Effects of intravenous and intracoronary adenosine 5'-triphosphate as compared with adenosine on coronary flow and pressure dynamics.

BACKGROUND: Measurements of Doppler derived coronary flow reserve (CFR) and pressure derived fractional flow reserve (FFR) for coronary stenosis assessment depend on the induction of maximal hyperemia. Adenosine is the most widely used pharmacological agent but is expensive and poorly tolerated by some patients. METHODS AND RESULTS: The objective of this study was to test the equivalency of adenosine 5'-triphosphate (ATP) to adenosine in their ability to cause maximal hyperemia as compared with the hyperemic response of complete coronary occlusion in 6 canines. Intracoronary administration of either ATP or adenosine resulted in a significant increase in CFR (2.79+/-0.64 and 2.22+/-0.7 for 10 microgram versus 4. 65+/-1.22 and 4.25+/-0.78 for 100 microgram for ATP and adenosine, respectively, P for trend <0.001) but not reaching the level of coronary occlusion (6.35+/-2.26). Additionally, FFR and CFR were measured in 35 different stenoses using ATP, adenosine, and coronary occlusion. There was an excellent linear correlation between ATP and adenosine for both CFR (R=0.934, P<0.001) and FFR (R=0.985, P<0.001). However, hyperemia with either ATP or adenosine was less than postocclusion hyperemia, resulting in significantly different reserve measurements (CFR: 1.93+/-0.66 and 2.08+/-0.81 versus 2.35+/-0.97, P<0.001; FFR: 0.62+/-0.24 and 0.63+/-0.23 versus 0.58+/-0.2, P<0.001). CONCLUSIONS: 1) Step up in dosage of ATP and adenosine beyond currently recommended clinical doses resulted in a significant increase in coronary hyperemia; 2) ATP was equivalent to adenosine for both CFR and FFR; and 3) complete coronary occlusion yielded a better hyperemic response than either drug, indicating that maximal hyperemia was not achieved by either pharmacological stimulus.

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.

Enhancement of spatial orientation of intravascular ultrasound images with side holes in guiding catheters.

BACKGROUND: Intravascular ultrasound (IVUS) images are typically viewed and recorded in an arbitrary rotational orientation. This study was performed to validate a new method for improved orientation of sonographic vascular cross-sections. METHODS AND RESULTS: We have tested a simple technique for rotational indexing of IVUS in cases in which guiding catheters with side holes are used. Although guiding catheters are opaque to ultrasonography, the side holes transmit the beam and therefore can be easily identified. The orientation of the side holes, which is characteristic for each make of guiding catheter, can be used to determine the anatomically appropriate rotational orientation of the IVUS image. In this study images of four commercially available side-hole guiding catheters were viewed in vitro to confirm the visibility of the side holes and to characterize their orientation for purposes of rotational orientation of images. Feasibility tests of rotational orientation based on side holes were then performed in canine coronary arteries (n = 3) and in six human coronary arteries. Three serial imaging runs in each clinical case yielded a mean variability in rotational orientation of 7.5 +/- 1.5 degrees. CONCLUSION: Validation testing of the side-hole technique demonstrates the potential for consistent and anatomically appropriate orientation of intravascular ultrasound images.

Coronary AVE micro stents: serial quantitative angiography and histology in a canine model.

The AVE Micro Stent (AVE Inc., Santa Rosa, CA) is composed of helically welded 3 mm long, zigzag crowns with stent lengths from 6 to 39 mm and diameters from 2.5 to 4.5 mm. Quantitative coronary angiography and histologic analyses of acute and chronic implantation were obtained in 52 stented coronary segments of 18 dogs. Three hearts with 8 stented coronary segments were harvested after 24 hr, 3 hearts with 9 stented segments were harvested after 2 weeks, 6 hearts with 15 stented segments were harvested at 8 weeks, and 6 hearts with 20 stented segments were harvested at 24 weeks post-deployment. There were no procedural complications, deaths, or acute vessel closures. The average lumen diameter of the stented segment was largest at 2 weeks (3.3 +/- 0.3 mm). The smallest average diameters were observed at 8 weeks after the stent deployment (2.7 +/- 0.4, P < 0.05) with an increase again at 24 weeks (2.9 +/- 0.6). The pre-explant percent of stenosis was <30% in all animals. Histologically, a peak of inflammation was visible at 2 weeks; however, the extent of luminal narrowing reached its peak at 8 weeks and the lumen dimension increased somewhat at 24 weeks. The degree of intimal thickening remained relatively constant throughout the different time points (<200 microm). Overall, these data suggest that constrictive remodeling within the stented segment occurs at 8 weeks in this animal model. The later increase of the stented segment dimensions as well as higher net gain at 24 weeks compared to 8 weeks after deployment suggests that this constriction is a transitory phenomenon.

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.

Genetic engineering of vein grafts resistant to atherosclerosis.

Previously, researchers have speculated that genetic engineering can improve the long-term function of vascular grafts which are prone to atherosclerosis and occlusion. In this study, we demonstrated that an intraoperative gene therapy approach using antisense oligodeoxynucleotide blockage of medial smooth muscle cell proliferation can prevent the accelerated atherosclerosis that is responsible for autologous vein graft failure. Selective blockade of the expression of genes for two cell cycle regulatory proteins, proliferating cell nuclear antigen and cell division cycle 2 kinase, was achieved in the smooth muscle cells of rabbit jugular veins grafted into the carotid arteries. This alteration of gene expression successfully redirected vein graft biology away from neointimal hyperplasia and toward medial hypertrophy, yielding conduits that more closely resembled normal arteries. More importantly, these genetically engineered grafts proved resistant to diet-induced atherosclerosis. These findings establish the feasibility of developing genetically engineered bioprostheses that are resistant to failure and better suited to the long-term treatment of occlusive vascular disease.

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.

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)

Transvenous coronary angiography in humans using synchrotron radiation.

The risks and costs of the present method of visualizing the coronary arteries have limited the use of coronary angiography in long-term serial studies needed to establish the natural history of coronary atherosclerosis and its response to interventions. A less invasive method, in which the contrast agent is administered intravenously, has been developed using synchrotron radiation as the illuminating source. The present report describes the initial results in human subjects. The findings indicate that transvenous coronary angiograms can be acquired in this manner. Further refinements in the x-ray imaging system are expected to result in increased x-ray fluence and improved image quality.

Transvenous coronary angiography in dogs using synchrotron radiation.

The application of coronary angiography is limited because it requires arterial invasion and the direct injection of contrast agent into the coronary arteries. A prototype system has been developed which achieves sufficient sensitivity to the iodinated contrast agent to allow the visualization of coronary arteries in dogs after its intravenous injection. The system uses two fan beams of x-rays from an electron storage ring and a 300 element linear silicon detector. Two interlaced images, spaced at 150 eV above and below the K absorption edge of iodine (33.2 keV), are acquired and the logarithmic subtraction of these two images produces an image which has maximal sensitivity to iodine and minimal sensitivity to soft tissue and bone. This approach appears suitable for studies on human subjects.

Ultrasonic tissue characterization: detection of acute myocardial ischemia in dogs.

Ultrasonic tissue characterization is a new area of investigation in the field of cardiac ultrasound. The amplitude and frequency of the ultrasound signal are normally altered as the signal penetrates through tissue. It is assumed that the amplitude distribution and frequency shift of diseased or edematous tissue are different than those of normal tissue. A statistical approach to the analysis of the unprocessed radiofrequency signal in the amplitude domain was used to study the effect of acute myocardial ischemia on the parameter mean amplitude/standard deviation of the amplitude (MSR). Ten dogs were anesthetized and underwent left lateral thoracotomy. Baseline mean MSR from the interventricular septum was 1.99 +/- 0.05, but increased by 30 min after coronary artery occlusion and started to plateau at 1 hr (mean 2.24 +/- 0.06). Reproducibility in noninfarcted myocardium (left ventricular inferoposterior wall) was good, with a mean MSR of 2.00 +/- 0.05 at baseline and 1.98 +/- 0.04 3 to 4 hr later. There was no difference in mean MSR when data were obtained through chest wall and when they were obtained directly from the surface of the heart. We conclude that statistical analysis in the amplitude domain of the unprocessed radiofrequency signal can detect acute myocardial ischemia within 30 min after coronary artery occlusion, provides reproducible measurements, and is unaffected by chest wall filtering.

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 effect 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 less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 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 preocclusion 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.

Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release.

We evaluated the acute hemodynamic effects of doxorubicin in the open-chest dog. Doxorubicin at doses of 1-4 mg/kg administered over 2 min produced profound hemodynamic changes that were similar to those produced by histamine. These changes persisted despite administering the drug as a slow infusion. Histamine release in peripheral tissues was documented by a marked increase in venous histamine levels following doxorubicin administration. The heart extracted histamine during a period when arterial levels were increased, as indicated by consistently low coronary sinus/aortic ratios. Secondary catecholamine release occurred in response to histamine and histamine-mediated hemodynamic effects. Immunoreactive prostaglandins E and F were increased in coronary sinus blood beginning 30 min after the initiation of a continuous infusion of doxorubicin, and increased slowly thereafter. H1- and H2-receptor blockade with diphenhydramine and cimetidine prevented the early (2-30 min postinfusion) effects of doxorubicin, and combined histaminergic and adrenergic blockade prevented the late effects. A dose of doxorubicin (1 mg/kg) that released histamine and catecholamines produced primary cardiac effects acutely and a cardiomyopathy when administered chronically. The release of vasoactive substances could be part of the pathogenetic mechanism of anthracycline cardiomyopathy.

Muscle stiffness determined from canine left ventricular pressure-volume curves.

We measured pressure-volume curves in nine excised dog ventricles and stress-strain curves in two to five muscle specimens from each ventricle to verify a derived formula that relates muscle stiffness to the ventricular pressure-volume curve. The assumptions underlying this formula are: (1) the ventricle is a uniform spherical shell, (2) all muscle fibers carry average stress and deform as if they were at the midwall, (3) static equilibrium exists, (4) internal pressure induces the only load, and (5) the muscles exhibit an exponential stress-strain curve given by the equation sigma(epsilon) = alpha(ebeta epsilon - 1), where sigma = stress, epsilon = strain, and alpha and beta are constants. There was no significant difference between the stiffness constant, beta, inferred from the left ventricle pressure-volume curves (14+/-4.3[SD]) and that measured directly from the muscle stress-strain curves (16+/-2.8).