Rodriguez‐Porcel, Martin

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.

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: Treatment options for refractory angina not amenable to revascularization are limited. Extracorporeal shockwave myocardial revascularization (ESMR) is a novel non-invasive application of low intensity shock waves that stimulates angiogenesis to improve ischemia. We aimed to determine the safety and efficacy of ESMR in patients with refractory angina. Methods: A single-arm multicenter U.S. prospective trial was implemented to assess safety and efficacy of ESMR therapy in patients with Class III/Class IV refractory angina. Each patient received 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy was assessed at baseline and 4 months after treatment by maximal treadmill exercise time and ischemic burden on pharmacological single photon emission computed tomography (SPECT). Safety was assessed by incidence of adverse events, electrocardiography, echocardiography, laboratory markers, and pain questionnaires. Results: Fifteen patients with medically refractory angina were enrolled. Exercise treadmill time from baseline to last follow-up after ESMR increased significantly (38%) by 122.3±156.9 seconds (319.8±157.2 vs. 422.1±183.3 seconds, p=0.016) (Figure 1). There was no difference in the mean summed stress score (SSS) on pharmacological-SPECT 4 months after treatment vs. baseline (17.8±14.9 vs. 21.2±15.3, p=0.233). However, SPECT SSS revealed that untreated areas had greater progression in ischemic burden vs. treated areas (3.69±6.2 vs. 0.31±4.5, p=0.038). There was no significant change in the mean summed echo score from baseline to post treatment (0.4±5.1, p=0.79).There were no changes in electrocardiography, echocardiographic parameters, or laboratory markers. No serious adverse events or complications occurred, and pain with ESMR was minimal (score of 0.5±1.2 to 1.1±1.2 out of 10). Conclusions: We find that ESMR is a safe and efficacious treatment which may be clinically feasible for patients with refractory angina pectoris.

Increased oxidative stress has been suggested to play an important role in the biology of mesenchymal stem cells (MSCs). However, little is known of the effect of increased oxidative stress in-vivo, partly due to the lack of appropriate imaging technologies for monitoring of stem cell biology in the living subject. Recent developments in molecular imaging permit, for the first time, the longitudinal monitoring of stem cell biology in vivo. We hypothesize that changes in oxidative stress can be monitored using a reporter gene strategy (molecular imaging). Methods: We have developed a novel oxidative stress sensor, using a two-step transcriptional amplification strategy to enhance the expression of firefly luciferase (Fluc), driven by the pro-oxidant enzyme NAD(P)H promoter, and used to monitor oxidative stress in rMSCs. rMSCs was induced by hypoxia (1% O2 for 24 hours) and serum deprivation (SD) and confirmed using a dichlorofluorescein colorimetric assay (measures the production of hydrogen peroxide-H2O2-) and NAD(P)H protein expression. Results: Both serum deprivation and hypoxia led to a pro-oxidant state (Fig. A–B ). Most importantly, increased oxidative stress led to increased activity of the novel reporter gene sensor (Fig. C ) which was decreased in the presence of antioxidants (superoxide dismuatse mimetic Tempol, 5mM, SD+T, Fig D ). Results were reproduced in a different cell type (rat cardiomyoblast, data not shown). Conclusion: Changes in oxidative stress in MSCs can be monitored using molecular imaging. Reporter Gene-based Molecular Imaging, a strategy that is clinically applicable, provides the opportunity to monitor stem cell survival in the living subject.

Background: Sarcoidosis is multi-system disease characterized by non-caseating granulomas, often presenting with pulmonary involvement. However, in the United States at least one-fourth of sarcoid patients have cardiovascular involvement. Sarcoid can also present as isolated cardiac sarcoidosis (CS), with symptoms that include heart failure (HF), advanced atrioventricular (AV) nodal block, ventricular tachycardia (VT), or sudden cardiac death. Consequently, it has been suggested that CS should be considered in patients presenting with high grade AV block, VT, or heart failure, with a non-ischemic presentation. Here, we present the CS experience at a tertiary medical center. Methods: Patients who underwent 18 F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) PET/CT to assess perfusion and inflammation for clinical suspicion of CS between 2009-2015 at a tertiary referral center were included in the study. These patients were retrospectively assessed for frequency of presenting features. Results: Inclusion criteria were met by 71 patients. VT was the most common presenting symptom seen in 40 of 71 patients (56%). High grade AV block was seen in 24 of 71 patients (34%). VT and high grade AV block was seen concomitantly in 9 (13%). An abnormal PET result was seen in 51 out of 71 patients (72%) with 30 of 51 having VT (59%) and 21 of 51 having AV block (41%). Of the patients with both VT and AV block, 8 of 9 had abnormal PET studies. In 34 of 71 (47%) patients with known extracardiac sarcoid, 18 (53%) had VT and 11 (32%) had AV block. HF symptoms (New York Heart Association class II-IV) were seen in 24 (34%). An abnormal resting ECG was seen in 64 out of 71 patients (90%). Conclusions: In our retrospective cohort VT is the most common presenting symptom in patients with suspicion of CS, and the combination of AV block with VT should raise concerns for an infiltrative process. In patients with extracardiac sarcoid and rhythm disturbance, cardiac involvement should be suspected and screened. Early identification of cardiovascular involvement is critical to ensure that appropriate management of the source of rhythm disturbance or heart failure is addressed before cardiovascular dysfunction is sustained.

Sarcoidosis is a multi-system inflammatory disease characterized by the development of inflammation and noncaseating granulomas that can involve nearly every organ system, with a predilection for the pulmonary system. Cardiac involvement of sarcoidosis (CS) occurs in up to 70% of cases, and accounts for a significant share of sarcoid-related mortality. The clinical presentation of CS can range from absence of symptoms to conduction abnormalities, heart failure, arrhythmias, valvular disease, and sudden cardiac death. Given the significant morbidity and mortality associated with CS, timely diagnosis is important. Traditional imaging modalities and histologic evaluation by endomyocardial biopsy often provide a low diagnostic yield. Cardiac positron emission tomography (PET) has emerged as a leading advanced imaging modality for the diagnosis and management of CS. This review article will summarize several aspects of the current use of PET in CS, including indications for use, patient preparation, image acquisition and interpretation, diagnostic and prognostic performance, and evaluation of treatment response. Additionally, this review will discuss novel PET radiotracers currently under study or of potential interest in CS.

Abstract Background Myocarditis following coronavirus disease 2019 (COVID-19) mRNA vaccines (Pfizer-BioNTech and Moderna) has been increasingly reported. Incidence rates in the general population are lacking, with pericarditis rather than myocarditis diagnostic codes being used to estimate background rates. This comparison is critical for balancing the risk of vaccination with the risk of no vaccination. Methods A retrospective case series was performed using the Mayo Clinic COVID-19 Vaccine Registry. We measured the incidence rate ratio (IRR) for myocarditis temporally related to COVID-19 mRNA vaccination compared with myocarditis in a comparable population from 2016 through 2020. Clinical characteristics and outcomes of the affected patients were collected. A total of 21 individuals were identified, but ultimately 7 patients met the inclusion criteria for vaccine-associated myocarditis. Results The overall IRR of COVID-19–related myocarditis was 4.18 (95% confidence interval [CI], 1.63–8.98), which was entirely attributable to an increased IRR among adult males (IRR, 6.69; 95% CI, 2.35–15.52) compared with females (IRR 1.41; 95% CI, .03–8.45). All cases occurred within 2 weeks of a dose of the COVID-19 mRNA vaccine, with the majority occurring within 3 days (range, 1–13) following the second dose (6 of 7 patients, 86%). Overall, cases were mild, and all patients survived. Conclusions Myocarditis is a rare adverse event associated with COVID-19 mRNA vaccines. It occurs in adult males with significantly higher incidence than in the background population. Recurrence of myocarditis after a subsequent mRNA vaccine dose is not known at this time.

Background: Myocardial infarction (MI) often results in permanent cardiac tissue necrosis and reduced heart functionality. Even with heart disease being the number one cause of death in the US, there are currently no effective methods of fully regenerating heart muscle post-myocardial infarction. Mesenchymal stem cells (MSCs) are a promising therapeutic option given their multi-potent nature and low host immune reaction. Bioengineered polymeric nanofiber scaffolds provide a structured growing environment and encourage cell elongation. Overview: This study characterizes MSC biology on poly-ε-caprolactone (PCL) nanofiber scaffolds in order to establish electrospun PCL nanofibers as a working biological scaffold for MSC growth, and to exhibit potential for further exploration of PCL nanofiber-grown MSC implants as a treatment for MI. Methods: MSCs were seeded on PCL scaffolds; cell viability was analyzed via XTT, cell apoptosis was analyzed via TUNEL/DAPI staining, and differentiation markers were analyzed via RT-PCR. Results: TUNEL/DAPI staining of confluent MSCs on PCL scaffolds showed low cell apoptosis over time. RT-PCR results showed no amplification of CD40 expression. Conclusion: PCL nanofibers seem to provide a suitable microenvironment for MSC seeding and proliferation. Further Direction: RT-PCR for CD80, CD86, COL1A1 (collagen), aSMA/Acta2 (smooth muscle), Flk1/VEGF2 (endothelial), Sparc (Osteonectin, osteogenic), Adipoq (Adiponectin, adipogenic), Agre-cano (chondrogenic).

Introduction: Stem cells have poor survival after transplantation, what can limit the use of these therapies. Mitochondrial dysfunction has been recognized as a limiting event that can lead to cell death. Here, we hypothesized that the mitochondrial function of progenitor cells can be monitored in vivo using reporter gene-based molecular imaging. A better understanding of the biology of transplanted stem cells in the ischemic myocardium can lead to optimization of cell therapies. Methods: Using RT-PCR we identified the antioxidant NAD(P)H:Quinone oxidoreductase (NQO1) enzyme as a marker of mitochondrial dysfunction in mouse Mesenchymal Stem Cells (MSCs) that were treated with a mitochondrial stressor, diethyl maleate (DEM). We then constructed a luciferase reporter gene driven by the NQO1 promoter. After in vitro validation, MSCs were transplanted into a mouse model of ischemia/reperfusion (IR, n=4) and mitochondrial function was monitored by bioluminescence imaging. Results: MSCs treated with DEM had an increase in NQO1 reporter gene signal that inversely correlated with the amount of the mitochondrial by-product adenosine tri-phosphate (ATP, r = -0.9643, p = 0.0028; Fig 1A). Mitochondrial dysfunction was preserved by the use of a mitochondria-targeted antioxidant Mito-Tempo (MT), correcting ATP and NQO1 luciferase signal. In vivo studies showed that MSCs yielded higher Firefly luciferase activity in IR mice compared to sham and this signal was normalized when cells were pre-treated with MT (Fig 1B). Data was confirmed by ex vivo measurement of Firefly luciferase activity, which was 4.9-fold higher in the IR group than in shams, after correction for cell number (Fig 1C). Conclusions: We have developed a novel imaging strategy that allows noninvasive assessment of the mitochondrial status of transplanted stem cells in the ischemic myocardium. Knowing when transplanted cells “suffer’ from mitochondrial dysfunction may allow optimization of these therapies.