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Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure.

ABSTRACT: BACKGROUND:Atrial fibrillation (AF) is sustained by reentrant mechanisms that depend, in part, on atrial structural remodeling. Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity occurs in persistent AF. A general consensus has been that electrophysiological actions of CaMKII must be the contributing factor, but electrical remodeling in AF differs considerably with electrophysiological effects of CaMKII. CaMKII has been associated with structural remodeling in several tissues, but not the cardiac atria. The role of CaMKII in sustaining AF remains undefined. OBJECTIVE:The purpose of this study was to assess the effects of CaMKII on AF-related structural remodeling. METHODS:We evaluated the objective in a porcine AF-heart failure model using atrial gene transfer of the CaMKII inhibitory peptide CaMKIIn. We used conventional methods including in vivo electrophysiological study, telemetry, western blot, echocardiography, and histology to quantify rhythm, function, microstructure, and signaling pathways relevant to CaMKII and structural remodeling. RESULTS:CaMKII levels and activity increased progressively in the early stages of AF-heart failure. Inhibiting CaMKII preserved atrial contractile function and attenuated atrial hypertrophy, fibrosis, and apoptosis but did not affect inflammation or myolysis. These effects were accompanied by significantly decreased phosphorylation of HDAC4, decreased expression of p38MAP-kinase, and alterations in the phosphorylation pattern and relative ratios of JNK isoforms. CONCLUSION:Our findings suggest that CaMKII mediates signaling pathways related to atrial contractile function and structural remodeling in AF. CaMKII inhibition is potentially a novel therapy for AF. These findings are of importance because no clinically relevant mediators of either atrial contractile function or structural remodeling have yet been identified.

SUBMITTER: Liu Z

PROVIDER: S-EPMC6800146 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure.

Liu Zhao Z Finet J Emanuel JE Wolfram Julie A JA Anderson Mark E ME Ai Xun X Donahue J Kevin JK

Heart rhythm 20190114 7

<h4>Background</h4>Atrial fibrillation (AF) is sustained by reentrant mechanisms that depend, in part, on atrial structural remodeling. Increased Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) activity occurs in persistent AF. A general consensus has been that electrophysiological actions of CaMKII must be the contributing factor, but electrical remodeling in AF differs considerably with electrophysiological effects of CaMKII. CaMKII has been associated with structural remodelin ...[more]

PMID: 30654134

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Project description:Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

Project description:Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive ?-adrenoceptor (?-AR) stimulation. Recent studies indicate a significant cross talk between ?-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental ?-AR signaling in HF. In this study, we investigated the effect of chronic ?-AR blocker treatment on CaMKII activity in human and experimental HF.Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with ?-AR blockers revealed no difference in CaMKII activity when compared with non-?-AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKII?C transgenic mice were treated with the ?1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n?29; P<0.001), attenuated the development of cardiac hypertrophy (-14±6% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (-70±22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A-dependent phospholamban and ryanodine receptor 2 phosphorylation (-42±9% for P-phospholamban-S16 and -22±7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n?11). The lack of CaMKII modulation by ?-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol.Chronic ?-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of ?-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to ?-AR blockade.

Project description:ImportanceAfter anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling.ObjectiveTo determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction.Design, setting, and participantsA randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018.InterventionsPatients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo.Main outcomes and measuresThe primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed.ResultsA total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period.Conclusions and relevanceThree months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated.Trial registrationClinicalTrials.gov Identifier: NCT02557217.

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Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure.

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Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure.

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