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.

Effect of coronary sinus occlusion on coronary flow, resistance, and zero flow pressure during maximum vasodilatation in swine.

The effects of coronary sinus occlusion on the relation between coronary artery pressure and flow during maximum vasodilatation were studied in seven swine. The left anterior descending (LAD) coronary artery was instrumented with two catheters, a hydraulic occluder, and a flowprobe. Mean flow was measured at a series of pressures produced by partial LAD occlusion during maximum vasodilatation induced by an intracoronary infusion of adenosine. Observations were made under control conditions and during occlusion of the coronary sinus produced by inflating the balloon on the catheter positioned in the coronary sinus. Systemic haemodynamic variables did not change significantly after the coronary sinus was occluded. The mean right atrial pressure was 4 mmHg. At any given LAD perfusion pressure mean flow during coronary sinus occlusion was always less than during the control state: at LAD pressure 30 mmHg, control flow was 53 ml.min-1 vs occluded flow 24 ml.min-1; at LAD pressure 40 mmHg, control flow 79 ml.min-1 vs occluded flow 49 ml.min-1; and at LAD pressure 50 mmHg, control flow 105 ml.min-1 vs occluded flow 74 ml.min-1; p less than 0.001 for all comparisons. The mean (SD) LAD pressure at which flow stopped (Pzf) when the coronary sinus was unobstructed was 10(2) mmHg. The Pzf during occlusion of the coronary sinus was significantly higher at 20(4) mmHg (p less than 0.001). The slopes of the mean pressure-flow relations were not significantly different during the control state (2.62(0.65) ml.min-1 per mmHg) vs the occluded state (2.47(0.63) ml.min-1 per mmHg), indicating no change in vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of lactate production to postischaemic reduction in function and myocardial oxygen consumption after partial coronary occlusion in swine.

Postischaemic myocardial dysfunction (stunning) induced by partial occlusion of the left anterior descending coronary artery and its relation to lactate production during reperfusion were studied in nine swine. A 40% reduction in regional left ventricular wall thickening, as measured by ultrasonic crystals, was prospectively defined as stunning. A perfusion pressure of 20 mmHg was maintained with a hydraulic occluder for each ischaemic period and was monitored by a distal arterial catheter. To achieve a 40% reduction in function, four animals required three ischaemic periods (mean ischaemic flow reduction 73%), four two (86% flow reduction), and one one (93% flow reduction). At 25 min of reperfusion transmural flow was slightly reduced from 0.67 ml.g-1.min-1 at control to 0.58 ml.g-1.min-1 (p less than 0.05), whereas regional flow endocardial to epicardial flow ratio was unchanged. At 60 min reperfusion, percentage systolic wall thickening was reduced to 25% from a control of 39% (p less than 0.01) and parallel reductions in regional myocardial oxygen consumption from 4.3 ml.min-1 to 2.7 ml.min-1 occurred (p less than 0.01). Lactate extraction was depressed at 15 min reperfusion (-4.0% compared with control +18.0% (p less than 0.05)) but returned to control values by 30 min. It is concluded that postischaemic myocardial dysfunction (stunning) can be induced by partial coronary occlusions and that the extent of dysfunction depends on the degree of flow reduction. The reductions in myocardial oxygen consumption parallel those of wall thickening during reperfusion after stunning. Finally, lactate production occurs during early reperfusion but does not persist with the postischaemic reductions in function and myocardial oxygen consumption.

Vasopressin-induced coronary constriction at low perfusion pressures.

We studied the effects of intracoronary vasopressin on the relationship between pressure and flow in the coronary circulation of anaesthetised swine. In addition to measurements at control levels, diastolic pressure-flow relationships were constructed from steady-state points below a coronary pressure of 50 mmHg, where endogenous vasodilatation is strongly stimulated. At baseline pressures, flow fell 28% with maximal vasopressin effect. At all levels of diastolic pressure below 50 mmHg vasopressin also decreased flow, eg, at 30 mmHg flow was depressed by 40%. The slope of the steady-state pressure-flow relationship fell from 1.21 to 0.75 ml.min-1.mmHg-1. The diastolic pressure at which coronary flow ceased rose slightly from 13 to 15 mmHg. Intracoronary adenosine completely prevented vasopressin's effect, and the vasodilator response to adenosine was not attenuated by simultaneous administration of vasopressin. The porcine coronary circulation will constrict in response to vasopressin, not only at normal perfusion pressure, but also at low levels when metabolic vasodilatation is intense. Our study has implications about the therapeutic use of vasopressin, and demonstrates interaction of vasoactive stimuli in the coronary circulation.

A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man.

The coronary circulation of swine was studied to establish adequate baseline information for using swine in cardiovascular research. Of 65 hearts from domestic and miniature pigs, 45 were injected with a methacrylate plastic and prepared as coronary artery casts whose branches were described and measured, and 20 were injected with different coloured dyes in the right, left anterior descending, and circumflex coronary arteries so that horizontal sections of the heart showed the distribution of each artery and the source of blood supply to particular areas or structures of the heart. Like man, the swine had a left coronary artery that was larger in diameter and longer than the right coronary artery. The right coronary artery was almost always dominant (78%), supplying the posterior septum and atrioventricular node via the posterior descending coronary artery. Eight (17%) of the hearts possessed a balanced blood supply. Two (5%) hearts had a left dominant supply. The intracoronary artery dye injections showed that 72.4% of the right ventricular mass was supplied by the right coronary artery and 27.6% by the left anterior descending coronary artery. In the left ventricle 49% of the mass was supplied by the left anterior descending coronary artery, 25.5% by the right coronary artery, and 25.5% by the circumflex coronary artery. The left anterior descending coronary artery supplied 58% of the interventricular septal mass, while the posterior descending coronary artery supplied 42%. The distribution of the left anterior descending coronary artery branches to the ventricular wall varied inversely in number and size of its diagonal branches (2-9) with the obtuse marginal branches of the circumflex coronary artery which were occasionally more numerous or extended to the apex. The blood supply to the sinoatrial node was always by a branch of the right coronary artery. This analysis shows that not only the coronary anatomy but also the distribution of blood supply to particular areas or structures of the swine heart are very similar to that of humans.

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.

Monocular blindness secondary to calcific embolization. An unusual presentation of rheumatic mitral valvular disease.

This report of a patient with systemic calcific embolization resulting in nonocular blindness represents an unusual presentation and complication of mitral valvular disease.

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.

The lack of predictive value of preoperative psychologic distress for postoperative medical outcome in heart transplant recipients.

This follow-up study of 58 heart recipients an average of 2 years after transplantation did not show that the Symptom Checklist 90R, a self-report measure of psychologic distress, predicted medical outcome. Mortality and medical morbidity (graft rejection and infection rate) were the outcome variables used. The findings tend to argue against the validity of some aspects of the psychiatric screening of transplant candidates if prediction of patients' ultimate risk of mortality or medical morbidity is the validation standard.

Late infection in cardiac allograft recipients: profiles, incidence, and outcome.

Infection continues to cause substantial morbidity and mortality after heart transplantation. Studies focusing on this problem have concentrated on the early posttransplant period, and it is uncertain to what extent infection continues to add to morbidity later after transplantation. Fifty-four patients surviving at least 1 year after heart transplantation made up the study population in this study, and they were surveyed for infections beyond 1 year. In this group there were 15 infections, an incidence of 0.3 infections per patient or 0.016 infections per patient-months of follow-up. Only nine of these infections necessitated hospitalization; two, however, were fatal. Actuarial risk of all late infections and late infections necessitating hospitalization was 13% and 6%, respectively, at 2 years. As expected, bacterial infections made up the largest group (60%), followed by viral disease (27%). Two patients had pulmonary infections, one with Aspergillus and one with Pneumocystis. These data demonstrate that although rates of infection in heart recipients continue to exceed those in the general population, the rates are considerably lower than those in what is seen early after heart transplantation. Despite this, the more unusual infectious agents associated with immune compromise continue to be present.

Cleft in the anterior and posterior leaflet of the mitral valve: a rare anomaly.

A rare entity that causes congenital mitral regurgitation is an isolated cleft mitral valve. The cleft in the mitral valve can be seen in either the anterior or posterior leaflet of the valve. We present a unique case of an individual with a history of congenital mitral regurgitation caused by a cleft in both the anterior and posterior leaflets of the mitral valve.

Academic physicians' opinions on preliminary reporting of echocardiographic data.

Preliminary reporting of echocardiographic data by cardiac sonographers has become a key issue in the echocardiography community. A survey on this issue was sent to 248 academic physicians and 89 (35.8%) were returned. In response to a question in the survey, 76 physicians stated that they had at least a limited amount of knowledge in echocardiography. For the group, 62% wanted a written or verbal preliminary report and 52% concluded that this report should be a part of the cardiac sonographer's position. If cardiac abnormalities are suspected, 65% wanted the results before the cardiologist reviewed the study, but only 42% of the physicians wanted a diagnostic versus a descriptive type of report. About 49% stated that if necessary they would attempt to influence the cardiac sonographer to give them a preliminary report, whereas 67% of the physicians would possibly use this information to medically manage the patient. Fifty percent believed that it was legal for a cardiac sonographer to give a preliminary report. Another 70% said that the cardiac sonographer would NOT be "practicing medicine without a license" and 66% concluded that they would NOT be "aiding and abetting the unauthorized practice of medicine" if given this information. These data have important potential ramifications for both cardiac sonographers as well as for the practice of cardiology regarding the issue of preliminary echocardiographic reports.

Ischemic cardiomyopathy.

The term "ischemic cardiomyopathy" was used initially to describe a clinical syndrome that was indistinguishable from primary congestive cardiomyopathy but due to severe, diffuse coronary artery disease. The term has been expanded to include the larger category of myocardial disease secondary to coronary artery disease. Using this expanded definition, we have discussed the varied clinical presentations of congestive ischemic cardiomyopathy and restrictive ischemic cardiomyopathy (stiff heart syndrome and right ventricular infarction), and how the effects of ischemia on left ventricular systolic and diastolic performance may cause these varied presentations. The prognosis of any ischemic cardiomyopathy is related primarily to the degree of ventricular dysfunction and the extent of coronary artery disease. Therapy is aimed at preventing or ameliorating myocardial ischemia and halting the progression of, or even reversing, the deterioration in myocardial function.

Low zero-flow pressure and minimal capacitance effect on diastolic coronary arterial pressure-flow relationships during maximum vasodilation in swine.

During maximum dilation with adenosine in dogs, the diastolic coronary pressure at which flow ceases (Pzf) has been observed to be up to 27 mm Hg above coronary sinus and right atrial pressures. We studied swine to measure the Pzf and to determine the effects of interventions that change collateral flow and coronary capacitance. In 44 swine, the left anterior descending coronary artery (LAD) was instrumented with two catheters, a hydraulic occluder, and a flowmeter. Late diastolic and mean pressure-flow relationships were constructed at a series of pressures produced by partial LAD occlusions during maximum vasodilation. The late diastolic Pzf was 7.0 +/- 2.2 mm Hg (mean +/- SD), less than 4 mm Hg above right atrial pressure; the mean Pzf was 12.1 +/- 3.1 mm Hg, less than 9 mm Hg above right atrial pressure. The Pzf in the LAD did not change significantly (1) during transient simultaneous occlusion of the right coronary artery (RCA) in seven swine (late diastolic Pzf with the RCA open was 6.6 +/- 1.5 mm Hg and with the RCA closed it was 6.0 +/- 1.5 mm Hg), (2) during increased left ventricular systolic pressure (LVSP) in seven swine (late diastolic Pzf with LVSP of 123 mm Hg was 5.5 +/- 2.2 mm Hg and with LVSP of 184 mm Hg it was 7.3 +/- 2.8 mm Hg), or (3) during increased heart rate in eight swine (late diastolic Pzf at heart rate of 107 per minute was 10.8 +/- 2.9 mm Hg and at 180 per minute it was 12.7 +/- 2.1 mm Hg). Similar results were obtained from analysis of the mean pressure and flow data. The Pzf in the LAD of swine is very close to right atrial pressure, and it did not change significantly during interventions that would modify collateral flow (reduced by RCA occlusion and enhanced by increased LVSP) and coronary capacitance (increased LVSP and increased heart rate). This low Pzf is beneficial in maintaining flow at lower coronary arterial perfusion pressures.

Low-dose oral prednisone in the treatment of acute cardiac allograft rejection not associated with hemodynamic compromise.

The standard therapy for acute cardiac allograft rejection is intravenous methylprednisolone, usually in doses of about 3 gm per treatment. Treatment is undertaken in most cases solely on the basis of a histologic diagnosis of rejection, irrespective of hemodynamic status. To reduce total corticosteroid dose and administer therapy in an outpatient environment, low-dose oral prednisone protocols were developed for the treatment of acute rejection in the absence of important hemodynamic compromise. A high-dose oral prednisone pulse (2 gm total for the average 75 kg male patient) was used in the first month. Thereafter a series of low-dose oral prednisone pulses were used (range, 0.5 to 1.0 gm total for the average 75 kg male patient). Of 85 transplant recipients at risk, 188 rejection episodes were treated over a 1477 total patient-months of follow-up. The high-dose oral pulse resulted in successful therapy (no subsequent therapy required) in 34 of 65 treatments (52%). The low-dose oral pulse was successful in treating 80 of 123 treatments (65%). This approach to acute rejection did not appear to adversely affect patient or graft outcome based on progression of stable to unstable hemodynamics, survival (84% and 82%, 1- and 2-year actuarial survival, respectively), or left ventricular ejection fraction (0.56 +/- 0.09 and 0.54 +/- 0.08, at 1 and 2 years, respectively). There did not appear to be discriminating factors that determined the therapeutic outcome, other than the higher failure rate within 1 month of transplant. We conclude that acute allograft rejection in the absence of important hemodynamic compromise responds to lower-than-conventional doses of corticosteroids in the majority of cases.

Late exercise test results from a prospective randomized study of bypass surgery for stable angina.

A prospective randomized study comparing coronary bypass surgery (group 1, 51 patients) to drug therapy (group 2, 49 patients) was initiated in 1981. Supine graded exercise testing (SGXT) was performed initially, at 6 months, and annually with a bicycle ergometer. The presence or absence of ischemic ST segment changes (positive or negative SGXT) and chest pain were recorded. Initially, 63% of all patients had positive SGXT. For group 2, the frequency of positive SGXT results did not change significantly at 6 months (58%) or at 5 years (52%). At 6 months the number of patients without chest pain increased in group 1 compared with group 2 (28/41 vs 13/41, respectively; p less than .002), but there was no difference in the frequency of positive SGXT results (20/41 vs 24/41, respectively; p = NS). This occurred because a majority of the group 1 patients with positive SGXT no longer had associated chest pain (group 1, 11/20, group 2, 3/24; p less than .007). This response was associated with incomplete revascularization in eight of these 11 group 1 patients and may result from "silent ischemia." At 5 years, no significant difference existed in the incidence of positive SGXT (group 1, 10/32 vs group 2, 12/23; p = NS), but group 1 patients continued to have a reduction (although not statistically significant) in the number of patients without chest pain (group 1, 19/32 vs group 2, 7/23). The incidences of death and myocardial infarction were not significantly different between groups. Fewer episodes of unstable angia occurred in group 1 (10/51 vs 19/49; p less than .05). The prognosis of group 1 patients with positive SGXT and no chest pain and incomplete revascularization was not different from that of the entire group.