Impaired myocardial perfusion is associated with increasing end-systolic- and end-diastolic volumes in patients with non-ischemic systolic heart failure: a cross-sectional study using Rubidium-82 PET/CT.

BACKGROUND: Myocardial flow reserve (MFR, stress/rest myocardial blood flow) is a strong marker of myocardial vasomotor function. MFR is a predictor of adverse cardiac events in patients with non-ischemic systolic heart failure and previous studies using different methods have found association between myocardial blood flow and left ventricular dilatation. The aim of this study was to investigate whether there is an association between increasing end-systolic- and end-diastolic volumes (ESV and EDV) and MFR in these patients measured with Rubidium-82 positron emission tomography computed tomography (82Rb-PET/CT) as a quantitative myocardial perfusion gold-standard. METHODS: We scanned 151 patients with non-ischemic heart failure with initial left ventricular ejection fraction ≤35% with 82Rb-PET/CT at rest and adenosine-induced stress to obtain MFR and volumes. To account for differences in body surface area (BSA), we used indexed ESV (ESVI): ESV/BSA (ml/m2) and EDV (EDVI). We identified factors associated with MFR using multiple regression analyses. RESULTS: Median age was 62 years (55-69 years) and 31% were women. Mean MFR was 2.38 (2.24-2.52). MFR decreased significantly with both increasing ESVI (estimate - 3.7%/10 ml/m2; 95% confidence interval [CI] -5.6 to - 1.8; P < 0.001) and increasing EDVI (estimate - 3.5%/10 ml/m2; 95% CI -5.3 to - 1.6; P < 0.001). Results remained significant after multivariable adjustment. Additionally, coronary vascular resistance during stress increased significantly with increasing ESVI (estimate: 3.1 mmHg/(ml/g/min) per (10 ml/m2); 95% CI 2.0 to 4.3; r = 0.41; P < 0.0001) and increasing EDVI (estimate: 2.7 mmHg/(ml/g/min) per (10 ml/m2); 95% CI 1.6 to 3.8; r = 0.37; P < 0.0001). CONCLUSIONS: Impaired MFR assessed by 82Rb-PET/CT was significantly associated with linear increases in ESVI and EDVI in patients with non-ischemic systolic heart failure. Our findings support that impaired microvascular function may play a role in heart failure development. Clinical trials investigating MFR with regard to treatment responses may elucidate the clinical use of MFR in patients with non-ischemic systolic heart failure. TRIAL REGISTRATION: Sub study of the randomized clinical trial: A DANish randomized, controlled, multicenter study to assess the efficacy of Implantable cardioverter defibrillator in patients with non-ischemic Systolic Heart failure on mortality (DANISH), ClinicalTrials.gov Identifier: NCT00541268 .

Saline-push improves rubidium-82 PET image quality.

INTRODUCTION: Rubidium-82 (82Rb) PET is used widely for myocardial perfusion imaging. The purpose of this study was to investigate if an additional saline-push following the 82Rb elution improves PET image quality. METHODS: 82Rb PET scans were acquired with and without 26 mL saline-push in six patients as part of a clinical quality improvement program. Dynamic images were analyzed to measure the total activity delivered to the superior vena cava (SVC) and retained in the left ventricle (LV) myocardium. Tracer uptake images were used to measure blood background coefficient-of-variation (COV), myocardium-to-blood signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) to assess image quality. RESULTS: Similar eluted activity was measured with/without the saline-push (830 vs 795 MBq; P = 0.24). The activity delivered to the heart and retained in the myocardium was consistently increased more than twofold (SVC: + 114% and LV: + 104%; P < 0.001) with the saline-push. Image quality was improved in all patients, with lower background noise (COV: - 19%), higher SNR (+ 24%) and CNR (+ 27%) (all P ≤ 0.01). CONCLUSIONS: The saline-push used to flush 82Rb activity out of the infuser tubing, patient injection and intravenous access lines consistently increased the activity delivered to the heart by twofold. This technique is recommended to maximize image quality with 82Rb PET.

Randomized Trial Comparing the Effects of Ticagrelor Versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease.

BACKGROUND: Ticagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non-antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine-induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine-induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel. METHODS AND RESULTS: This randomized double-blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate- and high-dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate-dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high-dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline. CONCLUSIONS: Ticagrelor potentiates global and regional adenosine-induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.

Rb-82 PET/CT left ventricular mass-to-volume ratios.

Left ventricular (LV) mass:volume ratios indexed to body size (Mi/Vi) provide risk stratification for cardiac events. We sought to determine whether Rb-82 PET mass and volume indices are similar to MRI normal values for low likelihood subjects, and whether abnormal indices are related to abnormal myocardial blood flow (MBF). Data were analyzed retrospectively for 194 patients referred for rest/stress Rb-82 PET. LV EF, volume and mass values were calculated and mass:volume ratios were indexed to patients' height and weight. MBF was computed from the first pass dynamic component of PET data. 53 patients at low likelihood of CAD had PET Mi/Vi = 1.35 ± 0.27, consistent with the MRI literature range of 1.0-1.5. Compared to patients with normal indexed volume (Vi), patients with abnormally high Vi had lower rest MBF (0.56 ± 0.24 vs 0.93 ± 0.57 ml/g/min, p = 0.0001), and lower stress MBF (0.97 ± 0.52 vs. 1.83 ± 0.96 ml/g/min, p < 0.0001). Stress EF < 50% predicted abnormal Vi with 90% accuracy. Patients with Mi/Vi < 1.0 had abnormally low rest EF (45 ± 16% vs. 60 ± 15%, p < 0.0001) and low rest MBF (0.58 ± 0.25 vs. 0.96 ± 0.59 ml/g/min, p < 0.0001). In our study population, abnormal LV volume and mass correlated with lower rest and stress MBF and EF, suggesting that the pathophysiologic explanation of these patients' increased risk is more extensive obstructive CAD.

Optimal Adenosine Stress for Maximum Stress Perfusion, Coronary Flow Reserve, and Pixel Distribution of Coronary Flow Capacity by Kolmogorov-Smirnov Analysis.

BACKGROUND: Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease. METHODS AND RESULTS: In 127 volunteers, serial rest-stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test-retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov-Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients. CONCLUSIONS: The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients.

Semi-quantitative myocardial perfusion measured by computed tomography in patients with refractory angina: a head-to-head comparison with quantitative rubidium-82 positron emission tomography as reference.

INTRODUCTION: Computed tomography (CT) is a novel method for assessment of myocardial perfusion and has not yet been compared to rubidium-82 positron emission tomography (PET). We aimed to compare CT measured semi-quantitative myocardial perfusion with absolute quantified myocardial perfusion using PET and to detect stenotic territories in patients with severe coronary artery disease. MATERIALS AND METHODS: Eighteen patients with stenosis narrowing coronary arteries ≥70% demonstrated on invasive coronary angiography underwent rest and adenosine stress imaging obtained by 320-multidetector CT scanner and CT/PET 64-slice scanner. CT measured myocardial attenuation density (AD) and perfusion index (PI) were correlated to absolute PET myocardial perfusion values. RESULTS: Rest AD, rest and stress PI did not correlate to PET findings (r = 0·412, P = 0·113; r = 0·300, P = 0·259; and r = 0·508, P = 0·064, respectively). However, there was a significant correlation between stress AD and stress PET values (r = 0·670, P = 0·009) and between stress and rest differences for AD and PI with PET differences (r = 0·620, P = 0·006; and r = 0·639, P = 0·004, respectively). Furthermore, significant differences were observed between remote and stenotic territories for rest and stress AD (48 ± 14HU and 37 ± 16HU, P = 0·002; 76 ± 19HU and 58 ± 13HU, P<0·001, respectively), PI (9·6 ± 2·9 and 7·5 ± 3·1, P = 0·002; 21·6 ± 4·1 and 16·9 ± 3·9, P<0·001, respectively) and PET (0·96 ± 0·37 ml g-1  min-1 and 0·86 ± 0·26 ml g-1  min-1 , P = 0·036; 2·07 ± 0·76 ml g-1  min-1 and 1·61 ± 0·76 ml g-1  min-1 , P = 0·006, respectively). CONCLUSIONS: Semi-quantitative CT parameters may be useful in the detection of myocardium subtended by stenotic coronary arteries.

An Analysis of 3 Common CardioGen-82 82Rb Infusion System Injection Methods and Their Impact on Clinical Volume and Image Counts.

UNLABELLED: In the wake of the Food and Drug Administration (FDA) recall, many clinics have had to reduce their examination volumes to meet the new generator volume usage requirements. This review tests 3 common infusion methods and how they affect patient dose, generator volume usage, image counts, and generator volume limits. METHODS: Three common configurations of the (82)Rb infusion system settings--standard 50-mL, volume-limiting, and bolus methods--were tested to determine how they affect patient dose, generator volume, and image counts. Each injection configuration was tested daily for the duration of 3 consecutive generators by injection into separate vials. Each injection configuration was also infused into a beaker and imaged to determine the impact of image counts for each method. The total estimated volumes for multiple examination and quality assurance clinical situations were simulated to observe the use of each method relative to the new FDA volume alert and expiration limits. RESULTS: Vial tests confirmed that the bolus method used the least amount of volume per infusion and stayed the most consistent throughout the life of the generator. The bolus method also produced a lower patient dose after approximately 10 d of use. The beaker tests in the scanner showed that the standard 50-mL method produced the greatest number of total counts for the flow and uptake images. On the basis of the estimated total volume simulations, the bolus method allowed for the most examinations over the life of the generator while staying within the new FDA limits. CONCLUSION: All 3 methods for augmenting the (82)Rb infusion system produced different outcomes for patient dose, image counts, and total generator volume use. The standard 50-mL method ensured the maximum amount of counts available for imaging throughout the life of the generator. The bolus method provided a consistent and predictable amount of volume use. The volume-limiting method fell somewhere in the middle of volume predictability and count preservation.

Radiation dosimetry of 82Rb in humans under pharmacologic stress.

UNLABELLED: (82)Rb is used with PET for cardiac perfusion studies. Using human biokinetic measurements, in vivo, we recently reported on the resting-state dosimetry of this agent. The objective of this study was to obtain (82)Rb dose estimates under stress. METHODS: (82)Rb biokinetics were obtained in 10 healthy volunteers (5 male, 5 female; mean age ± SD, 33 ± 10 y; age range, 18-50 y) using whole-body PET/CT. The 76-s half-life of (82)Rb and the corresponding need for pharmacologic vasodilation require that all imaging be completed within 10 min. To accommodate these constraints, while acquiring the data needed for dosimetry we used the following protocol. First, a whole-body attenuation correction CT scan was obtained. Then, a series of 3 whole-body PET scans was acquired after a single infusion of 1.53 ± 0.12 GBq of (82)Rb at rest. Four minutes after the infusion of a 0.56 mg/kg dose of the vasodilator, dipyridamole, 3 serial whole-body PET scans were acquired after a single infusion of 1.50 ± 0.16 GBq of (82)Rb under stress. The time-integrated activity coefficient (TIAC) for stress was obtained by scaling the mean rest TIAC obtained from our previous rest study by the stress-to-rest TIAC ratio obtained from the rest-stress measurements described in this report. RESULTS: The highest mean organ-absorbed doses under stress were as follows: heart wall, 5.1, kidneys, 5.0, lungs, 2.8, and pancreas, 2.4 µGy/MBq (19, 19, 10.4, and 8.9 mrad/mCi, respectively). The mean effective doses under stress were 1.14 ± 0.10 and 1.28 ± 0.10 µSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection, publications 60 and 103, respectively. CONCLUSION: Appreciable differences in source-organ biokinetics were observed for heart wall and kidneys during stress when compared with the previously reported rest study. The organ receiving the highest dose during stress was the heart wall. The mean effective dose calculated during stress was not significantly different from that obtained at rest.

Human biodistribution and radiation dosimetry of 82Rb.

UNLABELLED: Prior estimates of radiation-absorbed doses from (82)Rb, a frequently used PET perfusion tracer, yielded discrepant results. We reevaluated (82)Rb dosimetry using human in vivo biokinetic measurements. METHODS: Ten healthy volunteers underwent dynamic PET/CT (6 contiguous table positions, each with separate (82)Rb infusion). Source organ volumes of interest were delineated on the CT images and transferred to the PET images to obtain time-integrated activity coefficients. Radiation doses were estimated using OLINDA/EXM 1.0. RESULTS: The highest mean absorbed organ doses (µGy/MBq) were observed for the kidneys (5.81), heart wall (3.86), and lungs (2.96). Mean effective doses were 1.11 ± 0.22 and 1.26 ± 0.20 µSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection (ICRP), publications 60 and 103, respectively. CONCLUSION: Our current (82)Rb dosimetry suggests reasonably low radiation exposure. On the basis of this study, a clinical (82)Rb injection of 2 × 1,480 MBq (80 mCi) would result in a mean effective dose of 3.7 mSv using the weighting factors of the ICRP 103-only slightly above the average annual natural background exposure in the United States (3.1 mSv).

Drug-induced alterations in tumour perfusion yield increases in tumour cell radiosensitivity.

The perfusion of human tumour xenografts was manipulated by administration of diltiazem and pentoxifylline, and the extent that observed changes in tumour perfusion altered tumour radiosensitivity was determined. 2 tumour systems having intrinsically different types of hypoxia were studied. The responses of SiHa tumours, which have essentially no transient hypoxia, were compared to the responses of WiDr tumours, which contain chronically and transiently hypoxic cells. We found that relatively modest increases in net tumour perfusion increased tumour cell radiosensitivity in WiDr tumours to a greater extent than in SiHa tumours. Moreover, redistribution of blood flow within WiDr tumours was observed on a micro-regional level that was largely independent of changes in net tumour perfusion. Through fluorescence-activated cell sorting coupled with an in vivo-in vitro cloning assay, increases in the radiosensitivity of WiDr tumour cells at intermediate levels of oxygenation were observed, consistent with the expectation that a redistribution of tumour blood flow had increased oxygen delivery to transiently hypoxic tumour cells. Our data therefore suggest that drug-induced changes in tumour micro-perfusion can alter the radiosensitivity of transiently hypoxic tumour cells, and that increasing the radiosensitivity of tumour cells at intermediate levels of oxygenation is therapeutically relevant.