IMPROvE-CED Trial: Intracoronary Autologous CD34+ Cell Therapy for Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. METHODS: Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×105 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. RESULTS: Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [-18.0 to 32.4] to 57.6 [16.3-98.3]%; P=0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P=0.00018), and sublingual nitroglycerin use/day (1 [0.4-3.5] to 0 [0-1], Wilcoxon signed-rank test, P=0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. CONCLUSIONS: A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03471611.

Comparison of Photon-counting Detector and Energy-integrating Detector CT for Visual Estimation of Coronary Percent Luminal Stenosis.

Background Compared with energy-integrating detector (EID) CT, the improved resolution of photon-counting detector (PCD) CT coupled with high-energy virtual monoenergetic images (VMIs) has been shown to decrease calcium blooming on images in phantoms and cadaveric specimens. Purpose To determine the impact of dual-source PCD CT on visual and quantitative estimation of percent diameter luminal stenosis compared with dual-source EID CT in patients. Materials and Methods This prospective study recruited consecutive adult patients from an outpatient facility between January and March 2022. Study participants underwent clinical dual-source EID coronary CT angiography followed by a research dual-source PCD CT examination. For PCD CT, multienergy data were used to create VMIs at 50 and 100 keV. Two readers independently reviewed EID CT images followed by PCD CT images after a washout period. Readers visually graded the most severe stenosis in terms of percent diameter luminal stenosis for the left main, left anterior descending, right, and circumflex coronary arteries, unblinded to scanner type. Quantitative measures of percent stenosis were made using commercial software. Visual and quantitative estimates of percent stenosis were compared between EID CT and PCD CT using the Wilcoxon signed-rank test. Results A total of 25 participants (median age, 59 years [range, 18-78 years]; 16 male participants) were enrolled. On EID CT images, readers 1 and 2 identified 39 and 32 luminal stenoses, respectively, with a percent diameter luminal stenosis greater than 0%. Visual estimates of percent stenosis were lower on PCD CT images than EID CT images (reader 1: median 20.6% [IQR, 8.8%-61.2%] vs 31.8% [IQR, 12.9%-69.7%], P < .001; reader 2: 6.5% [IQR, 0.4%-54.1%] vs 22.9% [IQR, 1.8%-67.4%], P = .002). No difference was observed between EID CT and PCD CT for quantitative measures of percent stenosis (median difference, -1.5% [95% CI: -3.0%, 2.5%]; P = .51). Conclusion Relative to using EID CT, using PCD CT led to decreases in visual estimates of percent stenosis. © RSNA, 2023 See also the editorial by Murphy and Donnelly in this issue.

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.

Cardiac resynchronization therapy response in cardiac sarcoidosis.

INTRODUCTION: Cardiac sarcoidosis (CS) is a nonischemic cardiomyopathy (NICM) characterized by infiltration of noncaseating granulomas involving the heart with highly variable clinical manifestations that can include conduction abnormalities and systolic heart failure. Cardiac resynchronization therapy (CRT) has shown significant promise in NICM, though little is known about its efficacy in patients with CS. OBJECTIVE: To determine if CRT improved cardiac remodeling in patients with CS. METHODS: We retrospectively reviewed all patients with a clinical or histological diagnosis of CS who underwent CRT implantation at the Mayo Clinic enterprise from 2000 to 2021. Baseline characteristics, imaging parameters, heart failure hospitalizations and need for advanced therapies, and major adverse cardiac events (MACE) were assessed. RESULTS: Our cohort was comprised of 55 patients with 61.8% male and a mean age of 58.7 ± 10.9 years. Eighteen (32.7%) patients had definite CS, 21 (38.2%) had probable CS, while 16 (29.1%) had presumed CS, and 26 (47.3%) with extracardiac sarcoidosis. The majority underwent CRT-D implantation (n = 52, 94.5%) and 3 (5.5%) underwent CRT-P implantation with 67.3% of implanted devices being upgrades from prior pacemakers or implantable cardioverter defibrillators. At 6 months postimplantation there was no significant improvement in ejection fraction (34.8 ± 10.9% vs. 37.7 ± 14.2%, p = .331) or left ventricular end-diastolic diameter (58.5 ± 10.2 vs. 57.5 ± 8.1 mm, p = .236), though mild improvement in left ventricular end systolic diameter (49.1 ± 9.9 vs. 45.7± 9.9 mm, p < .0001). Within the first 6 months postimplantation, 5 (9.1%) patients sustained a heart failure hospitalization. At a mean follow-up of 4.1± 3.7 years, 14 (25.5%) patients experienced a heart failure hospitalization, 11 (20.0%) underwent cardiac transplantation, 1 (1.8%) underwent left ventricular assist device implantation and 7 (12.7%) patients died. CONCLUSIONS: Our findings suggest variable response to CRT in patients with CS with no overall improvement in ventricular function within 6 months and a substantial proportion of patients progressing to advanced heart failure therapies.

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.

A lifelong preoccupation with the sociality of moral obligation.

Tomasello provides compelling evidence that children understand that people are morally obligated toward members of their social group. We call for expanding the scope of inquiry to encompass the full developmental trajectory of humans' understanding of the relation between moral obligation, sociality, and stancetaking in interaction. We suggest that humans display a lifelong preoccupation with the sociality of moral obligation.

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.

Progression rate of severity of aortic stenosis in patients with rheumatoid arthritis.

OBJECTIVE: Valvular heart disease is common in patients with rheumatoid arthritis (RA). However, there is uncertainty about how often to perform echocardiographic surveillance in this population. The objective of this study was to assess the progression rate of mild and moderate aortic stenosis (AS) in patients with RA. METHODS: A population-based cohort of patients with RA and either mild (2.0-2.9 m/second) or moderate (3.0-3.9 m/second) AS was identified. Demographic, clinical, and echocardiographic data were collected. Annual progression rate of AS was then calculated for the study cohort and the impact of pertinent RA variables on progression rate determined. RESULTS: Sixty-eight patients with RA and mild or moderate AS met the inclusion requirements. Peak aortic valve (AV) velocity and mean AV gradient increased during the study period, whereas AV area decreased, consistent with progression of AS (P<.001). Mean (SD) annual increase in peak AV jet velocity was 0.05 m/second (0.01) and in mean AV gradient was 1.0 mm Hg (0.18). Mean annual decrease in AV area was 0.04 (0.01) cm2 . The progression rate of AS was higher in patients with increased erythrocyte sedimentation rates (ESR) (P=.001). CONCLUSIONS: The rate of AS progression in the RA population was higher in patients with increased ESR but less than that of the reported rate of AS progression in the general population. Although the cause for this finding is uncertain, these results suggest that patients with RA who have mild or moderate AS should undergo echocardiographic surveillance for disease progression similar to that of the general population.

Impact of acute left ventricular apical thrombus on cardioversion for atrial fibrillation.

Among patients undergoing cardioversion for atrial fibrillation, the presence of left ventricular thrombus is a relatively uncommon and challenging clinical dilemma. While left atrial appendage thrombus is a contraindication to cardioversion, there is paucity of data regarding the safety of cardioversion in with the presence of left ventricular apical thrombus. Also, thrombus characteristics such as protrusion and mobility on echocardiography are known risk factors for systemic embolism. In this article, we present a case highlighting the management of atrial fibrillation in the setting of left ventricular dysfunction, acute heart failure, and echocardiographic evidence of acute left ventricular apical thrombus.

Considering experimental and observational evidence of priming together, syntax doesn't look so autonomous.

We agree with Branigan & Pickering (B&P) that structural priming experiments should supplant grammaticality judgments for testing linguistic representation. However, B&P overlook a vast (corpus-)linguistic literature that converges with - but extends - the experimental findings. B&P conclude that syntax is functionally independent of the lexicon. We argue that a broader approach to priming reveals cracks in the façade of syntactic autonomy.

Postprandial Hemodynamics in Hypertrophic Cardiomyopathy.

OBJECTIVES: Prior analysis at our institution found that patients with hypertrophic cardiomyopathy (HCM) who experience postprandial symptoms (PPS) are more likely to have resting left ventricular outflow tract (LVOT) obstruction and reduced quality of life. Our objective was to determine whether PPS in patients with HCM vs healthy subjects occur as a result of measurable hemodynamic alterations in the postprandial hemodynamic response. METHODS: We conducted a prospective cross-sectional study examining 45 patients with HCM and 10 controls who underwent fasting and postprandial 2-dimensional Doppler echocardiography. Postprandial echocardiographic measurements were obtained at symptom onset or 30 minutes after consumption of a standardized meal, whichever occurred first. RESULTS: The HCM population included 18 (40%) patients with PPS and 27 (60%) without PPS. Compared to controls, mean resting peak LVOT gradient was 23.4 ± 17.6 mmHg in HCM patients with PPS and 25.1 ± 33.1 mmHg in those without PPS (P = 0.10). The mean change in peak LVOT gradient after a meal was 0.7 ± 1.1 mmHg for controls, 5.0 ± 8.3 mmHg for HCM patients with PPS, and 1.5 ± 18.2 mmHg for HCM patients without PPS (P = 0.64). CONCLUSION: Although the ability to provoke an increased LVOT gradient with a postprandial, upright exercise study protocol was recently reported, the current study suggests that a resting, supine, postprandial protocol does not elicit evidence of LVOT obstruction. Therefore, future investigations should consider whether simply performing an upright postprandial study in HCM patients with PPS will provide evidence of dynamic LVOT or if the addition of an exercise component is necessary.

Severe Hypertriglyceridemia in a Patient With Metabolic Syndrome and Psoriasis on Risankizumab-Rzaa.

We report a case of severe hypertriglyceridemia (HTG) complicated by hyperviscosity syndrome as a possible adverse reaction to risankizumab-rzaa in a 49-year-old male with a history of longstanding uncontrolled type 2 diabetes, obesity, and coronary artery disease with prior ST-elevation myocardial infarction. On admission, the patient presented with xanthomatous plaques, chest and epigastric discomfort, and headache. Subsequent blood testing revealed severely elevated triglyceride (TG) levels at 7670 mg/dL (86.59 mmol/L) [reference range: <150 mg/dL; 1.69 mmol/L] and total cholesterol at 934 mg/dL (24.14 mmol/L) [reference range: <200 mg/dL; 5.17 mmol/L]. Triglyceride levels decreased and symptoms resolved with dietary restrictions and plasmapheresis. At follow-up, his TG remained elevated but improved, and he was advised to continue lipid-lowering medications as well as cessation of risankizumab. While the patient presented with high risk factors, we posit that the subacute presentation of severe HTG is a possible result of his recent course of risankizumab-rzaa therapy for management of psoriasis. This is noteworthy as pharmaceutical surveys and clinical trials do not list severe HTG as an adverse effect. Postmarketing surveillance studies are essential to confirm this potential association and monitor drug safety. In summary, this case highlights a possible link between risankizumab and severe HTG, emphasizing the importance of ongoing pharmacovigilance to identify and manage unexpected adverse effects associated with new medications.

Imaging of Cardiac Sarcoidosis: An Update and Future Aspects.

Cardiac sarcoidosis (CS), an increasingly recognized disease of unknown etiology, is associated with significant morbidity and mortality. Given the limited diagnostic yield of traditional endomyocardial biopsy (EMB), there is increasing reliance on multimodality cardiovascular imaging in the diagnosis and management of CS, with EMB being largely supplanted by the use of 18F-fluorodeoxyglucose (FDG-PET) and cardiac magnetic resonance imaging (CMR). This article aims to provide a comprehensive review of imaging modalities currently utilized in the screening, diagnosis, and monitoring of CS, while highlighting the latest developments in each area.