Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling After Myocardial
Andrew J Boyle1,2,3, Carl Schultz4,5, Joseph B Selvanayagam6,7
1Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
Insights
NP202 did not prevent left ventricular remodeling after myocardial infarction. This study found the drug safe and well-tolerated but ineffective in improving cardiac function post-STEMI.
Area of Science:
- Cardiology
- Molecular Medicine
- Clinical Trials
Background:
- Anterior ST-segment elevation myocardial infarction (STEMI) can lead to adverse left ventricular (LV) remodeling, increasing the risk of heart failure and mortality.
- Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) plays a crucial role in mediating this detrimental LV remodeling process.
Purpose of the Study:
- To evaluate the efficacy of NP202, an oral CaMKIId inhibitor, in preventing LV remodeling in patients following anterior STEMI with early residual LV dysfunction.
- To assess the safety and tolerability of NP202 in this patient population.
Main Methods:
- A randomized, double-blind, placebo-controlled, multicenter trial involving 147 patients with anterior STEMI treated with primary percutaneous coronary intervention (PCI).
- Patients received either NP202 (1000 mg daily) or placebo for 3 months.
- Left ventricular remodeling was assessed using cardiovascular magnetic resonance (CMR) imaging at baseline and 3-month follow-up, with changes in LV end-systolic volume index (LVESVi) as the primary endpoint.
Main Results:
- No significant difference was observed in the primary endpoint, change in LVESVi, between the NP202 and placebo groups at 3 months (P = .78).
- Secondary endpoints, including changes in LV end-diastolic volume index, LVEF, and infarct size, also showed no significant differences between the groups.
- NP202 demonstrated an acceptable safety profile and was well tolerated, with similar rates of major adverse cardiac and cerebrovascular events and mortality compared to placebo.
Conclusions:
- Three months of NP202 treatment did not significantly improve LV remodeling in patients with anterior STEMI and residual LV dysfunction after primary PCI.
- The drug was found to be safe and well-tolerated in the studied population.
- Further research may be needed to explore alternative therapeutic strategies targeting CaMKIId or other pathways in post-STEMI cardiac remodeling.
Importance:
After 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.
Objective:
To 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 Participants:
A 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.
Interventions:
Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo.
Main Outcomes And Measures:
The 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.
Results:
A 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 Relevance:
Three 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 Registration:
ClinicalTrials.gov Identifier: NCT02557217.
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