bims-hafaim 2023-06-18 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–06–18
six papers selected by
Kyle McCommis, Saint Louis University

Dapagliflozin and Physical and Social Activity Limitations in Heart Failure With Reduced Ejection Fraction.
Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.
Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart.
Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3-Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects.
Sex differences in cardiovascular outcomes of SGLT-2 inhibitors in heart failure randomized controlled trials: A systematic review and meta-analysis.
The triglyceride glucose index predicts short-term mortality in non-diabetic patients with acute heart failure.

JACC Heart Fail. 2023 Jun 02. pii: S2213-1779(23)00233-0. [Epub ahead of print]

Dapagliflozin and Physical and Social Activity Limitations in Heart Failure With Reduced Ejection Fraction.

Jawad H Butt, Kieran F Docherty, Mikhail N Kosiborod, Silvio E Inzucchi, Lars Køber, Anna Maria Langkilde, Felipe A Martinez, Olof Bengtsson, Piotr Ponikowski, Marc S Sabatine, Mikaela Sjöstrand, Scott Solomon, Pardeep S Jhund, John J V McMurray.

   BACKGROUND: Heart failure (HF) is associated with impaired physical function and poor quality of life and affects health status more profoundly than many other chronic diseases.
OBJECTIVES: The authors examined the effects of dapagliflozin on specific physical and social limitations as reported by patients in the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial.
METHODS: The effect of dapagliflozin on the change from baseline to 8 months in each of the individual physical and social activity limitation questions answered by patients completing the Kansas City Cardiomyopathy Questionnaire (KCCQ), and overall scores, were examined with mixed-effects models and responder analyses.
RESULTS: In total, 4,269 (90.0%) and 3,955 (83.4%) patients had complete data for both the physical and social activity limitation scores at baseline and 8 months, respectively. Compared with placebo, dapagliflozin significantly increased (improved) the mean KCCQ physical and social activity limitation scores at 8 months (placebo-corrected mean difference 1.94 [95% CI: 0.73-3.16] and 1.84 [95% CI: 0.43-3.25], respectively). Dapagliflozin also increased each of the individual components that comprise the physical and social activity limitations domains at 8 months, with the largest improvement seen in "hobbies or recreational activities" (placebo-corrected mean difference: 2.76 [95% CI: 1.06-4.46]) and "doing yardwork, housework, or carrying groceries" (placebo-corrected mean difference: 2.59 [95% CI: 0.76-4.42]). The proportion of patients with a 5-point improvement from baseline to 8 months in the KCCQ physical and social activity limitation scores was greater with dapagliflozin than with placebo (ORs: 1.23 [95% CI: 1.09-1.40] and 1.19 [95% CI: 1.05-1.35], respectively).
CONCLUSIONS: In patients with HFrEF, dapagliflozin, compared with placebo, improved physical and social activity limitations as measured by KCCQ. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure [DAPA-HF]; NCT03036124).

Keywords:  dapagliflozin; heart failure; quality of life; randomized trial

DOI:  https://doi.org/10.1016/j.jchf.2023.04.016
Acta Pharmacol Sin. 2023 Jun 16.

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Xin-Xin Zhu, Xia Wang, Shi-Yu Jiao, Ye Liu, Li Shi, Qing Xu, Jing-Jing Wang, Yun-Er Chen, Qi Zhang, Yan-Ting Song, Ming Wei, Bao-Qi Yu, Jens Fielitz, Frank J Gonzalez, Jie Du, Ai-Juan Qu.

  Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in Ppara△CM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

Keywords:  cardiac dysfunction; inflammation; mitochondrial dysfunction; mitophagy; peroxisome proliferator-activated receptor α; sepsis

DOI:  https://doi.org/10.1038/s41401-023-01107-5
iScience. 2023 Jun 16. 26(6): 106942

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart.

Manling Zhang, Ning Feng, Zishan Peng, Dharendra Thapa, Michael W Stoner, Janet R Manning, Charles F McTiernan, Xue Yang, Michael J Jurczak, Danielle Guimaraes, Krithika Rao, Sruti Shiva, Brett A Kaufman, Michael N Sack, Iain Scott.

  General control of amino acid synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC in vivo, which was linked to a reduction in mtDNA levels in vitro. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output.

Keywords:  Hematology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.106942
J Am Heart Assoc. 2023 Jun 10. e029849

Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3-Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects.

Nigopan Gopalasingam, Kristian Hylleberg Christensen, Kristoffer Berg Hansen, Roni Nielsen, Mogens Johannsen, Lars Christian Gormsen, Ebbe Boedtkjer, Rikke Nørregaard, Niels Møller, Henrik Wiggers.

  Background The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3-OHB activates the hydroxycarboxylic acid receptor 2 (HCA2), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3-OHB involved HCA2 activation and if the potent HCA2-stimulator niacin may increase CO. Methods and Results Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA2 downstream cyclooxygenase enzyme, followed by 3-OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3-OHB increased CO (2.3 L/min, P<0.01), stroke volume (19 mL, P<0.01), heart rate (10 bpm, P<0.01), and mixed venous saturation (5%, P<0.01) with preceding aspirin. 3-OHB did not change prostaglandin levels, neither in the ketone/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3-OHB-induced changes in CO (P=0.43). 3-OHB decreased free fatty acids by 58% (P=0.01). Niacin increased prostaglandin D2 levels by 330% (P<0.02) and reduced free fatty acids by 75% (P<0.01) but did not affect CO. Conclusions The acute increase in CO during 3-OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA2 receptor-mediated effects were not involved in the hemodynamic response to 3-OHB. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04703361.

Keywords:  HCA2 receptor; heart failure; hemodynamics; ketone body; metabolic

DOI:  https://doi.org/10.1161/JAHA.123.029849
Am Heart J Plus. 2023 Feb;pii: 100261. [Epub ahead of print]26

Sex differences in cardiovascular outcomes of SGLT-2 inhibitors in heart failure randomized controlled trials: A systematic review and meta-analysis.

Frederick Berro Rivera, Vincent Anthony S Tang, Deogracias Villa De Luna, Edgar V Lerma, Krishnaswami Vijayaraghavan, Amir Kazory, Nilay S Shah, Annabelle Santos Volgman.

   Background: In patients with heart failure (HF), randomized controlled trials (RCTs) of sodium-glucose transporter-2 inhibitors (SGLT-2is) have proven to be effective in decreasing the primary composite outcome of cardiovascular death and hospitalizations for HF. A recently published meta-analysis showed that the use of SGLT-2is among women with diabetes resulted in less reduction in primary composite outcomes compared with men. This study aims to explore potential sex differences in primary composite outcomes among patients with HF treated with SGLT-2is.
Methods: We systematically searched the medical database from 2017 to 2022 and retrieved all the RCTs using SGLT-2is with specified cardiovascular outcomes. We used the PRISMA (Preferred Reporting Items for a Review and Meta-analysis) method to screen for eligibility. We evaluated the quality of studies using the Cochrane Risk of Bias tool. We pooled the hazard ratio (HR) of the primary composite outcomes in both sexes, performed a meta-analysis, and calculated the odds ratio (OR) of the primary composite outcomes based on sex.
Results: We included 5 RCTs with a total number of 21,947 patients. Of these, 7837 (35.7 %) were females. Primary composite outcomes were significantly lower in males and females taking SGLT-2is compared to placebo (males - HR 0.77; 95 % CI 0.72 to 0.84; p = 0.00001; females - HR 0.75; 95 % CI 0.67 to 0.84; p = 0.00001). Pooled data from four of the RCTs (n = 20,725) revealed a greater occurrence of the primary composite outcomes in females compared with males (OR 1.32; 95 % CI 1.17 to 1.48; p = 0.0002).
Conclusion: SGLT-2is reduce the risk of primary composite outcomes in patients with HF, regardless of sex; however, the benefits were less pronounced in women. Further research needs to be done to better explain these observed differences in outcomes.

Keywords:  Cardiorenal; Cardiovascular outcomes; Heart failure; SGLT-2 inhibitors; Sex differences

DOI:  https://doi.org/10.1016/j.ahjo.2023.100261
Adv Clin Exp Med. 2023 Jun 16.

The triglyceride glucose index predicts short-term mortality in non-diabetic patients with acute heart failure.

Hongji Cheng, Weijun Huang, Xiaohui Huang, Wang Miao, Yuli Huang, Yunzhao Hu.

   BACKGROUND: The triglyceride glucose index (TyG) has previously been considered a reliable indicator of insulin resistance (IR) and an independent prognostic predictor in heart failure (HF).
OBJECTIVES: To clarify the association between the TyG and short-term death in non-diabetic patients admitted for acute heart failure (AHF).
MATERIAL AND METHODS: We examined 886 out of 1620 consecutive AHF patients who were admitted to Shunde Hospital, Southern Medical University, Foshan, China, from June 1, 2014, to June 1, 2022. The median of the patientsf TyG values was used to divide them into 2 groups. The following formula was used to calculate the TyG: ln [fasting triglycerides (mg/dL) ~ fasting glucose (mg/dL)/2]. The data on all-cause mortality of AHF patients during their hospital stay were collected. The 30-day Enhanced Feedback for Effective Cardiac Treatment (EFFECT) death risk score was used to assess the risk of death.
RESULTS: The TyG level was positively correlated with a poor AHF prognostic marker (N-terminal B-type natriuretic peptide (NT-proBNP)) (Ď = 0.207, p < 0.001) and negatively correlated with a protective marker (serum albumin) (Ď = .0.43, p < 0.001). Higher TyG values were associated with an elevated EFFECT score and hospital mortality (p < 0.001). According to multivariate logistic regression analysis, higher TyG levels raised the risk of death in hospital (odds ratio (OR) = 1.73; 95% confidence interval (95% CI): 1.03.3.27; p = 0.031) after adjusting for multiple variables, including age, EFFECT score and NT-proBNP. The TyG had a greater area under the receiver operating characteristic (ROC) curve (AUC: 0.688) for predicting hospital death compared to NT-proBNP (AUC: 0.506).
CONCLUSIONS: Our findings show that the TyG is associated with the short-term mortality rate of non-diabetic patients admitted to the hospital for AHF. The TyG testing could be a useful prognostic indicator for these patients.

Keywords:  acute heart failure; all-cause mortality; non-diabetics; prognostic value; triglyceride glucose index

DOI:  https://doi.org/10.17219/acem/166043