Document text
Principal Investigator: Crystal May Ripplinger
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $719,415
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Cardiovascular diseases, including ventricular arrhythmias and heart failure, are an important cause of
morbidity and mortality in the U.S. Ventricular arrhythmias (VT/VF), after myocardial infarction (MI) and in the
setting of cardiomyopathy, remain an important cause of sudden cardiac death (SCD). While important sex
differences in the incidence of SCD and VT/VF exist in the setting of ischemic and non-ischemic cardio-
myopathy, the mechanisms behind these sex differences remain unknown. It is established that the autonomic
nervous system plays an important role in the genesis of VT/VF and progression of heart failure. Chronic
sympathetic activation and reduced parasympathetic function increase the risk of VT/VF and SCD.
Pathological autonomic neural remodeling in response to MI alters myocardial responses to catecholamines,
modifies myocardial innervation patterns that exacerbate electrical heterogeneities, and leads to alterations in
sympathetic and parasympathetic efferent and afferent signaling, setting up the substrate for VT/VF and its
dynamic modulation by the autonomic nervous system. Yet, it is unknown if there are sex differences in cardiac
autonomic remodeling that underly the clinical differences observed in the presentation and outcomes of
VT/VF after MI and in ischemic cardiomyopathy in men vs. women, and whether the sex hormone, estrogen, is
a mediator of these differences. In order develop tailored and targeted therapies, it is critical to understand
mechanisms that underly sex differences in sympathetic and parasympathetic dysfunction in the setting of
cardiac disease. In this proposal, we aim to test the novel hypotheses that (1) sex differences exist in
cardiac autonomic remodeling after MI and that these differences underly the occurrence of ventricular
arrhythmias in males vs. females, and (2) estrogen plays a critical role in responses of the autonomic
nervous system to myocardial injury, and hence pathogenesis of ventricular arrhythmias. In specific
aim 1, we will test whether myocardial signaling in response to sympathetic and parasympathetic
neurotransmitters and neuropeptides differ between male and female infarcted mice using optical mapping and
novel FRET imaging techniques of intracellular cyclic AMP signaling. In aim 2, we will test whether sex
differences exist in (i) cardiac innervation patterns (using tissue clearing), (ii) afferent and efferent responses to
optogenetic stimulation of specific autonomic neural pathways, and (iii) autonomic ganglia neuronal changes
and oxidative stress after MI. Aim 3 will evaluate the role of estrogen in improving MI induced myocardial and
autonomic remodeling. Understanding sex differences in these fundamental autonomic and myocardial
pathways has the potential to accelerate development of personalized, novel, sex-based disease-modifying
therapies and tailor available therapies more appropriately by sex, reducing complications and side-effects.
Terms: <3'5'-cyclic ester of AMP><Acceleration><Acetylcholine><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adrenaline><Age><Animals><Anti-Arrhythmia Agents><Anti-Arrhythmia Drugs><Anti-Arrhythmics><Autonomic ganglion><Autonomic nervous system><Body Tissues><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiomyopathies><Cardiovascular Diseases><Catecholamines><Cell Communication and Signaling><Cell Signaling><Chronic><Clinical><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Dangerousness><Data><Development><Differences between sexes><Differs between sexes><Disease><Disorder><Dysfunction><Efferent Neurons><Electrophysiology><Electrophysiology (science)><Epinephrine><Estrogens><Evaluation><FRET><Female><Fluorescence Resonance Energy Transfer><Functional disorder><Förster Resonance Energy Transfer><Gonadal Steroid Hormones><Health><Heart><Heart Diseases><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Heterogeneity><Histologic><Histologically><Hormonal><Imaging Procedures><Imaging Technics><Imaging Techniques><Incidence><Infarction><Intracellular Communication and Signaling><Ischemia><Knowledge><Levarterenol><Levonorepinephrine><Maps><Mediating><Mediator><Mice><Mice Mammals><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Muscle Cells><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardiopathies><Myocytes><Nerve><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Transmitter Substances><Nerve Unit><Nervous System><Neural Cell><Neural Pathways><Neurocyte><Neurologic Body System><Neurologic Organ System><Neuronal Transmission><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Neurotransmitters><Noradrenaline><Norepinephrine><Oophorectomy><Optics><Outcome><Output><Ovariectomy><Oxidative Stress><PKA><Pathogenesis><Pathologic><Pathway interactions><Pattern><Peptides><Perimenopausal><Perimenopause><Peripheral><Physiopathology><Play><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Protein Kinase A><Public Health><Reporting><Risk><Role><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Signal Transduction><Signal Transduction Systems><Signaling><Stress cardiomyopathy><Structural defect><Structural malformation><Sudden Death><Sympathins><Syndrome><Takotsubo><Techniques><Testing><Therapeutic Epinephrine><Therapeutic Estrogen><Tissues><Ventricular Arrhythmia><Woman><Women's mortality><adenosine 3'5' monophosphate><afferent nerve><after menopause><ages><arrhythmic agent><axon signaling><axon-glial signaling><axonal signaling><biological sex as a modifier><biological signal transduction><cAMP><cAMP-Dependent Protein Kinases><cardiac failure><cardiac infarct><cardiac injury><cardiac innervation><cardiac rhythm><cardiomyocyte><cardiovascular disorder><coronary attack><coronary infarct><coronary infarction><customized therapy><customized treatment><death among females><death among women><death in females><death in women><death rate among women><death rate in women><developmental><efferent nerve><electrophysiological><female death><female gonadectomy><female mortality><following menopause><glia signaling><glial signaling><gonadal steroids><heart attack><heart disorder><heart infarct><heart infarction><heart innervation><heart rhythm><hemodynamics><improved><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><infarct><injury to the myocardium><innervation><insight><ischemic cardiomyopathy><male><men><menopause transition><mid life><mid-life><middle age><middle aged><midlife><mortality><mortality among females><mortality among women><mortality in females><mortality in women><myocardial injury><myocardium disease><myocardium disorder><nerve signaling><nerve supply><neural><neural signaling><neuronal><neuronal signaling><neurotransmission><neurotransmitter release><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><optical><optogenetics><past menopause><pathophysiology><pathway><patient specific therapies><patient specific treatment><peri-menopausal><peri-menopause><post-menopausal><postmenopausal><postmenopausal status><response><sensory nerve><sex><sex as a biological factor><sex as a biological measure><sex as a biological risk factor><sex as a biological variable><sex as a biological variance><sex as a biologically significant variable><sex as a fundamental variable><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><side effect><social role><stress-induced cardiomyopathy><structural abnormalities><structural anomalies><sudden cardiac death><tailored medical treatment><tailored therapy><tailored treatment><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transition to menopause><transitional menopause><unique treatment><women's death><women's death rate>