K.Lance Gould

Physiologic basis for assessing critical coronary stenosis: Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve

Abstract Quantitative hemodynamic assessment of coronary stenosis has not been previously reported. Resting coronary blood flow and its regional distribution are insensitive indexes for determining critical stenosis, but flow response to a hyperemic stimulus quantifies restrictions on maximal flow due to coronary arterial lesions. Coronary flow responses to temporary occlusion and to selective main coronary arterial injection of sodium diatrizoate (Hypaque-M 75 percent) were studied in 12 consecutive dogs with a surgically implanted electromagnetic flowmeter and separate micrometer constrictor on the left circumflex coronary artery. Selective Hypaque injection adequate for coronary cineangiography increased coronary flow to four times the resting base-line value, peaking at 6 seconds and lasting 3 minutes, a response equivalent to hyperemia after 10 seconds of circumflex arterial occlusion. With progressive micrometer constriction, resting flow measurements did not decrease until there was 85 percent stenosis. Hyperemia after intracoronary injection of Hypaque decreased when there was 30 to 45 percent stenosis and disappeared when there was 88 to 93 percent stenosis. Myocardial images obtained by gamma camera after left atrial injection of 131 iodine-macroaggregated albumin demonstrated uniform regional distribution of resting flow in spite of severe constriction. However, 6 seconds after selective Hypaque injection, left atrial injection of 99m technetium macroaggregates demonstrated distinct perfusion abnormalities in the region of circumflex stenosis. Thus, flow distribution with a severe lesion was normal at rest but showed marked differences due to restricted circumflex versus normal anterior descending hyperemic response after injection of Hypaque. Flow response and regional distribution during coronary hyperemia caused by Hypaque are quantitative measures for physiologically assessing critical coronary stenosis and flow reserve with potential applicability to patients.

Effects of coronary stenoses on coronary flow reserve and resistance

Abstract Resting coronary flow and regional distribution are not affected by narrowing of up to 85 percent of arterial diameter and therefore provide little insight into the effects of stenoses on coronary hemodynamics. However, maximal coronary flow and coronary flow reserve are markedly reduced by constrictions that do not affect resting flow. Accordingly, coronary flow reserve and its relations to pressure-flow-resis-tance characteristics of 177 single (10 dogs) and 125 double coronary stenoses in series (7 dogs) were studied in open chest preparations. Coronary flow, aortic pressure and left circumflex coronary pressure distal to a single or to each of two separate adjustable coronary constrictors in series were simultaneously recorded while flow was varied from basal to maximum by intracoronary injections of contrast medium. The hyperemic response to contrast medium is a quantitative measure of coronary flow reserve which was closely related to, and predictive of, the following characteristics of single and double stenoses in series: (1) total pressure gradient and distal circumflex perfusion pressure at resting coronary flow; (2) total pressure gradient and distal circumflex pressure at hyperemic flow when effects of stenoses are greatest; and (3) coronary stenoses resistance. Thus, the hyperemic response after injection of contrast medium, or coronary flow reserve, is in itself a quantitative measure of the pressure-flow-resistance characteristics of coronary constrictions. In addition, resistances of coronary stenoses in series are shown to be additive; the flow effects of stenoses in series are not generally determined by the dominant or most severe lesion, contrary to common clinical precepts. These concepts are applicable to patients in assessing the effects of stenoses on coronary hemodynamics.

Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation. III. Clinical trial

Thallium-201 myocardial imaging was performed at rest, after maximal treadmill exercise and during coronary vasodilatation induced by the intravenous administration of dipyridamole in 62 patients undergoing coronary angiography. Myocardial images after dipyridamole infusion were compared with rest and exercise thallium-201 images to determine the utility of pharmacologic stress for detecting coronary artery disease. Dipyridamole, 0.142 mg/min, was infused for 4 minutes with electrocardiographic and blood pressure monitoring, and thallium-201 was injected intravenously 4 minutes after infusion. Myocardial/background count ratios of 2.3 ± 0.5 (mean ± 1 standard deviation) after the administration of dipyridamole were higher than similar ratios for exercise images (2.1 ± 0.5; P < 0.001). The sensitivity of thallium-201 imaging for detecting significant coronary artery disease was equal for dipyridamole and exercise stress. In 51 patients with a 50 percent or greater stenosis of one or more coronary arteries, image defects were identified in 34 of 51 (67 percent) exercise and dipyridamole images. Twenty of 51 patients (39 percent) had abnormal rest images; in 17 of 20 patients, new or increased image defects were present after exercise and the infusion of dipyridamole. One of 11 patients (9 percent) with no stenosis of 50 percent or greater had a defect on exercise and dipyridamole images. Six of seven patients with new or enlarged image defects after the intravenous administration of dipyridamole also had new or enlarged defects after the oral administration of dipyridamole. After the infusion of dipyridamole, the heart rate increased from 64 ±10 beats/min supine to 88 ± 13 beats/min standing (P < 0.001), and blood pressure decreased from 129 ± 1680 ± 9 to 120 ± 1775 ± 9 mm Hg (P < 0.001). Angina and S-T depression occurred more frequently with exercise than with dipyridamole. S-T depression occurred in only two patients (3 percent) with dipyridamole, suggesting that diagnostic images were often obtained without significant ischemia. This study demonstrates that pharmacologic coronary vasodilatation is as effective as maximal treadmill exercise in creating myocardial perfusion abnormalities detectable with thallium-201 imaging in man.

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

Abstract 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 imaging during pharmacologic coronary vasodilatation: II. Clinical methodology and feasibility

Abstract A noninvasive method has been developed utilizing myocardial imaging of thallium-201 injected intravenously at rest and during coronary vasodilatation induced with intravenously administered dipyridamole, a potent selective coronary vasodllator. The method has been validated in experimental animals and shown to be more sensitive than exercise imaging in identifying moderate experimental coronary stenoses. This report describes the clinical feasibility and methodology of applying the technique to man. Study of a total of 162 myocardial perfusion images in 62 patients revealed the following: (1) The quality of myocardial perfusion images of thallium-201 injected during coronary vasodilatation induced with intravenously administered dipyridamole was equal to or better than that of myocardial images of thallium-201 injected during treadmill stress. (2) Myocardial uptake of thallium-201 measured with external imaging was considerably greater during dipyridamole-induced coronary vasodilatation than during treadmill stress. (3) The optimal dose rate of intravenously administered dipyridamole for this imaging technique was 0.142 mg/kg per min for 4 minutes with the thallium injected in the 3rd to 4th minute after completion of infusion while the patient was upright, walking in place. (4) With this dose rate regimen, side effects were minimal except for the occasional development of angina pectoris; the latter was eliminated by intravenous administration of aminophylline, a complete and virtually instantaneous antagonist of dipyridamole, after thallium had been taken up by the myocardium. This new method is therefore applicable to man and the initial results warrant a larger clinical study in order to define the diagnostic sensitivity and specificity of the technique.

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.

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.

Relation of left ventricular shape, function and wall stress in man

Abstract The relations among left ventricular hypertrophy, equatorial and meridional wall stresses, ventricular chamber shape and performance are described for the first time on the basis of data from 122 patients with valvular, coronary or primary myocardial heart disease. Patients were studied by biplane anglocardiograms; pressure-volume data were processed by computer. The results Indicate that if the left ventricle dilates because of myocardial injury, the following changes occur: Ventricular shape becomes more spherical, circumferential shortening and wall thickening diminish, myocardial fiber orientation changes, meridional stress increases and equatorial stress remains within normal limits. However, If the ventricle dilates because of volume overload with intact myocardial function, then ventricular shape, circumferential shortening, wall thickening and fiber orientation remain relatively intact compared with findings in impaired hearts of equivalent size; both meridional and equatorial wall stresses increase, and to the same degree, but the alterations may not reflect increased force per myocardial fiber If shape and fiber orientation are taken into consideration.

Myocardial imaging with intravenously injected thallium-201 in patients with suspected coronary artery disease: Analysis of technique and correlation with electrocardiographic, coronary anatomic and ventriculographic findings

Myocardial imaging was performed after intravenous injection of thallium-201 at rest in 50 patients with suspected coronary artery disease and the results were compared with electrocardiographic, ventriculographic and coronary arteriographic findings. The thallium-201 myocardial images were of good quality and compared favorably with images previously obtained with intracoronary particle injection. Myocardial to background ratios averaged 2:1, a considerable improvement over ratios reported with potassium-43. There was complete intra- and interobserver agreement in the interpretation of images in 90 and 82 percent of cases, respectively. Major disagreement occurred in less than 5 percent of cases. Overall, 15 (30 percent) had an abnormal, 10 patients (20 percent) a borderline abnormal and 25 patients (50 percent) a normal myocardial image. Of patients with electrocardiographic Q waves, 91 percent had an image defect. Of 39 patients without Q waves, 13 percent had an image defect. All 30 patients with a normal or borderline abnormal thallium-201 image had a normal ventricular contraction pattern. All patients with a segmental ventriculographic abnormality had an image defect. In all cases, the area of electrocardiographic or ventriculographic abnormality corresponded to the area of the thallium-201 image defect. The systolic ejection fraction was depressed (0.49 +/- 0.18 [mean +/- standard deviation]) in patients with an image defect compared with that in patients with a normal image (0.64 +/- 0.06, P less than 0.005). Coronary arterial lesions were present and usually of high grade in all patients with an abnormal image; however, the presence of high grade coronary stenosis or occlusion as such correlated with image defects only to the extent that prior myocardial infraction was associated. Thus, satisfactory myocardial images at rest appear to be obtained with intravenously administered thallium-201 and electrocardiographic, ventriculographic and coronary arteriographic data suggest that image defects denote regions of prior myocardial infarction.

Mechanism of the effect of coronary artery stenosis on coronary flow in the dog

The hemodynamic mechanism of the effect of coronary artery stenosis on coronary flow was studied in the circumflex artery of 10 open-chest dogs by simultaneously measuring coronary flow, aortic pressure, and coronary artery pressure distal to an adjustable constrictor; while the distal coronary bed was intermittently maximally vasodilated by intracoronary injections of angiographic contrast media (Hypaque-M, 75 per cent). For each stenosis, the pressure gradient across the stenosis varied directly with the flow through the stenosis (r equals 0.99), the slope of the regression indicating the severity of the stenosis. An important observation was that this regression line did not intercept the flow axis at zero flow, but at a positive flow, meaning that for a given regression line slope the pressure gradient was much less than expected. At rest, distal bed resistance decreased as progressive stenosis lowered the distal bed pressure, maintaining flow at control level until the distal bed pressure dropped below 60 mm. HG. However, at maximum hyperemia, distal bed resistance was at a fixed minimum value such that flow was directly proportional to distal bed pressure. Hence, progressive stenosis decreased the ratio of hyperemic to resting flow by: (1) causing the vasodilatory reserve to be used to maintain resting flow, decreasing that available for hyperemia, and (2) dropping the distal bed pressure relatively more for smaller increases in flow. This study provides a hemodynamic explanation for the known fact that progressive stenosis initially limits the maximum hyperemic flow, and only after this flow is decreased almost to resting level, does resting flow fall.

Method for assessing stress-induced regional malperfusion during coronary arteriography. Experimental validation and clinical application.

Abstract Resting myocardial regional perfusion may be normal in spite of severe coronary stenosis. Accordingly, regional perfusion was evaluated during coronary hyperemia in order to quantify maldistribution occurring at high flow rates but not at rest. In eight open chest dogs quantitative regional distribution of left coronary flow was determined by electromagnetic flowmeters on the anterior descending and circumflex coronary arteries and simultaneously by double radionuclide studies. Coronary flow was varied from basal to maximum by intracoronary injection of Hypaque-M, 75 percent, previously shown to be a potent, repeatable stimulus for maximal hyperemia. Malperfusion due to coronary stenoses quantified with the gamma camera correlated closely with results obtained by electromagnetic flowmeters ( r = 0.96). In the presence of balanced lesions on the circumflex and anterior descending arteries, hyperemic responses were equally reduced in these branches, and regional perfusion by gamma camera and electromagnetic flowmeters was normal. To demonstrate the applicability of this approach in man, patients were studied by intracoronary injection of 113m indium-macro-aggregated albumin in the resting state and 99m technetium-macro-aggregated albumin during the hyperemia following intracoronary injection of contrast medium. Scintiphotographs from patients whose angiograms revealed moderate coronary lesions demonstrated normal regional distribution at rest but maldistribution during hyperemia. The results in patients also demonstrated that collateral vessels failed to maintain normal distribution during hyperemia despite normal regional perfusion at rest.