This study was undertaken to establish the basic hemodynamic conditions necessary to cause abnormalities in external myocardial perfusion images of thallium-201 and technetium-99M-labeled particles as a result of defined coronary stenoses ranging from mild to severe narrowing. Twenty dogs underwent long-term instrumentation with a flow transducer and adjustable constrictor on the left circumflex coronary artery. Catheters were implanted in the aortic root and distal left circumflex coronary artery to measure pressure loss across the stenosis and in the pulmonary artery and left atrium for the injection of drugs or radionuclides, or both. All data were obtained in intact unsedated trained animals. The results from 145 images obtained at rest, during exercise or after coronary vasodilators in dogs with mild to severe coronary stenoses demonstrate the following: (1) The ratio of maximal flow in a normal to stenotic coronary artery must be at least 2:1 before defects appear in the myocardial perfusion image of thallium-201. (2) A diagnostic technique that utilizes a maximal stimulus for increasing coronary flow and an imaging agent that is distributed to the myocardium in linear proportion to coronary flow at flow rates up to 4 or 5 times resting levels will be the most sensitive method for detecting mild coronary stenoses; a diagnostic technique utilizing a submaximal stimulus for coronary flow or an imaging agent whose distribution is not proportional to flow at high flow rates will be least sensitive. (3) Myocardial perfusion imaging during coronary vasodilatation induced with intravenously administered dipyridamole is a better method for identifying moderate coronary stenoses than perfusion imaging during exercise stress in experimental animals. (4) The effect of intravenously administered dipyridamole on the coronary circulation can be closely regulated by adjusting the dose rate of infusion and can be instantaneously reversed with intravenous administration of aminophylline, a dipyridamole antagonist; dipyridamole infusion does not increase myocardial oxygen demands as much as exercise and does not Invoke myocardial ischemia as a diagnostic end point. This stimulus may therefore be more readily controlled than exercise stress and is not subject to the effects on treadmill testing of motivation, chronic lung disease, peripheral vascular disease or musculoskeletal impairment.

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilatation. I. Physiologic basis and experimental validation.

BACKGROUNDGap junctions are a determinant of myocardial conduction. Disturbances of gap-junctional content may account for abnormalities of impulse propagation, contributing to the arrhythmic tendency and mechanical inefficiency of ischemic and hypertrophied myocardium. The aim of this study was to characterize gap junction organization in normal human ventricular myocardium and to establish whether abnormalities exist in myocardium of chronically ischemic and hypertrophied hearts.METHODS AND RESULTSCardiac gap-junctional connexin43 antibodies and confocal microscopy were used in a quantitative immunohistochemical study of surgical myocardial samples to explore the structural basis of electromechanical ventricular dysfunction in chronic ischemic and hypertrophic heart diseases. Normal adult human left ventricular myocardium had a gap-junctional surface area of 0.0051 micron2/micron3 myocyte volume; gap junctions were confined to intercalated disks, of which there was a mean of 11.6 per cell. The right ven...

Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts.

To determine the minimal coronary lesions detectable with perfusion imaging, 16 stenoses of 43 to 66 percent diameter narrowing were applied to the left circumflex coronary artery of three chronically instrumented intact dogs. Orthogonal diastolic coronary arteriograms, obtained on cut film by triggering X-ray exposures from the electrocardiogram while injecting contrast medium through a chronically implanted coronary arterial catheter, were analyzed quantitatively by computer. Fifteen millicuries of nitrogen-13 ammonia was injected intravenously during resting conditions, and emission-computed tomography was performed without electrocardiographic gating. One hour later, after residual nitrogen-13 ammonia had decayed, 15 mg of intravenous dipyridamole was given followed by a second dose of intravenous nitrogen-13 ammonia and repeat performance of emission-computed tomography. The cross-sectional tomographs of the heart were of high quality and revealed in the images obtained with dipyridamole definite perfusion defects with coronary stenoses of 47 percent or greater diameter narrowing. Stenoses of 45 percent diameter narrowing or less did not produce perfusion defects. Quantitative perfusion abnormalities approximated the quantitative severity of stenoses. It is concluded that noninvasive myocardial emission-computed tomography with nitrogen-13 ammonia during dipyridamole-induced coronary vasodilatation detects mild coronary stenoses for purposes of potential medical intervention.

Noninvasive assessment of coronary stenoses with myocardial perfusion imaging during pharmacologic coronary vasodilatation. V. Detection of 47 percent diameter coronary stenosis with intravenous nitrogen-13 ammonia and emission-computed tomography in intact dogs.

The vulnerability of subendocardial muscle to ischemic damage is due primarily to the greater risk of underperfusion. Recent studies of coronary autoregulation have shown that as myocardial oxygen needs increase beyond the ability of coronary blood flow to supply oxygen, maximal vasodilatation occurs earliest in subendocardial vessels; any further imbalance then causes subendocardial ischemia, since no further compensatory vasodilatation is possible. In animal experiments relative subendocardial perfusion (the ratio of flow per gram in subendocardial to subepicardial muscle) can be predicted from the DPTI: SPTI ratio of two pressure-time areas, where DPTI = the area between coronary and left ventricular pressures in diastole and SPTI = the area beneath the left ventricular systolic pressure. Early studies demonstrated subendocardial underperfusion when DPTI: SPTI was below 0.7, but more recent studies show that this critical ratio is about 0.4. Applying the results of these animal studies to man must be done very cautiously. Peak ventricular systolic pressure is better than SPTI in predicting myocardial oxygen needs, but neither measure allows for changes in wall tension

Determinants and prediction of transmural myocardial perfusion.

A new echocardiographic contrast agent, gelatin-encapsulated microbubbles, that an intramyocardial contrast effect, was evaluated as a marker for the detection of regions of abnormal myocardial perfusion in nine open-chest dogs. The gelatin-encapsulated microbubbles were injected into the aortic root under control conditions and during circumflex coronary artery occlusion. Myocardial perfusion was simultaneously assessed with radioactive microspheres. Echocardiographic contrast enhancement (ECE) was measured in footlamberts (Ft-L) from the videoscreen of an off-line playback system, using a commercially available light meter. A single short-axis section of the left ventricle was divided into octants to analyze myocardial perfusion. The equivalent regions of the echocardiographic image were analyzed for contrast enhancement and wall motion. An ECE > 0.3 Ft-L was seen in all 120 octants analyzed before circumflex coronary artery occlusion and in 48 of 51 (94%) octants with > 50% of normal zone flow during circumflex artery occlusion. An ECE ≤ 0.3 Ft-L identified 19 of 21 octants (with ≤ 50% normal zone flow and all 13 octants with ≤ 25% normal zone flow during coronary artery occlusion. In contrast, wall motion abnormalities (akinesis or dyskinesis) were seen in 13 of 51 octants (25%) with > 50% normal zone flow, and normal wall motion was seen in two of 21 octants (10%) with blood flow ≤ 50% of normal zone flow during circumflex coronary artery occlusion. We could not demonstrate a linear correlation between ECE and the absolute level of myocardial blood flow. We feel this was due to the limitations imposed by imaging an open-chest animal preparation, variation in the number of gelatin-encapsulated microbubbles used for each injection and variations in the echocardiographic gain settings among experiments. We conclude that contrast-enhanced two-dimensional echocardiography with gelatin-encapsulated microbubbles can accurately identify ischemic regions of the left ventricular myocardium. This technique is more accurate than wall motion analysis for detecting myocardial ischemia.

Assessment of myocardial perfusion abnormalities with contrast-enhanced two-dimensional echocardiography.

The reliability of myocardial perfusion scintigrams with thallium-201 (201Tl) for detecting areas of hypoperfusion was assessed in 16 closed-chest dogs. Variable areas of ischemia were produced either by occluding or stenosing the left anterior descending coronary artery. Cardiac scintigrams taken in four projections were compared with regional myocardial perfusion maps. Segmental concentrations and segmental perfusions were quantitated by counting the emissions from 201Tl and the microspheres in each of 96 segments of the left ventricle. In addition, studies with a phantom were performed. The results indicate: 1) The emissions from 201Tl and from microspheres correlated well in ischemic segments (r = 0.93 +/- SE 0.02). 2) Seven of twelve ischemic hearts had definitely abnormal scintigrams and in each of these the hypoperfused zone was greater than 4.9 grams and perfusion was decreased by more than 45%. 3) In the phantom, abnormal scintigrams could be detected in the presence of lesser deficits than in the dogs. The limitation of the thallium perfusion scintigrams will be the inconsistent detection of small perfusion deficits.

T. M. Mueller

Papers

Limitations of thallium 201 myocardial perfusion scintigrams