Advances in the use of therapeutic pheresis for the management of rheumatic diseases

Twenty-two patients with rheumatoid arthritis, 3 with seronegative juvenile rheumatoid arthritis, 4 with systemic lupus erythematosus, and 4 with psoriatic arthritis have undergone therapeutic pheresis at our institution over the last 3 yr. Lymphoplasmapheresis appears to be the most effective form of pheresis in treating rheumatoid arthritis. After achieving a remission with 20 treatments performed in 11 wk, a flare may be preventable by pheresing patients 3 times a week every 6 wk provided the patient is on a concomitant, long-acting agent. Therapeutic pheresis has been disappointing in seronegative juvenile rheumatoid arthritis. Life-threatening complications of systemic lupus erythematosus may respond dramatically to pheresis. In treating less severe disease on a long-term basis, pheresis has demonstrated excellent steroid sparing properties. Nonspondylytic psoriatic arthritis responds slowly to pheresis, but arthritic remissions may be prolonged, even though skin response is variable. Experience in the use of pheresis for treating these diseases has allowed for the development of criteria for deciding whether to institute such therapy as an adjunct to more standard modes of treatment for individual patients. Also, a variety of “technical” factors can influence the outcome of therapy, and these must be managed appropriately. Therapeutic pheresis is a promising tool for investigating and treating rheumatic diseases.     

Autoregulation by glucose of hepatic glucose balance: Permissive effect of insulin

To study the pathways involved and the effect of insulin on the autoregulation of hepatic glucose balance, isolated hepatocytes from normal, diabetic and treated diabetic rats were incubated with varying concentrations of glucose (100–400 mg/dl) with and without pyruvate (10 mM). Net glucose production or utilization was calculated from the change in media glucose concentrations before and after incubation, net glycogenolysis by the change in tissue glycogen levels before and after incubation, net glycolysis by following the incorporation of glucose-C¹⁴ into lactate C¹⁴ and gluconeogenesis by the difference in glucose production in the presence and absence of pyruvate. Hepatocytes from control and insulin-treated animals manifested autoregulation of glucose balance. Glucose modulated the glycogen and glycolytic pathways but did not affect gluconeogenesis. In hepatocytes from diabetic rats, there was no autoregulation, tissue glycogen was unmeasurable both before and after incubation, glycolysis was markedly curtailed and gluconeogenesis was increased. It may be concluded that (1) glucose autoregulates its own production or utilization by modulating the glycogen and glycolytic pathways, (2) autoregulation is lost in severe diabetes leading to fasting hyperglycemia, and (3) insulin has a permissive effect on the autoregulation of glucose balance by maintaining the rate-limiting enzymes, glycogen synthase and glucokinase, so that glucose can exert its effect on these pathways.     

Effect of growth hormone administration to hypophysectomized rats on muscle lipid metabolism.

This study was undertaken to determine whether increased oxidation of intracellular muscle lipids could explain the impaired carbohydrate metabolism of that tissue following growth hormone (GH) administration. Pieces of diaphragm from either hypophysectomized (hypox) rats injected for 10 days with saline or 1 mg bovine GH or animals of similar weight with intact pituitary glands were studied. In hypox rats, GH administration increased both weight gain and plasma glucose concentrations at sacrifice and impaired glucose uptake by diaphragms in vitro. Tissue triglyceride (TG) content was markedly decreased in hypox muscle compared to diaphragms removed from animals with intact pituitary glands. GH administration lowered TG levels even further. Initial phospholipid (PL) content was similar in all groups and fell significantly during the second hour of incubation only in hypox muscle. GH administration had no effect on PL changes. The differences in TG- and PL-specific activities strongly suggested that most of the C¹⁴O₂ produced in the second hour of incubation was derived from TG. Approximately 25% of diaphragm TG was oxidized to CO₂ in all three groups of animals. Changes in lipid-specific activities during the second hour indicated that in tissue from hypox animals, TG-fatty acids were converted to PL-fatty acids, whereas no such exchange occurred in muscle from intact rats. In conclusion: (1) enhanced oxidation of intracellular muscle lipids does not explain the effect of GH on carbohydrate metabolism; (2) diaphragm TG content is markedly decreased in hypox animals and is not secondary to GH deficiency; (3) diaphragms incubated in vitro will utilize PL for energy only if TG levels are low; and (4) as PI content falls, some TG-fatty acids are shifted into PL, possibly in an attempt to maintain the important “structural-functional elements” of muscle.     

Peripheral hemodynamics in anephric patients with hypertension

Peripheral hemodynamics were examined in a group of four anephric patients with hypertension and the results were compared with a group of 10 normal subjects. Measurements of systemic hemodynamics in these anephric patients showed increased arterial blood pressure and a modest increase in cardiac index. Renin blood levels were negligible. Mean forearm blood flow was significantly higher in the anephric patients. This was probably a reflection of the increased arterial blood pressure since mean forearm vascular resistance was within normal limits. Mean forearm venous capacitance was also within normal limits.Oscillometric examination showed markedly increased pulsation amplitudes proximally in the limbs of anephric patients, while at the wrist, elbow, fingers, and toes pulsation amplitudes were either normal or diminished.Skin blood flow, as reflected in both fingers and toes, was significantly diminished in anephric patients while skin temperature was normal. While this may indicate normal capillary blood flow in anephric hypertension, constriction at the precapillary network level, as seen by the increased resistance occurring in the skin, is present. Changes in the 1 and 10 minute reactive hyperemia and 30 pound/30 second active hyperemia reactions showed that in anephric patients a greater time period of increased levels of flow was obtained in all three reactions.These data suggest that the difference seen between anephric and normal subjects in their peripheral vasculature in part result from the hypertension, severe anemia, and other factors which may be present.     

Post-extrasystolic potentiation of ischemic myocardium by atrial stimulation

The response of acutely ischemic myocardium to post-extrasystolic potentiation (PESP) was evaluated in 11 mongrel dogs. Mercury-in-silastic length gauges were sutured to the epicardial surface of the left ventricle; left ventricular pressure was determined via an apical large-bore catheter-transducer system and controlled by volume manipulation. The anterior descending coronary artery was then ligated, and single premature atrial contractions were introduced via an external stimulator. Thirty minutes after occlusion, shortening during ejection had decreased an average of 81 +/- 8 per cent, from 1.30 +/- 0.29 to 0.32 +/- 0.05 mm. PESP initially induced a marked restoration toward normal segmental contraction as systolic shortening increased significantly to 1.14 +/- 0.23 mm. Additionally, paradoxic systolic expansion, when present, reverted to a normal pattern of contraction during PESP. Responsiveness to PESP deteriorated progressively with time over 3 hours following occlusion until the muscle became essentially totally unresponsive to this stimulus. It is concluded that a single premature atrial beat may be used to induce PESP and provides an effective stimulus for contractile reserve of acutely dysfunctional ischemic myocardium. Loss of responsiveness to PESP may represent the progression to nonviability following acute ischemia.     

The electrophysiologic effects of intravenous propranolol in the Wolff-Parkinson-White syndrome.

Fourteen patients with the Wolff-Parkinson-White (WPW) syndrome were studied by means of intracardiac stimulation techniques, before and after the intravenous administration of propranolol, 0.1 mg./Kg. There were no significant change, or only a slight increase, in the effective refractory periods of all parts of the re-entry tachycardia circuit studied, in either anterograde or retrograde directions. Re-entry tachycardia was initiated in nine patients in the control state, and in 10 patients after propranolol. The rate of re-entry atrioventricular node-accessory pathway tachycardia was decreased, but by only 10 per cent. The duration and outer limit of the tachycardia zone of atrial extrastimuli were not significantly decreased. Propranolol, by rapid intravenous infusion administration, is unlikely to be effective primary therapy for PSVT in the WPW syndrome.     

Atrioventricular node reentry: Intravenous verapamil as a method of defining multiple electrophysiologic types

Fourteen patients with recurrent supraventricular tachycardia (SVT) underwent electrophysiological evaluation. Each patient was shown to have reentry confined to the region of the atrioventricular (AV) node. Verapamil, 0.075 to 0.15 mg/kg was administered intravenously to each patient during a stable episode of SVT, resulting in termination in each instance. There was more than one mechanism for termination of SVT. Nine patients showed termination by anterograde AV node block preceded by an increase in conduction time in the anterograde limb of the tachycardia circuit (Ae-H intervals) with no change in the conduction time in the retrograde limb (H-Ae intervals). Three patients showed termination by block in the retrograde limb of the circuit preceded by increases in both Ae-H and H-Ae intervals. An additional example of termination by spontaneous ventricular premature complexes and usurpation by sinus rhythm were also seen. Common features were that verapamil had significant effects on anterograde and retrograde conduction and refractoriness in the AV node. It prolonged the refractory periods of both fast and slow pathways in patients with dual anterograde AV node pathways, and observable effects on retrograde conduction and refractoriness were seen even in patients with constant ventriculoatrial conduction times during incremental ventricular pacing in a control study. However, three distinct groups of patients were identified on the basis of their response to ventricular pacing in a control study and upon verapamil effects recorded during their SVT. An explanation for these latter findings may be that there is a normal variation in the retrograde response of parts of the AV node to ventricular pacing, and a variability in some of the patients' responses to verapamil.     

Intracoronary thrombolysis in acute myocardial infarction: Experimental background and clinical experience

Occlusive intracoronary (IC) thrombosis was produced experimentally in dogs by placement of a copper coil. The thrombus was consistently lysed by application of Thrombolysin (streptokinase and plasminogen) at the site of occlusion, 1 to 6 hours after thrombosis. Thrombolysin has no toxic effect on the coronary artery wall or the myocardium. Reperfusion after 30 to 60 minutes of occlusion frequently resulted in ventricular fibrillation, but gradual reperfusion reduced the probability of ventricular fibrillation. Intramyocardial bleeding was noted after reperfusion in areas of advanced necrosis and was shown to be the consequence, rather than the cause, of necrosis. The reperfused myocardium remained hypocontractile, but in contrast to the occlusion period, its mechanical function could be enhanced by inotropic stimulation. After experimental studies confirmed the feasibility and safety of IC thrombolysis, the technique was applied within 3 hours of onset of pain in 29 patients with evolving acute myocardial infarction (AMI) and showing ST elevations without pathologic Q waves. Nitroglycerin (NTG), 0.1 mg, was injected into the occluded coronary artery to rule out spasm; NTG failed to open the occluded artery. A special, very flexible, radiopaque No. 2 French catheter was advanced through the angiography catheter to the site of occlusion. Thrombolysin was infused at a rate of 4000 to 6000 IU/min until patency was achieved, followed by 2000 IU/min for 60 minutes. Lysis of clot was achieved in 27 of 29 patients. The single death (unrelated to the procedure) occurred subsequently in a patient in whom the artery was not reopened. After successful thrombolysis, 12 patients underwent elective coronary bypass surgery because of multiple stenoses. The need for early reperfusion is emphasized for effective IC thrombolysis therapy in evolving AMI.     

Thallium-201 stress redistribution abnormalities of the right ventricle: A manifestation of proximal right coronary artery stenosis

Thallium imaging in conjunction with electrocardiographic stress testing has become a widely utllized method for evaluating the presence and location of coronary artery disease. The literature has emphasized the appearance of the left ventricle with little mention of the right ventricle. This report presents the initial demonstration of abnormal right ventricular myocardial radionuclide visualization due to right coronary artery stenosis, as exemplified in two patients. In both patients a perfusion defect was documented in the free wall of the right ventricle with early redistribution imaging showing reversibility of these defects. Both patients were found to have proximal stenosis of the right coronary artery at cardiac catheterization. Thereby, the appearance of the free right ventricular wall on thallium imaging may provide useful additional information regarding presence and location of right coronary artery stenosis.     

The electrophysiologic effects of intravenous lidocaine in the Wolff-Parkinson-White syndrome

Twelve patients with the Wolff-Parkinson-White syndrome underwent electrophysiologic study, before and after the bolus intravenous administration of lidocaine, 1 mg./kg. There was no significant increase in the effective refractory period of the anterograde AV node pathway, the anterograde or retrograde accessory pathway, or the atrial or ventricular muscle; intravenous bolus administration of lidocaine is unlikely to terminate the re-entry tachycardias, or decrease the rate of the ventricular response in atrial fibrillation, in the WPW syndrome. There was no significant increase in the anterograde or retrograde AV conduction times; bolus administration of lidocaine is unlikely to decrease the rates of the re-entry tachycardias. In addition, lidocaine failed to alter significantly features related to tachycardia initiation. Except in isolated, unpredictable cases, intravenous bolus administration of lidocaine is not likely to be of benefit in the supreventricular tachyarrhythmias of the WPW syndrome.     

Electrophysiologic studies in survivors of late cardiac arrest after myocardial infarction

Nine patients resuscitated from life-threatening ventricular arrhythmias (VA) within 3 months of an acute myocardial infarction (AMI) underwent electrophysiologic studies (EPS) with clinical follow-up for at least 12 months. Neither reinfarction, drug therapy, nor electrolyte imbalance was a precipitating factor. VA was induced by ventricular pacing in six of nine patients. Five patients were prescribed empiric drug therapy, while the four other patients had repeated EPS to select optimal drug therapy. One patient remained unstable and died of VA in the hospital. No patient was discharged and successfully maintained on a drug known to prevent induction of VA, yet only two patients (25%) had a further recurrence of VA, one fatal. Our findings suggested that either drug therapy that is determined empirically or found not to suppress the induction of VA during EPS can be associated with a successful outcome in some of these patients, or the natural history of VA after myocardial infarction is that they are self-limiting in the absence of a new ischemic event.     

Effects of intravenous verapamil on hemodynamics in patients with heart disease.

The hemodynamic effects of intravenous verapamil (10 mg.) were evaluated in 13 patients with coronary artery disease and in seven patients with rheumatic valvular disease during cardiac catheterization. The peak effects were apparent at 3 to 5 minutes after injection and lasted about 10 minutes. The mean arterial pressure fell from 97.8 +/- 3.4 to 85.9 +/- 2.7 mm. Hg (-12%; p less than 0.01) accompanied by a significant decrease (-21%, p less than 0.001) in systemic vascular resistance (from 1435 +/- 80 to 1131 +/- 82 dynes-sex.-cm.-5) with an increase in left ventricular end-diastolic pressure (from 11.0 +/- 0.9 to 15.0 +/- 1.0 mm. Hg; +36%, p less than 0.01) and a reduction in LV dp/dt max (from 1343 +/- 152 to 1007 +/- 102 mm. Hg/sex.; -25%, p less than 0.05). The changes in heart rate (from 75.7 +/- 3.0 to 80.2 +/- 2.8 beats/min.), cardiac index (from 3.17 +/- 0.15 to 3.61 +/- 0.17 L./min./M.2), left ventricular minute work (from 3.63 +/- 0.28 to 3.31 +/- 0.23 Kg.-m./min./M.2) and mean pulmonary artery pressures (from 15.7 +/- 1.0 to 18.1 +/- 0.8 mm. Hg) were not statistically significant. The intrinsic negative inotropic action of verapamil is, therefore, minimized by its effect on afterload so that cardiac index is not reduced by the drug in patients with cardiac disease.     

Detection of occult pericardial hemorrhage early after open-heart surgery using technetium-99m red blood cell radionuclide ventriculography

Pericardial or mediastinal hemorrhage requiring reoperation occurs in 2% to 5% of patients, usually early (0 to 48 hours), after open-heart surgery. This hemorrhage may be occult, and resulting cardiac tamponade may easily be misinterpreted as ventricular dysfunction, common early postoperatively. In such cases, appropriate and timely intervention may not occur. Of 50 patients evaluated by technetium-99m red blood cell gated equilibrium radionuclide ventriculography (RNV) because of early postoperative cardiogenic shock of uncertain etiology, 17 had unique scintigraphic images suggestive of intrathoracic hemorrhage. Of these 17, 5 had a generalized “halo” of abnormal radioactivity surrounding small hyperdynamic right and left ventricles, 11 had localized regions of intense blood pool activity outside the cardiac chambers (two with compression of single chambers), and one demonstrated marked radionuclide activity in the right hemithorax (2000 ml of blood at reoperation). Twelve patients had exploratory reoperation for control of hemorrhage as a direct result of the scintigraphic findings, three were successfully treated with fresh frozen plasma and platelet infusions along with medical interventions to optimize cardiac performance, and two patients died in cardiogenic shock (presumed tamponade) without reoperation. In the 12 reoperated patients, all were confirmed to have active pericardial bleeding. Scintigraphic localization of abnormal blood pools within the pericardium corresponded to the sites at which active bleeding was witnessed at reoperation. The abnormal bleeding was etiologically related to the tamponade state, with marked improvement in hemodynamics after reoperation. Nine additional patients were reoperated for presumed tamponade after RNV revealed an exaggerated halo of photon deficiency surrounding the cardiac chambers. None of these patients were observed to have an active bleeding site at reoperation. Thus, abnormal accumulations of radioactivity surrounding the cardiac chambers should be regarded as specific for the presence of active pericardial or mediastinal bleeding. Repeat imaging 30 minutes to 3 hours after initial imaging, multiple imaging positions, and acquiring RNV in non-zoomed as well as zoomed mode were helpful additions to standard imaging protocols for evaluating early postoperative patients for the presence of significant hemorrhage. From this study, we conclude that the utility of technetium-99m red blood cell RNV in evaluating the etiology of early postoperative cardiogenic shock is enhanced by its ability to detect significant but occult pericardial or mediastinal hemorrhage.     

Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique

Gross histochemical delineation of myocardium which has lost dehydrogenase enzyme activity has been shown to facilitate macroscopic recognition of necrotic myocardium. The present study was undertaken to assess the accuracy of the triphenyl tetrazolium chloride (TTC) technique for quantitating myocardial infarct size very early after coronary occlusion. In 16 closed-chest dogs the left anterior descending coronary artery was occluded with an intra-arterial balloon. Twelve dogs were killed 6 hours after occlusion, their hearts excised, cut from apex to base into 1 cm thick slices, and incubated in TTC. Whole-mount histologic sections of each slice were prepared. Myocardial infarct size was measured by planimetry of photographs of each gross slice and histologic section using classical criteria of necrosis. Myocardial infarct size determined in 54 slices by the TTC technique and histologically was similar (25 +/- 16% vs 27 +/- 16% of the left ventricular mass, mean +/- SD) with close correlation between the two methods (r = 0.91). Four dogs were killed 3 hours after occlusion and TTC stained and unstained myocardium was studied by electron microscopy. When the TTC technique identified necrosis so did electron microscopy. Areas identified by the TTC technique as non-necrotic were either normal or only ischemic by electron microscopy. Thus, using TTC, necrosis can be quantitated reliably 6, and even 3 hours after coronary occlusion, before histologic changes are clearly diagnostic. This technique represents a reliable, practical means for quantitation of recent infarction and for studying the evolution of ischemic injury in its early phase.     

Real time computerization of two-dimensional echocardiography

A computerized system was developed for real time acquisition, enhanced processing, analysis, and display of cross-sectional images of the left ventricle derived by two-dimensional echocardiography (2DE). The new methodology couples a standard medical imaging computer system to the video output of any current 2DE unit, uses a 128 × 128 or 64 × 64 matrix window and stores the real time 30 frames/sec digitized images on a magnetic disk. Computerized beat-to-beat and frame-by-frame processing employs space-time smoothing and automatic detection of endocardial interfaces by standard threshold and second derivative techniques. Multiple views are displayed in real time with 256 levels of gray and color. The methodology was used to analyze and graphically display frame-by-frame changes throughout the cardiac cycle. In addition, regional wall motlon and thickness were analyzed in 12 sectors of individual cross-sections using a standardized angular subdivision originating at the center of area and indexed by an external reference point. An algorithm was developed to correct cross-sectional interface definition from the commonly used trailing-to-leading edge to the more valid leading-to-leading outline technique. Computerized analysis of spatial and temporal variations of cardiac contraction were demonstrated in several clinical and experimental applications, including bicycle exercise testing, investigation of acute myocardial infarction, and assessment of interventions. Initial evaluation indicates that the new real time computerized digital acquisition and data analysis represents a major advance toward quantitation of left ventricular function using 2DE.     

Verapamil effects in AV node reentry tachycardia with intermittent supra-Hisian AV block

The electrophysiologic details of two patients with atrioventricular (AV) node reentry tachycardia with intermittent 2:1 supra-Hisian block are presented. Both patients had clear evidence for atrial arrhythmias as well, emphasizing the need for a careful diagnostic analysis. Evidence supporting a diagnosis of AV node reentry tachycardia included: (1) short ventriculoatrial (VA) coupling intervals, (2) normal retrograde sequence of atrial activation, (3) dependence on critical AV node conduction times for initiation of tachycardia by atrial pacing, (4) ability to pace and capture the atria or ventricles without interrupting the tachycardia, and (5) fixed VA coupling intervals despite changes in tachycardia cycle length. Ten milligrams of verapamil was administered during sustained supraventricular tachycardia with 1:1 AV conduction, but despite prompt termination of tachycardia in both cases, 2:1 AV block was not induced. Atrial echoes could still be induced after verapamil, and diagnostic features (3) and (5) were particularly evident after the drug. Further analysis confirmed that verapamil did not have any observable effects on the likely site for supra-Hisian block—that is, the “final common pathway” of the AV node. This would support a contention that verapamil may have a selective effect on tissues within the confines of the AV node.