James A. Thompson

The oxygen free radical system: A fundamental mechanism in the production of myocardial necrosis

0 XIDATION/REDUCTION reactions are fundamental reactions in both physical and organic chemistry that have been extensively studied. However, it was not until 193 1 that the basis for oxidation/reduction reactions involving oxygen in biologic systems was first described by Haber and Willstatter’ when they discovered that the univalent reduction of molecular oxygen resulted in the production of a reduced oxygen intermediate, the superoxide anion. In 1935, Haber and Weiss* found that the sequential trivalent reduction of molecular oxygen, in combination with an iron catalyst, resulted in the production of a highly reactive oxygen intermediate that was an extremely strong oxidizing species. The biologic importance of this discovery had to wait until 1969 when McCord and Fridovich3 identified the enzyme superoxide dismutase that catalyzed the production of hydrogen peroxide from superoxide anion. They further observed that all mammalian cells contain this unique enzyme. These basic observations defined the new field of oxygen metabolism in biologic systems and a potential role of oxidation/reduction reactions in both physiologic and pathologic conditions.

Increased morbidity with increased pulmonary albumin flux in sepsis-related adult respiratory distress syndrome

ObjectiveTo determine the feasibility of utilizing a scintigraphic technique to differentiate patients with adult respiratory distress syndrome due to sepsis syndrome from control volunteers and patients with congestive heart failure. Gamma scintigraphy was compared with chest roentgenograms to predict mortality rate and morbidity in adult respiratory distress syndrome (ARDS) patients. DesignProspective study. SettingUniversity hospital ICUs. PatientsThirty-five control volunteers, 19 patients with congestive heart failure, 30 patients with a diagnosis of sepsis. Measurements and Main ResultsAll patients were infused iv with technetium 99m-labeled albumin and underwent computerized gamma-scintigraphic analysis with a portable gamma camera. Lung-to-heart ratio of tracer was calculated and expressed as the slope index. Increase in slope index indicated increased pulmonary albumin flux. Slope index was no different in controls compared with congestive heart failure patients, unless the pulmonary artery occlusion pressure (PAOP) was >30 mm Hg. Patients with a diagnosis of sepsis had an overall increased slope index compared with the other groups. A subgroup of patients in the septic group had a normal slope index. Septic patients with an increased slope index had a significantly (p < .01) longer duration of mechanical ventilation (36 ± 5 vs. 7 ± 1 days), spent longer in the ICU (67 ± 9 vs. 11 ± 1 days), and had a longer hospital stay (113 ± 20 vs. 35 ± 5 days) than septic patients with a normal slope index. ConclusionsGamma scintigraphy successfully differentiated between control volunteers and patients with congestive heart failure with PAOP <30 mm Hg from patients with sepsis-induced ARDS. Although all of the patients with a clinical diagnosis of septic ARDS had similar impairments in oxygenation and chest roentgenograms, those patients with a significantly increased pulmonary albumin flux (>2 SD above control mean) had a markedly increased morbidity. (Crit Care Med 1992; 20:28)

Echocardiographic left ventricular mass to differentiate chronic hypertension from preeclampsia during pregnancy

In order to differentiate pregnancy-induced hypertension from chronic systemic hypertension, we measured left ventricular mass for comparison in each trimester of pregnancy in 11 normotensive patients and 14 patients with chronic hypertension and in the third trimester in 10 patients with pregnancy-induced hypertension. The mean left ventricular mass was comparably increased above normal in the patients with chronic hypertension in all three trimesters. In the third trimester in the normotensive women, left ventricular mass (147 +/- 12 gm) was similar to that of the group with pregnancy-induced hypertension (157 +/- 16 gm), whereas the group with chronic hypertension had an elevated left ventricular mass (238 +/- 39 gm) (p less than 0.01). However, three patients with chronic hypertension developed superimposed pregnancy-induced hypertension. We concluded that an elevated left ventricular mass during pregnancy is consistent with underlying chronic hypertension but does not rule out superimposed pregnancy-induced hypertension. A normal left ventricular mass in the third trimester of a hypertensive pregnancy is most consistent with pregnancy-induced hypertension.

Cyclosporine-induced pericardial effusion after cardiac transplantation

Abstract In the last 5 years, there has been a significant proliferation in the number of centers in which orthotopic cardiac transplantation is performed. This has been attributed to better surgical management, patient selection criteria and the introduction of cyclosporine as the immunosuppressant of choice. 1 Initially, it was hoped that cyclosporine would prevent the problems of sudden, catastrophic rejection, development of a Cushingoid appearance and other complications of high-dose steroid therapy. It was also hoped that by monitoring drug levels and titrating the dose, the incidence and severity of rejection would decrease, the length of hospitalization in the immediate postoperative period would decrease and both short-term and long-term survival would increase. 2 It soon became apparent, however, that long-term cyclosporine immun osuppression is associated with severe systemic hypertension and progressive chronic renal insufficiency. 3 Both complications of cyclosporine therapy may lead to the necessity of decreasing the dose of cyclosporine, a readjustment of immunosuppressive protocols to low-dose triple drug therapy (azathioprine, prednisone and cyclosporine) and even the necessity of withdrawing cyclosporine. 4 Less frequently, we have observed significant pericardial effusions in patients who have received cardiac allografts. We will discuss our observations of pericardial disease in the orthotopic cardiac recipient maintained on cyclosporine.

Response to dynamic exercise of the orthotopically transplanted human heart in men immunosuppressed with cyclosporine

Abstract Experimental and human studies of the orthotopically transplanted human heart have shown that, at rest, the denervated heart is characterized by a high resting heart rate and a diminished chronotropic reserve. 1−5 Human studies have been carried out in relatively small numbers of patients before the more recent advances in immunosuppressive therapy and the increasingly sophisticated management of the patient who has had transplantation. We quantified the hemodynamic response to graded treadmill exercise in stable patients who continue their contemporary immunosuppressive therapy including cyclosporine, and undergo stress testing within 12 months of their successful orthotopic cardiac transplantation.

Radionuclide detection of abnormal ventricular filling patterns in rejecting human allografts.

Parameters of systolic and diastolic function obtained from radionuclide ventriculography (RNV) were evaluated in nine cardiac allograft recipients. In 25 examinations, left end-diastolic volume (LEDV), cardiac output (CO), left ejection fraction (LEF), right ejection fraction (REF), heart rate (HR), peak filling rate (PFR), time to peak filling rate (TPFR), peak ejection rate (PER), and average filling rate for the first half of diastole (DFRH) were determined. Endomyocardial blopsy was obtained within 48 hours. Biopsies were divided into three treatment classes (0 = normal; 1 = rejection but not requiring supplemental therapy; and 2 = rejection requiring supplemental immunotherapy). Two independent variables of diastolic function proved to be significant (DFRH P > 0.00001, and PFR P > 0.002) predictors of the dependent variable class when regression analysis was applied to the data. Alterations in diastolic function associated with acute rejection are detectable on RNV and simulate changes anticipated in a primary restrictive cardiomyopathy.

T-Lymphocyte Analysis in Cardiac Allograft Recipients Treated with Cyclosporine

To assess the usefulness of circulating T-lymphocyte analysis in cardiac transplantation, T helper (Th) and T suppressor-cytotoxic (Ts-c) subsets were serially monitored in 33 cardiac allograft recipients treated with cyclosporine. The short-term prognosis of their 47 treated rejection episodes were retrospectively correlated with the changes in T-cell subpopulations. The data indicate three main findings. Reversed Th to Ts-c ratio (less than 1) was associated with a reduced incidence of rejection onset and a benign clinical course after treatment for rejection. Reversed Th:Ts-c ratio caused by antirejection therapy was associated with less chance of recurrence during the rest of hospitalization, regardless of the mode of therapy and irrespective of whether the rejection was primary or recurrent. These changes were mainly mediated by a reduction in T helper cells rather than changes in the T suppressor-cytotoxic subset or total T cells. Titration of antirejection therapy based on these T-cell dynamics may reduce either overtreatment or undertreatment. A prospective randomized study seems warranted to evaluate this approach as an alternative to a predetermined antirejection protocol.

MYOCARDIAL FAILURE AND EXCITATION-CONTRACTION UNCOUPLING DURING THE COURSE OF CANINE ENDOTOXIN AND HEMORRHAGIC SHOCK

Failure of the myocardium and vascular smooth muscle to maintain and regulate intracellular calcium homeostasis (intracellular calcium overload) results in cell death and tissue necrosis. Conditions under which this phenomenon occurs in cardiac muscle have been documented in such diverse etiologies as catecholamine necrosis of the myocardium, prolonged periods of hypoxia, low flow states and after reperfusion of a previously ischemic vascular bed (1). Such conditions exist during the course of both hemorrhagic and endotoxin shock. The later stages of septic and endotoxin shock are associated with increasing peripheral vascular resistance and decreasing cardiac output (2). Experimental and clinical hemorrhagic shock are both associated with prolonged periods of low flow and then with subsequent transfusion, reperfusion of a previously ischemic vascular bed occurs (3). Thus in both of these shock syndromes, the potential for intracellular calcium overload exists.