Luis I. Araujo

Noninvasive quantification of regional myocardial blood flow in coronary artery disease with oxygen-15-labeled carbon dioxide inhalation and positron emission tomography

BackgroundOxygen-15-labeled water is a diffusible, metabolically inert myocardial blood flow tracer with a short half-life (2 minutes) that can be used quantitatively with positron emission tomography (PET). The purpose of this study was to validate a new technique to quantify myocardial blood flow (MBF) in animals and to assess its application in patients. Methods and ResultsThe technique involves the administration of 150-labeled carbon dioxide (C1502) and rapid dynamic scanning. Arterial and myocardial time activity curves were fitted to a single tissue compartment tracer kinetic model to estimate MBF in each myocardial region. Validation studies consisted of 52 simultaneous measurements ofMBF with PET and y-labeled microspheres in nine closed-chest dogs over a flow range of 0.5-6.1 ml/g/min. A good correlation between the two methods was obtained (y = 0.36 + 1.0x, r = 0.91). Human studies consisted of 11 normal volunteers and eight patients with chronic stable angina and single-vessel disease, before and after intravenous dipyridamole infusion. In the normal group, MBF was homogeneous throughout the left ventricle both at rest and after administration of dipyridamole (0.88 ± 0.08 ml/g/min and 3.52 ± + 1.12 ml/g/min, respectively; p≤0.001). In patients, resting MBF was similar in the distribution of the normal and stenotic arteries (1.03 ± 0.23 and 0.93 ± 0.21 ml/g/min, respectively). After dipyridamole infusion, MBF in normally perfused areas increased to 2.86 ± 0.83 ml/g/min, whereas in the regions supplied by stenotic arteries it increased to only 1.32 ± 0.27 ml/g/min (p<0.001). ConclusionsPET with C1502 inhalation provides an accurate noninvasive quantitative method for measuring regional myocardial blood flow in patients. (Circulation 1991;83:875–885)

Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina.

It has been shown in different groups of patients with variant angina that coronary spasm can be reproduced by physiologic maneuvers and pharmacologic agents. It is not known, however, to what extent different stimuli can induce spasm in the same patient. To investigate whether coronary arterial spasm results from specific abnormal agonist-receptor interactions or from a local nonspecific coronary supersensitivity to different stimuli, 28 patients with vasospastic angina were submitted to a series of diverse vasoconstrictive stimuli known to provoke coronary spasm. Ergonovine, hyperventilation, handgrip, cold pressor, and exercise-tests, were carried out in all 28 patients. In the last 15 patients histamine was also administered. Spasm was provoked by ergonovine in 96% of patients, by hyperventilation in 54%, by histamine in 47%, by exercise in 46%, and by the cold pressor and handgrip tests in 11% and 7%, respectively. No significant differences were found in the responses to provocative tests of patients with normal coronary arteries or nonsignificant stenoses and those with significant lesions. In the same individual, spasm was induced by at least two vasoconstrictive stimuli, although with a different mechanism of action, in 82% of patients and spasm was induced by three or more stimuli in 39%. Tests were repeated in at least 23 patients and short-term reproducibility paralleled sensitivity. These results suggest that in patients with variant angina, a local nonspecific supersensitivity rather than an abnormal specific agonist-receptor interaction plays a major role in the genesis of coronary arterial spasm.

A new strategy for the assessment of viable myocardium and regional myocardial blood flow using 15O-water and dynamic positron emission tomography.

BackgroundWe have developed a new measure of myocardial viability, the water-perfusable tissue index (PTI), which is calculated from transmission, C1550, and H215O positron emission tomography (PET) data sets. It is defined as the proportion of the total anatomical tissue within a given region of interest (ROI) that is capable of rapidly exchanging water and has units g (perfusable tissue)/g (total anatomical tissue). The aim of this study was to assess the prognostic value of PMI in predicting improvement in regional wall motion after successful thrombolysis for acute myocardial infarction (AMI) and to measure the myocardial blood flow to the perfusable tissue (MBFp, ml/min/g [perfusable tissue]). Furthermore, PTI was compared with 18FDG metabolic imaging in patients with old myocardial infarction (OMI). Methods and ResultsPET scans were performed in healthy volunteers (group 1, n = 8), patients with OMI (group 2, n = 15), and in patients who were successfully thrombolysed after an AMI (group 3, n = 11). Systolic wall thickening was measured by two-dimensional echocardiography within 2–4 days of AMI and after 4 months to assess contractile recovery. In the healthy volunteers, MBFp was 0.95±0.13 ml/min/g (perfusable tissue). PTI in these regions was 1.08±0.07 g (perfusable tissue)/g (total anatomical tissue), which was consistent with all normal myocardium being perfusable by water. In the OMI group, the ratio of the relative 18FDG activity to the relative MBFp defect (metabolism-flow ratio) was calculated for each asynergic segment. Regions in which the metabolism-flow ratio was ≥1.20 were considered reversibly injured, whereas those in which the ratio was < 1.20 were deemed irreversibly injured. PTI in the former group of regions (n = 9) was 0.75±0.14 g (perfusable tissue)/g (total anatomical tissue) and was significantly higher than in irreversibly injured regions (n = 6) (0.53±0.12 g [perfusable tissue]/g [total anatomical tissue], p<0.01). Values of MBFp were similar in these segments. Seven of 12 segments in the AMI patients showed improved systolic wall thickening on follow-up. PTI in these recovery segments was 0.88±0.10 g (perfusable tissue)/g (total anatomical tissue) (p = NS versus control). PTI in the nonrecovery regions was 0.53±0.11 g (perfusable tissue)/g (total anatomical tissue), which was similar to the segments in group 2 in which 18FDG uptake was absent. MBFp was similar in both the recovery and nonrecovery segments in the subacute phase. ConclusionsThese data indicate that PTI may be a good prognostic indicator for the recovery of contractile function after successful thrombolysis and show that myocardial viability may be assessed by PET without metabolic imaging.

Noninvasive Quantification of Regional Myocardial Metabolic Rate for Oxygen by Use of 15O2 Inhalation and Positron Emission Tomography Theory, Error Analysis, and Application in Humans

BACKGROUND A method has been developed to measure the regional myocardial metabolic rate of oxygen consumption (rMMRO2) and oxygen extraction fraction (rOEF) quantitatively and noninvasively in humans by use of 15O2 inhalation and positron emission tomography. This article describes the theory, an error analysis of the technique, and procedures of the method used in a human feasibility study. METHODS AND RESULTS Inhaled 15O2 is transported to peripheral tissues, where it is converted to 15O-labeled water of metabolism, which exchanges with the relatively large extravascular tissue space. Quantification of this buildup of radioactivity allows the calculation of rMMRO2 and rOEF. However, a correction for the spillover of the pulmonary gas radioactivity signal into myocardial regions is required and has been made by use of a gas volume distribution estimated from the transmission scan. This was validated by comparative measurements using the inert gas [11C]CH4 in four greyhounds. Spillover of the cardiac chamber radioactivity has been corrected for with an inhaled [13O]CO (blood volume) scan. The underestimation of myocardial radioactivity due to wall motion and thickness has been corrected for by use of values of tissue fraction obtained from the flow measurement [15OKCO2 scan). Values of rOEF were similar (within 4%) whether obtained from gas volume measurements determined from the transmission or [11C]CH4 scan data. 15O2 scan information from six healthy volunteers showed a clear distribution of myocardial radioactivity after the vascular and pulmonary gas 15O background was subtracted. Subsequent compartmental analysis resulted in values for rOEF and rMMRO2 of 0.60 +/- 0.11 and 0.10 +/- 0.03 mL.min-1.g-1 in the human myocardium at rest. CONCLUSIONS The results of this study are in good agreement with established values. This is the first known approach to allow the direct quantitative determination of rOEF and oxygen metabolism to be made noninvasively on a regional basis.

Intracoronary endothelin induces myocardial ischemia by small vessel constriction in the dog

Abstract Since the original observations made with acetylcholine, 1 several vasodilators have been shown to cause smooth muscle relaxation by stimulating the secretion of endothelium-derived relaxing factors. 2 It has also been shown that the vasoconstrictor effect of noradrenaline, neuropeptide Y, thrombin and hypoxia may be mediated by diffusable endothelium-derived contracting factors, 3,4 such as the pressor agent present in the supernatant of cultured endothelial cells described by Hickey et al. 5 Subsequently, Yanagisawa et al 6 have isolated endothelin, a vasoconstrictor peptide, from the supernatant of cultured porcine aortic endothelial cells. This 21 amino acid peptide induces potent, prolonged dose-dependent contraction of isolated arterial and vein preparations from several mammalian species, including porcine coronary and human pulmonary arteries. 6 In vitro endothelin is the most potent mammalian vasoconstrictor known to date, with a median effective concentration of less than the values reported for angiotensin II, neuropeptide Y and vasopressin. 7,8 We have investigated the effects of locally infused endothelin on the canine coronary circulation in vivo.

Comparison of regional myocardial blood flow in syndrome X and one-vessel coronary artery disease

Myocardial blood flow (MBF) was measured using continuous inhalation of oxygen-15-labeled carbon dioxide, and positron emission tomography before and after intravenous dipyridamole in 13 patients with syndrome X (angina pectoris, angiographically normal coronary arteries, positive exercise test and negative ergonovine test), 7 healthy subjects and 8 patients with 1-vessel coronary artery disease (CAD). In patients with syndrome X, baseline MBF was greater than in healthy subjects and patients with CAD (1.24 +/- 0.27 vs 0.87 +/- 0.07 and 1.03 +/- 0.23 ml/g/min, respectively; p < 0.05), and more heterogeneous (34 +/- 7 vs 26 +/- 5 and 25 +/- 6, respectively; p < 0.05) as assessed by the coefficient of variation among myocardial regions < or = 2.3 cm3. After dipyridamole, MBF in patients with syndrome X was similar to that in healthy subjects (2.95 +/- 0.75 vs 3.40 +/- 0.82 ml/g/min; p = NS) and greater than in patients with CAD (1.78 +/- 0.76 ml/g/min; p < 0.05). However in patients with both syndrome X and CAD, MBF was more heterogeneous than in healthy subjects (48 +/- 12 and 48 +/- 11, respectively, vs 30 +/- 7; p < 0.01). Thus, in patients with syndrome X, MBF is abnormally heterogeneous both at baseline and after dipyridamole. These findings are compatible with the presence of dynamic alterations of small coronary arteries. Because these alterations appear to be very sparse within the myocardium, they can be undetected when myocardial perfusion, function and metabolism are assessed using conventional methods that are unable to detect small myocardial regions.

The hyperventilation test as a method for developing successful therapy in Prinzmetal's angina.

In 10 cases of Prinzmetals angina in which episodes of myocardial ischemia were easily and reproducibly induced by hyperventilation, this test was performed 111 times, 41 times under control conditions and 70 times during treatment with one or more of the following drugs: phentolamine, isosorbide dinitrate, propranolol, verapamil, nifedipine and amiodarone. Seventeen of 18 negative tests performed under the influence of a long-acting drug coincided with total remission of the patients anginal episodes when this drug was administered on a short- or long-term basis. No patient died or sustained infarction during a follow-up period of 10.9 months. A negative test was thus a good indication that the clinical response to the corresponding drug would be favorable. The electrocardiographic changes and chest pain provoked by hyperventilation occurred not when alkalosis was greatest (hydrogen ion [pH] change from 7.42 to 7.58, p less than 0.001), but when pH was approaching normal or control values. The onset of electrocardiographic changes occurred an average of 175 seconds after the end of hyperventilation and, in two cases, the time lag was as much as 480 and 705 seconds, respectively. This raises several questions regarding the true mechanism triggering coronary spasm under such conditions. The hyperventilation test appears to be a useful and safe procedure for selecting the best possible drug for long-term treatment of Prinzmetals angina as well as for comparing the relative efficacy of different drugs.

Dipyridamole vasodilator response after human orthotopic heart transplantation : quantification by oxygen-15-labeled water and positron emission tomography

To assess coronary vasodilator reserve after orthotopic heart transplantation, regional myocardial perfusion was measured with oxygen-15-labeled water and dynamic positron emission tomography in 14 cardiac allograft recipients who were not experiencing rejection and who had no angiographic evidence of epicardial coronary sclerosis 15 to 73 months (mean +/- SD 43 +/- 19) after transplantation (group I). Twelve normal men with an average age of 31 years (group II) served as a control group. Regional perfusion was measured at rest and after the intravenous administration of 0.6 mg/kg body weight of dipyridamole. Rest regional myocardial blood flow was homogeneously distributed throughout the left ventricle and was significantly higher in transplant recipients (mean 1.16 +/- 0.26 ml/g per min [range 0.8 to 1.73] than in normal subjects (mean 0.85 +/- 0.13 ml/g per min [range 0.57 to 0.99]; p = 0.001) as was rest heart rate-systolic blood pressure product (rate-pressure product 11,255 +/- 2,540 vs. 7,073 +/- 1,306; p less than 0.001). After dipyridamole, perfusion in the transplant recipients was homogeneous and slightly lower (2.73 +/- 1.03 vs. 3.40 +/- 1.09 ml/g per min; p = NS), whereas rate-pressure product was slightly higher (12,179 +/- 2,266 vs. 10,885 +/- 1,895; p = NS) than the value in normal subjects. Dipyridamole vasodilator response (dipyridamole/rest myocardial blood flow) ranged from 1.23 to 4.92 (mean 2.50 +/- 1.13) in group I and from 2.65 to 5.45 (3.97 +/- 0.89) in group II (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Improved coronary supply: Prevailing mechanism of action of nitrates in chronic stable angina☆

Exercise tolerance before and after sublingual isosorbide dinitrate (ISDN), 10 mg, was assessed in 217 consecutive patients with stable angina, positive exercise test, and angiographically proved coronary artery disease. In 65 patients (30%), ISDN prevented exercise-induced ST segment depression and/or increased exercise time to 1 mm ST segment depression (greater than or equal to 3 minutes), despite the significantly higher (greater than or equal to 25 X 10(2) increment) rate-pressure product attained (increased coronary reserve). On the contrary, in 40 other patients, exercise test remained positive, and neither time to 1 mm ST segment depression nor rate-pressure product increased significantly (fixed coronary reserve). The remaining 106 patients had an intermediate response. To assess the mechanisms underlying the beneficial action of nitrates, we further investigated 13 patients with increased coronary reserve (group 1) and five with fixed coronary reserve (group 2) by the exercise response to ISDN and verapamil, the changes in left ventricular volumes after ISDN and verapamil, the ECG response to intravenous ergonovine, and the changes in coronary stenosis severity following intravenous ergonovine and intracoronary nitrates. ISDN dramatically improved exercise capacity only in group 1 patients. However, it induced a significant reduction of left ventricular volumes in both groups (p less than 0.01). Ergonovine provoked angina and ST segment depression in 62% of group 1 patients and significantly increased the severity of their coronary stenoses (p less than 0.01). In all group 2 patients, ergonovine was negative, and no significant increase in stenosis severity was observed. Intracoronary nitrates reduced stenosis severity in group 1 (p less than 0.01) but not in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of regional myocardial blood flow using C15O2 and positron emission tomography: comparison of tracer models

Eight different modifications of the same single tissue compartment model to measure myocardial blood flow, based on inhalation of 15O-labelled CO2 and positron emission tomography, were assessed in both dogs and human normal volunteers. Several models provided results with the same degree of accuracy in dogs. However, a number of these models gave poorer results in humans. It was established that the model containing components for blood flow, fraction of water exchanging tissue and spill-over arterial blood volume provided the most accurate and reproducible results. This model contains inherent corrections for the limited spatial resolution of positron emission tomographs. For ease of computation, linearisation of the operational (fitting) equation was tested, but found not to be satisfactory. The left atrium was slightly better than the left ventricle for determining the arterial input function. Inclusion of the blood volume term in the fitting procedure was significantly better than subtracting blood volume prior to analysis, both in terms of accuracy and precision.