| Title |
Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability
|
|---|---|
| Published in |
Basic Research in Cardiology, June 2017
|
| DOI | 10.1007/s00395-017-0637-y |
| Pubmed ID | |
| Authors |
Stefan Neef, Christian Mann, Anne Zwenger, Nataliya Dybkova, Lars S. Maier |
| Abstract |
Sarcoplasmic reticulum (SR) Ca(2+) leak induced by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is centrally involved in atrial and ventricular arrhythmogenesis as well as heart failure remodeling. Consequently, treating SR Ca(2+) leak has been proposed as a novel therapeutic paradigm, but compounds for use in humans are lacking. SMP-114 ("Rimacalib") is a novel, orally available CaMKII inhibitor developed for human use that has already entered clinical phase II trials to treat rheumatoid arthritis. We speculated that SMP-114 might also be useful to treat cardiac SR Ca(2+) leak. SMP-114 significantly reduces SR Ca(2+) leak (as assessed by Ca(2+) sparks) in human atrial (0.72 ± 0.33 sparks/100 µm/s vs. control 3.02 ± 0.91 sparks/100 µm/s) and failing left ventricular (0.78 ± 0.23 vs. 1.69 ± 0.27 sparks/100 µm/s) as well as in murine ventricular cardiomyocytes (0.30 ± 0.07 vs. 1.50 ± 0.28 sparks/100 µm/s). Associated with lower SR Ca(2+) leak, we found that SMP-114 suppressed the occurrence of spontaneous arrhythmogenic spontaneous Ca(2+) release (0.356 ± 0.109 vs. 0.927 ± 0.216 events per 30 s stimulation cessation). In consequence, post-rest potentiation of Ca(2+)-transient amplitude (measured using Fura-2) during the 30 s pause was improved by SMP-114 (52 ± 5 vs. 37 ± 4%). Noteworthy, SMP-114 has these beneficial effects without negatively impairing global excitation-contraction coupling: neither systolic Ca(2+) release nor single cell contractility was compromised, and also SR Ca(2+) reuptake, in line with resulting cardiomyocyte relaxation, was not impaired by SMP-114 in our assays. SMP-114 demonstrated potential to treat SR Ca(2+) leak and consequently proarrhythmogenic events in rodent as well as in human atrial cardiomyocytes and cardiomyocytes from patients with heart failure. Further research is necessary towards clinical use in cardiac disease. |
Mendeley readers
The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 32 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 8 | 25% |
| Student > Ph. D. Student | 5 | 16% |
| Professor | 4 | 13% |
| Student > Master | 3 | 9% |
| Student > Bachelor | 2 | 6% |
| Other | 5 | 16% |
| Unknown | 5 | 16% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 9 | 28% |
| Biochemistry, Genetics and Molecular Biology | 6 | 19% |
| Agricultural and Biological Sciences | 4 | 13% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
| Psychology | 1 | 3% |
| Other | 0 | 0% |
| Unknown | 10 | 31% |
Attention Score in Context
This research output has an Altmetric Attention Score of 44. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 May 2018.
All research outputs
#800,659
of 22,988,380 outputs
Outputs from Basic Research in Cardiology
#8
of 650 outputs
Outputs of similar age
#18,416
of 317,514 outputs
Outputs of similar age from Basic Research in Cardiology
#1
of 12 outputs
Altmetric has tracked 22,988,380 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 96th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 650 research outputs from this source. They receive a mean Attention Score of 5.0. This one has done particularly well, scoring higher than 98% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 317,514 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 94% of its contemporaries.
We're also able to compare this research output to 12 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 91% of its contemporaries.