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Myocardial infarction augments sleep to limit cardiac inflammation and damage

Nature volume 635, pages 168–177 (2024)Cite this article

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Abstract

Sleep is integral to cardiovascular health1,2. Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting inflammation and promoting healing. After MI, microglia rapidly recruit circulating monocytes to the brain’s thalamic lateral posterior nucleus (LPN) via the choroid plexus, where they are reprogrammed to generate tumour necrosis factor (TNF). In the thalamic LPN, monocytic TNF engages Tnfrsf1a-expressing glutamatergic neurons to increase slow wave sleep pressure and abundance. Disrupting sleep after MI worsens cardiac function, decreases heart rate variability and causes spontaneous ventricular tachycardia. After MI, disrupting or curtailing sleep by manipulating glutamatergic TNF signalling in the thalamic LPN increases cardiac sympathetic input which signals through the β2-adrenergic receptor of macrophages to promote a chemotactic signature that increases monocyte influx. Poor sleep in the weeks following acute coronary syndrome increases susceptibility to secondary cardiovascular events and reduces the heart’s functional recovery. In parallel, insufficient sleep in humans reprogrammes β2-adrenergic receptor-expressing monocytes towards a chemotactic phenotype, enhancing their migratory capacity. Collectively, our data uncover cardiogenic regulation of sleep after heart injury, which restricts cardiac sympathetic input, limiting inflammation and damage.

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Fig. 1: MI augments sleep.
Fig. 2: Monocytes are recruited to the brain after MI to augment sleep.
Fig. 3: Monocytic TNF engages Tnfrsf1a-expressing glutamatergic neurons in the thalamic LPN to augment sleep after MI.
Fig. 4: Sleep disruption worsens cardiac function and outcome after MI.
Fig. 5: Sleep limits cardiac sympathetic input to curtail macrophage chemotactic programming and recruitment after MI.

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Data availability

scRNA-seq data have been deposited to NCBI Gene Expression Omnibus under the following accession numbers: GSE275071 for the human PBMC sequencing from the sleep restriction study and GSE275089 for all mouse sequencing. snRNA-seq data for human brain tissue have been deposited to NCBI Gene Expression Omnibus under the accession number GSE227781. All other necessary data are contained within the manuscript. Requests for materials can be made to the corresponding author. Source data are provided with this paper.

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Acknowledgements

The authors thank the Human Immune Monitoring Core at the Icahn School of Medicine at Mount Sinai for help with sequencing; the BioMedical Engineering and Imaging Institute and the small animal imaging facility at the Icahn School of Medicine at Mount Sinai for help with MRI and echo imaging and analysis; the Mount Sinai Neuropathology Brain bank for human brain tissue; the Mount Sinai Microscopy and Advanced Bioimaging Core for help with lightsheet, confocal and immunofluorescence imaging; and K. Joyes for copy editing the manuscript text. This work was funded by the National Institutes of health (NIH) R01HL158534, R00HL151750, the Cure Alzheimer’s Fund, and an ISMMS Karen Strauss Cook Research Scholar Award (to C.S.M.); NIH R01AG082185 (to C.S.M., P.R. and D. Lee); an American Heart Association postdoctoral fellowship 24POST1196847 (to P.H.); NIH 5T32HL007824-25 (supported J.D.H.); an EMBO Long Term Fellowship (ALTF 750-2022; to J.F.d.S.); a Kayden-Lambert MGH Research Scholar Award and NIH P01-HL142494 and DP2-CA281401 (to B.P.K.); NINIH R01HL128226 and R35HL155670 (to M.-P.S.-O.); NIH T32HL007343 (supported F.M.Z.); and NIH UL1TR001873 (to Columbia University).

Author information

Author notes

  1. These authors contributed equally: Pacific Huynh, Jan D. Hoffmann

Authors and Affiliations

  1. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Pacific Huynh, Jan D. Hoffmann, Teresa Gerhardt, Máté G. Kiss, Oren Cohen, Abi G. Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Seonghun Yoon, Laura L. Koekkoek, Walter Jacob, Jazz Munitz, Jazz Munitz, Mandy M. T. van Leent, Filip K. Swirski & Cameron S. McAlpine

  2. Department of Medicine, Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Pacific Huynh, Jan D. Hoffmann, Teresa Gerhardt, Máté G. Kiss, Oren Cohen, Abi G. Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Seonghun Yoon, Laura L. Koekkoek, Walter Jacob, Mandy M. T. van Leent, Filip K. Swirski & Cameron S. McAlpine

  3. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Pacific Huynh, Jan D. Hoffmann, Teresa Gerhardt, Máté G. Kiss, Abi G. Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Laura L. Koekkoek, Walter Jacob, Donghoon Lee, John F. Fullard, Panos Roussos & Cameron S. McAlpine

  4. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Pacific Huynh, Jan D. Hoffmann, Teresa Gerhardt, Máté G. Kiss, Abi G. Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Laura L. Koekkoek, Walter Jacob, Donghoon Lee, John F. Fullard, Panos Roussos & Cameron S. McAlpine

  5. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Pacific Huynh, Jan D. Hoffmann, Teresa Gerhardt, Máté G. Kiss, Abi G. Yates, Alexander Leunig, Merlin Heiser, Lena Gaebel, Matteo Gianeselli, Sukanya Goswami, Annie Khamhoung, Jeffrey Downey, Laura L. Koekkoek, Walter Jacob, Filip K. Swirski & Cameron S. McAlpine

  6. Department of Medicine, NYC Health and Hospitals/Elmhurst, Elmhurst, Queens, NY, USA

    Jan D. Hoffmann

  7. Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Germany and Berlin Institute of Health, Berlin, Germany

    Teresa Gerhardt, Christopher Wolfram & David Leistner

  8. Center of Excellence for Sleep and Circadian Research, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Faris M. Zuraikat & Marie-Pierre St-Onge

  9. Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Faris M. Zuraikat & Marie-Pierre St-Onge

  10. Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Oren Cohen & Neomi Shah

  11. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Zhihong Chen, Vladimir Roudko, Travis Dawson, Darwin D’Souza & Seunghee Kim-Schulze

  12. Center for Genomic Medicine, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Joana Ferreira da Silva, Jarod Morgenroth-Rebin & Benjamin P. Kleinstiver

  13. Department of Pathology, Harvard Medical School, Boston, MA, USA

    Joana Ferreira da Silva, Natalie J. Ameral & Benjamin P. Kleinstiver

  14. BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jazz Munitz, Mandy M. T. van Leent & Filip K. Swirski

  15. Department of Diagnostic, Molecular, and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jazz Munitz & Mandy M. T. van Leent

  16. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Donghoon Lee, John F. Fullard & Panos Roussos

  17. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Donghoon Lee, John F. Fullard & Panos Roussos

  18. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Donghoon Lee, John F. Fullard & Panos Roussos

  19. Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Donghoon Lee, John F. Fullard & Panos Roussos

  20. Department of Medicine, Cardiology/Angiology, Goethe University Hospital, Frankfurt, Germany

    David Leistner

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Contributions

P.H. and J.D.H. conceived the project, designed and performed experiments, analysed and interpreted data, offered intellectual input and edited the manuscript. T.G. designed and performed experiments, analysed and interpreted data, conducted the sleep and ACS trial, offered intellectual input and edited the manuscript. M.G.K. aided experiments, interpreted data and offered intellectual input. F.M.Z. and M.-P.S.-O. conducted the human sleep restriction trial and offered intellectual input. O.C. aided in implementation of the sleep questionnaire for the ACS trial, interpreted data and offered intellectual input. C.W. and D. Leistner conducted the sleep and ACS trial. S.G., A.K., A.G.Y., J.D., L.L.K., W.J., L.G., M.H., A.L. and M.G. conducted and aided experiments. Z.C., V.R., T.D., J.M.-R., D.D. and S.K.-S. conducted sequencing experiments and aided in analysis. J.F.d.S., N.J.A. and B.P.K. designed and cloned the AAV vector for Tnfrsf1a knockout and offered technical advice. J.M. and M.M.T.v.L. conducted cMRI imaging and analysis. D. Lee, J.F.F. and P.R. conducted human brain snRNA-seq and analysis. S.Y. performed MI and sham surgeries. N.S. and F.K.S. aided in supervision and offered intellectual input. C.S.M. conceived the project, supervised, directed and managed the study, performed experiments, interpreted data, designed the figures and wrote the manuscript.

Corresponding author

Correspondence to Cameron S. McAlpine.

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Competing interests

C.S.M. is a consultant for Granite Bio. J.F.d.S. and B.P.K. are inventors on patents or patent applications filed by Mass General Brigham (MGB) that describe genome engineering technologies. B.P.K. is a consultant for EcoR1 capital and Novartis Venture Fund, and is on the scientific advisory board of Acrigen Biosciences, Life Edit Therapeutics and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, a company that is developing therapeutic CRISPR–Cas technologies for gene editing. The interests of B.P.K. were reviewed and are managed by Massachusetts General Hospital (MGH) and MGB in accordance with their conflict-of-interest policies. The other authors declare no competing interests.

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Nature thanks Hafid Ait-Oufella, Rachel Rowe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer review reports are available.

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Extended data figures and tables

Extended Data Fig. 1 Sleep parameters in mice with cardiovascular diseases.

a, Quantification of sleep in WT mice that consumed a chow diet and atherosclerotic Apoe−/− mice what consumed a HFD for 16 weeks. n = 8 WT mice; n = 5 Apoe−/− HFD mice. b, Quantification of SWS in sham controls and TAC mice 7 days after surgery. n = 4 sham; n = 3 TAC. c, Quantification of REM sleep in MI and sham mice up to 21 days after infarct. n = 5 mice per group. d, Hypnogram of sleep and wake states in sham and MI mice. e, Quantification of locomotor activity up to 21 days after infarct (p < 0.0001, F = 64.71). n = 4 mice per group. f, Quantification of body temperature up to 21 days after infarct (p < 0.0001, F = 19.68). n = 4 mice per group. g, SWS analysis in naïve and sham mice. n = 5 sham mice; n = 4 naive mice. Data are mean ± s.e.m. Statistical analysis was done using two-way analysis of variance. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 2 Analysis of microglia after myocardial infarction.

a, UMAP of cells identified in scRNAseq of mouse brain. n = 5 pooled mice per group. b, UMAP of microglia subclusters and their frequency in day 3 sham and MI mice. n = 5 pooled mice per group. c, Expression of chemokines and activation markers in non-microglial macrophages. n = 5 pooled mice per group. d, Analysis of microglia activation markers in naive mice injected with sham or day 1 MI plasma and sacrificed 4 h later. n = 4 sham plasma; n = 5 MI plasma. e, Measurement of IL-3, IL-6, and IL-1β in plasma one day after sham or MI. n = 3-8 f, Analysis of microglia and quantification of brain monocytes 1 day after stereotactic injection of IL-3, IL-6, IL-1β or PBS into the thalamus of naive mice. n = 5. g, Microglial responses to IL-3, IL-6, and IL-1β in an ex-vivo culture assay. n = 3. Data are mean ± s.e.m. Statistical analysis was done using one-way analysis of variance and two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 3 Brain immune parameters after myocardial infarction.

a, Flow cytometry quantification of brain macrophages, microglia, T cells and neutrophils in sham and MI mice 1, 3, and 7 days after infarct. Each data point represents an individual mouse. b, Histograms of tdTomato (TdT) positivity in blood monocytes and brain microglia in Ms4a3CreRosaTomato mice. c, Analysis of GFP+ cells in the heart, brain, lung, bone marrow, and liver 1 day after sham or infarct and adoptive transfer. n = 5 per group. d, Quantification of CCL2 protein in plasma and brain, and Ccl2 mRNA transcript in blood monocytes and brain tissue. n = 12 sham and n = 14 MI plasma; n = 4 per group for monocyte transcript; n = 5 sham and n = 4 MI brain CCL2 protein; n = 15 per group for brain transcript. e, Representative immunofluorescent images and quantification of CCR2+ monocytes in the cortex and hypothalamus. n = 7 per group. f, Representative image of secondary antibody only control on human liver sections. g, Analysis of FITC-dextran signal in the brain after peripheral delivery one day after MI or sham operation. scRNAseq analysis of brain endothelial and epithelial cells 3 days after sham or MI. n = 5 sham and n = 5 MI for FITC dextran; n = 5 pooled mice per group for scRNAseq. h, Microglial analysis in CCL2RFP mice one day after sham or MI. n = 4 mice per group. i, Representative images and quantification of thalamic microglia morphology by skeletal analysis. n = 3, each dot represents one cell. j, Analysis of blood monocyte and brain microglia CD123 (IL-3Ra), brain monocytes, and microglia CCL2 in Il3rafl/fl and Cx3cr1CreERT2Il3rafl/fl mice injected with tamoxifen over 5 consecutive days and subjected to MI 3 weeks later. n = 4 per group except brain monocytes n = 7 Il3rafl/fl and n = 8 Cx3cr1CreERT2Il3rafl/fl mice. Data are mean ± s.e.m. Statistical analysis was done using two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 4 Analysis of brain monocytes, sleep regulation, and Tnfrsf1a targeting vector design.

a, Enumeration of blood Ly6Chi monocytes in MI and MI + CCR2 antagonist mice one day after injury. CCR2 antagonist was delivered to the brain via the cisterna magna. n = 5 mice per group. b, Quantification of brain Ly6Chi monocytes 1 day after MI and SWS analysis in WT sham, WT MI, and Ccr2−/− MI mice. n = 4 for immune cell quantification; for sleep analysis n = 4 WT MI; n = 5 WT sham, n = 4 Ccr2−/− MI. c, WT MI mice were injected with an anti-TCRβ antibody in the cisterna magna immediately after MI. Monocytes and SWS were quantified one day later. n = 4 control and n = 5 anti-TCRβ. d, Naive mice were injected with PBS or 30,000 monocytes sorted from the blood of a GFP mouse. Flow cytometry analysis of the transferred monocytes in the brain 2 h later. n = 5 mice per group. e, UMAP of brain monocytes and analysis of their frequencies in sham and MI mice. n = 5 pooled mice per group. f, Flow cytometry analysis of brain monocyte TNF. g, qPCR analysis of blood monocyte Tnf mRNA 1 day after sham or MI, n = 4 mice per group. scRNAseq analysis of blood monocytes 3 days after MI or sham. n = 5 pooled mice per group. h, Quantification of SWS in WT sham, WT MI, and Tnf−/− MI mice. n = 3 WT sham; n = 5 WT MI; n = 4 Tnf−/− MI. i, Schematic of the AAV genome encoding Cre expressed from the CaMKII promoter, along with an SpCas9 gRNA targeted to Tnfrsf1a and expressed from the human U6 promoter. j, Schematic for in vivo tissue specific knockdown or Tnfrsf1a, where AAV viral vectors encoding pCaMKII-Cre and the Tnfrsf1a-targeted SpCas9 gRNA are delivered via bilateral stereotactic injection into the thalamic LPN. Neuron-specific Cre recombination activates SpCas9 nuclease expression, leading to complexation of the nuclease with the Tnfrsf1a gRNA to target and knockout the Tnfrsf1a gene. k, Schematic of brain regions analysed by qPCR. Whole brain tissue was used. Expression of Tnfrsf1a in whole thalamic and cortex tissue. n = 5 WT + AAV2 MI mice; n = 4 Stopfl/fl-Cas9GFP + AAV2 MI mice. l, Enumeration of Ly6Chi monocytes in the brain of WT + AAV2 MI mice and Stopfl/fl-Cas9GFP + AAV2 MI mice 3 days after infarct. n = 3 WT + AAV2 MI mice; n = 4 Stopfl/fl-Cas9GFP + AAV2 MI mice. Data are mean ± s.e.m. Statistical analysis was done using two-way analysis of variance and two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 5 Extended analysis of sleep and cardiac function in MI and MI + SF mice.

a, Analysis of wake bouts (transitions from a sleep state to a wake state) in MI and MI + SF mice. n = 4 MI mice; n = 3 MI + SF mice. b, Evaluation of stroke volume (SV) and cardiac output (CO) by echocardiography in MI and MI + SF mice on days 3, 7, and 21 after infarct. n = 8 mice on day 3; n = 9 MI mice on day 7; n = 10 MI + SF mice on day 7; n = 8 MI mice on day 21; n = 10 MI + SF mice on day 21. c, Analysis of EF in sham mice, and mice that received a ‘medium’ or ‘large’ MI and exposed to SF or habitual sleep. Analysis was completed 3 days after sham or MI. n = 5 sham; n = 8 ‘medium’ MI ± SF; n = 5 ‘large’ MI ± SF. d, mRNA expression of Col3a1 and Col4a1 in infarcts 7 days after MI. n = 13 MI and n = 14 MI + SF. Data are mean ± s.e.m. Statistical analysis was done using one-way analysis of variance and two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 6 Inflammation and haematopoiesis in MI and MI + SF mice.

a, Flow cytometry enumeration of cardiac cells in MI and MI + SF mice. n = 7 MI; n = 8 MI + SF. b, Enumeration of monocytes and neutrophils in the infarcts of mice 3 days after receiving a ‘large’ MI and sleeping habitually or exposed to SF. n = 5 mice per group. c, Flow cytometry enumeration of blood leukocytes in MI and MI + SF mice. n = 11 MI on day 3; n = 12 MI + SF on day 3; n = 7 MI on day 7; n = 8 MI + SF on day 7; n = 7 MI day 21 monocytes; n = 9 MI + SF day 21 monocytes; n = 11 MI day 21 neutrophils; n = 12 MI + SF day 21 neutrophils. d, Flow cytometry gating and enumeration of progenitor cells in the BM of MI and MI + SF mice. Each data point represents an individual mouse. e, Analysis of BrdU incorporation into BM progenitor cells of MI and MI + SF mice 3 days after infarct. n = 5 per group. Data are mean ± s.e.m. Statistical analysis was done using two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 7 Assessment of cardiac and blood leukocytes and plasma corticosterone.

a, UMAP of heart leukocytes. n = 5 pooled mice per group. b, Subclustering of cardiac macrophages and cluster frequencies in MI and MI + SF mice. n = 5 pooled mice per group. c, UMAP depicting resident and recruited heart macrophages and defining genes. n = 5 pooled mice per group. d, DEGs in recruited macrophages. n = 5 pooled mice per group. e, UMAP of blood leukocytes and monocytes along with monocyte DEGs and top pathways of genes enriched in MI + SF versus MI mice. n = 5 pooled mice per group. f, Plasma corticosterone levels. Each data point represents an individual mouse. g, Leukocyte enumeration in the infarct. n = 9 MI + SF; n = 8 MI + SF + ADRβ2 blocker. h, Analysis of ejection fraction (EF) and infarct leukocyte abundance in WT mice transplanted with WT BM or Adrb2−/− BM and exposed to MI and SF. Analysis was performed 3 days after infarct. n = 5 WTbmWT; n = 4 WTbmAdrb2−/−. Data are mean ± s.e.m. Statistical analysis was done using two-tailed unpaired t-tests. Experiments were conducted in female mice. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Fig. 8 Extended analysis of human sleep restriction study and schematic of hypothesis.

a, Actigraphy measured nightly total sleep time of study participants during the habitual sleep (HS) and sleep restriction (SR) phases of the randomized crossover trial. n = 4 participants per condition. b, UMAP of scRNAseq data of PBMCs. n = 4 participants per condition. c, Pathway analysis of cluster defining genes among monocyte clusters and the top 10 cluster defining genes in cluster 2. n = 4 participants per condition. d, UMAP of chemotactic genes enriched in monocyte cluster 3. n = 4 participants per condition. e, Schematic of hypothesis. (1) Myocardial infarction activates microglia via IL-1β and (2) enhances their production of myeloid chemoattractants including CCL2 and CCL5. (3) Circulating monocytes are actively recruited to the MI brain where they release TNF which signals to glutamatergic neurons in the thalamic LPN to (4) augment sleep. (5) Enhanced sleep after MI suppresses sympathetic input to the heart which limits signalling through ADRB2 and the generation of the myeloid chemoattractants CCL3 and CCL4 to (6) suppress monocyte recruitment to the infarcted heart thus limiting inflammation and promoting healing. Data are mean ± s.e.m. Statistical analysis was done using one-way analysis of variance and two-tailed paired t-tests. *p < 0.05, **p < 0.01, ***p < 0.001.

Extended Data Table 1 Characteristics of human participants and samples in the study
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Supplementary Video 1

Representative iDISCO imaging of CCR2+ monocytes in the brain one day after Sham or MI operation. n = 4, representative of one experiment.

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Huynh, P., Hoffmann, J.D., Gerhardt, T. et al. Myocardial infarction augments sleep to limit cardiac inflammation and damage. Nature 635, 168–177 (2024). https://doi.org/10.1038/s41586-024-08100-w

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