Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line (DSP-/-). At baseline, DSP-/- EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, DSP-/- EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to DSP-/- EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-κB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine.

Introduction: Cells respond to inflammatory stimuli in settings of sterile and pathologic cardiac inflammation. Nuclear factor Kappa B (NFKB) is a transcriptional mediator of innate immune responses. Lipopolysaccharide (LPS) promotes NFKB activation through toll-like receptors (TLR) to initiate cell autonomous processes that resist infection. High-mobility box group 1 (HMGB1) is a chromatin associated protein released upon nuclear rupture that similarly promotes cytokine release in response to injury. Few studies have interrogated multiple inflammatory stimuli and their impacts on iPSC-CM function. We examined innate immune activation using distinct TLR agonists and assessed functional responses in both 2D iPSC-CM monoculture and 3D collagen-based engineered heart tissues. Methods and Results: We measured electric field potential duration (Nanion CardioExcyte 96) of iPSC-CM monolayers after exposure to LPS and HMGB1. We observed a four fold increase in downstroke velocity after exposure to HMGB1 (512.7±126.9 V/s; p=0.0002 n=12) and a 30% decrease in downstroke velocity after LPS treatment (-188.9±61.4 V/s; p=0.004 n=12). This response was associated with nuclear localization of phosphorylated NFKB. Collagen-based engineered heart tissues demonstrated contractile defects in response to 48h of exposure to TLR agonists. A 50% reduction in fractional shortening was observed following HMGB1 treatment (-0.0060±0.0009; p<0.0001 n=6) and an 80% reduction was associated with LPS exposure (-0.0088±0.0006; p<0.0001 n=6). To identify gene expression regulatory regions associated with this response, we examined transcriptional activity of three candidate enhancer regions implicated in cytokine production in iPSC-CMs. These regions demonstrated a 0.5- to 20-fold increase in enhancer activity in iPSC-CMs. One enhancer demonstrated a 22% increase in activity following 48h of LPS, consistent with a direct role for NFKB in innate immune activation in human iPSC-CMs; this enhancer regulates a gene with increased expression in dilated cardiomyopathy. Conclusion: These data indicate that cardiomyocytes respond directly to inflammatory stimuli and demonstrate the utility of 2D and 3D human tissue culture models for cardiac inflammation.

The role of stress in the prognosis of heart failure (HF) is unclear. This study investigated whether the death of a close family member, a severe source of stress, is associated with mortality in HF.This study assessed whether the death of a close family member is associated with mortality in HF.Patients from the Swedish Heart Failure Registry during 2000-2018 and/or in the Swedish Patient Register with a primary diagnosis of HF during 1987-2018 (N = 490,527) were included in this study. Information was obtained on death of family members (children, partner, grandchildren, siblings, and parents), mortality, sociodemographic variables, and health-related factors from several population-based registers. The association between bereavement and mortality was analyzed by using Poisson regression.Loss of a family member was associated with an increased risk of dying (adjusted relative risk: 1.29; 95% CI: 1.27-1.30). The association was present not only in case of the family member’s cardiovascular deaths and other natural deaths but also in case of unnatural deaths. The risk was higher for 2 losses than for 1 loss and highest in the first week after the loss. The association between bereavement and an increased mortality risk was observed for the death of a child, spouse/partner, grandchild, and sibling but not of a parent.Death of a family member was associated with an increased risk of mortality among patients with HF. Further studies are needed to investigate whether less severe sources of stress can also contribute to poor prognosis in HF and to explore the mechanisms underlying this association.

As students do not qualify as essential health care workers, medical education faced severe disruptions during the COVID-19 pandemic including initial suspension of all in-person lectures and on-site rotations. Our Pathology Department was among the first at Northwestern to offer a completely virtual rotation with the goals of: (1) providing a comprehensive introduction to the practice of anatomic and clinical pathology, (2) emphasizing uninterrupted and continued excellence in education, and (3) minimizing exposure risk during the pandemic. The innovative 2-week curriculum incorporated diverse teaching modalities including live and recorded lectures; live and recorded video demonstrations; interactive small group discussions; interactive virtual sign-outs; and written and multimedia assignments, quizzes, and projects. The virtual elective ran from March to July 2020 with 52 total participating medical students. On post-rotation evaluations, students rated the pathology virtual elective 4.7/5.0 compared to other virtual rotations and 4.0/5.0 compared to all rotations (including in-person and virtual). Furthermore, continual improvements were made to the established framework based on rotation feedback such that curriculum content was more abundant and more favorably rated by the last cohort when compared to the first. Finally, although students identified interest in over 10 different medical specialties, all participants expressed increased interest in choosing pathology as a specialty and better understanding of pathology's role in patient care. We hope our detailed description of creating and evaluating a completely virtual elective rotation serves as a model for other departments to improve pathology education and visibility.

Mutations in the gene that codes for lamin A/C (LMNA) are a common cause of adult-onset cardiomyopathy and heart failure. In this issue of the JCI, Guénantin and Jebeniani et al. identify impaired cardiomyocyte development and maturation as a prenatal feature in a model of laminopathy. Cardiomyocytes carrying the Lmna point mutation H222P misexpressed genes involved in the epithelial-mesenchymal transition and showed decreased methylation at the fourth lysine of histone H3 (H3K4). Notably, inhibiting lysine-specific demethylase 1 in the LMNA H222P mouse model treated this congenital form of cardiomyopathy and improved survival in utero. These data highlight early epigenomic modifications in lamin A/C-mediated pathology and indicate a unique therapeutic strategy for cardiomyopathy.

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways 1 , how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells—integrin β7 + natural gut intraepithelial T lymphocytes (natural IELs)—that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7 − mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-1 2 , which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.