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Published on: July 27, 2022
Genetic deletion of NOS3 increases lethal cardiac dysfunction following mouse cardiac arrest
David G Beiser1, Gerasim A Orbelyan, Brendan T Inouye
1Emergency Resuscitation Center, Section of Emergency Medicine, University of Chicago, 5841 S. Maryland Ave., MC 5068, Chicago, IL 60637, USA. dbeiser@uchicago.edu
Study Aims:
Cardiac arrest mortality is significantly affected by failure to obtain return of spontaneous circulation (ROSC) despite cardiopulmonary resuscitation (CPR). Severe myocardial dysfunction and cardiovascular collapse further affects mortality within hours of initial ROSC. Recent work suggests that enhancement of nitric oxide (NO) signaling within minutes of CPR can improve myocardial function and survival. We studied the role of NO signaling on cardiovascular outcomes following cardiac arrest and resuscitation using endothelial NO synthase knockout (NOS3(-/-)) mice.
Methods:
Adult female wild-type (WT) and NOS3(-/-) mice were anesthetized, intubated, and instrumented with left-ventricular pressure-volume catheters. Cardiac arrest was induced with intravenous potassium chloride. CPR was performed after 8min of untreated arrest. ROSC rate, cardiac function, whole-blood nitrosylhemoglobin (HbNO) concentrations, heart NOS3 content and phosphorylation (p-NOS3), cyclic guanosine monophosphate (cGMP), and phospho-troponin I (p-TnI) were measured.
Results:
Despite equal quality CPR, NOS3(-/-) mice displayed lower rates of ROSC compared to WT (47.6% [10/21] vs. 82.4% [14/17], p<0.005). Among ROSC animals, NOS3(-/-) vs. WT mice exhibited increased left-ventricular dysfunction and 120min mortality. Prior to ROSC, myocardial effectors of NO signaling including cGMP and p-TnI were decreased in NOS3(-/-) vs. WT mice (p<0.05). Following ROSC in WT mice, significant NOS3-dependent increases in circulating HbNO were seen by 120min. Significant increases in cardiac p-NOS3 occurred between end-arrest and 15min post-ROSC, while total NOS3 content was increased by 120min post-ROSC (p<0.05).
Conclusions:
Genetic deletion of NOS3 decreases ROSC rate and worsens post-ROSC left-ventricular function. Poor cardiovascular outcomes are associated with differences in NOS3-dependent myocardial cGMP signaling and circulating NO metabolites.
Insights
Endothelial nitric oxide synthase (NOS3) is crucial for survival after cardiac arrest. Deleting NOS3 impairs return of spontaneous circulation (ROSC) and worsens heart function post-resuscitation, highlighting NO signaling
Area of Science:
- Cardiovascular Research
- Cardiology
- Physiology
Background:
- Cardiac arrest survival is limited by poor return of spontaneous circulation (ROSC) and post-resuscitation myocardial dysfunction.
- Nitric oxide (NO) signaling is a potential therapeutic target to improve outcomes after cardiopulmonary resuscitation (CPR).
Purpose of the Study:
- To investigate the role of endothelial NO synthase (NOS3) in cardiovascular outcomes following cardiac arrest and resuscitation.
- To determine the impact of NOS3 deficiency on ROSC, cardiac function, and survival post-CPR.
Main Methods:
- Adult female wild-type (WT) and NOS3 knockout (NOS3(-/-)) mice underwent induced cardiac arrest and CPR.
- Measurements included ROSC rate, cardiac function (pressure-volume loops), blood nitrosylhemoglobin (HbNO), and myocardial signaling molecules (cGMP, p-TnI).
Main Results:
- NOS3(-/-) mice had significantly lower ROSC rates (47.6%) compared to WT mice (82.4%) despite equivalent CPR quality.
- Post-ROSC, NOS3(-/-) mice exhibited worse left-ventricular dysfunction and increased 120-minute mortality.
- Myocardial cGMP and p-TnI levels were reduced in NOS3(-/-) mice, indicating impaired NO signaling.
Conclusions:
- Genetic deletion of NOS3 significantly impairs ROSC and exacerbates left-ventricular dysfunction after resuscitation.
- Reduced cardiovascular outcomes in NOS3-deficient mice are linked to impaired NOS3-dependent cGMP signaling and NO metabolite levels.
