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Principal Investigator: Francisco J Alvarado
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $604,478
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Sympathetic stimulation of ventricular myocytes activates PKA, which phosphorylates L-type Ca2+
channels and phospholamban, among other substrates, to increase Ca2+ entry and SR Ca2+ uptake. This β-
adrenergic-induced increase of intracellular Ca2+ (Ca2+ overload) is a natural and efficient mechanism to
increase cardiac performance, inasmuch as the magnitude and force of cardiac contractions greatly depend on
the amount of Ca2+ supplied to the myofilaments. However, Ca2+ overload also increases arrhythmia vulnerability
because it brings ryanodine receptors (RyR2) closer to threshold for spontaneous Ca2+ release (SCR). SCR
during diastole activates the Na+/Ca2+ exchanger of the sarcolemma and generates a depolarizing inward current
(delayed after-depolarization or DAD) that may trigger extemporaneous actions potentials. Ca2+ overload and its
subsequent SCRs are indeed the primary events that evolve in malignant cardiac arrhythmias, as observed in
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and quite possibly in some forms of atrial
fibrillation, long QT, and heart failure. To prevent these Ca2+-dependent arrhythmias, an emergent group of RyR2
blockers aim to stop SCR, despite the fact that the key process that spawns SCR, namely, Ca2+ overload, may
not be affected or in some cases may be even exacerbated by the RyR2 blockers. We have found that
imperacalcin, a high-affinity, membrane-permeable selective agonist of RyRs, paradoxically decreases
arrhythmia burden and prevents Ca2+-dependent arrhythmias in animal models of CPVT. We hypothesize that
this unexpected and remarkable anti-arrhythmic effect of imperacalcin is due to a partial and controlled
depletion of SR Ca2+ load, which decreases the propensity of SCR events and thus dissipates the main
arrhythmogenic substrate in CPVT. Our research program will systematically and rigorously test this
hypothesis at the molecular, cellular, whole heart and intact animal levels using established (mouse) and novel
(rabbit) models of CPVT. The first specific aim will determine the defining structural and functional characteristics
that confer to imperacalcin and other members of the calcin family their capacity to permeate membranes and
their anti-arrhythmic properties. In the second aim, we will use native and modified calcins on intact
cardiomyocytes, Langendorff-perfused working hearts and intact animals for a rationalized design of a novel
group of RyR2 ligands capable of preventing Ca2+-triggered arrhythmias. These studies use animal models of
CPVT to develop a novel paradigm for the treatment of Ca2+ overload-generated cardiac arrhythmias; results
may be applied to other cardiomyopathies where controlled unloading of SR Ca2+ may be desirable.
Terms: <0-11 years old><Actin Filaments><Action Potentials><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adrenergic Agents><Adrenergic Drugs><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Adrenergics><Affect><Affinity><Agonist><Animal Model><Animal Models and Related Studies><Animals><Anti-Arrhythmia Agents><Anti-Arrhythmia Drugs><Anti-Arrhythmics><Arrhythmia><Arrhythmogenic Right Ventricular Cardiomyopathy><Arrhythmogenic Right Ventricular Dysplasia><Assay><Atrial Fibrillation><Auricular Fibrillation><Binding><Bioassay><Biological Assay><Buffers><Ca Release Channel-Ryanodine Receptor><Calcium><Calcium-Ryanodine Receptor Complex><Calsequestrin><Cardiac><Cardiac Arrhythmia><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Catecholaminergic Polymorphic Ventricular Tachycardia><Cell Body><Cell Communication and Signaling><Cell Function><Cell Membrane Permeability><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Membrane><Cellular Physiology><Cellular Process><Characteristics><Child><Child Youth><Children (0-21)><Cyclic AMP-Dependent Protein Kinases><Development><Diastole><Disease><Disorder><Domestic Rabbit><Dysfunction><Environment><Event><Family><Functional disorder><Genes><Genetic Alteration><Genetic Change><Genetic defect><Heart><Heart Arrhythmias><Heart Muscle Cells><Heart failure><Heart myocyte><Hyperactivity><Individual><Intracellular Communication and Signaling><Knock-in><Ligands><Malignant><Malignant - descriptor><Mediating><Membrane><Metabolic><Mice><Mice Mammals><Microfilaments><Modeling><Molecular><Molecular Interaction><Murine><Mus><Muscle Cells><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myocytes><Myofilaments><Oryctolagus cuniculus><Output><PKA><Pathologic><Penetration><Peptides><Performance><Perfusion><Phosphorylation><Physiopathology><Play><Process><Property><Protein Kinase A><Protein Phosphorylation><Proteins><Rabbits><Rabbits Mammals><Rationalization><Receptor Gene><Research><Role><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><Sarcolemma><Sarcoplasmic Reticulum><Scorpion Venoms><Signal Transduction><Signal Transduction Systems><Signaling><Strenuous Exercise><Stress><Subcellular Process><Syndrome><Testing><Ventricular><Ventricular Fibrillation><Ventricular Tachycardia><adult youth><arrhythmic agent><autosome><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><biological signal transduction><cAMP-Dependent Protein Kinases><cardiac failure><cardiomyocyte><design><designing><developmental><genome mutation><insight><intense exercise><kids><knockin><member><membrane permeability><membrane structure><model of animal><myocardium disease><myocardium disorder><novel><pathophysiology><phospholamban><prevent><preventing><programs><social role><stem><strenuous activity><strenuous physical activity><uptake><vigorous exercise><vigorous physical activity><young adult><young adulthood><youngster>