bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2021–12–12
nine papers selected by
Kyle McCommis, Saint Louis University
  1. Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload.
  2. Effects of Lipid Overload on Heart in Metabolic Diseases.
  3. Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload.
  4. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction.
  5. Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients.
  6. N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.
  7. FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.
  8. mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.
  9. Sodium-glucose co-transporter 2 inhibitors as an early, first line therapy in patients with heart failure and reduced ejection fraction.
  1. Sci Rep. 2021 Dec 06. 11(1): 23469
    Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload.
    Dan Shao, Peiyong Zhai, Chengchen Hu, Risa Mukai, Sebastiano Sciarretta, Dominic Del Re, Junichi Sadoshima.
      The Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.
    DOI:  https://doi.org/10.1038/s41598-021-02846-3
  2. Horm Metab Res. 2021 Dec;53(12): 771-778
    Effects of Lipid Overload on Heart in Metabolic Diseases.
    An Yan, Guinan Xie, Xinya Ding, Yi Wang, Liping Guo.
      Metabolic diseases are often associated with lipid and glucose metabolism abnormalities, which increase the risk of cardiovascular disease. Diabetic cardiomyopathy (DCM) is an important development of metabolic diseases and a major cause of death. Lipids are the main fuel for energy metabolism in the heart. The increase of circulating lipids affects the uptake and utilization of fatty acids and glucose in the heart, and also affects mitochondrial function. In this paper, the mechanism of lipid overload in metabolic diseases leading to cardiac energy metabolism disorder is discussed.
    DOI:  https://doi.org/10.1055/a-1693-8356
  3. Front Pharmacol. 2021 ;12 716884
    Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload.
    Nan Zhang, Hai-Han Liao, Hong Feng, Shan-Qi Mou, Wen-Jing Li, Xiahenazi Aiyasiding, Zheng Lin, Wen Ding, Zi-Ying Zhou, Han Yan, Si Chen, Qi-Zhu Tang.
      Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2. Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60-70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout. Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.
    Keywords:  AMPKα; Sestrin2; cardiac hypertrophy; fibrosis; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2021.716884
  4. Eur Heart J. 2021 Dec 08. pii: ehab798. [Epub ahead of print]
    Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction.
    Javed Butler, Milton Packer, Gerasimos Filippatos, Joao Pedro Ferreira, Cordula Zeller, Janet Schnee, Martina Brueckmann, Stuart J Pocock, Faiez Zannad, Stefan D Anker.
       AIMS : No therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes.
    METHODS AND RESULTS : A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: <25% (n = 999), 25-34% (n = 2230), 35-44% (n = 1272), 45-54% (n = 2260), 55-64% (n = 2092), and ≥65% (n = 865). Outcomes assessed included (i) time to first hospitalization for heart failure or cardiovascular mortality, (ii) time to first heart failure hospitalization, (iii) total (first and recurrent) hospitalizations for heart failure, and (iv) health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The risk of cardiovascular death and hospitalization for heart failure declined progressively as ejection fraction increased from <25% to ≥65%. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization, mainly by reducing heart failure hospitalizations. Empagliflozin reduced the risk of heart failure hospitalization by ≈30% in all ejection fraction subgroups, with an attenuated effect in patients with an ejection fraction ≥65%. Hazard ratios and 95% confidence intervals were: ejection fraction <25%: 0.73 (0.55-0.96); ejection fraction 25-34%: 0.63 (0.50-0.78); ejection fraction 35-44%: 0.72 (0.52-0.98); ejection fraction 45-54%: 0.66 (0.50-0.86); ejection fraction 55-64%: 0.70 (0.53-0.92); and ejection fraction ≥65%: 1.05 (0.70-1.58). Other heart failure outcomes and measures, including KCCQ, showed a similar response pattern. Sex did not influence the responses to empagliflozin.
    CONCLUSION : The magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions <25% to <65%, but was attenuated in patients with an ejection fraction ≥65%.
    KEY QUESTION: How does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction?
    KEY FINDING: The magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions <25% to <65%, but it was attenuated in patients with an ejection fraction ≥65%.
    TAKE HOME MESSAGE: The consistency of the response in patients with ejection fractions of <25% to <65% distinguishes the effects of empagliflozin from other drugs that have been evaluated across the full spectrum of ejection fractions in patients with heart failure.
    Keywords:  Ejection fraction; Empagliflozin; Hospitalization; Sex;  Heart failure
    DOI:  https://doi.org/10.1093/eurheartj/ehab798
  5. Front Immunol. 2021 ;12 755782
    Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients.
    Priscila Camillo Teixeira, Axel Ducret, Hanno Langen, Everson Nogoceke, Ronaldo Honorato Barros Santos, João Paulo Silva Nunes, Luiz Benvenuti, Debora Levy, Sergio Paulo Bydlowski, Edimar Alcides Bocchi, Andréia Kuramoto Takara, Alfredo Inácio Fiorelli, Noedir Antonio Stolf, Pablo Pomeranzeff, Christophe Chevillard, Jorge Kalil, Edecio Cunha-Neto.
      Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients' myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.
    Keywords:  chronic Chagas disease cardiomyopathy; energy metabolism; idiopathic dilated cardiomyopathy; interferon-gamma; ischemic cardiomyopathy; mitochondria; proteomics; two-dimensional electrophoresis with fluorescent labeling
    DOI:  https://doi.org/10.3389/fimmu.2021.755782
  6. Molecules. 2021 Nov 30. pii: 7285. [Epub ahead of print]26(23):
    N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.
    Iram Mushtaq, Zainab Bashir, Mehvish Sarwar, Maria Arshad, Ayesha Ishtiaq, Wajiha Khan, Uzma Khan, Sobia Tabassum, Tahir Ali, Tahzeeb Fatima, Hadi Valadi, Muhammad Nawaz, Iram Murtaza.
      Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.
    Keywords:  diabetes linked cardiac hypertrophy; mitochondrial stress markers; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules26237285
  7. Circ Heart Fail. 2021 Dec 06. CIRCHEARTFAILURE121008910
    FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.
    Salah Sommakia, Naredos H Almaw, Sandra H Lee, Dinesh K A Ramadurai, Iosif Taleb, Christos P Kyriakopoulos, Chris J Stubben, Jing Ling, Robert A Campbell, Rami A Alharethi, William T Caine, Sutip Navankasattusas, Guillaume L Hoareau, Anu E Abraham, James C Fang, Craig H Selzman, Stavros G Drakos, Dipayan Chaudhuri.
       BACKGROUND: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling.
    METHODS: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.
    RESULTS: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4-1040.3] pg/mL, n=40; controls: 146.0 [86.3-205.7] pg/mL, n=20, P=1.9×10-5). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion.
    CONCLUSIONS: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.
    Keywords:  bilirubin; fibroblast growth factor; ketones; metabolism; natriuretic peptides
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.121.008910
  8. J Endocrinol. 2021 Dec 01. pii: JOE-21-0284.R2. [Epub ahead of print]
    mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.
    Jianshu Chen, Jing Yu, Ruowen Yuan, Ningyin Li, Caie Li, Xiaofang Zhang.
      Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team's previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly im) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8mg/kg/day Vs 1.5mg/kg/day Vs 2mg/kg/day ip) in OVX+ estrogens(E 9.6 mg/Kg/day, ig)+T group was further evaluated. After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length (TL), area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, β- myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor (mTOR), ribosomal protein S6 kinase (S6K1),4E-bindiong protein 1(4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.
    DOI:  https://doi.org/10.1530/JOE-21-0284
  9. Eur J Heart Fail. 2021 Dec 10.
    Sodium-glucose co-transporter 2 inhibitors as an early, first line therapy in patients with heart failure and reduced ejection fraction.
    Daniela Tomasoni, Gregg C Fonarow, Marianna Adamo, Stefan D Anker, Javed Butler, Andrew Js Coats, Gerasimos Filippatos, Stephen J Greene, Theresa A McDonagh, Piotr Ponikowski, Giuseppe Rosano, Petar Seferovic, Muthiah Vaduganathan, Adriaan A Voors, Marco Metra.
      Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recently recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended the use of dapagliflozin and empagliflozin regardless of diabetes history in patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant type 2 diabetes mellitus (T2DM), the timing and practical integration of this class of therapies in practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin-system inhibitors and mineralocorticoid receptor antagonists. This review, therefore, supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with T2DM) to rapidly improve clinical outcome and quality of life of HFrEF patients.
    Keywords:  dapaglifliflozin; empagliflozin; heart failure with reduced ejection fraction; medical treatment; sodium-glucose co-transporter 2 inhibitors; sotagliflozin
    DOI:  https://doi.org/10.1002/ejhf.2397
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