Contribution of Medullary Pre-Sympathetic Neurons on the Progression of Breathing Disorders and Autonomic Dysfunction in Heart Failure with Preserved Ejection Fraction

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is a public health problem affecting more than 26 million people worldwide. Currently, there are no effective strategies for managing HFpEF and projections indicate that its prevalence will double by the next decade. In the past years, we have been able to provide compelling evidence to support the pivotal role played by pre-sympathetic neurons located in the ventral aspect of the medulla (RVLM-C1) on experimental HFpEF pathophysiology, by orchestrating autonomic, cardiac, and respiratory failure during disease progression, since their selective ablation reduces sympathetic activity and arrhythmogenesis, restored normal respiratory function and improve cardiac diastolic function in rodents with HFpEF. Accordingly, knowing the therapeutic window to target RVLM-C1 neurons during HFpEF progression may offer salutary potential to improve HFpEF outcomes. Then, having the ability to create neuronal activity maps from the RVLM during HFpEF progression along with cardiorespiratory physiological monitoring should generate precious data for the development of diagnostic and therapeutic tools in the setting of HFpEF. Therefore, our primary aim will be to provide, for the first time, RVLM-C1 neuronal activity mapping in-vivo and in-vitro, during the early, mid- and long-term experimental HFpEF in combination with longitudinal cardiorespiratory and cardiac function monitoring. Obtaining all this physiological information in the setting of HFpEF will deliver comprehensive evidence about the precise changes in the neural control of hemodynamic and respiratory function serving to design therapeutic interventions during each HFpEF stage. In addition, our secondary aim will be to perform an un-precedented molecular characterization at both the transcriptomic and metabolomic level of the changes involved in RVLM-C1 neuron aberrant activity in HFpEF. Finally, we will test whether FDA-approved sympatholytics applied within a defined therapeutic window (i.e. at the onset of RVLM hyperactivation) offers salutary potential in cardiorespiratory outcomes in experimental HFpEF. Altogether, our results should provide compelling information about precise timing for the alterations in the neural control of cardiorespiratory function in HFpEF uncovering potentially relevant therapeutic windows for the treatment of the neural origin of autonomic and breathing disorders.