Cancer is associated with arterial and venous thrombotic events (ATE/VTE). Platelet FcγRIIa (pFCG) impacts platelet activation that contributes to ATE/VTE. Recurrent myocardial infarction (MI) and death are predicted by pFCG in patients with MI. Crosstalk between platelets and malignant cells that may promote cell invasion and cancer progression is mediated by pFCG. The objective is to determine whether pFCG (high vs. low) identifies cancer patients at greater risk of thrombosis and death. Ambulatory patients with cancer (n = 219) initiating cancer directed therapy were enrolled in a prospective translational study. The pFCG test was performed at study initiation and used flow cytometry to quantify mean fluorescence intensity that was translated to molecules of FCG/platelet. Outcomes of VTE/ATE and all cause death were abstracted from the Electronic Health Record at least 6 months after enrollment. Hazard ratios (HR) were analyzed with Kaplan-Meier analysis. Risk of the composite endpoint (ATE/VTE/death) was increased in patients with high pFCG (HR 1.9, 95
BACKGROUND AND AIMS:Atrial cardiomyopathy (AtCM) is increasingly recognized as an important substrate for atrial fibrillation (AF). This study aimed to examine potential markers and risk factors of AtCM, and associations with incident AF, heart failure (HF), and stroke. METHODS:Individuals from the UK Biobank with cardiac magnetic resonance imaging and electrocardiographic information were included. Atrial cardiomyopathy markers included left atrial dilation, left atrial mechanical dysfunction, P-wave prolongation, and abnormal P-wave terminal force. Risk factors for AtCM were assessed using logistic regressions. Incident AF, HF, and stroke according to AtCM markers were assessed in multivariable Cox-regression and cumulative incidence models. AF risk according to AtCM markers, clinical and genetic risk factors was evaluated by integrating the HARMS2-AF score and a polygenic risk score for AF. We used net reclassification improvement (NRI) to evaluate reclassification of risk when considering AtCM markers. RESULTS:Among 26 467 individuals, 4145 (15.7%) had ≥1 marker and 619 (2.3%) had ≥2 markers of AtCM. Age, coronary artery disease, and hypertension were consistently associated with AtCM. Having one AtCM marker conferred a hazard ratio (HR) for AF of 1.88 [95% confidence interval (CI): 1.54-2.31; P < .001], with higher rates observed in individuals with ≥2 markers (HR: 4.59; 95% CI: 3.52-5.99; P < .001). Addition of AtCM markers was associated with an NRI of 13.7% (95% CI: 9.2%-18.3%). Integration of clinical and genetic risk factors indicated an additive effect on AF rates. Having ≥2 markers associated with HF (HR: 3.08, 95% CI: 2.03-4.66, P < .001), and stroke (HR: 3.07, 95% CI: 1.78-5.28, P < .001). CONCLUSIONS:One in seven individuals had at least one marker of AtCM. Atrial cardiomyopathy markers were associated with AF, HF, and stroke, supporting AtCM as a common substrate for all three outcomes.
The vertebrate central nervous system is protected by the blood-brain barrier and meningeal membranes, which ensure immune privilege1. In the mammalian brain, microglia and barrier-associated or border-associated macrophages (BAMs) provide immune surveillance and scavenge wastes2, yet how evolution shaped immune-cell diversity and function is not understood. In zebrafish, a vascular-derived mural lymphatic endothelial cell (muLEC) lineage fulfils scavenger cell functions at central nervous system borders3-5. Here we identify the transcription factor odd-skipped related 2 (osr2) as a specific marker and regulator of muLEC differentiation and maintenance. osr2 controls the transition of muLECs from interconnected endothelial cells to individual scavenger cells in part by means of control of cadherin-6. muLECs are more transcriptionally similar to BAMs than to other mammalian meningeal cells and share several functions in tissue homeostasis. However, BAMs are absent from zebrafish and muLECs from mice and humans. Analysis of osr2, lymphatic endothelial cell (LEC) and BAM markers in diverse vertebrate species reveals muLECs as an ancient lineage and BAMs a recent mammalian specialization. muLECs and BAMs share functional analogies but are not homologous, providing an example of convergent evolution. This highlights the physiological importance of meningeal scavenger cells and the developmental plasticity of LECs in generating specialized cell types throughout evolution.
Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer’s disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.
BACKGROUND:Mechanisms that restrict class switch recombination (CSR) to IgE may limit the subsequent production of IgE antibodies in allergic diseases. A role for B-cell receptor (BCR) signaling in IgE regulation was revealed in mice and in cultured B cells with altered BCR signaling. While prior work has focused on BCR signaling in IgE-switched cells, BCR signaling also reportedly inhibits CSR. OBJECTIVE:We sought to determine whether BCR signaling selectively inhibits IgE CSR. METHODS:We assessed whether BCR signaling strength affected IgE responses in immunized mice. For mechanistic evaluation, primary mouse or human B cells were induced to switch to IgE in cell culture and were perturbed with antibodies or cognate antigen to ligate the BCR, pharmacologic inhibitors of signaling proteins, and/or additional cytokines. Primary readouts were flow cytometry and RNA analysis. RESULTS:In immunized mice, BCR signaling strength inversely correlated with the relative frequencies of IgE-switched germinal center B cells and plasma cells. In mouse B-cell cultures, BCR signaling selectively inhibited IgE CSR in a manner dependent on ligand concentration, affinity, and avidity. This inhibition required Syk, whereas blockade of the PI3K subunit p110δ increased IgE cell frequencies independently of BCR ligation. The cytokines IL-21 or TGF-β1, in combination with BCR ligation, cooperatively inhibited IgE CSR. Similar results were observed in cultures of human tonsillar B cells. CONCLUSION:IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.
