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Regadenoson is an FDA approved adenosine receptor agonist which increases blood–brain barrier (BBB) permeability in rodents. Regadenoson is used clinically for pharmacologic cardiac stress testing using SPECT or CT imaging agents that do not cross an intact BBB. This study was conducted to determine if standard doses of regadenoson transiently disrupt the human BBB allowing higher concentrations of systemically administered imaging agents to enter the brain. Patients without known intracranial disease undergoing clinically indicated pharmacologic cardiac stress tests were eligible for this study. They received regadenoson (0.4 mg) followed by brain imaging with either 99m Tc-sestamibi for SPECT or visipaque for CT imaging. Pre- and post-regadenoson penetration of imaging agents into brain were quantified [SPECT: radioactive counts, CT: Hounsfield units (HU)] and compared using a matched-pairs t-test. Twelve patients (33% male, median 60 yo) were accrued: 7 SPECT and 5 CT. No significant differences were noted in pre- and post-regadenoson values using mean radionuclide counts (726 vs. 757) or HU (29 vs. 30). While animal studies have demonstrated that regadenoson transiently increases the permeability of the BBB to dextran and temozolomide, we were unable to document changes in the penetration of contrast agents in humans with intact BBB using the FDA approved doses of regadenoson for cardiac evaluation. Further studies are needed exploring alternate regadenoson dosing, schedules, and studies in patients with brain tumors; as transiently disrupting the BBB to improve drug entry into the brain is critical to improving the care of patients with CNS malignancies.

Evinacumab, an angiopoietin‐like 3 inhibitor, significantly reduces low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). Herein, we report pharmacokinetic and efficacy analyses of evinacumab in < 5‐year‐old patients with HoFH. Population pharmacometric models characterizing evinacumab exposure and LDL‐C response accounting for lipoprotein apheresis effect in ≥ 5‐year‐old patients were adapted for growth and maturation to predict and compare evinacumab and LDL‐C concentrations across age/weight groups in virtual ≥ 6‐month‐old patients receiving 15 mg/kg evinacumab intravenous (iv) infusions every 4 weeks (q4w). As expected from allometric theory, weight‐based dosing resulted in decreasing evinacumab exposures with declining body weight. Consistent with trends observed in > 5‐year‐old patients, the predicted percent change from LDL‐C baseline (%∆LDL‐C) was generally comparable or even higher in < 5‐year‐old patients (63.0%–68.5%) than in 5‐ to < 18‐year‐old patients (61.3%–67.8%) or adults (51.7%), with the predicted percentages of patients achieving %∆LDL‐C > 50% also higher in < 5‐year‐old patients (82.0%–86.9%) versus 5‐ to < 18‐year‐old patients (72.0%–84.5%) and adults (54.8%). Through a managed access program, six 1‐ to < 5‐year‐old patients received between 5 and 23 iv infusions of 15 mg/kg evinacumab q4w. Rapid and clinically meaningful LDL‐C reductions were observed, with %∆LDL‐C at the last reported dose ranging from 41.3% to 77.3%. Based on the actual patient dosing and plasmapheresis history, model‐predicted evinacumab and LDL‐C concentrations were comparable to the observed data collected in the managed access program. Overall, this analysis provides evidence for the use of evinacumab 15 mg/kg iv q4w dosing regimen in 6‐month‐old to 5‐year‐old patients.

In the past 5 years, technological advances in multidetector CT imaging have enabled the development of complementary myocardial applications beyond coronary imaging. In this Review, the authors describe these advances and discuss the clinical potential of such imaging for a broad range of applications. Noninvasive imaging of the coronary arteries using multidetector CT (MDCT) represents one of the most promising diagnostic imaging advances in contemporary cardiology. This challenging application has driven a rapid and impressive advancement in CT technology over the past 10 years; leading to increased spatial and temporal resolution, decreased scan times and substantial reductions in radiation dose. Recent technological improvements have not only improved the status of CT coronary angiography but have also enabled new functional myocardial applications that are gaining a foothold in clinical practice as adjuncts or replacements for conventional coronary angiographic studies. Wide-detector CT designs along with prospective ECG-triggered protocols have opened the possibility of performing multiple complementary myocardial measurements during a coronary CT exam with acceptable radiation and contrast exposure. In this Review, we discuss recent technical developments in cardiac MDCT and outline newly enabled noncoronary cardiac applications including viability assessment, myocardial perfusion and molecular imaging. Key Points Advances in scanner technology and imaging protocols have enabled noncoronary applications of multidetector CT (MDCT) MDCT can be used to evaluate myocardial viability Assessment of myocardial blood flow by MDCT is feasible under conditions of rest and stress Current MDCT technology has the potential to visualize cells and molecular targets

The relation between insulin resistance (IR) and coronary artery disease in patients with human immunodeficiency virus (HIV) infection remains incompletely defined. Fasting serum insulin and glucose measurements from 448 HIV-infected and 306 uninfected men enrolled in the Multicenter AIDS Cohort Study were collected at semiannual visits from 2003 to 2013 and used to compute the homeostatic model assessment of IR (HOMA-IR). Coronary computed tomographic angiography (CTA) was performed at the end of the study period to characterize coronary pathology. Associations between HOMA-IR (categorized into tertiles and assessed near the time of the CTA and over the 10-year study period) and the prevalence of coronary plaque or stenosis ≥50% were assessed with multivariate logistic regression. HOMA-IR was higher in HIV-infected men than HIV-uninfected men when measured near the time of CTA (3.2 vs 2.7, p = 0.002) and when averaged over the study period (3.4 vs 3.0, p <0.001). The prevalence of coronary stenosis ≥50% was similar between both groups (17% vs 15%, p = 0.41). Both measurements of HOMA-IR were associated with greater odds of coronary stenosis ≥50% in models comparing men with values in the highest versus the lowest tertiles, although the effect of mean HOMA-IR was stronger than the single measurement of HOMA-IR before CTA (odds ratio 2.46, 95% CI 1.95 to 3.11, vs odds ratio 1.43, 1.20 to 1.70). This effect was not significantly modified by HIV serostatus. In conclusion, IR over nearly a decade was greater in HIV-infected men than HIV-uninfected men, and in both groups, was associated with significant coronary artery stenosis.

Purpose Absolute quantification of myocardial blood flow expands the diagnostic potential of PET for assessment of coronary artery disease. 82 Rb has significantly contributed to increasing utilization of PET; however, clinical studies are still mostly analysed qualitatively. The aim of this study was to reevaluate the feasibility of 82 Rb for flow quantification, using hybrid PET-CT in an animal model of coronary stenosis. Methods Nine dogs were prepared with experimental coronary artery stenosis. Dynamic PET was performed for 8 min after 82 Rb(1480–1850 MBq) injection during adenosine-induced vasodilation. Microspheres were injected simultaneously for reference flow measurements. CT angiography was used to determine the myocardial regions related to the stenotic vessel. Two methods for flow calculation were employed: a two-compartment model including a spill-over term, and a simplified retention index. Results The two-compartment model data were in good agreement with microsphere flow ( y  = 0.84 x + 0.20; r  = 0.92, p <0.0001), although there was variability in the physiological flow range <3 ml/g per minute ( y  = 0.54 x + 0.53; r = 0.53, p  = 0.042). Results from the retention index also correlated well with microsphere flow ( y  = 0.47 x + 0.52; r  = 0.75, p  = 0.0004). Error increased with higher flow, but the correlation was good in the physiological range ( y  = 0.62 x + 0.29; r  = 0.84, p  = 0.0001). Conclusion Using current state-of-the-art PET-CT systems, quantification of myocardial blood flow is feasible with 82 Rb. A simplified approach based on tracer retention is practicable in the physiological flow range. These results encourage further testing of the robustness and usefulness in the clinical context of cardiac hybrid imaging.

Background. Heightened immune activation among human immunodeficiency virus (HIV)-infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and soluble CD14 (sCD14), and monocyte chemoattractant protein 1 (CCL2) with subclinical atherosclerosis among men with and those without HIV infection in the Multicenter AIDS Cohort Study. Methods. We performed noncontrast computed tomography on 906 men (566 HIV-infected men and 340 HIV-uninfected men), 709 of whom also underwent coronary computed tomographic angiography. Associations between each biomarker and the prevalence of coronary plaque, the prevalence of stenosis of ≥50%, and the extent of plaque were assessed by logistic and linear regression, adjusting for age, race, HIV serostatus, and cardiovascular risk factors. Results. Levels of all biomarkers were higher among HIV-infected men, of whom 81% had undetectable HIV RNA, and were associated with lower CD4⁺ T-cell counts. In the entire population and among HIV-infected men, higher biomarker levels were associated with a greater prevalence of coronary artery stenosis of ≥50%. Higher sCD163 levels were also associated with greater prevalences of coronary artery calcium, mixed plaque, and calcified plaque; higher CCL2 levels were associated with a greater extent of noncalcified plaque. Conclusions. sCD163, sCD14, and CCL2 levels were elevated in treated HIV-infected men and associated with atherosclerosis. Monocyte activation may increase the risk for cardiovascular disease in individuals with HIV infection.

Cardiac multidetector computed tomography has evolved from early four detector systems that first demonstrated the feasibility of non-invasive angiography to today’s wide-area detector computed tomography systems, such as 320-row detector computed tomography. As detector arrays have widened, there have been great improvements in image quality that have improved test accuracy. In addition, wider detector arrays have allowed for the application of prospective ECG-gating for CT angiography, although the current 64-row detector systems have some limitations. 320-row detector computed tomography with full cardiac coverage allows for cardiac imaging in a single heart beat. This technology has realized some of the great advantages provided by full cardiac coverage in regards to image quality (elimination of step artifacts and variation in contrast enhancement), patient safety (reductions in overall radiation and contrast dose), and the prospects for combined CT angiography and myocardial perfusion imaging are very promising. We will review the technical aspects of 320-row detector computed tomography and their implications for coronary angiography and perfusion imaging.

The purpose of this study was to develop a method for automatic and stable determination of the optimal time range for fitting with a Patlak plot model in order to measure myocardial perfusion using coronary X-ray angiography images. A conventional two-compartment model is used to measure perfusion, and the slope of the Patlak plot is calculated to obtain a perfusion image. The model holds for only a few seconds while the contrast agent flows from artery to myocardium. Therefore, a specific time range should be determined for fitting with the model. To determine this time range, automation is needed for routine examinations. The optimal time range was determined to minimize the standard error between data points and their least-squares regression straight line in the Patlak plot. A total of 28 datasets were tested in seven porcine models. The new method successfully detected the time range when contrast agent flowed from artery to myocardium. The mean cross correlation in the linear regression analysis (R 2 ) was 0.996 ± 0.004. The mean length of the optimal time range was 3.61 ± 1.29 frames (2.18 ± 1.40 s). This newly developed method can automatically determine the optimal time range for fitting with the model.

Background The blood–brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A 2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A 2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. Methods Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m 2 ). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. Results Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h µg/ml for temozolomide alone and 16.6 ± 2.87 h µg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h µg/ml with temozolomide alone and 3.0 ± 1.7 h µg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and T max in brain were not significantly different. Conclusions Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.