bims-hafaim 2022-12-04 papers

Issue of 2022–12–04
five papers selected by
Kyle McCommis, Saint Louis University

FASEB J. 2022 Dec;36(12): e22672

Activation of FMS-like tyrosine kinase 3 protects against isoprenaline-induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics.

Xixi Jiang, Kaina Zhang, Chenying Gao, Wenzhuo Ma, Mengqing Liu, Xinyu Guo, Gaowa Bao, Bing Han, Hao Hu, Zhenghang Zhao.

FMS-like receptor tyrosine kinase 3 (Flt3) expression was reported to increase in the heart in response to pathological stress, but the role of Flt3 activation and its underlying mechanisms remain poorly elucidated. This study was designed to investigate the role of Flt3 activation in sympathetic hyperactivity-induced cardiac hypertrophy and its mechanisms through autophagy and mitochondrial dynamics. In vivo, cardiac hypertrophy was established by subcutaneous injection of isoprenaline (6 mg/kg·day) in C57BL/6 mice for 7 consecutive days. The Flt3-ligand intervention was launched 2 h prior to isoprenaline each day. In vitro, experiments of cardiomyocyte hypertrophy, autophagy, and mitochondrial dynamics were performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that the expression level of Flt3 protein was significantly increased in the hypertrophic myocardium provoked by isoprenaline administration. Flt3-ligand intervention alleviated isoprenaline-induced cardiac oxidative stress, hypertrophy, fibrosis, and contractile dysfunction. Isoprenaline stimulation impaired autophagic flux in hypertrophic mouse hearts, supported by the accumulation of LC3II and P62 proteins, while Flt3-ligand restored the impairment of autophagic flux. Flt3 activation normalized the imbalance of mitochondrial fission and fusion in the hearts of mice evoked by isoprenaline as evidenced by the neutralization of elevated mitochondrial fission markers and reduced mitochondrial fusion markers. In NRCMs, Flt3-ligand treatment attenuated isoprenaline-stimulated hypertrophy, which was abolished by a Flt3-specific blocker AC220. Activating Flt3 reversed isoprenaline-induced autophagosome accumulation and impairment of autophagic flux probably by enhancing SIRT1 expression and consequently TFEB nuclear translocation. Flt3 activation improved the imbalance of mitochondrial dynamics induced by isoprenaline in NRCMs through the SIRT1/P53 pathway. Activation of Flt3 mitigated ISO-stimulated hypertrophy probably involves the restoration of autophagic flux and balance of mitochondrial dynamics. Therefore, activation of Flt3 attenuates isoprenaline-induced cardiac hypertrophy in vivo and in vitro, the potential mechanism probably attributes to SIRT1/TFEB-mediated autophagy promotion and SIRT1/P53-mediated mitochondrial dynamics balance. These findings suggest that activation of Flt3 may be a novel target for protection against cardiac remodeling and heart failure during sympathetic hyperactivity.

Keywords: FMS-like receptor tyrosine kinase 3; autophagy; cardiac hypertrophy; isoprenaline; mitochondrial dynamics

DOI: https://doi.org/10.1096/fj.202200419RR

Geroscience. 2022 Dec 03.

The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.

Ping Li, Maria F Newhardt, Satoshi Matsuzaki, Craig Eyster, Atul Pranay, Frederick F Peelor, Albert Batushansky, Caroline Kinter, Kumar Subramani, Sandeep Subrahmanian, Jasimuddin Ahamed, Pengchun Yu, Michael Kinter, Benjamin F Miller, Kenneth M Humphries.

SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype.

Keywords: Flexibility; Mitochondria; Proteostasis

DOI: https://doi.org/10.1007/s11357-022-00695-0

Cardiovasc Diabetol. 2022 Nov 28. 21(1): 260

Association between triglyceride glucose index and worsening heart failure in significant secondary mitral regurgitation following percutaneous coronary intervention.

Haozhang Huang, Qiang Li, Jiulin Liu, Linfang Qiao, Shiqun Chen, Wenguang Lai, Yu Kang, Xiaozhao Lu, Yang Zhou, Yibo He, Jiyan Chen, Ning Tan, Jin Liu, Yong Liu.

BACKGROUND: The triglyceride glucose (TyG) index is an alternative to insulin resistance (IR) as an early indicator of worsening heart failure (HF). Patients with secondary mitral regurgitation (sMR) often experience progressive deterioration of cardiac function. This study aimed to investigate the relationship between the TyG index and worsening of HF in significant sMR (grade ≥ 2) following percutaneous coronary intervention (PCI).
METHODS: This study enrolled participants with significant sMR following PCI from a multicenter cohort study. The patients were divided into the following 3 groups according to tertiles of TyG index: T1, TyG ≤ 8.51; T2, TyG > 8.51 to ≤ 8.98; and T3, TyG > 8.98. The main clinical outcome was worsening HF including unplanned rehospitalization or unscheduled physician office/emergency department visit due to HF and unplanned mitral valve surgery.
RESULTS: A total of 922 patients (mean ± SD age, 64.1 ± 11.0 years; 79.6% male) were enrolled. The incidence of worsening HF was 15.5% in T1, 15.7% in T2, and 26.4% in T3. In the multivariable model, the highest TyG tertile (T3 group) was more strongly correlated with worsening HF than the lowest tertile (T1 group) after adjusting for confounders (adjusted hazard ratio, 2.44; 95% confidence interval, 1.59-3.72; P < 0.001). The addition of TyG to risk factors such as N-terminal pro brain natriuretic peptide and clinical models improved the predictive ability of TyG for worsening HF.
CONCLUSIONS: Elevated preprocedural TyG index is a significant and independent risk factor for worsening HF in sMR following PCI that can be used for risk stratification.

Keywords: Heart failure; Percutaneous coronary intervention; Secondary mitral regurgitation; Triglyceride glucose index

DOI: https://doi.org/10.1186/s12933-022-01680-9

Am J Cardiol. 2022 Nov 12. pii: S0002-9149(22)01114-6. [Epub ahead of print]187 93-99

Meta-Analysis on the Safety and Efficacy of Sodium Glucose Cotransporters 2 Inhibitors in Patients With Heart Failure With and Without Diabetes.

Mohammed Tarek Hasan, Ahmed K Awad, Mohamed Shih, Amir N Attia, Heba Aboeldahab, Mohamed Bendary, Ahmed Bendary.

Heart failure (HF) is the most common cardiovascular cause of hospitalization in patients over 60 years, affecting about 64.3 million patients worldwide. Few studies have investigated the role of sodium glucose cotransporter inhibitors (SGLT2Is) in patients with HF without and without diabetes. Thus, we conducted our meta-analysis to further investigate the role of SGLT2I role in patients with HF without and without diabetes. PubMed, Scopus, Web of Science, and Embase were searched. All clinical trials that compared the effect of SGLT2Is versus placebo on patients with HF were included. Dichotomous data were extracted, pooled as risk ratio (RR) with 95% confidence interval (CI), and analyzed using RevMan version 5.3 for windows using the Mantel-Haenszel method. A total of 13 randomized clinical trials were included for analysis, with a total number of 75,287 patients. SGLT2Is significantly lowered the risk of hospitalization for HF in patients with (RR = 0.68, 95% CI 0.63 to 0.74) and without diabetes (RR = 0.75, 95% CI 0.62 to 0.89). Furthermore, they lowered the mortality risk in both patients with diabetes with statistical significance (RR = 0.87, 95% CI 0.77 to 0.99), yet without statistical significance in patients without diabetes (RR = 0.93, 95% CI 0.70 to 1.23). Further analyses for serious adverse events were conducted, and SGLT2I showed a significant lower risk in patients with diabetes (RR = 0.94, 95% CI 0.90 to 0.98) and without diabetes (RR = 0.72, 95% CI 0.38 to 1.39). in patients with diabetes, SGLT2Is significantly reduced cardiovascular mortality, HHF, and serious adverse events. However, in patients without, despite showing a significant reduction in HHF, SGLT2I reduced cardiovascular mortality or serious adverse events but without statistical significance.

DOI: https://doi.org/10.1016/j.amjcard.2022.10.027

Int J Cardiol. 2022 Nov 28. pii: S0167-5273(22)01739-9. [Epub ahead of print]

Efficacy of SGLT2 inhibitors in patients with heart failure: An overview of systematic reviews.

Andrew Sephien, Mike Ghobrial, Tea Reljic, Xavier Prida, Nishant Nerella, Ambuj Kumar.

AIMS: Sodium-Glucose transporter 2 inhibitors (SGLT2i) have been shown to have benefit in patients with heart failure (HF). Multiple systematic reviews and meta-analyses (SR and MA) of randomized control trials (RCTs) comparing SGLT2i to placebo have been performed. However, there is uncertainty in the quality of the evidence and associated efficacy. We performed an overview of SR and MA of RCTs to summarize the evidence related to the efficacy of SGLT2i for the management of HF.
METHODS AND RESULTS: A comprehensive search of three databases (the Cochrane Library, EMBASE, and PubMed) was conducted until February 21, 2021. All SRs and MA of RCTs evaluating the efficacy of SGLT2i in patients with HF were eligible for inclusion. The primary outcome was all-cause mortality. Methodological quality was evaluated using the AMSTAR-2 assessment tool. The overall quality of evidence was summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. The initial search yielded 3431 references, of which, eight SRs and MA met the inclusion criteria. The methodological quality ranged from critically low to high. The overall quality of evidence ranged from very low to moderate. Most of the SRs and MA showed benefits in all-cause mortality, HF-related hospitalizations, and change in Kansas City Questionnaire Score.
CONCLUSIONS: SGLT2i are possibly beneficial in patients with HF, however, none of the SRs and MA compared the efficacy between different types of SGLT2i. Furthermore, this paper emphasizes the need for consistent reproducible conduct and reporting of SRs to generate high-quality evidence and facilitate clinical decision-making.

Keywords: Evidence appraisal; Heart failure related hospitalization; KCCQ score; Kidney outcomes

DOI: https://doi.org/10.1016/j.ijcard.2022.11.052