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BACKGROUND: Treatment of in-stent restenosis presents a critical limitation of intracoronary stent implantation. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models and in initial clinical trials. We studied the effects of intracoronary gamma-radiation therapy versus placebo on the clinical and angiographic outcomes of patients with in-stent restenosis. METHODS AND RESULTS: One hundred thirty patients with in-stent restenosis underwent successful coronary intervention and were then blindly randomized to receive either intracoronary gamma-radiation with (192)Ir (15 Gy) or placebo. Four independent core laboratories blinded to the treatment protocol analyzed the angiographic and intravascular ultrasound end points of restenosis. Procedural success and in-hospital and 30-day complications were similar among the groups. At 6 months, patients assigned to radiation therapy required less target lesion revascularization and target vessel revascularization (9 [13.8%] and 17 [26.2%], respectively) compared with patients assigned to placebo (41 [63.1%, P=0.0001] and 44 [67.7%, P=0.0001], respectively). Binary angiographic restenosis was lower in the irradiated group (19% versus 58% for placebo, P=0.001). Freedom from major cardiac events was lower in the radiation group (29.2% versus 67.7% for placebo, P<0.001). CONCLUSIONS: Intracoronary gamma-radiation used as adjunct therapy for patients with in-stent restenosis significantly reduces both angiographic and clinical restenosis.

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Cardiovascular brachytherapy, the use of high intensity radiation to inhibit the growth of neointimal tissue after coronary revascularization by either balloon angioplasty or other methods is being tested in a number of clinical trials to assess the efficacy of the treatment. This new use of radiation to aleviate the suffering of individuals with coronary artery disease has excited many interventionalists and has caused others to view the new technique with skepticism. There are a number of operational and safety concerns to face in incorporating this treatment modality into the cardiac catheterization laboratory. Delivering the radiation dose to the patient with a minimum of radiation exposure to both patient and operating personnel requires close attention to the physical characteristics of the radiation source as well as the administrative and regulatory requirements imposed on the facility by federal and state regulators. The insertion of the source into the proper artery and location is the task of the cardiologist in collaboration with the radiation oncologist. The determination of the appropriate radiation dose is the responsibility of the medical physicist. The safe handling of the radioisotope source is the responsibility of the radiation safety specialist. State and federal regulations dictate minimum requirements of safety in the handling of radioactive sources used in cardiovascular brachytherapy. These requirements involve close monitoring of the patient and operating personnel to insure that radiation exposures are minimized. They involve the restricted access of nonessential personnel to the cath lab during the treatment. The entrances to the cath lab must be monitored to prevent unauthorized entry. Operating personnel must be closely monitored to maintain radiation exposures as low as reasonably achievable (ALARA). The patient must be monitored to insure that the source is implanted for the prescribed time and the patient's exposure is also ALARA consistent with the medical benefit expected. Public corridors must be monitored to prevent public exposures to the radiation emanating from the patient. The radiation exposure field around the patient during a typical gamma treatment presents what the regulators define as a high radiation area. This means that the exposure levels are in excess of 100 milli-rem (mrem) per hour at 30 cm from the patient. In fact, the exposure levels around the patient for a typical treatment are in the roentgens per hour range. The use of beta particle emitting radionuclides (Sr90/Y90 and P32) presents a much lower safety problem. But the use of radioactive materials in the cath lab still presents new safety concerns such as training, monitoring, record keeping, and public relations among the cath lab technologists.

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BACKGROUND: The efficacy of fibrinolytic therapy is limited by the small surface area of the clot that is available for the binding of the thrombolytic agent, such as tissue-type plasminogen activator (t-PA). We hypothesized that exposure of the clot to ultrasound during thrombolytic treatment could enhance lysis through perturbation of the thrombus, which would expose additional fibrin binding sites for t-PA. METHODS AND RESULTS: Whole human blood clots containing radiolabeled fibrinogen were incubated in vitro for 200 minutes with Tris-albumin buffer containing t-PA at concentrations ranging from 3 to 3,000 IU/ml. In paired experiments, one of the clots also was exposed to intermittent ultrasound (1 MHz, 1.75 W/cm2) throughout the experiment. The ultrasound was delivered as a 2-second exposure followed by a 2-second rest interval. The overall difference in mean clot lysis between thrombi receiving ultrasound and those receiving no ultrasound was significant (p less than 0.001) at all concentrations of t-PA. For clots incubated with t-PA at a concentration of 300 IU/ml, ultrasound increased the percent lysis at 200 minutes from 42 +/- 5% (mean +/- SEM) to 64 +/- 10%. In six paired experiments in a rabbit jugular vein thrombosis model, rabbits received 1 mg t-PA alone or t-PA and intermittent ultrasound (1 MHz, 1.75 W/cm2) for 200 minutes. For rabbits receiving ultrasound and t-PA, lysis was 55 +/- 11% at 100 minutes compared with 30 +/- 12% for rabbits receiving only t-PA. Lysis was 6 +/- 10% for rabbits (n = 4) receiving ultrasound alone. No evidence for tissue damage was noted in rabbits exposed to intermittent ultrasound. CONCLUSIONS: Exposure of whole blood clots in vitro to intermittent ultrasound combined with t-PA caused a significant enhancement of thrombolysis compared with t-PA alone. Intermittent ultrasound also showed a trend toward enhancement of t-PA-induced clot lysis in an animal thrombosis model. These data suggest that noninvasive intermittent ultrasound may be a useful adjunct to thrombolytic therapy.

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To study the effect of histamine (HA) on brain blood flow and capillary permeability, bilateral parietal craniectomies were made in cats anesthetized with nitrous oxide and ketamine. The dura was removed and solutions of HA in mock cerebrospinal fluid (CSF) in varying concentrations ranging from 10(-5) M to 10(-1) M were irrigated continuously onto the exposed brain while local cerebral blood flow was determined polarographically by hydrogen clearance. Capillary permeability was assessed by determining HA's effect on the 125I-albumin space of the brain. Electrical activity was monitored by electrocorticography. HA consistently dilated pial blood vessels and produced within 15 min a dose-related local hyperemia that subsided 30--60 min after HA was removed. Hyperemia was blocked by cimetidine. HA had no appreciable effect on either the blood-brain barrier to albumin or the electrical activity of the cortex. HA is pharmacologically capable of participating directly in the acute hyperemic response of the brain's microcirculation to physiologic and pathologic stimuli but has little effect on cerebrovascular permeability to protein.

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A previously existing model of cross-bridge kinetics is modified to make it applicable to cardiac muscle and incorporated into a macroscopic model of isolated heart muscle. Equations are formulated which describe the responses of this model during simulated isometric and isotonic contractions. These equations allow one to calculate the time variation of the activation parameter in the model when given the contraction time history, i.e. the time course of length and tension changes. The activation parameter is defined as the instantaneous rate constant for cross bridge attachment. We calculate the time course of the activation parameter with the model's responses set equal to the measured responses of isolated cat papillary muscle and the model parameters chosen appropriately for cat papillary muscle. It is found that in order for the model and muscle response to match, the degree of activation of the muscle model must first increase and then decrease with shortening. The behavior of the activation parameter in the muscle model is consistent with physiological investigations which suggest that shortening in cardiac muscle is associated with both activation and deactivation.

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An implantable beta-radiation detector suitable for the measurement of reginal blood flow in the experimental animal by the indicator clearance principle is described. A lithium-drifted silicon diode encapsulated in a stainless steel case is sutured over the site of interest. A suitable beta-emitting isotope, such as 85Kr in saline solution, is injected into the arterial supply and its calibrated against a mechanical system and showed excellent agreement up to 600 ml/100 g per min. At very high rates beyond the physiological range, flow was underestimated by a maximum of 10%. In vivo comparisons of myocardial blood flow assessed by the beta detector did not agree well with estimates of flow from a precordial counter or by the microsphere technique. Possible reasons are spatial heterogeneity of regional myocardial blood flow, the greatly different masses of tissue involved, or our inability to achieve sufficient numbers of spheres for accuracy in a 50-mg mass of tissue. The unit was still functional after 50 days in a chronic animal.

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1. The mechanical and electrophysiological effects of Sr were evaluated and compared to those of Ca in isolated, electrically driven toad ventricular muscle strips. The effects of Ca and Sr were compared at concentrations from control (2 mM) to 10 mM either by substitution of Sr for Ca at equimolar concentration, or by maintenance of a constant total Ca plus Sr concentration within which individual Ca and Sr concentrations were varied. 2. Changes in the degree of contractile activation were evaluated in terms of changes in maximal dT/dt of isometric contractions, maximal dL/dt of very lightly loaded isotonic contractions, and the shape of after-loaded force-velocity curves, with specific attention directed to the shape of the curves as they approached Vmax on the velocity axis. Effects on the cell membrane were evaluated in terms of changes in the transmembrane action potential (recorded with glass micro-electrodes) and in the mechanical parameters directly related to its duration in amphibian ventricle, viz. the duration of isometric tension and of isotonic shortening. Isometric tension and action potentials were recorded simultaneously. 3. Ca and Sr, at concentrations above control, had similar but not identical effects on dT/dt and dL/dt. Both ions alone in equimolar concentrations, or together at constant total Ca plus Sr concentration, increased dT/dt and dL/dt and shifted force-velocity curves upward. At constant total Ca plus Sr concentration, force-velocity curves were virtually superimposable as they approached the velocity intercept. 4. The duration of the action potential was markedly prolonged by Sr and shortened by Ca in concentrations above control. Unlike dT/dt and dL/dt, the total duration of isometric tension and isotonic shortening depended upon the specific Ca and Sr concentrations within a constant total concentration, and were progressively prolonged as the Sr concentration was increased. 5. The similar effects of Ca and Sr on dT/dt, dL/dt, and on the force-velocity relationship at light loads depended upon the presence of Ca ions. In Sr alone, dT/dt and dL/dt were faster than in an equimolar concentration of Ca, and time to maximal dT/dt and dL/dt was prolonged. The force-velocity curve in Sr alone was consistently shifted upward beyond the other curves in which Ca was present. These differences between the two ions are attributed in part to the rapid and early repolarization of the action potential in elevated Ca and the resultant abbreviation of the build up in active state and slower dT/dt and dL/dt. 6. The results suggest that Ca and Sr act in a similar although not identical way in activating contraction but are competitive at the cell membrane.

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Contractility during relaxation of isometric tension was studied in isolated, electrically driven cat papillary muscle by interpolation of test extrasystoles, all of whichpartially fused with their antecedent (control) contractions, were separated by computer from the fused contractions and then analyzed. The time course of the restitutionof contractility during relaxation was defined by plotting maximal positive dT/dt andtime-to-peak tension of the computer-separated extrasystole versus delay preceding the extrasystole. The dT/dt and time-to-peak tension, which steadily decline with progressive prematurity between contractions, both increase again during late relaxation, become progressively greater still earlier in relaxation, peak shortly after peak isometric tension, and then again decline. This phase of an apparently enhanced contractilityduring relaxation is depressed in low Ca'++ and is transmitted into the postextrasystolic period (in which it is superimposed on the usual postextrasystolic potentiation). The possible contributions of variations in series-elastic component and contractile-element lengths, actionpotential characteristics, and other factors on contractility during relaxation are discussed. It is suggested that enhanced contractility during relaxation may also be related in part to the decay of the intracellular free Ca'++ transient.

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