Feasibility of somatostatin receptor-targeted imaging for detection of myocardial inflammation: A pilot study.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: Thirteen patients, with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG-PET (median time 37 days [IQR 25-55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n = 6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8-7.1] higher in the heart, but only 2.25 times [1.7-3.0; P = .019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggest that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy.

Aims: Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results: We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P < 0.001), respectively. Conclusion: Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease.

BACKGROUND: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Pete and the Missing Scissors: a primary literature-focused case study that highlights the impact of SARS-CoV-2 on splicing.

This case study was designed to help students explore the molecular mechanisms of the spliceosome and how SARS-CoV-2 impacts host cell spliceosomal function while interpreting figures from primary literature (A. K. Banjeree, et al., Cell 183:1325-1339, e1-e10, 2020, https://doi.org/10.1016/j.cell.2020.10.004). "Pete and the Missing Scissors" was designed and implemented in the spring of 2022 and fall of 2022 in two large-enrollment (150+) introductory molecular biology courses at a large, public research institution. The case study was formatted in alignment with the National Center for Case Study Teaching in Science (NCCSTS) framework, which has been shown to be an effective, student-centered approach to teaching complex biological concepts at the undergraduate level. The case study had four student learning objectives (SLOs) that aligned with Bloom's Revised Taxonomy and required students to develop an understanding of the molecular mechanisms of splicing and analyze and interpret a figure from primary literature. Both formative and summative assessment questions are included in this activity, with each question mapping to one of the case study SLOs. Summative assessment questions were given in a pre-/post-manner, and a paired t-test was used to evaluate differences between students' pre- and post-assessment scores. Assessment results demonstrated that students in both courses mastered each of the SLOs of this case study, given the significant increase in post-assessment scores compared to the pre-assessment. These findings indicate that the "Pete and the Missing Scissors" case study is an effective approach to develop students' understanding of the spliceosome, as well as ability to interpret figures from primary literature.

Accuracy and Reproducibility of Myocardial Blood Flow Quantification by Single Photon Emission Computed Tomography Imaging in Patients With Known or Suspected Coronary Artery Disease.

BACKGROUND: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate 99mTc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with 13N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. METHODS: Accuracy was assessed in 34 participants who underwent dynamic 99mTc-sestamibi SPECT and 13N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 99mTc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model' and MFR was derived as the stress/rest MBF ratio. RESULTS: SPECT global MBF with splines showed good correlation with 13N-ammonia positron emission tomography (r=0.81, P<0.001) and MFR estimates (r=0.74, P<0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61, P<0.001 and r=0.34, P=0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P<0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68, P<0.001) and MFR correlations (r=0.33, P=0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm (P>0.05 for all). CONCLUSIONS: MBF and MFR quantification using 99mTc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with 13N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

Myocardial Scar But Not Ischemia Is Associated With Defibrillator Shocks and Sudden Cardiac Death in Stable Patients With Reduced Left Ventricular Ejection Fraction.

OBJECTIVES: This study sought to investigate the association of myocardial scar and ischemia with major arrhythmic events (MAEs) in patients with left ventricular ejection fraction (LVEF) ≤35%. BACKGROUND: Although myocardial scar is a known substrate for ventricular arrhythmias, the association of myocardial ischemia with ventricular arrhythmias in stable patients with left ventricular dysfunction is less clear. METHODS: A total of 439 consecutive patients (median age, 70 years; 78% male; 55% with implantable cardioverter defibrillator [ICD]) referred for stress/rest positron emission tomography (PET) and resting LVEF ≤35% were included. Primary outcome was time-to-first MAE defined as sudden cardiac death, resuscitated sudden cardiac death, or appropriate ICD shocks for ventricular tachyarrhythmias ascertained by blinded adjudication of hospital records, Social Security Administration's Death Masterfile, National Death Index, and ICD vendor databases. RESULTS: Ninety-one MAEs including 20 sudden cardiac deaths occurred in 75 (17%) patients during a median follow-up of 3.2 years. Transmural myocardial scar was strongly associated with MAEs beyond age, sex, cardiovascular risk factors, beta-blocker therapy, and resting LVEF (adjusted hazard ratio per 10% increase in scar, 1.48 [95% confidence interval: 1.22 to 1.80]; p < 0.001). However, non transmural scar/hibernation or markers of myocardial ischemia on PET including global or peri-infarct ischemia, coronary flow reserve, and resting or hyperemic myocardial blood flows were not associated with MAEs in univariable or multivariable analysis. These findings remained robust in subgroup analyses of patients with ICD (n = 223), with ischemic cardiomyopathy (n = 287), and in patients without revascularization after the PET scan (n = 365). CONCLUSIONS: Myocardial scar but not ischemia was associated with appropriate ICD shocks and sudden cardiac death in patients with LVEF ≤35%. These findings have implications for risk-stratification of patients with left ventricular dysfunction who may benefit from ICD therapy.