Myocarditis Following Coronavirus Disease 2019 mRNA Vaccine: A Case Series and Incidence Rate Determination.

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.

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.

Pathway-specific reporter genes to study stem cell biology.

Little is known on the phenotypic characteristics of stem cells (SCs) after they are transplanted to the myocardium, in part due to lack of noninvasive platforms to study SCs directly in the living subject. Reporter gene imaging has played a valuable role in the noninvasive assessment of cell fate in vivo. In this study, we validated a pathway-specific reporter gene that can be used to noninvasively image the phenotype of SCs transplanted to the myocardium. Rat mesenchymal SCs (MSCs) were studied for phenotypic evidence of myogenic characteristics under in vitro conditions. After markers of myogenic characteristics were identified, we constructed a reporter gene sensor, comprising the firefly luciferase (Fluc) reporter gene driven by the troponin T (TnT) promoter (cardio MSCs had threefold expression in polymerase chain reaction compared to control MSCs) using a two-step signal amplification strategy. MSCs transfected with TnT-Fluc were studied and validated under in vitro conditions, showing a strong signal after MSCs acquired myogenic characteristics. Lastly, we observed that cardio MSCs had higher expression of the reporter sensor compared to control cells (0.005 ± 0.0005 vs 0.0025 ± 0.0008 Tnt-Fluc/ubiquitin-Fluc, P < .05), and that this novel sensor can detect the change in the phenotype of MSCs directly in the living subject. Pathway-specific reporter gene imaging allows assessment of changes in the phenotype of MSCs after delivery to the ischemic myocardium, providing important information on the phenotype of these cells. Imaging sensors like the one described here are critical to better understanding of the changes that SCs undergo after transplantation.

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.

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.

How to Develop a Cardio-Oncology Clinic.

Cardiovascular demands to the care of cancer patients are common and important given the implications for morbidity and mortality. As a consequence, interactions with cardiovascular disease specialists have intensified to the point of the development of a new discipline termed cardio-oncology. As an additional consequence, so-called cardio-oncology clinics have emerged, in most cases staffed by cardiologists with an interest in the field. This article addresses this gap and summarizes key points in the development of a cardio-oncology clinic.

Polycystic kidneys have decreased vascular density: a micro-CT study.

OBJECTIVE: Polycystic kidney disease (PKD) is a common cause of end-stage renal failure and many of these patients suffer vascular dysfunction and hypertension. It remains unclear whether PKD is associated with abnormal microvascular structure. Thus, this study examined the renovascular structure in PKD. METHODS: PKD rats (PCK model) and controls were studied at 10 weeks of age, and mean arterial pressure (MAP), renal blood flow, and creatinine clearance were measured. Microvascular architecture and cyst number and volume were assessed using micro-computed tomography, and angiogenic pathways evaluated. RESULTS: Compared with controls, PKD animals had an increase in MAP (126.4 ± 4.0 vs. 126.2 ± 2.7 mmHg) and decreased clearance of creatinine (0.39 ± 0.09 vs. 0.30 ± 0.05 mL/min), associated with a decrease in microvascular density, both in the cortex (256 ± 22 vs. 136 ± 20 vessels per cm2) and medullar (114 ± 14 vs. 50 ± 9 vessels/cm2) and an increase in the average diameter of glomeruli (104.14 ± 2.94 vs. 125.76 ± 9.06 mm). PKD animals had increased fibrosis (2.2 ± 0.2 fold vs. control) and a decrease in the cortical expression in hypoxia inducible factor 1-α and vascular endothelial growth factor. CONCLUSIONS: PKD animals have impaired renal vascular architecture, which can have significant functional consequences. The PKD microvasculature could represent a therapeutic target to decrease the impact of this disease.

Endothelial dysfunction occurs prior to clinical evidence of polycystic kidney disease.

OBJECTIVE: Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end-stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and its relationship with renal dysfunction remain to be determined. METHODS: ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied. RESULTS: Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in mean arterial pressure or renal function. The abnormal vasoreactivity was corrected with L-arginine (a precursor of nitric oxide, NO), while the expression of endothelial NO synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6-week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively). CONCLUSION: ARPKD leads to impairments in aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.

CAR-T Therapy in Lymphoma Patients With Coexisting Cardiomyopathy or Cardiac Lymphomatous Involvement.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the management of aggressive hematologic malignancies. However, its role in patients with lymphoma and cardiac metastasis or cardiomyopathy remains undefined due to potentially life-threatening complications such as ventricular rupture, cardiac tamponade, and circulatory failure. We present a case series of patients with lymphoma and cardiomyopathy or cardiac metastasis managed with chimeric antigen receptor T-cell therapy. (Level of Difficulty: Advanced.).

Emerging roles for integrated imaging modalities in cardiovascular cell-based therapeutics: a clinical perspective.

Despite preclinical promise, the progress of cell-based therapy to clinical cardiovascular practice has been slowed by several challenges and uncertainties that have been highlighted by the conflicting results of human trials. Most telling has been the revelation that current strategies fall short of achieving sufficient retention and engraftment of cells to meet the ambitious objective of myocardial regeneration. This has sparked novel research into the refinement of cell biology and delivery to overcome these shortcomings. Within this context, molecular imaging has emerged as a valuable tool for providing noninvasive surveillance of cell fate in vivo. Direct and indirect labelling of cells can be coupled with clinically relevant imaging modalities, such as radionuclide single photon emission computed tomography and positron emission tomography, and magnetic resonance imaging, to assess their short- and long-term distributions, along with their viability, proliferation and functional interaction with the host myocardium. This review details the strengths and limitations of the different cell labelling and imaging techniques and their potential application to the clinical realm. We also consider the broader, multifaceted utility of imaging throughout the cell therapy process, providing a discussion of its considerable value during cell delivery and its importance during the evaluation of cardiac outcomes in clinical studies.

Molecular imaging of cell therapy for gastroenterologic applications.

Stem cell therapy has appeared as a possible therapeutic alternative for numerous diseases. Furthermore, cancer stem cells are a focus of significant interest as they may allow for a better understanding of the genesis of different malignancies. The ultimate goal of stem cell therapeutics is to ensure the viability and functionality of the transplanted cells. Similarly, the ultimate goal of understanding cancer stem cells is to understand how they behave in the living subject. Until recently, the efficacy of stem cell therapies has been assessed by overall organ function recovery. Understanding the behavior and biology of stem cells directly in the living subject can also lead to therapy optimization. Thus, there is a critical need for reliable and accurate methods to understand stem cell biology in vivo. Recent advances in both imaging and molecular biology have enabled transplanted stem cells to be successfully monitored in the living subject. The use of molecular imaging modalities has the capability to answer these questions and may one day be translated to patients. In this review, we will discuss the potential imaging strategies and how they can be utilized, depending on the questions that need to be answered.

Stem Cell-Laden Coaxially Electrospun Fibrous Scaffold for Regenerative Engineering Applications.

Stem cell-based therapies for various ailments have attracted significant attention for over a decade. However, low retention of transplanted cells at the damaged site has hindered their potential for use in therapy. Tissue engineered grafts with fibrillar structures mimicking the extracellular matrix (ECM) can be potentially used to increase the retention and engraftment of stem cells at the damaged site. Moreover, these grafts may also provide mechanical stability at the damaged site to enhance function and regeneration. Among all the methods to produce fibrillar structures developed in recent years, electrospinning is a simple and versatile method to produce fibrous structures ranging from a few nanometers to micrometers. Coaxial electrospinning enables production of a mechanically stable core with a cell-binding sheath for enhanced cell adhesion and proliferation. Furthermore, this process provides an alternative to functionalized engineered scaffolds with specific compositions. The present article describes the protocol for developing a polycaprolactone (PCL) core and gelatin/gelatin methacrylate (GelMA) sheath laden with stem cells for various regenerative engineering applications. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Uniaxial PCL electrospinning Basic Protocol 2: Coaxial electrospinning Support Protocol 1: Scaffold characterization for Basic Protocols 1 and 2 Basic Protocol 3: Cell seeding on uniaxial and coaxial electrospun scaffolds and MTS assay Support Protocol 2: Preparation of scaffold with cells for scanning electron microscopy.

PET Imaging in Cardiac Sarcoidosis: A Narrative Review with Focus on Novel PET Tracers.

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.

Senolytic agents lessen the severity of abdominal aortic aneurysm in aged mice.

Age is a major risk factor for abdominal aortic aneurysm (AAA), for which treatment options are limited to surgical intervention for large AAA and watchful waiting for small aneurysms. However, the factors that regulate the expansion of aneurysms are unclear. Development of new therapeutic strategies to prevent or treat small aneurysms awaits a more thorough understanding of the etiology of AAA formation and progression with aging. A variety of structural and functional changes have been reported in aging vasculature, but emerging evidence implicates senescent cells in the formation of AAA through their paracrine effects on vascular wall cell populations. Here we show that aging is associated with transcriptional changes in abdominal aortic tissue consistent with loss of smooth muscle cells, leukocyte adhesion, inflammation, and accumulation of senescent cells in the vascular wall and surrounding perivascular adipose tissue. Furthermore, aged mice demonstrated anatomical and histopathological features of AAA development in response to administration of angiotensin II over 28 days. Importantly, in our study we sought to determine if reducing senescent cells could lessen the severity of AAA in aged mice. We find that pretreatment of aged mice with oral senolytic agents (dasatinib + quercetin) reduced senescent cell abundance in the arterial walls and surrounding tissues and lessened the severity of AAA in response to angiotensin II administration. These data provide important preliminary evidence supporting a role of senescent cells in age-related AAA formation and progression and suggest that strategies to reduce senescent cell burden hold promise to lessen AAA severity.

Cardio Phenotypic Potential of Mesenchymal Stem Cells.

Cell therapy is being investigated as a powerful intervention to ameliorate the consequences of coronary artery disease. Among the different stem cell options, mesenchymal stem cells (MSCs) are particularly attractive due to their high availability, as well as immune-privileged status. However, it is still unclear whether mesenchymal stem cells can acquire cardiomyogenic characteristics after they are transplanted to the myocardium. In this article, we outline protocols that illustrate the plasticity of MSCs and their ability to acquire cardiogenic characteristics when they are in an ischemic-like environment, as typically encountered after transplantation into the ischemic heart. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Isolation of mesenchymal stem cells (MSCs) Support Protocol 1: Characterization of MSCs by flow cytometry Basic Protocol 2: Isolation of neonatal cardiomyoctes (NCMs) Support Protocol 2: Characterization of NCMs Basic Protocol 3: Cardiogenic plasticity of MSCs under ischemic-like conditions Support Protocol 3: Characterization of the cardiomyogenic potential of MSCs.

In vivo imaging and monitoring of transplanted stem cells: clinical applications.

Regenerative medicine using stem cells has appeared as a potential therapeutic alternative for coronary artery disease, and stem cell clinical studies are currently on their way. However, initial results of these studies have provided mixed information, in part because of the inability to correlate organ functional information with the presence/absence of transplanted stem cells. Recent advances in molecular biology and imaging have allowed the successful noninvasive monitoring of transplanted stem cells in the living subject. In this article, different imaging strategies (direct labeling, indirect labeling with reporter genes) to study the viability and biology of stem cells are discussed. In addition, the limitations of each approach and imaging modality (eg, single photon emission computed tomography, positron emission tomography, and MRI) and their requirements for clinical use are addressed. Use of these strategies will be critical as the different regenerative therapies are being tested for clinical use.

Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model.

There is significant interest in the use of stem cells (SCs) for the recovery of cardiac function in individuals with myocardial injuries. Most commonly, cardiac stem cell therapy is studied by delivering SCs concurrently with the induction of myocardial injury. However, this approach presents two significant limitations: the early hostile pro-inflammatory ischemic environment may affect the survival of transplanted SCs, and it does not represent the subacute infarction scenario where SCs will likely be used. Here we describe a two-part series of surgical procedures for the induction of ischemia-reperfusion injury and delivery of mesenchymal stem cells (MSCs). This method of stem cell administration may allow for the longer viability and retention around damaged tissue by circumventing the initial immune response. A model of ischemia reperfusion injury was induced in mice accompanied by the delivery of mesenchymal stem cells (3.0 x 105), stably expressing the reporter gene firefly luciferase under the constitutively expressed CMV promoter, intramyocardially 7 days later. The animals were imaged via ultrasound and bioluminescent imaging for confirmation of injury and injection of cells, respectively. Importantly, there was no added complication rate when performing this two-procedure approach for SC delivery. This method of stem cell administration, collectively with the utilization of state-of-the-art reporter genes, may allow for the in vivo study of viability and retention of transplanted SCs in a situation of chronic ischemia commonly seen clinically, while also circumventing the initial pro-inflammatory response. In summary, we established a protocol for the delayed delivery of stem cells into the myocardium, which can be used as a potential new approach in promoting regeneration of the damaged tissue.

The Myocardial Microenvironment Modulates the Biology of Transplanted Mesenchymal Stem Cells.

PURPOSE: The maximal efficacy of cell therapy depends on the survival of stem cells, as well as on the phenotypic and biologic changes that may occur on these cells after transplantation. It has been hypothesized that the post-ischemic myocardial microenvironment can play a critical role in these changes, potentially affecting the survival and reparative potential of mesenchymal stem cells (MSCs). Here, we use a dual reporter gene sensor for the in vivo monitoring of the phenotype of MSCs and study their therapeutic effect on cardiac function. PROCEDURES: The mitochondrial sensor was tested in cell culture in response to different mitochondrial stressors. For in vivo testing, MSCs (3 × 105) were delivered in a murine ischemia-reperfusion (IR) model. Bioluminescence imaging was used to assess the mitochondrial biology and the viability of transplanted MSCs, while high-resolution ultrasound provided a non-invasive analysis of cardiac contractility and dyssynchrony. RESULTS: The mitochondrial sensor showed increased activity in response to mitochondrial stressors. Furthermore, when tested in the living subject, it showed a significant increase in mitochondrial dysfunction in MSCs delivered in IR, compared with those delivered under sham conditions. Importantly, MSCs delivered to ischemic hearts, despite their mitochondrial stress and poor survival, were able to induce a significant improvement in cardiac function, through decreased collagen deposition and resynchronization/contractility of left ventricular wall motion. CONCLUSIONS: The ischemic myocardium induces changes in the phenotype of transplanted MSCs. Despite their limited survival, MSCs still elicit a certain therapeutic response, as evidenced by improvement in myocardial remodeling and cardiac function. Maximization of the survival and reparative efficacy of stem cells remains a key for the success of stem cell therapies.