Measurement of regional myocardial blood flow with N-13 ammonia and positron-emission tomography in intact dogs

N-13 ammonia mimics certain properties of microspheres. It rapidly clears from blood into myocardium where it becomes fixed in proportion to myocardial blood flow. Used with positron emission tomography as a means for quantifying in vivo myocardial indicator concentrations, N-13 ammonia may be useful for noninvasive determination of myocardial blood flow with the arterial reference sampling technique. This possibility was examined in 27 experiments in 10 chronically instrumented dogs at control, high and low blood flows. Myocardial blood flow was calculated in vivo from the myocardial N-13 tissue activity concentrations derived from serial cross-sectional images of the heart, the 2 minute arterial input function and the withdrawal rate of arterial blood. These calculations were compared with blood flow determined by the standard microsphere technique. Blood flow determined in vivo with N-13 ammonia and positron emission tomography correlated with microsphere blood flow by y = -36.2 + 1.53x -0.0027x2 (r = 0.94 with a standard error of the estimate of 16 ml/min per 100 g). For flows from 44 to 200 ml/min per 100 g, the relation between in vivo and in vitro measured myocardial blood flow was nearly linear but reached a plateau at flows higher than 200 ml/min per 100 g. These results indicate that in dogs, blood flow in the physiologic range can be quantified in vivo with N-13 ammonia and positron emission tomography.     

Regional myocardial blood flow, metabolism and function assessed noninvasively with positron emission tomography

Positron emission computed tomography is a new technique of potential value for the noninvasive measurement of myocardial blood flow, mechanical function and, in particular, metabolism. The capability of this new study method is attributable to the technologic innovations of the imaging device and the availability of radioactive tracers that are specific for blood flow and metabolism. The device permits recording of cross-sectional images of the left ventricular myocardium that quantitatively reflect regional tracer tissue concentrations. Use of tracer kinetic models with this new technique permits measurements of regional glucose and fatty acid metabolism of the heart. Positron emission tomography is already an important new tool for investigative studies of cardiac physiology and pathophysiology; its clinical utility remains to be defined.     

Hemodynamic evaluation of the Carpentier-Edwards bioprosthesis in the aortic position.

The Carpentier-Edwards bioprosthesis is a glutaraldehyde-fixed porcine xenograft with a fully flexible thin-walled stent. Cardiac catheterization studies were performed in 17 patients to evaluate use of this valve in the aortic position. Hemodynamic studies established a mean peak gradient across the prosthesis of 19 mm Hg (range 5 to 65). The mean effective orifice area was calculated to be 1.6 cm2 (range 0.8 to 3.3). All patients demonstrated an improvement in functional class after operation. Mean left ventricular ejection fraction increased from 51 +/- 16 to 68 +/- 9 percent (P less than 0.004) in eight patients operated on for aortic stenosis, but was not significantly changed in patients operated on for aortic insufficiency. Hemodynamic comparison of the Carpentier-Edwards bioprosthesis with the standard Hancock xenograft showed similar effective orifice areas for the 23 and 25 mm diameter valves. In two patients studied the 21 mm Carpentier valve demonstrated a greater effective orifice area than that previously reported for the standard Hancock xenograft. The Carpentier-Edwards bioprosthesis affords both clinical and hemodynamic improvement when used in the aortic position and may allow improved effective orifice area when used in the smaller aortic root.     

Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model

Positron emission tomography allows noninvasive assessment of myocardial blood flow and metabolism, and may aid in defining the extent and severity of an ischemic injury. This hypothesis was tested by studying, in chronically instrumented dogs, regional blood flow and metabolism during and after a 3 hour balloon occlusion of the left anterior descending coronary artery. The metabolic findings after ischemia were compared with the recovery of regional function over a 4 week period. N-13 ammonia was used as a blood flow tracer, and C-11 palmitic acid and F-18 deoxyglucose as tracers of fatty acid and glucose metabolism, respectively. Regional myocardial function was monitored with ultrasonic crystals implanted subendocardially. Regional function improved most between 24 hours and 1 week after reperfusion, but was still attenuated at 4 weeks. The slow functional recovery was paralleled by sustained metabolic abnormalities, reflected by segmentally delayed clearance of C-11 activity from myocardium and increased uptake of F-18 deoxyglucose. Absence of blood flow and C-11 palmitic acid uptake at 24 hours of reperfusion correlated with extensive necrosis as evidenced by histologic examination. Conversely, uptake of C-11 palmitic acid with delayed C-11 clearance and increased F-18 deoxyglucose accumulation identified reversibly injured tissue that subsequently recovered functionally and revealed little necrosis. Thus, recovery of metabolism after 3 hours of ischemia is slow in canine myocardium and paralleled by slow recovery of function. Metabolic indexes by positron tomography early after reperfusion can identify necrotic and reversibly injured tissue. Positron tomography may therefore aid in defining the extent and prognosis of an ischemic injury in patients undergoing reperfusion during evolving myocardial infarction.     

Regional myocardial dysfunction in patients with angina at rest and response to isosorbide dinitrate assessed by phase analysis of radionuclide ventriculograms

Left and right ventricular synchrony was assessed in 15 patients with angina at rest but no previous infarction by phase analysis of equilibrium radionuclide ventriculograms. Transient thallium-201 perfusion defects were noted in all during angina at rest and coronary vasospasm was documented in nine of the patients. Radionuclide ventriculograms were performed at control, during the ischemic episodes and after intravenous isosorbide dinitrate. Left and right ventricular phase histograms were quantified by the standard deviation from the mean of the peak (SD). Left ventricular ejection fraction averaged 65 +/- 11% (mean +/- standard deviation) at control, decreased in all patients during angina at rest to 49 +/- 14% (p less than 0.01) and increased in all patients after isosorbide dinitrate to 66 +/- 12%. However, ejection fraction during ischemia was abnormal in only nine patients and changed in two by less than 5% from the control value. Regional wall motion abnormalities were noted in all patients during the ischemic episodes but resolved after isosorbide dinitrate administration. Control left ventricular SD was 14.5 +/- 4 degrees, increased in all patients to 22.8 +/- 5 degrees during angina at rest (p less than 0.01) and returned to control values after isosorbide dinitrate administration (14.2 +/- 4 degrees). In contrast, right ventricular SD did not significantly change during ischemia as compared with control and isosorbide dinitrate. It is concluded that in angina at rest, a normal left ventricular ejection fraction does not exclude severe regional dysfunction; separate left and right ventricular SD is a sensitive index in detecting transient left ventricular dysfunction, and relief of ischemia is associated with rapid normalization of regional left ventricular function.     

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 $\text{129 ±}\text{16}\text{80}\text{± 9}\text{to}\text{120 ±}\text{17}\text{75}\text{± 9}\text{mm Hg}\text{(P < 0.001)}$. 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 imaging during pharmacologic coronary vasodilatation. II. Clinical methodology and feasibility

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.     

Retention and clearance of C-11 palmitic acid in ischemic and reperfused canine myocardium

Free fatty acids are the major energy source for cardiac muscle. Oxidation of fatty acid decreases or even ceases during ischemia. Its recovery after transient ischemia remains largely unexplored. Using intracoronary carbon-11 palmitic acid as a tracer of myocardial fatty acid metabolism in an open chest dog model, retention and clearance of tracer in myocardium were evaluated at control, during ischemia and after reperfusion following a 20 minute occlusion of the left anterior descending coronary artery. Myocardial C-11 time-activity curves were analyzed with biexponential curve-fitting routines yielding fractional distribution and clearance half-times of C-11 palmitic acid in myocardial tissue. In animals with permanent occlusion and intracoronary injection of C-11 palmitic acid distal to the occlusion site, the relative size and half-time of the early clearance curve component differed markedly from control values and did not change with ongoing ischemia. Conversely, in animals with only 20 minutes of coronary occlusion, the relative size of the early C-11 clearance phase was still significantly depressed at 20 and 90 minutes of reperfusion but returned to control level at 180 minutes. Tissue C-11 clearance half-times remained significantly prolonged throughout the reperfusion period. Regional function in reperfused myocardium monitored with ultrasonic crystals recovered slowly and was still less than control after 3 hours of reperfusion. The data indicate that after transient ischemia, myocardial fatty acid metabolism fails to recover immediately. Because the metabolic recovery occurs in parallel with recovery of regional function, C-11 palmitic acid in conjunction with positron tomography may be useful for studying regional fatty acid metabolism noninvasively after an ischemic injury, and may be helpful in identifying reversible tissue injury.     

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

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.     

The American Heart Journal: Progress report on publication goals

The value of phase analysis of multiple gated acquisition blood pool images for identifying wall motion abnormalities due to stress-induced ischemia was examined. Myocardial segments with an abnormal phase, i.e., delayed onset of wall motion, were localized on a phase distribution image of the LV and the synchrony of LV systolic wall motion was assessed from histograms of the LV phase distribution, i.e., the standard deviation (SD) from the mean of this peak, which was defined as SDP. Its upper limits of normal at rest and exercise were established in seven normals as the mean +2 SD and were 12 degrees at rest and 10 degrees at maximum exercise. Of the 56 patients, 37 had coronary artery disease (CAD), 11 had valvular disease but normal coronary arteries, and eight had normal coronary arteries, no valvular disease, but had either cardiomyopathy or typical angina. In the CAD patients, SDP was abnormal in 95% during exercise while only 86% had an abnormal ejection fraction (EF) response and/or exercise-induced wall motion abnormalities by visual interpretation. By contrast, in the 11 valvular heart disease patients, SDP was abnormal in only two despire exercise-induced wall motion abnormalities in five and an abnormal EF response in all 11. Thus although an abnormal EF response to exercise is a sensitive indicator of cardiac disease, it is, however like exercise induced wall motion abnormalities, not specific for CAD. By contrast, phase analysis not only permitted separation of wall motion abnormalities induced by ischemia from those associated with valvular disease, but was also an objective, highly sensitive, and specific indicator of regional myocardial ischemia.     

Relation of coronary arterial spasm to sites of organic stenosis

Among 63 patients with Prinzmetal's variant angina, coronary arterial spasm responsible for attacks of variant angina was documented arteriographically in 9 patients. In each observed episode (11 attacks in nine patients), coronary spasm producing myocardial ischemia occurred at and was superimposed on a site of preexisting organic stenosis. Measurements of normal portions of "spastic" and "nonspastic" vessels suggested a generalized uniform constriction of all major coronary arteries during attacks, with "spasm" limited to the site of an organic lesion in most cases. In two cases the magnitude of constriction in all vessels was consistent with generalized coronary hypercontractility or spasm. Among 104 patients with organic coronary artery disease and documented single vessel coronary spasm (foregoing 9 patients combined with 95 others from published reports), there were 70 patients with essentially single vessel organic coronary disease in 90 percent of whom the spasm involved the diseased vessel. Of 60 cases abstracted from the literature in which the relation of coronary spasm to the site of organic disease was described, 88 percent had the spasm causing ischemia localized to the site of an organic lesion. Hypotheses attempting to describe the pathophysiologic aspects of coronary spasm in variant angina must account for the intimate association of spasm with sites of organic stenosis in the majority of cases.     

Left ventricular dynamics during long-term digoxin treatment in patients with stable coronary artery disease

Ten patients with stable coronary artery disease who did not have clinical congestive heart failure and had recovered (3 or more months) from coronary bypass graft surgery were given both intravenous and oral digoxin. Left ventricular performance was assessed weekly for 3 control weeks, during 4 weeks of long-term oral digoxin treatment and during 2 to 3 weeks of recovery. Serial noninvasive measurements of velocity of circumferential fiber shortening, ejection fraction, end-diastolic volume and cardiac output were obtained with computer-assisted fluoroscopic analysis of the motion of surgically implanted mid wall myocardial markers that outline the left ventricular cavity. During 4 weeks of oral digoxin therapy, mean serum digoxin levels were maintained between 1.2 ± 0.1 and 1.4 ± 0.1 ng/ml (mean ± standard error of the mean). Mean velocity of circumferential fiber shortening increased 15.6 percent from 0.65 ± 0.05 to 0.75 ± 0.05 circumferences/sec (P < 0.001) and ejection fraction increased 8.5 percent from 0.51 ± 0.03 to 0.55 ± 0.03 (P < 0.001). End-diastolic volume and cardiac output were not changed significantly. The inotropic response to oral digoxin was similar during the 4th week of treatment to that seen during the first week and the mean inotropic effect of chronic oral digoxin was not significantly less than that achieved by administration of 1 mg intravenously over 15 minutes. These data suggest that chronic oral digoxin treatment exerts a sustained inotropic effect on the nonfailing heart that persists for at least 4 weeks and is equivalent to that achieved with rapid intravenous digitalization.     

Exercise electrocardiography: recognition of the ischemic response, false positive and negative patterns

The ischemic electrocardiographic response is characterized by S-T segment depression in the left ventricular leads. When this response is elicited by exercise and is accompanied by anginal discomfort, it constitutes powerful diagnostic evidence of the presence of coronary arterial obstructive disease. The amount of exercise required to elicit the response is closely related to the extent of the obstruction. S-T segment elevation provoked by exercise rarely occurs with proximal severe stenosis in the left anterior descending coronary artery or in leads exploring the region of healed myocardial infarcts. Depression of the J point may be an ischemic manifestation reversible by administration of nitroglycerin.The ischemic electrocardiographic response may be obscured by conduction defects as in bundle branch block and healed myocardial infarcts. False positive ischemic responses may be encountered in patients taking digitalis glycosides or potassium-depleting drugs, or in patients with hyperadrenergic states, pectus excavatum or short P-R Intervals.     

Two-dimensional echocardiographic assessment of right ventricular volume in children with congenital heart disease

The ability of 2-dimensional echocardiography to measure right ventricular (RV) volume and ejection fraction was assessed in 22 children with congenital heart disease. From the apical 4 chamber 2-dimensional echocardiographic image, the long-axis length of the right ventricle was measured and the area planimetered. On the anteroposterior and lateral cineangiocardiographic planes, the right ventricle was separated into 2 parts: RV sinus and outflow tract. The longest length, inflow tract length, and area of the sinus were measured from biplane cineangiographic views. The echographic long-axis length correlated well with the longest length of the RV sinus measured from both anteroposterior and lateral cineangiographic views at both end-systole and end-diastole. Moreover, the echographic area correlated well with the sinus area obtained from both cineangiographic views. From these regression analyses, the echographic long axis length and area were corrected to the angiographie longest length and area of the sinus. The new corrected echographic longest length and area were applied to 3 formulas (2 biplane and 1 uniplane) to calculate the sinus volume of the right ventricle. Total RV volume was then derived from the sinus volume. RV volumes and ejection fraction determined by 2-dimensional echocardiography were compared with those obtained from biplane cineangiography using Simpson's rule method. All formulas tested predicted RV volumes and ejection fraction with equal accuracy. Thus, 2-dimensional echocardiography can assess RV volume and ejection fraction in children with congenital heart disease.     

Myocardial protection during surgical coronary reperfusion

Reperfusion injury in the surgical setting is defined as those metabolic, functional and structural consequences of restoring coronary flow (that is, aortic unclamping and revascularization) that can be avoided or reversed by modification of the conditions of reperfusion by the operating surgeon. The potential for reperfusion damage exists during cardiac surgery because temporary myocardial ischemia (that is, aortic clamping) is needed to produce a quiet, bloodless surgical field. Cold cardioplegic techniques have decreased the risks of ischemic myocardial damage during aortic clamping, but reperfusion damage can still occur when there is poor cardioplegic distribution (that is, coronary artery disease) or in hearts that have suffered ischemic damage before extracorporeal circulation is started (such as extending myocardial infarction, cardiogenic shock and the like). The surgical setting affords the ideal opportunity for reperfusate modification because the components and conditions of the reperfusate are in the surgeon's control. This study reviews present understanding of the nature of reperfusion damage in the surgical setting and summarizes studies over the past 6 years which suggest that much of reperfusion damage can be avoided or reversed by adjusting the temperature, pressure and composition of reperfusate blood.