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Myocardial infarction accelerates atherosclerosis.

ABSTRACT: During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.

SUBMITTER: Dutta P

PROVIDER: S-EPMC3401326 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Myocardial infarction accelerates atherosclerosis.

Dutta Partha P Courties Gabriel G Wei Ying Y Leuschner Florian F Gorbatov Rostic R Robbins Clinton S CS Iwamoto Yoshiko Y Thompson Brian B Carlson Alicia L AL Heidt Timo T Majmudar Maulik D MD Lasitschka Felix F Etzrodt Martin M Waterman Peter P Waring Michael T MT Chicoine Adam T AT van der Laan Anja M AM Niessen Hans W M HW Piek Jan J JJ Rubin Barry B BB Butany Jagdish J Stone James R JR Katus Hugo A HA Murphy Sabina A SA Morrow David A DA Sabatine Marc S MS Vinegoni Claudio C Moskowitz Michael A MA Pittet Mikael J MJ Libby Peter P Lin Charles P CP Swirski Filip K FK Weissleder Ralph R Nahrendorf Matthias M

Nature 20120701 7407

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. Th ...[more]

PMID: 22763456

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Project description:Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

Dataset Information

Myocardial infarction accelerates atherosclerosis.

Publications

Myocardial infarction accelerates atherosclerosis.

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