Therapeutic angiogenesis: time for the next phase.
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Animals↗
Biomedical subjects
G A Pantely
Publications and source records attributed to G A Pantely.
Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.
The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.
Adaptation, Physiological↗
Phase II, placebo-controlled trial of MRX115 (Aerosomes) for left heart and myocardial perfusion imaging.
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Adult↗
Therapeutic angiogenesis: just the basic fact(or)s, please.
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Animals↗
Ultrasound-mediated destruction of contrast agents. Effect of ultrasound intensity, exposure, and frequency.
RATIONALE AND OBJECTIVES: Although ultrasound contrast microbubbles theoretically could serve as tracers for the noninvasive quantification of blood flow, results have been inconsistent. Accurate quantification may be limited by ultrasound energy-mediated microbubble destruction. This study examined the effect of different ultrasound delivery parameters on microbubble destruction. METHODS: Experiments were performed in an in vitro hydraulic perfusion model consisting of a thin-walled rubber tube encased in agar. Ultrasonic parameters tested during different parts of the experiment were (1) intensity, (2) duration, and (3) frequency. Four ultrasound contrast agents: Aerosomes MRX115 (ImaRx Pharmaceuticals Corp., Tucson, AZ), Imagent AF0150 US (Alliance Pharmaceutical Corp., San Diego, CA), Levovist (Berlex Laboratories, Wayne, NJ), and Echogen (Sonus Pharmaceuticals, Bothel, WA) were imaged with three different ultrasound systems: ATL Ultramark AM-9 HDI, Vingmed 800 and Hewlett-Packard 2500. RESULTS: Microbubble destruction and reductions in reflectivity were noted in all agents tested. Although no significant reductions in counts or reflectivity occurred at 0.3 W/cm2 with any agent, exposure to 25 W/cm2 produced more than 80% reductions in both microbubble counts (P < 0.0001) and reflectivity (P < 0.0001). Declines in reflectivity were increased by longer exposure to ultrasound (P < 0.0001); slower flow through an ultrasound beam (P < 0.0001); continuous, rather than intermittent, imaging (P = 0.0002); use of a higher pulse repetition rate (P < 0.0001); and exposure to 2.5 MHz, rather than 7.5 MHz, ultrasound (P < 0.0001). CONCLUSIONS: Ultrasound energy-mediated destruction of contrast microbubbles is a function of many factors, including ultrasound intensity, duration, and frequency. Optimization of ultrasound delivery parameters may be used to maximize or minimize the destruction of ultrasound contrast agents.
Contrast Media↗
Myocardial imaging with a new transpulmonary lipid-fluorocarbon echo contrast agent: experimental studies in pigs.
The development of echo contrast agents that can provide reliable opacification of the myocardium after intravenous injection is an important advancement for the clinical application of contrast echocardiography. In this study, the hemodynamic effects and echocardiographic characteristics of a new lipid-fluorocarbon echo contrast agent, Aerosomes MRX 115 (ImaRx Pharmaceutical Corp., Tucson, Ariz.) were studied in six anesthetized ventilated pigs. Intravenous injection of this new agent in doses ranging from 0.0005 to 0.01 ml/kg produced significant measurable and visible myocardial opacification without any effect on heart rate, systemic pressure, partial pressure of oxygen, or left ventricular systolic function. The two largest doses (0.005 and 0.01 ml/kg), however, resulted in mild reversible increases in mean pulmonary artery pressure of 12 and 16 mm Hg, respectively. In four animals, epicardial images were obtained before and during coronary artery occlusion. Intravenous contrast injection during coronary occlusion permitted delineation of the hypoperfused myocardial segment. This capability may further expand the utility of contrast echocardiography.
Animals↗
MRX 115, an echocardiographic contrast agent, produces myocardial opacification after intravenous injection in primates: studies before and after occlusion of left anterior descending coronary artery.
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Animals↗
Metabolic adaptation to a gradual reduction in myocardial blood flow.
BACKGROUND: Studies during 20% to 50% reductions in regional coronary blood flow have revealed a number of metabolic and functional adaptations that suggest the heart downregulates energy requirements and contractility in response to ischemia. In contrast to prior studies of sudden changes in coronary blood flow, we tested whether the heart could reduce ATP consumption commensurate with a gradual decrease in coronary blood flow or whether transient metabolic abnormalities are a necessary trigger in this process. METHODS AND RESULTS: From 0 to 35 minutes, mean left anterior descending coronary artery blood flow was reduced by approximately 1% per minute in 10 acutely anesthetized and instrumented swine. Coronary blood flow then was held constant between 35 and 60 minutes at the resulting 35% net blood flow reduction. Although systemic hemodynamics remained stable, a significant decrease in regional left ventricular systolic wall thickening developed (from control value of 45 +/- 11% to 18 +/- 11% at 60 minutes, P < .001) without a sustained decrease in the phosphorylation potential (as assessed by a < 2% decrease in either the transmural or subendocardial phosphocreatine-to-ATP ratio) and with minimal myocardial lactate production (4 +/- 44 mumol.min-1 x 100 g-1). CONCLUSIONS: Metabolic markers of ischemia such as ratio of phosphocreatine to ATP, ATP content, lactate content, and lactate production were blunted during this protocol of gradually worsening ischemia. Thus, contractile abnormalities of mild ischemia can develop with minimal metabolic evidence of ischemia. The downregulation of myocardial energy requirements can almost keep pace with the gradual decline in coronary blood flow.
Adaptation, Physiological↗
Metabolic aspects of hibernating myocardium.
Myocardial hibernation describes the clinical entity of a dysfunctional region of myocardium with reduced flow that shows improvement in function after flow is restored. It is postulated that despite the reduced flow, metabolic activity is sufficient to prevent tissue necrosis. Experimental work in animals supports this. A moderate reduction in flow to a region of the left ventricle in pigs initially results in the typical metabolic picture of ischemia: ATP and PCr fall and anaerobic metabolism is present. However, over the next hour, a hypometabolic response occurs that eliminates almost all metabolic findings of ischemia despite ongoing flow reductions. This appears to be an actively and tightly regulated response. The reduction in systolic function is an important part of the hypometabolic state, but cannot fully account for the downregulation of energy use.
Adenosine Triphosphate↗
Energy metabolism and contractile function after 15 beats of moderate myocardial ischemia.
Difficulties in studying myocardial metabolism with adequate time resolution have led to contradictory conclusions regarding the mechanisms causing contractile abnormalities during the early stages of ischemia. In acutely instrumented swine, we investigated whether abnormalities in subendocardial ATP, phosphocreatine, or lactate content develop rapidly enough during the first few heart beats after onset of partial myocardial ischemia to contribute to contractile failure. Within the first 15 beats of a 40-50% reduction in left anterior descending coronary artery blood flow, regional myocardial function was significantly reduced but continuing to deteriorate. Rapidly frozen transmural left ventricular biopsies obtained on the 15th heart beat (+/- 1.5 beats) after the onset of ischemia revealed significant decrements in subendocardial phosphocreatine and ATP levels to 77% (p less than 0.05) and 84% (p less than 0.005) of control values, respectively, but minimal change in lactate content. Metabolic effects as assessed by transmural averages took longer to become detectable; thus, there was a tendency to underestimate the importance of subendocardial metabolic effects on myocardial function. When left ventricular preload was assessed during this early time period, left ventricular end-diastolic wall thickness only decreased by 3%, and left ventricular end-diastolic pressure did not change significantly despite a large fall in coronary perfusion pressure. Thus, in an in vivo pig model with techniques optimized to detect subendocardial metabolic changes within the period of very early moderate myocardial ischemia, abnormalities in high energy phosphate compounds occurred rapidly enough to contribute to developing myocardial dysfunction, whereas preload-mediated mechanisms related to vascular distending pressure could not explain the functional deterioration under these conditions.
Adenosine Triphosphate↗
Response to myocardial ischemia as a regulated process.
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Adaptation, Physiological↗
Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine.
We studied the effects of rapid atrial pacing during the final 10 minutes of a 70-minute, 31% reduction in coronary blood flow in anesthetized swine to understand the significance of apparent metabolic improvements during the initial 60 minutes of segmental ischemia. Within 5-10 minutes of ischemia, subendocardial phosphocreatine (PCr) and ATP were depleted to 47% and 63% of control, respectively; lactate accumulated within the subendocardium to 300% of control; and net arteriovenous lactate production occurred. Despite continued ischemia and no significant changes in the external determinants of myocardial oxygen consumption, by 60 minutes subendocardial PCr and lactate contents returned to near control levels and there was net arteriovenous lactate consumption. Ischemic left ventricular wall thickening and ATP levels remained depressed throughout the experiment. Atrial pacing during the final 10 minutes of ischemia again resulted in depletion of PCr and lactate production. Since the myocardium was capable of hydrolyzing PCr in response to atrial pacing at 60 minutes of ischemia, we conclude it was capable of hydrolyzing PCr during the period of constant ischemia when instead it was accumulating PCr. We propose the ischemic myocardium downregulates regional energy requirements below blood flow-limited rates of energy production during ischemia. This appears to be an active adaptation to ischemia and not a result of passive damage or cellular injury.
Adaptation, Physiological↗
Importance of vasomotor tone to myocardial function and regional metabolism during constant flow ischaemia in swine.
STUDY OBJECTIVE: The aim was to test the hypothesis that the release of vascular tone with adenosine during constant flow ischaemia alters both transmural function and regional metabolism in a detrimental way. DESIGN: In one group of anaesthetised swine, the effects of graded reductions of flow on segmental left ventricular function, myocardial oxygen consumption (MVO2), and lactate production in the distribution of the left anterior descending coronary artery (LAD) were determined. In a second group, a model of constant flow ischaemia was induced to test how altering vascular tone with adenosine changed the relationship of flow, function, and metabolism. EXPERIMENTAL MATERIAL: The experiments were performed in 20 open chest, anaesthetised swine. Protocol A consisted of 11 animals and protocol B of nine animals. MEASUREMENTS AND MAIN RESULTS: In protocol A, during graded ischaemia, reductions in flow, % systolic wall thickening (WTh), normalised MVO2 and % lactate extraction (%LE) correlated well with reductions in coronary perfusion pressure when fitted with 3rd order polynominal curves (r = 0.78, 0.87, 0.85 and 0.81 respectively; p less than 0.00001). In protocol B, during constant flow ischaemia, at control, % WTh was 33 (SD 11)%, mean coronary artery pressure was 72(10) mm Hg, mean LAD transmural flow was 0.99(0.43) ml.min-1.g-1, and % LE was +14(9)%. With inflation of a hydraulic occluder on the LAD, perfusion pressure was lowered to 38(5) mm Hg and transmural flow dropped to 0.76(0.31) ml.min-1.g-1 (intact vasomotion). During an infusion of intracoronary adenosine with flow held constant (absent vasomotion), %WTh was further reduced from 27(9) to 13(10) (p less than 0.001), and %LE from -18(42) to -70(61) (p less than 0.05). MVO2 with and without vasomotion did not differ significantly at 3.14(0.75) and 3.18(0.86) ml.min-1.g-1 respectively. CONCLUSION: In swine coronary circulation, reductions in regional function, MVO2 and lactate production correlate well with reductions in flow and perfusion pressure during ischaemia with vasomotor tone intact. The effect of adenosine on vascular tone during constant flow ischaemia caused dramatic reductions in function and lactate extraction without altering MVO2. This emphasises the important role of vascular tone in protecting both transmural function and regional metabolism during moderate ischaemia.
Adenosine↗
Adenosine. Renewed interest in an old drug.
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Adenosine↗
Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia.
The effects of 1 hour of mild and moderate reductions in coronary blood flow on myocardial high-energy phosphate levels were evaluated. Thirty anesthetized pigs were instrumented with left anterior descending arterial and venous catheters, crystals for instantaneous wall thickness, and a fluid-filled occluder. Measurement of myocardial blood flow was performed with microspheres, and a series of myocardial biopsies also was performed. In 10 pigs, overall coronary blood flow was lowered by 22%, with a fall in subendocardial-to-subepicardial flow ratio from 1.11 to 0.54 and in wall thickening from 33% to 15%. Subendocardial flow fell 48%. Coronary blood flow and thickening were constant during 1 hour of ischemia. Phosphocreatine (mumol/g wet wt) in the subendocardial third of the ischemic zone fell from 7.6 to 3.8 at 5 minutes of ischemia (p less than 0.005 versus control) and returned to normal (7.9) at 60 minutes (p = NS), despite ongoing ischemia. Subendocardial ATP (mumol/g wet wt) fell slowly from 4.3 and leveled off at 2.1 at 60 minutes of ischemia (p less than 0.001 versus control). Similar regeneration of phosphocreatine was found in seven additional pigs, with a 43% transmural reduction in coronary blood flow and a 66% reduction in subendocardial flow. No significant changes in ATP and phosphocreatine were noted in two different control groups (n = 13 pigs). The regeneration of phosphocreatine despite ongoing ischemia and low ATP levels was not related to changes in myocardial oxygen demand or consumption, or in regional function during the period of ischemia. This may reflect 1) a successful downregulation of the energy needs of the ischemic myocardium to maintain cell viability, or 2) a metabolic abnormality in the ability of the cells to produce ATP primarily or by use of phosphocreatine.
Adenosine Triphosphate↗
A critical analysis of morbidity and mortality as it relates to recipient age following cardiac transplantation.
Older patients (age greater than 55) are now being accepted as candidates for cardiac transplantation. The outcome following cardiac transplantation in this older age group has been largely limited to an analysis of mortality and rejection and infection incidence. In addition to these factors, this report investigates whether morbidity related to other organ system disease is greater in older patients. Seventy-eight cardiac transplant operations in patients aged 15 through 64 have been performed using the identical immunosuppression protocol from December 1985 to May 1989. Of these, 58 patients were under the age of 55 (younger), and 20 were 55 years of age or older (older). One- and 2-yr survival tended to be lower in the older group compared to the younger group, but was not statistically significant (1 yr--87% vs. 77%, respectively; 2 yr--84% vs. 77%, respectively, p=0.143). There were no statistical differences between groups in length of initial transplant hospitalization, number of readmissions or total duration of time in hospital (including readmissions) either absolutely or normalized to total months of follow-up for each patient. Neurologic and vascular problems represented a greater proportion of readmissions and rejection a lower proportion of readmissions in the older group compared to the younger group (p less than 0.05). Using hospitalization as a marker for important morbidity, there appears to be little impact of older age on post-cardiac transplant outcome.
Adolescent↗
Abnormal exercise hemodynamics in cardiac allograft recipients 1 year after cardiac transplantation. Relation to preload reserve.
The well-established elevation in left ventricular filling pressures during exercise in patients after transplantation may contribute to decreased exercise tolerance. A proposed mechanism for this increase in filling pressures is an abnormal pressure-volume homeostasis of the transplanted heart. Twenty-three patients undergoing routine 1-year evaluations performed supine bicycle exercise during right heart catheterization. Within 24 hours, these patients underwent supine bicycle exercise to the identical work load during radionuclide ventriculography. For the group, resting hemodynamics and resting left and right ventricular ejection fractions were normal. With exercise, right atrial and pulmonary wedge pressure rose markedly (from 6 +/- 2 to 14 +/- 7 mm Hg, p less than 0.0001, and from 10 +/- 3 to 20 +/- 6 mm Hg, p less than 0.0001, respectively). Left ventricular ejection fraction increased appropriately with exercise (from 0.58 +/- 0.08 to 0.63 +/- 0.07, p = 0.004). End-diastolic volume also increased mildly (from 100 +/- 31 to 117 +/- 39 ml, p = 0.001), but change in end-diastolic volume was highly variable. Patients with little or no change in end-diastolic volume with exercise had the greatest resting and exercise left ventricular filling pressures resulting in significant negative correlations between filling pressures and change in end-diastolic volume (r = -0.64, p = 0.002 and r = -0.50, p = 0.025, respectively). Negative linear relations between exercise left ventricular filling pressures or resting heart rates and donor to recipient body weight ratio (r = -0.35, p = 0.10, and r = -0.37, p = 0.06, respectively) suggested that initial donor heart size influenced subsequent cardiac function.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Increased vascular resistance due to a reduction in red cell deformability in the isolated hind limb of swine.
This study investigated whether red cells with reduced deformability impeded flow through the microcirculation. Red cells were made less deformable in their normal biconcave disc shape by incubation with 2% formaldehyde (fRBCs). The blood supply to the right hind limb was isolated in 26 swine and the femoral artery was instrumented with two fine catheters, a flow probe, and an inflatable occluder. Flow was measured over a range of different perfusion pressures during adenosine-induced vasodilation under control conditions (C) and during an infusion of fRBCs at 1 ml/kg per minute (not to exceed 20 ml) into the femoral artery. At the same perfusion pressure (P), flow was significantly reduced 5 min after the fRBC infusion: Flow at P = 20 mm Hg, C = 41 ml/min vs fRBC = 10 ml/min; at P = 40, C = 160 ml/min vs fRBC = 79 ml/min; and at P = 60, C = 278 ml/min vs fRBC = 147 ml/min, with P less than 0.02 for all comparisons. Flow was still significantly reduced 15 min after the fRBCs, but by 30 min, it had returned to the control value. Chromium-51-labeling of red cells revealed that about one-third of fRBCs was trapped in the microcirculation compared to less than 3% of normal cells. This reduction in flow with fRBC infusion was not altered by alpha blockade, indicating that adrenergically mediated spasm was not responsible for the reduced flow. Aspirin 35 mg/kg iv completely prevented the reduction in flow despite an absence of change in the percentage of fRBCs trapped. Thus, red cells with reduced deformability infused into the circulation caused a significant, but transient, reduction in flow. The reduction in flow was not primarily related to entrapment of the abnormal RBCs, but may be mediated through platelet aggregation or release of potent vasoconstrictor substances from platelets or endothelial cells.
Adenosine↗