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Background Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis. Methods Rats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls. Results The bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31. Conclusions SPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.

PURPOSE: FDG-PET/CT has the potential to play an important role in the diagnosis of sternal wound infections (SWI). The purpose of this study was to analyze the diagnostic accuracy of FDG-PET/CT for SWI in patients following sternotomy. METHODS: We performed a single-center, retrospective analysis of patients who had undergone median sternotomy and FDG-PET/CT imaging. The gold standard consisted of positive bacterial culture and/or the presence of purulent material at surgery. Qualitative patterns of sternal FDG uptake, SUV(max), and associated CT findings were determined, and an imaging scoring system was developed. The diagnostic performances were studied in both the recent (≤ 6 months between sternotomy and imaging) and remote surgery phase (> 6 months). RESULTS: A total of 40 subjects were identified with 11 confirmed SWI cases. Consensus interpretation was associated with a sensitivity of 91% and specificity of 97%. Combination of uptake patterns yielded an AUC of 0.96 while use of SUVmax yielded an AUC of 0.82. CONCLUSIONS: Results suggest that FDG-PET/CT may be useful for the diagnosis of SWI with optimal diagnostic accuracy achieved by identifying specific patterns of uptake. SUV(max) can be helpful in assessing subjects with remote surgery, but its use is limited in the context of recent surgery. Further studies are required to confirm these results.

Purpose The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Methods Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. Results PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. Conclusions In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. Clinical trial ClinicalTrials.gov, NCT02216279 Electronic supplementary material The online version of this article (doi:10.1007/s00259-017-3655-y) contains supplementary material, which is available to authorized users.

Myocardial perfusion imaging (MPI) with positron emission tomography allows accurate measurements of myocardial blood flow (MBF). Stress MBF thresholds have been proposed to provide diagnostic and prognostic information in different pathology. Most studies relying on dipyridamole use a 5-minute infusion protocol, while current guidelines recommend a 4-minute infusion. The purpose of this study is to compare the effects of different dipyridamole infusion times on stress MBF. The charts of 2,207 patients who underwent rubidium-82 MPI were retrospectively reviewed and 147 subjects with low likelihood of significant coronary artery disease (CAD) defined as calcium score = 0, body mass index

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and 17 age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-minutes hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4 ± 6.8 [CTx] vs -24.2 ± 6.0% O2 [HC], P < 0.05) and following exercise (-23.2 ± 4.9 [CTx] vs -26.2 ± 4.7% O2 [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.

We evaluated the accuracy of planar radionuclide angiography and different count-based and space-based electrocardiogram (ECG)-gated blood-pool single-photon emission computed tomography (GBPS) algorithms for assessment of left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), and ejection fraction (LVEF) compared with the gold standard of cardiac magnetic resonance imaging (cMRI). The goal is to assess the accuracy of a recently developed GBPS algorithm.Subjects had planar, GBPS, and cMRI sequentially. Datasets were processed by QBS software (Cedar-Sinai) and by MHI software (Montreal Heart Institute). Space-based approaches were used to compute LVEDV, LVESV, and LVEF. Count-based techniques were also used to assess LVEF. All results were compared to cMRI. Fifty-five patients (85% male; mean age 63 +/- 9 years) completed the study. LVEFs and their correlations to cMRI values were 43 +/- 12% (r = .82), 39 +/- 14% (r = .82), and 39 +/- 13% for MHI(space), QBS(space), and cMRI methodologies, respectively. LVEF by count-based methods also demonstrated good correlation to LVEF provided by cMRI (42 +/- 13%, r = .88 for MHI(count) and 46 +/- 15%, r = .84 for QBS(count)). Strong correlations were obtained for LVEDV (r = .96 for MHI and r = .92 for QBS) and for LVESV (.97 for MHI and r = .94 for QBS).All Gated blood-pool SPECT algorithms had significant variation in estimating LVEF. Nevertheless our software provides good estimates of LV volumes and LVEF. Such software may, therefore, be applied to assess LV morphology and function.

Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the adrenomedullin receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with 99mTc-PulmoBind for SPECT imaging. Results were compared with 99mTc-PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. PulmoBind uptake in humans was 58 ± 1 % (mean ± SEM) of the injected dose. Dorsal activity was 18.1 ± 2.1 % greater than ventral, and caudal activity was 25.7 ± 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 ± 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 ± 2.5 %, caudal 34.1 ± 5.0 % and lateral 18.1 ± 2.0 %. The perfused pulmonary circulation of supine humans, assessed by an adrenomedullin receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. ClinicalTrial.gov, NCT01539889

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99m Tc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99m Tc-PulmoBind. SPECT imaging was serially performed, and 99m Tc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99m Tc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99m Tc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.

Precise identification of left ventricular (LV) systolic mechanical dyssynchrony may be useful in optimizing the response to cardiac resynchronization therapy in heart failure (HF) patients. However, LV dyssynchrony is mostly measured at rest; patients often suffer from the HF symptoms during exercise.Our objective was to examine the impacts of stress on LV synchronism with phase analysis of gated SPECT myocardial perfusion imaging (GMPS) within a normal animal cohort.Stress was induced with different levels of dobutamine infusion in six healthy canine subjects. Hemodynamic properties were assessed by LV pressure measurements. Also, LV mechanical synchronism (coordination of LV septal and lateral wall at the time of contraction) was determined by phase analysis of GMPS using commercially available QGS software and in-house MHI4MPI software, with the thickening- and displacement-based method. Synchrony indexes in MHI4MPI included the septal-to-lateral delay and homogeneity index, derived from each of the two methods. Also, bandwidth, SD, and entropy (synchrony indexes) of the QGS software were assessed.LVEF increased from 36.7% ± 8.7% at rest to 53.67% ± 12.34% at 20 μg · kg(-1) · minute(-1) (P.001). Also, cardiac output increased from 3.67 ± 1.0 L · minute(-1) at rest to 8.4 ± 2.6 L · minute(-1) at 10 μg · kg(-1) · minute(-1) (P.001). The same trend was observed for dP/dt max which increased from 1,247 ± 382.7 at rest to 5,062 ± 1,800 mm Hg · s(-1) at 10 μg · kg(-1) · minute(-1) (P.01). Entropy decreased from 55.2% ± 8% at baseline to 43.5% ± 8.5% at 5 and 43.0% ± 3.7% at 10 μg · kg(-1) · minute(-1) dobutamine (P.01). Thickening homogeneity index showed a difference from 91.7% ± 5.53% at rest to 98.2% ± 0.75% at 20 μg · kg(-1) · minute(-1) (P.05).Dobutamine stimulation could amplify the ventricular synchronism, and the thickening-based approach is more accurate than wall displacement for assessment of mechanical dyssynchrony in GMPS.

In cardiac resynchronization therapy, many devices need to be optimized to take into account the magnitude and characteristics of patients' ventricular mechanical dyssynchrony. The optimization process is mostly performed at rest; however, mechanical resynchronization might be more important under stress, while patients need to improve their cardiac efficiency. The objective of this study was to observe if levels of cardiac stress could modify the ventricular contraction synchronism. Cardiac stress was induced with dobutamine infusion in eight healthy canine subjects. Hemodynamic and ventricular synchronism assessments were performed by left ventricular pressure measurements and radionuclide tomographic-gated blood pools. Cardiac output increased from 2.8 ± 1.0 at rest to 5.7 ± 2.2 L min(-1) at 20 µg kg(-1) min(-1), while the ventricular performance (dP/dtmax) increased from 1588 ± 374 to 8004 ± 710 mmHg s(-1). At baseline, the interventricular delay (in degrees) was -6.3 ± 2.6°, the left ventricle contraction preceding the right. The delay significantly increased to -21.6 ± 3.1° with dobutamine stress (p < 0.0001). On assessment of the left intraventricular synchrony, septal-to-lateral delay was -6.9 ± 5.1° at baseline which revealed a preceded contraction of the left lateral wall from the septum. Cardiac stress produced a significant modulation (p = 0.01), with an inversion of the contraction pattern, the septum contraction preceding the lateral wall contraction by 15.5 ± 5.6° at maximum dobutamine infusion; a significant linear trend (p < 0.001) was found between cardiac stress levels and septal-to-lateral delays. Cardiac activity levels modified the ventricular synchronism supporting the fact that optimizations of cardiac resynchronization devices could be improved by taking cardiac stress into account.

The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. To evaluate the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular

Cardiac resynchronization therapy may improve survival and quality of life in patients suffering from heart failure with left ventricular (LV) contraction dyssynchrony. While several studies have investigated electrical or mechanical determinants of synchronous contraction, few have focused on activation contraction coupling at a macroscopic level. The objective of the study was to characterize LV electromechanical behavior and response to pacing in a heart failure model. We analyzed data from 3D electroanatomic non-contact mapping and blood pool SPECT for 12 dogs with right ventricular (RV) tachycardia pacing-induced dilated cardiomyopathy. Surfaces generated by the two modalities were registered. Electrical signals were analyzed, and endocardial wall displacement curves were portrayed. Rapid pacing decreased the mean LV ejection fraction (LVEF) to 20.9 % and prolonged the QRS duration to 79 ± 10 ms (normal range: 40–50 ms). QRS duration remained unchanged with biventricular pacing (88.5 ms), while single site pacing further prolonged the QRS duration (113.3 ms for RV pacing and 111.6 ms for LV pacing). No trend was observed in LV systolic function. Activation duration time was significantly increased with all pacing modes compared to baseline. Finally, electromechanical delay, as defined by the delay between electrical activation and mechanical response, was increased by single site pacing (172.9 ms for RV pacing and 174.6 ms for LV pacing) but not by biventricular pacing (162.4 ms). Combined temporal and spatial coregistration electroanatomic maps and baseline gated blood pool SPECT imaging allowed us to quantify activation duration time, electromechanical delay, and LVEF for different pacing modes. Even if pacing modes did not significantly modify LVEF or activation duration, they produced alterations in electromechanical delay, with biventricular pacing significantly decreasing the electromechanical delay as measured by surface tracings and endocardial non-contact mapping.

Peripheral arterial flow has been assessed for a variety of indications including characterization of endothelial function during reactive hyperemia. However, quantification of this blood flow as a surrogate remains an imperfect reflection of endothelial function. We sought to better characterize hyperemic reaction to (1) elucidate the influence of the endothelial function and (2) assess the reproducibility of our modeling over time. Sixteen normal subjects underwent simultaneous forearm reactive hyperemia testing with a near-infrared system at baseline, baseline +24 h and baseline +27 h. Baseline flow was measured to 3.6 +/- 0.2 ml dl(-1) min(-1), and was highly reproducible 24 and 27 h later. With reactive hyperemia, the blood flow increased to 20.5 +/- 4.6 ml dl(-1) min(-1). Arterial blood flow curves during reactive hyperemia displayed a bimodal pattern, with the second peak occurring 59.1 +/- 10.6 s after the onset of hyperemia. We believe that this latest peak represents the contribution of endothelial factors to the hyperemic reaction. Modeling of hyperemic curves led to the introduction of a reproducible new parameter (etafactor) that reflects the normalized contribution of this second peak. In conclusion, forearm arterial flow during reactive hyperemia revealed a bimodal distribution where functional interpretation allowed distinction of the two components. Basal flow measurements and results of this modeling were reproducible 24 and 27 h later.