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Effects of Cardiomyocyte-Specific Deletion of STAT3-A Murine Model of Heart Failure With Preserved Ejection Fraction.

ABSTRACT: Aims: There is a high incidence of heart failure with preserved ejection fraction (HFpEF), but the options of treatment are limited. A new animal model of HFpEF is urgently needed for in-depth research on HFpEF. Signal transducer and activator of transcription 3 (STAT3) may affect the passive stiffness of myocardium, which determines cardiac diastolic function. We hypothesized that cardiomyocyte-specific deletion of STAT3 increases cardiac passive stiffness, which results the murine features of HFpEF. Methods and Results: Cardiomyocyte-specific deletion of STAT3 (STAT3cKO) mice was generated by the Cre/FLOXp method. The STAT3cKO mice showed heavier cardiac fibrosis and cardiac hypertrophy comparing with wild-type (WT) mice. Furthermore, STAT3cKO mice showed increased serum brain natriuretic peptide (BNP) level, and growth stimulation expressed gene 2 (ST2) level. Other indicators reflecting cardiac passive stiffness and diastolic function, including end diastolic pressure volume relation, MV A value, MV E value, E/A and E/E' had different fold changes. All these changes were accompanied by decreasing levels of protein kinase G (PKG). Bioinformatic analysis of STAT3cKO mice hearts suggested cGMP-PKG signaling pathway might participate in the pathogenesis of HFpEF by means of adjusting different biological functions. Conclusions: Cardiomyocyte-specific deletion of STAT3 results in a murine HFpEF model which imitates the clinical characteristics partly by affecting cardiac PKG levels. Better understanding of the factors influencing HFpEF may finally provided innovative therapies.

SUBMITTER: Zhao W

PROVIDER: S-EPMC7750364 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effects of Cardiomyocyte-Specific Deletion of STAT3-A Murine Model of Heart Failure With Preserved Ejection Fraction.

Zhao Weilin W Chen Yanjia Y Yang Wenbo W Han Yanxin Y Wang Zhiyan Z Huang Fanyi F Qiu Zeping Z Yang Ke K Jin Wei W

Frontiers in cardiovascular medicine 20201207

<b>Aims:</b> There is a high incidence of heart failure with preserved ejection fraction (HFpEF), but the options of treatment are limited. A new animal model of HFpEF is urgently needed for in-depth research on HFpEF. Signal transducer and activator of transcription 3 (STAT3) may affect the passive stiffness of myocardium, which determines cardiac diastolic function. We hypothesized that cardiomyocyte-specific deletion of STAT3 increases cardiac passive stiffness, which results the murine featu ...[more]

PMID: 33365331

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Project description:BackgroundWhereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.ObjectivesThis study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.MethodsT-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions.ResultsHFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.ConclusionsAlthough t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

Project description:Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.

Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

Dataset Information

Effects of Cardiomyocyte-Specific Deletion of STAT3-A Murine Model of Heart Failure With Preserved Ejection Fraction.

Publications

Effects of Cardiomyocyte-Specific Deletion of STAT3-A Murine Model of Heart Failure With Preserved Ejection Fraction.

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