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).

Emerging Role of Scintigraphy Using Bone-Seeking Tracers for Diagnosis of Cardiac Amyloidosis: AJR Expert Panel Narrative Review.

Amyloidoses are a complex group of clinical diseases that result from progressive organ dysfunction due to extracellular protein misfolding and deposition. The two most common types of cardiac amyloidosis are transthyretin amyloidosis (ATTR) and light-chain (AL) amyloidosis. Diagnosis of ATTR cardiomyopathy (ATTR-CM) is challenging owing to its phenotypic similarity to other more common cardiac conditions, the perceived rarity of the disease, and unfamiliarity with its diagnostic algorithms; endomyocardial biopsy was historically required for diagnosis. However, myocardial scintigraphy using bone-seeking tracers has shown high accuracy for detection of ATTR-CM and has become a key noninvasive diagnostic test for the condition, receiving support from professional society guidelines and transforming prior diagnostic paradigms. This AJR Expert Panel Narrative Review describes the role of myocardial scintigraphy using bone-seeking tracers in the diagnosis of ATTR-CM. The article summarizes available tracers, acquisition techniques, interpretation and reporting considerations, diagnostic pitfalls, and gaps in the current literature. The critical need for monoclonal testing of patients with positive scintigraphy results to differentiate ATTR-CM from AL cardiac amyloidosis is highlighted. Recent updates in guideline recommendations that emphasize the importance of a qualitative visual assessment are also discussed.

18F-FDG/13N-ammonia cardiac PET findings in ATTR cardiac amyloidosis.

18F-flurodeoxyglycose (FDG)/13N-ammonia positron emission tomography/computed tomography (PET/CT) is frequently utilized to evaluate cardiac sarcoidosis (CS) but findings can reflect other forms of myocardial inflammation or altered myocardial metabolic activity. Herein, we present five cases where cardiac PET findings suggested CS, but right ventricular endomyocardial biopsy samples revealed ATTR-type cardiac amyloidosis.

Rituximab for the Treatment of Refractory Cardiac Sarcoidosis: A Single-Center Experience.

BACKGROUND: We sought to examine the effect of anti-B-cell therapy (rituximab) on cardiac inflammation and function in corticosteroid-refractory cardiac sarcoidosis. Cardiac sarcoidosis (CS) is a rare cause of cardiomyopathy characterized by granulomatous inflammation involving the myocardium. Although typically responsive to corticosteroid treatment, there is a critical need for identifying effective steroid-sparing agents for disease control. Despite increasing evidence on the role of B cells in the pathogenesis of sarcoidosis, there is limited data on the efficacy of anti-B-cell therapy, specifically rituximab, for controlling CS. METHODS AND RESULTS: We reviewed the clinical experience at a tertiary care referral center of all patients with CS who received rituximab after failing to improve with initial immunosuppression therapy, which included corticosteroids. Fluorodeoxyglucose positron emission tomography (FDG PET/CT) images before and after rituximab treatment were evaluated. All images were interpreted by 2 experienced nuclear medicine trained physicians. We identified 7 patients (5 men, 2 women; mean age at diagnosis, 49.0 ± 7.9 years) with active CS who were treated with rituximab. The median length of follow-up was 5.1 years. All individuals, but 1, had received prior steroid-sparing agents in addition to corticosteroids. Rituximab was administered either as 1000 mg intravenously ×1 or ×2 doses, separated by 2 weeks. Repeat dosing, if appropriate, was considered after 6 months. All tolerated the infusions well. Inflammation as assessed by maximum standardized uptake value on cardiac FDG PET/CT uptake significantly decreased in 6 of 7 patients (median 6.0-4.5, Wilcoxon signed rank z -1.8593, W 3), whereas the left ventricular ejection fraction improved or stabilized in 4 patients but decreased in 3. The mean left ventricular ejection fraction was 40.1% and 43.3% before and after treatment, respectively (P = .28). Three patients reported improved physical capacity, and 5 patients showed improved arrhythmic burden on Holter monitoring or implantable cardioverter-defibrillator interrogation. One patient subsequently developed a fungal catheter-associated infection and sepsis requiring discontinuation. CONCLUSIONS: Rituximab was well-tolerated and seemed to decrease inflammation, as assessed by cardiac FDG PET/CT in all but 1 patient with active CS. These data suggest that rituximab may be a promising therapeutic option for CS, which deserves merits further study.

Performance of cardiac PET/CT with and without phase analysis for detection of scar in cardiac sarcoidosis: Comparison to cardiac magnetic resonance imaging.

BACKGROUND: The presence of myocardial scar in CS patients results in poor prognosis and worse outcomes. 18F-fluorodeoxyglucose (18F-FDG) PET/CT excels at visualizing inflammation but is suboptimal at detecting scar. We evaluated PET/CT sensitivity to detect scar and investigated the incremental diagnostic value of automated PET-derived data. METHODS: 176 patients who underwent cardiac magnetic resonance (CMR) and N-13 ammonia/18F-FDG cardiac PET/CT for suspected CS within 3 months were enrolled. Scar was defined as late gadolinium enhancement (LGE) on CMR without concordant 18F-FDG uptake on 18F-FDG PET/CT. Accuracy of cardiac PET/CT at detecting scar (perfusion defect without concordant 18F-FDG uptake) was assessed before and after addition of automated PET-derived data. RESULTS: Sensitivity of PET/CT for scar detection was 45.3% (specificity 88.9%). Addition of PET-derived LV volumes and function in a logistic regression model improved sensitivity to 57.0% (specificity: 80.0%, AUC 0.72). Addition of phase analysis maximum segmental onset of myocardial contraction > 61 improved AUC to 0.75, correctly relabeling 16.3% of patients as scar (net reclassification index 8.2%). CONCLUSION: Sensitivity of gated PET MPI alone for scar detection in CS is suboptimal. Adding PET-derived volumes/function and phase analysis data results in improved detection and characterization of scar.

Electrogram-guided endomyocardial biopsy yield in patients with suspected cardiac sarcoidosis and relation to outcomes.

OBJECTIVE: Endomyocardial biopsy (EMB) is a useful diagnostic tool though the yield may be limited in many myocardial diseases. Data on the diagnostic yield and prognostic significance of EMB guided by abnormal electrograms (EGM-Bx) in suspected cardiac sarcoidosis (CS) are scarce. METHODS: Seventy-nine patients (mean age: 56 ± 12 years; 61% men) with suspected CS based on clinical and imaging features underwent right or left ventricular EGM-Bx guided by electroanatomic mapping. Tissue samples were obtained from sites with abnormal EGMs and/or abnormal cardiac imaging. The diagnostic yield of EGM-Bx was evaluated in reference to histopathologic analysis. Left ventricular assist device (LVAD) and transplantation-free survival were compared between patients with positive and negative EGM-Bx for CS. RESULTS: A total of 254 samples were obtained from abnormal EGM sites, and 126 samples from normal EGM sites guided by pre-procedure imaging findings. Abnormal histopathology was noted in 65 (26%) and 10 (8%) samples from abnormal and normal EGM sites, respectively. Histopathology confirmed CS in 16 (20%) patients, while an alternative tissue diagnosis emerged in 10 (13%) patients. Abnormal EGMs at the biopsy site had sensitivity 89% and specificity 33% for a histopathologic diagnosis of CS. LVAD and transplantation-free survival were not significantly associated with the EGM-Bx result (log-rank p = .91). CONCLUSION: In patients with suspected CS, abnormal EGM-Bx has high sensitivity and low specificity for establishing a definite CS diagnosis. Consideration of substrate abnormalities apparent on preprocedural imaging as an adjunct for selection of biopsy sites may further improve EGM-Bx yield.

Suppressing physiologic 18-fluorodeoxyglucose uptake in patients undergoing positron emission tomography for cardiac sarcoidosis: The effect of a structured patient preparation protocol.

OBJECTIVE: Myocardial positron emission tomography (PET) to detect cardiac sarcoidosis requires adequate patient preparation; however, in many cases physiologic myocardial 18F-fluorodeoxyglucose (18F-FDG) uptake may not be adequately suppressed. We sought to evaluate the efficacy of a structured patient preparation protocol as recommended by the joint SNMMI/ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. The SNMMI/ASNC preparation protocol recommends at least two high-fat (> 35 g), low-carbohydrate (< 3 g) (HFLC) meals the day before testing followed by fasting for at least 4-12 hours. METHODS: All unique PET scans performed for cardiac sarcoidosis before (group 1) and after (group 2) application of the new preparation protocol were included in the study. In group 1, patients were given a preparation protocol of HFLC meals with suggested meals examples, while patients in group 2 received detailed diet instructions, together with accepted and non-accepted meal examples along. In group 2, reinforcement of instructions by nursing staff and review of dietary log were performed prior to testing. All PET images were evaluated for suppression of physiologic myocardial 18F-FDG uptake. RESULTS: Group 1 included 124 unique patients, and group 2 included 232 unique patients. There were no significant differences in baseline patient characteristics between the two groups. Suppression of physiologic myocardial 18F-FDG uptake was achieved in 91% of patients in group 2, compared to 78% of patients in group 1 (P < .001). A "diffuse" myocardial uptake pattern, indicating inadequate 18F-FDG suppression, was seen in 2% of studies in group 2 vs 12% in group 1 (P < .001). CONCLUSION: In this single-center study, application of a structured preparation protocol was highly successful in achieving suppression of physiologic myocardial 18F-FDG uptake in patients undergoing myocardial PET for cardiac sarcoidosis.

Imaging cardiac sarcoidosis and infiltrative diseases: diagnosis and therapeutic response.

Infiltrative heart disease is an encompassing term referring to different pathological entities that involve infiltration of the myocardium by either abnormal substances or inflammatory cells. These infiltrates can impair cellular function, induce necrosis and fibrosis, or otherwise disrupt myocardial architecture resulting in a wide spectrum of structural and functional impairment. Depending on the specific disorder and stage of disease, patients may present with minimal cardiac abnormalities, or may have findings of advanced restrictive and/or dilated cardiomyopathy. Furthermore, patients may often be misdiagnosed with more common conditions such as hypertensive, hypertrophic or ischemic cardiomyopathies. Correlation of cardiac findings with clinical, serologic or pathologic data is critical in many of these conditions. While cardiac involvement may be detected by echocardiography, other imaging modalities such as cardiac magnetic resonance, single-photon emission computed tomography, or positron emission tomography provide additional critical diagnostic, prognostic and therapeutic information. Advanced imaging modalities also provide quantitative data that can further risk stratify patients, monitor disease progression, and guide management. In this review we provide an overview of infiltrative heart disease from an imaging perspective, with a particular focus on cardiac sarcoidosis and cardiac amyloidosis.

Patient page-sarcoidosis imaging.

Optimizing our imaging capabilities for patients with cardiac sarcoidosis is critical as it has diagnostic, prognostic, and therapeutic implications. 18FDG PET/CT has the highest sensitivity for the detection of CS but requires specific dietary preparation that is difficult for patients to follow which may lead to ineffective suppression of physiologic 18FDG uptake. This may result in inconclusive scan results in up to 30% of patients undergoing 18FDG PET/CT imaging for CS. Therefore, it is imperative that we relay to our patients the importance of dietary preparation for CS PET imaging and then provide simple, easy to follow instructions for them. The current patient protocol is designed to achieve these two objectives.

The impact of combined cardiopulmonary exercise testing and SPECT myocardial perfusion imaging on downstream evaluation and management.

OBJECTIVE: The diagnostic yield of combined cardiopulmonary exercise testing (CPET) and myocardial perfusion imaging (MPI) in patients referred for stress testing has received limited study. METHODS: We evaluated consecutive patients who underwent combined CPET-MPI at a single tertiary referral center between 2011 and 2015. An abnormal CPET was defined as any of the following: reduced oxygen consumption, cardiac output impairment, or pulmonary impairment. Normal MPI was defined as the absence of resting or stress perfusion defect. The primary study outcome was change in clinical decision-making after CPET-MPI including management of pulmonary disease, management of deconditioning, heart failure management, and referral for cardiac catheterization. Outcomes of patients with normal and abnormal MPI were presented based on the specific CPET abnormality. RESULTS: 415 patients were included in the study. Of the 269 patients that had normal MPI, 206 (77%) had abnormal CPET. Patients with abnormal CPET and normal MPI, compared with patients that had normal CPET and normal MPI, were more frequently diagnosed with pulmonary disease (11.7% vs 3.2%, P = .04) and deconditioning (33.5% vs 17.4%, P = .01). Of the 146 patients that had abnormal MPI, 128 (88%) had abnormal CPET. Patients with abnormal CPET and abnormal MPI, compared with patients that had normal CPET and abnormal MPI, did not statistically differ with regard to the study outcome. CONCLUSION: An abnormal CPET, if the MPI was normal, prompted further evaluation and led to management of pulmonary disease and deconditioning.

Meta-analysis of 18F-FDG PET/CT in the diagnosis of infective endocarditis.

BACKGROUND: The current diagnosis of infective endocarditis (IE) is based on the modified Duke criteria, which has approximately 80% sensitivity for the diagnosis of native valve endocarditis (NVE), with lower sensitivity for the diagnosis of prosthetic valve endocarditis (PVE) and culture-negative endocarditis. There is preliminary evidence that 18F-FDG PET/CT is an adjunctive diagnostic test with high accuracy reported in small studies to date. We therefore performed a meta-analysis of studies evaluating the use of PET/CT in the diagnosis of IE to establish a more precise estimate of accuracy. METHODS: PubMed, Embase, Cochrane library, CINAHL, Web of Knowledge, and www.clinicaltrials.gov were searched from January 1990 to April 2017 for studies evaluating the accuracy of PET/CT for the evaluation of possible IE. RESULTS: We identified 13 studies involving 537 patients that were included in the meta-analysis. The pooled sensitivity of PET/CT for diagnosis of IE was 76.8% (95% CI 71.8-81.4%; Q = 39.9, P < 0.01; I2 = 69.9%) and the pooled specificity was 77.9% (95% CI 71.9-83.2%; Q = 44.42, P < 0.01; I2 = 73.0%). Diagnostic accuracy was improved for PVE with sensitivity of 80.5% (95% CI 74.1-86.0%; Q = 25.5, P < 0.01; I2 = 72.5%) and specificity of 73.1% (95% CI 63.8-81.2%; Q = 32.1, P < 0.01; I2 = 78.2%). Additional extracardiac foci of infection were found on 17% of patients on whole body PET/CT. CONCLUSION: PET/CT is a useful adjunctive diagnostic tool in the evaluation of diagnostically challenging cases of IE, particularly in prosthetic valve endocarditis. It also has the potential to detect clinically relevant extracardiac foci of infection, malignancy, and other sources of inflammation leading to more appropriate treatment regimens and surgical intervention.

Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: A meta-analysis.

OBJECTIVE: We performed a meta-analysis evaluating the use of fluorine-18-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in the diagnosis of cardiovascular implantable electronic device (CIED) infections. BACKGROUND: PET/CT may be helpful in the diagnosis of CIED infection, particularly in patients with the absence of localizing signs or definitive echocardiographic findings. METHODS: PubMed, Embase, Cochrane library, CINAHL, Web of Knowledge, and www.clinicaltrials.gov from January 1990 to April 2017 were searched for studies evaluating the accuracy of PET/CT in the diagnosis of CIED infections. RESULTS: Overall, 14 studies involving 492 patients were included in the meta-analysis. The pooled sensitivity of PET/CT for diagnosis of CIED infection was 83% (95% CI 78%-86%) and the pooled specificity was 89% (95% CI 84%-94%). PET/CT demonstrated a higher sensitivity of 96% (95% CI 86%-99%) and specificity of 97% (95% CI 86%-99%) for diagnosis of pocket infections. Diagnostic accuracy for lead infections or CIED-IE was lower with pooled sensitivity of 76% (95% CI 65%-85%) and specificity of 83% (95% CI 72%-90%). CONCLUSION: Use of PET/CT in the evaluation of CIED infection has both a high sensitivity (83%) and specificity (89%) and deserves consideration in the management of selected patients with suspected CIED infections.

Isolated cardiac sarcoidosis: A focused review of an under-recognized entity.

There is accumulating evidence for the existence of a phenotype of isolated cardiac sarcoidosis (ICS), or sarcoidosis that only involves the heart. In the absence of biopsy-confirmed cardiac sarcoidosis (CS), existing diagnostic criteria require the presence of extra-cardiac sarcoidosis as an inclusion criterion for the diagnosis of CS. Consequently, in the absence of a positive endomyocardial biopsy, ICS is not diagnosable by current guidelines. Therefore, there is uncertainty regarding the epidemiology, pathobiology, clinical characteristics, prognosis, and optimal treatment of ICS. This review will summarize the available data related to the prevalence and prognosis of ICS and will discuss challenges surrounding the diagnosis and management of this under-recognized entity.

Correction to: Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC.

The above position statement originally published containing errors in the author metadata; specifically, the Expert Content Reviewers-Andrew Einstein, Raymond Russell and James R. Corbett-were tagged as full authors of the paper. The article metadata has now been corrected to remove Drs. Einstein, Russell and Corbett from the author line, and the PubMed record has been updated accordingly.