Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure.
BACKGROUND
In cardiomyocytes from failing hearts, insufficient mitochondrial Ca(2+) accumulation secondary to cytoplasmic Na(+) overload decreases NAD(P)H/NAD(P)(+) redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca(2+) with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger.


OBJECTIVE
Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD).


RESULTS
Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily β-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group <4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham-operated animals.


CONCLUSIONS
The findings demonstrate the critical role played by altered mitochondrial Ca(2+) dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF.
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Ting
T
Liu
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Eiki
E
Takimoto
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Veronica L
VL
Dimaano
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Deeptankar
D
DeMazumder
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Sarah
S
Kettlewell
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Godfrey
G
Smith
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Agnieszka
A
Sidor
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.).
Theodore P
TP
Abraham
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.L., E.T., V.L.D., D.D., A.S., T.P.A., B.O.'R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (S.K., G.S.). bor@jhmi.edu.
Brian
B
O'Rourke
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013841:Thiazepines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D002998:Clonazepam; C079032:CGP 37157; D002118:Calcium
calcium; energy metabolism; heart failure; mitochondria; oxidative stress; reactiveoxygen species; sudden cardiac death