Abstract
Sensitization of the Cardiac Sympathetic Afferent Reflex Contributes to Increased Sympathetic Tone in a Mouse Model of Hypertrophic Cardiomyopathy
The FASEB journal, Vol.33(S1), pp.745.4-745.4
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.745.4
Abstract
Familial hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, results in cardiac hypertrophy, myocyte disarray, fibrosis, and increased risk of arrhythmias and sudden death. Humans with HCM exhibit increased cardiac sympathetic tone in the absence of heart failure, but the mechanism is poorly understood. We previously reported a selective increase in sympathetic tone to the heart in mice with cardiacâspecific expression of mutated alphaâtropomyosin (Glu180Gly), an established model of HCM. In this study, using the same mouse model, we tested the hypothesis that cardiac spinal (âsympatheticâ) afferents are sensitized by metabolites produced in the HCM heart, resulting in an enhanced cardiac sympathetic afferent reflex (CSAR). The CSAR was assessed by measuring heart rate (HR) and mean arterial pressure (MAP) responses to epicardial application of the TRPV1 agonist capsaicin (2.5mM, 2ÎŒL) to the left ventricle (LV) in anesthetized, ventilated HCM (n=5) and wildâtype (WT) littermate control (n=5) mice. HR (HCM +33±10 bpm vs. WT +8±2 bpm) and MAP (HCM +19±2 mmHg vs. WT +9±3 mmHg) responses to capsaicin were markedly enhanced in HCM mice (p<0.05). Pretreatment with the ganglionic blocker hexamethonium (30ÎŒg/g, IV) abolished HR (+3±1 bpm) and MAP (+3±2 mmHg) responses to capsaicin in HCM mice (n=3) indicating that the responses were reflex mediated. Inhibiting the activity of endogenouslyâactive cardiac afferents by application of the local anesthetic lidocaine (2%) to LV epicardium decreased HR markedly in HCM mice (â42±5 bpm, n=5, p<0.05), with no effect in WT (+2±1 bpm, n=5). We considered the possibility that increases in cardiac and vascular responsiveness to sympathetic activation may have contributed to the enhanced reflex HR and MAP responses to epicardial capsaicin in HCM mice. Tachycardic responses to the ÎČâreceptor agonist isoproterenol (500pg/g, IV) and pressor responses to the αâreceptor agonist phenylephrine (60ng/g, IV) were attenuated (p<0.01), not enhanced in HCM mice (n=4 per group). Thus, capsaicinâinduced reflex increases in HR and MAP were enhanced in HCM mice despite decreases in endâorgan responsiveness. To explore the mechanism of the enhanced CSAR in HCM mice, we measured mRNA expression (qPCR) of acidâsensing ion channel 3 (ASIC3) in dorsal root ganglia (T1âT9), and found that expression increased by 2âfold in HCM vs. WT mice (n=6 each, P<0.05). We conclude that the CSAR is enhanced in HCM mice, and speculate that acidâinduced sensitization of cardiac âsympatheticâ afferents contributes to increased efferent sympathetic activity, arrhythmias and disease progression in HCM.
Support or Funding Information
NIH HL14388, F32HL140880, T32HL007121, AASâLundbeck Fellowship
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- Sensitization of the Cardiac Sympathetic Afferent Reflex Contributes to Increased Sympathetic Tone in a Mouse Model of Hypertrophic Cardiomyopathy
- Creators
- Robert A Larson - University of IowaYongjun Lu - University of IowaChristopher J Benson - Veterans Affairs Medical CenterMark W Chapleau - Veterans Affairs Medical Center
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.33(S1), pp.745.4-745.4
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2019.33.1_supplement.745.4
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Grant note
- AASâLundbeck Fellowship NIH (HL14388; F32HL140880; T32HL007121)
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Stead Family Department of Pediatrics; Critical Care
- Record Identifier
- 9984302196102771
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