Hypertension remains a major cause of morbidity and mortality worldwide, and development of hypertensive heart disease (HTN-HD) is an important contributor. HTN-HD develops secondary to left ventricle (LV) pressure overload and neurohormonal hyperactivation. Chronic HTN can lead to the development of HF with a preserved ejection fraction (HFpEF) - which accounts for 50% of HF admission, yet has no approved therapies. HFpEF reflects initially adaptive remodeling aimed at normalizing wall stress during HTN, but progresses to increased LV stiffness and filling pressures and, if chronic, depressed LV function [HF with reduced EF (HFrEF)]. Mechanisms that lead to HTN-HD involve numerous pathways and are typically intertwined with unbalance of autonomic nervous system (ANS) regulation.
The spleen, a primary immune organ, is an important and underappreciated target of ANS during HTN-HD progression. We previously found in the Angiotensin II model of hypertension, ANS activates a previously unknown sympathetic efferent modulating immune responses: the splenic sympathetic nerve activity (SSNA). We also found that the activation of SSNA during hypertension is dependent on a preganglionic parasympathetic pathway passing through the celiac efferent branch of the vagus nerve (CVN). Interestingly, vagus nerve functions are also modulated by hemodynamic challenges imposed by hypertension on the LV. Whether and how the two functions (immune modulating and hemodynamic) of the vagus nerve are related to each other is still unknow. We have preliminary data showing that not only AngII but also a direct mechanic hemodynamic challenge imposed on the LV by ligation of the transverse aortic arch (TAC model) activates the SSNA.
This project will focus on dissecting how the neuroimmune vagus-splenic connection is recruited by hemodynamic overload during the different phases of HTN-HD and how this ANS pathway affects immune responses involved in adaptive versus maladaptive cardiac remodeling.
Hypertension is a clinical condition affecting a large part of the population worldwide and is one of the leading causes of morbidity and mortality. Moreover, chronic hypertension exposure results in several associated conditions caused by organ damage due to chronic high pressure. Among the hypertension consequences the hypertensive heart disease (HTN-HD) plays a major role, further impairing the cardiovascular system and lowering the quality of life and life expectancy of affected patients, even when the ejection fraction is preserved (HFpEF). HFpEF is the systemic response to the increased blood pressure in the ventricle, necessary to normalize the wall stress in chronic hypertension. The progress of this condition is a further remodelling of the heart in which LV increases the stiffness and goes toward a reduction of its functionality, lowering the ejection fraction [HF with reduced EF (HFrEF)].
Following the direction of Tracey's group works, demonstrating a link between immune modulation in the spleen and the vagus nerve[2], in our previous works we demonstrated that the cholinergic fibers of the vagus nerve are involved in the onset of the adrenergic drive on the splenic nerve, finally resulting in priming of the splenic immune response involved in blood pressure raising to hypertensive stimuli[7,8]. It is well known that heart failure results in a massive stimulation of the vagal fibers when the LV experiences pressure overload and diastolic dysfunction. Although it is well known that this autonomic reflex is able to modulate several functions of the cardiovascular system, with the aim of balancing the impelling progression of cardiac dysfunction, it remains unexplored whether this neural reflex is also involved in modulating immune functions relevant for cardiac remodelling. In this perspective, it becomes of primary importance to fully explore the link between the vagal autonomic reflex and the immune response summoned by heart failure. A significant amount of work has been done in the past decade to clarify how the immune response participates to the process of cardiac remodelling to acute ischemic challenges in the heart[10]. Interestingly, it is also known that two important immune reservoirs participating in tuning the cardiac response to stress challenges, namely the spleen and the bone marrow, are both importantly innervated by adrenergic fibers, thus suggesting that neural signals potently dominate and regulate immune responses. Thus, the increased vagal activity induced by LV pressure overload may be a sensor pathway recruited to organize the immune response through neural signals conveyed by the neuroimmune pathway that we have recently identified in hypertension as a part of the complex cholinergic inflammatory pathway (CIP). Our goal is to induce heart failure by different stimuli in order to analyse both vagal and splenic nervous drive by direct neural recording in presence of heart failure and in presence / absence of hypertensive stimulus. By doing this we want to fully investigate the role of vagal activity in the priming of immune response and establish whether this mechanism can be part of the CIP, paving the way for alternative treatment for heart failure made potentially possible by modulating the neuroimmune response to control the inflammatory drive toward reparative and protective processes.
References
1. Triposkiadis F et al. Journal of the American College of Cardiology 2009;54:1747-1762.
2. Rosas-Ballina M et al. Proceedings of the National Academy of Sciences 2008;105:11008-11013.
3. Tracey KJ Nature Reviews Immunology 2009;9:418.
4. Perrotta M et al. Current hypertension reports 2018;20:7.
5. Carnevale D et al Immunity 2014;41:737-752.
6. Nahrendorf M Nature medicine 2018:1.
7. Carnevale D et al Nature communications 2016;7:13035.
8. Perrotta M et al Cardiovascular Research 2018;114:456-467.
9. Carnevale D et al Circulation 2011;124:1337-1350.
10. Swirski FK et al Science 2013;339:161-166.