The chronic heart failure state (CHF) is characterized by neurohumoral activation and cardiac remodeling (fibrosis, dilation and hypertrophy). Sympatho-excitation is mediated by several mechanisms that have been the focus of previous studies from this laboratory. In the CHF state a potent cardiogenic reflex known as the cardiac sympathetic afferent reflex (CSAR) is activated by an increase in the activity of sympathetic afferents on or near the surface of the ventricles. This excitatory reflex, in part, drives sympathetic efferent nerve activity to the heart and the periphery. In a recent study we demonstrated that selective removal of these afferents using the ultrapotent TRPV1 receptor agonist Resiniferitoxn (RTX), at the time of myocardial infarction (MI) in rats, resulted in a decrease in cardiac and renal sympathetic nerve activity and norepinephrine excretion 9-11 weeks following the MI. In addition, this intervention decreased the remodeling process by reducing extracellular matrix proteins (fibronectin, collagen, ? smooth muscle actin). The resultant effect of RTX treatment was a decrease in LV end diastolic pressure and an increase in diastolic function along with an increase in the cardiac response to isoproterenol (cardiac reserve). The current proposal extends these observations and seeks to further understand the mechanisms responsible for the beneficial effects of CSAR ablation post MI and in CHF. In order to determine if the beneficial effects of CSAR ablation are mediated by reducing cardiac efferent sympathetic outflow Specific Aim 1 will compare RTX treatment with both global sympathetic blockade (6 hydroxy dopamine) or specific ?1 or ?1 blockade on the remodeling process. In addition, this aim will determine if abrogation of the renin-angiotensin system compares to RTX treatment for both sympathetic outflow and remodeling in the rat MI model.
Specific Aim 2 will address the issue of afferent neuropeptide depletion by RTX evoking anti-inflammatory effects which, in turn, reduces the remodeling process. Cardiac vascular permeability (Evans Blue) and blockade of Substance P receptors will be used to address this question. In order for this novel paradigm to be clinically applicable, we must determine the optimal therapeutic window where RTX treatment reverses or attenuates the autonomic and fibrotic events in the CHF state. Therefore, Specific Aim 3 will examine the responses to epicardial RTX treatment at various time points following MI in the rat model and will determine autonomic and remodeling effects of epidural peri- ganglion (T1-T4 DRGs containing the predominant CSAR afferent soma) application of RTX, which is considered as an alternative CSAR denervation strategy. The novelty of these studies is that, for the first time, a classical afferent nociceptive pathway is the target for improvement in cardiac function in the CHF or post MI states. While these afferents have been viewed as primarily transmitting cardiac pain, our data clearly show they are polymodal and should be considered as new targets for therapy.

Public Health Relevance

The studies proposed in this application seek to further understand the role of cardiac sensory endings in mediating progressive cardiac disease following a reduction in coronary blood flow. We will determine if substances released from these nerve endings in response to low blood flow participate in cardiac inflammation, setting the stage for disease progression. These studies will provide the physiological underpinning of potential new therapies in the treatment of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126796-03
Application #
9390491
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Tjurmina, Olga A
Project Start
2015-12-18
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Wang, Han-Jun (2017) Mineralocorticoids: the secret of muscle reflex dysfunction in hypertension? Am J Physiol Heart Circ Physiol 313:H931-H933
Becker, Bryan K; Tian, Changhai; Zucker, Irving H et al. (2016) Influence of brain-derived neurotrophic factor-tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure. J Physiol 594:5711-25
Wang, Hanjun; Case, Adam J; Wang, Wei-Zhong et al. (2016) Redox Signaling and Neural Control of Cardiovascular Function. Oxid Med Cell Longev 2016:7086018