Uptake of hematoporphyrin derivative by atheromatous plaques: studies in human in vitro and rabbit in vivo.

Hematoporphyrin derivative, a photosensitive material used to identify and treat neoplastic tissue in humans, has been found to localize in atheromatous plaques in animals and has recently been found in postmortem human atherosclerotic plaques. It is not known whether human plaques take up hematoporphyrin derivative in vivo. In five patients undergoing surgical vascular procedures, specimens containing atheromatous plaques were removed and immediately incubated in autologous oxygenated blood at 37 degrees C with hematoporphyrin derivative at a clinically relevant concentration for 2 hours. On exposure to ultraviolet light, porphyrin fluorescence was noted throughout each plaque, whereas adjacent plaque-free tissue showed no fluorescence. To compare in vitro with in vivo hematoporphyrin derivative uptake by plaques, the fluorescence of three types of arterial lesions (induced by a high cholesterol diet, catheters or balloon injury) was studied in 16 New Zealand White rabbits. Each lesion fluoresced selectively with the same intensity whether hematoporphyrin derivative exposure was performed in vitro or in vivo. Fluorescence microscopy did not show a difference in the pattern of hematoporphyrin derivative fluorescence between in vitro and in vivo specimens. The results suggest that human atheromatous plaques should take up hematoporphyrin derivative in vivo and are, therefore, potentially suitable for photochemical treatment as a new therapeutic approach to atherosclerosis.

An experimental model of acute and subacute viral myocarditis in the pig.

Twenty-six young pigs were infected with encephalomyocarditis virus, observed clinically, studied at intervals by noninvasive and invasive methods to assess cardiac function and eventually examined pathologically. All infected animals appeared ill, usually manifesting diminished appetite, lethargy and fever. Spontaneous mortality occurred either 1 to 4 or 20 to 21 days after infection. Electrocardiographic abnormalities, seen in the majority of animals, comprised ST-T wave changes, conduction disturbances or ventricular ectopic rhythm. The majority of animals manifested echocardiographic evidence of left ventricular dilation and decreased systolic function, which improved with time in some animals. Hemodynamic studies revealed elevation of biventricular filling pressures in 3 of 10 animals; as a group, infected animals manifested significantly elevated right ventricular filling pressures. In selected animals, the feasibility of gallium scans as well as left ventriculography and coronary angiography was demonstrated. At autopsy, heart weight/body weight ratio was significantly elevated in infected animals. The heart of all but two animals showed active myocarditis associated with fibrosis and focal calcification in the later stages. In general, the cardiovascular manifestations were parallel with those seen in acute and subacute myocarditis in humans. It is concluded that encephalomyocarditis infection in the pig is a large animal model of viral myocarditis suitable for assessing alterations in the structure and function of the cardiovascular system and the effects of interventions.

Vascular resistance changes distal to progressive arterial stenosis: a critical re-evaluation of the concept of vasodilator reserve.

Previous studies have shown that with progressive arterial stenosis, resting blood flow does not start to diminish until 85-95% luminal area stenosis is reached. However, during hyperemic states, peak flow starts to diminish at only 40-60% stenosis. An autoregulatory mechanism has been postulated, whereby peripheral arterioles undergo compensatory vasodilatation, thereby maintaining resting flow. During hyperemia, some vasodilator reserve is presumably already used up, resulting in flow dropoff at an earlier stage. We measured flow and pressure and calculated peripheral vascular resistance (Rp) distal to progressive iliac artery stenoses in five dogs. Contrast injections proximal to the stenoses allowed precise angiographic quantitation of the lesions and provided reproducible hyperemic stimuli. Flow-stenosis relationships proved similar to those discussed above, but Rp distal to the lesions failed to show progressive decrease as stenosis increased. Thus, compensatory peripheral vasodilatation does not occur during most phases of progressive arterial stenosis. The contours of resting and hyperemic flow-stenosis curves are not related to the concept of vasodilator reserve but instead are readily explained by basic hydrodynamic principles.

Comparative effects of three radiographic contrast agents in isolated normal and ischemic canine hearts.

Investigators have sought to improve contrast agents by changing the ionic content or decreasing osmolarity. This study compared the effects of meglumine sodium diatrizoate, sodium meglumine calcium metrizoate, and metrizamide on coronary blood flow, myocardial contractile force, and perfusion pressure under normal and ischemic conditions in eight isolated canine hearts. Diatrizoate had an initial negative inotropic effect, but contractile force returned to baseline within 1 minute during normal perfusion and within 2 minutes under ischemic conditions. Calcium-enriched metrizoate and metrizamide had only a positive inotropic effect under normal perfusion (127 +/- 3.9% and 116 +/- 2.9% of baseline, respectively). During ischemia, however, the positive inotropic effect of sodium meglumine calcium metrizoate was followed by a decrease in contractile force to 93 +/- 5% of baseline after 2 minutes. Metrizamide showed only a positive inotropic effect during ischemia. The myocardial depression that follows the initial positive inotropic effect of calcium may further alter the instability between normal and ischemic areas of the heart, thus increasing the risk of coronary arteriography in patients with severe coronary artery disease.

Fabrication of microballoons for interventional neuroradiology: preliminary report.

A simple and inexpensive method of making latex microballoons for neuroradiologic procedures is described. The balloons have been tested in experimental animals and used in human clinical procedures. Preliminary experience and results are presented.

Impermeability of the blood-brain barrier to intravenous high-iodine-dose meglumine diatrizoate in the normal dog.

The effect of an intravenous bolus of 4.3 ml/kg of 60% meglumine diatrizoate on the blood-brain barrier (BBB) was studied in five adult unanesthetized dogs. Intravenous 3% Evans blue dye (4 ml/kg) was used as an indicator of BBB disruption. The animals were observed for signs of neurotoxicity for 1 hr after contrast-medium injection and then sacrificed. Their brains were removed and sectioned. None of the dogs displayed clinical evidence of neurotoxicity, and none of the brain specimens showed evidence of BBB disruption. The authors concluded that there is a statistically significant lack of correlation between the intravenous administration of 4.3 ml/kg of 60% meglumine diatrizoate and BBB disruption (p less than 0.05 with a probability of 90%). A previous publication reported focal BBB disruption in anesthetized dogs with dosages of 4 ml/kg and 6 ml/kg of 60% intravenous contrast agent given as an initial bolus followed by a drip infusion. The present study duplicated this prior experiment using the 6 ml/kg dose followed by infusion in three additional unanesthetized dogs and failed to substantiate the previous findings. This discrepancy leads to the assumption that the BBB damage noted in the previous experiment was somehow related to a factor(s) other than the intravenous contrast-medium injection. The BBB cannot be disrupted in the unanesthetized dog with intravenous doses of 60% contrast media of even 6 ml/kg.

Optical isomers of verapamil on canine heart. Prevention of ventricular fibrillation induced by coronary artery occlusion, impaired atrioventricular conductance and negative inotropic and chronotropic effects.

Effects of optical isomers of verapamil on the canine heart were measured with a pressure catheter in the left ventricle and with the electrocardiogram. 1. Both isomers of verapamil caused impaired atrioventricular conduction. slowed the rate of the sinus pacemaker and depressed the contractile state of the myocardium. (-)-Verapamil was consistently more potent than (+)-verapamil in producing these effects. (-)/(+) potency ratios of 10 and 3 were estimated for atrioventricular blockade and for the negative chronotropic effect, respectively. 2. Negative inotropic effects of 0.06-2.0 mg/kg of (+)-verapamil were determined on hearts paced at constant rate. A similar dose-response relationship could not be established with (-)-verapamil because at concentration higher than 0.06 mg/kg the hearts did not follow the supraventricular driving stimulus. With doses of (-)- and (+)-verapamil which produced the same slowing of the sinus pacemaker rate in spontaneously beating hearts, (-)-verapamil caused greater negative inotropic effects than (+)-verapamil. 3. The following doses of isomers of verapamil reduced the incidence of ventricular fibrillation induced by coronary artery ligation: 0.2 mg/kg (-)-verapamil (P less than 0.001), 0.6 mg/kg (-)-verapamil (P less than 0.001) and 0.6 mg (+)-verapamil (P less than 0.01). 4. Intravenous administration of CaCl2 to dogs treated with either isomer of verapamil restored the contractile state and reversed atrioventricular blockade to sinus rhythm. Dog ventricles under the influence of concentrations of isomers of verapamil which, with normal plasmatic Ca2+-content, prevent fibrillation, consistently fibrillated after coronary artery occlusion when high doses of CaCl2 were administered. 5. The effects of the optical isomers of verapamil may occur predominantly via a blockade of the slow inward Ca2+-current.

Experimental myocardial ischemia II: radiographic contrast media toxicity.

The comparative effects of meglumine sodium diatrizoate (MSD), sodium meglumine calcium metrizoate (SMCM), and metrizamide (M) were studied in an isolated canine heart preparation. The parameters observed were coronary blood flow (CBF), myocardial contractile force (MCF), positive and negative dF/dt, and perfusion pressure during normal and ischemic perfusion conditions. MSD had an initial negative inotropic effect but baseline MCF returned in 1 min during normal perfusion and 2 min under ischemic conditions. SMCM and M had only a positive inotropic effect under normal perfusion. However, during ischemia, the positive effect of SMCM was followed by a decrease in contractile force. M showed only a positive effect on force during ischemia. Our results indicate that calcium additive may increase the risk of coronary arteriography in patients with severe coronary artery disease.

Differential effects of sodium meglumine calcium metrizoate on the inotropic state of normal and ischemic myocardium.

Sodium meglumine calcium metrizoate was injected into isolated blood-perfused canine hearts to evaluate the effect of contrast agents containing calcium on normal and ischemic myocardium. Under normal perfusion pressure and mild ischemia, this contrast agent produced a positive inotropic effect, but during profound ischemia, this positive effect was followed by a period of myocardial depression. These findings indicate that the addition of an inotropic agent to contrast medium can produce a paradoxical depressant effect which can be deleterious to the ischemic myocardium.

The effects of left ventricular load and contractility on mitral regurgitant orifice size and flow in the dog.

Acute mitral regurgitation (MR) was produced in 12 dogs by closed chest partial valvulectomy and the relative contributions of MR pressure gradient (MRG), the time for regurgitant flow (VSI), and the MR orifice area (MRA) to mitral regurgitant volume (MRV) assessed. Aortic and left atrial pressures, biplane left ventricular (LV) angiography, forward flow and mitral regurgitant flow (MRF) were measured following MR induction and following augmentation of left ventricular end-diastolic volume (EDV), increased aortic resistance (angiotensin), and in the presence of increased ventricular contractility (calcium or epinephrine). Mitral regurgitation orifice area was determined by calculation and the diameters of the mitral anulus and subvalvular areas measured angiographically. Angiotensin and volume infusion induced a substantial increase in MRF which was largely dependent on an increase in MRA but not MRG, while augmentation of contractility decreased MRF accompanied by a decrease in MRA, relatively independent of MRG. Left ventricular size and shape are major determinants of MRA and resultant MRF in acute mitral regurgitation. These findings may help to explain the effects of such factors as ventricular loading and volume on the clinical course of mitral regurgitation in man.

Experimental myocardial ischemia: dynamic alterations in ventricular contractility and relaxation with dissociation of speed and force in the isovolumic dog heart.

Although the time course of changes in myocardial function during ischemia has been demonstrated for the papillary muscle, this time course in the intact heart is less well understood. Accordingly, in 24 isolated, isovolumic, perfused dog hearts, coronary perfusion pressure (PP) was lowered to various fixed levels. Left ventricular developed pressure (LVP) rapidly fell and reached 63 +/- 3% of control at 1 minute of ischemia 50 +/- 5% at 6 minutes; this was due primarily to an abbreviation of time to peak tension (TPP). dP/dt was 70 +/- 3% of control at 1 minute and 56 +/- 5% at 6 minutes. The rate of relaxation as reflected by negative dP/dt declined as well to 49 +/- 4% of control at 1 minute of ischemia and to 41 +/- 4% control at 6 minutes. These changes were directly correlated with the decrease in PP. When PP was restored to normal, an overshoot of LVP and dP/dt was noted, peaking at 1 minute, returning to control by 5 minutes, and then gradually declining to 90 +/- 2% of control following 25 minutes of recovery. Depression of the rate of relaxation was reduced, but persisted throughout recovery. Diminution of force development early in ishcemia is due primarily to decreased duration of contraction accompanied by a decrease in relaxation rate. Later, the rate of force development also falls, but some preservation of force development may result from the return toward normal of the duration of contraction.

Experimental myocardial ischemia. IV. Shape and volume changes during "isolvolumetric relaxation" in normal and ischemic ventricles.

Shape and volume changes were studied in mongrel dogs between end-systole and mitral valve opening (MVO). Biplane left ventricular cineangiograms were performed at 200 frames/sec. The dogs were studied during the control state and during regional myocardial ischemia produced by balloon occlusion of the left anterior descending coronary artery. Outward wall motion, called pre-inflow relaxation (PIR), occurred in all 10 dogs in the control state, most frequently in the apical (seven of 10) and equatorial planes (seven of 10). PIR was seen less frequently during ischemia (13 of 40 measurements vs 19 of 40 measurements during control state), usually in the basal plane (five of 10). The ventricular volume between end-systole and MVO increased in all 10 dogs during the control state (mean increment 4.4 +/- 0.7 ml). Volume increased in eight of 10 dogs during ischemia (mean increment 3.0 +/+ 1.1 ml). The characteristic patterns of wall motion occurring between end-systole and MVO are altered by regional myocardial ischemia. During ischemia PIR occurs in segments of the myocardium with normal perfusion, but usually not in ischemic segments. Biplane ventricular volume between end-systole and MVO increased in 18 of 20 measurements (mean increment 3.6 +/- 0.9 ml).

Computerized image analysis for quantitative measurement of vessel diameter from cineangiograms.

Subjective estimates of the angiographic severity of coronary artery stenoses show variability and inaccuracy. We therefore tested the accuracy of a newly developed computerized image analysis system for quantitating vessel diameter from cineangiograms. Fourteen cylindrical phantoms of known diameter were filled with contrast medium and filmed over a wide range of clinically relevant radiographic conditions in order to develop regression equations that related computer-derived to anatomic diameters. Computer measurements of vessel diameter were unaffected by vessel size, magnification, focal spot size, thickness of scattering medium, kilovolt peak, or location within the radiographic field, but a correction factor was necessary for a small but significant (p less than .01) linear dependence on contrast medium concentration. The accuracy of computerized vessel diameter measurements ranged between +/- 59 and +/- 137 mu for all conditions except for rapid vessel motion and contrast medium concentrations of 50% or less meglumine diatrizoate (Renografin 76), both of which resulted in reduced accuracy as well as in the inability to locate lumen edges of vessels less than 1 mm in diameter.