Related Experiment Videos
Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade
David M Plank1, Atsuko Yatani, Honda Ritsu
1Divisions of Molecular Cardiovascular Biology, The Children's Hospital and Research Foundation, Cincinnati, OH 45229, USA.
Insights
Beta-blocker treatment improved calcium (Ca2+) handling in dilated cardiomyopathy mouse models by normalizing Ca2+ dynamics and protein levels. Functional cardiac improvements were observed after 10 weeks of treatment.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Dilated cardiomyopathy involves impaired calcium (Ca2+) regulation, leading to contractile dysfunction.
- Beta-blockers are used clinically for heart failure, but their impact on Ca2+ dynamics in failing hearts is unclear.
Purpose of the Study:
- To investigate the effects of beta-blocker treatment on Ca2+ dynamics and protein expression in a mouse model of dilated cardiomyopathy.
Main Methods:
- Tropomodulin-overexpressing transgenic (TOT) mice with dilated cardiomyopathy were treated with propranolol for 2 weeks.
- Ca2+ dynamics were assessed in isolated cardiomyocytes.
- Protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and Na+/Ca2+ exchanger (NCX) were analyzed via immunoblotting.
Main Results:
- Propranolol treatment normalized Ca2+ dynamics, including diastolic and transient amplitudes, in TOT mice.
- Treatment reversed reduced SERCA and increased NCX protein levels observed in untreated TOT mice.
- While Ca2+ dynamics improved within 2 weeks, significant cardiac contractility improvements took 10 weeks.
Conclusions:
- Beta-adrenergic blockade effectively restores Ca2+ handling and protein expression in cardiomyopathic hearts.
- Normalized Ca2+ dynamics precede functional recovery of cardiac contractility.
Abstract:
Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using beta-adrenergic receptor antagonists (beta-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of beta-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective beta-receptor blocker (5 mg. kg-1. day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of beta-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that beta-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.