Dissertation
Contribution of acid-sensing ion channels to cardiac remodeling and dysautonomia associated with heart failure
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008366
Abstract
Myocardial infarction (MI) is a leading cause of heart failure and continues to impose substantial healthcare costs. Improved survival after MI has paradoxically increased the number of patients who progress to heart failure, underscoring the need to better define the mechanisms underlying this transition. Adverse cardiac remodeling after MI is characterized by dilation of the left ventricle (LV) and thinning of the ventricular wall. Chronic overactivation of neurohormonal systems is the principal driver of adverse cardiac remodeling following MI. Recent data suggest that ablating cardiac afferent neurons in rats attenuates LV remodeling following MI by blocking this overactivation. Our lab has shown that acid-sensing ion channels (ASICs) are highly expressed in cardiac afferents and may sense ischemia-induced myocardial acidosis. We hypothesized that genetic deletion of ASICs might abrogate disadvantageous remodeling after MI by disrupting afferent signaling pathways otherwise resulting in overactivation of neurohormonal responses.
One goal of this thesis was to explore the role of ASICs in cardiac remodeling following MI. To do that we induced MI by coronary artery ligation in wild type (WT) and ASIC3-/- mice and assessed cardiac remodeling by serial echocardiography before as well as 48 hours and 3 weeks after surgery. Both WT and ASIC3-/- MI mice experienced remodeling after MI. However, we found that ASIC3-/- mice had less LV dilation relative to MI size, increased LV mass, and increased stroke volume compared to WT mice after MI. Knocking out ASIC3 seemed to shift the cardiac remodeling to more closely resemble concentric hypertrophy which is characterized by a thickening of the LV walls, generally associated with pressure overload.
The second goal of this thesis was to determine how ASIC3 could be altering the autonomic nervous system after MI and whether knocking out ASIC3 could prevent the sympathoexcitation associated with disease progression. To test the autonomic nervous system, we measured renal and splanchnic sympathetic nerve activity, heart rate and systolic blood pressure variability (sBPV), and heart rate and blood pressure responses to atropine and propranolol. These measures of the autonomic nervous system did not reveal dysautonomia after MI in either genotype or differences between the genotypes. In addition, we assessed baroreceptor-renal sympathetic nerve activity (RSNA) reflex function. Following MI, ASIC3-/- mice had lower baroreceptor-RSNA reflex sensitivity than WT mice, associated with elevated sBPV. Importantly, sBPV correlated significantly with post-MI changes in LV mass in ASIC3-/- but not WT mice. Our data show that ASIC3 plays an important role in cardiac remodeling after MI by decreasing baroreflex sensitivity and subsequently increasing sBPV.
Details
- Title: Subtitle
- Contribution of acid-sensing ion channels to cardiac remodeling and dysautonomia associated with heart failure
- Creators
- Karley Michele Monaghan
- Contributors
- Christopher Benson (Advisor)Kamal Rahmouni (Committee Member)Yuriy Usachev (Committee Member)Mark Chapleau (Committee Member)Kim Johnson (Committee Member)Denice Hodgson-Zingman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008366
- Publisher
- University of Iowa
- Number of pages
- xvii, 102 pages
- Copyright
- Copyright 2026 Karley Monaghan
- Language
- English
- Date submitted
- 04/24/2026
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Include bibliographical references (pages 78-102).
- Public Abstract (ETD)
A myocardial infarction (MI), also known as a heart attack, remains one of the leading causes of heart failure (HF) around the world. Slowing and even preventing the progression of MI to HF continues to be of top concern for physicians and researchers alike. Drugs can do this by preventing the MI-induced adverse cardiac remodeling, characterized by a thinning of the ventricle wall and dilation of the left ventricle. When an MI occurs, cardiac tissue becomes ischemic from a lack of blood flow and oxygen delivery which activate sensory nerves around the heart. This leads to systemic compensatory responses, including the activation of the sympathetic nervous system, the body’s “fight or flight” response, that help maintain physiological functions. Many current therapies effectively target this response and help minimize remodeling; however, more work needs to be done to understand these mechanisms to further improve treatments for patients. This thesis aims to understand the potential role for acid-sensing ion channels (ASICs) in sensory nerves to sense ischemia and activate the sympathetic nervous system. We found that deleting ASIC3 altered the cardiac remodeling following MI, with less LV dilation and an increase in heart mass and wall thickness. However, we found this shift in remodeling was not due to overactivation of the sympathetic nervous system. We suspect that the change may be caused by the increase in blood pressure variability in ASIC3-/- MI mice. This research highlights a potential role for ASICs in cardiac remodeling and blood pressure regulation following MI.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9985176974502771
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