World Cardiology Conference 2026

Abstract

Ischemic Heart Disease (IHD) remains a dominant cause of cardiovascular mortality worldwide, yet the physiological mechanisms connecting vascular pathology, metabolic remodeling, and cardiomyocyte dysfunction are still incompletely elucidated. To address this knowledge gap, this project employs an integrated translational strategy combining ex vivo molecular and metabolic profiling of human biofluids with in vitro mechanistic investigations in human cardiomyocytes, aimed at defining the biological pathways that link vascular stress to myocardial injury.

In the clinical component, plasma, pericardial fluid, and pleural fluid were collected from patients undergoing cardiac surgery for IHD and from non-ischemic controls. Profiling of microRNAs revealed a consistent and marked upregulation of miR-21-5p across all biological compartments of IHD patients, suggesting the activation of a shared vascular myocardial stress pathway. Complementary ¹H-NMR metabolomics uncovered a distinctive metabolic signature characterized by altered energy substrate handling, enhanced ketone body utilization, and notably elevated levels of 3-hydroxybutyrate and succinate in pericardial fluid. These metabolic perturbations reflect mitochondrial redox strain and energetic inflexibility, features strongly associated with ischemia-induced tissue stress.

To probe the mechanistic implications of these findings, AC16 human cardiomyocytes were used as an in vitro model of myocardial response to stress. Gain- and loss-of-function approaches demonstrated that miR-21-5p is a central regulator of mitochondrial quality control, inflammatory signaling, and cellular stress adaptation. Overexpression of miR-21-5p attenuated protective and homeostatic programs, while inhibition restored adaptive pathways and improved cellular resilience. Functional mitochondrial assays, including membrane potential analysis and Seahorse XF bioenergetic profiling, confirmed that miR-21-5p silencing enhances maximal respiration, improves metabolic flexibility, and strengthens mitochondrial performance under hypoxic and inflammatory conditions mimicking vascular ischemia.

The ex vivo and in vitro data converge to support the presence of a vascular mitochondrial stress axis in which miR-21-5p acts as a physiological integrator of inflammatory cues, metabolic remodeling, and mitochondrial dysfunction. This work provides a coherent mechanistic model explaining how vascular-driven stress signals
 
propagate to cardiomyocytes and impair myocardial adaptation during ischemic injury. The integrative approach, combining clinical biofluid signatures with controlled mechanistic studies, underscores the importance of bridging human physiology with cellular models to unravel complex cardiovascular pathophysiology. These findings may ultimately inform future therapeutic strategies aimed at enhancing myocardial resilience and mitigating the progression of ischemic damage.