Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice
Abstract
:1. Introduction
2. Results
2.1. The 0.2% Cholesterol 10% Coconut Oil (CC) Diet Induces Cardiac Hypertrophy, Reduces Myocardial Capillary Density, and Increases Myocardial Fibrosis
2.2. Hemodynamic Deterioration in CC Diet Mice Is Consistent with Heart Failure with Preserved Ejection Fraction
2.3. Reconstituted HDLMilano Significantly Decreases Cardiac Hypertrophy, Increases Myocardial Capillary Density, and Decreases Myocardial Fibrosis in CC Diet Mice
2.4. Hemodynamic Function Is Restored in CC Diet Mice following Intervention with MDCO-216
2.5. MDCO-216 Normalizes Myocardial Acetyl-Coenzyme A (Acetyl-CoA) Carboxylase (ACC) Levels and DECREASES Myocardial Transforming Growth Factor (TGF)-β1 Levels in CC Diet Mice
2.6. MDCO-216 Significantly Improves Exercise Capacity in CC DIET mice
3. Discussion
4. Materials and Methods
4.1. Reconstituted HDLMilano
4.2. In Vivo Experiments and Study Design
4.3. In Vivo Hemodynamic Measurements
4.4. Lipoprotein and Murine Apo A-I Quantification in Plasma
4.5. Quantification of Myocardial Protein Levels by Western Blot
4.6. Histological Analyses
4.7. Exercise Treadmill Testing
4.8. Statistical Analysis
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
HFpEF | Heart failure with preserved ejection fraction |
HFrEF | Heart failure with reduced ejection fraction |
CC | 0.2% cholesterol 10% coconut oil |
SC | standard chow |
apo | apolipoprotein |
HDL | high-density lipoprotein |
LV | left ventricle |
POPC | 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine |
TAC | transverse aortic constriction |
MPVS | Millar Pressure-Volume (PV) Loop System |
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Standard Chow (n = 15) | CC Diet (n = 22) | |
---|---|---|
Heart rate (bpm) | 588 ± 11 | 572 ± 9 |
Pmax (mm Hg) | 98.2 ± 1.2 | 81.8 ± 2.1 **** |
Pes (mm Hg) | 96.3 ± 1.0 | 74.7 ± 2.1 **** |
dP/dtmax (mmHg/ms) | 9.57 ± 0.67 | 8.00 ± 0.67 * |
PRSW (mmHg) | 82.7 ± 7.9 | 65.4 ± 2.9 * |
Ees (mmHg/μL) | 8.48 ± 0.61 | 3.97 ± 0.33 **** |
Pmin (mm Hg) | −0.528 ± 0.830 | 1.41 ± 0.36 * |
Ped (mm Hg) | 1.90 ± 0.47 | 4.43 ± 0.30 **** |
dP/dtmin (mmHg/ms) | −9.94 ± 0.71 | −7.95 ± 0.38 * |
Tau (ms) | 5.39 ± 0.19 | 6.77 ± 0.26 *** |
Slope EDPVR (mmHg/μL) | 0.259 ± 0.039 | 0.765 ± 0.176 * |
EDV (μL) | 27.0 ± 2.0 | 23.3 ± 1.3 |
ESV (μL) | 10.5 ± 1.3 | 10.4 ± 1.2 |
Stroke volume (μL) | 16.5 ± 1.0 | 12.9 ± 0.9 * |
Ejection fraction (%) | 62.2 ± 2.8 | 56.5 ± 3.4 |
Cardiac output (ml/min) | 9.67 ± 0.62 | 7.40 ± 0.55 * |
Stroke work (mmHg·μL) | 1290 ± 80 | 856 ± 74 *** |
dV/dtmax (μL/s) | 773 ± 66 | 579 ± 43 * |
dV/dtmin (μL/s) | −821 ± 63 | −607 ± 42 ** |
Ea (mmHg/μL) | 6.33 ± 0.55 | 6.10 ± 0.37 |
Ea/Ees | 0.809 ± 0.105 | 2.03 ± 0.38 **** |
Reference SC Diet (n = 10) | Buffer SC Diet (n = 10) | MDCO-216 SC Diet (n = 10) | Reference CC Diet (n = 10) | Buffer CC Diet (n = 10) | MDCO-216 CC Diet (n = 10) | |
---|---|---|---|---|---|---|
Total cholesterol | 1.62 ± 0.08 | 1.61 ±0.08 | 1.64 ±0.10 | 1.67 ± 0.08 | 1.69 ±0.09 | 1.61 ±0.10 |
Non-HDL cholesterol | 0.325 ± 0.048 | 0.365 ± 0.047 | 0.389 ± 0.052 | 0.409 ± 0.060 | 0.416 ± 0.040 | 0.331 ± 0.052 |
HDL cholesterol | 1.29 ± 0.07 | 1.24 ± 0.10 | 1.25 ± 0.12 | 1.26 ±0.06 | 1.27 ± 0.06 | 1.28 ± 0.12 |
Reference SC Diet (n = 15) | Buffer SC Diet (n = 11) | MDCO-216 SC Diet (n = 10) | Reference CC Diet (n = 22) | Buffer CC Diet (n = 13) | MDCO-216 CC Diet (n = 14) | |
---|---|---|---|---|---|---|
Heart rate (bpm) | 588 ± 11 | 584 ± 22 | 594 ± 13 | 572 ± 9 | 579 ± 20 | 587 ± 19 |
Pmax (mm Hg) | 98.2 ± 1.2 | 96.6 ±3.7 | 100 ± 1 | 81.8 ± 2.1 !!!! | 83.3 ± 4.2 ! | 97.7 ± 3.7 §§* |
Pes (mm Hg) | 96.3 ± 1.0 | 93.0 ±3.6 | 95.5 ± 1.3 | 74.7 ± 2.1 !!!! | 80.5 ± 4.0 ! | 93.3 ± 3.2 §§§* |
dP/dtmax (mmHg/ms) | 9.57 ± 0.67 | 10.3 ± 0.4 | 10.2 ± 0.5 | 8.00 ± 0.67 ! | 8.22 ± 0.31 !!! | 12.2 ± 0.6 §§§** |
PRSW (mmHg) | 82.7 ± 7.9 | 80.0 ± 7.3 | 79.5 ± 4.7 | 65.4 ± 2.9 ! | 64.0 ± 2.4 ! | 77.6 ± 4.2 §* |
Ees (mmHg/μL) | 8.48 ± 0.61 | 8.23 ± 0.74 | 8.23 ± 0.74 | 3.97 ± 0.33 !!!! | 4.58 ± 0.42 !!! | 8.31 ± 0.63 §§*** |
Pmin (mm Hg) | −0.528 ± 0.830 | 1.58 ± 0.41 | 0.0839 ± 0.648 | 1.41 ± 0.36 ! | 2.38 ± 0.36 | 0.601 ± 0.534* |
Ped (mm Hg) | 1.90 ± 0.47 | 2.64 ± 0.51 | 1.92 ± 0.54 | 4.43 ± 0.30 !!!! | 4.30 ± 0.34 ! | 3.80 ± 0.47 |
dP/dtmin (mmHg/ms) | −9.94 ± 0.71 | −9.98 ± 0.31 | −10.3 ± 0.5 | −7.95 ± 0.38 ! | −8.01 ± 0.33 !!! | −9.99 ± 0.32 §§§** |
Tau (ms) | 5.39 ± 0.19 | 5.38 ± 0.25 | 5.05 ± 0.27 | 6.77 ± 0.26 !!! | 7.67 ± 0.44 !!! | 5.23 ± 0.24 §§§*** |
Slope EDPVR (mmHg/μL) | 0.259 ± 0.039 | 0.314 ± 0.052 | 0.237 ± 0.035 | 0.765 ± 0.176 ! | 0.617 ± 0.138 | 0.336 ± 0.061 |
EDV (μL) | 27.0 ± 2.0 | 25.0 ±0.8 | 26.2 ± 1.2 | 23.3 ± 1.3 | 24.5 ± 1.2 | 26.8 ± 1.4 |
ESV (μL) | 10.5 ± 1.3 | 9.56 ± 0.41 | 9.58 ± 1.29 | 10.4 ± 1.2 | 11.1 ± 0.9 | 9.76 ± 1.11 |
Stroke volume (μL) | 16.5 ± 1.0 | 15.4 ± 0.7 | 16.6 ± 0.8 | 12.9 ± 0.9 ! | 13.4 ± 0.6 ! | 17.0 ± 0.9 §§* |
Ejection fraction (%) | 62.2 ± 2.8 | 61.5 ±1.6 | 64.3 ± 3.8 | 56.5 ± 3.4 | 55.3 ± 2.0 | 64.4 ± 2.9* |
Cardiac output (ml/min) | 9.67 ± 0.62 | 9.00 ± 0.56 | 9.84 ± 0.49 | 7.40 ± 0.55 ! | 7.84 ± 0.55 | 10.0 ± 0.7 §§* |
Stroke work (mmHg·μL) | 1290 ± 80 | 1180 ± 80 | 1330 ± 70 | 856 ± 74 !!! | 909 ± 78 ! | 1330 ± 100 §§§** |
dV/dtmax (μL/s) | 773 ± 66 | 725 ± 44 | 778 ± 87 | 579 ± 43 ! | 536 ± 51 ! | 774 ± 90 * |
dV/dtmin (μL/s) | −821 ± 63 | −766 ± 31 | −829 ± 64 | −607 ± 42 !! | −538 ± 67 !! | −717 ± 80 |
Ea (mmHg/μL) | 6.33 ± 0.55 | 6.15 ± 0.34 | 5.89 ± 0.33 | 6.10 ± 0.37 | 6.04 ± 0.26 | 5.70 ± 0.36 |
Ea/Ees | 0.809 ± 0.105 | 0.820 ± 0.091 | 0.752 ± 0.078 | 2.03 ± 0.38 !!!! | 1.51 ± 0.21 !! | 0.740 ± 0.074 §§§*** |
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Mishra, M.; Muthuramu, I.; Aboumsallem, J.P.; Kempen, H.; De Geest, B. Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice. Int. J. Mol. Sci. 2018, 19, 3399. https://doi.org/10.3390/ijms19113399
Mishra M, Muthuramu I, Aboumsallem JP, Kempen H, De Geest B. Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice. International Journal of Molecular Sciences. 2018; 19(11):3399. https://doi.org/10.3390/ijms19113399
Chicago/Turabian StyleMishra, Mudit, Ilayaraja Muthuramu, Joseph Pierre Aboumsallem, Herman Kempen, and Bart De Geest. 2018. "Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice" International Journal of Molecular Sciences 19, no. 11: 3399. https://doi.org/10.3390/ijms19113399