Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy

Eur Heart J. 2017 Feb 1;38(5):349-361. doi: 10.1093/eurheartj/ehw086.


Aims: The benefit of the β1-adrenergic receptor (β1-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 β-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 β-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 β1-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 β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

MeSH terms

  • Adrenergic beta-1 Receptor Agonists / adverse effects*
  • Adrenergic beta-1 Receptor Agonists / toxicity*
  • Adult
  • Animals
  • Blood Glucose / metabolism
  • Cardiomyopathies / chemically induced*
  • Dobutamine / adverse effects*
  • Female
  • Heart Failure / drug therapy*
  • Humans
  • Isoproterenol / pharmacology
  • Male
  • Mice, Knockout
  • MicroRNAs / physiology
  • Mitochondria, Heart / metabolism
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • Peripartum Period
  • Puerperal Disorders / drug therapy*
  • Purine Nucleotides / metabolism
  • Random Allocation
  • Reactive Oxygen Species / metabolism
  • Receptor, ErbB-4 / metabolism
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / deficiency
  • STAT3 Transcription Factor / physiology*
  • Ventricular Dysfunction, Left / chemically induced


  • Adrenergic beta-1 Receptor Agonists
  • Blood Glucose
  • MIRN7 microRNA, mouse
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • Purine Nucleotides
  • Reactive Oxygen Species
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Dobutamine
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • Isoproterenol