bims-hafaim 2022-03-27 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–03–27
eightteen papers selected by
Kyle McCommis, Saint Louis University

2-Arachidonoylglycerol Attenuates Myocardial Fibrosis in Diabetic Mice Via the TGF-β1/Smad Pathway.
Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases.
Chronic Lactate Exposure Decreases Mitochondrial Function by Inhibition of Fatty Acid Uptake and Cardiolipin Alterations in Neonatal Rat Cardiomyocytes.
Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts.
Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated With Diabetic Cardiomyopathy.
Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway.
Sodium-glucose cotransporter-2 inhibitors in heart failure: an updated meta-analysis.
Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects.
Sodium Glucose Cotransporter Type 2 Inhibitors Improve Cardiorenal Outcome of Patients With Coronary Artery Disease: A Meta-Analysis.
Metabolic Transformation of Fat in Obesity Determines the Inflammation Resolving Capacity of Splenocardiac and Cardiorenal Networks in Heart Failure.
Whole Blood Metabolite Profiles Reflect Changes in Energy Metabolism in Heart Failure.
Heart Failure and Drug Therapies: A Metabolic Review.
SGLT2 Inhibitors in Type 2 Diabetes Mellitus and Heart Failure-A Concise Review.
Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors and Combined SGLT1/2 Inhibitors on Cardiovascular, Metabolic, Renal, and Safety Outcomes in Patients with Diabetes: A Network Meta-Analysis of 111 Randomized Controlled Trials.
Mineralocorticoid Receptor Antagonists and Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction.
Long-chain omega-3 polyunsaturated fatty acids and the risk of heart failure.
AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium.
Beneficial cardiovascular and remodeling effects of SGLT2 inhibitors: pathophysiologic mechanisms.

Cardiovasc Drugs Ther. 2022 Mar 19.

2-Arachidonoylglycerol Attenuates Myocardial Fibrosis in Diabetic Mice Via the TGF-β1/Smad Pathway.

Zhengjie Chen, Liangyu Zheng, Gang Chen.

   PURPOSE: Diabetic cardiomyopathy (DM) is the cause of late cardiac dysfunction in diabetic patients. Myocardial fibrosis is the main pathological mechanism, and it is associated with transforming growth factor-β1(TGF-β1) expression up-regulation. 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that can effectively improve myocardial cell energy metabolism and cardiac function. Here, we evaluated the protective effect of 2-AG on diabetic cardiomyopathy.
METHODS: Male C57BL/6 mice were injected with 2-AG intraperitoneally for 4 weeks (10 micro g/kg/day) after 12 weeks of diabetic modeling. After 4 weeks, heart function was evaluated by echocardiography. Heart structure was assessed by hematoxylin and eosin staining. Cardiac fibrosis was analyzed using immunohistochemistry, Sirius red stain, and western blot.
RESULTS: After modeling in diabetic mice, cardiac ultrasonography showed decreased cardiac function and pathological findings showed myocardial fibrosis. 2-AG could effectively inhibit the up-regulation of TGF-β1 and Smad2/3, reduce myocardial fibrosis, and ultimately improve cardiac function in diabetic mice.
CONCLUSION: 2-AG reduces cardiac fibrosis via the TGF-β1/Smad2/3 pathway and is a potential pathway for the treatment of cardiac dysfunction in diabetic mice.

Keywords:  2-Arachidonoylglycerol; Diabetic cardiomyopathy; Myocardial Fibrosis; TGF-β1

DOI:  https://doi.org/10.1007/s10557-021-07307-7
Metabolites. 2022 Feb 25. pii: 210. [Epub ahead of print]12(3):

Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases.

Hidenori Moriyama, Jin Endo, Hidehiko Ikura, Hiroki Kitakata, Mizuki Momoi, Yoshiki Shinya, Seien Ko, Genki Ichihara, Takahiro Hiraide, Kohsuke Shirakawa, Atsushi Anzai, Yoshinori Katsumata, Motoaki Sano.

  Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, but when in excess, they exhibit cardio-lipotoxicity that causes cardiac dysfunction or heart failure with preserved ejection fraction. FAs also play a role as part of phospholipids that compose cell membranes, and the changes in mitochondrial phospholipid cardiolipin and the FA composition of plasma membrane phospholipids affect cardiomyocyte survival. In addition, FA metabolites exert a wide variety of bioactivities in the heart as lipid mediators. Recent advances in measurement using mass spectrometry have identified trace amounts of n-3 polyunsaturated fatty acids (PUFAs)-derived bioactive metabolites associated with heart disease. n-3 PUFAs have a variety of cardioprotective effects and have been shown in clinical trials to be effective in cardiovascular diseases, including heart failure. This review outlines the contributions of FAs to cardiac function and pathogenesis of heart diseases from the perspective of three major roles and proposes therapeutic applications and new medical perspectives of FAs represented by n-3 PUFAs.

Keywords:  cardiolipin; fatty acid; heart failure; lipid droplet; lipid dynamics; lipid mediator; lipotoxicity; n-3 PUFA

DOI:  https://doi.org/10.3390/metabo12030210
Front Nutr. 2022 ;9 809485

Chronic Lactate Exposure Decreases Mitochondrial Function by Inhibition of Fatty Acid Uptake and Cardiolipin Alterations in Neonatal Rat Cardiomyocytes.

Iñigo San-Millan, Genevieve C Sparagna, Hailey L Chapman, Valerie L Warkins, Kathryn C Chatfield, Sydney R Shuff, Janel L Martinez, George A Brooks.

   Introduction: Lactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism. Levels of lactate are increased chronically in diseases associated with cardiometabolic disease such as heart failure, type 2 diabetes, and cancer. Using neonatal ventricular myocytes, we tested the hypothesis that chronic lactate exposure could decrease the activity of cardiac mitochondria that could lead to metabolic inflexibility in the heart and other tissues.
Methods: Neonatal rat ventricular myocytes (NRVMs) were treated for 48 h with 5, 10, or 20 mM lactate and CPT I and II activities were tested using radiolabelled assays. The molecular species profile of the major mitochondrial phospholipid, cardiolipin, was determined using electrospray ionization mass spectrometry along with reactive oxygen species (ROS) levels measured by Amplex Red and mitochondrial oxygen consumption using the Seahorse analyzer.
Results: CPT I activity trended downward (p = 0.07) and CPT II activity significantly decreased with lactate exposure (p < 0.001). Cardiolipin molecular species containing four 18 carbon chains (72 carbons total) increased with lactate exposure, but species of other sizes decreased significantly. Furthermore, ROS production was strongly enhanced with lactate (p < 0.001) and mitochondrial ATP production and maximal respiration were both significantly down regulated with lactate exposure (p < 0.05 and p < 0.01 respectively).
Conclusions: Chronic lactate exposure in cardiomyocytes leads to a decrease in fatty acid transport, alterations of cardiolipin remodeling, increases in ROS production and decreases in mitochondrial oxygen consumption that could have implications for both metabolic health and flexibility. The possibility that both intra-, or extracellular lactate levels play roles in cardiometabolic disease, heart failure, and other forms of metabolic inflexibility needs to be assessed in vivo.

Keywords:  fatty acid metabolism; fatty acids transport; lactate; metabolic flexibility; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fnut.2022.809485
Front Aging. 2021 ;pii: 681513. [Epub ahead of print]2

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts.

Yuxin Chu, Cheng Zhang, Min Xie.

  One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart's energy metabolism as an alternative "fuel source." Utilization of β-OHB in the failing heart increases, and this serves as a "fuel switch" that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative "fuel," β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes' expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.

Keywords:  HDAC inhibition; ROS; cardiac metabolism; heart failure; ketone bodies; myocardial ischemia/reperfusion injury; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fragi.2021.681513
Front Cardiovasc Med. 2022 ;9 791700

Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated With Diabetic Cardiomyopathy.

Karina P Gomes, Anshul S Jadli, Luiz G N de Almeida, Noura N Ballasy, Pariya Edalat, Ruchita Shandilya, Daniel Young, Darrell Belke, Jane Shearer, Antoine Dufour, Vaibhav B Patel.

  Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, leading to heart failure and increased risk for death in diabetic patients. To investigate the molecular mechanisms involved in DbCM, we performed a quantitative proteomic profiling analysis in the left ventricle (LV) of type 2 diabetic mice. Six-month-old C57BL/6J-lepr/lepr (db/db) mice exhibited DbCM associated with diastolic dysfunction and cardiac hypertrophy. Using quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in the LVs of db/db mice, majorly associated with the regulation of energy metabolism. The subunits of ATP synthase that form the F1 domain, and Cytochrome c1, a catalytic core subunit of the complex III primarily responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by diabetic heart, resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1β subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, the atypical kinase COQ8A, an essential lipid-soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from diabetic mice to augment mitochondrial ATP energetics, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production. Preserved basal mitochondrial respiration along with the markedly reduced maximal respiratory capacity in the LVs of db/db mice corroborate the association between altered mitochondrial metabolic profile and cardiac dysfunction in DbCM.

Keywords:  diabetes; diabetic cardiomyopathy; diastolic dysfunction; electron transport chain; shotgun proteomics

DOI:  https://doi.org/10.3389/fcvm.2022.791700
Free Radic Biol Med. 2022 Mar 19. pii: S0891-5849(22)00107-1. [Epub ahead of print]183 75-88

Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway.

Lang Hu, Yanjie Guo, Liqiang Song, He Wen, Nan Sun, Ying Wang, Bingchao Qi, Qi Liang, Jing Geng, Xuteng Liu, Feng Fu, Yan Li.

  Myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics in patients with diabetes. However, effective strategies to regulate mitochondrial dynamics in the diabetic heart are still lacking. Nicotinamide riboside (NR) supplementation ameliorated mitochondrial dysfunction and oxidative stress in both cardiovascular and aging-related diseases. This study investigated whether NR protects against diabetes-induced cardiac dysfunction by regulating mitochondrial fusion/fission and further explored the underlying mechanisms. Here, we showed an evident decrease in NAD+ (nicotinamide adenine dinucleotide) levels and mitochondrial fragmentation in the hearts of leptin receptor-deficient diabetic (db/db) mouse models. NR supplementation significantly increased NAD+ content in the diabetic hearts and promoted mitochondrial fusion by elevating Mfn2 level. Furthermore, NR-induced mitochondrial fusion suppressed mitochondrial H2O2 and O2•- production and reduced cardiomyocyte apoptosis in both db/db mice hearts and neonatal primary cardiomyocytes. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase reporter assay analyses revealed that PGC1α and PPARα interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1α and promoting the transcription of Mfn2. These findings suggested the promotion of mitochondrial fusion via oral supplementation of NR as a potential strategy for delaying cardiac complications in patients with diabetes.

Keywords:  Diabetic cardiomyopathy; Mfn2; Mitochondrial dynamics; Nicotinamide riboside; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.03.012
ESC Heart Fail. 2022 Mar 25.

Sodium-glucose cotransporter-2 inhibitors in heart failure: an updated meta-analysis.

Yang Cao, Pengxiao Li, Yi Li, Yaling Han.

   AIMS: We aimed to examine efficacy and safety outcomes of sodium-glucose cotransporter-2 inhibitor (SGLT2i) for the treatment of heart failure (HF), especially in patients with heart failure with preserved ejection fraction (HFpEF).
METHODS AND RESULTS: PubMed, Web of Science, and Cochrane Library were searched to identify randomized controlled trials comparing SGLT2i vs. placebo in HF patients. A total of 10 studies with 23 852 HF patients were eventually included. Compared with placebo, SGLT2i is associated with a lower incidence of composite of first hospitalization for heart failure (HHF) or cardiovascular death (CV death) [hazard ratio (HR) = 0.76 95% confidence interval (CI) = 0.71-0.81], which is consistent regardless of the diabetes status, type of gliflozines used, and follow-up duration. SGLT2i can reduce the risk of total HHF or CV death (HR = 0.74, 95%CI = 0.68-0.81), first HHF (HR = 0.69, 95%CI = 0.64-0.75), CV death (HR = 0.88, 95%CI = 0.80-0.96), any death (HR = 0.90, 95%CI = 0.83-0.97), and any serious events (HR = 0.90, 95%CI = 0.87-0.93) in HF patients, at the cost of increased risk of urinary tract infections (risk ratio = 1.17, 95%CI = 1.03-1.33). In HFpEF patients, SGLT2i is associated with a significant reduction of composite of first HHF or CV death (HR = 0.81, 95%CI = 0.73-0.91), first HHF (HR = 0.71, 95%CI = 0.62-0.82), and total HHF or CV death (HR = 0.61, 95%CI = 0.43-0.86).
CONCLUSIONS: Sodium-glucose cotransporter-2 inhibitor contributed to better efficacy outcomes in overall HF patients and showed an inspiring breakthrough in the treatment of HFpEF.

Keywords:  Heart failure; Heart failure with preserved ejection fraction; Meta-analysis; Sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.1002/ehf2.13905
J Mol Cell Cardiol. 2022 Mar 21. pii: S0022-2828(22)00049-9. [Epub ahead of print]

Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects.

Jason R B Dyck, Samuel Sossalla, Nazha Hamdani, Ruben Coronel, Nina C Weber, Peter E Light, Coert J Zuurbier.

  Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute a promising drug treatment for heart failure patients with either preserved or reduced ejection fraction. Whereas SGLT2i were originally developed to target SGLT2 in the kidney to facilitate glucosuria in diabetic patients, it is becoming increasingly clear that these drugs also have important effects outside of the kidney. In this review we summarize the literature on cardiac effects of SGLT2i, focussing on pro-inflammatory and oxidative stress processes, ion transport mechanisms controlling sodium and calcium homeostasis and metabolic/mitochondrial pathways. These mechanisms are particularly important as disturbances in these pathways result in endothelial dysfunction, diastolic dysfunction, cardiac stiffness, and cardiac arrhythmias that together contribute to heart failure. We review the findings that support the concept that SGLT2i directly and beneficially interfere with inflammation, oxidative stress, ionic homeostasis, and metabolism within the cardiac cell. However, given the very low levels of SGLT2 in cardiac cells, the evidence suggests that SGLT2-independent effects of this class of drugs likely occurs via off-target effects in the myocardium. Thus, while there is still much to be understood about the various factors which determine how SGLT2i affect cardiac cells, much of the research clearly demonstrates that direct cardiac effects of these SGLT2i exist, albeit mediated via SGLT2-independent pathways, and these pathways may play a role in explaining the beneficial effects of SGLT2 inhibitors in heart failure.

Keywords:  Arrhythmia; Heart failure; Inflammation; Oxidative stress; SGLT2; Sodium; Stiffness

DOI:  https://doi.org/10.1016/j.yjmcc.2022.03.005
Front Endocrinol (Lausanne). 2022 ;13 850836

Sodium Glucose Cotransporter Type 2 Inhibitors Improve Cardiorenal Outcome of Patients With Coronary Artery Disease: A Meta-Analysis.

Wen Wei, Jin Liu, Shiqun Chen, Xinghao Xu, Dachuan Guo, Yibo He, Zhidong Huang, Bo Wang, Haozhang Huang, Qiang Li, Jiyan Chen, Hong Chen, Ning Tan, Yong Liu.

   Objective: Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM), heart failure (HF) or chronic kidney disease (CKD). However, whether or not the patients with coronary artery disease (CAD) have prognostic benefit from SGLT-2i treatment has not been fully studied. The purpose of this meta-analysis is to determine the prognostic benefit of SGLT-2i administration in CAD patients.
Methods: We searched the PubMed, Embase and Cochrane Library from inception until October 15, 2021. We included randomized controlled trials (RCTs) reporting the effect of SGLT-2i on major adverse cardiovascular event (MACE), hospitalization for heart failure (HHF), cardiovascular (CV) death and cardiorenal parameters in CAD patients. Hazard ratio (HR) with 95% confidence interval (CI) and mean difference (MD) from trials were meta-analyzed using fixed-effects models.
Results: Nine trials enrolling 15,301 patients with CAD were included in the analyses. Overall, SGLT2i were associated with a reduced risk of MACE (HR: 0.84; 95% CI 0.74-0.95; I2 = 0%), HHF (HR: 0.69; 95% CI 0.58-0.83; I2 = 0%) and a composite of CV death or HHF (HR: 0.78; 95% CI 0.71-0.86; I2 = 37%) in CAD patients. Compared with control group, estimated glomerular filtration rate (eGFR) level decreased less in SGLT-2i group (mean difference [MD] = -3.60, 95% CI, -5.90 to -1.30, p = 0.002; I2 = 0%).
Conclusions: SGLT-2i can improve cardiorenal outcomes in CAD patients. Further RCTs and real world studies are need to investigate the effect of SGLT2i on CAD patients.
Systematic Review Registration: PROSPERO, CRD42021258237.

Keywords:  cardiorenal outcomes; coronary artery disease; improve; meta-analysis; sodium glucose cotransporter type 2 inhibitors

DOI:  https://doi.org/10.3389/fendo.2022.850836
Am J Physiol Heart Circ Physiol. 2022 Mar 25.

Metabolic Transformation of Fat in Obesity Determines the Inflammation Resolving Capacity of Splenocardiac and Cardiorenal Networks in Heart Failure.

Ganesh V Halade, Vasundhara Kain, Xavier De La Rosa, Merry L Lindsey.

  All fats are not created equal, and despite the extensive literature, the effect of fat intake is the most debated question in obesity, cardiovascular, and cardiorenal research. Cellular and molecular mechanisms underlying cardiac dysfunction and consequent heart failure in the setting of obesity are not well understood. Our understanding of how fats are metabolically transformed after non-reperfused myocardial infarction (MI), in particular, is incomplete. Here, using male C57BL/6J mice (2 months old), we determined the role of omega-6 fatty acids (provided as safflower oil, SO, for 12 weeks) followed by supplementation with docosahexaenoic acid (DHA; n-3 fatty acids) for 8 weeks prior to MI. With SO feeding, inflammation resolution was impaired. Specialized pro-resolving mediators (SPMs) increased in DHA fed-mice to reverse the effects of SO, while prostaglandins and thromboxane B2 reduced in the spleen and amplified multiple resolving mechanisms in heart and kidney post-MI. DHA amplified the number of resolving macrophages and cardiac reparative pathways of the splenocardiac and cardiorenal networks in acute heart failure, with higher Treg cellsin chronic heart failure with marked expression of Foxp3+ in the myocardium. Our findings indicate that surplus ingestion of SO intensified systemic, baseline, non-resolving inflammation, and DHA intake dominates splenocardiac resolving phase with the biosynthesis of SPMs and controlled cardiorenal inflammation in heart failure survivor mice.

Keywords:  Inflammation resolution signaling; acute inflammation; cardiac remodeling; chronic inflammation; cyclooxygenase-lipoxygenase signaling

DOI:  https://doi.org/10.1152/ajpheart.00684.2021
Metabolites. 2022 Feb 27. pii: 216. [Epub ahead of print]12(3):

Whole Blood Metabolite Profiles Reflect Changes in Energy Metabolism in Heart Failure.

Carl Beuchel, Julia Dittrich, Janne Pott, Sylvia Henger, Frank Beutner, Berend Isermann, Markus Loeffler, Joachim Thiery, Uta Ceglarek, Markus Scholz.

  A variety of atherosclerosis and cardiovascular disease (ASCVD) phenotypes are tightly linked to changes in the cardiac energy metabolism that can lead to a loss of metabolic flexibility and to unfavorable clinical outcomes. We conducted an association analysis of 31 ASCVD phenotypes and 97 whole blood amino acids, acylcarnitines and derived ratios in the LIFE-Adult (n = 9646) and LIFE-Heart (n = 5860) studies, respectively. In addition to hundreds of significant associations, a total of 62 associations of six phenotypes were found in both studies. Positive associations of various amino acids and a range of acylcarnitines with decreasing cardiovascular health indicate disruptions in mitochondrial, as well as peroxisomal fatty acid oxidation. We complemented our metabolite association analyses with whole blood and peripheral blood mononuclear cell (PBMC) gene-expression analyses of fatty acid oxidation and ketone-body metabolism related genes. This revealed several differential expressions for the heart failure biomarker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in peripheral blood mononuclear cell (PBMC) gene expression. Finally, we constructed and compared three prediction models of significant stenosis in the LIFE-Heart study using (1) traditional risk factors only, (2) the metabolite panel only and (3) a combined model. Area under the receiver operating characteristic curve (AUC) comparison of these three models shows an improved prediction accuracy for the combined metabolite and classical risk factor model (AUC = 0.78, 95%-CI: 0.76-0.80). In conclusion, we improved our understanding of metabolic implications of ASCVD phenotypes by observing associations with metabolite concentrations and gene expression of the mitochondrial and peroxisomal fatty acid oxidation. Additionally, we demonstrated the predictive potential of the metabolite profile to improve classification of patients with significant stenosis.

Keywords:  acylcarnitines; amino acids; association study; cardiovascular disease; coronary artery disease; fatty acid oxidation; gene expression; observational studies

DOI:  https://doi.org/10.3390/metabo12030216
Int J Mol Sci. 2022 Mar 09. pii: 2960. [Epub ahead of print]23(6):

Heart Failure and Drug Therapies: A Metabolic Review.

Frank Yu, Bianca McLean, Mitesh Badiwala, Filio Billia.

  Cardiovascular disease is the leading cause of mortality globally with at least 26 million people worldwide living with heart failure (HF). Metabolism has been an active area of investigation in the setting of HF since the heart demands a high rate of ATP turnover to maintain homeostasis. With the advent of -omic technologies, specifically metabolomics and lipidomics, HF pathologies have been better characterized with unbiased and holistic approaches. These techniques have identified novel pathways in our understanding of progression of HF and potential points of intervention. Furthermore, sodium-glucose transport protein 2 inhibitors, a drug that has changed the dogma of HF treatment, has one of the strongest types of evidence for a potential metabolic mechanism of action. This review will highlight cardiac metabolism in both the healthy and failing heart and then discuss the metabolic effects of heart failure drugs.

Keywords:  heart failure; metabolism; pharmacology

DOI:  https://doi.org/10.3390/ijms23062960
J Clin Med. 2022 Mar 08. pii: 1470. [Epub ahead of print]11(6):

SGLT2 Inhibitors in Type 2 Diabetes Mellitus and Heart Failure-A Concise Review.

Daria M Keller, Natasha Ahmed, Hamza Tariq, Malsha Walgamage, Thilini Walgamage, Azad Mohammed, Jadzia Tin-Tsen Chou, Marta Kałużna-Oleksy, Maciej Lesiak, Ewa Straburzyńska-Migaj.

  The incidence of both diabetes mellitus type 2 and heart failure is rapidly growing, and the diseases often coexist. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new antidiabetic drug class that mediates epithelial glucose transport at the renal proximal tubules, inhibiting glucose absorption-resulting in glycosuria-and therefore improving glycemic control. Recent trials have proven that SGLT2i also improve cardiovascular and renal outcomes, including reduced cardiovascular mortality and fewer hospitalizations for heart failure. Reduced preload and afterload, improved vascular function, and changes in tissue sodium and calcium handling may also play a role. The expected paradigm shift in treatment strategies was reflected in the most recent 2021 guidelines published by the European Society of Cardiology, recommending dapagliflozin and empagliflozin as first-line treatment for heart failure patients with reduced ejection fraction. Moreover, the recent results of the EMPEROR-Preserved trial regarding empagliflozin give us hope that there is finally an effective treatment for patients with heart failure with preserved ejection fraction. This review aims to assess the efficacy and safety of these new anti-glycemic oral agents in the management of diabetic and heart failure patients.

Keywords:  diabetes mellitus type 2; heart failure; sodium-glucose co-transporter 2; sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.3390/jcm11061470
Am J Cardiovasc Drugs. 2022 Mar 22.

Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors and Combined SGLT1/2 Inhibitors on Cardiovascular, Metabolic, Renal, and Safety Outcomes in Patients with Diabetes: A Network Meta-Analysis of 111 Randomized Controlled Trials.

Yao Neng Teo, Adriel Z H Ting, Yao Hao Teo, Elliot Yeung Chong, Joshua Teik Ann Tan, Nicholas L Syn, Alys Z Q Chia, How Ting Ong, Alex Jia Yang Cheong, Tony Yi-Wei Li, Kian Keong Poh, Tiong Cheng Yeo, Mark Yan-Yee Chan, Raymond C C Wong, Ping Chai, Ching-Hui Sia.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-hyperglycemic drugs that has been steadily increasing in popularity due to its cardiovascular and renal benefits. Dual SGLT1/SGLT2 (SGLT1/2) inhibitors have potentially augmented anti-hyperglycemic action due to additional SGLT1 inhibition. This network meta-analysis aimed to compare the treatment effect across various outcomes between pure SGLT2 inhibitors and combined SGLT1/2 inhibitors in patients with diabetes.
METHODOLOGY: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for randomized controlled trials published from inception to 15th January 2022. Frequentist network meta-analysis was conducted to summarize the treatment effects reported in individual trials, stratified by type 1 (T1DM) and type 2 diabetes mellitus (T2DM). This meta-analysis was registered on PROSPERO (CRD42020222031).
RESULTS: Our meta-analysis included 111 articles, comprising a combined cohort of 103,922 patients. SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, and luseogliflozin) and SGLT1/2 inhibitors (licogliflozin and sotagliflozin) were compared. Frequentist network meta-analysis demonstrated that in T2DM patients, SGLT1/2 inhibitors led to a decreased hazard rate of myocardial infarction (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.56-0.98) and stroke (HR 0.65, 95% CI 0.47-0.92) compared with SGLT2 inhibitors. SGLT2 inhibitors achieved a greater hemoglobin A1c (HbA1c) reduction than SGLT1/2 inhibitors (0.16%, 95% CI 0.06-0.26). In patients with T2DM, the risk of diarrhea (risk ratio [RR] 1.42, 95% CI 1.07-1.88) and severe hypoglycemia (RR 5.89, 95% CI 1.41-24.57) were found to be higher with SGLT1/2 inhibitor use compared with SGLT2 inhibitor use. No differences were observed for cardiovascular, metabolic, and safety outcomes between SGLT1/2 inhibitors and SGLT2 inhibitors in patients with T1DM.
CONCLUSIONS: In patients with T2DM, compared with pure SGLT2 inhibitors, combined SGLT1/2 inhibitors demonstrated a lower risk of myocardial infarction and of stroke, but were associated with a higher risk of diarrhea and severe hypoglycemia.

DOI: https://doi.org/10.1007/s40256-022-00528-7
J Am Coll Cardiol. 2022 Mar 29. pii: S0735-1097(22)00249-2. [Epub ahead of print]79(12): 1129-1137

Mineralocorticoid Receptor Antagonists and Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction.

João Pedro Ferreira, Javed Butler, Faiez Zannad, Gerasimos Filippatos, Elke Schueler, Dominik Steubl, Cordula Zeller, James L Januzzi, Stuart Pocock, Milton Packer, Stefan D Anker.

   BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) may be beneficial in reducing heart failure (HF) hospitalizations in patients with HF with preserved ejection fraction. The effect of sodium-glucose cotransporter 2 inhibitors in patients with HF with preserved ejection fraction according to MRA background therapy has not been reported.
OBJECTIVES: The aim of this study was to examine the effect of empagliflozin in MRA users and nonusers in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial.
METHODS: Survival analyses were conducted comparing the effects of empagliflozin vs placebo in MRA users and nonusers at baseline with treatment-by-MRA use interaction terms.
RESULTS: A total of 5,988 patients were included, of whom 2,244 (37.5%) were using MRAs at baseline. MRA users had higher event rates than MRA nonusers (placebo group primary outcome 9.4 vs 8.2 events per 100 person-years). The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users (HR: 0.73 [95% CI: 0.62-0.87] and HR: 0.87 [95% CI: 0.71-1.06]; interaction P = 0.22). The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers than in MRA users (HR: 0.60 [95% CI: 0.47-0.77] and HR: 0.90 [95% CI: 0.68-1.19]; interaction P = 0.038). MRA users experienced almost twice as many hyperkalemia events as MRA nonusers, and empagliflozin reduced the risk for hyperkalemia or initiation of potassium binders regardless of MRA use (MRA nonusers: HR: 0.90 [95% CI: 0.69-1.19]; MRA users: HR: 0.74 [95% CI: 0.56-0.96]; interaction P = 0.29).
CONCLUSIONS: The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users. The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers. Empagliflozin reduced hyperkalemia, with no significant treatment-by-MRA subgroup interaction. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT03057951).

Keywords:  empagliflozin; heart failure with preserved ejection fraction; hyperkalemia; mineralocorticoid receptor antagonists; treatment effect

DOI:  https://doi.org/10.1016/j.jacc.2022.01.029
Ther Adv Chronic Dis. 2022 ;13 20406223221081616

Long-chain omega-3 polyunsaturated fatty acids and the risk of heart failure.

Sulin Zheng, Min Qiu, Jason H Y Wu, Xiong-Fei Pan, Xiong Liu, Lichang Sun, Hailan Zhu, Jiandi Wu, Yuli Huang.

   Aims: Adequate intake of long-chain (LC) omega-3 polyunsaturated fatty acids (n-3 PUFAs) is considered important for cardiovascular health. However, the effects of LC n-3 PUFAs on the risk of heart failure (HF) remain unclear. This systematic review and meta-analysis aimed to determine the role of LC n-3 PUFAs in the incidence of HF.
Materials and Methods: Electronic databases were searched for studies up to 31 July 2021. Studies were included for the meta-analysis if they reported the adjusted associations between different dietary intakes or circulating concentrations of LC n-3 PUFAs and the risk of HF. A random-effect model was used to calculate the pooled estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for higher LC n-3 PUFA concentrations.
Results: Thirteen studies were included in the meta-analysis. Eight studies comprising 316,698 individuals (11,244 incident HF cases), with a median follow-up of 10.7 years, showed that a higher dietary intake of LC n-3 PUFAs was associated with a lower risk of HF (highest versus lowest quintile: HR = 0.84, 95% CI = 0.75-0.94). Six studies, comprising 17,163 participants (2520 HF cases) with a median follow-up of 9.7 years, showed that higher circulating LC n-3 PUFA concentrations were associated with a lower risk of HF (highest versus lowest quintile: HR = 0.59, 95% CI = 0.39-0.91). Higher circulating docosahexaenoic acid concentrations were associated with a decreased risk of HF (top versus bottom quintile: HR = 0.44, 95% CI = 0.26-0.77). The associations between eicosapentaenoic acid (HR = 0.58, 95% CI = 0.26-1.25), docosahexaenoic acid (HR = 0.66, 95% CI = 0.24-1.82), and the risk of HF were not significant.
Conclusion: High LC n-3 PUFA concentrations measured by dietary intake or circulating biomarkers are associated with a lower risk of developing HF.

Keywords:  heart failure; meta-analysis; polyunsaturated fatty acids; risk

DOI:  https://doi.org/10.1177/20406223221081616
Biology (Basel). 2022 Mar 16. pii: 448. [Epub ahead of print]11(3):

AMPK Activation Is Indispensable for the Protective Effects of Caloric Restriction on Left Ventricular Function in Postinfarct Myocardium.

Bernd Niemann, Ruping Pan, Hassan Issa, Andreas Simm, Rainer Schulz, Susanne Rohrbach.

   BACKGROUND: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium.
METHODS: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice.
RESULTS: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes.
CONCLUSIONS: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.

Keywords:  AMPK; caloric restriction; heart failure; ischemia; mitochondria

DOI:  https://doi.org/10.3390/biology11030448
Expert Rev Cardiovasc Ther. 2022 Mar 23.

Beneficial cardiovascular and remodeling effects of SGLT2 inhibitors: pathophysiologic mechanisms.

Steven G Chrysant, George S Chrysant.

   INTRODUCTION: The intent of this paper is to review the data regarding the multipotential effects of the sodium-glucose cotransporter 2 (SGLT 2) inhibitors, their cardiovascular protective effects, and their mechanism of action.
AREAS COVERED: The SGLT2 inhibitors exert their beneficial antidiabetic and cardioprotective effects through increased glucose excretion from the kidneys, blood pressure and weight lowering, vasodilation and other potential beneficial effects. They have been used for the treatment of patients with type 2 diabetes mellitus (T2DM) as well as in patients with cardiovascular disease (CVD), coronary artery disease (CAD),and heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). In order to get a better understanding of their mechanism of action for their multiple cardiovascular protective effects, a Medline search of the English language literature was conducted between 2015 and February 2022 and 46 pertinent papers were selected.
EXPERT OPINION: The analysis of data clearly demonstrated that the use of the SGLT2 inhibitors besides their antidiabetic effects, provide additional protection against CVD, CAD, and HFrEF and HFpEF, and death, but not stroke, in both diabetic and non-diabetic patients. Therefore, they should be preferably used for the treatment of patients with T2DM with preexisting CVD, CAD, and HFrEF and HFpEF.

Keywords:  SGLT2 inhibitors; cardiovascular disease; coronary artery disease; death; diabetes; heart failure

DOI:  https://doi.org/10.1080/14779072.2022.2057949