Department of Biomedical Engineering Posters and Presentations
Sodium-Calcium Exchanger Inhibition Results in Ventricular Fibrillation in Hearts with Pressure Overload Induced Hypertrophy
Document Type
Poster
Keywords
heart; calcium; contractile dysfunction; fibrillation; hypertrophy
Publication Date
4-2017
Abstract
Introduction:
5.1 million people in the United States have heart failure (HF). Improved treatment of heart failure is critically important because approximately half of patients diagnosed with HF die within 5 years. Cardiac myocyte calcium (Ca2+) imbalance is a characteristic of HF and may cause diastolic dysfunction and focal arrhythmias. During contraction, ryanodine receptors release Ca2+, which is primarily removed by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and the sarcolemmal sodium calcium exchanger (NCX) to initiate relaxation. There is evidence that NCX activity is elevated in failing hearts to compensate for reduced SERCA activity. We tested the hypothesis that NCX inhibition in HF hearts would result in greater contractile dysfunction and arrhythmias than in sham hearts.
Methods:
Rats underwent either sham or trans-aortic constriction (TAC) surgery to induce pressure-overload HF. Rat hearts were excised and Langendorff perfused with a Krebs-Hensleit solution, pH=7.4, oxygenated with 95%O2/5%CO2. Left ventricular developed pressure (LVDP), heart rate, and coronary flow rate were acquired. After a stabilization period, increasing concentrations of the NCX inhibitor SEA0400 were added. In a subset of hearts, Western blots were performed using SERCA, NCX, and Cx43 antibodies.
Results:
During perfusion, baseline LVDP was reduced in TAC animals compared to the sham animals (75.5±19.6 vs 136.2±5.4 mmHg), while heart rate did not differ (222±25 vs 199±22 bpm). Immediately after the final addition of SEA0400, heart rate remained constant (231±21 vs 215±26 bpm). However, approximately one minute after the final concentration of SEA0400 was added, 3 out of the 4 TAC hearts experienced ventricular fibrillation (VF). Western blot analysis did not show a significant change in SERCA or NCX protein expression in the TAC model.
Conclusion:
Most notably, NCX inhibition resulted in VF for 3 out of 4 TAC hearts, while no sham (n=3) hearts experienced VF. LVDP dropped to 84±4% of baseline in TAC hearts, while sham hearts exhibited no change in LVDP. Surprisingly, this decrease in LVDP was not accompanied by an increase in diastolic pressure (7.6±1.7 vs 6.5±2.6 mmHg). Our results suggest that the sodium calcium exchanger is more important for maintaining contractile function in failing hearts than in healthy hearts. As inhibition of NCX results in decreased LVDP and induces VF in TAC hearts, it is likely that increased NCX activity compensates for decreased SERCA activity in hypertrophic/failing hearts.
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Open Access
1
Sodium-Calcium Exchanger Inhibition Results in Ventricular Fibrillation in Hearts with Pressure Overload Induced Hypertrophy
Introduction:
5.1 million people in the United States have heart failure (HF). Improved treatment of heart failure is critically important because approximately half of patients diagnosed with HF die within 5 years. Cardiac myocyte calcium (Ca2+) imbalance is a characteristic of HF and may cause diastolic dysfunction and focal arrhythmias. During contraction, ryanodine receptors release Ca2+, which is primarily removed by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and the sarcolemmal sodium calcium exchanger (NCX) to initiate relaxation. There is evidence that NCX activity is elevated in failing hearts to compensate for reduced SERCA activity. We tested the hypothesis that NCX inhibition in HF hearts would result in greater contractile dysfunction and arrhythmias than in sham hearts.
Methods:
Rats underwent either sham or trans-aortic constriction (TAC) surgery to induce pressure-overload HF. Rat hearts were excised and Langendorff perfused with a Krebs-Hensleit solution, pH=7.4, oxygenated with 95%O2/5%CO2. Left ventricular developed pressure (LVDP), heart rate, and coronary flow rate were acquired. After a stabilization period, increasing concentrations of the NCX inhibitor SEA0400 were added. In a subset of hearts, Western blots were performed using SERCA, NCX, and Cx43 antibodies.
Results:
During perfusion, baseline LVDP was reduced in TAC animals compared to the sham animals (75.5±19.6 vs 136.2±5.4 mmHg), while heart rate did not differ (222±25 vs 199±22 bpm). Immediately after the final addition of SEA0400, heart rate remained constant (231±21 vs 215±26 bpm). However, approximately one minute after the final concentration of SEA0400 was added, 3 out of the 4 TAC hearts experienced ventricular fibrillation (VF). Western blot analysis did not show a significant change in SERCA or NCX protein expression in the TAC model.
Conclusion:
Most notably, NCX inhibition resulted in VF for 3 out of 4 TAC hearts, while no sham (n=3) hearts experienced VF. LVDP dropped to 84±4% of baseline in TAC hearts, while sham hearts exhibited no change in LVDP. Surprisingly, this decrease in LVDP was not accompanied by an increase in diastolic pressure (7.6±1.7 vs 6.5±2.6 mmHg). Our results suggest that the sodium calcium exchanger is more important for maintaining contractile function in failing hearts than in healthy hearts. As inhibition of NCX results in decreased LVDP and induces VF in TAC hearts, it is likely that increased NCX activity compensates for decreased SERCA activity in hypertrophic/failing hearts.
Comments
To be presented at GW Annual Research Days 2017.