Robert S. Kernoff

Cardiac damage produced by direct current countershock applied to the heart.

This study examined the pathophysiology of the myocaridal damage produced by direct current shock over a dose range of 10 to 90 watt-seconds, applied directly to the heart in 26 dosgs. The extent of injury produced was assessed with creatine kinase depletion and light and electron microscopy, and was correlated with in vivo imaging and tissue distributions of the isotopes technetium-99m pyrophosphate and thallium-201. Changes in intramyocardial temperature and regional myocardial blood flow were also measured. Uptake of technetium-99m pyrophosphate occurred exponentially with graded increases in shocks, and this agent was more sensitive than thallium-201 in detecting injury both on imaging and at tissue level. The threshold for significant injury was approximately 30 watt-seconds, and on electron microscopy a characteristic feature was marked dehiscence of the intercalated disks between the damaged myocytes. The use of different-size paddles did not appear to affect the total number of cells damaged. However, with large paddles the injury was more superficial and spread over a wider area. With short time intervals between successive shocks, a greater amount of injury occurred, in part because of a compounding of the thermal component of the damage. Hypothermia can reduce the degree of injury.

Local Intramural Delivery of l-Arginine Enhances Nitric Oxide Generation and Inhibits Lesion Formation After Balloon Angioplasty

BACKGROUND Long-term oral administration of L-arginine has been shown to enhance production of nitric oxide (NO) and to reduce lesion formation. The goal of this study was to determine whether local intramural administration of L-arginine could enhance NO generation and reduce intimal thickening. METHODS AND RESULTS New Zealand White rabbits (n = 27) received a 1% cholesterol diet. For the short-term study, after 1 week of diet, both iliac arteries were balloon injured. Four weeks later, vasoreactivity was assessed angiographically during infusion of acetylcholine (Ach) before and after delivery of L-arginine or saline into the right or left iliac artery (800 mg/5 mL; 0.2 mL/min, 15 minutes) by use of a local drug-delivery balloon. Vessels were then harvested for measurements of NO. For the long-term study, after balloon injury, drugs were delivered as above into the iliac arteries. Two and 4 weeks after L-arginine delivery, vasoreactivity was determined. Subsequently, the iliac arteries were harvested for histomorphometric analysis and measurements of NO. In the short-term study, local delivery of L-arginine restored endothelium-dependent vasodilatation (Ach 10(-5) mol/L; L-arginine +35 +/- 10%; saline -14 +/- 5%; P < .001) and enhanced local production of nitrogen oxides (L-arginine 152 +/- 28; saline 78 +/- 12 nmol/L per milligram of tissue per hour; P < .04). In the long-term study, local administration of L-arginine enhanced vascular NO production as long as 1 week after the injury (L-arginine 394.4 +/- 141.6; saline 86.3 +/- 34.3 nmol/L per milligram of tissue per hour; P < .01) and reduced intimal thickening 4 weeks later (intima/ media ratio: L-arginine 0.56 +/- 0.1; saline 1.40 +/- 0.2; P < .001), largely due to suppression of macrophage accumulation. CONCLUSIONS A single intramural administration of L-arginine enhances vascular NO generation and inhibits lesion formation. Local augmentation of NO production at the site of balloon angioplasty may be a novel strategy to prevent restenosis.

Transesophageal echocardiography and its potential for esophageal damage

The purpose of this study was to determine whether the pressure produced by contact between a transesophageal echocardiography (TEE) probe and the esophagus was sufficient to cause esophageal damage. The authors studied the effects of sustained contact and associated surface pressure on the esophagus by a TEE probe in anesthetized dogs and humans. Contact pressure between the tip of the probe and the esophageal wall in dogs was measured using a previously described flat balloon of Silastic fitted to the end of a TEE probe and the recording system calibrated with a mercury manometer. In the dog studies, the probe was inserted, maximally flexed, and its position fixed for 4, 6, 8, and 12 h. The maximum surface pressure generated by contact between a probe and the esophageal wall was 10 mmHg. Subsequent pathologic studies failed to reveal either gross or microscopic evidence of tissue damage. The same system was used in short-term patient studies with the surface contact pressure transducer connected to a Camino Catheter 420 Digital Pressure Monitor. In five of six patients contact pressure was less than 17 mmHg despite maximal rotation of the TEE controls. However, one of the six patients developed very high contact pressure, up to 60 mmHg, between the probe and the esophagus. This patient had no history of esophageal disease but did have intrathoracic pathology.(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous method of laser transmyocardial revascularization

Laser transmyocardial revascularization (TMR) creates conduits from the left ventricular cavity into the myocardium and has been forwarded as a potential method of perfusing ischemic myocardium. The procedure typically employs a CO2 laser to produce transmyocardial channels from the epicardial to the endocardial surface via an open thoracotomy. Preliminary studies in animals and human subjects have yielded promising results, and clinical trials evaluating the long-term efficacy of the procedure are in progress. We now report the use of a percutaneous method of TMR using a laser delivered through a novel catheter system. To assess the feasibility of performing percutaneous TMR, studies were performed on 15 adult canine subjects utilizing a holmium:YAG laser. Via a femoral artery approach, novel laser catheters were introduced into the left ventricular cavity under fluoroscopic guidance. Biplane coronary angiography, ventriculography, and transesophageal echocardiography were employed to direct catheters to specific regions and assess the efficacy of creating transmyocardial channels. Multiple channels could be created in the anterior, lateral, inferoposterior, and septal regions as demonstrated by contrast ventriculography with confirmation by subsequent gross and histologic examination. The procedure was tolerated well without any ventricular dysfunction or sustained ventricular arrhythmias. We have demonstrated that laser transmyocardial revascularization via a percutaneous approach is feasible with creation of channels from the endocardial surface of the left ventricle into the myocardium. On gross and histological examination, these channels are similar in appearance to those created by the currently employed open chest, epicardial method of TMR.

External beam irradiation inhibits neointimal hyperplasia following balloon angioplasty.

Restenosis is a serious problem limiting the long-term efficacy of percutaneous transluminal coronary angioplasty. Neointimal smooth muscle proliferation is the major process underlying restenosis. The objective of this study was to investigate the effects of external irradiation on neointimal hyperplasia following balloon angioplasty. We examined the ability of external X-ray irradiation to inhibit intimal hyperplasia following balloon angioplasty in a non-atherosclerotic rabbit model. Baseline quantitative angiography (day 0) was performed in all rabbits and balloon angioplasty was performed in the right (control) and the left iliac arteries. Five days after balloon angioplasty, the left iliac in each rabbit was irradiated with either 600 cGy (n = 5) or 1200 cGy (n = 5). Twenty-eight days following angioplasty final angiography was performed. All rabbits were sacrificed, and the iliac arteries were fixed for morphometric measurements. Comparison of baseline and final angiographic measurements revealed a significant decrease in average and minimum lumen dimensions for both control and irradiated segments (600 and 1200 cGy) [average: P (baseline vs. final) 0.008 (control), 0.001 (600 cGy); 0.05 (control), 0.007 (1200 cGy)]. Morphometric analysis showed no difference in neointimal cross-sectional area between control (0.29 +/- 0.05 mm2) and 600 cGy irradiated segments (0.32 +/- 0.07 mm2) (P = 0.82). However, there was a statistically significant reduction in neointimal hyperplasia in the 1200 cGy irradiated segments (0.09 +/- 0.02 mm2) compared to control (0.23 +/- 0.06 mm2, P = 0.02). There was no significant difference in medial cross-sectional area between control and irradiated segments (600 and 1200 cGy). We conclude that in this model, external beam X-ray irradiation (1200 cGy) was successful in reducing neointimal proliferation after balloon angioplasty. Whether or not this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation.

Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effects on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic injury potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15–25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 ± 2.7 mV before diltiazem and 6.1 ± 1.6 mV afterward (P ± 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P ± 10–5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocdusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.

Local l-Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

BACKGROUND Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. METHODS AND RESULTS New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 microCi L-[2,3-(3)H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676+/-223 versus 453+/-93 cpm/mg; P<0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4+/-141.6 versus 86.3+/-34.3 nmol/mg; P<0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (P<0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (P<0.05). CONCLUSIONS Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.

Antiarrhythmic and circulatory effects of astra W36095: A new lidocaine-like agent☆

Abstract Although lidocaine is an effective antiarrhythmic agent, it must be administered parenterally and its duration of activity is short. Astra W36095 has a basic chemical structure similar to that of lidocaine but has a plasma half-life of 8 to 12 hours after administration to conscious dogs. Ventricular arrhythmias were produced in unanesthetized dogs, using ameroid constrictors on the proximal left anterior descending and circumflex coronary arteries. Stable ectopic beats were completely suppressed with plasma levels of 15 to 30 μg/ml of W36095. The duration of effect was 0.25 to 5 hours. In anesthetized dogs, an effective antiarrhythmic concentration of W36095 produced some depression of cardiac function. Thus, W36095 appears to be a long-acting, orally absorbed antiarrhythmic agent requiring clinical trials and metabolic studies. In addition, the arrhythmia model provides a sensitive method for studying new antiarrhythmic drugs.

Time course and cellular characteristics of the iliac artery response to acute balloon injury. An angiographic, morphometric, and immunocytochemical analysis in the cholesterol-fed New Zealand white rabbit.

Evaluation of the response of the arterial vessel wall to acute arterial injury in experimental models has taken on substantial importance because of an increasing interest in angioplasty treatment of human atherosclerotic lesions. In this study, the response of normal arterial vessels to acute balloon injury was studied in 45 iliac artery segments from 24 New Zealand White rabbits fed a 2% cholesterol diet. At specified time points between 1 and 41 days after the initial balloon pullback injury, the iliac arteries were analyzed by angiographic, morphometric, and immunocytochemical techniques. Angiographic measurements indicated progressive compromise of the iliac artery lumen with increasing duration of time from injury. Morphometric measurements showed that intimal area increased from 0.004 +/- 0.01 mm2 3 days after injury to 1.15 +/- 0.30 mm2 34-41 days after injury. Cell line-specific immunocytochemical analysis identified the macrophage as a prominent component of the earliest intimal cellular infiltrate. Smooth muscle cells appeared within the intima 7-9 days after injury. As the intima increased in area, macrophages predominated along the internal elastic lamina aspect of the intimal lesion while smooth muscle cells occupied the portion of the intima adjacent to the lumen. In summary, retrograde balloon pullback injury followed by cholesterol feeding results in progressive arterial luminal narrowing due to a progressively enlarging intimal cellular infiltrate. The temporal and spatial contributions of smooth muscle cell and macrophage components of the developing intimal cellular infiltrate have been characterized.

The application of synchrotron radiation to non-invasive angiography☆

Abstract Synchrotron radiation provides a new source of X-rays highly-suited to iodine K-edge Digital Subtraction Angiography (DSA). The use of such beams provides maximum sensitivity to intra-arterial iodine and virtually eliminates image contrast due to non-vascular body structures. The intensity of the beams permits short exposure times and allows images to be recorded, in line-scan fashion, in sharp focus despite arterial motions. The sensitivity of this method offers the prospect of visualizing arteries, and in particular the coronary arteries, by peripheral venous injection. The principles of DSA have been demonstrated using phantoms and excised animal hearts, and in vivo studies in animals have begun. The instrumentation developed for this purpose and the results obtained to date are summarized.