Cardiac Protection by Neuromodulation after Myocardial Infarction

About This Grant

Project Summary Myocardial infarction (MI) remains a principal cause of global morbidity, commonly progressing to heart failure despite contemporary treatments. Evidence from basic and clinical research highlights a critical, yet incompletely defined, interplay between cardiac injury signals, brain integration, and peripheral sympathetic outflow. Based on preliminary data, this proposal adopts a cardiac-neuro-immune perspective, hypothesizing that three key hubs- transient receptor potential vanilloid 1 (TRPV1) vagal sensory neurons (VSNs) projecting to the infarcted ventricle, hypothalamic angiotensin II receptor type 1 (AT1aR) neurons activated by MI, and interleukin-1 beta (IL1β) signaling in the superior cervical ganglia (SCG) - constitute an interoceptive loop that drives or mitigates adverse remodeling after MI. Preliminary findings indicate that ablating TRPV1 VSNs diminishes infarct size and inflammatory cytokines, while blocking IL1β in the SCG enhances cardiac function. Moreover, inhibiting AT1aR neurons in the hypothalamus appears to reduce maladaptive sympathetic output. The central hypothesis is that coordinating interventions at these three nodes can mitigate pathological remodeling and improve cardiac outcomes. In Aim 1, viral tracers, genetic profiling, and neuromodulatory techniques will determine how TRPV1 VSNs sense and modulate ischemic injury, including the resulting changes in ischemic, border, and remote zones characterized by single-nucleus RNA sequencing and spatial transcriptomics. Aim 2 will employ a “chemo-ultrasound” platform - combining long-term chemogenetic modulation of AT1aR neurons with real-time echocardiography and EEG/ECG - to elucidate how hypothalamic circuits shape MI outcomes. Aim 3 will investigate whether IL1β blockade in the SCG disrupts neuroinflammation and sympathetic hyperactivation, thereby preventing adverse remodeling. Through these integrated approaches, these studies will reveal a precise map of the heart–brain axis following MI and identify new therapeutic targets that minimize off-target effects. By bridging cardiac physiology, neuroscience, and immunology, the project proposes a next-generation framework for MI management. Understanding how vagal nociceptors interface with hypothalamic circuitry and peripheral sympathetic ganglia could introduce novel interventions that harness neuroimmune modulation, offering more effective long-term protection against heart failure and advancing personalized care for cardiovascular disease.