Rationale Macrophages reside in the healthy myocardium, participate in ischemic heart disease and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of non-ischemic remote myocardium, however, remain unclear. Objective This study investigated the number, origin, phenotype and function of remote cardiac macrophages residing in the non-ischemic myocardium in mice with chronic heart failure after coronary ligation. Methods and Results Eight weeks post-MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6Chigh monocytes rose from 64±5 to 108±9 /μl blood (p<0.05). Cardiac monocyte recruitment declined in Ccr2−/− mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the MAPK pathway, while specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (p<0.05). Steady-state cardiac macrophages, monocyte-derived and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 vs.19.1±2%, p<0.05). Conclusions Myocardial failure is influenced by an altered myeloid cell repertoire.

Rationale Superficial erosion currently causes up to a third of acute coronary syndromes (ACS), yet we lack understanding of its mechanisms. Thrombi due to superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. Objective This study tested in vivo the involvement of disturbed flow, and of neutrophils, hyaluronan, and TLR2 ligation in superficial intimal injury, a process implicated in superficial erosion. Methods and Results : In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell (EC) activation, neutrophil accumulation, EC death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. TLR2 agonism activated luminal ECs, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing EC injury and local thrombosis (p<0.05). Conclusions These results implicate flow disturbance, neutrophils, and TLR2 signaling as mechanisms that contribute to superficial erosion, a cause of ACS of likely growing importance in the statin era.

Cases of de novo immune thrombocytopenia (ITP) - including a fatality - following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in pre-existing ITP. In this study, four data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a ten-center retrospective study of adults with pre-existing ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA, United States) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] x109/L approximately 1-week post-vaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 109 patients with pre-existing ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count &lt;30x109/L with &gt;20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK ITP patients, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in pre-existing ITP or be identified de novo post-SARS-CoV2-vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those post-splenectomy and with more refractory disease, is indicated.