Christopher G. Rhodes

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)

Glucose Utilization In Vivo by Human Pulmonary Neoplasms

Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission tomography (PET) we measured the rate of uptake of the glucose analogue 18fluoro‐2‐deoxy‐D‐glucose (18FDG) in 12 patients with carcinoma of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carcinoma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of 18FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scans over 1 hour. In each patient the rate of uptake of 18FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group the rate of uptake by the tumor was 211.4 ± 69.4 ml/100 g/hr (mean ± SD) compared to 31.9 ± 13.2 in the contralataral lung (P < 0.05). The tumor‐to‐normal tissue ratio of 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to brain tumors there was little correlation between tumor type and rate of 18FDG uptake. Measurements of glucose metabolism taken in vivo in human pulmonary tumors may lead to advances in screening, staging, and therapy.

Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography.

Regional pulmonary glucose metabolism (MRglu; μmol h−1 g−1), extravascular lung density (DEV; g cm−3) and vascular volume (VB; ml cm−3) were measured in a single midthoracic transaxial slice (≈2 cm thick) using positron emission tomography (PET) in seven patients with histologically proven sarcoidosis. The measurements were repeated 1–7 months later after steroid therapy (in two cases, no treatment) in order to assess MRglu as an index of inflammation and relate it to routine pulmonary function tests, chest radiography and serum angiotensin converting enzyme (SACE) levels. MRglu was computed from serial lung scans and peripheral venous blood samples for 60 min following an i.v. injection of 18F-2-fluoro-2-deoxy-D-glucose (18FDG). Both MRgu (which was increased in six of seven patients) and elevated SACE levels returned to normal in those patients treated with high-dose steroids. Regional vascular volume was normal in six of seven cases and did not change significantly with therapy. The high tissue density measured in all patients decreased significantly in two of three patients treated with 40 mg prednisolone daily. The abnormal MR& observed in active sarcoidosis becomes normal pari passu with SACE levels during high-dose steroid therapy. We conclude that MRglu measured with 18FDG and PET may reflect “disease activity” in sarcoidosis in quantitative terms (per gram lung tissue) and in respect of disease distribution.

Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy

Although hypertrophic cardiomyopathy (HCM) is genetically determined, several other factors, including autonomic dysfunction, may play a role in the phenotypic expression. A recent study using positron emission tomography with [11C]CGP 12177 ([11C]CGP) demonstrated that beta-adrenoceptor (betaAR) density is reduced in HCM and is correlated with disease progression. This present study tested the hypothesis that this downregulation is associated with reduced catecholamine reuptake (uptake 1) by myocardial sympathetic nerve terminals leading to increased local norepinephrine concentration. Myocardial presynaptic catecholamine reuptake was assessed by measuring the volume of distribution (Vd) of the catecholamine analogue [11C]hydroxyephedrine ([11C]HED) in 9 unrelated HCM patients aged 45+/-15 years. The maximum number of binding sites (Bmax) for myocardial betaAR density was measured in 13 unrelated HCM patients aged 40+/-12 years using the nonselective beta blocker [11C]CGP. Six patients were studied with both [11C]HED and [11C]CGP. Comparison was made with two groups of healthy control subjects for each ligand ([11C]HED, n=10, aged 35+/-8 years; [11C]CGP, n=19, aged 44+/-16 years). Myocardial Vd of [11C]HED (33.4+/-4.3 mL/g tissue) and betaAR density (7.3+/-2.6 pmol/g tissue) were significantly reduced in HCM patients compared with control subjects (71.0+/-18.8 mL/g tissue, P<.001, and 10.2+/-2.9 pmol/g tissue, P=.008, respectively). These results are consistent with our hypothesis that myocardial betaAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.

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.

Abnormalities of Cardiac Sympathetic Innervation in Arrhythmogenic Right Ventricular Cardiomyopathy Quantitative Assessment of Presynaptic Norepinephrine Reuptake and Postsynaptic β-Adrenergic Receptor Density With Positron Emission Tomography

BACKGROUND The frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergic properties suggest an involvement of the cardiac adrenergic system in arrhythmogenesis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by (123)I-MIBG-single-photon emission computed tomography. METHODS AND RESULTS This study investigated neuronal reuptake of norepinephrine (uptake-1) and beta-adrenergic receptor density in 8 patients with ARVC and 29 age-matched control subjects. All subjects underwent positron emission tomography with the volume of distribution (V(d)) of [(11)C]hydroxyephedrine ((11)C-HED) used to assess presynaptic norepinephrine reuptake, the maximum binding capacity (B(max)) of [(11)C]CGP-12177 ((11)C-CGP-12177) to assess postsynaptic beta-adrenergic receptor density, and [(15)O]H(2)O for quantification of myocardial blood flow. Patients with ARVC demonstrated a highly significant global reduction in postsynaptic beta-adrenergic receptor density compared with that in control subjects (B(max) of (11)C-CGP-12177: 5.9+/-1.3 vs 10.2+/-2.9 pmol/g tissue, P<0.0007), whereas the presynaptic uptake-1 tended toward reduction only (V(d) of (11)C-HED: 59.1+/-25.2 vs 71.0+/-18.8 mL/g tissue, NS). There were no differences in myocardial blood flow between the groups, and plasma norepinephrine was within normal limits in patients and control subjects. CONCLUSIONS The findings demonstrate a significant reduction of myocardial beta-adrenergic receptor density in patients with ARVC. This may result from a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the result of impaired presynaptic catecholamine reuptake. These findings give new insights into the pathophysiology of arrhythmogenesis in ARVC, with potential impact on diagnostic evaluation and therapeutic management.

Detection of intrapulmonary hemorrhage with carbon monoxide uptake. Application in goodpasture's syndrome.

We devised a noninvasive measure of pulmonary hemorrhage of value in the management of Goodpastures syndrome. We reasoned that alveolar uptake of inhaled carbon monoxide during breath holding would increase in the presence of extravascular blood, but clearance of its radioisotope (C15O) from a lung field would be delayed. Thus, the ratio of uptake to clearance would indicate lung hemorrhage. In 15 controls and six patients with renal failure without hemorrhage, this ratio ranged from 0.73 to 1.5. In eight patients with Goodpastures syndrome the ratio ranged from 1.5 to 16.5, returning to normal between episodes of bleeding. Measurements of carbon monoxide uptake alone in 10 patients with Goodpastures syndrome were at times well above that predicted for their hemoglobin level, whereas in renal failure with acute pulmonary edema increased carbon monoxide uptake was rarely found. Thus, monitoring of the single-breath carbon monoxide uptake alone can detect episodes of lung hemorrhage.

Correction for the Presence of Intravascular Oxygen-15 in the Steady-State Technique for Measuring Regional Oxygen Extraction Ratio in the Brain: 2. Results in Normal Subjects and Brain Tumour and Stroke Patients

Values of regional cerebral oxygen extraction ratio and oxygen utilisation obtained with the oxygen-15 steady-state inhalation technique have been found to be overestimated due to the signal from intravascular oxygen-15. A previously described method to correct for this intravascular component has been applied to a series of studies on normal subjects, and on brain tumour and stroke patients. With this correction the regional cerebral oxygen extraction ratio in normals becomes comparable to the global values previously reported with arteriovenous sampling techniques. Within the lesions of brain tumour and stroke patients, the corrections have been found to be variable and often substantial. It is concluded that failure to apply this correction may result in major errors in the values for regional oxygen extraction ratio and oxygen utilisation. This is especially true when the regional blood flow and oxygen extraction ratio of a tissue is low and regional blood volume is high.

Quantitative measurement of regional extravascular lung density using positron emission and transmission tomography

A technique has been developed to measure regional values of vascular and extravascular lung density using positron emission and transmission tomography. Quantitative values of lung density in a transaxial plane are obtained by recording transmission scans during the exposure of a ring source of positron emitting germanium/gallium-68, which encircles the subject in the plane of the scan. Values of blood density are obtained by scanning in the emission mode following the labelling of the subjects red blood cells with a quantity of 11C-carbon monoxide inhaled as a bolus. Subtraction of the normalised blood volume scan from the normalised lung density (transmission) scan provides regional values of extravascular lung density. The response of the transmission scan to changes in density was obtained by scanning different tissue equivalent materials in the density range 0.02 to 1.0 g cm-3. This resulted in a linear relationship between pixel counts and density. Density measurements made in vitro on simulated chest phantoms suggest that, at worst, random errors of 3.5% and systematic errors (due to the influence of the chest wall) of between 10 and 15% will be incurred when measurements are made in vivo on lungs of average normal density (0.3 g cm-3). The random error associated with the emission scan (arising from counting statistics alone) was found to be 1.2%. Measurements of lung density made on five normal subjects (supine) resulted in a mean density of 0.29 g cm-3 for a region in the lower (caudal) part of the lung, with a range of values between 0.26 and 0.32 g cm-3 from subject to subject. A pronounced anteroposterior gradient of both lung density and blood density was observed, while the gradient of extravascular lung density was quite small. The mean value of the ratio extravascular:vascular lung density for both caudal and cranial lung regions was 0.92 ± 0.25.

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.