As it remains unclear whether hypoxia of cardiomyocytes could trigger the release of brain natriuretic peptide (BNP) in humans, we investigated whether breathing normobaric hypoxic gas mixture ...increases the circulating NT-proBNP in healthy male subjects.
Ten healthy young men (age 29 ± 5 yrs, BMI 24.7 ± 2.8 kg/m2) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for one hour. Venous blood samples were obtained immediately before, during, and 2 and 24 hours after hypoxic exposure. Cardiac function and flow velocity profile in the middle left anterior descending coronary artery (LAD) were measured by Doppler echocardiography.
Arterial oxygen saturation decreased steadily from baseline value of 99 ± 1% after the initiation hypoxia challenge and reached steady-state level of 73 ± 6% within 20-30 minutes. Cardiac output increased from 6.0 ± 1.2 to 8.1 ± 1.6 L/min and ejection fraction from 67 ± 4% to 75 ± 6% (both p < 0.001). Peak diastolic flow velocity in the LAD increased from 0.16 ± 0.04 to 0.28 ± 0.07 m/s, while its diameter remained unchanged. In the whole study group, NT-proBNP was similar to baseline (60 ± 32 pmol/ml) at all time points. However, at 24 h, concentration of NT-proBNP was higher (34 ± 18%) in five subjects and lower (17 ± 17%), p = 0.002 between the groups) in five subjects than at baseline.
In conclusion, there is no consistent increase in circulating NT-proBNP in response to breathing severely hypoxic normobaric gas mixture in healthy humans, a possible reason being that the oxygen flux to cardiac myocytes does not decrease because of increased coronary blood flow. However, the divergent individual responses as well as responses in different cardiac diseases warrant further investigations.
Abstract
Aims
Despite high variability in coronary anatomy, quantitative positron emission tomography (PET) perfusion in coronary territories is traditionally calculated according to the American ...Heart Association (AHA) 17-segments model. This study aimed to assess the impact of individualized segmentation of myocardial segments on the diagnostic accuracy of hyperaemic myocardial blood flow (MBF) values for haemodynamically significant coronary artery disease (CAD).
Methods and results
Patients with suspected CAD (n = 204) underwent coronary computed tomography angiography (CCTA) and 15OH2O PET followed by invasive coronary angiography with fractional flow reserve assessment of all major coronary arteries. Hyperaemic MBF per vascular territory was calculated using both standard segmentation according to the AHA model and individualized segmentation, in which CCTA was used to assign coronary arteries to PET perfusion territories. In 122 (59.8%) patients, one or more segments were redistributed after individualized segmentation. No differences in mean MBF values were seen between segmentation methods, except for a minor difference in hyperaemic MBF in the LCX territory (P = 0.001). These minor changes resulted in discordant PET-defined haemodynamically significant CAD between the two methods in only 5 (0.8%) vessels. The diagnostic value for detecting haemodynamically significant CAD did not differ between individualized and standard segmentation, with area under the curves of 0.79 and 0.78, respectively (P = 0.34).
Conclusions
Individualized segmentation using CCTA-derived coronary anatomy led to redistribution of standard myocardial segments in 60% of patients. However, this had little impact on 15OH2O PET MBF values and diagnostic value for detecting haemodynamically significant CAD did not change. Therefore, clinical impact of individualized segmentation seems limited.
Cardiac hybrid imaging combines different modalities in order to obtain complementary anatomical and functional information in a single imaging study. Coronary CT angiography (CTA) and myocardial ...perfusion imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET) are established noninvasive modalities for the diagnosis of coronary artery disease (CAD). Hybrid SPECT-CT or PET-CT is a promising tool for evaluation of CAD since it allows visualization of coronary atherosclerotic lesions and their consequences on myocardial blood flow in a single study. This appears to offer superior diagnostic accuracy for the detection of flow-limiting stenosis in patients with intermediate risk for CAD as compared with stand-alone imaging, especially by improving the positive predictive value. This article will review the concepts and currently available clinical experiences from cardiac hybrid imaging as well as discuss potential future applications.
Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-18F-fluoro-d- glucose (18FFDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the ...anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic 18FFDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr−/−Apob100/100).
Thirty-six Ldlr−/−Apob100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, 18FFDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta.
Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, 18FFDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). 18FFDG uptake correlated with plasma total cholesterol levels.
Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr−/−Apob100/100 mice, as determined by histology and 18FFDG PET, whereas a cholesterol-lowering diet intervention was effective.
•PET tracer 18FFDG is a sensitive marker of atherosclerotic plaque inflammation.•Potential anti-inflammatory effects of interventions were studied by 18FFDG.•Atorvastatin had no effect on plaque inflammation in Ldlr−/−Apob100/100 mice.•Chow diet reduced plasma cholesterol, plaque size and inflammation.•We found no evidence of cholesterol-independent effects on vascular inflammation.
Abstract Background and aims Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-18 F-fluoro- D - glucose (18 FFDG) into macrophages is a sensitive marker of inflammation in ...atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic 18 FFDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 ( Ldlr−/− Apob 100/100 ). Methods Thirty-six Ldlr−/− Apob 100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, 18 FFDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta. Results Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, 18 FFDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs . 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs . 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo ). 18 FFDG uptake correlated with plasma total cholesterol levels. Conclusions Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr−/− Apob 100/100 mice, as determined by histology and 18 FFDG PET, whereas a cholesterol-lowering diet intervention was effective.
Increased glutamine metabolism by macrophages is associated with development of atherosclerotic lesions. Positron emission tomography/computed tomography (PET/CT) with a glutamine analog (2S,4
)-4-
...F-fluoroglutamine (
F-FGln) allows quantification of glutamine consumption
. Here, we investigated uptake of
F-FGln by atherosclerotic lesions in mice and compared the results with those obtained using the glucose analog 2-deoxy-2-
F-fluoro-
-glucose (
F-FDG). Uptake of
F-FGln and
F-FDG by healthy control mice (C57BL/6JRj) and atherosclerotic low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR
ApoB
) was investigated. The mice were injected intravenously with
F-FGln or
F-FDG for
PET/CT imaging. After sacrifice at 70 minutes post-injection, tracer uptake was analyzed by gamma counting of excised tissues and by autoradiography of aorta cryosections, together with histological and immunohistochemical analyses. We found that myocardial uptake of
F-FGln was low. PET/CT detected lesions in the aortic arch, with a target-to-background ratio (SUV
, aortic arch/SUV
, blood) of 1.95 ± 0.42 (mean ± standard deviation). Gamma counting revealed that aortic uptake of
F-FGln by LDLR
ApoB
mice (standardized uptake value SUV, 0.35 ± 0.06) was significantly higher than that by healthy controls (0.20 ± 0.08,
= 0.03). More detailed analysis by autoradiography revealed that the plaque-to-healthy vessel wall ratio of
F-FGln (2.90 ± 0.42) was significantly higher than that of
F-FDG (1.93 ± 0.22,
= 0.004). Immunohistochemical staining confirmed that
F-FGln uptake in plaques co-localized with glutamine transporter SLC7A7-positive macrophages. Collectively these data show that the
F-FGln PET tracer detects inflamed atherosclerotic lesions. Thus, exploiting glutamine consumption using
F-FGln PET may have translational relevance for studying atherosclerotic inflammation.
The peptide-based radioactive compound 68GaGa-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of 68GaGa-DOTA-Siglec-9 is vascular ...adhesion protein 1. Previous studies have obtained promising results with 68GaGa-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats. The study was performed using 60 adult Hsd: Sprague Dawley rats and included a control group and a treatment group to investigate the toxicity of DOTA-Siglec-9 solution at a final concentration of 0.2 mg/mL after a single iv injection of 582 µg/kg. The maximum dose tested was 1,000-fold the clinical dose on a mg/kg basis as indicated in European Medicines Agency International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline M3(R2). The planned human clinical dose is approximately 0.582 µg of DOTA-Siglec-9 per kg of body mass. This study demonstrates that iv administration of DOTA-Siglec-9 at a dose of 582 µg/kg was well tolerated in rats and did not produce toxicologically significant adverse effects.
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