Regulation of cardiac fibroblasts by lymphocytes after a myocardial infarction: playing in the major league.

Cardiac fibrosis is a pathological condition characterized by excessive accumulation of extracellular matrix components within the myocardium, which can lead to impaired cardiac function and heart failure. Studies have shown that lymphocytes including B and T cells play important roles in the development and progression of cardiac fibrosis after a myocardial infarction. In this review, we focus on the regulation of cardiac fibrosis by lymphocyte subsets, with a particular emphasis on CD4+ and CD8+ T cells and their effects on fibroblasts and cardiac remodeling. We also highlight areas for further exploration of the interactions between T cells and fibroblasts necessary for understanding and treating cardiac fibrosis and heart failure.

Cardiac and vascular complications in lupus: Is there a role for sex?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disorder and is characterized by autoantibody formation and subsequent immune complex deposition into target organs. SLE affects nearly nine women to every one man worldwide. Patients with SLE are at an enhanced risk for cardiovascular disease (CVD) morbidity and mortality. CVD is the leading cause of death worldwide and includes heart and blood vessel disorders, cerebrovascular disease, and rheumatic heart disease. Specific mechanisms by which cardiac and vascular pathophysiology develops in patients with SLE are still not fully known. Not only do we not understand this correlation between SLE and CVD, but there is also a critical gap in scientific knowledge on the contribution of sex. In this review, we will discuss the cardiac and vascular pathological disease states that are present in some patients with SLE. More importantly, we will discuss the potential mechanisms for the role of sex and sex hormones in the development of CVD with SLE.

Riding the wave: a quantitative report of electrocardiogram utilization for myocardial infarction confirmation.

The purpose of this study was to generate a quantitative profile of electrocardiograms (ECGs) for confirming surgical success of permanent coronary artery ligation. An ECG was recorded at baseline, and 0, 1, and 5 min after ligation and analyzed using iWorkx LabScribe software. Cohort 1 (C57Bl6/J, n = 8/sex) was enrolled to determine ECG characteristics that were confirmed in cohort 2 (C57Bl6/J, n = 6/sex; CD8-/-n = 6 males/4 females). Of the 16 mice in cohort 1, 12 (6/sex) had an infarct ≥35% and four mice (2/sex) had <35% based on 2,3,5-triphenyltetrazolium chloride staining. After ligation, the QRS complex and R-S amplitude were significantly different compared with baseline. No differences were observed in the R-S amplitude between mice with infarcts ≥35% versus <35% at any time point, whereas the QRS complex was significant 1 min after ligation. Receiver operating characteristic (ROC) curve linked changes in the QRS complex but not the R-S amplitude at 1 and 5 min with surgical success. Data were normalized to baseline values to calculate fold change. ROC analysis of the normalized QRS data indicated strong sensitivity and specificity for infarcts ≥35%; normalized R-S amplitude remained nonsignificant. With a cutoff generated by ROC analysis of cohort 1 (>80% sensitivity; >90% specificity), the non-normalized QRS complex of cohort 2 had an 86% success rate (2 false positives; 1 false negative). The normalized data had a 77% success rate (2 false positives; 3 false negatives). Neither sex nor genotype was associated with false predictions (P = 0.18). Our data indicate that the area under the QRS complex 1 min after ligation can improve reproducibility in MI surgeries.NEW & NOTEWORTHY Our study describes a quantitative method for using an electrocardiogram (ECG) to determine which animals have infarcts that reflect coronary artery ligation. Using a quantitative ECG, investigators will have the benefit of having real-time feedback during the procedure, which will ultimately decrease the amount of time investigators spend performing experiments. This overall increase in efficiency will help investigators decrease animal numbers used due to better surgical outcomes.

Elevated Neutrophil Gelatinase-Associated Lipocalin Is Associated With the Severity of Kidney Injury and Poor Prognosis of Patients With COVID-19.

INTRODUCTION: Loss of kidney function is a common feature of COVID-19 infection, but serum creatinine (SCr) is not a sensitive or specific marker of kidney injury. We tested whether molecular biomarkers of tubular injury measured at hospital admission were associated with acute kidney injury (AKI) in those with COVID-19 infection. METHODS: This is a prospective cohort observational study consisting of 444 consecutive patients with SARS-CoV-2 enrolled in the Columbia University emergency department (ED) at the peak of the pandemic in New York (March 2020-April 2020). Urine and blood were collected simultaneously at hospital admission (median time: day 0, interquartile range: 0-2 days), and urine biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA) and a novel dipstick. Kidney biopsies were probed for biomarker RNA and for histopathologic acute tubular injury (ATI) scores. RESULTS: Admission urinary neutrophil gelatinase-associated lipocalin (uNGAL) level was associated with AKI diagnosis (267 ± 301 vs. 96 ± 139 ng/ml, P < 0.0001) and staging; uNGAL levels >150 ng/ml had 80% specificity and 75% sensitivity to diagnose AKI stages 2 to 3. Admission uNGAL level quantitatively associated with prolonged AKI, dialysis, shock, prolonged hospitalization, and in-hospital death, even when admission SCr level was not elevated. The risk of dialysis increased almost 4-fold per SD of uNGAL independently of baseline SCr, comorbidities, and proteinuria (odds ratio [OR] [95% CI]: 3.59 [1.83-7.45], P < 0.001). In the kidneys of those with COVID-19, NGAL mRNA expression broadened in parallel with severe histopathologic injury (ATI). Conversely, low uNGAL levels at admission ruled out stages 2 to 3 AKI (negative predictive value: 0.95, 95% CI: 0.92-0.97) and the need for dialysis (negative predictive value: 0.98, 95% CI: 0.96-0.99). Although proteinuria and urinary (u)KIM-1 were implicated in tubular injury, neither was diagnostic of AKI stages. CONCLUSION: In the patients with COVID-19, uNGAL level was quantitatively associated with histopathologic injury (ATI), loss of kidney function (AKI), and severity of patient outcomes.

Antimicrobial-induced oral dysbiosis exacerbates naturally occurring alveolar bone loss.

Periodontitis-mediated alveolar bone loss is caused by dysbiotic shifts in the commensal oral microbiota that upregulate proinflammatory osteoimmune responses. The study purpose was to determine whether antimicrobial-induced disruption of the commensal microbiota has deleterious effects on alveolar bone. We administered an antibiotic cocktail, minocycline, or vehicle-control to sex-matched C57BL/6T mice from age 6- to 12 weeks. Antibiotic cocktail and minocycline had catabolic effects on alveolar bone in specific-pathogen-free (SPF) mice. We then administered minocycline or vehicle-control to male mice reared under SPF and germ-free conditions, and we subjected minocycline-treated SPF mice to chlorhexidine oral antiseptic rinses. Alveolar bone loss was greater in vehicle-treated SPF versus germ-free mice, demonstrating that the commensal microbiota drives naturally occurring alveolar bone loss. Minocycline- versus vehicle-treated germ-free mice had similar alveolar bone loss outcomes, implying that antimicrobial-driven alveolar bone loss is microbiota dependent. Minocycline induced phylum-level shifts in the oral bacteriome and exacerbated naturally occurring alveolar bone loss in SPF mice. Chlorhexidine further disrupted the oral bacteriome and worsened alveolar bone loss in minocycline-treated SPF mice, validating that antimicrobial-induced oral dysbiosis has deleterious effects on alveolar bone. Minocycline enhanced osteoclast size and interface with alveolar bone in SPF mice. Neutrophils and plasmacytoid dendritic cells were upregulated in cervical lymph nodes of minocycline-treated SPF mice. Paralleling the upregulated proinflammatory innate immune cells, minocycline therapy increased TH 1 and TH 17 cells that have known pro-osteoclastic actions in the alveolar bone. This report reveals that antimicrobial perturbation of the commensal microbiota induces a proinflammatory oral dysbiotic state that exacerbates naturally occurring alveolar bone loss.

Chronic Porphyromonas gingivalis lipopolysaccharide induces adverse myocardial infarction wound healing through activation of CD8+ T cells.

Oral and gum health have long been associated with incidence and outcomes of cardiovascular disease. Periodontal disease increases myocardial infarction (MI) mortality by sevenfold through mechanisms that are not fully understood. The goal of this study was to evaluate whether lipopolysaccharide (LPS) from a periodontal pathogen accelerates inflammation after MI through memory T-cell activation. We compared four groups [no MI, chronic LPS, day 1 after MI, and day 1 after MI with chronic LPS (LPS + MI); n = 68 mice] using the mouse heart attack research tool 1.0 database and tissue bank coupled with new analyses and experiments. LPS + MI increased total CD8+ T cells in the left ventricle versus the other groups (P < 0.05 vs. all). Memory CD8+ T cells (CD44 + CD27+) were 10-fold greater in LPS + MI than in MI alone (P = 0.02). Interleukin (IL)-4 stimulated splenic CD8+ T cells away from an effector phenotype and toward a memory phenotype, inducing secretion of factors associated with the Wnt/ß-catenin signaling that promoted monocyte migration and decreased viability. To dissect the effect of CD8+ T cells after MI, we administered a major histocompatibility complex-I-blocking antibody starting 7 days before MI, which prevented effector CD8+ T-cell activation without affecting the memory response. The reduction in effector cells diminished infarct wall thinning but had no effect on macrophage numbers or MertK expression. LPS + MI + IgG attenuated macrophages within the infarct without effecting CD8+ T cells, suggesting these two processes were independent. Overall, our data indicate that effector and memory CD8+ T cells at post-MI day 1 are amplified by chronic LPS to potentially promote infarct wall thinning.NEW & NOTEWORTHY Although there is a well-documented link between periodontal disease and heart health, the mechanisms are unclear. Our study indicates that in response to circulating periodontal endotoxins, memory CD8+ T cells are activated, resulting in an acceleration of macrophage-mediated inflammation after MI. Blocking activation of effector CD8+ T cells had no effect on the macrophage numbers or wall thinning at post-MI day 1, indicating that this response was likely due in part to memory CD8+ T cells.

Organized Chaos: Deciphering Immune Cell Heterogeneity's Role in Inflammation in the Heart.

During homeostasis, immune cells perform daily housekeeping functions to maintain heart health by acting as sentinels for tissue damage and foreign particles. Resident immune cells compose 5% of the cellular population in healthy human ventricular tissue. In response to injury, there is an increase in inflammation within the heart due to the influx of immune cells. Some of the most common immune cells recruited to the heart are macrophages, dendritic cells, neutrophils, and T-cells. In this review, we will discuss what is known about cardiac immune cell heterogeneity during homeostasis, how these cell populations change in response to a pathology such as myocardial infarction or pressure overload, and what stimuli are regulating these processes. In addition, we will summarize technologies used to evaluate cell heterogeneity in models of cardiovascular disease.

Rule Out Acute Kidney Injury in the Emergency Department With a Urinary Dipstick.

INTRODUCTION: The identification of acute injury of the kidney relies on serum creatinine (SCr), a functional marker with poor temporal resolution as well as limited sensitivity and specificity for cellular injury. In contrast, urinary biomarkers of kidney injury have the potential to detect cellular stress and damage in real time. METHODS: To detect the response of the kidney to injury, we have tested a lateral flow dipstick that measures a urinary protein called neutrophil gelatinase-associated lipocalin (NGAL). Analysis of urine was performed in a prospective cohort of 479 patients (final cohort N = 426) entering an emergency department in New York City and subsequently admitted for inpatient care. RESULTS: Colorimetric development had high interrater reliability (88% concordance rate) and correlated with traditional enzyme-linked immunosorbent assay (ELISA) measurements (ρ = 0.732, P < .0001). Of the 14% of the cohort who met Acute Kidney Injury Network (AKIN) SCr criteria for acute kidney injury (AKI), 67% demonstrated transient (<2 days) and 33% demonstrated sustained (>2 days) elevation of SCr. Comparing the outcomes of patients with sustained versus transient or undetectable changes in SCr revealed that the urinary NGAL (uNGAL) dipstick had high specificity and negative predictive value (NPV) (high- vs. low-intermediate readings, sensitivity = 0.55, specificity = 0.91, positive predictive value = 0.24, NPV = 0.97, χ2 = 20.39, P < 0.001). CONCLUSION: We show that the introduction of a bedside uNGAL dipstick permits accurate triage by identifying individuals who do not have tubular injury. In an era of shortening length of stay and rapid decisions based on isolated SCr measurements, real-time exclusion of kidney injury by a dipstick will be particularly useful to overcome the retrospective, insensitive, and nonspecific attributes of SCr.