Myocardial infarction is a leading cause of death worldwide¹. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality². Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

心肌梗塞是全世界死亡的主要原因¹ 。尽管急性治疗已取得进展，但对重塑过程的不完全了解限制了降低晚期死亡率的治疗效果² 。在这里，我们利用单细胞基因表达、染色质可及性和心肌梗塞患者和对照组不同时间点心肌多个生理区的空间转录组分析，生成心肌梗塞后人类心脏重塑的综合高分辨率图。多模式数据集成使我们能够以更高的分辨率评估心脏细胞类型组成，通过识别损伤、修复和重塑的不同组织结构，深入了解心脏转录组和表观基因组的变化。我们识别并验证了主要细胞类型的疾病特异性心脏细胞状态，并在其空间背景下分析它们，评估它们对其他细胞类型的依赖性。我们的数据阐明了人类心肌组织组织的分子原理，概括了缺血性损伤后逐渐出现的心肌细胞和骨髓连续体。总之，我们的研究提供了人类心肌梗死的综合分子图谱，为该领域提供了重要的参考，并为心脏病的高级机制和治疗研究铺平了道路。