Personalized coronary and myocardial blood flow models incorporating CT perfusion imaging and synthetic vascular trees.

Computational simulations of coronary artery blood flow, using anatomical models based on clinical imaging, are an emerging non-invasive tool for personalized treatment planning. However, current simulations contend with two related challenges - incomplete anatomies in image-based models due to the exclusion of arteries smaller than the imaging resolution, and the lack of personalized flow distributions informed by patient-specific imaging. We introduce a data-enabled, personalized and multi-scale flow simulation framework spanning large coronary arteries to myocardial microvasculature. It includes image-based coronary anatomies combined with synthetic vasculature for arteries below the imaging resolution, myocardial blood flow simulated using Darcy models, and systemic circulation represented as lumped-parameter networks. We propose an optimization-based method to personalize multiscale coronary flow simulations by assimilating clinical CT myocardial perfusion imaging and cardiac function measurements to yield patient-specific flow distributions and model parameters. Using this proof-of-concept study on a cohort of six patients, we reveal substantial differences in flow distributions and clinical diagnosis metrics between the proposed personalized framework and empirical methods based purely on anatomy; these errors cannot be predicted a priori. This suggests virtual treatment planning tools would benefit from increased personalization informed by emerging imaging methods.

Prognostic Value of Qualitative and Quantitative Stress CMR in Patients With Known or Suspected CAD.

BACKGROUND: Recent studies suggest that quantitative cardiac magnetic resonance (CMR) may have more accuracy than qualitative CMR in coronary artery disease (CAD) diagnosis. However, the prognostic value of quantitative and qualitative CMR has not been compared systematically. OBJECTIVES: The objective was to conduct a systematic review and meta-analysis assessing the utility of qualitative and quantitative stress CMR in the prognosis of patients with known or suspected CAD. METHODS: A comprehensive search was performed through Embase, Scopus, Web of Science, and Medline. Studies that used qualitative vasodilator CMR or quantitative CMR assessments to compare the prognosis of patients with positive and negative CMR results were extracted. A meta-analysis was then performed to assess: 1) major adverse cardiovascular events (MACE) including cardiac death, nonfatal myocardial infarction (MI), unstable angina, and coronary revascularization; and 2) cardiac hard events defined as the composite of cardiac death and nonfatal MI. RESULTS: Forty-one studies with 38,030 patients were included in this systematic review. MACE occurred significantly more in patients with positive qualitative (HR: 3.86; 95% CI: 3.28-4.54) and quantitative (HR: 4.60; 95% CI: 1.60-13.21) CMR assessments. There was no significant difference between qualitative and quantitative CMR assessments in predicting MACE (P = 0.75). In studies with qualitative CMR assessment, cardiac hard events (OR: 7.21; 95% CI: 4.99-10.41), cardiac death (OR: 5.63; 95% CI: 2.46-12.92), nonfatal MI (OR: 7.46; 95% CI: 3.49-15.96), coronary revascularization (OR: 6.34; 95% CI: 3.42-1.75), and all-cause mortality (HR: 1.66; 95% CI: 1.12-2.47) were higher in patients with positive CMR. CONCLUSIONS: The presence of myocardial ischemia on CMR is associated with worse clinical outcomes in patients with known or suspected CAD. Both qualitative and quantitative stress CMR assessments are helpful tools for predicting clinical outcomes.

A quality improvement project to optimize access to psychosocial care for cancer survivors who experience fear of recurrence.

BACKGROUND: The prevalence of moderate to high levels of fear of cancer recurrence (FCR) in cancer survivors may vary from 22% to 87%, although most are not usually referred to psychosocial support. The After Cancer Treatment Transition (ACTT) clinic in Women's College Hospital (Toronto) provides follow-up care to cancer survivors but in a sample of 2893 patients seen April 2019 to March 2022, only 1.5% were referred to a social worker for psychosocial needs. A single-question screening tool is currently available to screen for FCR. OBJECTIVE: To evaluate the use of the single-question screening tool for FCR among cancer survivors and its impact on social work referrals. RESULTS: Between July and October 2022, 788 patients were seen in the ACTT clinic. Generally, most patients in ACTT are breast cancer survivors (75%), and the remaining survivors are a mix of other cancer types (colorectal cancer, ovarian cancer, thyroid cancer, melanoma). Three hundred thirty (41.9%) ACTT patients completed the single-question screening tool for FCR. Most screened patients were female (96%), the average age was 60 years, and most were diagnosed with breast cancer (90%). Among screened patients, 37 (11%) indicated a moderately severe to high level of FCR and efforts were made to refer these 37 patients to a social worker. In the end, 22 (59.5%) patients with moderately severe/high levels of FCR were offered and accepted referral to a social worker. In comparison to the 1.5% referred to social work (among 2893 patients) prior to FCR screening, referrals increased to 6.7% (among 330 screened). CONCLUSION: Use of a single-question FCR screening tool improved identifying cancer survivors in need of psychosocial support and improved access to a social worker.

A Combination of Distinct Vascular Stem/Progenitor Cells for Neovascularization and Ischemic Rescue.

BACKGROUND: Peripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia. METHODS: The ActinCreER/R26VT2/GK3 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation. Prospective isolation and transplantation were used to determine vessel-forming capacity of different populations. Single-cell RNA-sequencing was used to characterize distinct vessel-forming populations and their interactions. RESULTS: Two populations of distinct vascular stem/progenitor cells (VSPCs) were identified from adipose-derived mesenchymal stromal cells: VSPC1 is CD45-Ter119-Tie2+PDGFRa-CD31+CD105highSca1low, which gives rise to stunted vessels (incomplete tubular structures) in a transplant setting, and VSPC2 which is CD45-Ter119-Tie2+PDGFRa+CD31-CD105lowSca1high and forms stunted vessels and fat. Interestingly, cotransplantation of VSPC1 and VSPC2 is required to form functional vessels that improve perfusion in the mouse hindlimb ischemia model. Similarly, VSPC1 and VSPC2 populations isolated from human adipose tissue could rescue the ischemic condition in mice. CONCLUSIONS: These findings suggest that autologous cotransplantation of synergistic VSPCs from nonessential adipose tissue can promote neovascularization and represents a promising treatment for ischemic disease.

Assessing and Addressing Social Determinants of Cardiovascular Health: JACC State-of-the-Art Review.

Social determinants of health (SDOH) are the social conditions in which people are born, live, and work. SDOH offers a more inclusive view of how environment, geographic location, neighborhoods, access to health care, nutrition, socioeconomics, and so on are critical in cardiovascular morbidity and mortality. SDOH will continue to increase in relevance and integration of patient management, thus, applying the information herein to clinical and health systems will become increasingly commonplace. This state-of-the-art review covers the 5 domains of SDOH, including economic stability, education, health care access and quality, social and community context, and neighborhood and built environment. Recognizing and addressing SDOH is an important step toward achieving equity in cardiovascular care. We discuss each SDOH within the context of cardiovascular disease, how they can be assessed by clinicians and within health care systems, and key strategies for clinicians and health care systems to address these SDOH. Summaries of these tools and key strategies are provided.

NK-like CD8+ γδ T cells are expanded in persistent Mycobacterium tuberculosis infection.

The response of gamma delta (γδ) T cells in the acute versus chronic phases of the same infection is unclear. How γδ T cells function in acute Mycobacterium tuberculosis (Mtb) infection is well characterized, but their response during persistent Mtb infection is not well understood, even though most infections with Mtb manifest as a chronic, clinically asymptomatic state. Here, we analyze peripheral blood γδ T cells from a South African adolescent cohort and show that a unique CD8+ γδ T cell subset with features of "memory inflation" expands in chronic Mtb infection. These cells are hyporesponsive to T cell receptor (TCR)-mediated signaling but, like NK cells, can mount robust CD16-mediated cytotoxic responses. These CD8+ γδ T cells comprise a highly focused TCR repertoire, with clonotypes that are Mycobacterium specific but not phosphoantigen reactive. Using multiparametric single-cell pseudo-time trajectory analysis, we identified the differentiation paths that these CD8+ γδ T cells follow to develop into effectors in this infection state. Last, we found that circulating CD8+ γδ T cells also expand in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may drive similar γδ T cell effector programs and differentiation fates.

Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research.

Purpose of the Review: Even as immune checkpoint inhibitors (ICIs) have transformed the lifespan of many patients, they may also trigger acceleration of long-term cardiovascular disease. Our review aims to examine the current landscape of research on ICI-mediated atherosclerosis and address key questions regarding its pathogenesis and impact on patient management. Recent Findings: Preclinical mouse models suggest that T cell dysregulation and proatherogenic cytokine production are key contributors to plaque development after checkpoint inhibition. Clinical data also highlight the significant burden of atherosclerotic cardiovascular disease (ASCVD) in patients on immunotherapy, although the value of proactively preventing and treating ASCVD in this population remains an open area of inquiry. Current treatment options include dietary/lifestyle modification and traditional medications to manage hypertension, hyperlipidemia, and diabetes risk factors; no current targeted therapies exist. Summary: Early identification of high-risk patients is crucial for effective preventive strategies and timely intervention. Future research should focus on refining screening tools, elucidating targetable mechanisms driving ICI atherosclerosis, and evaluating long-term cardiovascular outcomes in cancer survivors who received immunotherapy. Moreover, close collaboration between oncologists and cardiologists is essential to optimize patient outcomes.

Sex differences in ICI myocarditis: Hormones to the rescue.

Sex hormones may account for sex differences observed in the prevalence and susceptibility of ICI myocarditis (Zhang et al., this issue).

Outcomes of Early Transition of Low-Risk Thyroid Cancer Patients from Specialist to Primary Care.

BACKGROUND: Recently published clinical pathways for management of thyroid cancer outlined the criteria for transitioning low-risk patients to primary care within one to five years from diagnosis. However, discharge patterns among endocrinologists remain heterogeneous as there lacks a consensus regarding post-treatment care for thyroid cancer patients. OBJECTIVE: This study described general characteristics and outcomes of thyroid cancer patients who were discharged from specialist care and transitioned to a primary care-based follow-up clinic. METHODS: Thyroid cancer patients seen in the After Cancer Treatment Transition (ACTT) clinic at Women's College Hospital (Toronto, Canada) were included in the study. Electronic medical records were reviewed between May and October 2021 to collect patient characteristics and outcomes. Descriptive statistics were calculated. RESULTS: The study cohort included 148 thyroid cancer patients and 76% were female. All cases were papillary thyroid cancer and most diagnoses were classified as T2 (42%), N0 (55%), M0 (91%), and stage 1 (83%). Nearly all patients (n = 147) had complete thyroidectomy. Levels of thyroglobulin and thyroglobulin antibodies (TgAb) were low overall, with only 5% of the study cohort deemed TgAb positive. Mean levels of thyroid stimulating hormone (TSH) measured at 2 time points (1.37 mIU/L, 1.42 mIU/L) were within normal range. About 91% of the study cohort had normal TSH levels and 82% met target TSH levels. There were 2 cases of recurrence; however, investigation determined that they were not initially appropriate candidates for transition to primary care. Nearly 99% (n = 146) of patients had excellent response to therapy, showed no evidence of disease recurrence, and have not required re-referral to specialist care. CONCLUSIONS: These findings may reassure specialists that low-risk, stable thyroid cancer patients can be safely transitioned to primary care for post-treatment follow-up.

Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown. METHODS: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis. RESULTS: Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls. CONCLUSIONS: Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

An examination of depression, anxiety, and fear of recurrence among cancer survivors who participated in a virtual cognitive behavioral therapy (CBT)-based telephone coaching program.

BACKGROUND: Depression, anxiety, and fear of recurrence (FOR) are prevalent among cancer survivors, and it is recommended that they have access to supportive services and resources to address psychosocial needs during follow-up care. This study examined the impact of a virtual cognitive behavioral therapy (CBT)-based telephone coaching program (BounceBack®) on depression, anxiety, and FOR. METHOD: Through the After Cancer Treatment Transition (ACTT) clinic at the Women's College Hospital (Toronto, Canada), eligible participants were identified, consented, and referred to the BounceBack® program. Program participation involved completion of self-selected online workbooks and support from trained telephone coaches. Measures of depression (PHQ-9), anxiety (GAD-7), and FOR (fear of cancer recurrence inventory, FCRI) were collected at pre-intervention (baseline) and post-intervention (6-month and 12-month time points). For each psychosocial measure, paired t-tests compared mean scores between study time points. Participant experiences and perceptions were collected through a survey. RESULTS: Measures of depression and anxiety significantly improved among participants from pre-intervention to post-intervention. Scores for PHQ-9 and GAD-7 decreased from moderate to mild levels. Measure of FOR also significantly improved, while FCRI sub-scale scores significantly improved for 5 of the 7 factors that characterize FOR (triggers, severity, psychological distress, functional impairment, insight). Participants rated the intervention a mean score of 7 (out of 10), indicating a moderate level of satisfaction and usefulness. CONCLUSION: This study suggested that a virtual CBT-based telephone coaching program can be an effective approach to managing depression, anxiety, and fear of recurrence in cancer survivors.

Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self.

BACKGROUND: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. METHODS: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. RESULTS: In addition to macrophages, we found a high proportion of αß T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αß T cells (CD4

The development and implementation of the After Cancer Treatment Transition (ACTT) Program for survivors of cancer.

Background: The After Cancer Treatment Transition (ACTT) program at Women's College Hospital (Toronto) is a transitional follow-up program for patients, their families, and healthcare providers to address the broad range of post-cancer treatment and survivorship needs. This publication describes the systematic development and implementation of the ACTT program, with a focus on the advanced practice nursing (APN) role. Program Development: ACTT development required the collaboration of an APN, a general practitioner in oncology (GPO), and an inter-professional team. ACTT developers proposed a clinic structure in an ambulatory setting, linking healthcare professionals to provide post-treatment follow-up and ongoing survivorship care. Post-treatment guidelines were developed based on expert oncologist consensus, cancer site group input, and evidence-informed guidelines or best practice recommendations. Program Implementation: Initial challenges and concerns were rooted in the requirements that post-cancer treatment care was maintained and survivor needs were addressed. Cancer site groups and the inter-professional teams provided continuous feedback on processes and protocols. ACTT established a standard approach to transition patients safely and effectively out of tertiary care and, ultimately, to primary care. Current ACTT Program: ACTT delivers comprehensive posttreatment and survivorship care through close collaboration between the GPO and APN. Both roles specialize in managing late or persistent effects, cancer surveillance and prevention, and addressing psychosocial needs prior to discharge to primary care. The survivorship care plan provided by ACTT is an informative tool for both patient and primary care provider to continue post-treatment follow-ups. Future Directions: Next steps for ACTT include expanding to other cancer specialties, exploring new ways to deliver care, optimizing the transition of care, and conducting comprehensive evaluations of patient reported outcomes.

Gastrointestinal duplication masquerading as intussusception in an adult.

Gastrointestinal duplication is a rare congenital condition that involves tissues anywhere along the alimentary tract. It may also be referred to as enteric duplication or alimentary tract duplication. It typically presents in children and is hardly found in adults because the presentation varies and the diagnosis is often incidental. Surgical resection is generally indicated to prevent future complications. We present a case of duplicated small bowel discovered during surgery in a young female with the initial diagnosis of small bowel intussusception on CT.

Dynamic Myocardial Perfusion CT for the Detection of Hemodynamically Significant Coronary Artery Disease.

OBJECTIVES: In this international, multicenter study, using third-generation dual-source computed tomography (CT), we investigated the diagnostic performance of dynamic stress CT myocardial perfusion imaging (CT-MPI) in addition to coronary CT angiography (CTA) compared to invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR). BACKGROUND: CT-MPI combined with coronary CTA integrates coronary artery anatomy with inducible myocardial ischemia, showing promising results for the diagnosis of hemodynamically significant coronary artery disease in single-center studies. METHODS: At 9 centers in Europe, Japan, and the United States, 132 patients scheduled for ICA were enrolled; 114 patients successfully completed coronary CTA, adenosine-stress dynamic CT-MPI, and ICA. Invasive FFR was performed in vessels with 25% to 90% stenosis. Data were analyzed by independent core laboratories. For the primary analysis, for each coronary artery the presence of hemodynamically significant obstruction was interpreted by coronary CTA with CT-MPI compared to coronary CTA alone, using an FFR of ≤0.80 and angiographic severity as reference. Territorial absolute myocardial blood flow (MBF) and relative MBF were compared using C-statistics. RESULTS: ICA and FFR identified hemodynamically significant stenoses in 74 of 289 coronary vessels (26%). Coronary CTA with ≥50% stenosis demonstrated a per-vessel sensitivity, specificity, and accuracy for the detection of hemodynamically significant stenosis of 96% (95% CI: 91%-100%), 72% (95% CI: 66%-78%), and 78% (95% CI: 73%-83%), respectively. Coronary CTA with CT-MPI showed a lower sensitivity (84%; 95% CI: 75%-92%) but higher specificity (89%; 95% CI: 85%-93%) and accuracy (88%; 95% CI: 84%-92%). The areas under the receiver-operating characteristic curve of absolute MBF and relative MBF were 0.79 (95% CI: 0.71-0.86) and 0.82 (95% CI: 0.74-0.88), respectively. The median dose-length product of CT-MPI and coronary CTA were 313 mGy·cm and 138 mGy·cm, respectively. CONCLUSIONS: Dynamic CT-MPI offers incremental diagnostic value over coronary CTA alone for the identification of hemodynamically significant coronary artery disease. Generalized results from this multicenter study encourage broader consideration of dynamic CT-MPI in clinical practice. (Dynamic Stress Perfusion CT for Detection of Inducible Myocardial Ischemia [SPECIFIC]; NCT02810795).

Infection, inflammation and thrombosis: a review of potential mechanisms mediating arterial thrombosis associated with influenza and severe acute respiratory syndrome coronavirus 2.

Thrombosis has long been reported as a potentially deadly complication of respiratory viral infections and has recently received much attention during the global coronavirus disease 2019 pandemic. Increased risk of myocardial infarction has been reported during active infections with respiratory viruses, including influenza and severe acute respiratory syndrome coronavirus 2, which persists even after the virus has cleared. These clinical observations suggest an ongoing interaction between these respiratory viruses with the host's coagulation and immune systems that is initiated at the time of infection but may continue long after the virus has been cleared. In this review, we discuss the epidemiology of viral-associated myocardial infarction, highlight recent clinical studies supporting a causal connection, and detail how the virus' interaction with the host's coagulation and immune systems can potentially mediate arterial thrombosis.