Adiponectin is independently associated with NT-proBNP: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: To investigate the associations between selected adipokines and the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). METHODS AND RESULTS: As many as 1489 individuals enrolled in the Multi-Ethnic Study of Atherosclerosis were evaluated at 4 clinic visits about every 2 years. The evaluation included fasting venous blood, which was analyzed for NT-proBNP (at visits 1 and 3) and the adipokines adiponectin and leptin (at visits 2 and 3). The mean age was 64.8 ± 9.6 years and 48% were female. After multivariable adjustment, a 1-SD increment in adiponectin was associated with a 14 pg/ml higher NT-proBNP level (p < 0.01), while, compared to the 1st quartile of adiponectin, the 2nd, 3rd and 4th quartiles had 28, 45 and 67% higher NT-proBNP levels (p < 0.01 for all). For changes in NT-proBNP over the follow-up period, and after multivariable adjustment including baseline NT-proBNP, a 1-SD increment in adiponectin was associated with a 25 pg/ml absolute increase in NT-proBNP (p < 0.01), while those in the 2nd, 3rd and 4th quartiles of adiponectin were associated with increases of 5, 28 and 65 pg/ml (p = 0.74, 0.09 and <0.01, respectively). There was a significant interaction between adiponectin and sex for visit 3 NT-proBNP (p-interaction < 0.01), with significantly stronger associations in men. Leptin was not associated with NT-proBNP. CONCLUSION: Higher adiponectin, but not leptin, is significantly associated with higher levels of NT-proBNP, as well as with greater longitudinal increases in NT-proBNP. The associations were stronger in men.

Externalization of beta-adrenergic receptors promoted by myocardial ischemia.

beta-Adrenergic receptors were identified in two fractions of guinea pig myocardium: a purified sarcolemmal fraction and a light vesicle (presumably intracellular) fraction. In the light vesicle fraction, which contained approximately 25 percent of the myocardial receptors under control conditions, the receptors appeared to be segregated from the stimulatory guanine nucleotide binding and catalytic components of adenylate cyclase. During myocardial ischemia, beta-adrenergic receptors were redistributed from the intracellular vesicles to the sarcolemmal fraction, where isoproterenol-stimulated adenylate cyclase activity was increased. These findings should facilitate further studies on cellular and molecular mechanisms that regulate adrenergic receptor traffic in the myocardium and may explain the rapid enhancement in adrenergic receptor expression that occurs with myocardial ischemia.

In vivo regulation of beta-adrenergic receptors on mononuclear leukocytes and heart. Assessment of receptor compartmentation after agonist infusion and acute aortic constriction in guinea pigs.

In animals injected with a bolus of isoproterenol, beta-adrenergic receptors in both mononuclear leukocytes (MNL) and heart were sequestered away from the cell surface, and the time course (0-120 min) and dose-response patterns were similar in the two tissues. In guinea pigs given a constant infusion of isoproterenol, 0.15 mg/(kg.h), down-regulation of total receptor number occurred more quickly and to a greater extent in the MNL than in the heart. We also compared receptor sequestration after aortic constriction-induced acute heart failure. Negligible sequestration (9%) of beta-adrenergic receptors occurred in the MNL of animals treated in this manner, whereas the number of receptors in the sarcolemmal fraction decreased 61%. This selective sequestration of cardiac receptors may result from the action of high concentrations of norepinephrine (which is selective for beta 1 over beta 2 receptors) present at sympathetic nerve-cardiac cell synapses. We conclude that although receptor redistribution occurs similarly in MNL and heart in response to a circulating nonselective agonist, beta-adrenergic receptor redistribution may occur selectively in the heart in response to such stimuli as aortic constriction-induced acute heart failure that activate the sympathetic nervous system.

Adrenergic control of circulating lymphocyte subpopulations. Effects of congestive heart failure, dynamic exercise, and terbutaline treatment.

The current studies were undertaken to explore the relationship between enhanced sympathetic nervous activity and lymphocyte subset distribution in three settings: congestive heart failure, dynamic exercise, and beta-adrenergic agonist treatment. We compared the number and subset distribution of circulating lymphocytes in 36 patients with congestive heart failure and 31 age-matched control subjects. The number of circulating lymphocytes was lower in heart failure than in control. This was due to a reduction in Tsuppressor/cytotoxic and natural killer cells without significant alteration of Thelper cells. The extent of the alteration was similar in patients with idiopathic and ischemic heart failure, but the reduction was more pronounced in patients with New York Heart Association class III-IV than in class I-II. The plasma catecholamine elevation in heart failure was also independent of etiology but more pronounced in the more severely ill patients. We also assessed lymphocyte subsets after acute stimulation of sympathetic activity by dynamic exercise and after treatment with the beta-adrenergic agonist terbutaline. Dynamic exercise until exhaustion increased the number of circulating lymphocytes in healthy controls and heart failure patients in a subset-selective manner. By contrast, a 7-d treatment with terbutaline caused a reduction in the circulating number of lymphocytes in some subsets that was identical to that seen in heart failure patients. We conclude that prolonged sympathetic activity reduces the number of circulating lymphocytes by a beta-adrenergic mechanism. Such alterations might be involved in the pathophysiology of heart failure and other disease states involving increased activity of the sympathetic nervous system.

Effect of prolonged catecholamine infusion on immunoregulatory function: implications in congestive heart failure.

OBJECTIVES: This study sought to characterize the effects of prolonged catecholamine infusion on immunoregulatory cell traffic and activation. BACKGROUND: Immunoregulation has been shown to be partially controlled by the sympathetic nervous system. Although short-term elevation of catecholamine levels is known to alter immunoregulatory cell traffic and activation, the effects of prolonged heightened sympathetic nervous system activity have not adequately been studied. We believe that the alterations in immune function seen in patients with congestive heart failure are linked to a prolonged elevation of circulating catecholamine levels. METHODS: To characterize the effects of prolonged elevation of catecholamine levels, rats received 4 weeks of constant infusion of epinephrine or norepinephrine through implanted osmotic minipumps. Peripheral and splenic leukocyte subsets, T cell proliferation and interleukin-2 receptor expression were quantified. Antibody production to the novel antigen keyhole limpet hemocyanin was assessed over the 4-week treatment period. RESULTS: Both epinephrine and norepinephrine caused significant splenic atrophy and cardiac hypertrophy; both were blocked by propranolol. Epinephrine induced lymphocytosis; both catecholamines caused an increase in natural killer cells. In the spleen, both epinephrine and norepinephrine led to a dose-dependent decrease in total T cells, suppressor/cytotoxic T cells and natural killer cells and a significant increase in B cells. Epinephrine at the low dose enhanced mitogen-induced proliferation and interleukin-2 receptor expression. Norepinephrine at the low dose appeared to diminish proliferation. Epinephrine tended to inhibit IgG antibody production, whereas norepinephrine had no effect. CONCLUSIONS: The results of our study indicate that prolonged elevation of catecholamine levels alters immune cell proliferation and differentiation. These alterations differ greatly from those induced by short-term stimulation but, for the most part, parallel those found in patients with congestive heart failure. We postulate that the shifts in immunoregulatory cell type and function seen in patients with congestive heart failure are due, in part, to longstanding increases in circulating catecholamine levels and may play an important role in the pathogenesis and progression of disease.

Absence of cardioversion-induced ventricular arrhythmias in patients with therapeutic digoxin levels.

To determine the incidence of cardioversion-induced ventricular arrhythmias in patients with therapeutic serum levels of digoxin, 19 patients (average age [+/- standard deviation] 61 +/- 12 years) undergoing elective direct current cardioversion for atrial fibrillation were studied. Only patients with therapeutic serum digoxin levels (range 0.5 to 1.9 ng/ml; mean 1.1 +/- 0.5) at the time of cardioversion were included. Patients with acute myocardial ischemia or unstable angina, serious electrolyte disturbance or those requiring class I antiarrhythmic agents for control of ventricular or supraventricular arrhythmias were excluded. Ambulatory electrocardiograms were recorded for 24 hours before and 6 hours after cardioversion. No patient developed malignant ventricular arrhythmias (ventricular triplets or tachycardia) in the immediate 3 hour period after cardioversion. Furthermore, there were no significant (p less than 0.05) differences in the frequency of ventricular premature beats or couplets before and after cardioversion. To determine whether the level of serum digoxin or the strength of the applied shock had a significant effect on the development of postcardioversion arrhythmias, the change in frequency of single premature ventricular beats after cardioversion was compared with the serum digoxin level (ng/ml) and the applied energy level (joules) by means of linear regression analysis. There was no significant (p less than 0.05) relation between these variables. These findings suggest that patients with therapeutic serum levels of digoxin may safely undergo cardioversion without the concomitant use of class I antiarrhythmic agents.

Survival after hospital discharge in matched populations with inferior or anterior myocardial infarction.

Prognostic differences between patients with anterior or inferior myocardial infarction are often related to such variables as previous infarction or the size of the myocardial infarct. We examined the determinants of mortality in 997 hospital survivors of acute Q wave infarction (anterior in 449, inferior in 548) who, although not preselected, were well matched with respect to age, sex and prior infarction or congestive heart failure. Additionally, there was no significant difference in peak serum creatine kinase (CK) between the groups with anterior and inferior infarction (1,459 +/- 1,004 versus 1,357 +/- 1,036). Among the patients with anterior infarction who died during the 1 year follow-up period, 56% died in the first 60 days after hospital discharge compared with 18% of those without inferior infarction (p less than 0.01). Survival curves then became nearly identical at 3 months, and remained so until 1 year when the total mortality rate was 10% for the anterior and 7% for the inferior infarction group (p = NS). Variables associated with heart failure during the hospital phase were more prevalent in anterior infarction, but rales above the scapulae during the hospital stay (p less than 0.0001) and ventricular gallop at the time of discharge (p less than 0.0001) were the top two predictors of 1 year mortality by both univariate and multivariate analysis in inferior infarction. Age (p less than 0.0001) and peripheral edema (p less than 0.0001) were the strongest predictors of mortality in anterior infarction. Previous infarction, although just as common in the group with anterior infarction, was present at 1 year in 48% of nonsurvivors of the group with inferior infarction compared with only 19% of survivors (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting.

OBJECTIVES: The goal of this study was to evaluate the utility of a rapid "bedside" technique for measurement of B-type natriuretic peptide (BNP) in the diagnosis of congestive heart failure (CHF) in an urgent-care setting. BACKGROUND: B-type natriuretic peptide is a protein secreted from the cardiac ventricles in response to pressure overload. One potential application of measurements of BNP in blood is distinguishing dyspnea due to CHF from other causes. METHODS: B-type natriuretic peptide concentrations were measured in a convenience sample of 250 predominantly male (94%) patients presenting to urgent-care and emergency departments of an academic Veteran's Affairs hospital with dyspnea. Results were withheld from clinicians. Two cardiologists retrospectively reviewed clinical data (blinded to BNP measurements) and reached a consensus opinion on the cause of the patient's symptoms. This gold standard was used to evaluate the diagnostic performance of the BNP test. RESULTS: The mean BNP concentration in the blood of patients with CHF (n = 97) was higher than it was in patients without (1,076 +/- 138 pg/ml vs. 38 +/- 4 pg/ml, p < 0.001). At a blood concentration of 80 pg/ml, BNP was an accurate predictor of the presence of CHF (95%); measurements less than this had a high negative predictive value (98%). The overall C-statistic was 0.97. In multivariate analysis, BNP measurements added significant, independent explanatory power to other clinical variables in models predicting which patients had CHF. The availability of BNP measurements could have potentially corrected 29 of the 30 diagnoses missed by urgent-care physicians. CONCLUSIONS: B-type natriuretic peptide blood concentration measurement appears to be a sensitive and specific test to diagnose CHF in urgent-care settings.

In vivo regulation of beta-adrenergic receptors on human mononuclear leukocytes: assessment of receptor number, location, and function after posture change, exercise, and isoproterenol infusion.

We studied the regulation of beta-adrenergic receptors in human mononuclear leukocytes (MNL). Total receptor number was determined as specific binding at 4 C of [3H] dihydroalprenolol or [125I]iodopindolol, and redistributed receptors were defined as those binding sites to which the hydrophilic antagonist CGP-12177 did not have access. Receptor function was assessed as cAMP accumulation stimulated by isoproterenol. In in vitro experiments, high concentrations of isoproterenol desensitized receptor function and promoted redistribution of about 80% of the receptors away from the cell surface. However, three in vivo protocols (upright posture for 3 h, moderate exercise, and infusion of isoproterenol for 30 min) redistributed few beta-adrenergic receptors on MNL. The 30-min isoproterenol infusion did not alter later cAMP accumulation, but posture change and exercise increased isoproterenol-stimulated cAMP accumulation in intact MNL. Infusion of isoproterenol for 120 min redistributed 9 +/- 2% (+/- SEM) of the receptors and decreased isoproterenol-stimulated cAMP accumulation by 19 +/- 6%. Isoproterenol-stimulated adenylate cyclase activity in membranes isolated from MNL previously was found to be decreased with upright posture, and we confirmed these findings in assays that did not include exogenous GTP, but instead relied upon guanine nucleotides retained in the membrane preparation. However, when excess GTP was included, isoproterenol-stimulated adenylate cyclase activity in MNL membranes was not altered by posture change. We conclude that substantial receptor redistribution of beta-receptors on MNL does not readily occur in physiological situations.

Receptor redistribution does not accompany terbutaline-induced down regulation of beta-adrenergic receptors on human mononuclear leukocytes.

Mononuclear leukocytes are easily accessible cells for investigating the regulation of beta-adrenergic receptors in humans. We have previously shown that brief incubations with agonists redistribute (? internalize) most of the beta-adrenergic receptors on mononuclear leukocytes away from the cell surface without changing total receptor number. However, negligible redistribution occurred after exercise or an infusion of isoproterenol. The current study was designed to ask whether receptor redistribution occurs over a longer time course after administration of terbutaline, a beta 2-adrenergic agonist that is known to cause a decrease in receptor number. Normal volunteers were given terbutaline, 5 mg t.i.d. for 6 days. As expected, the number of beta-adrenergic receptors decreased. However, the remaining receptors were not redistributed. Redistribution also did not occur after 1 or 2 days of terbutaline, at which time down regulation was minimal. We also found that terbutaline did not alter the ability of the receptors to be redistributed or desensitized by a preincubation with isoproterenol.

A new method for isolation of human lymphocyte subsets reveals differential regulation of beta-adrenergic receptors by terbutaline treatment.

We adapted a technique for isolation of mononuclear leukocyte (MNL) subsets with immunomagnetic beads to the study of beta-adrenergic receptors. Mixed MNL cells were sequentially incubated with monoclonal antibodies specific for certain MNL subsets. Sheep antimouse antibodies coupled to magnetic beads were then added, and the desired MNL subset was pulled out with a magnet. This method yielded subsets with high purity and did not alter beta-receptor density or function. Healthy volunteers were treated for 7 days with the beta 2-selective agonist terbutaline (5 mg t.i.d.). Terbutaline treatment decreased beta-receptor number and isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) generation in natural killer cells, helper T cells, and suppressor/cytotoxic T cells but not in B cells. The decrease was greatest in suppressor/cytotoxic T cells and least in helper T cells. Thus beta-adrenergic receptor regulation by agonists appears to differ among MNL subsets.

Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction.

PURPOSE: Although echocardiography is important for making the diagnosis of left ventricular dysfunction, its cost and lack of availability limit its use as a routine screening test. B-Natriuretic peptide levels accurately reflect ventricular pressure, and preliminary studies with a rapid assay have found that levels are sensitive and specific for diagnosing heart failure in patients with dyspnea. We hypothesized that B-natriuretic peptide levels obtained through the use of a rapid assay should correlate with echocardiographic abnormalities of ventricular function. SUBJECTS AND METHODS: We studied 400 patients who were referred for echocardiography at the San Diego Veteran's Healthcare System between June and August 2000 to evaluate ventricular function. B-natriuretic peptide levels were measured by a point-of-care immunoassay; cardiologists assessing left ventricular function were blinded to the assay results. Patients were grouped into those with normal ventricular function, systolic dysfunction only, diastolic dysfunction only, and both systolic and diastolic dysfunction. RESULTS: Mean (+/- SD) B-natriuretic peptide concentration was 416 +/- 413 pg/mL in the 253 patients diagnosed with abnormal left ventricular function, compared with 30 +/- 36 pg/mL in the 147 patients with normal left ventricular function. Patients with both systolic and diastolic dysfunction had the highest levels (675 +/- 423 pg/mL). The area under the receiver operating characteristic (ROC) curve for B-natriuretic peptide levels to detect any abnormal echocardiographic finding was 0.95 (91% confidence interval: 0.93 to 0.97). B-Natriuretic peptide levels were unable to differentiate systolic vs. diastolic dysfunction. In patients with symptoms of heart failure and normal systolic function, B-natriuretic peptide levels >57 pg/mL had a positive predictive value of 100% for diastolic abnormalities. CONCLUSIONS: A simple, rapid test for B-natriuretic peptide levels can reliably predict the presence or absence of left ventricular dysfunction on echocardiogram. For some patients, a normal level may preclude the need for echocardiography.

Elevation of plasma neuropeptide Y levels in congestive heart failure.

PURPOSE: Our objectives were to assess whether plasma neuropeptide Y (NPY) levels are elevated in patients with congestive heart failure (CHF) and whether or not NPY levels can serve as a reliable indicator of sympathetic activity in CHF. PATIENTS AND METHODS: Plasma levels of the sympathetic neurotransmitters norepinephrine and epinephrine and of the sympathetic co-transmitter NPY were measured in 17 patients with CHF and 14 healthy control subjects at rest and after maximal exercise. RESULTS: Under resting conditions, plasma NPY and norepinephrine levels were elevated in patients with CHF compared with control subjects (551 +/- 48 pg/ml versus 311 +/- 22 pg/ml, p less than or equal to 0.001 for NPY, and 306 +/- 73 pg/ml versus 124 +/- 22 pg/ml, p less than or equal to 0.02 for norepinephrine). Plasma NPY correlated better with plasma norepinephrine than with epinephrine, indicating its origin from sympathetic nerve terminals. Acute stimulation of sympathetic activity by dynamic exercise increased plasma norepinephrine levels in control subjects and patients with CHF, but did not significantly alter the mean plasma NPY value in the latter group. CONCLUSION: NPY may play a role in the pathophysiology of CHF.

Peripheral blood mononuclear cell-endothelial adhesion in human hypertension following exercise.

OBJECTIVE: To determine the effects of hypertension and exercise on interleukin-6 (IL-6) levels and mononuclear cell adhesion to endothelial cells. DESIGN: Twelve hypertensive and 33 normotensive volunteers were studied prior to and following exhaustive exercise. End points were stimulated IL-6 levels and peripheral blood mononuclear cell (PBMC) CD11a (LFA-1) expression and in vitro PBMC adhesion to human umbilical venous endothelial cells (HUVEC). RESULTS: In response to exercise, all subjects showed a significant increase in lymphocyte CD11a a density and in IL-6 levels (P < 0.001). Compared to normotensives, hypertensives showed significantly greater mean density of CD11a on lymphocytes (P< 0.05) and on monocytes (P < 0.05). In response to exercise, hypertensive subjects showed a twofold greater increase in IL-6 as compared to normotensives (+ 240 pg/ml versus + 123 pg/ml, respectively; P< 0.05). PBMC adhesion to HUVEC was increased in hypertensives but decreased in normotensives following exercise (P< 0.03). CONCLUSION: The findings suggest that exercise leads to increased mononuclear cell adhesion to endothelial cells in patients with hypertension, possibly through cytokine-induced activation of mononuclear cell CD11a. These findings, coupled with prior data indicating increased endothelial activation in hypertension, may be relevant to the increased risk of atherosclerosis in human hypertension.

Myocardial ischemia alters immunoregulatory cell traffic and function in the rat independent of exogenous catecholamine administration.

Recent investigation has suggested there is an adrenergically-driven efflux of beta 2-receptor rich lymphocyte subsets into the circulation with altered function following either exercise or infusion of exogenous catecholamines. Myocardial ischemia, like exercise, is associated with generalized sympathoadrenal activation. To determine whether ischemia influences immunoregulatory cell traffic and function in a manner comparable to beta 2-adrenergic stimulation via isoproterenol, rats underwent thoracotomy with or without coronary ligation. Another group of rats received either isoproterenol (1 mg/kg) or vehicle (10 mM HCl) intraperitoneally. Thoracotomy, regardless of whether or not myocardial ischemia was induced, led to lymphocytosis, reflected primarily by an increase in Thelper (Th) cells and, to a lesser degree, in Tsuppressor/cytotoxic (Ts/c) and natural killer (NK) cells, with a tendency toward an increased Th/Ts/c ratio. To the contrary, isoproterenol injection resulted in a relative lymphopenia characterized by diminished B and Th cell numbers, preserved Ts/c and increased NK cell numbers leading to a significant decrease in the Th/Ts/c ratio. With respect to splenic composition, 60 but not 15 min of myocardial ischemia led to diminished Th and B cell numbers compared to sham operated controls, whereas isoproterenol appeared to stimulate an efflux of only NK cells. Both ischemia and isoproterenol enhanced basal splenocyte function; however, only ischemia significantly boosted splenocyte responsiveness to the mitogen Concanavalin A. Surgically induced myocardial ischemia leads to alterations in immunoregulatory cell migration and function which are distinct from those found with beta 2-adrenergic stimulation via isoproterenol.

Leukocyte adhesion molecule expression and T cell naïve/memory status following isoproterenol infusion.

This study examined adhesion molecules on peripheral leukocytes following a 30-min infusion of the beta-adrenergic agonist isoproterenol in 23 healthy subjects. In response to isoproterenol, the number of CD8 +CD62L- T cells and both CD62L+ and CD62L-natural killer (NK) (CD3 CD16+ 56+) cells increased markedly in circulation (p < 0.001). In addition, the surface density of CD62L was significantly lower on both CD8+ and CD4+ T cells (p < 0.001). Plasma levels of soluble CD62L remained unchanged, arguing against an isoproterenol-induced shedding of L-selectin. In contrast to CD62L, the surface density of the beta2 integrin LFA-1 (CD11a) was higher on circulating lymphocytes (p < 0.001) (but not monocytes or lymphocytes) post-infusion. Isoproterenol also led to a mobilization of memory/activated CD8+CD29high T cells (p < 0.01), but had no significant effect on the number of circulating CD8+ CD45RA+ CD62L+ naïve T cells. beta blockade with the non-specific antagonist propranolol eliminated these isoproterenol-induced effects.

Increased production of antigen-specific immunoglobulins G and M following in vivo treatment with the medicinal plants Echinacea angustifolia and Hydrastis canadensis.

A number of immunomodulatory effects have been attributed to the medicinal plants Echinacea angustifolia and Goldenseal (Hydrastis canadensis); however, little is known about whether treatment with these plants can enhance antigen-specific immunity. We investigated the antigen-specific in vivo immunomodulatory potential of continuous treatment with Echinacea and Goldenseal root extract over a period of 6 weeks using rats that were injected with the novel antigen keyhole limpet hemocyanin (KLH) and re-exposed to KLH after the initial exposure. Immunoglobulin production was monitored via ELISA continuously over a period of 6 weeks. The Echinacea-treated group showed a significant augmentation of their primary and secondary IgG response to the antigen, whereas the Goldenseal-treated group showed an increase in the primary IgM response during the first 2 weeks of treatment. Our results suggest that medicinal plants like Echinacea or Goldenseal may enhance immune function by increasing antigen-specific immunoglobulin production.

Ninety-minute accelerated critical pathway for chest pain evaluation.

Rapid, efficient, and accurate evaluation of chest pain patients in the emergency department optimizes patient care from public health, economic, and liability perspectives. To evaluate the performance of an accelerated critical pathway for patients with suspected coronary ischemia that utilizes clinical history, electrocardiographic findings, and triple cardiac marker testing (cardiac troponin I [cTnI], myoglobin, and creatine kinase-MB [CK-MB]), we performed an observational study of a chest pain critical pathway in the setting of a large Emergency Department at the Veterans Affairs Medical Center in 1,285 consecutive patients with signs and symptoms of cardiac ischemia. The accelerated critical pathway for chest pain evaluation was analyzed for: (1) accuracy in triaging of patients within 90 minutes of presentation, (2) sensitivity, specificity, positive predictive value, and negative predictive value of cTnI, myoglobin, and CK-MB in diagnosing acute myocardial infarction (MI) within 90 minutes, and (3) impact on Coronary Care Unit (CCU) admissions. All MIs were diagnosed within 90 minutes of presentation (sensitivity 100%, specificity 94%, positive predictive value 47%, negative predictive value 100%). CCU admissions decreased by 40%. Ninety percent of patients with negative cardiac markers and a negative electrocardiogram at 90 minutes were discharged home with 1 patient returning with an MI (0.2%) within the next 30 days. Thus, a simple, inexpensive, yet aggressive critical pathway that utilizes high-risk features from clinical history, electrocardiographic changes, and rapid point-of-care testing of 3 cardiac markers allows for accurate triaging of chest pain patients within 90 minutes of presenting to the emergency department.

Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers.

The ability to differentiate between true positives, false positives, and sporadically elevated cardiac troponin levels has grown in importance as cardiac troponins assume an increasingly dominant role in the diagnosis of coronary syndromes. In a population sample of 1,000 patients who presented consecutively to a large urban hospital emergency room, 50 of 112 patients who had elevated troponin levels (> 0.6 ng/ml) during evaluation for myocardial injury were subsequently found to have had an isolated, spurious elevation of cardiac troponin, and not a diagnosed myocardial infarction. Logistic regression analysis shows that by hierarchically analyzing electrocardiographic changes with concurrent creating kinase-MB and myoglobin levels at the time of the troponin elevation, one may predict with 91% accuracy whether the troponin elevation is actually indicative of a myocardial infarction in a patient. Spurious troponin elevations may be a common occurrence, and if not detected, may result in an increased number of falsely diagnosed myocardial infarctions.

Cyclic AMP counteracts mitogen-induced inositol phosphate generation and increases in intracellular Ca2+ concentrations in human lymphocytes.

1. The effects of increases in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on mitogen-induced generation of inositol phosphates and increases in intracellular Ca2+ concentration were investigated in human peripheral blood mononuclear leukocytes (MNL). 2. The mitogens concanavalin A (Con A), pokeweed mitogen (PWM) and phytohaemagglutinin (PHA) concentration-dependently stimulated generation of inositol phosphates. Catecholamines inhibited this process with an order of potency: isoprenaline greater than adrenaline greater than noradrenaline indicating involvement of beta 2-adrenoceptors. This order of potency was also consistent with the catecholamine potencies for stimulating the generation of cyclic AMP. 3. In addition to catecholamines, the cyclic AMP formation-stimulating agents prostaglandin E1 (PGE1) and forskolin concentration-dependently inhibited mitogen-induced inositol phosphate generation, too. Moreover, the inhibitory effect of isoprenaline was potentiated by co-incubation with the phosphodiesterase inhibitor isobutylmethylxanthine demonstrating that these inhibitory effects were mediated by cyclic AMP. 4. Con A and PHA concentration-dependently increased the intracellular Ca2+ concentration in human MNL (assessed by the fluorescent indicator dye Fura-2). This increase was almost completely blocked by chelation of extracellular Ca2+, demonstrating influx rather than mobilization from intracellular stores. 5. The elevation of intracellular Ca2+ was not blocked by pretreatment with pertussis toxin, 100 ng ml-1, for 16 h. 6. Isoprenaline, PGE1, and forskolin, however, inhibited the mitogen-stimulated elevation of intracellular Ca2+. This inhibition was enhanced by the phosphodiesterase inhibitors isobutylmethylxanthine and Ro 20-1724, demonstrating mediation by cyclic AMP. 7. We conclude that catecholamines and other cyclic AMP increasing agents can inhibit mitogen-stimulated generation of inositol phosphates and elevation of intracellular Ca2+ in resting human MNL.