The immunology of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of new heart failure diagnoses and continues to increase in prevalence in the United States. Importantly, HFpEF is a highly morbid, heterogeneous syndrome lacking effective therapies. Inflammation has emerged as a potential contributor to the pathogenesis of HFpEF. Many of the risk factors for HFpEF are also associated with chronic inflammation, such as obesity, hypertension, aging, and renal dysfunction. A large amount of preclinical evidence suggests that immune cells and their associated cytokines play important roles in mediating fibrosis, oxidative stress, metabolic derangements, and endothelial dysfunction, all potentially important processes in HFpEF. How inflammation contributes to HFpEF pathogenesis, however, remains poorly understood. Recently, a variety of preclinical models have emerged which may yield much needed insights into the causal relationships between risk factors and the development of HFpEF, including the role of specific immune cell subsets or inflammatory pathways. Here, we review evidence in animal models and humans implicating inflammation as a mediator of HFpEF and identify gaps in knowledge requiring further study. As the understanding between inflammation and HFpEF evolves, it is hoped that a better understanding of the mechanisms underlying immune cell activation in HFpEF can open up new therapeutic avenues.

Immune profiling of murine cardiac leukocytes identifies triggering receptor expressed on myeloid cells 2 as a novel mediator of hypertensive heart failure.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction, and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodelling. METHODS AND RESULTS: Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. A modified single-cell sequencing approach, cellular indexing of transcriptomes and epitopes by sequencing, of cardiac immune cells reveals an altered abundance and transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including up-regulation of Trem2, which has been recently implicated in obesity and atherosclerosis. The role of Trem2 in hypertensive heart failure, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy, diastolic dysfunction, renal injury, and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls. Moreover, Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programmes and increased expression of pro-inflammatory cytokines. Furthermore, we found that plasma levels of soluble TREM2 are elevated in DOCA-salt treated mice and humans with heart failure. CONCLUSIONS: Together, our data provide an atlas of immunological alterations that can lead to improved diagnostic and therapeutic strategies for HFpEF. We provide our dataset in an easy to explore and freely accessible web application making it a useful resource for the community. Finally, our results suggest a novel cardioprotective role for Trem2 in hypertensive heart failure.

Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes.

OBJECTIVE: To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D). DESIGN: Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels. SETTING: University Medical Center. PATIENT(S)/ANIMAL(S): Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center. INTERVENTION(S): Nonobese diabetic mice were administered 200 µg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation. MAIN OUTCOME MEASURE(S): Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c. RESULT(S): Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values. CONCLUSION(S): The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.