Reducing radiation dose from myocardial perfusion imaging in subjects with complex congenital heart disease.

INTRODUCTION: The prevalence of defects and effective radiation dose from various myocardial perfusion imaging (MPI) strategies in congenital heart disease (CHD) is unknown. METHODS: We studied 75 subjects with complex CHD (ages 5 to 80 years) referred for MPI between 2002 and 2015. A rest and exercise or pharmacologic stress MPI was performed using 99mTechnetium sestamibi, 82rubidium or 13N-ammonia, and Sodium iodide SPECT (single-photon emission computed tomography), SPECT/CT or Cadmium zinc telluride (CZT) SPECT or PET (positron emission tomography)/CT scanners. Deidentified images were interpreted semi-quantitatively in three batches: stress only MPI, stress/rest MPI, and stress/rest MPI with taking into account a history of ventricular septal defect repair. Effective radiation dose was estimated for stress/rest MPI and predicted for 1-day stress-first (normal stress scans), and for 2-day stress/rest MPI (abnormal stress scans). RESULTS: The median age was 18.6 years. The most common type of CHD was transposition of the great arteries (63%). Rest/stress MPI was abnormal in 43% of subjects and 25% of the abnormal scans demonstrated reversible defects. Of the subjects with abnormal MPI, 33% had significant underlying anatomic coronary artery obstruction. Estimated mean effective radiation dose ranged from 2.1 ± 0.6 mSv for 13N-ammonia PET/CT to 12.5 ± 0.9 mSv for SPECT/CT. Predicted effective radiation dose was significantly lower for stress-first MPI and for 2-day stress/rest protocols. CONCLUSIONS: Due to the relatively high prevalence of abnormal stress MPI, tailored protocols with a stress-first MPI as well as the use of 2-day protocols and advanced imaging technologies including CZT SPECT, novel image reconstruction software, and PET MPI could substantially reduce radiation dose in complex CHD.

Left atrial enlargement increases the risk of major adverse cardiac events independent of coronary vasodilator capacity.

PURPOSE: Longstanding uncontrolled atherogenic risk factors may contribute to left atrial (LA) hypertension, LA enlargement (LAE) and coronary vascular dysfunction. Together they may better identify risk of major adverse cardiac events (MACE). The aim of this study was to test the hypothesis that chronic LA hypertension as assessed by LAE modifies the relationship between coronary vascular function and MACE. METHODS: In 508 unselected subjects with a normal clinical (82)Rb PET/CT, ejection fraction ≥40 %, no prior coronary artery disease, valve disease or atrial fibrillation, LAE was determined based on LA volumes estimated from the hybrid perfusion and CT transmission scan images and indexed to body surface area. Absolute myocardial blood flow and global coronary flow reserve (CFR) were calculated. Subjects were systematically followed-up for the primary end-point - MACE - a composite of all-cause death, myocardial infarction, hospitalization for heart failure, stroke, coronary artery disease progression or revascularization. RESULTS: During a median follow-up of 862 days, 65 of the subjects experienced a composite event. Compared with subjects with normal LA size, subjects with LAE showed significantly lower CFR (2.25 ± 0.83 vs. 1.95 ± 0.80, p = 0.01). LAE independently and incrementally predicted MACE even after accounting for clinical risk factors, medication use, stress left ventricular ejection fraction, stress left ventricular end-diastolic volume index and CFR (chi-squared statistic increased from 30.9 to 48.3; p = 0.001). Among subjects with normal CFR, those with LAE had significantly worse event-free survival (risk adjusted HR 5.4, 95 % CI 2.3 - 12.8, p < 0.0001). CONCLUSION: LAE and reduced CFR are related but distinct cardiovascular adaptations to atherogenic risk factors. LAE is a risk marker for MACE independent of clinical factors and left ventricular volumes; individuals with LAE may be at risk of MACE despite normal coronary vascular function.

Usability evaluation and adaptation of the e-health Personal Patient Profile-Prostate decision aid for Spanish-speaking Latino men.

BACKGROUND: The Personal Patient Profile-Prostate (P3P), a web-based decision aid, was demonstrated to reduce decisional conflict in English-speaking men with localized prostate cancer early after initial diagnosis. The purpose of this study was to explore and enhance usability and cultural appropriateness of a Spanish P3P by Latino men with a diagnosis of prostate cancer. METHODS: P3P was translated to Spanish and back-translated by three native Spanish-speaking translators working independently. Spanish-speaking Latino men with a diagnosis of localized prostate cancer, who had made treatment decisions in the past 24 months, were recruited from two urban clinical care sites. Individual cognitive interviews were conducted by two bilingual research assistants as each participant used the Spanish P3P. Notes of user behavior, feedback, and answers to direct questions about comprehension, usability and perceived usefulness were analyzed and categorized. RESULTS: Seven participants with a range of education levels identified 25 unique usability issues in navigation, content comprehension and completeness, sociocultural appropriateness, and methodology. Revisions were prioritized to refine the usability and cultural and linguistic appropriateness of the decision aid. CONCLUSIONS: Usability issues were discovered that are potential barriers to effective decision support. Successful use of decision aids requires adaptation and testing beyond translation. Our findings led to revisions further refining the usability and linguistic and cultural appropriateness of Spanish P3P.

Imaging cardiac amyloidosis: a pilot study using ¹8F-florbetapir positron emission tomography.

PURPOSE: Cardiac amyloidosis, a restrictive heart disease with high mortality and morbidity, is underdiagnosed due to limited targeted diagnostic imaging. The primary aim of this study was to evaluate the utility of (18)F-florbetapir for imaging cardiac amyloidosis. METHODS: We performed a pilot study of cardiac (18)F-florbetapir PET in 14 subjects: 5 control subjects without amyloidosis and 9 subjects with documented cardiac amyloidosis. Standardized uptake values (SUV) of (18)F-florbetapir in the left ventricular (LV) myocardium, blood pool, liver, and vertebral bone were determined. A (18)F-florbetapir retention index (RI) was computed. Mean LV myocardial SUVs, target-to-background ratio (TBR, myocardial/blood pool SUV ratio) and myocardial-to-liver SUV ratio between 0 and 30 min were calculated. RESULTS: Left and right ventricular myocardial uptake of (18)F-florbetapir were noted in all the amyloid subjects and in none of the control subjects. The RI, TBR, LV myocardial SUV and LV myocardial to liver SUV ratio were all significantly higher in the amyloidosis subjects than in the control subjects (RI median 0.043 min(-1), IQR 0.034 - 0.051 min(-1), vs. 0.023 min(-1), IQR 0.015 - 0.025 min(-1), P = 0.002; TBR 1.84, 1.64 - 2.50, vs. 1.26, IQR 0.91 - 1.36, P = 0.001; LV myocardial SUV 3.84, IQR 1.87 - 5.65, vs. 1.35, IQR 1.17 - 2.28, P = 0.029; ratio of LV myocardial to liver SUV 0.67, IQR 0.44 - 1.64, vs. 0.18, IQR 0.15 - 0.35, P = 0.004). The myocardial RI, TBR and myocardial to liver SUV ratio also distinguished the control subjects from subjects with transthyretin and those with light chain amyloid. CONCLUSION: (18)F-Florbetapir PET may be a promising technique to image light chain and transthyretin cardiac amyloidosis. Its role in diagnosing amyloid in other organ systems and in assessing response to therapy needs to be further studied.

Reliability and validity of the Overactive Bladder Symptom Score in Spanish (OABSS-S).

PURPOSE: To validate the Spanish translation of the Overactive Bladder Symptom Score (OABSS) questionnaire. MATERIALS AND METHODS: The OABSS was translated into Spanish (OABSS-S) and back translated. The OABSS-S was self-administered to subjects, following internal IRB and ISPOR Good Practices guidelines. Spanish speaking patients >18 years of age were recruited from primary care clinics. Content validity was achieved by having the first 25 subjects complete the questionnaire in privacy; afterwards they were interviewed and the clarity of each question was discussed with the patient. All subjects recruited, including the first 25, were divided into two groups by the presence of OAB as determined by a previously validated intake question. Subjects completed the OABSS-S in privacy on two occasions within 10 days. Patients were excluded if their symptoms changed between the first and second administration of the questionnaire. Internal consistency was determined with Cronbach's alpha. Test-retest was determined by Spearman's rho. Discriminant validity was assessed between each group using one-way ANOVA and the Tukey post hoc test. RESULTS: One hundred and seventeen of 128 enrolled subjects completed this study (mean age 55; SD 18). Of 117, 74 (63%) were women 29 with OAB and 45 without OAB. There were 43 men (37%), 18 with OAB and 25 without OAB. A high level of consistency was observed among the seven items answered at visit 1 and 2, with a Cronbach's raw alpha statistic of 0.92. No differences in OABSS-S with age or gender were noted. However, subgroup analysis showed patients in the OAB group were significantly older and post-test analysis showed they had higher scores both for each individual question as well as overall symptom severity scores. Spearman's rank order correlation coefficients showed that there was significant difference between the seven items of the OABSS-S; a strong association (Spearman's rho) was also observed between the total seven-item score at visits 1 and 2 for the total score of all subjects r = 0.84, with OAB: r = 0.81, and without OAB: r = 0.83. Comparison of average total scores obtained for all patients at visits 1 and 2 was not significant (10.47 ± 6.53 vs. 11.02 ± 0.66). Discriminant validity testing revealed that there were significant differences in the responses between all diagnostic groups at visits 1 and 2: with OAB versus without OAB; total versus with OAB; total versus without OAB. CONCLUSION: The Spanish version of the OABSS is valid and reliable and will allow health care providers to easily and quickly assess a Spanish-speaking patient's symptoms.

Anxiety sensitivity correlates with two indices of right anterior insula structure in specific animal phobia.

BACKGROUND: Anxiety sensitivity (AS) is a dispositional trait involving fear of anxiety-related symptoms. Functional imaging research suggests that the activity of the anterior insular cortex, particularly the right insula, may both mediate AS and play a role in the pathophysiology of phobias. However, no imaging studies have examined whether AS relates to insula morphology. We examined whether AS was significantly correlated with right anterior insula volume and thickness among adults with specific animal phobia (SAP) and healthy comparison (HC) subjects. METHODS: Nineteen adults with SAP and 20 demographically group-matched HC subjects underwent magnetic resonance imaging at 3 Tesla. Subjects also completed the Anxiety Sensitivity Index (ASI). Regression and correlation analyses examined ASI scores in relation to anterior and posterior insular cortex volume and thickness within and across subject groups. RESULTS: SAP subjects had significantly higher ASI scores than HC, but did not differ in terms of insula volumes or thickness. ASI scores predicted right anterior insula thickness in SAP but not HC subjects, and right anterior insula volume in the sample as a whole. Correlations of ASI scores with the anterior and posterior insula volume and thickness were not significant in either group. CONCLUSIONS: These findings suggest that the right anterior insular cortex size is a neural substrate of AS within specific phobia, rather than an independent diagnostic marker of the disorder. Future investigations should examine whether heightened AS represents a shared intermediate phenotype across anxiety disorders, manifesting functionally as increased insular reactivity and clinically as a fear of anxiety symptoms.

Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.

OBJECTIVES: The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. BACKGROUND: Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD). METHODS: Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product. RESULTS: Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p < 0.0001), and CFR (1.19 ± 0.38 vs. 2.23 ± 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function. CONCLUSIONS: Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.

Detection of obstructive coronary artery disease using regadenoson stress and 82Rb PET/CT myocardial perfusion imaging.

UNLABELLED: Our objective was to study the diagnostic performance of regadenoson (82)Rb myocardial perfusion PET imaging to detect obstructive coronary artery disease (CAD). METHODS: We studied 134 patients (mean age, 63 ± 12 y; mean body mass index, 31 ± 9 kg/m(2)) without known CAD (96 with coronary angiography and 38 with low pretest likelihood of CAD). Stress left ventricular ejection fraction (LVEF) minus rest LVEF defined LVEF reserve. The Duke score was used to estimate the anatomic extent of jeopardized myocardium. RESULTS: Regadenoson PET had a high sensitivity, 92% (95% confidence interval [CI], 83%-97%), in detecting obstructive CAD, with a normalcy rate of 97% (95% CI, 86%-99%), specificity of 77% (54/70 patients; 95% CI, 66%-86%), and area under the receiver-operator-characteristic curve of 0.847 (95% CI, 0.774-0.903; P < 0.001). Regadenoson PET demonstrated high sensitivity to detect CAD in patients with single-vessel CAD (89%; 95% CI, 70%-98%). The mean LVEF reserve was significantly higher in patients with normal myocardial perfusion imaging results (6.5% ± 5.4%) than in those with mild (4.3 ± 5.1, P = 0.03) and moderate to severe reversible defects (-0.2% ± 8.4%, P = 0.001). Also, mean LVEF reserve was significantly higher in patients with a low likelihood of CAD (7.2% ± 4.5%, P < 0.0001) and mild or moderate jeopardized myocardium than in those with significant jeopardized myocardium (score ≥ 6), -2.8% ± 8.3%. CONCLUSION: Regadenoson (82)Rb myocardial perfusion imaging is accurate for the detection of obstructive CAD. LVEF reserve is high in patients without significant ischemia or significant angiographic jeopardized myocardium.

A novel volume-age-KPS (VAK) glioblastoma classification identifies a prognostic cognate microRNA-gene signature.

BACKGROUND: Several studies have established Glioblastoma Multiforme (GBM) prognostic and predictive models based on age and Karnofsky Performance Status (KPS), while very few studies evaluated the prognostic and predictive significance of preoperative MR-imaging. However, to date, there is no simple preoperative GBM classification that also correlates with a highly prognostic genomic signature. Thus, we present for the first time a biologically relevant, and clinically applicable tumor Volume, patient Age, and KPS (VAK) GBM classification that can easily and non-invasively be determined upon patient admission. METHODS: We quantitatively analyzed the volumes of 78 GBM patient MRIs present in The Cancer Imaging Archive (TCIA) corresponding to patients in The Cancer Genome Atlas (TCGA) with VAK annotation. The variables were then combined using a simple 3-point scoring system to form the VAK classification. A validation set (N = 64) from both the TCGA and Rembrandt databases was used to confirm the classification. Transcription factor and genomic correlations were performed using the gene pattern suite and Ingenuity Pathway Analysis. RESULTS: VAK-A and VAK-B classes showed significant median survival differences in discovery (P = 0.007) and validation sets (P = 0.008). VAK-A is significantly associated with P53 activation, while VAK-B shows significant P53 inhibition. Furthermore, a molecular gene signature comprised of a total of 25 genes and microRNAs was significantly associated with the classes and predicted survival in an independent validation set (P = 0.001). A favorable MGMT promoter methylation status resulted in a 10.5 months additional survival benefit for VAK-A compared to VAK-B patients. CONCLUSIONS: The non-invasively determined VAK classification with its implication of VAK-specific molecular regulatory networks, can serve as a very robust initial prognostic tool, clinical trial selection criteria, and important step toward the refinement of genomics-based personalized therapy for GBM patients.

Probes of the catalytic site of cysteine dioxygenase.

The first major step of cysteine catabolism, the oxidation of cysteine to cysteine sulfinic acid, is catalyzed by cysteine dioxygenase (CDO). In the present work, we utilize recombinant rat liver CDO and cysteine derivatives to elucidate structural parameters involved in substrate recognition and x-ray absorption spectroscopy to probe the interaction of the active site iron center with cysteine. Kinetic studies using cysteine structural analogs show that most are inhibitors and that a terminal functional group bearing a negative charge (e.g. a carboxylate) is required for binding. The substrate-binding site has no stringent restrictions with respect to the size of the amino acid. Lack of the amino or carboxyl groups at the alpha-carbon does not prevent the molecules from interacting with the active site. In fact, cysteamine is shown to be a potent activator of the enzyme without being a substrate. CDO was also rendered inactive upon complexation with the metal-binding inhibitors azide and cyanide. Unlike many non-heme iron dioxygenases that employ alpha-keto acids as cofactors, CDO was shown to be the only dioxygenase known to be inhibited by alpha-ketoglutarate.