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Glycaemic variability identified as a critical determinant of myocyte dysfunction and risk for myocardial injury in preclinical models of diabetes

ABSTRACT: Heart disease is the leading cause of morbidity and mortality in individuals with diabetes, due largely to risks associated with ischaemic injuries such as myocardial infarction (MI). We use human population genetic data to demonstrate that current biomarkers of hyperglycaemia do not account for risk of post-MI mortality in diabetes patients. This study therefore systematically evaluates glycaemic stress underpinning cardiovascular risk in diabetes. Using in vivo and in vitro models, we demonstrate that glycaemic variability rather than hyperglycaemia alone is a dominant risk factor for heart muscle dysfunction and myocardial injury sensitivity in diabetes. These findings provide new preclinical models for mechanistic and drug discovery studies and inform strategies for managing cardiovascular outcomes in patients with diabetes.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase, Gas Chromatography MS - positive

PROVIDER: MTBLS11411 | MetaboLights | 2026-02-06

REPOSITORIES: MetaboLights

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			Action	DRS
	240326_NickCao_CCM-results summary-batch2.xlsx	Xlsx
	240405_cardiomyocytes HMDB summary.xlsx	Xlsx
	NC-pool_1ul_023.lcd	Other
	NC-pool_2ul_024.lcd	Other
	NC1_Control 1_015.lcd	Other

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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

Glycaemic variability identified as a critical determinant of myocyte dysfunction and risk for myocardial injury in preclinical models of diabetes

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