Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide clues for the establishment of new biomarkers and therapeutic approaches targeting post-MI HF. Here, we investigate the spatiotemporal dynamics of MI-associated immune cells in a mouse model of MI using spatial transcriptomics and single-cell RNA-sequencing (scRNA-seq). We identify twelve major immune cell populations; their proportions dynamically change after MI. Macrophages are the most abundant population at all-time points (>60%), except for day 1 post-MI. Trajectory inference analysis shows upregulation of Trem2 expression in macrophages during the late phase post-MI. In vivo injection of soluble Trem2 leads to significant functional and structural improvements in infarcted hearts. Our data contribute to a better understanding of MI-driven immune responses and further investigation to determine the regulatory factors of the Trem2 signaling pathway will aid the development of novel therapeutic strategies for post-MI HF.

Background: Inflammatory responses play a critical role in left ventricular remodeling after myocardial infarction (MI). Tolerogenic dendritic cells (tDCs) can modulate immune responses, inducing regulatory T cells in a number of inflammatory diseases. Methods: We generated tDCs by treating bone marrow–derived dendritic cells with tumor necrosis factor-α and cardiac lysate from MI mice. We injected MI mice, induced by a ligation of the left anterior descending coronary artery in C57BL/6 mice, twice with tDCs within 24 hours and at 7 days after the ligation. Results: In vivo cardiac magnetic resonance imaging and ex vivo histology confirmed the beneficial effect on postinfarct left ventricular remodeling in MI mice treated with tDCs. Subcutaneously administered infarct lysate–primed tDCs near the inguinal lymph node migrated to the regional lymph node and induced infarct tissue–specific regulatory T-cell populations in the inguinal and mediastinal lymph nodes, spleen, and infarcted myocardium, indicating that a local injection of tDCs induces a systemic activation of MI-specific regulatory T cells. These events elicited an inflammatory-to-reparative macrophage shift. The altered immune environment in the infarcted heart resulted in a better wound remodeling, preserved left ventricular systolic function after myocardial tissue damage, and improved survival. Conclusions: This study showed that tDC therapy in a preclinical model of MI was potentially translatable into an antiremodeling therapy for ischemic tissue repair.

Background: Myocardial infarction with nonobstructive coronary arteries ( MINOCA ) is a heterogeneous disease entity. Its prognosis and predictor of mortality remain unclear. This study aimed to compare the prognosis between MINOCA and myocardial infarction with obstructive coronary artery disease and identify factors related to all‐cause death in MINOCA using a nation‐wide, multicenter, and prospective registry. Methods and Results: Among 13 104 consecutive patients enrolled, patients without previous history of significant coronary artery disease who underwent coronary angiography were selected. The primary outcome was 2‐year all‐cause death. Secondary outcomes were cardiac death, noncardiac death, reinfarction, and repeat revascularization. Patients with MINOCA (n=396) and myocardial infarction with obstructive coronary artery disease (n=10 871) showed similar incidence of all‐cause death (9.1% versus 8.8%; hazard ratio [ HR ], 1.04; 95% CI, 0.74–1.45; P =0.83). Risks of cardiac death, noncardiac death, and reinfarction were not significantly different between the 2 groups ( HR , 0.82; 95% CI , 0.53–1.28; P =0.38; HR , 1.55; 95% CI , 0.93–2.56; P =0.09; HR , 1.23; 95% CI , 0.65–2.31; P =0.38, respectively). MINOCA patients had lower incidence of repeat revascularization (1.3% versus 7.2%; HR , 0.17; 95% CI , 0.07–0.41; P <0.001). Results were consistent after multivariable regression and propensity‐score matching. In a multivariate model, several significant predictors of all‐cause death of MINOCA were found, including the nonuse of renin‐angiotensin system blockers ( HR , 2.63; 95% CI , 1.08–6.25; P =0.033) and statins ( HR , 2.17; 95% CI , 1.04–4.54; P =0.039). Conclusions: Patients with MINOCA and those with myocardial infarction with obstructive coronary artery disease had comparable clinical outcomes. Use of renin‐angiotensin system blockers and statins was associated with lower mortality in patients with MINOCA .

Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10⁻⁵⁴; CES1 G143E, P = 1.3 × 10⁻¹⁶; CYP2C19*17, P = 9.5 × 10⁻¹⁰; CYP2B6 1294 + 53 C > T, P = 3.0 × 10⁻⁴; CYP2B6 516 G > T, P = 1.0 × 10⁻³; CYP2C9*2, P = 1.2 × 10⁻³; and CYP2C9*3, P = 1.5 × 10⁻³). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14–2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35–14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.