Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Study Approval
2.3. Assessment of SDB by Polygraphy
2.4. Confocal Ca Measurements
2.5. Statistical Analysis
3. Results
3.1. Patients
3.2. Increased CaMKII Oxidation and Activity in Patients with SDB
3.3. Ca Spark Frequency Is Increased in Patients with SDB
3.4. CaMKII Inhibition Reduces SDB-Dependent Ca Spark Frequency
3.5. SR Ca Content Was Reduced in Patients with SDB
3.6. SDB-Dependent Atrial Remodeling Was Also Observed in Patients with Sinus Rhythm
4. Discussion
4.1. SDB Results in Increased CaMKII Oxidation
4.2. SDB Patients Show Increased CaMKII-Dependent SR Ca Leak and Reduced SR Ca Content
4.3. SDB-Dependent Pro-Arrhythmic Signaling Is Independent of Pre-Existing AF or HF
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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No SDB (n = 25) | SDB (n = 14) | p Value | |
---|---|---|---|
Age (years), mean ± SD | 67 ± 10 | 70 ± 9 | 0.386 |
Male gender, n (%) | 20 (80) | 14 (100) | 0.073 |
Body mass index (kg/m2), mean ± SD | 28.8 ± 4.5 | 28.9 ± 4.5 | 0.962 |
CABG and valve replacement, n (%) | 5 (20) | 5 (36) | 0.281 |
Cardiovascular risk factors | |||
Hypertension, n (%) | 21 (84) | 12 (86) | 0.887 |
Diabetes mellitus, n (%) | 6 (25) | 5 (36) | 0.482 |
Previous Smoker, n (%) * | 10 (67) | 6 (75) | 0.679 |
Hypercholesterolemia, n (%) | 16 (64) | 8 (57) | 0.673 |
Atrial fibrillation, n (%) | 3 (12) | 6 (43) | 0.028 |
Paroxysmal AF | 1 (4) | 3 (21) | 0.085 |
Persistent AF | 2 (8) | 3 (21) | 0.229 |
Previous stroke n (%) | 3 (12) | 6 (42.9) | 0.028 |
Heart and renal function | |||
Heart Failure, n (%) | 15 (60) | 10 (71) | 0.475 |
NT-pro BNP (pg/mL), median (IQR) | 226 (85, 1128) | 1024 (414, 4575) | 0.129 |
LVEF (%), mean ± SD ** | 55 ± 13 | 37 ± 11 | 0.004 |
GFR (mL/min), mean ± SD | 77 ± 16 | 69 ± 28 | 0.262 |
Dilated left atrium, n (%) *** | 3 (33) | 9 (90) | 0.011 |
Medication at admission | |||
ACE-inhibitors and/or AT1 blockers, n (%) | 22 (88) | 9 (64) | 0.079 |
Betablockers | 19 (76) | 10 (71) | 0.750 |
Statins, n (%) | 20 (80) | 8 (57) | 0.128 |
Digitalis, n (%) | 0 (0) | 1 (7) | 0.176 |
Aldosterone receptor antagonists, n (%) | 3 (12) | 2 (14) | 0.838 |
Thiazid diuretics, n (%) | 6 (24) | 7 (50) | 0.098 |
Loop diuretics, n (%) | 6 (24) | 6 (43) | 0.221 |
No SDB (n = 25) | SDB (n = 14) | p Value | |
---|---|---|---|
Total recording time, min | 548 ± 91 | 516 ± 117 | 0.336 |
Apnea–hypopnea index, /h | 6 ± 3 | 26 ± 13 | <0.001 |
Apnea index, /h | 2 ± 2 | 12 ± 13 | 0.012 |
Obstructive apnea index, /h | 1 ± 1 | 5 ± 4 | <0.001 |
Oxygen desaturation index (4%), /h | 6.1 ± 3.3 | 24.1 ± 11.2 | <0.001 |
Minimal oxygen saturation, % | 79.1 ± 8.7 | 76.0 ± 5.9 | 0.249 |
Oxygen saturation below 90%, % of TRT | 16 ± 20 | 24 ± 20 | 0.220 |
Cheyne–Stokes respiration, %/TRT | 1 ± 3 | 9 ± 15 | 0.020 |
Simple Linear Regression Analysis | Multiple Linear Regression Analysis | |||||
---|---|---|---|---|---|---|
Model I | R2 0.505 | Model II | R2 0.585 | |||
Variable | B (95% CI) | p Value | B (95% CI) | p Value | B (95% CI) | p Value |
AHI, /h | 0.052 (0.032; 0.071) | <0.001 | 0.048 (0.028; 0.068) | <0.001 | 0.040 (0.017; 0.062) | <0.001 |
ODI, /h | 0.059 (0.038; 0.080) | <0.001 | ||||
MinO2, % | −0.021 (−0.061; 0.019) | 0.288 | ||||
O2 below 90%, % of TRT | 0.009 (−0.007; 0.024) | 0.255 | ||||
Age/10, years | 0.04 (−0.291; 0.370) | 0.810 | −0.002 (−0.257; 0.253) | 0.985 | 0.025 (−0.255; 0.306) | 0.855 |
Male gender | 1.031 (0.153; 1.909) | 0.023 | 0.591 (−0.140; 1.322) | 0.110 | 0.703 (−0.049; 1.456) | 0.066 |
Body-mass index, kg/m2 | 0.029 (−0.042; 0.100) | 0.417 | 0.038 (−0.17; 0.093) | 0.170 | 0.057 (−0.001; 0.115) | 0.053 |
NT-pro BNP/1000, pg/mL | 0.047 (−0.019; 0.114) | 0.160 | 0.034 (−0.018; 0.087) | 0.193 | ||
Diabetes | 0.188 (−0.554; 0.790) | 0.724 | 0.161 (−0.367; 0.690) | 0.538 | ||
AF | 0.169 (−0.550; 0.889) | 0.636 | −0.262 (−0.873; 0.349) | 0.388 | ||
ACEi/ARB therapy | −0.799 (−1.532; −0.065) | 0.034 | −0.591 (−1.276; 0.094) | 0.088 | ||
Beta blocker therapy | −0.081 (−0.802; 0.640) | 0.821 | ||||
Valve replacement | −0.036 (−0.757; 0.686) | 0.921 | ||||
LVEF < 50% | 0.362 (−0.437; 1.160) | 0.361 | ||||
Dilated left atrium | 0.345 (0.726; 1.417) | 0.506 |
Simple Linear Regression Analysis | Multiple Linear Regression Analysis | |||||
---|---|---|---|---|---|---|
Model I | R2 0.343 | Model II | R2 0.436 | |||
Variable | B (95% CI) | p Value | B (95% CI) | p Value | B (95% CI) | p Value |
AHI, /h | −1.042 (−1.794; −0.291) | 0.009 | −1.048 (−1.952; −0.144) | 0.026 | −0.123 (−0.241; −0.005) | 0.043 |
ODI, /h | −0.133 (−0.213; −0.053) | 0.003 | ||||
MinO2, % | 0.075 (−0.061; 0.211) | 0.264 | ||||
O2 below 90%, % of TRT | −0.045 (−0.097; 0.008) | 0.090 | ||||
Age/10, years | −0.252 (−1.723; 1.219) | 0.724 | −0.588 (−2.088; 0.911) | 0.418 | 0.317 (−2.284; 2.918) | 0.795 |
Male gender | −1.915 (−4.764; 0.934) | 0.176 | −0.503 (−3.568; 2.562) | 0.732 | 0.585 (−4.114; 5.285) | 0.791 |
Body-mass index, kg/m2 | −0.010 (−0.306; 0.286) | 0.945 | 0.054 (−0.255; 0.364) | 0.715 | 0.112 (−0.296; 0.519) | 0.562 |
NT-pro BNP/1000, pg/mL | −0.141 (−0.352; 0.071) | 0.181 | −0.112 (−0.406; 0.183) | 0.426 | ||
Diabetes | 0.201 (−2.507; 2.908) | 0.878 | 0.808 (−2.305; 3.921) | 0.582 | ||
AF | −0.883 (−3.662; 1.896) | 0.515 | −1.716 (−6.904; 3.474) | 0.485 | ||
ACEi/ARB therapy | 0.254 (−2.430; 2.937) | 0.846 | −1.313 (−4.922; 2.297) | 0.444 | ||
Beta blocker therapy | −2.071 (−4.577; 0.436) | 0.100 | ||||
Valve replacement | −2.125 (−4.754; 0.503) | 0.107 | ||||
LVEF < 50% | −1.585 (−3.654; 0.483) | 0.123 | ||||
Dilated left atrium | −2.342 (−5.508; 0.824) | 0.130 |
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Arzt, M.; Drzymalski, M.A.; Ripfel, S.; Meindl, S.; Biedermann, A.; Durczok, M.; Keller, K.; Mustroph, J.; Katz, S.; Tafelmeier, M.; et al. Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing. Antioxidants 2022, 11, 331. https://doi.org/10.3390/antiox11020331
Arzt M, Drzymalski MA, Ripfel S, Meindl S, Biedermann A, Durczok M, Keller K, Mustroph J, Katz S, Tafelmeier M, et al. Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing. Antioxidants. 2022; 11(2):331. https://doi.org/10.3390/antiox11020331
Chicago/Turabian StyleArzt, Michael, Marzena A. Drzymalski, Sarah Ripfel, Sebastian Meindl, Alexander Biedermann, Melanie Durczok, Karoline Keller, Julian Mustroph, Sylvia Katz, Maria Tafelmeier, and et al. 2022. "Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing" Antioxidants 11, no. 2: 331. https://doi.org/10.3390/antiox11020331
APA StyleArzt, M., Drzymalski, M. A., Ripfel, S., Meindl, S., Biedermann, A., Durczok, M., Keller, K., Mustroph, J., Katz, S., Tafelmeier, M., Lebek, S., Flörchinger, B., Camboni, D., Wittmann, S., Backs, J., Schmid, C., Maier, L. S., & Wagner, S. (2022). Enhanced Cardiac CaMKII Oxidation and CaMKII-Dependent SR Ca Leak in Patients with Sleep-Disordered Breathing. Antioxidants, 11(2), 331. https://doi.org/10.3390/antiox11020331