Towards universal comparability of pericoronary adipose tissue attenuation: a coronary computed tomography angiography phantom study.

OBJECTIVES: Different computed tomography (CT) scanners, variations in acquisition protocols, and technical parameters employed for image reconstruction may introduce bias in the analysis of pericoronary adipose tissue (PCAT) attenuation derived from coronary computed tomography angiography (CCTA). Therefore, the aim of this study was to establish the effect of tube voltage, measured as kilovoltage peak (kVp), and iterative reconstruction on PCAT mean attenuation (PCATMA). METHODS: Twelve healthy ex vivo porcine hearts were injected with iodine-enriched agar-agar to allow for ex vivo CCTA imaging on a 256-slice CT and a dual-source CT system. Images were acquired at tube voltages of 80, 100, 120, and 140 kVp and reconstructed by using both filtered back projection and iterative reconstruction algorithms. PCATMA was measured semi-automatically on CCTA images in the proximal segment of coronary arteries. RESULTS: The tube voltage showed a significant effect on PCATMA measurements on both the 256-slice CT scanner (p < 0.001) and the dual-source CT system (p = 0.013), resulting in higher attenuation values with increasing tube voltage. Similarly, the use of iterative reconstructions was associated with a significant increase of PCATMA (256-slice CT: p < 0.001 and dual-source CT: p = 0.014). Averaged conversion factors to correct PCATMA measurements for tube voltage other than 120 kVp were 1.267, 1.080 and 0.947 for 80, 100, and 140 kVp, respectively. CONCLUSION: PCATMA values are significantly affected by acquisition and reconstruction parameters. The same tube voltage and reconstruction type are recommended when PCAT attenuation is used in multicenter and longitudinal studies. KEY POINTS: • The tube voltage used for CCTA acquisition affects pericoronary adipose tissue attenuation, resulting in higher attenuation values of fat with increasing tube voltage. • Conversion factors for pericoronary adipose tissue attenuation values could be used to adjust for differences in attenuation between scans performed at different tube voltages. • In longitudinal CCTA studies employing pericoronary adipose tissue attenuation as imaging endpoint, it is recommended to maintain tube voltage and image reconstruction type constant across serial scans.

Impact of deep learning image reconstructions (DLIR) on coronary artery calcium quantification.

BACKGROUND: Deep learning image reconstructions (DLIR) have been recently introduced as an alternative to filtered back projection (FBP) and iterative reconstruction (IR) algorithms for computed tomography (CT) image reconstruction. The aim of this study was to evaluate the effect of DLIR on image quality and quantification of coronary artery calcium (CAC) in comparison to FBP. METHODS: One hundred patients were consecutively enrolled. Image quality-associated variables (noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR)) as well as CAC-derived parameters (Agatston score, mass, and volume) were calculated from images reconstructed by using FBP and three different strengths of DLIR (low (DLIR_L), medium (DLIR_M), and high (DLIR_H)). Patients were stratified into 4 risk categories according to the Coronary Artery Calcium - Data and Reporting System (CAC-DRS) classification: 0 Agatston score (very low risk), 1-99 Agatston score (mildly increased risk), Agatston 100-299 (moderately increased risk), and ≥ 300 Agatston score (moderately-to-severely increased risk). RESULTS: In comparison to standard FBP, increasing strength of DLIR was associated with a significant and progressive decrease of image noise (p < 0.001) alongside a significant and progressive increase of both SNR and CNR (p < 0.001). The use of incremental levels of DLIR was associated with a significant decrease of Agatston CAC score and CAC volume (p < 0.001), while mass score remained unchanged when compared to FBP (p = 0.232). The underestimation of Agatston CAC led to a CAC-DRS misclassification rate of 8%. CONCLUSION: DLIR systematically underestimates Agatston CAC score. Therefore, DLIR should be used cautiously for cardiovascular risk assessment. KEY POINTS: • In coronary artery calcium imaging, the implementation of deep learning image reconstructions improves image quality, by decreasing the level of image noise. • Deep learning image reconstructions systematically underestimate Agatston coronary artery calcium score. • Deep learning image reconstructions should be used cautiously in clinical routine to measure Agatston coronary artery calcium score for cardiovascular risk assessment.

Rest/stress myocardial perfusion imaging by positron emission tomography with 18F-Flurpiridaz: A feasibility study in mice.

BACKGROUND: Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. METHODS: Rest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 27 mice aged 7-8 months. Regadenoson (0.1 µg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. RESULTS: Tracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7 to 20.0 mL·cm-3·min-1, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL·cm-3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological vasodilation for all time intervals assessed. However, while Spearman's coefficients (rs) ranged between 0.478 and 0.681, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20 to 40 min post tracer injection (R2 ≥ 0.98). Notably, K1 and VT were similarly sensitive to pharmacological vasodilation induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate coronary flow reserve (CFR) in mice. CONCLUSION: Our findings suggest that a simplified assessment of relative myocardial perfusion and CFR, based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

Role of sex hormones in modulating myocardial perfusion and coronary flow reserve.

BACKGROUND: A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. METHODS: Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. RESULTS: Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. CONCLUSION: Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

Quantification of perivascular inflammation does not provide incremental prognostic value over myocardial perfusion imaging and calcium scoring.

AIMS: Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)-based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). METHODS AND RESULTS: A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > - 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220-6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218-3.686, p = 0.008; and HR 2.071, 95% CI: 1.111-3.861, p = 0.022). CONCLUSION: FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex.

Age- and sex-dependent changes of resting amygdalar activity in individuals free of clinical cardiovascular disease.

PURPOSE: Amygdalar metabolic activity was shown to independently predict cardiovascular outcomes. However, little is known about age- and sex-dependent variability in neuronal stress responses among individuals free of cardiac disease. This study sought to assess age- and sex-specific differences of resting amygdalar metabolic activity in the absence of clinical cardiovascular disease. METHODS: Amygdalar metabolic activity was assessed in 563 patients who underwent multimodality imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography and echocardiography for the evaluation of cardiac function. RESULTS: After exclusion of 294 patients with structural or functional cardiovascular pathologies, 269 patients (128 women) remained in the final population. 18F-FDG amygdalar activity significantly decreased with age in men (r = - 0.278, P = 0.001), but not in women (r = 0.002, P = 0.983). Similarly, dichotomous analysis confirmed a lower amygdalar activity in men ≥ 50 years as compared to those < 50 years of age (0.79 ± 0.1 vs. 0.84 ± 0.1, P = 0.007), which was not observed in women (0.81 ± 0.1 vs. 0.82 ± 0.1, P = 0.549). Accordingly, a fully adjusted linear regression analysis identified age as an independent predictor of amygdalar activity only in men (B-coefficient - 0.278, P = 0.001). CONCLUSION: Amygdalar activity decreases with age in men, but not in women. The use of amygdalar activity for cardiovascular risk stratification merits consideration of inherent age- and sex-dependent variability.

Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF).

BACKGROUND: Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown. METHODS: A total of 1367 patients (352 women, mean age 63.1 ± 11.6 years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization. RESULTS: The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing-a surrogate marker for autonomic dysregulation-were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6 years, women with snLVEF experienced more often a MACE than women with normal (55-65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76). CONCLUSION: snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

The choice of an autocorrelation length in dark-field lung imaging.

Respiratory diseases are one of the most common causes of death, and their early detection is crucial for prompt treatment. X-ray dark-field radiography (XDFR) is a promising tool to image objects with unresolved micro-structures such as lungs. Using Talbot-Lau XDFR, we imaged inflated porcine lungs together with Polymethylmethacrylat (PMMA) microspheres (in air) of diameter sizes between 20 and 500 [Formula: see text] over an autocorrelation range of 0.8-5.2 [Formula: see text]. The results indicate that the dark-field extinction coefficient of porcine lungs is similar to that of densely-packed PMMA spheres with diameter of [Formula: see text], which is approximately the mean alveolar structure size. We evaluated that, in our case, the autocorrelation length would have to be limited to [Formula: see text] in order to image [Formula: see text]-thick lung tissue without critical visibility reduction (signal saturation). We identify the autocorrelation length to be the critical parameter of an interferometer that allows to avoid signal saturation in clinical lung dark-field imaging.

Potential Impact of Statins on Neuronal Stress Responses in Patients at Risk for Cardiovascular Disease.

BACKGROUND: Recent studies indicate that enhanced neuronal stress responses are associated with adverse cardiovascular outcomes. A chronic inflammatory state seems to mediate this detrimental neuro-cardiac communication. Statins are among the most widely prescribed medications in primary and secondary cardiovascular disease (CVD) prevention and not only lower lipid levels but also exhibit strong anti-inflammatory and neuroprotective effects. We therefore sought to investigate the influence of statins on neuronal stress responses in a patient cohort at risk for CVD. METHODS: 563 patients (61.5 ± 14.0 years) who underwent echocardiography and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were retrospectively identified. Metabolic activity of the amygdala, a part of the brain's salience network, was quantified by 18F-FDG uptake, while normal cardiac morphology and function were assured by echocardiography. Vertebral bone marrow metabolism, a marker of inflammatory activity, was measured by 18F-FDG PET. RESULTS: Increased neuronal stress responses were associated with an increased inflammatory activity in the bone marrow (r = 0.152, p = 0.015) as well as with a subclinical reduction in left ventricular ejection fraction (LVEF, r = -0.138, p = 0.025). In a fully-adjusted linear regression model, statin treatment was identified as an independent, negative predictor of amygdalar metabolic activity (B-coefficient -0.171, p = 0.043). CONCLUSIONS: Our hypothesis-generating investigation suggests a potential link between the anti-inflammatory actions of statins and reduced neuronal stress responses which could lead to improved cardiovascular outcomes. The latter warrants further studies in a larger and prospective population.

Myocardial 18F-FDG Uptake Pattern for Cardiovascular Risk Stratification in Patients Undergoing Oncologic PET/CT.

OBJECTIVE: Positron emission tomography/computed tomography with 18F-fluorodeoxy-glucose (18F-FDG-PET/CT) has become the standard staging modality in various tumor entities. Cancer patients frequently receive cardio-toxic therapies. However, routine cardiovascular assessment in oncologic patients is not performed in current clinical practice. Accordingly, this study sought to assess whether myocardial 18F-FDG uptake patterns of patients undergoing oncologic PET/CT can be used for cardiovascular risk stratification. METHODS: Myocardial 18F-FDG uptake pattern was assessed in 302 patients undergoing both oncologic whole-body 18F-FDG-PET/CT and myocardial perfusion imaging by single-photon emission computed tomography (SPECT-MPI) within a six-month period. Primary outcomes were myocardial 18F-FDG uptake pattern, impaired myocardial perfusion, ongoing ischemia, myocardial scar, and left ventricular ejection fraction. RESULTS: Among all patients, 109 (36.1%) displayed no myocardial 18F-FDG uptake, 77 (25.5%) showed diffuse myocardial 18F-FDG uptake, 24 (7.9%) showed focal 18F-FDG uptake, and 92 (30.5%) had a focal on diffuse myocardial 18F-FDG uptake pattern. In contrast to the other uptake patterns, focal myocardial 18F-FDG uptake was predominantly observed in patients with myocardial abnormalities (i.e., abnormal perfusion, impaired LVEF, myocardial ischemia, or scar). Accordingly, a multivariate logistic regression identified focal myocardial 18F-FDG uptake as a strong predictor of abnormal myocardial function/perfusion (odds ratio (OR) 5.32, 95% confidence interval (CI) 1.73-16.34, p = 0.003). Similarly, focal myocardial 18F-FDG uptake was an independent predictor of ongoing ischemia and myocardial scar (OR 4.17, 95% CI 1.53-11.4, p = 0.005 and OR 3.78, 95% CI 1.47-9.69, p = 0.006, respectively). CONCLUSIONS: Focal myocardial 18F-FDG uptake seen on oncologic PET/CT indicates a significantly increased risk for multiple myocardial abnormalities. Obtaining and taking this information into account will help to stratify patients according to risk and will reduce unnecessary cardiovascular complications in cancer patients.