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Because vincristine has immunosuppressive activity in animal models, has specific cytotoxic effects on lymphocytes, and does not have overlapping toxicity with other immunosuppressive agents, we designed a prospective randomized trial to evaluate the efficacy of the addition of vincristine to standard immunosuppressive therapy in heart transplantation. Patients received equine antithymocyte globulin for the first week or murine antihuman mature T cell (OKT3) monoclonal antibody for the first 2 weeks after transplantation and were maintained on azathioprine and cyclosporine. A steroid pulse was administered 1 day after completion of antithymocyte globulin or OKT3 monoclonal antibody and tapered off over 21 days. Vincristine was given at 0.025 mg/kg intravenously for eight dosages over 12 weeks, beginning 2 days after completion of antithymocyte globulin or OKT3 monoclonal antibody. Fifty-two patients were randomized (26 were given vincristine, and 26 were not). The addition of vincristine to the regimen of patients receiving antithymocyte globulin resulted in significantly fewer episodes of rejection at 1 month (vincristine, 0.2 +/- 0.1; no vincristine, 1.2 +/- 0.2; p less than 0.001), at 3 months (vincristine, 1.2 +/- 0.1; no vincristine, 2.5 +/- 0.3; p less than 0.001), and at 6 months (vincristine, 1.9 +/- 0.2; no vincristine, 2.9 +/- 0.3; p less than 0.001). It also resulted in significantly more patients being successfully weaned off daily steroids (vincristine, 67%; no vincristine, 20%; p = 0.04). The addition of vincristine to the regimen of patients receiving early rejection prophylaxis with OKT3 monoclonal antibody did not alter rejection incidence or steroid usage.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of the sympathetic nervous system has traditionally been regarded as an important compensatory mechanism that helps to maintain myocardial contractility in severe heart failure. Recent findings suggest that increased catecholamine levels are linked to decreased beta-adrenergic receptor density and myocardial damage. Thus, rather than aiding the failing heart, increased myocardial exposure to catecholamines may actually contribute to further deterioration in myocardial function. Beta-adrenergic blocking drugs may ameliorate these harmful effects and paradoxically result in improved ventricular performance.

In 43 patients with variant angina, the cardiovascular event rate during diltiazem therapy was compared with that in an equal time period before initiation of therapy. Cardiovascular events, that is, myocardial infarction, sudden death and hospitalization for prolonged angina, were decreased significantly (p less than 0.01) during the initial 6 months and mean 19.6 months of therapy. Based on the binomial principle, there were 22 events during the mean 19.6 months before therapy and 2 events during the equal time period on therapy. No patient died during follow-up. The frequency of angina was decreased by 94%. Diltiazem was well tolerated by all patients and no patient had to discontinue therapy because of adverse effects. It is concluded that long-term diltiazem therapy reduces cardiovascular events in patients with variant angina.

We examined alpha-1 adrenergic receptor density in ventricular myocardium from nonfailing and failing human hearts, utilizing the alpha-1 radioligand [125I]IBE2254. The alpha-1 receptor population comprised a relatively small portion of the total adrenergic receptors, 14.6 +/- 1.9%. However, in failing human ventricular myocardium the alpha-1 adrenergic receptor population constituted a much greater portion, 27.3 +/- 2.1% (P less than .01). The reason for the increased proportion of alpha-1 adrenergic receptors was not that the total concentration of alpha-1 receptors was increased, but instead was due to selective down-regulation of the beta-1 adrenergic receptor population. Beta-2 adrenergic receptors behaved similarly to alpha-1 adrenergic receptors in the failing human heart, and were increased in proportion and unchanged in total number. Additionally, the ability of alpha-1 stimulation to increase the incorporation of label from [3H]inositol into inositol phosphates was examined in tissue homogenates. Maximal doses of norepinephrine produced only marginal stimulation of phosphatidylinositol hydrolysis, in contrast to a more substantial response produced by muscarinic stimulation. We conclude that human ventricular myocardium contains alpha-1 adrenergic receptors that 1) are of relatively low density, 2) are unchanged in density by heart failure and 3) mediate relatively low-level stimulation of phosphatidylinositol hydrolysis.

Alpha-adrenergic receptors may play an important role in regulating vascular tone and reactivity. To study alpha-adrenergic receptors in blood vessels, we have developed a method to characterize and quantitate alpha-adrenergic receptors in a particulate fraction of individual rabbit aortas using the high specific activity alpha antagonist [125I] BE2254. [125I] BE2254 specifically labels a single class of binding sites with a dissociation constant of 286 pM and a maximal binding capacity of 16.7 fmoles/mg protein. Catecholamines compete for [125I] BE2254 binding stereospecifically and with the characteristic alpha-adrenergic potency series of (-)epinephrine greater than or equal to (-)norepinephrine much greater than (-)isoproterenol. The alpha 1-selective antagonist prazosin (KD = 0.7 nM) is much more potent in competing for [125I] BE2254 binding than is the alpha 2-selective antagonist yohimbine (KD = 1000 nM), which suggests that the alpha adrenergic receptor identified is predominantly of the alpha 1 subtype. Also, the dissociation constants from these binding studies were in good agreement with those reported in rabbit aorta from classical pharmacological experiments where contraction was found to be mediated via alpha 1 receptors. This extension of radioligand binding techniques to individual rabbit aortas should simplify the study of vascular alpha adrenergic receptor regulation, and provide a basis for broadening the understanding of vascular alpha adrenergic receptors.

The efficacy of low dose oral enoximone (MDL 17,043) was evaluated in the treatment of congestive heart failure (CHF). Fourteen male patients with stable, moderately severe CHF (New York Heart Association functional class II or III) and mean left ventricular ejection fraction of 0.21 +/- 0.02 were randomized to receive 50, 75, 100, 150 or 200 mg of enoximone (mean dose 1.46 +/- 0.16 mg/kg). Hemodynamic data were measured before and during the first 24 hours of therapy. An oral dose was given in the first 24 hours, and then every 8 hours. Acute administration of enoximone resulted in significant improvement in cardiac index (2.07 +/- 0.18 to 2.36 +/- 0.16 liters/min/m2, p less than 0.05), mean pulmonary arterial pressure (35 +/- 4 to 30 +/- 4 mm Hg, p less than 0.02), mean pulmonary artery wedge pressure (22 +/- 3 to 18 +/- 2 mm Hg, p less than 0.05) and systemic vascular resistance (1,712 +/- 148 to 1,384 +/- 82 dynes s cm-5, p less than 0.02). Neither hypotension nor tachycardia was observed. Although there was a trend toward a dose-response relation, hemodynamic responses to doses less than 1.5 mg/kg and greater than 1.5 mg/kg were not significantly different. Clinical symptoms improved with long-term therapy, but left ventricular ejection fraction and exercise treadmill time did not change. In patients with moderate and severe CHF, low doses of enoximone result in significant acute hemodynamic improvement.

We examined radionuclide-determined left ventricular ejection fractions (LVEF) at rest and during graded exercise in 37 patients receiving doxorubicin (Adriamycin) therapy in whom the risk of developing congestive heart failure (CHF) was precisely defined by endomyocardial biopsy and right heart catheterization. Echocardiographic (Echo %FS) and phonocardiographic (PEP/LVET) measurements of LV function were also determined. An abnormal LVEF at rest (less than or equal to 45%) had a sensitivity of 53% and a specificity of 75% for detecting patients at moderate or high risk of developing CHF. The addition of exercise LVEF increased the sensitivity of detection of moderate or high-risk patients to 89% but lowered the specificity to 41%. Exercise LVEF improved the sensitivity of detection of high-risk patients from 58% to 100%. Echo %FS and PEP/LVET yielded lower sensitivities than rest or exercise LVEF. As a single test, exercise LVEF possesses the sensitivity for use as a screening method for anthracycline cardiotoxicity, but the lack of specificity prevents the use of single values as a definitive test. Single rest LVEF determinations, although more specific than exercise LVEF, do not possess the sensitivity for use as screening or definitive tests.

Twelve patients with nonexertional chest pain and nonobstructive fixed coronary disease (less than 50% luminal diameter narrowing) were given histamine to investigate the potential role (coronary artery H1 receptor agonism) of the endogenous agent in producing coronary artery spasm (CAS). Histamine, at intravenous dose of 0.5 to 1.0 microgram/kg/min, provoked CAS in four patients. In six patients neither histamine nor ergonovine provoked spasm, and these patients were considered by chronic follow-up evaluation to have noncardiac etiology for their chest pain syndrome. In one patient CAS was provoked with ergonovine but not by histamine, and one ergonovine-positive patient had an equivocally positive histamine result. Pretreatment with cimetidine (H2 receptor antagonism) was necessary to avoid unpleasant side effects of histamine. Thus these observations indicate that histamine should be included among the specific agents capable of inducing CAS and provide new insight concerning the mechanism(s) causing variant angina pectoris.

We prospectively studied 551 sequential endomyocardial biopsies from 36 consecutive cardiac allografts. With the use of a combination of light microscopy (including careful evaluation of vascular changes) and immunofluorescence to detect the deposition of immunoglobulin and complement, we identified three patterns of allograft rejection, designated as cellular rejection, vascular (humoral) rejection, and mixed rejection. Cellular rejection was diagnosed with modified Billingham criteria. Vascular rejection was diagnosed by finding the combination of prominent endothelial cell swelling and/or vasculitis on light microscopy and the vascular deposition of immunoglobulin and complement by immunofluorescence. In such patients, cellular lymphoid infiltrates were uniformly absent at the time the vascular changes were detected. Mixed rejection consisted of findings of both cellular and vascular rejection occurring simultaneously. Twenty of 36 allografts exhibited cellular rejection; seven allografts showed vascular rejection, and nine allografts developed mixed rejection. The vascular (humoral) pattern of rejection was important to identify because the patients with this type of rejection had a significantly decreased survival compared with that of patients with cellular rejection (p less than 0.05). Survival in the mixed rejection category was intermediate. Positive donor-specific cross-match and/or panel-reactive antibody greater than or equal to 5% and systolic dysfunction were seen in three of the seven allografts with vascular (humoral) rejection but not in the other types. In the early period after transplant (up to 3 weeks after transplant), the only reliable identifying characteristics of patients with vascular (humoral) rejection were the presence of vascular immunoglobulin and complement assessed by immunofluorescence and endothelial cell swelling and interstitial edema as confirmed by histologic examination. We conclude that immunofluorescence should be routinely done on all heart biopsies for the first month after transplantation. Patients with vascular (humoral) rejection cannot be reliably identified by any other means.

[3H]-nitrendipine binding data and isolated tissue response for five calcium antagonists were evaluated in rabbit myocardium and aorta. The [3H]-nitrendipine binding site was qualitatively identical in myocardium and aorta, as the [3H]-nitrendipine KD, KIS for nicardipine and nifedipine and interactions with verapamil, D600 and diltiazem were not different in aortic and cardiac membranes prepared by similar means. In contrast, the inhibition of the Ca2+-induced contractile response in right ventricular myocardium and aortic ring segments indicated a greater than 10,000 fold selectivity of nicardipine for antagonism of vascular responses. This resulted in a different order of potency for calcium antagonist interaction with the [3H]-nitrendipine binding site in cardiac membranes (nicardipine greater than nifedipine greater than D600 greater than verapamil greater than diltiazem) as compared to antagonism of myocardial tissue response (D600 greater than verapamil greater than or equal to nifedipine greater than nicardipine greater than or equal to diltiazem). In heart the difference between the potency of nicardipine in binding experiments and tissue response approached 4 orders of magnitude. We conclude that tissue response selectivity of calcium antagonists is not explained by heterogeneity of [3H]-nitrendipine binding sites.

Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.

An increase in cardiac beta-adrenergic sensitivity or beta-receptor density or both has been described in several animal species after denervating the heart. The transplanted human heart is also denervated and, therefore, may exhibit supersensitivity to beta-adrenergic agonists and an increase in beta-adrenergic receptor density. In 16 patients examined 1-3 months after orthotopic cardiac transplantation, beta-adrenergic receptor density measured by [125I]iodocyanopindolol binding in endomyocardial biopsy specimens was not significantly different in transplant recipients compared with normal controls (transplant = 1,429 +/- 199, control = 1,728 +/- 263 fmol/g wet wt; p = NS). However, when normalized to Lowry protein, the [125I]iodocyanopindolol in beta-adrenergic receptor density in biopsy tissue from transplant recipients was significantly lower than in tissue from controls (transplant = 58.1 +/- 6.2, control = 93.5 +/- 13.4 fmol/g Lowry protein; p = 0.011). Atrial sinus node activity of the denervated donor heart and the innervated atrial cuff of the native recipient heart could be detected on the surface electrocardiogram in six patients. In these six patients, the heart rate response to graded infusions of epinephrine (taken up by the adrenergic nerve terminals) and isoproterenol (not taken up by the adrenergic nerve terminals) was measured. The epinephrine dose-response curve in transplanted donor atria was significantly to the left of the native recipient atrial dose-response curve (p less than 0.0001). The isoproterenol dose-response curves for native and transplanted atria were not different. We conclude that myocardial beta-adrenergic receptors are not increased in human orthotopic cardiac allografts and that there is no evidence for beta-receptor-mediated supersensitivity of postsynaptic origin.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of acute vascular rejection occurring in a cardiac allograft is presented. The rejection was characterized by prominent lymphocytic infiltration of the major coronary arteries in a pattern similar to that observed in acute vascular rejection occurring in renal allografts. Additionally, there was electron microscopic evidence of endothelial damage of smaller vessels. In addition to routine light microscopic evaluation of heart biopsies obtained in this case, immunofluorescent staining of biopsies for IgG, IgM, C3, Clq, fibrinogen, T cells, B cells, and Ia human leukocyte antigen (HLA-DR) was also performed. These studies suggest that antibodies may have been important in the terminal rejection episode described in this case. Furthermore, immunofluorescent staining detected continuing endothelial cell damage, reflected as Ia antigen positivity of allograft blood vessels, despite apparent improvement of rejection as judged by light microscopy.

Seventy-six endomyocardial biopsies obtained from 60 patients receiving adriamycin (ADM) and other anthracycline analogs were studied. The biopsies were studied by light and electron microscopy. Two main types of myocyte degeneration were consistently present, the lesions were focal, and inflammatory infiltrate was absent. The severity of pathologic changes was graded on a scale from 0 (normal) to 3 (marked abnormality). Twelve patients receiving previous mediastinal irradiation (600-5700 rads) showed a mean pathology grade (2.0 +/- 0.89) that was significantly higher than in those patients receiving a comparable dose of ADM but who were not irradiated (1.18 +/- 0.23) (P less than 0.01). This study indicated that radiation, even if remote, enhances ADM-induced cardiotoxicity and evokes a "recall" phenomenon of latent acute irradiation changes. Our data suggest that a specific, progressive, subclinical injury to the heart occurs with anthracycline therapy that cannot be detected reliably by conventional tests. Anthracycline-induced cardiotoxicity in rabbits, monkeys, and dogs shows the same basic cellular lesions as in man. The analogs, adria-DNA and rubidazone, also show lesions similar to those produced by ADM in the human heart. The endomyocardial biopsy is a reliable method for monitoring cardiac damage due to anthracyclines in man.

OKT3 is a murine monoclonal antibody that is reactive against the CD3 surface antigen on T lymphocytes. This antigen appears to be essential for recognition of foreign antigen and for initiation of the process of cell-mediated rejection. One hundred and two patients having orthotopic cardiac transplantation in a single program during a 3-year period received prophylactic immune suppression with OKT3, along with azathioprine and low-dose steroids. Patients began receiving cyclosporine on Day 11; steroid-weaning was attempted 3 weeks after transplantation. In this group of patients, the time to the first rejection was 76 +/- 11 days (mean +/- SEM), and 85% were successfully weaned from maintenance steroids. Avoidance of the side effects of cyclosporine and/or high dose steroids during the perioperative period, combined with a long rejection-free interval and the likelihood of long-term maintenance free of steroids, make the use of OKT3 or similar agents an attractive alternative to conventional immunosuppression.

We tested the hypothesis that cardiac histamine release mediates subacute doxorubicin (DXR) cardiotoxicity in rabbits. New Zealand white rabbits given DXR 20 mg/kg i.v. over 30 min developed myocardial damage 24 h later that was similar to that observed in humans. In isolated heart preparations, DXR produced dose-related cardiac histamine release at DXR concentrations of 1, 5, and 25 micrograms/ml given as 1-min exposures. Prior exposure of isolated hearts to 10 microM cromolyn sodium completely prevented histamine release from 5 micrograms/ml DXR. Pretreatment of animals with cromolyn produced significant protection against DXR-mediated subacute cardiotoxicity. We conclude that the release of cardiac histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.

Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.

The first 36 patients with coronary arterial spasm treated with diltiazem and followed up at the Stanford University Coronary Artery Spasm Clinic for 6 months or longer are described. There were 13 men and 23 women with a mean age of 50.2 years; the mean duration of angina was 36.1 months. All patients had angina at rest with a good or fail response to sublingual nitroglycerin. During a mean of 17.5 months of diltiazem therapy, the frequency of angina was reduced from a mean of 21.5 to 1.3 attacks/week. This 94 percent reduction in pain frequency occurred when either 240 or 360 mg of diltiazem was administered daily. Sixteen patients required the addition of isosorbide dinitrate to achieve a painfree state. Pain breakthrough occurred a mean of 1.7 times during the 17.5 month follow-up period but tended to be of short duration. Six patients had trace to 1+ pedal edema and no other adverse effects occurred. It is concluded that diltiazem is highly effective and well tolerated for the long-term prophylaxis and treatment of angina in patients with coronary spasm.

Cytomegalovirus (CMV) infection is a frequent cause of serious illness in heart transplant patients and may cause life-threatening pneumonia, with a reported mortality of greater than 50%. We investigated the clinical efficacy of a new antiviral agent, 9(1,3-dihydroxy-2-proproxymethyl)-guanine (DHPG) in the treatment of CMV pneumonia in heart transplant patients. Four of these patients with biopsy-proved CMV pneumonia were treated with DHPG, with resolution of pneumonia and no relapse at a mean follow-up period of 21 weeks. DHPG may be useful in the treatment of CMV pneumonia in heart transplant patients.

Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.

The effects of intracoronary injections of vasoactive intestinal peptide (VIP) on left ventricular (LV) dp/dt, coronary blood flow (CBF), and myocardial oxygen consumption (MVO2) were compared with isoproterenol (ISO) and forskolin in 18 dogs using a preparation in which cardiac output, mean systemic arterial pressure, and heart rate were fixed. In eight dogs in which the effects of VIP and ISO were compared using doses ranging from 2 x 10(-12) to 2 x 10(-8) mol, both agents significantly increased LV dp/dt at doses greater than or equal to 6.6 x 10(-10) mol. At maximal doses (2 x 10(-9) to 2 x 10(-8) mol) the effect of ISO was significantly greater than VIP. Both VIP and ISO significantly increased CBF at all doses, but at maximal doses the effect of VIP on CBF was significantly greater than ISO. The increase in CBF relative to the increase in MVO2, an index of direct coronary vasodilation, was significantly greater for VIP compared with ISO. In 10 additional dogs the effects of VIP and ISO were compared with forskolin given in doses ranging from 2 x 10(-9) to 2 x 10(-7) mol. At maximal doses (2 x 10(-7) mol) the increase in LV dp/dt was similar to VIP but significantly less than ISO, whereas the increase in CBF was similar to ISO but significantly less than VIP. The increase in CBF relative to the increase in MVO2 was significantly greater for forskolin compared with ISO, indicating a direct vasodilator effect.(ABSTRACT TRUNCATED AT 250 WORDS)