bims-hafaim 2022-05-29 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–05–29
nine papers selected by
Kyle McCommis, Saint Louis University

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction: DEFINE-HF.
Glutaminolysis is Essential for Myofibroblast Persistence and In Vivo Targeting Reverses Fibrosis and Cardiac Dysfunction in Heart Failure.
Effect of Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Metabolic Signatures of Pregnancy-Induced Cardiac Growth.
Knockout of TIGAR enhances myocardial phosphofructokinase activity and preserves diastolic function in heart failure.
Fine-Tuning Cardiac Insulin/Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.
Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus.
Mitochondria-Mediated Cardiovascular Benefits of Sodium-Glucose Co-Transporter 2 Inhibitors.
Dapagliflozin Impact on the Exercise Capacity of Non-Diabetic Heart Failure with Reduced Ejection Fraction Patients.

Circulation. 2022 May 23.

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction: DEFINE-HF.

Senthil Selvaraj, Zhuxuan Fu, Philip Jones, Lydia C Kwee, Sheryl L Windsor, Olga Ilkayeva, Christopher B Newgard, Kenneth B Margulies, Mansoor Husain, Silvio E Inzucchi, Darren K McGuire, Bertram Pitt, Benjamin M Scirica, David E Lanfear, Michael E Nassif, Ali Javaheri, Robert J Mentz, Mikhail N Kosiborod, Svati H Shah.

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), yet underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between SGLT2i treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry-based profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis (PCA)-defined metabolite clusters that changed differentially with treatment, and also examined the relationship between change in metabolite clusters with change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Models were adjusted for relevant clinical covariates, and nominal p<0.05 with FDR-adjusted p-value<0.10 were used to determine statistical significance. Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short/medium-chain acylcarnitine PCA metabolite clusters compared with placebo (nominal p=0.01, FDR-adjusted p-value=0.08 for both clusters). However, ketosis (Β-hydroxybutyrate levels > 500 μM), was infrequently achieved (3 [2.5%] in dapagliflozin arm vs. 1 [0.9%] in placebo arm), and supraphysiologic levels were not observed. Conversely, increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in KCCQ scores (i.e. worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of SGLT2i in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with SGLT2i in patients with HFrEF. Reassuringly, only physiologic levels of ketosis were observed. Additionally, we identified several metabolic biomarkers associated with adverse HFrEF outcomes.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.060402
Circulation. 2022 May 24. 145(21): 1625-1628

Glutaminolysis is Essential for Myofibroblast Persistence and In Vivo Targeting Reverses Fibrosis and Cardiac Dysfunction in Heart Failure.

Andrew A Gibb, Emma K Murray, Anh T Huynh, Ryan B Gaspar, Tori L Ploesch, Ken Bedi, Alyssa A Lombardi, Pawel K Lorkiewicz, Rajika Roy, Zolt Arany, Daniel P Kelly, Kenneth B Margulies, Bradford G Hill, John W Elrod.



Keywords:  fibrosis; glutamine; heart failure; metabolism; myofibroblasts

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.121.057879
Front Cardiovasc Med. 2022 ;9 875327

Effect of Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Hufang Zhou, Wenhua Peng, Fuyao Li, Yuelin Wang, Baofu Wang, Yukun Ding, Qian Lin, Ying Zhao, Guozhong Pan, Xian Wang.

   Background: Heart failure with preserved ejection fraction (HFpEF) is associated with a high risk of mortality and frequent hospitalization. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have favorable cardiovascular protective effect and could decrease the risk of mortality and hospitalization in patients with heart failure with reduced ejection fraction. However, the effect of SGLT2 inhibitors for HFpEF has not been well studied.
Purpose: The aim of this meta-analysis is to systematically assess the effects of SGLT2 inhibitors in patients with HFpEF.
Methods: MEDLINE, EMBASE, Ovid, Cochrane Library, Chinese National Knowledge Infrastructure Database, VIP database, Chinese Biomedical Database, and Wanfang Database were searched from inception to November 2021 for randomized controlled trials (RCTs) of SGLT2 inhibitors for HFpEF. Risk bias was assessed for included studies according to Cochrane handbook. The primary outcome was the composite of first hospitalization for heart failure (HHF) or cardiovascular mortality. First HHF, cardiovascular mortality, total HHF, all-cause mortality, exercise capacity, ventricular diastolic function, and adverse events were considered as secondary endpoints. PROSPERO registration: CRD42021291122.
Results: A total of 12 RCTs including 10,883 patients with HFpEF (SGLT2 inhibitors group: 5,621; control group: 5,262) were included. All included RCTs were at low risk of bias. Meta-analysis showed that SGLT2 inhibitors significantly reduced the composite of first HHF or cardiovascular mortality (HR:0.78, 95% CI: [0.70, 0.87], P< 0.00001, I 2 = 0%), first HHF (HR:0.71, 95% CI: [0.62, 0.83], P < 0.00001, I 2 = 0%), total HHF (RR:0.75, 95% CI: [0.67, 0.84], P<0.00001, I 2 = 0%), E/e' (MD: -1.22, 95% CI: [-2.29, -0.15], P = 0.03, I 2 = 59%) and adverse events (RR:0.92, 95% CI: [0.88, 0.97], P = 0.001, I 2 = 0%). No statistical differences were found in terms of cardiovascular mortality, all-cause mortality, NT-proBNP, BNP and 6-min walk test distance.
Conclusion: SGLT2 inhibitors significantly improve cardiovascular outcomes with a lower risk of serious adverse events in patients with HFpEF. However, these findings require careful recommendation due to the small number of RCTs at present. More multi-center, randomized, double-blind, placebo-controlled trials are needed.
Systematic Review Registration: [https://www.crd.york.ac.Uk/prospero/], identifier [CRD42021291122].

Keywords:  heart failure with preserved ejection fraction; meta-analysis; randomized controlled trials; sodium-glucose cotransporter 2 inhibitors; systematic review

DOI:  https://doi.org/10.3389/fcvm.2022.875327
Am J Physiol Heart Circ Physiol. 2022 May 27.

Metabolic Signatures of Pregnancy-Induced Cardiac Growth.

Kyle L Fulghum, Juliette B Smith, Julia Chariker, Lauren F Garrett, Kenneth R Brittian, Pawel Lorkiewicz, Lindsey A McNally, Shizuka Uchida, Steven P Jones, Bradford G Hill, Helen E Collins.

  The goal of this study was to develop an atlas of the metabolic, transcriptional, and proteomic changes that occur with pregnancy in the maternal heart. Timed pregnancy studies in FVB/NJ mice revealed significant increases in heart size by day 8 of pregnancy (mid-pregnancy; MP), which was sustained throughout the rest of the term compared with non-pregnant controls. Cardiac hypertrophy and myocyte cross-sectional area were highest 7 d after birth (post-birth; PB) and were associated with significant increases in end-diastolic and end-systolic left ventricular volumes and cardiac output. Metabolomics analyses revealed that, by day 16 of pregnancy (late pregnancy; LP), metabolites associated with nitric oxide production as well as acylcholines, sphingomyelins, and fatty acid species were elevated, which coincided with a lower activation state of phosphofructokinase and higher levels of pyruvate dehydrogenase kinase 4 (Pdk4). In the postpartum period, urea cycle metabolites, polyamines, and phospholipid levels were markedly elevated in the maternal heart. Cardiac transcriptomics in LP revealed significant increases in not only Pdk4, but also genes that regulate glutamate and ketone body oxidation, which were preceded in MP by higher expression of transcripts controlling cell proliferation and angiogenesis. Proteomics analysis of the maternal heart in LP and PB revealed significant reductions in several contractile filaments and mitochondrial complex subunits. Collectively, these findings describe the coordinated molecular changes that occur in the maternal heart during and after pregnancy.

Keywords:  hypertrophy; metabolomics; pregnancy; proteomics; transcriptomics

DOI:  https://doi.org/10.1152/ajpheart.00105.2022
J Cell Physiol. 2022 May 27.

Knockout of TIGAR enhances myocardial phosphofructokinase activity and preserves diastolic function in heart failure.

Xiaochen He, Heng Zeng, Aubrey C Cantrell, Quinesha A Williams, Jian-Xiong Chen.

  Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in diastolic dysfunction. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism and heart failure (HF). In the present study, we investigated the role of TIGAR in diastolic function and cardiac fibrosis during pressure overload (PO)-induced HF. WT mice subjected to transverse aortic constriction (TAC), a commonly used method to induce diastolic dysfunction, exhibited diastolic dysfunction as evidenced by increased E/A ratio and E/E' ratio when compared to its sham controls. This was accompanied by increased cardiac interstitial fibrosis. In contrast, the knockout of TIGAR attenuated PO-induced diastolic dysfunction and interstitial fibrosis. Mechanistically, the levels of glucose transporter Glut-1, Glut-4, and key glycolytic enzyme phosphofructokinase 1 (PFK-1) were significantly elevated in TIGAR KO subjected to TAC as compared to that of WT mice. Knockout of TIGAR significantly increased fructose 2,6-bisphosphate levels and phosphofructokinase activity in mouse hearts. In addition, PO resulted in a significant increase in perivascular fibrosis and endothelial activation in the WT mice, but not in the TIGAR KO mice. Our present study suggests a necessary role of TIGAR-mediated glucose metabolism in PO-induced cardiac fibrosis and diastolic dysfunction.

Keywords:  TIGAR; cardiac fibrosis; diastolic function; glucose metabolism

DOI:  https://doi.org/10.1002/jcp.30790
Circulation. 2022 May 26. 101161CIRCULATIONAHA122059863

Fine-Tuning Cardiac Insulin/Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.

Mahmoud Abdellatif, Viktoria Trummer-Herbst, Alexander Martin Heberle, Alina Humnig, Tobias Pendl, Sylvère Durand, Giulia Cerrato, Sebastian J Hofer, Moydul Islam, Julia Voglhuber, José Miguel Ramos Pittol, Oliver Kepp, Gerald Hoefler, Albrecht Schmidt, Peter P Rainer, Daniel Scherr, Dirk von Lewinski, Egbert Bisping, Julie R McMullen, Abhinav Diwan, Tobias Eisenberg, Frank Madeo, Kathrin Thedieck, Guido Kroemer, Simon Sedej.

   BACKGROUND: The insulin/insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial.
METHODS: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1 receptor overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well.
RESULTS: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity.
CONCLUSIONS: Our findings indicate that the relationship between IGF1R signaling, and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Keywords:  aging; autophagy; cardiomyopathies; insulin-like growth factor-1, mouse; mitochondria; phosphatidylinositol 3-kinases

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.059863
Antioxidants (Basel). 2022 May 17. pii: 982. [Epub ahead of print]11(5):

Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus.

Camila Moreno Rosa, Dijon Henrique Salome Campos, David Rafael Abreu Reyes, Felipe Cesar Damatto, Lucas Yamada Kurosaki, Luana Urbano Pagan, Mariana Janini Gomes, Camila Renata Corrêa, Ana Angelica Henrique Fernandes, Marina Politi Okoshi, Katashi Okoshi.

  Clinical trials have shown that sodium glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcomes in diabetes mellitus (DM) patients. As most studies were performed in Type 2 DM, the cardiovascular effects of SGLT2 inhibition still require clarification in Type 1 DM. We analyzed the effects of SGLT2 inhibitor dapagliflozin on cardiac remodeling in rats with streptozotocin-induced diabetes, an experimental model of Type 1 DM.
METHODS: Male Wistar rats were assigned into four groups: control (C, n = 14); control treated with dapagliflozin (C + DAPA, n = 14); diabetes (DM, n = 20); and diabetes treated with dapagliflozin (DM + DAPA, n = 20) for 8 weeks. Dapagliflozin dosage was 5 mg/kg/day.
STATISTICAL ANALYSES: ANOVA and Tukey or Kruskal-Wallis and Dunn.
RESULTS: DM + DAPA presented decreased blood pressure and glycemia and increased body weight compared to DM (C 507 ± 52; C + DAPA 474 ± 50; DM 381 ± 52 *; DM + DAPA 430 ± 48 # g; * p < 0.05 vs. C; # p < 0.05 vs. C + DAPA and DM + DAPA). DM echocardiogram presented left ventricular and left atrium dilation with impaired systolic and diastolic function. Cardiac changes were attenuated by dapagliflozin. Myocardial hydroxyproline concentration and interstitial collagen fraction did not differ between groups. The expression of Type III collagen was lower in DM and DM + DAPA than their controls. Type I collagen expression and Type I-to-III collagen ratio were lower in DM + DAPA than C + DAPA. DM + DAPA had lower lipid hydroperoxide concentration (C 275 ± 42; C + DAPA 299 ± 50; DM 385 ± 54 *; DM + DAPA 304 ± 40 # nmol/g tissue; * p < 0.05 vs. C; # p < 0.05 vs. DM) and higher superoxide dismutase and glutathione peroxidase activity than DM. Advanced glycation end products did not differ between groups.
CONCLUSION: Dapagliflozin is safe, increases body weight, decreases glycemia and oxidative stress, and attenuates cardiac remodeling in an experimental rat model of Type 1 diabetes mellitus.

Keywords:  SGLT2 inhibitor; cardiac function; dapagliflozin; myocardial fibrosis; oxidative stress; ventricular remodeling

DOI:  https://doi.org/10.3390/antiox11050982
Int J Mol Sci. 2022 May 11. pii: 5371. [Epub ahead of print]23(10):

Mitochondria-Mediated Cardiovascular Benefits of Sodium-Glucose Co-Transporter 2 Inhibitors.

Siarhei A Dabravolski, Alexander D Zhuravlev, Andrey G Kartuesov, Evgeny E Borisov, Vasily N Sukhorukov, Alexander N Orekhov.

  Several recent cardiovascular trials of SGLT 2 (sodium-glucose cotransporter 2) inhibitors revealed that they could reduce adverse cardiovascular events in patients with T2DM (type 2 diabetes mellitus). However, the exact molecular mechanism underlying the beneficial effects that SGLT2 inhibitors have on the cardiovascular system is still unknown. In this review, we focus on the molecular mechanisms of the mitochondria-mediated beneficial effects of SGLT2 inhibitors on the cardiovascular system. The application of SGLT2 inhibitors ameliorates mitochondrial dysfunction, dynamics, bioenergetics, and ion homeostasis and reduces the production of mitochondrial reactive oxygen species, which results in cardioprotective effects. Herein, we present a comprehensive overview of the impact of SGLT2 inhibitors on mitochondria and highlight the potential application of these medications to treat both T2DM and cardiovascular diseases.

Keywords:  SGLT2 inhibitors; cardiovascular diseases; dapagliflozin; diabetes mellitus; empagliflozin; mitochondria

DOI:  https://doi.org/10.3390/ijms23105371
J Clin Med. 2022 May 23. pii: 2935. [Epub ahead of print]11(10):

Dapagliflozin Impact on the Exercise Capacity of Non-Diabetic Heart Failure with Reduced Ejection Fraction Patients.

João Reis, Ana Rita Teixeira, António Valentim Gonçalves, Rita Ilhão Moreira, Tiago Pereira Silva, Ana Teresa Timóteo, Rui Cruz Ferreira.

   BACKGROUND: Dapagliflozin has been shown to reduce morbidity and mortality in Heart Failure with reduced Ejection Fraction (HFrEF), but its impact on exercise capacity of non-diabetic HF outpatients is unknown.
METHODS: Adult non-diabetic HF patients with a left ventricular ejection fraction (LVEF) <50% were randomized 1:1 to receive dapagliflozin 10 mg or to continue with HF medication. Patients underwent an initial evaluation which was repeated after 6 months. The variation of several clinical parameters was compared, with the primary endpoint being the 6 month peak oxygen uptake (pVO2) variation.
RESULTS: A total of 40 patients were included (mean age 61 ± 13 years, 82.5% male, mean LVEF 34 ± 5%), half being randomized to dapagliflozin, with no significant baseline differences between groups. The reported drug compliance was 100%, with no major safety events. No statistically significant difference in HF events was found (p = 0.609). There was a 24% reduction in the number of patients in New York Heart Association (NYHA) class III in the treatment group as opposed to a 15.8% increase in the control group (p = 0.004). Patients under dapagliflozin had a greater improvement in pVO2 (3.1 vs. 0.1 mL/kg/min, p = 0.030) and a greater reduction in NT-proBNP levels (-217.6 vs. 650.3 pg/mL, p = 0.007).
CONCLUSION: Dapagliflozin was associated with a significant improvement in cardiopulmonary fitness at 6 months follow-up in non-diabetic HFrEF patients.

Keywords:  Heart Failure with reduced Ejection Fraction; cardiopulmonary exercise test; heart failure; peak oxygen uptake; sodium–glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.3390/jcm11102935