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

Abstract

AimsThe 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 resultsFollow-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.ConclusionsIso 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.

Cardiac metabolism — A promising therapeutic target for heart failure

“…Perhexiline treatment also attenuated cardiac dysfunction caused by energy depletion and oxidative stress in mice with induced irreversible HF (Stapel, et al, 2016).…”

Complete recovery of fulminant peripartum cardiomyopathy on mechanical circulatory support combined with high‐dose bromocriptine therapy

“…bromocriptine) unfolds its therapeutic effects (bridge to recovery) or until implantation of long‐term left ventricular assist device (LVAD) or heart transplantation is pursued (bridge to LVAD/bridge to transplantation) . In contrast, high‐dose inotropes were recently considered to be detrimental in PPCM, and therefore, MCS should be considered in patients with cardiogenic shock due to PPCM . However, here, clinical experience is particularly limited.…”

Peripartum cardiomyopathy

“…In a mouse model of PPCM with cardiomyocyte specific STAT3 deficiency, administration of isoproterenol, a non-selective β agonist, induced heart failure in STAT3 knockout mice but not wild-type mice, seemingly as a result of decreased glucose uptake and increased oxidative stress in cardiomyocytes of knockout mice 124. These observations, which warrant further study, may argue for preferential use of mechanical circulatory support over positive inotropic agents in women with PPCM and cardiogenic shock as a bridge to recovery (or to durable mechanical support or transplant in those who do not recover).…”

“…In an observational cohort series of 27 women with PPCM and severe left ventricular dysfunction (LVEF ≤25%), the seven patients who received dobutamine required LVAD or transplantation (or both), whereas 19 of the 20 who did not receive dobutamine improved without advanced cardiac therapies, despite similar reported baseline clinical characteristics 124. By their nature, however, these retrospective data are subject to confounding by indication.…”

“…In human studies, perhexiline improved heart failure symptom class145146 and, in one study, systolic function in heart failure with reduced ejection fraction 146. In the previously mentioned study of β agonism in a STAT3 deficient mouse, administration of perhexiline improved left ventricular function and survival in mice treated with isoproterenol 124. Perhexiline has not been studied to date in women with PPCM and is not clinically available in the US owing to concerns about hepatotoxicity and neuropathy.…”