Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1 ⁺ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2 ^−∕− HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1 ⁺ macrophages as targets for immunotherapy in atrial fibrillation.

Mechanical ventilation is a life-saving therapy in patients with acute respiratory distress syndrome (ARDS). However, mechanical ventilation itself causes severe co-morbidities in that it can trigger ventilator-associated lung injury (VALI) in humans or ventilator-induced lung injury (VILI) in experimental animal models. Therefore, optimization of ventilation strategies is paramount for the effective therapy of critical care patients. A major problem in the stratification of critical care patients for personalized ventilation settings, but even more so for our overall understanding of VILI, lies in our limited insight into the effects of mechanical ventilation at the actual site of injury, i.e., the alveolar unit. Unfortunately, global lung mechanics provide for a poor surrogate of alveolar dynamics and methods for the in-depth analysis of alveolar dynamics on the level of individual alveoli are sparse and afflicted by important limitations. With alveolar dynamics in the intact lung remaining largely a “black box,” our insight into the mechanisms of VALI and VILI and the effectiveness of optimized ventilation strategies is confined to indirect parameters and endpoints of lung injury and mortality. In the present review, we discuss emerging concepts of alveolar dynamics including alveolar expansion/contraction, stability/instability, and opening/collapse. Many of these concepts remain still controversial, in part due to limitations of the different methodologies applied. We therefore preface our review with an overview of existing technologies and approaches for the analysis of alveolar dynamics, highlighting their individual strengths and limitations which may provide for a better appreciation of the sometimes diverging findings and interpretations. Joint efforts combining key technologies in identical models to overcome the limitations inherent to individual methodologies are needed not only to provide conclusive insights into lung physiology and alveolar dynamics, but ultimately to guide critical care patient therapy.

BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2–associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2 ⁺ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2 ⁺ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α–neutralizing antibody reduced cardiac monocytes and inflammatory MHCII ^lo CCR2 ⁺ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2 ⁺ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.

Traditionally, the lung has been excluded from the ultrasound organ repertoire and, hence, the application of lung ultrasound (LUS) was largely limited to a few enthusiastic clinicians. Yet, in the last decades, the recognition of the previously untapped diagnostic potential of LUS in intensive care medicine has fueled its widespread use as a rapid, non-invasive and radiation-free bedside approach with excellent diagnostic accuracy for many of the most common causes of acute respiratory failure, e.g., cardiogenic pulmonary edema, pneumonia, pleural effusion and pneumothorax. Its increased clinical use has also incited attention for the potential usefulness of LUS in preclinical studies with small animal models mimicking lung congestion and pulmonary edema formation. Application of LUS to small animal models of pulmonary edema may save time, is cost-effective, and may reduce the number of experimental animals due to the possibility of serial evaluations in the same animal as compared with traditional end-point measurements. This review provides an overview of the emerging field of LUS with a specific focus on its application in animal models and highlights future perspectives for LUS in preclinical research.

Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel tissue tracking technique developed for noninvasive assessment of myocardial motion and deformation. This preliminary study aimed to evaluate the observer’s reproducibility of CMR-FT in a small animal (mouse) model and define sample size calculation for future trials. Six C57BL/6 J mice were selected from the ongoing experimental mouse model onsite and underwent CMR with a 3 Tesla small animal MRI scanner. Myocardial deformation was analyzed using dedicated software (TomTec, Germany) by two observers. Left ventricular (LV) longitudinal, circumferential and radial strain (EllLAX, EccSAX and ErrSAX) were calculated. To assess intra-observer agreement data analysis was repeated after 4 weeks. The sample size required to detect a relative change in strain was calculated. In general, EccSAX and EllLAX demonstrated highest inter-observer reproducibility (ICC 0.79 (0.46–0.91) and 0.73 (0.56–0.83) EccSAX and EllLAX respectively). In contrast, at the intra-observer level EllLAX was more reproducible than EccSAX (ICC 0.83 (0.73–0.90) and 0.74 (0.49–0.87) EllLAX and EccSAX respectively). The reproducibility of ErrSAX was weak at both observer levels. Preliminary sample size calculation showed that a small study sample (e.g. ten animals to detect a relative 10% change in EccSAX) could be sufficient to detect changes if parameter variability is low. This pilot study demonstrates good to excellent inter- and intra-observer reproducibility of CMR-FT technique in small animal model. The most reproducible measures are global circumferential and global longitudinal strain, whereas reproducibility of radial strain is weak. Furthermore, sample size calculation demonstrates that a small number of animals could be sufficient for future trials.