. After 8 weeks pacing training of the latissimus dorsi muscle (LDM), cardiac assist was begun with 1:2 synchronous bursts in 6 sheep (d-CMP, n = 6), and the LDM in the passive group (p-CMP, n = 5) remained unstimulated. Four (base line) and 30 weeks after induction of heart failure, the pressure-volume relationship was derived., Results: After 30 weeks in d-CMP the slope (Emax) of the end-systolic pressure-volume relationship increased by 66% +/- 55% (p < 0.05) and external work efficiency by 48% +/- 41% (p < 0.01). In the passive CMP and control groups, slope and external work efficiency were unchanged. Conversely, left ventricular end-diastolic volume decreased (-14% +/- 12%, p < 0.05) in the dynamic CMP group compared with a static course in the passive CMP group (3% +/- 10%, p > 0.05) and an increase (18% +/- 15%, p < 0.05) in controls., Conclusions: Dynamic CMP improved native heart's contractility and external work efficiency. In addition, whereas passive CMP has simply a girdling effect, dynamic CMP also induces reverse left ventricular chamber remodeling.

Experiments are described in which a fatigue index is determined for the latissimus dorsi muscle of sheep in situ, using capacitive strain gauges. Parallel experiments for invasive and non-invasive measurements are conducted, measuring global contraction and relaxation rates and shortening duration for paced muscle. The results show that, above one pulse per burst (5 V, 100 microseconds pulsewidth), contraction rates (62 +/- 11 mm s-1) and relaxation rates (50 +/- 7 mm s-1) are constant for unloaded muscle. For one animal, fatigue testing with a 2.5 kg load at six pulses per burst shows shortening rates increasing to a maximum (80 mm s-1) after 30 s and reducing to 5 mm s-1 after 150 s. The decrease in shortening amplitude is used as a fatigue index, log displacement against time. Power output is load dependent, measuring 4.7 W kg-1 with a 2.5 kg load. There is good agreement between the invasive and non-invasive measurements, thus providing a method for monitoring changes in muscle parameters non-invasively during future pacing transformation.

Blood pressure presentation mode and personality are likely to influence biofeedback outcome. Thirty-six normotensive subjects were randomly assigned to visual or auditory continuous systolic feedback. "Distracting speech" and "broad band noise" were also superimposed and the effect on the biofeedback response was investigated. Psychological influence was also investigated. Systolic pressure reduction of 4 +/- 4.3 mmHg (visual, p = .04) and 5 +/- 5.5 mmHg (visual + auditory, p = .03) were achieved compared with auditory feedback (2 +/- 4.7 mmHg), which was less effective. The addition of noise or speech had no effect on the systolic response, but speech adversely affected diastolic reduction (p = .04). Mood (p = .003) was associated with systolic lowering, whereas increased trait anxiety (p = .06) and expectation (p = .03) had trends for opposite effects. Increased anger-hostility, state-anxiety, and expectation (p = .06) had links with systolic raising capability. We conclude that feedback modality and psychological characteristics have implications for studies investigating blood pressure manipulation capability.

Objective: Cardiomyoplasty is a surgical procedure to support the failing heart, in which a burst-stimulated latissimus dorsi muscle flap is transposed and wrapped around the ventricles. The effect of dynamic cardiac compression, implemented as cardiomyoplasty, on left ventricular performance remains controversial; the mechanism by which clinical symptoms are improved remains unclear. To investigate the mechanism for improvement of patients' symptoms, it is important to evaluate the effects of cardiomyoplasty on left ventricular energetics and on left ventricular systolic and diastolic function. We therefore evaluated the efficiency of energy transfer from the native pressure-volume area to external work under conditions of 1:3 skeletal muscle burst pacing in an animal model with chronic heart failure., Methods: In seven Merino-Wether sheep, cardiomyoplasty was performed after stable heart failure was induced by staged coronary embolizations (ejection fraction < 35%). Hemodynamic assessment including the assessment of the pressure-volume relationship was performed 8 weeks after cardiomyoplasty when the latissimus dorsi muscle was fully trained. Instantaneous left ventricular pressure and volume were measured with a catheter-tipped manometer and a conductance catheter during steady-state conditions and after a transient inferior vena cava occlusion. The effect of dynamic cardiac compression on left ventricular systolic function was assessed by comparing pre-assisted and assisted beats and on diastolic function by comparing assisted and post-assisted beats., Result: The slope of the end-systolic pressure-volume relationship decreased by 30.5% +/- 27.8% (p = 0.02) during assisted beats. However, left ventricular pump performance improved by increasing stroke volume and external work by 35.9% +/- 36.0% (p = 0.03) and 9.7% +/- 6.8% (p = 0.03), respectively, resulting in a reduction of the volume intercept. As a result, the end-systolic pressure-volume relationship shifted to the left. The efficiency of energy transfer from the native pressure-volume area to the overall external work improved by 7.6% +/- 8.2% (p = 0.04). Cardiomyoplasty did not affect the time constant of left ventricular isovolumic pressure decline or the maximal rate of pressure decay, which suggested that cardiomyoplasty did not affect left ventricular relaxation., Conclusions: Dynamic cardiac compression in the form of cardiomyoplasty enhanced left ventricular pump performance without interrupting left ventricular filling. The ratio of energy transfer from the native pressure-volume area to the overall external work suggests a myocardial oxygen-sparing effect of cardiomyoplasty.

Similarities in coronary circulation and heart size of sheep to that of humans are specific advantages of a sheep model of congestive heart failure (CHF). CHF was created in 11 sheep (51 +/- 4 kg) by selective sequential intracoronary injection of 90 microns microspheres under 1.5% isoflurane anesthesia. Hemodynamic characteristics were assessed at baseline, 4 weeks after establishment of CHF (ejection fraction [EF] < 35%, n = 11), and 26 weeks (n = 7) later. Baseline echocardiographic EF was 59 +/- 5% and fell to 26 +/- 5% after 5 +/- 2 embolizations. The left ventricular (LV) pressure-volume relationship showed stable decreases in LV end-systolic elastance (Ees) and preload recruitable stroke work. Intravenous infusion of dobutamine increased Ees from 2.8 +/- 1.7 to 4.3 +/- 2.2 and 4.5 +/- 1.4 mmHg/ml at heart rates of 140 and 160/min, respectively, at baseline. Increases of Ees (from 1.3 +/- 0.5 to 2.3 +/- 0.7 and 1.9 +/- 0.5 mmHg/ml at heart rates of 140 and 160/min, respectively) with dobutamine under CHF conditions did not exceed Ees values at baseline without dobutamine. This response to dobutamine infusion did not change 26 weeks after establishment of CHF. This stable ovine CHF model is proposed for studies on the long-term effects of cardiac assist devices.

The role of biofeedback in blood pressure control remains ill-defined because of nonspecific (placebo) effects, small study numbers, and the technical limitations of continuous pressure feedback. Clarification of its potential is awaited by those seeking a nonpharmacological approach to blood pressure control. This study examines the capability for systolic pressure lowering of 5 mm Hg or more using continuous pressure feedback in a statistical sample of untreated, well-characterized, mildly hypertensive individuals. Subjects were randomized in a double-blind study to active or placebo biofeedback. Placebo consisted of a modified contingency approach, using a partial disguise based on a digital high pass filter with 15 elements. Blood pressure-lowering capability was assessed during two laboratory sessions. Continuous visual feedback resulted in 11 of 28 subjects on active treatment and 12 of 28 on placebo treatment lowering their systolic pressure by 5 mm Hg or more (11 +/- 5.6 and 12 +/- 8.4 mm Hg, respectively; P = NS). Prestudy pressure was well-matched (153 +/- 9/97 +/- 4 and 154 +/- 8/98 +/- 4 mm Hg, respectively). An initial small difference in diurnal profile did not change. These findings indicate that among mildly hypertensive individuals, almost half can lower systolic pressure at will for short periods. This capability is independent of the real or placebo nature of the feedback signal. We conclude that there is no specific short-term biofeedback pressure-lowering capability in hypertensive individuals. Further exploration is needed to determine whether specific components of the placebo effect can be delineated, whether personality characteristics influence the response, and whether further biofeedback training can alter the outcome.

Because of the clinical and experimental utility of continuous finger blood pressure measurements and the need for accuracy, we tested the performance of a new hydraulic device in 22 consecutive hypertensive subjects during physiological and pharmacological interventions. Ipsilateral brachial intra-arterial pressure was monitored during rest, Valsalva's maneuver, static handgrip, and mental arithmetic and after sublingual glyceryl trinitrate. In excess of 40,000 blood pressure values were analyzed. Average bias (intra-arterial minus finger blood pressure) was 8.2 +/- 17.0 mm Hg (mean +/- SD, P = NS) for systolic and 2.8 +/- 10.4 mm Hg (P = NS) for diastolic pressure. Two-way ANOVA of biases with subject and task factors showed a subject effect (P < .001). Intersubject and intrasubject standard deviations of bias were 13.8 and 9.8 mm Hg systolic and 8.7 and 5.7 diastolic, respectively. Linear drift (millimeters of mercury per minute) of finger pressure was greater (P < .001) for systolic than diastolic pressure during static exercise and math and after glyceryl trinitrate. Coefficients of determination for blood pressure ranged from 0.4 +/- 0.3 to 0.8 +/- 0.3 during the tasks. We conclude that (1) noninvasive finger blood pressure faithfully follows intra-arterial changes but with clinically relevant offsets, (2) this technique is best suited for assessing pressure changes, (3) physiological and pharmacological interventions do not consistently affect finger pressure accuracy, (4) many reports of finger blood pressure measuring devices are based on direct readings obtained with inadequate system response characteristics, and (5) the tested instrument falls short of the standard requirements (bias < or = 5 +/- 8 mm Hg) for devices that measure intermittently.

Nine adult subjects with documented cardiac arrhythmia were studied during 4 nights of sleep in a laboratory. A sleep polygraph and single-channel electrocardiogram were recorded continuously throughout each night. After the 1st night's familiarization, the subjects were presented with 1 night each of 50 calibrated aircraft or truck noise events. One other night was noise-free. Intervals containing noise and paired quiet intervals were examined for sleep stage at interval onset, number of sleep stage changes and ventricular premature contractions (VPCs). Overnight urinary catecholamines were also assayed. It was found that noise increased the likelihood of arousal responses to the same extent in all sleep stages (p < 0.05). Four subjects showed frequent VPCs during the experiment. These VPCs were significantly related to sleep stage (p < 0.05) but not to noise events. Excretion of urinary catecholamines did not differ between noise and quiet nights.

Objective: To determine whether treatment of borderline hypertension reverses the cardiac 'amplifier' effect associated with increased left ventricular mass., Design: Randomized, double-blind, placebo-controlled trial involving treatment for 6 months., Setting: Ambulant outpatients in a teaching hospital., Participants: Recruited by local doctor referral or worksite screening. Average of two readings of entry blood pressures taken 1 week apart 140-160 mmHg (systolic) or 90-95 mmHg diastolic, or both. Twenty-six previously untreated males, mean +/- SD age 33 +/- 9.2 years with mean +/- SD blood pressure 138 +/- 7.4/90 +/- 7.0 mmHg entered and completed the study., Interventions: Twelve subjects received captopril, average dose 72 mg/day for 24 weeks, the remainder receiving placebo., Main Outcome Measures: Echocardiographic left ventricular dimensions, mass and transmitral Doppler flow, as well as office, ambulatory and exercise blood pressure., Results: In the captopril group blood pressure was reduced significantly. Left ventricular mass decreased significantly from 205 to 195 g at 8 weeks and to 202 g at 24 weeks, returning to 232 g 4 weeks after treatment. Interventricular septum thickness fell significantly at 24 weeks. Doppler parameters did not alter. Baseline 8-h ambulatory blood pressure did not change with treatment. The reduction in peak exercise systolic blood pressure in the captopril group was not different from the change in the placebo group., Conclusion: Blood pressure can be effectively lowered using captopril in young subjects with borderline hypertension. Treatment is well tolerated and leads to regression of left ventricular wall thickness and mass, suggesting that treatment of blood pressure elevations may be advisable at lower levels than currently recommended.

Objective: To test a prototype hydraulic, non-invasive, continuous finger blood pressure monitor based on the volume-clamp principle for procedure-related factors likely to influence precision., Design: The influence of these factors was determined by repeatability of finger blood pressure measurement and the relationship to contralateral arm-cuff blood pressure., Methods: Repeated blood pressure measurements from three different fingers were made in 60 subjects following re-initialization of the device and re-insertion of the finger into the cuff. Repeatability was assessed in relation to simultaneous arm-cuff readings. Drift in arm-finger discrepancy was measured over a 1-h period. Finger diameter, drug therapy and presence of peripheral vascular disease were correlated with arm-finger blood pressure difference., Results: Repeatability coefficients (twice the SD of the arm-finger difference) across device re-initialization were large, but similar to parallel repeated arm blood pressure determinations: 17.6 and 17.1 mmHg for systolic blood pressure (SBP) and 13.9 and 13.6 mmHg for diastolic blood pressure (DBP), respectively. Withdrawing and re-inserting the finger reduced repeatability substantially, with a 50% increase in repeatability coefficient. A trend towards a progressive 9-mmHg increase was observed in overestimation of SBP over the 1-h period. Mean +/- SD pooled arm-finger blood pressure differences were -10.8 +/- 14.6 mmHg for SBP and 4.5 +/- 9.4 mmHg for DBP. Blood pressure measured in different fingers was similar on average, with repeatability no poorer than for re-insertion of the same finger. The presence of peripheral vascular disease in 15 subjects correlated with a smaller arm-finger difference for DBP., Conclusions: Variations in positioning of the finger within the cuff influences blood pressure measurement during volume-clamp plethysmography, reducing its precision. Finger SBP exceeds brachial auscultatory readings and has similar precision.

The reproducibility of ambulatory blood pressure measurements was assessed in eight normotensive subjects who underwent three separate days of recording, using Takeda Medical TM-2420 (TM-2420) blood pressure monitors. The coefficients of variation of mean 24 hour systolic and diastolic blood pressure were 2.1% and 2.8% respectively. The corresponding values for systolic and diastolic blood pressure variability, were 19% and 14% respectively. Measurement intervals of greater than 30 minutes significantly reduced the reproducibility of mean day interval systolic measurements. The bias of the TM-2420 systolic and diastolic blood pressure measurements compared to standard sphygmomanometer measurement were 0 +/- 7 mmHg and 1 +/- 6 mmHg respectively. Ambulatory blood pressure monitoring provides reproducible estimates of mean systolic and diastolic blood pressure, however, blood pressure variability is poorly reproducible.

In order to test whether trained (n = 10) and sedentary (n = 29) pregnant women have different responses to weight-bearing exercise in the second trimester (range 23 to 28 weeks of gestation), subjects walked continuously on a treadmill for 26 minutes: at low intensity for 10 minutes, then an intermediate stage, followed by moderate intensity for 10 minutes. In the trained group, the mean heart rate was lower (p < 0.02) with both low [104.0 +/- 4.5 (SD) versus 117.4 +/- 2.3 bpm] and moderate intensity exercise (128.4 +/- 5.7 versus 145.2 +/- 2.9 bpm) and the associated mean stroke volume was higher (105 +/- 16 versus 84 +/- 17 ml; 103 +/- 15 versus 86 +/- 18 ml, respectively) (p < 0.02). The mean cardiac output, blood pressure and oxygen consumption were the same in the two groups (p > 0.02) at the same absolute workloads. The potential implications of these findings for exercise prescriptions for pregnant women, research evaluation and exercise testing are discussed.

Finger blood volume is commonly determined from measurement of infra-red (IR) light transmittance using the Lambert-Beer law of light absorption derived for use in non-scattering media, even when such transmission involves light scatter around the phalangeal bone. Simultaneous IR transmittance and finger volume were measured over the full dynamic range of vascular volumes in seven subjects and outcomes compared with data fitted according to the Lambert-Beer exponential function and an inverse function derived for light attenuation by scattering materials. Curves were fitted by the least-squares method and goodness of fit was compared using standard errors of estimate (SEE). The inverse function gave a better data fit in six of the subjects: mean SEE 1.9 (SD 0.7, range 0.7-2.8) and 4.6 (2.2, 2.0-8.0) respectively (p < 0.02, paired t-test). Thus, when relating IR transmittance to blood volume, as occurs in the finger during measurements of arterial compliance, an inverse function derived from a model of light attenuation by scattering media gives more accurate results than the traditional exponential fit.