TNFα-antagonist neither improve cardiac remodelling or cardiac function at early stage of heart failure in diabetic rats

Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet. NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals.

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Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats

Pharmaceutical Biology ◽

10.1080/13880209.2020.1761403 ◽

2020 ◽

Vol 58 (1) ◽

pp. 417-426

Author(s):

Xutao Sun ◽

Guozhen Chen ◽

Ying Xie ◽

Deyou Jiang ◽

Jieru Han ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Remodelling

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The Effects of Ivabradine on Cardiac Function after Myocardial Infarction are Weaker in Diabetic Rats

Cellular Physiology and Biochemistry ◽

10.1159/000447901 ◽

2016 ◽

Vol 39 (5) ◽

pp. 2055-2064 ◽

Cited By ~ 1

Author(s):

Xue Cao ◽

Zhijun Sun ◽

Boya Zhang ◽

Xueqi Li ◽

Hongyuan Xia

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Left Ventricular Function ◽

Ventricular Function ◽

Sympathetic Nerves ◽

Diabetic Rats ◽

Left Ventricular ◽

Plasma Norepinephrine ◽

Major Pathway ◽

Systemic Injection

Background/Aims: Plasma norepinephrine (NE) and brain natriuretic peptide (BNP, termed BNP-45 in rats) are considered as essential neurohormones indicating heart failure progression. The purposes of this study were to examine the effects of ivabradine (IBD) on cardiac function and plasma NE and BNP-45 after chronic ischemic heart failure (CHF) in non-diabetic rats and diabetic rats. We further determined if sympathetic NE uptake-1 (a major pathway to metabolize NE) mechanism is responsible for the role played by IBD. Methods: We ligated rat's coronary artery to induce CHF; and injected streptozotocin (STZ) to induce diabetic hyperglycemia. Echocardiography was employed to determine cardiac function. We used ELISA to examine plasma NE and BNP-45; and Western Blot analysis to examine the protein levels of NE uptake-1 in sympathetic nerves. Results: CHF increased the levels of NE and BNP-45 in non-STZ rats and STZ rats. Systemic injection of IBD significantly attenuated the augmented NE and BNP-45 and impaired left ventricular function induced by CHF in those rats. This effect appeared to be less in STZ rats. A liner relation was observed between the NE/BNP-45 levels and left ventricular function after administration of IBD. Also, IBD was observed to have a recovery effect on the downregulated NE uptake-1 evoked by CHF, but to a smaller degree in STZ rats. Conclusion: Our data revealed specific signaling mechanisms by which IBD improves the cardiac function as IBD alleviates impaired NE uptake-1and thereby decreases heightened NE and BNP-45 induced by CHF. Our data also demonstrated that the effects of IBD are weakened after diabetic hyperglycemia likely due to worsen NE uptake-1 pathway. Thus, targeting sympathetic NE uptake-1 signaling molecules has clinical implications for treatment and management of CHF in diabetes. Our data were also to shed light on strategies for application of this drug because NE and BNP play an important role in regulation of progression and prognosis of CHF, and in particular, because IBD affects NE uptake-1 pathway in hyperglycemic animals to a less degree.

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STING protects against cardiac dysfunction and remodelling by blocking autophagy

10.21203/rs.3.rs-154343/v2 ◽

2021 ◽

Author(s):

Rui Xiong ◽

Ning Li ◽

Wei Wang ◽

Bo Wang ◽

Wenyang Jiang ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Protein Expression ◽

Cardiac Fibroblasts ◽

Cardiac Remodelling ◽

Ang Ii ◽

Mrna And Protein Expression

Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

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Noninvasive Hemodynamic Profiles during Hemodialysis in Patients with and without Heart Failure

Cardiorenal Medicine ◽

10.1159/000506470 ◽

2020 ◽

Vol 10 (4) ◽

pp. 243-256

Author(s):

Ying-Kuang Lin ◽

Chih-Chin Kao ◽

Chi-Ho Tseng ◽

Ching-En Hsu ◽

Yi-Je Lin ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Mixed Model ◽

Cox Regression ◽

Early Stage ◽

Resistance Index ◽

Hemodynamic Parameters ◽

Mixed Model Analysis ◽

Deviation Coefficient ◽

Two Stages

Background: Although the dynamics of blood pressure (BP) during dialysis provide information related to the control system, the prognosis and relationships between temporal changes in intradialytic hemodynamic regulation, BP, and decreased cardiac function remain largely unclear. Methods: Hemodynamic parameters, including heart rate (HR), stroke volume (SV), cardiac index, and systemic vascular resistance index, were recorded using a noninvasive hemodynamic device on a beat-by-beat basis in 40 patients on dialysis who were divided into three groups, i.e., those with and without BP lability and those with heart failure (HF). Statistical measurements, including mean, standard deviation, coefficient of variation (CV), and index of nonrandomness of each hemodynamic parameter were derived from the three different phases divided equally during dialysis and compared using 3×3 two-way mixed-model analysis of variance to determine the effects of the different stages of hemodialysis (HD), cardiac function, and intradialytic changes in BP on the hemodynamic parameters. In addition, multivariate Cox regression was performed to determine the association between the changes in the derived parameters and BP lability. Results: The average SV tended to decrease during HD in all groups (p = 0.041). A significant decrease was observed in the CV of SV between the first two stages of HD in patients with labile BP and HF when compared to those without labile BP (p = 0.037). Significant interactions between group and stage of the index of nonrandomness for HR were also noted; this index was significantly higher in patients without labile BP than in those with labile BP or HF (p = 0.048). A higher difference between the early and middle stages of HD for nonrandomness indexes of HR was an independent predictor of reduced BP lability during HD (HR = 0.844, 95% confidence interval 0.722–0.987, p = 0.034). Conclusions: Increases in the CV of SV and the index of nonrandomness for HR during early-stage HD in response to decreased SV may be associated with better BP control during HD. This finding suggests that patients with more structurally meaningful hemodynamic control have a more favorable cardiovascular outcome.

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Dapagliflozin Protects Doxorubicin-induced Cardiotoxicity in Breast Cancer Patients With Diabetes via Suppressing ER Stress

10.21203/rs.3.rs-51771/v1 ◽

2020 ◽

Author(s):

Wei-Ting Chang ◽

Yu-Wen Lin ◽

Chung-Han Ho ◽

Zhih-Cherng Chen ◽

Ping-Yen Liu ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Er Stress ◽

Cancer Patients ◽

High Glucose ◽

Cardiac Fibrosis ◽

Diabetic Rats ◽

Major Adverse Cardiovascular Events ◽

Breast Cancer Patients ◽

Patients With Diabetes

Abstract Background: Cancer patients with diabetes have an increasing risk of Dox-induced cardiotoxicity. Despite previous studies reporting benefits of dapagliflozin on the cardiovascular system, it remains unknown whether dapagliflozin has a cardioprotective effect in cancer patients with diabetes receiving Dox therapy. The purpose of this study was to investigate the potential of dapagliflozin for preventing doxorubicin (Dox)-induced cardiotoxicity.Methods: Using Taiwan National Health Insurance Database, the incidence of heart failure of cancer patients with or without diabetes was investigated. Streptozotocin (STZ)-induced diabetic rats were pretreated with oral dapagliflozin (10 mg/kg/day) for 6 weeks followed by Dox (5 mg/kg/week) for 4 weeks via intraperitoneal injection. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes cultured in high glucose (30 mM) were treated with dapagliflozin at 10 M and subsequently exposed to Dox at 1 M. Apoptosis and endoplasmic reticulum (ER) stress-related protein expression were measured by immunohistochemistry and Western blotting.Results: Among the studied patients, those with diabetes had a higher risk of major adverse cardiovascular events including the development of heart failure. In diabetic rats, dapagliflozin reduced cardiac fibrosis and significantly improved cardiac function. Dapagliflozin effectively inhibited Dox-induced apoptosis and reactive oxygen species in cardiomyocytes under high glucose. Mechanistically, we showed that dapagliflozin decreased the cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2. Dapagliflozin also significantly reduced ER stress-associated proteins including GRP78, PERK, eIF-2, ATF-4, and CHOP. Conclusions: Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes via inhibiting ER stress. These results indicate that dapagliflozin could be useful for preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.

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STING Protects Against Cardiac Dysfunction and Remodelling by Blocking Autophagy

10.21203/rs.3.rs-154343/v1 ◽

2021 ◽

Author(s):

Rui Xiong ◽

Ning Li ◽

Bohao Liu ◽

Ruyuan He ◽

Wenyang Jiang ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Protein Expression ◽

Cardiac Fibroblasts ◽

Cardiac Remodelling ◽

Ang Ii ◽

Mrna And Protein Expression

Abstract Background: Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods: In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway.Results: In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757.Conclusion: STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

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PET Tracers for Imaging Cardiac Function in Cardio-oncology

Current Cardiology Reports ◽

10.1007/s11886-022-01641-4 ◽

2022 ◽

Author(s):

James M. Kelly ◽

John W. Babich

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Early Stage ◽

Systolic Dysfunction ◽

Healing Process ◽

Metabolic Imaging ◽

Oncology Research ◽

Positron Emission ◽

Highly Sensitive ◽

Gallium 68

Abstract Purpose of Review Successful treatment of cancer can be hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the injury to the heart is detected before the onset to irreversible cardiac impairment. The gold standard for cardiac imaging in cardio-oncology is echocardiography. Despite improvements in the application of this modality, it is not typically sensitive to sub-clinical or early-stage dysfunction. We identify in this review some emerging tracers for detecting incipient cardiotoxicity by positron emission tomography (PET). Recent Findings Vectors labeled with positron-emitting radionuclides (e.g., carbon-11, fluorine-18, gallium-68) are now available to study cardiac function, metabolism, and tissue repair in preclinical models. Many of these probes are highly sensitive to early damage, thereby potentially addressing the limitations of current imaging approaches, and show promise in preliminary clinical evaluations. Summary The overlapping pathophysiology between cardiotoxicity and heart failure significantly expands the number of imaging tools available to cardio-oncology. This is highlighted by the emergence of radiolabeled probes targeting fibroblast activation protein (FAP) for sensitive detection of dysregulated healing process that underpins adverse cardiac remodeling. The growth of PET scanner technology also creates an opportunity for a renaissance in metabolic imaging in cardio-oncology research.

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