Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration.

UCP3 (uncoupling protein-3) mitigates mitochondrial ROS (reactive oxygen species) production, but the mechanisms are poorly understood. Previous studies have also examined UCP3 effects, including decreased ROS production, during metabolic states when fatty acid oxidation is high (e.g. a fasting state). However, the role of UCP3 when carbohydrate oxidation is high (e.g. fed state) has remained largely unexplored. In the present study, we show that mitochondrial-bound HK (hexokinase) II curtails oxidative stress and enhances aerobic metabolism of glucose in the fed state in a UCP3-dependent manner. Genetic knockout or inhibition of UCP3 significantly decreased mitochondrial-bound HKII. Furthermore, UCP3 was required for the HKII-mediated decrease in mitochondrial ROS emission. Intriguingly, the UCP3-mediated modulation of mitochondria-associated HKII was only observed in cells cultured under high-glucose conditions. UCP3 was required to maintain high rates of aerobic metabolism in high-glucose-treated cells and in muscle of fed mice. Deficiency in UCP3 resulted in a metabolic shift that favoured anaerobic glycolytic metabolism, increased glucose uptake and increased sensitivity to oxidative challenge. PET (positron emission tomography) of [18F]fluoro-deoxyglucose uptake confirmed these findings in UCP3-knockout and wild-type mice. Collectively, our findings link the anti-oxidative and metabolic functions of UCP3 through a surprising molecular connection with mitochondrial-bound HKII.

Investigating the treatment phenotypes of cardiac sarcoidosis: A prospective cohort study.

Introduction: Data indicates there are 4 main pulmonary sarcoidosis duration/treatment phenotypes: asymptomatic, acute (disease duration <1-2 years), chronic and advanced. There are no data about disease duration/treatment phenotypes of cardiac sarcoidosis patients. Our study had 2 main aims (i) to assess the response to corticosteroids and (ii) to assess the incidence of relapse after a one-year course of corticosteroids (thereby classifying patients as acute or chronic treatment phenotype). Methods: Consecutive, treatment naive patients with CS were prospectively recruited and treated with 0.5 mg/kg prednisone, to a maximum dose of 40 mg/day. Patients had a follow-up PET after 3-6 months of therapy (PET 2). In the responders (PET definition of response) the prednisone was then weaned and stopped after 12 months. Three months after stopping, the PET was repeated to look for disease relapse (PET 3). Results: Twenty-one consecutive patients were included, and all patients showed a reduction in cardiac FDG uptake after 3-6 months and 19/21 (90.5 %) met the PET definition of response. Of these, 12/19 (63.1 %) relapsed after prednisone was stopped. There were no serious adverse effects during the trial of therapy cessation and there were no later relapses in the 7 non-relapsers during over 4 years of subsequent follow-up. Conclusion: The initial response rate to prednisone was high with all patients showing a reduction in FDG uptake and 19/21 meeting a PET definition of >25 % response. Secondly, a trial of therapy discontinuation was able to classify 7/19 patients as acute treatment phenotype and 12/19 as chronic.

FLT-PET for the assessment of systemic sarcoidosis including cardiac and CNS involvement: a prospective study with comparison to FDG-PET.

BACKGROUND: 2-deoxy-2-[18F]fluoro-D-glucose's (FDG) biodistribution limits the evaluation of cardiac sarcoidosis (CS) and neurosarcoidosis (NS). While protocols for cardiac suppression exist, they can be inconvenient for patients and lead to incomplete cardiac suppression in many cases. Furthermore, FDG PET is limited in the detection of neurosarcoidosis due to an inability to suppress high level of physiological uptake within the brain. 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been shown to accumulate in sarcoidosis lesions and this tracer lacks significant physiological myocardial and brain uptake, suggesting that this tracer may be useful for the assessment of sarcoidosis, including CS and NS, without the need for patient preparation. This prospective pilot study examined the performance of FLT vs FDG PET for systemic sarcoidosis, including cardiac and neural involvement. MATERIALS AND METHODS: Fourteen subjects with sarcoidosis were prospectively recruited and imaged with FDG- and FLT-PET. Two blinded, experienced readers independently reviewed the FLT-PET and FDG-PET images. Lesion distribution was compared between FLT and FDG. Agreement between FLT- and FDG-PET was determined using Cohen's kappa and the intra-class correlation coefficient. Inter-observer variability of FLT and FDG-PET was assessed. RESULTS: Twelve subjects had CS as per Heart Rhythm Society criteria and 1 had NS. FLT-PET was positive in 12 (86%), and FDG-PET in 11 (79%), with cardiac uptake present in 6 (50%) and 7 (58%) of subjects with CS, respectively. The subject with NS demonstrated uptake on both FLT and FDG-PET, with more lesions on FLT. There were no significant differences in the anatomical distribution of lesions between FLT and FDG. SUVs were significantly (p < 0.001) higher for FDG than FLT (5.8 ± 3.0 vs 2.3 ± 1.1, respectively), but not (p = 0.90) after adjusting for blood pool activity (2.8 ± 1.4 vs 2.8 ± 1.1, respectively). Agreement between FLT- and FDG-PET was good to excellent for the diagnosis of sarcoidosis, lung involvement, CS, and NS (κ = 0.76, 0.69, 0.86, and 1.0, respectively). Inter-observer agreement for FLT was excellent for diagnosing sarcoidosis, CS and NS (κ = 0.81, 0.85, and 1.0, respectively) and comparable to that of FDG. CONCLUSIONS: FLT-PET may be useful for the assessment of systemic sarcoidosis, as well as cardiac and neural involvement.

Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8-10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18-20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

Routine versus selective cardiac magnetic resonance in non-ischemic heart failure - OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B).

BACKGROUND: Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction. DESIGN: Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician's impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and 'other' cardiomyopathy than the selective CMR group. DISCUSSION: This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF. TRIAL REGISTRATION: NCT01281384.

PET measurements of cAMP-mediated phosphodiesterase-4 with (R)-[11C]rolipram.

Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.

Single-phase CT aligned to gated PET for respiratory motion correction in cardiac PET/CT.

UNLABELLED: Respiratory motion can induce artifacts in cardiac PET/CT because of the misregistration of the CT attenuation map and emission data. Some solutions to the respiratory motion problem use 4-dimensional CT, but this increases patient radiation exposure. Realignment of 3-dimensional CT and PET images can remove apparent uptake defects caused by mispositioning of the PET emission data into the lung regions on the CT scan. This realignment is typically done as part of regular clinical quality assurance. We evaluated a method to improve on this standard approach, without increasing the radiation exposure to the patient, by acquiring a respiration-gated PET scan and separately aligning the 3-dimensional CT scan to each phase of the PET study. METHODS: Three hundred ten clinical PET perfusion scans ((82)Rb [n = 187] and (13)N-ammonia [n = 123]) were retrospectively assessed. Studies were respiration-gated, and motion was measured between inspiration and expiration phases. Those studies with motion > or = 8 mm were evaluated for significant differences between inspiration and expiration. Studies with significant differences were reprocessed with the phase-alignment approach. The observed motion with (82)Rb and (13)N-ammonia for rest and stress imaging was also compared. RESULTS: Twenty-three scans (7.41%) had motion > or = 8 mm, and 9 of these had significant differences between inspiration and expiration, suggesting the presence of respiratory artifacts. Phase-aligned respiratory motion compensation reduced this difference in 8 of 9 cases (89%). No significant differences were observed between (82)Rb and (13)N-ammonia, and motion during stress imaging was correlated with motion at rest (r = 0.61, P < 0.001). CONCLUSION: Phase-aligned correction improves the consistency of PET/CT perfusion images by reducing discrepancies caused by respiratory motion. This new approach to CT-based attenuation correction has no additional patient radiation exposure and may improve the specificity of PET perfusion imaging.

Effect of lateral wall scar on reverse remodeling with cardiac resynchronization therapy.

BACKGROUND: Up to 50% of patients do not respond to cardiac resynchronization therapy (CRT). Recent work has focused on quantifying left ventricular (LV) scar, with conflicting results. Some studies have shown that the global extent of LV scar is important, whereas others found the size of the septal or lateral wall scar to be key. OBJECTIVE: This study sought to examine the relative importance of the size and distribution of LV scar in determining reverse remodeling to CRT. METHODS: Forty-nine patients had pre-implantation rubidium-82 and fluorine-18-fluorodeoxyglucose positron emission tomography scanning. Total and regional LV scar size were calculated. Response to CRT was pre-specified as > or =10% improvement in LV end-systolic volume and/or > or =5% absolute ejection fraction improvement. RESULTS: Responders (n = 31) had significantly less lateral wall scar than responders (5.6% compared with 24.5%, P = .008) but a similar extent of global and septal scar. In the ischemic group, responders' median lateral wall scar size was 11.2% (IQR 0.0 to 31.2), compared with 47.8% (IQR 21.2 to 73.4) P = .052. In the ischemic group, for each 5% absolute decrease in lateral scar size, the odds ratio of being a responder was 1.87 (95% CI: 1.11 to 3.15, P = .018). In the nonischemic group, median lateral wall scar size of responders was 3.4% (IQR 0.0 to 10.3) compared with the nonresponders, 14.4% (IQR 9.0 to 27.8), P = .046. CONCLUSION: Responders had significantly less lateral wall scar than nonresponders, but a similar extent of global and septal scar. This held true in both ischemic and nonischemic cardiomyopathy patients.