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BACKGROUND: Technetium-based cardiac amyloid radionuclide imaging enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), but conventional planar and visual semiquantitative approaches have important limitations. We developed the quantitative 3-dimensional Mayo 3D Score, defined as the ratio of mean left ventricular myocardial radiotracer uptake to right atrial blood-pool uptake using computed tomography (CT)-fused single-photon emission CT (SPECT) volumes of interest, and sought to validate its diagnostic performance against myocardial pathology. METHODS: Consecutive patients who underwent 99m Tc-pyrophosphate SPECT/CT at Mayo Clinic for suspected ATTR-CM between June 2017 and January 2025 with archived myocardial tissue were included. Baseline characteristics, including demographics, echocardiogram, biomarkers, visual semiquantitative, and Mayo 3D Score metrics, were collected. Myocardial specimens underwent histopathologic confirmation of amyloid, with amyloid subtype determination and further semiquantitative grading of amyloid burden and deposition patterns. RESULTS: Among 230 patients (median age, 72 years; 78% male), 107 (47%) had ATTR-CM, of whom 9 had hereditary ATTR-CM. The Mayo 3D Score showed excellent discrimination against pathology (area under the receiver operating characteristic curve, 0.92 [0.88–0.96]), exceeding planar Perugini (0.87 [0.83–0.92]; P =0.006), and heart-to-contralateral lung ratio (0.86 [0.81–0.91]; P =0.004) and comparable to SPECT Perugini (0.90 [0.86–0.94]; P =0.12). A cutoff ≥1.0 yielded 86.0% sensitivity, 92.7% specificity, 91.1% positive predictive value, and 88.4% negative predictive value. Among ATTR-positive cases, the Mayo 3D Score correlated strongly with semiquantitative amyloid burden (Spearman ρ=0.69), was higher in pericellular than nodular deposition patterns ( P <0.001), and was not associated with vascular involvement ( P =0.42). CONCLUSIONS: In patients with suspected ATTR-CM undergoing 99m Tc-pyrophosphate SPECT/CT, the Mayo 3D Score demonstrated superior diagnostic performance compared with planar metrics and comparable to SPECT Perugini, while correlating with myocardial ATTR burden and deposition patterns on pathology. These findings support its integration as a quantitative adjunct within clinical diagnostic ATTR-CM workflows.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1

BACKGROUND: Guidelines recommend 3-hour cardiac amyloid radionuclide imaging (CARI) for transthyretin amyloid cardiomyopathy. Citing rapid blood clearance of 99m Tc-hydroxymethylene-diphosphonate (HMDP) and efficient laboratory throughput, 1-hour imaging is increasingly practiced despite limited supporting evidence. We sought to compare diagnostic performance and interpreter experience of 1-hour versus 3-hour HMDP-CARI. METHODS: Consecutive patients with suspected transthyretin amyloid cardiomyopathy (n=114) underwent both 1-hour and 3-hour HMDP single photon emission computed tomography (CT)/CT. Two cardiologist-radiologist reader teams, blinded to imaging timepoint (1 versus 3 hours), assessed overall interpretation, single photon emission CT–based Perugini grade, interpretation difficulty, interpreter confidence, and need for CT-fused images for anatomic localization. Discordant, equivocal, and difficult cases were arbitrated by a third tie-breaking team. The myocardial-to-blood-pool radiotracer uptake ratio (3-dimensional Score) was measured as a surrogate of contrast resolution. RESULTS: Interinterpreter agreement was high at both time points (κ≥0.81), with more cases requiring arbitration at 3 hours versus 1 hour (22% versus 13%; P =0.049). Overall interpretation and Perugini grades were concordant between time points in 111/114 (97%) and 106/114 (93%) patients, respectively. Three patients (3%) were negative at 1 hour but equivocal at 3 hours, all of which were clinically ruled out for transthyretin amyloid cardiomyopathy. Interpreter confidence was comparable at both timepoints (97% versus 95%; P =0.317). Compared with 3-hour imaging, contrast resolution was inferior (lower 3-dimensional score, P <0.001) and CT fusion was more frequently needed (57% versus 31%, P <0.001) at 1-hour imaging. CONCLUSIONS: In a prospective, blinded comparison of 1-hour versus 3-hour HMDP-CARI, diagnostic performance and interpreter experience were similar, with readers requesting CT fusion more frequently at 1 hour to optimize myocardial-to-blood pool discrimination.

Background This study aimed to provide methodology to create a facial contour-informed normative 60-4 visual field and to apply the reference field to a glaucoma cohort to derive facial contour-informed 60-4 global indices. Methods Participant recruitment was completed at a tertiary medical centre. 60 eyes from 30 participants with no ocular pathology by clinical exam or optical coherence tomography were recruited for the healthy cohort. For the glaucoma cohort, 86 eyes from 43 patients diagnosed with glaucoma by clinical exam were recruited, with 30-2 visual field mean deviation used to stratify glaucoma severity. Results The median (range) age of the healthy participants was 33 (24–61) years old. A facial contour-informed 60-4 visual field reference field was developed. 43 glaucoma patients were recruited with a resulting median (range) age of 65 (30–84). Three algorithms compensating for facial contour were used for the derivation of 60-4 mean deviation and pattern SD. All mean deviation algorithms correlated with 30-2 mean deviation severity (ρ≤−0.62, p<0.0001) and retinal nerve fibre layer thickness (ρ≥0.36, p<0.05). For pattern SD, consideration of inferior nasal defects allowed correlation with both 30-2 mean deviation severity (ρ≥0.49, p<0.001) and retinal nerve fibre layer thickness (ρ≤−0.47, p<0.01). Conclusion This study provides methodology for deriving a facial contour-informed 60-4 reference field and illustrates the feasibility of applying facial contour information to refine global indices of the 60-4 visual field. Obtained metrics compensated for facial contour and correlated with functional and structural disease metrics.

Précis: Using a CNN-enhanced platform, 60-4 visual fields identified peripheral glaucomatous defects missed by central testing in mild cases; facial contour correction showed these defects occurred exclusively outside the temporal visual field. Purpose: To develop a methodology to separate facial contour-induced visual field defects from defects related to glaucoma in patients with peripheral field defects. Methods: Ninety-seven eyes from 50 patients previously diagnosed with glaucoma were enrolled in the study. Thirty-one (62%) participants were male, and 86% were white. The study involved patients with glaucoma who underwent visual field testing using standard automated perimetry, including 10-2, 24-2, 30-2, and 60-4 visual fields. A convolutional neural network (CNN)-enhanced platform, previously developed to identify facial contour-dependent defects in healthy subjects, was used to analyze the visual field data. Patients: The study included 97 eyes from 50 patients with glaucoma, with the majority having primary open angle glaucoma. Results: In 90 out of 97 eyes, there were 60-4 visual field defects. However, 20 (22%) of these eyes did not have glaucomatous defects on the 10-2 or 30-2 visual fields. All patients with 60-4 defects in the absence of more central defects had mild glaucoma, and these eyes comprised 38% of the mild glaucoma group. 60-4 visual field increased the sensitivity of identifying glaucoma in mild disease. Without facial contour, the 60-4 visual field mean threshold summation was 1099.6±346.6 dB, and decreased to 1057±331 dB when accounting for facial contour, which affected 8.03%±4.02% of test points. Facial contour-dependent visual field defects were exclusively found outside the temporal visual field. Conclusion: The study demonstrated the potential utility of 60-4 visual fields for identifying early functional glaucomatous changes that may not be detected by more central visual field tests (10-2 or 30-2). It may be important to consider peripheral visual field defects, which can be affected by facial contour, in the diagnosis and monitoring of glaucoma, particularly in mild cases.

ImportanceHealth-adjusted life expectancy, a measure of healthy longevity, lags longevity gains, resulting in a healthspan-lifespan gap.ObjectiveTo quantify the healthspan-lifespan gap across the globe, investigate for sex disparities, and analyze morbidity and mortality associations.Design, Setting, and ParticipantsThis retrospective cross-sectional study used the World Health Organization (WHO) Global Health Observatory as the global data source and acquired national-level data covering all continents. The 183 WHO member states were investigated. Statistical analysis was conducted from January to May 2024.ExposuresData represent 2 decades of longitudinal follow-up.Main Outcomes and MeasuresChanges in life expectancy and health-adjusted life expectancy, as well as the healthspan-lifespan gap were quantified for all participating member states. Gap assessment was stratified by sex. Correlations of the gap with morbidity and mortality were examined.ResultsThe healthspan-lifespan gap has widened globally over the last 2 decades among 183 WHO member states, extending to 9.6 years. A sex difference was observed with women presenting a mean (SD) healthspan-lifespan gap of 2.4 (0.5) years wider than men (P &amp;lt; .001). Healthspan-lifespan gaps were positively associated with the burden of noncommunicable diseases and total morbidity, and negatively with mortality. The US presented the largest healthspan-lifespan gap, amounting to 12.4 years, underpinned by a rise in noncommunicable diseases.Conclusions and RelevanceThis study identifies growing healthspan-lifespan gaps around the globe, threatening healthy longevity across worldwide populations. Women globally exhibited a larger healthspan-lifespan gap than men.

Introduction: Cardiac differentiation protocols enable derivation of cardiomyocytes (CM). from human induced pluripotent stem cell (iPS). However, limited tools are available to ensure enhanced iPS-CM maturation without the need for prolonged and complex culture. Research Question: This study assessed whether the mesodermal and cardiopoiesis inductor, Brachyury (T), complements standard cardiac differentiation and augments structural and functional maturation of iPS-CM. Aims: The impact of T mRNA introduction prior to initiation of cardiac differentiation was characterized on: i) cardiac transcription factor expression; ii) structural and functional hallmarks of maturity; and iii) cardiotoxicity. Methods: RT-qPCR was employed to monitor the expression of cardiac-specific transcription factors. Transmission electron microscopy enabled the assessment of cellular ultrastructure. Seahorse measurements were used to determine basal respiration. Fluo4 staining was used to measure calcium transients with external field stimulation. Cardiotoxicity was measured as the impact of doxorubicin on calcium handling and cell survival. Results: Transfection with T prompted early and sustained upregulation of the cardiac transcription factors Nkx2.5 (10-fold; FDR<0.001) and MEF2C (7.2-fold; FDR<0.001). Mitochondrial area was increased with T transfection (P<0.001) and T-transfected iPS-CM exhibited greater basal respiration (FDR<0.05), greater calcium handling resilience in response to field stimulation, and a more mature transient morphology. Following doxorubicin exposure T transfected iPS-CM exhibited a greater compromise in calcium handling (FDR<0.001), and exaggerated cell death. Conclusion: Induction of human iPS with T prior to initiation of cardiac differentiation enhanced signatures of structural and functional maturity, and provided more robust readouts of drug toxicity.

Abstract Cardiopoiesis-primed human stem cells exert sustained benefit in treating heart failure despite limited retention following myocardial delivery. To assess potential paracrine contribution, the secretome of cardiopoiesis conditioned versus naïve human mesenchymal stromal cells was decoded by directed proteomics augmented with machine learning and systems interrogation. Cardiopoiesis doubled cellular protein output generating a distinct secretome that segregated the conditioned state. Altering the expression of 1035 secreted proteins, cardiopoiesis reshaped the secretome across functional classes. The resolved differential cardiopoietic secretome was enriched in mesoderm development and cardiac progenitor signaling processes, yielding a cardiovasculogenic profile bolstered by upregulated cardiogenic proteins. In tandem, cardiopoiesis enhanced the secretion of immunomodulatory proteins associated with cytokine signaling, leukocyte migration, and chemotaxis. Network analysis integrated the differential secretome within an interactome of 1745 molecules featuring prioritized regenerative processes. Secretome contribution to the repair signature of cardiopoietic cell-treated infarcted hearts was assessed in a murine coronary ligation model. Intramyocardial delivery of cardiopoietic cells improved the performance of failing hearts, with undirected proteomics revealing 50 myocardial proteins responsive to cell therapy. Pathway analysis linked the secretome to cardiac proteome remodeling, pinpointing 17 cardiopoiesis-upregulated secretome proteins directly upstream of 44% of the cell therapy-responsive cardiac proteome. Knockout, in silico, of this 22-protein secretome-dependent myocardial ensemble eliminated indices of the repair signature. Accordingly, in vivo, cell therapy rendered the secretome-dependent myocardial proteome of an infarcted heart indiscernible from healthy counterparts. Thus, the secretagogue effect of cardiopoiesis transforms the human stem cell secretome, endows regenerative competency, and upregulates candidate paracrine effectors of cell therapy-mediated molecular restitution.

AbstractRamp studies are utilized for speed optimization of continuous flow left ventricular assist devices (CF‐LVADs). We here report the utility of combined left and right heart catheterization during a ramp study to ensure a comprehensive understanding of the hemodynamic implications on both ventricles. Pressure‐volume loop (PV loop) monitoring uncovered compromised systolic and mildly compromised right ventricular function with increasing LVAD speeds, despite improvement in left ventricular unloading. These findings informed patient management and highlight the potential utility of PV loop monitoring as an adjunct to left and right heart catheterization during ramp studies of next‐generation LVADs.