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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Inhibition of CaMKII Attenuates Progressing Disruption of Ca(2+) Homeostasis Upon Left Ventricular Assist Device
Thomas H Fischer1,2, Astrid Kleinwächter1, Jonas Herting1,2
1Department for Cardiology and Pulmonology, Georg-August University, Göttingen, Germany.
Insights
In heart failure patients, a leaky sarcoplasmic reticulum calcium (SR-Ca(2+)) release is linked to declining heart function after left ventricular assist device (LVAD) implantation. Ca(2+)-calmodulin kinase II (CaMKII) inhibition effectively reduces this leak, suggesting a potential therapeutic strategy.
Area of Science:
- Cardiology
- Molecular Biology
- Biomedical Engineering
Background:
- Heart failure often necessitates left ventricular assist device (LVAD) implantation to maintain cardiac output.
- Some patients require heart transplantation after LVAD support, indicating progressive cardiac dysfunction.
- Arrhythmogenic sarcoplasmic reticulum calcium (SR-Ca(2+)) leak is a potential mechanism underlying cardiac dysfunction in heart failure.
Purpose of the Study:
- To investigate the arrhythmogenic SR-Ca(2+) leak in cardiomyocytes from heart failure patients undergoing LVAD implantation (HF-Im) and heart transplantation (HF-Tx).
- To evaluate the efficacy of Ca(2+)-calmodulin kinase II (CaMKII) inhibition in reducing SR-Ca(2+) leak in these patient groups.
- To explore the correlation between SR-Ca(2+) leak and left ventricular (LV) function post-LVAD implantation.
Main Methods:
- Isolation of human left-ventricular cardiomyocytes from HF-Im and HF-Tx patients.
- Measurement of diastolic Ca(2+) spark frequency (CaSpF) using confocal microscopy after controlled pacing.
- Application of CaMKII inhibition (AIP, 1 μM) to assess its effects on Ca(2+) leak parameters.
Main Results:
- HF-Im patients exhibited a high CaSpF (0.76 ± 0.12 × 100 μm⁻¹ × s⁻¹), which was reduced by CaMKII inhibition (0.48 ± 0.10 × 100 μm⁻¹ × s⁻¹).
- HF-Tx patients showed significantly higher CaSpF (1.00 ± 0.10 × 100 μm⁻¹ × s⁻¹) compared to HF-Im patients, correlating with decreased LV function.
- CaMKII inhibition markedly reduced CaSpF (0.35 ± 0.09 × 100 μm⁻¹ × s⁻¹) and spark duration in HF-Tx patients, decreasing SR-Ca(2+) leak by 69%.
Conclusions:
- Elevated SR-Ca(2+) leak in cardiomyocytes is associated with the progression of LV dysfunction in heart failure patients post-LVAD.
- CaMKII inhibition demonstrates a significant capacity to reduce SR-Ca(2+) leak in advanced heart failure (HF-Tx).
- CaMKII inhibition presents a promising therapeutic avenue for improving clinical outcomes in patients with LVADs.
Abstract:
In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca(2+) leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1 Hz for 10 beats to ensure SR-Ca(2+) loading and scanned for diastolic Ca(2+) sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm(-1) × s(-1) could be reduced to 0.48 ± 0.10 × 100 μm(-1) × s(-1) by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca(2+) sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca(2+) leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm(-1) × s(-1) and a higher SR-Ca(2+) leak compared with HF-Im (increase by 81 ± 33%, n cells/patients = 156/7 vs. 130/7, P < 0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 ± 0.09 100 μm(-1) × s(-1,) P = 0.06) and significantly reduced spark duration (n sparks/patients = 58/3 vs. 159/3, P < 0.05). Conclusively, the SR-Ca(2+) leak was reduced by 69 ± 12% in HF-Tx upon CaMKII inhibition (n cells/patients = 53/3 vs. 91/3, P < 0.05). These data show that the SR-Ca(2+) leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca(2+) leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.
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