Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias.
BACKGROUND
Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood.


RESULTS
To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias.


CONCLUSIONS
Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death.
Ouvrard-Pascaud
Antoine
A
INSERM AVENIR, Collège de France, Paris, France.
Sainte-Marie
Yannis
Y
Bénitah
Jean-Pierre
JP
Perrier
Romain
R
Soukaseum
Christelle
C
Nguyen Dinh Cat
Aurelie
A
Royer
Anne
A
Le Quang
Khai
K
Charpentier
Flavien
F
Demolombe
Sophie
S
Mechta-Grigoriou
Fatima
F
Beggah
Ahmed T
AT
Maison-Blanche
Pierre
P
Oblin
Marie-Edith
ME
Delcayre
Claude
C
Fishman
Glenn I
GI
Farman
Nicolette
N
Escoubet
Brigitte
B
Jaisser
Frederic
F
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016638:Critical Illness; D003645:Death, Sudden; D004195:Disease Models, Animal; D004562:Electrocardiography; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007473:Ion Channels; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018161:Receptors, Mineralocorticoid / Q000235:genetics*
D007473:Ion Channels; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D002118:Calcium