期刊
EUROPEAN HEART JOURNAL
卷 38, 期 5, 页码 349-361出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehw086
关键词
Peripartum cardiomyopathy; Acute heart failure; beta-Adrenergic receptor stimulation; STAT3; Metabolism; Oxidative stress
资金
- Deutsche Forschungsgemeinschaft [Hi 842/9-1, SFB 894, BO3643/3-1]
- Rebirth II, Nieders
- Academy of Finland
- Abo Akademi University
- Medical School Hannover
- University of Turku
- Turku University Hospital
- Volkswagenstiftung
- HOMFOR
Aims The benefit of the beta 1-adrenergic receptor (beta 1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to b-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice. Methods and results Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction <= 25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The beta-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the beta(1)-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir. Conclusions Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via beta(1)-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.
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