bims-hafaim 2021-07-18 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–07–18
six papers selected by
Kyle McCommis, Saint Louis University

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index.
SGLT-2 inhibitors in heart failure: An updated systematic review and meta-analysis of 13 randomized clinical trials including 14618 patients with heart failure.
Schisandra chinensis polysaccharides prevent cardiac hypertrophy by dissociating thioredoxin-interacting protein/thioredoxin-1 complex and inhibiting oxidative stress.
Gastrodin Exerts Cardioprotective Action via Inhibition of Insulin-Like Growth Factor Type 2/Insulin-Like Growth Factor Type 2 Receptor Expression in Cardiac Hypertrophy.
Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury.
Specific amino acid supplementation rescues the heart from lipid overload-induced insulin resistance and contractile dysfunction by targeting the endosomal mTOR-v-ATPase axis.

Eur J Heart Fail. 2021 Jul 16.

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index.

Carly Adamson, Pardeep S Jhund, Kieran F Docherty, Jan Bělohlávek, Chern-En Chiang, Mirta Diez, Jarosław Drożdż, Andrej Dukát, Jonathan Howlett, Charlotta E A Ljungman, Mark C Petrie, Morten Schou, Silvio E Inzucchi, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Piotr Ponikowski, Marc S Sabatine, Scott D Solomon, Olof Bengtsson, Anna Maria Langkilde, Daniel Lindholm, Mikaela Sjöstrand, John Jv McMurray.

   BACKGROUND: In heart failure with reduced ejection fraction (HFrEF), there is an "obesity paradox", where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a SGLT2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
METHODS AND RESULTS: BMI was examined using standard categories i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 Kg/m2 ); overweight (25.0-29.9 Kg/m2 ); obesity class I (30.0-34.9 Kg/m2 ); class II (35.0-39.9 Kg/m2 ) and class III (≥40 Kg/m2 ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% CI) for the primary outcome with obesity category 1, the lowest risk group, as reference was: under-/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI e.g., HR for primary outcome: under-/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00); P for interaction=0.79. The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) Kg (p<0.001).
CONCLUSION: We confirmed an "obesity survival paradox" in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT03036124 (https://clinicaltrials.gov/ct2/show/NCT03036124).

Keywords:  Heart failure; SGLT2 inhibitor; adiposity; body-mass index; dapagliflozin; obesity

DOI:  https://doi.org/10.1002/ejhf.2308
J Cardiovasc Pharmacol. 2021 Jul 09.

SGLT-2 inhibitors in heart failure: An updated systematic review and meta-analysis of 13 randomized clinical trials including 14618 patients with heart failure.

Dhan Bahadur Shrestha, Pravash Budhathoki, Yub Raj Sedhai, Parag Karki, Suja Gurung, Sumit Raut, Juan Ignacio Damonte, Marco Giuseppe Del Buono, Mohammad Khalid Mojadidi, Islam Y Elgendy, Toralben Patel, Nimesh K Patel.

ABSTRACT: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors showed benefit in patients with heart failure. In this updated meta-analysis, we evaluate the therapeutic efficacy and safety of SGLT-2 inhibitors in heart failure patients. Different electronic databases were searched to find relevant articles. RevMan 5.4 was used for pooling data using a random/fixed-effect model, complemented by several sensitivity and subgroup analyses. A total of 13 randomized clinical trials including 14618 patients with heart failure were included in analysis among 6797 studies screened. The overall mortality rate was 12.45% in the SGLT-2 group and 14.67% among the placebo group with 18% lower odds of overall mortality (OR, 0.82; CI, 0.75-0.91) in the SGLT-2 group. Odds of cardiovascular mortality was 18% lower (OR, 0.82; CI, 0.74-0.92) in the SGLT-2 group. The odds of hospitalization for heart failure (HHF) was 38% lower during the study period (OR, 0.62; CI, 0.56-0.68) in the SGLT-2 group. Additionally, a benefit was seen for composite outcome HHF or mortality and considering subgrouping based on diabetes status, gender, and age groups. Though genital infection was significantly higher in the SGLT-2 group, the occurrence of severe adverse events, hypoglycemia, urinary tract infection, bone fracture, volume depletion, and other renal events did not differ between the two groups. Thus, SGLT-2 inhibitors improved cardiovascular outcomes among patients with heart failure with no significant difference in adverse events. Clinical benefit was comparable in diabetic and non-diabetic individuals, males and females, people in younger and older age groups with underlying heart failure, and HF with reduced ejection fraction.

DOI: https://doi.org/10.1097/FJC.0000000000001099
Biomed Pharmacother. 2021 Jul;pii: S0753-3322(21)00470-4. [Epub ahead of print]139 111688

Schisandra chinensis polysaccharides prevent cardiac hypertrophy by dissociating thioredoxin-interacting protein/thioredoxin-1 complex and inhibiting oxidative stress.

Xiaowen Shi, Bingjiang Han, Bin Zhang, Zhenliang Chu, Xueping Zhang, Qin Lu, Jibo Han.

  Cardiac hypertrophy is a current, major, global health challenge. Oxidative stress is an important mechanism that contributes to the pathogenesis of cardiac hypertrophy. Schisandra chinensis polysaccharides (SCP), the primary active constituent in Schisandra chinensis, have antioxidative properties. Here, we investigated the role played by SCP in a cardiac hypertrophy model mouse induced by transverse aortic constriction (TAC). We found that SCP treatment improved cardiac function by inhibiting myocardial hypertrophy and oxidative stress. Angiotensin II was used to induce cardiomyocyte hypertrophy and oxidative stress in vitro. We discovered that the antioxidant effects of SCP were mediated through the regulation of the thioredoxin-interacting protein (TXNIP)/Thioredoxin-1 (Trx-1) pathway. Using molecular docking, we found that SCP binds to Arg207, Ser169, Lys166, Lys286 and Ser285 in TXNIP through hydrogen bonds. TXNIP is an endogenous inhibitor of Trx-1, and the binding SCP with TXNIP may restrict or interfere with the binding between TXNIP and Trx-1, resulting in Trx-1 activation. In conclusion, our findings demonstrated that the potential use of SCP as a TXNIP inhibitor to attenuate oxidative stress, suggesting that TXNIP might represent a potential therapeutic target for the treatment of cardiac hypertrophy.

Keywords:  Angiotensin II; Oxidative stress; Schisandra chinensis polysaccharides; TXNIP; Transverse aortic constriction; Trx-1

DOI:  https://doi.org/10.1016/j.biopha.2021.111688
ACS Omega. 2021 Jul 06. 6(26): 16763-16774

Gastrodin Exerts Cardioprotective Action via Inhibition of Insulin-Like Growth Factor Type 2/Insulin-Like Growth Factor Type 2 Receptor Expression in Cardiac Hypertrophy.

Jun Lu, Xin Ma, Wen-Cong Gao, Xin Zhang, Yuanling Fu, Qian Liu, Lixiang Tian, Xiao-Dan Qin, Weimin Yang, Hong-Yi Zheng, Chang-Bo Zheng.

Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS's inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 (Igf2) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy.

DOI: https://doi.org/10.1021/acsomega.1c00797
Front Physiol. 2021 ;12 653349

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury.

Xiao-Hong Wei, Xiao Guo, Chun-Shui Pan, Huan Li, Yuan-Chen Cui, Li Yan, Jing-Yu Fan, Jing-Na Deng, Bai-He Hu, Xin Chang, Shu-Ya He, Lu-Lu Yan, Kai Sun, Chuan-She Wang, Jing-Yan Han.

   Background: T89, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T89 on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury.
Methods: Male Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T89 at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed.
Results: T89 obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T89 relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T89 inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T89 significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T89 in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641.
Conclusion: T89 reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T89 is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

Keywords:  cardiac hypertrophy; energy metabolism; fatty acid oxidation; glycolysis; mitochondrial electron transport chain

DOI:  https://doi.org/10.3389/fphys.2021.653349
Mol Metab. 2021 Jul 12. pii: S2212-8778(21)00138-1. [Epub ahead of print] 101293

Specific amino acid supplementation rescues the heart from lipid overload-induced insulin resistance and contractile dysfunction by targeting the endosomal mTOR-v-ATPase axis.

Shujin Wang, Francesco Schianchi, Dietbert Neumann, Li-Yen Wong, Aomin Sun, Frans A van Nieuwenhoven, Maurice P Zeegers, Agnieszka Strzelecka, Umare Col, Jan F C Glatz, Miranda Nabben, Joost J F P Luiken.

   OBJECTIVE: The diabetic heart is characterized by extensive lipid accumulation which often leads to cardiac contractile dysfunction. The underlying mechanism involves a pivotal role for vacuolar-type H+-ATPase (v-ATPase, functioning as endosomal/lysosomal proton pump). Specifically, lipid oversupply to the heart causes disassembly of v-ATPase and endosomal de-acidification. Endosomes are storage compartments for lipid transporter CD36. However, upon endosomal de-acidification, CD36 is expelled to translocate to the sarcolemma, thereby inducing myocardial lipid accumulation, insulin resistance and contractile dysfunction. Hence, v-ATPase assembly may be a suitable target for ameliorating diabetic cardiomyopathy. Another function of v-ATPase involves binding of anabolic master-regulator mTORC1 to endosomes, a prerequisite for activation of mTORC1 by amino acids (AAs). We examined whether the relationship between v-ATPase and mTORC1 also operates reciprocally, specifically whether AA induce v-ATPase reassembly in an mTORC1-dependent manner to prevent excess lipids from entering and damaging the heart.
METHODS: Lipid overexposed rodent/human cardiomyocytes and high-fat diet-fed rats were treated with a specific cocktail of AAs (lysine/leucine/arginine). Then, v-ATPase assembly status/activity, cell surface CD36 content, myocellular lipid uptake/accumulation, insulin sensitivity and contractile function were measured. To elucidate underlying mechanisms, specific gene knockdown was employed, followed by subcellular fractionation and co-immunoprecipitation.
RESULTS: In lipid-overexposed cardiomyocytes, lysine/leucine/arginine re-internalized CD36 to the endosomes, prevented/reversed lipid accumulation, and preserved/restored insulin sensitivity and contractile function. These beneficial AA actions required the mTORC1-v-ATPase axis, adaptor protein Ragulator and endosomal/lysosomal AA transporter SLC38A9, indicating an endosome-centric inside-out AA sensing mechanism. In high-fat diet-fed rats, lysine/leucine/arginine had similar beneficial actions at the myocellular level as in vitro in lipid-overexposed cardiomyocytes, and partially reversed cardiac hypertrophy.
CONCLUSION: Specific AAs acting via v-ATPase re-assembly reduce cardiac lipid uptake raising the possibility for treatment in situations of lipid overload and associated insulin resistance.

Keywords:  Contractile function; Diabetic heart; Endosomal CD36; Lipid-induced insulin resistance; Vacuolar H(+)-ATPase; mTORC1

DOI:  https://doi.org/10.1016/j.molmet.2021.101293