The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

Abstract

Sudden cardiac death due to malignant ventricular arrhythmias remains the major cause of mortality in the postindustrial world. Defective intracellular Ca²⁺ homeostasis has been well established as a key contributing factor to the enhanced propensity for arrhythmia in acquired cardiac disease, such as heart failure or diabetic cardiomyopathy. More recent advances provide a strong basis to the emerging view that hereditary cardiac arrhythmia syndromes are accompanied by maladaptive remodeling of Ca²⁺ homeostasis which substantially increases arrhythmic risk. This brief review will focus on functional changes in elements of Ca²⁺ handling machinery in cardiomyocytes that occur secondary to genetic mutations associated with catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome.

Keywords: Calcium homeostasis remodeling; Calcium-dependent arrhythmia; Catecholaminergic polymorphic ventricular tachycardia; Heart failure; Long QT syndrome.

Fig. 1

Proteins of cardiac excitation-contraction coupling associated with long QT syndrome or catecholaminergic polymorphic ventricular tachycardia, caused by pathogenic mutation. Proteins with mutations associated with long QT syndrome are colored red; proteins with mutations associated with CPVT are colored blue; proteins with mutations that can cause long QT syndrome or CPVT are colored purple. Kv7.1; KCNQ1 gene, α-subunit of I_Ks channel, mutations underlie LQT1. Kv11.1; KCNH2 gene, α-subunit of I_Kr channel, mutation underlies LQT2. Nav1.5; SCN5a gene, α-subunit of I_Na channel, mutations underlie LQT3. Ankyrin B; ANK2 gene, functions as an adaptor protein, mutations underlie LQT4. minK; KCNE1 gene, β-subunit of I_Ks channel, mutations underlie LQT5. MiRP1; KCNE2 gene, β-subunit of I_Kr channel, mutations underlie LQT6. Kir2.1; KCNJ2 gene, α-subunit of I_K1 channel, mutations underlie LQT7. LTCC; CACNA1C gene, mutations in α-subunit of I_Ca,L channel underlie LQT8 (Timothy syndrome). Cav3; CAV3 gene, caveolin-3 protein is a component of caveolae that co-localizes with Nav1.5, mutations underlie LQT9. β4; SCN4B gene, β-subunit of I_Na channel, mutation underlies LQT10. AKAP9; AKAP9 gene, protein mediates Kv7.1 phosphorylation, mutations underlie LQT11. Syntrophin1α; SNTA1 gene, protein regulates I_Na function, mutations underlie LQT12. Kir3.4; KCNJ5 gene, subunit of K_ACh channel, mutations underlie LQT13. Calm1; CALM1 gene, calmodulin serves as a Ca²⁺-binding messenger protein, mutations underlie LQT14 and CPVT4. Calm2; CALM2 gene, mutations underlie LQT15 and phenotype overlaps with CPVT. Calm3; CALM3 gene, mutations underlie LQT16 and CPVT6. TRDN; TRDN gene, triadin is an accessory protein of RyR2, mutations underlie LQT17, and phenotype overlaps with CPVT5. TECRL; TECRL gene, trans-2,3-enoyl-CoA reductase like protein belongs to the steroid 5-alpha reductase family, mutations underlie CPVT3 and LQT18. RyR2; RYR2 gene, ryanodine receptor is the major sarcoplasmic reticulum Ca²⁺ release channel, mutations underlie CPVT1. CASQ; CASQ2 gene, calsequestrin2 is an accessory protein of RyR2, mutations underlie CPVT2. JUN; ASPH gene, junctin is an accessory protein of RyR2, no CPVT or LQT-associated mutations reported. SERCa; ATP2A2 gene, protein functions as the sarcoplasmic reticulum Ca²⁺-ATPase, no CPVT or LQT-associated mutations reported. PLB; PLN gene, phospholamban functions as an inhibitory protein of SERCa, no CPVT or LQT-associated mutations reported

Fig. 2

Comparison of proarrhythmic changes in action potentials and Ca²⁺ homeostasis in HF, CPVT, and LQTS 2 and 3 ventricular myocytes. a Schematic of action potentials, Ca²⁺ transients, and changes in intra-SR Ca²⁺ in a healthy human ventricular myocyte under β-adrenergic stimulation. Grey dashed lines indicate minimum and maximum Ca²⁺ levels reached in healthy myocytes. b In HF, APD is prolonged due to decrease in K⁺ currents and increase in late I_Na. Ca²⁺-dependent EADs/DADs underlie arrhythmogenesis under β-adrenergic stimulation. Enhanced sensitivity of RyR2 to intra-SR [Ca²⁺] due to increased phosphorylation and oxidation of the channel leads to termination of systolic Ca²⁺ release at reduced intra-SR [Ca²⁺]. Faster RyR2-mediated SR Ca²⁺ leak and reduced refractoriness of RyR2 also contributes to the enhanced propensity for proarrhythmic spontaneous Ca²⁺ release. Enhanced NCX1 activity, depressed SERCa activity and SR Ca²⁺ leak underlie reduced intra-SR [Ca²⁺] and diminished Ca²⁺ transient amplitude. Loss of dyadic contacts between T-tubular LTCCs and jSR RyR2s impedes Ca²⁺ transient rise. c Under β-adrenergic stimulation, CPVT myocytes exhibit spontaneous Ca²⁺ release via defective RyR2 complexes, leading to reduced Ca²⁺ transient amplitude and reduced intra-SR [Ca²⁺]. Posttranslational remodeling, mitochondrial dysfunction, and subcellular structural remodeling contribute to the hyperactivity of RyR2 caused by CPVT-associated mutations. Proarrhythmic activity of RyR2 drives NCX1 activity, causing a depolarizing inward current and DADs. Uncoupling of LTCCs and RyR2s due to dyad remodeling may increase Ca²⁺ transient rise time and reduce LTCC Ca²⁺-dependent inactivation which can result in longer APD. d In LQT2, loss-of-function mutation in KCNH2 reduces outward I_Kr and prolongs APD during β-adrenergic stimulation. SR Ca²⁺ leak is accelerated due to hyperphosphorylation of RyR2. SERCa-mediated SR Ca²⁺ uptake is accelerated at baseline due to PLB phosphorylation. Enhanced activity of hyperphosphorylated RyR2s contributes to a reduction of SR [Ca²⁺], Ca²⁺ transients amplitude, and arrhythmogenic EADs under β-adrenergic stimulation. e In LQT3, gain-of-function mutation in SCN5A increases inward late I_Na and prolongs APD. Arrhythmogenic activity occurs at rest, in the absence of β-adrenergic stimulation. Longer APD increases LTCC-mediated Ca²⁺ influx. Na⁺/Ca²⁺ overload and increased activity of SERCa due to PLB phosphorylation underlies increase in SR Ca²⁺ content, Ca²⁺ transient amplitude, and spontaneous RyR2-mediated Ca²⁺ release thereby EADs at slow rates