In mammals, the postnatal increase in cardiac workload coincides with the loss of cardiomyocyte proliferative capacity, rendering adult cardiomyocytes permanently post-mitotic. Whether reducing load can restore regenerative potential in the adult heart remains unknown. Here we use a heterotopic heart transplantation model, in which the donor heart is vascularized but nonpumping, to show that mechanical unloading induces adult cardiomyocyte proliferation, revealed by Ki67-based and MADM (mosaic analysis with double markers) lineage tracing. Applying heterotopic transplantation to infarcted hearts to achieve mechanical unloading similarly promoted regeneration within peri-infarct regions. Single-nucleus RNA sequencing of unloaded hearts identified enhanced epicardial-cardiomyocyte communication via the NRG1-ERBB4-STAT3 axis. Epicardial Nrg1 deletion blocked STAT3 activation and cardiomyocyte proliferation. CUT&Tag revealed STAT3 directly upregulates H6pd in cardiomyocytes, boosting pentose phosphate pathway activity to supply nucleotides and reducing equivalents for proliferation. These findings delineate a mechanotransductive pathway linking epicardial signals to cardiomyocyte cell-cycle re-entry, providing a framework for leveraging unloading to promote cardiac regeneration.

Cerebral hemodynamic dysfunction is a key driver of unhealthy brain aging. Impaired microcirculatory reactivity leads to uneven perfusion, rendering deeper brain regions more vulnerable and thereby contributing to cognitive decline. Yet how capillaries contribute to these deficits remains poorly defined. Here we combined spatial transcriptomics with in vivo two-photon and three-photon imaging to measure layer-specific cerebral blood flow in control and small vessel disease model mice (CADASIL TgNotch3R169C). We found downregulation of ATP-synthesizing genes, indicating microvascular metabolic impairment that paralleled impaired pericyte bioenergetics. This energy deficit coincided with diminished tone in the arteriole-capillary transitional zone and reduced deep-layer perfusion. Complementary electrophysiology, ex vivo and in silico approaches, revealed that hyperactive KATP channels in pericytes drive a redistribution of cerebral blood flow toward superficial cortical layers. This loss of spatial perfusion equalization, despite preserved global flow, contributed to deep-layer hypoperfusion, establishing a previously underrecognized but tractable vascular function disrupted in aging pathology.

Stem-cell-based cardiac repair holds promise for the infarcted myocardium, yet the in vivo molecular behavior of transplanted cells is poorly understood. Using time series spatial transcriptomics, we profiled human pluripotent stem-cell-derived cardiovascular progenitors engrafted into a pig model. We show that the engrafted cardiovascular progenitors progressively upregulated genes associated with cardiac maturation, oxidative metabolism, calcium handling and fibrosis resolution. Cell-cell communication analysis identified Midkine (MDK), secreted by the human xenograft, as a key regulator of host neovascularization. We validated this using immunohistochemistry, lentiviral MDK overexpression and functional assays that demonstrated enhanced endothelial cell migration and increased CD31[+] vascular density in vivo. A publicly available interactive Shiny atlas of spatial and temporal transcriptomic data from myocardial infarction pig hearts with human xenografts is provided. These findings advance mechanistic understanding of stem-cell-mediated cardiac repair and identify MDK as a tractable target for therapeutic angiogenesis in ischemic heart disease.

Coronary artery disease often develops silently before myocardial infarction, and current risk-based prevention pathways miss some individuals with clinically important disease, particularly those without standard modifiable cardiovascular risk factors. High-sensitivity cardiac troponin I is a blood biomarker of low-level myocardial injury, but its relationship to silent coronary atherosclerosis remains incompletely understood. Here we show, in 1,613 adults undergoing coronary computed tomography (CT) imaging, that low-level high-sensitivity cardiac troponin I is associated with clinically actionable coronary disease, defined by coronary calcium score ≥100, and with quantitative CT markers of plaque burden. A threshold of 2.3 ng l[-1] enriched for actionable disease, especially in individuals without standard risk factors. Normalizing troponin for myocardial mass, age and renal function improved prediction and provided mechanistic insight into baseline troponin elevation in chronic coronary syndromes. A two-stage strategy using troponin before CT imaging increased diagnostic yield and reduced the number of scans required. Prospective validation is warranted before clinical implementation.